# Patent

## Title
Pharmaceutical composition comprising amphetamines complexed with ion-exchange resin particles

## Abstract

The invention relates to a pharmaceutical composition comprising amphetamines complexed with ion-exchanged resin particles to form drug-resin particles. The composition provides for prolonged therapy.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 13/844,537 filed Mar. 15, 2013, now U.S. Pat. No. 9,017,731, which is a continuation-in-part of International Application No. PCT/US2012/044698, filed Jun. 28, 2012, which claims priority to U.S. Provisional Application No. 61/502,189, filed Jun. 28, 2011, and U.S. Provisional Application No. 61/528,554, filed Aug. 29, 2011, the disclosures of each of which are hereby incorporated by reference in their entireties.


BACKGROUND OF THE INVENTION
(a) Field of the Invention
The invention relates to Attention Deficit Hyperactivity Disorder (ADHD) effective agent dosage forms that both facilitate oral ingestion and provide an effective treatment over a prolonged period of time. In particular, the invention provides for pharmaceutical compositions having a first and second plurality of drug-resin particles, where the first plurality of drug-resin particles does not have a delayed release coating and the second plurality of drug-resin particles does have a delayed release coating, where the drug is an ADHD effective agent and the composition achieves an escalating in vivo plasma concentration of the ADHD effective agent.
(b) Description of the Related Art
Many drug therapies use immediate-release oral dosage forms administered at spaced intervals to provide and maintain a desired therapeutic effect over a prolonged therapy period. For example, drugs used in treating Attention Deficit Disorder (ADD) and ADHD such as ADDERALL® and RITALIN® are administered two or three times a day.
For various reasons, subjects often experience difficulty complying with this administration schedule. In particular, because ADD and ADHD are commonly diagnosed in children, the dosage regimen generally requires that at least one dose is administered during the school day. Children are typically not permitted to self-administer the drug at school. As such, authorized school personnel generally take on the responsibility for administering the drug to children during the school day. However, this approach raises issues of medical privacy and potential stigmatizing of the child by peers. In addition, the compliance issue becomes further complicated as transportation, storage and supply of the drug typically must be documented and/or monitored, and the schedules of the different parties involved, i.e., the child, the educators and the authorized school personnel, must be coordinated and accommodated. The unfortunate result is that doses may be given late or missed altogether resulting in decreased efficacy of the therapy.
To avoid administering multiple doses during the day, once-a-day sustained and extended release medications have been developed. For example, ADDERALL XR®, a mixed amphetamine salts medication, is administered once-a-day for the treatment of ADD and ADHD. To achieve extended release, ADDERALL XR requires a mixture of four amphetamine salts: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate. U.S. Pat. Nos. 6,322,819 and 6,605,300, which disclose ADDERALL XR, are hereby incorporated by reference in their entirety. U.S. Pat. No. 6,913,768, which is hereby incorporated by reference, also discloses a four amphetamine salt composition.
METADATE CD® is another once-a-day ADHD treatment. This formulation comprises methylphenidate hydrochloride and achieves an extended-release profile through its make up of 30% immediate release beads and 70% extended release beads.
Prior art ADHD compositions such as ADDERALL XR and METADATE CD are only available in solid dosage forms. Many people, especially children, have difficulty swallowing standard solid dosage forms. Accordingly, there is a need in the art to develop easily ingested, once-daily oral compositions that provide effective, prolonged treatment.
U.S. Pat. No. 2,990,332 to Keating discloses adsorbing amphetamines onto a sulphonic acid cation exchange resin from which the drug is slowly and uniformly released by gastric and intestinal juices. In particular, this patent discloses a homogeneous pharmaceutical drug compound which will immediately release its drug continuously over a long period of time without the necessity of complicated and expensive enteric coating procedures. The amphetamine-resin complex of this patent is such that not more than approximately 50% of the amphetamine is released in one hour by elution with simulated gastric juice and at least approximately 10% in three hours by such elution.
Hinsvark, et al. (Journal of Phamacokinetics and Biophaaceutics, 1(4):319-328, 1973) reports the comparison of oral bioavailability and pharmacokinetics of between a resin-bound form of amphetamine and the soluble hydrochloride salt. The efficiency of absorption was the same for resinate as for soluble salt, but the speed of absorption was about three times slower for the resinate and blood levels after the resinate reached a lower, later and flatter peak. Without any coating, the resin-bound amphetamine produced more sustained blood levels.
Although, as described by Keating and Hinsvark, amphetamine adsorbed on ion exchange resin was released more slowly into gastric and/or intestinal juices than soluble salts, the pharmacokinetic profile is not comparable to ADDERALL XR or METADATE CD. As such, there is still a need for a once-a-day formulation that is easily ingested.
SUMMARY OF VARIOUS EMBODIMENTS OF THE INVENTION
The invention provides pharmaceutical compositions comprising drug-resin particles comprising at least one ADHD effective agent (e.g., amphetamine, methylphenidate), methods of making such compositions, and methods of treatment using these compositions. In particular, the invention provides for easily ingested, once-daily oral compositions that provide effective, prolonged treatment.
The invention provides various advantage over prior art compositions and methods. For example, the invention provides for liquid drug suspensions, chewable compositions, and orally disintegrating compositions—compositions favored by individuals who have difficulty swallowing conventional solid dosage forms (e.g., children or dysphagic individuals). Moreover, the compositions comprise ion-exchange resins and thus have enhanced taste masking properties as compared to traditional drug formulations. The use of multiple coated resin beads for the controlled release portions of the compositions reduces the risk of dose dumping when the composition is chewed or crushed, because there is no single point where failure of the controlled release mechanism can occur.
In some embodiments, the compositions of the invention are advantageous as compared to currently available amphetamine compositions. For example, the compositions minimize the amount of sulfates, which reduces the likelihood of formation alkyl sulfonates—toxic compounds that the FDA recommends limiting or excluding from drug formulations. Moreover, unlike ADDERALL XR, various compositions of the invention do not require four amphetamine salts. As such, the compositions streamline the supply chain by reducing the number of distinct components required, i.e., simplifies processing and handling.
Also, in the presence of ethanol, the compositions have an improved exposure level of amphetamines and methylphenidate compared to ADDERALL XR and METADATE CD, respectively, i.e., the invention reduces dose dumping when the composition and ethanol are ingested by a subject. For example, the inventors have shown that in the presence of varying concentrations of alcohol (e.g., 4%, 20%, and 40% ethanol) did not significantly alter the rate and extent of absorption of a controlled-release ODT amphetamine composition described herein.
Also in the presence of food, the liquid suspension amphetamine compositions have an increased exposure of amphetamines compared to fed ADDERALL XR during the first four hours or up to the Tmax, i.e., these compositions have less food effect than ADDERALL XR.
In particular, the invention relates to pharmaceutical compositions comprising a plurality of drug-resin particles, wherein the drug in said drug-resin particles comprises at least one ADHD effective agent. For example, in one embodiment, the pharmaceutical composition comprises (a) at least one pharmaceutically active ADHD effective agent drug-resin complex providing for immediate release; and (b) at least one pharmaceutically active ADHD effective agent drug-resin complex covered with a delayed release coating, wherein said component (a) provides for an immediate release of ADHD effective agent from the drug resin complex to provide a first blood level of ADHD effective agent and component (b) provides a delayed release of ADHD effective agent from the drug-resin complex that increases the blood level of ADHD effective agent to a second level.
In one embodiment, the ADHD effective agent is at least one amphetamine such as a mixture of amphetamine and dextroamphetamine (e.g., a mixture of 75% dextroamphetamine and 25% levoamphetamine). In one embodiment, the compositions are substantially free of dextroamphetamine saccharate and/or amphetamine asparate. Alternatively, where the compositions consist essentially of amphetamine salts, anions of those salts are polymeric. In another alternative, the compositions or the drug-resin particles are substantially free of soluble anions. In another embodiment, the ADHD effective agent is methylphenidate.
In preferred embodiments, the compositions comprise a first plurality of drug-resin particles that are not coated with a delayed release coating, and a second plurality of drug-resin particles that are coated with a delayed release coating. The delayed release may comprise a triggered-release coating (e.g., where a pH change triggers the triggered-release coating such as EUDRAGIT® L100). The particles covered by a triggered-release coating may further comprise an extended release coating such as a diffusion barrier coating (e.g., a water insoluble, water permeable membrane such as ethylcellulose).
The compositions may comprise various amounts of the first and second plurality of drug-resin particles. For example, in one embodiment, the compositions comprise 20%-50% of the first plurality of drug-resin particles and 50-80% of the second plurality of drug-resin particles. In particular, the compositions may comprise 40%-50%, or about 45%, of the first plurality of drug-resin particles and 50%-60% or about 55% of the second plurality of drug-resin particles. In other particular embodiments, the compositions may comprise 20%-30%, or about 25%, of the first plurality of drug-resin particles and 70%-80% or about 75% of the second plurality of drug-resin particles.
In some embodiments, the resin particles are strong acidic cation exchange resins such as polistirex, polacrilex, or polacrilin. In other embodiments, the resin particles are AMBERLITE® IRP64, IRP69, or IRP88 resins, or DUOLITETM AP143 resins. The compositions may be liquid suspensions, chewable compositions, or an orally disintegrating tablet compositions.
The invention provides for compositions having unique in vitro dissolution profiles. In particular, the rate of appearance of the drug in a dissolution medium increases after a period of decrease in the rate of appearance of the drug in the dissolution medium. The period of decrease in the rate of appearance of the drug may occur within 0.5, 1, 1.5, 2, or 2.25 hours after the composition is introduced into the dissolution medium. In some embodiments, 30-60% of the drug may be released before the rate of appearance of the drug in a dissolution medium increases. Typically, release of 80% or more of the drug is achieved only after the rate of appearance of the drug in the dissolution medium has decreased and then increased. In particular, 80% or more of the drug is released during the dissolution assay within the first half (i.e., within 12 hours) of the dosing interval (i.e., 24 hour dosing interval).
In other embodiments, 40-45% of the drug is released within the first 45 minutes after the drug-resin particles are introduced into a dissolution assay, followed by a period of substantially no drug release from 45 minutes to 2 hours, and concluding with period of from 2 to 8 hours during which substantially all of the remaining drug is released. In another embodiment, 40-45% of the drug is released within the first 45 minutes after the drug-resin particles are introduced into a dissolution assay, 45-50% of the drug is released within 2 hours, and 50-100% of the drug is released by 8 hours. In another embodiment, 30-33% of the drug is released the first 30 minutes after the drug-resin particles are introduced into a dissolution assay, 34-42% of the drug is released within 2 hours, 40-80% of the drug is released within 4 hours and 80-100% of the drug is released within 24 hours. In any of these embodiments, the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCL, and after 2 hours, the medium is adjusted to a pH of  ̃6.8; and dissolution testing is performed using a USP Apparatus 2.
The invention also provides for compositions having unique in vivo serum profiles. In some embodiments, the composition has an in vivo serum profile with a first and second peak (e.g., where the second peak is the Cmax). For example, the composition may have an in vivo serum profile with a first peak between 1 and 3 hours after ingestion of the composition, and with a second peak between 4 and 7 hours after ingestion of the composition. In a particular mode, the composition may have an in vivo serum profile with a first peak between 1 and 2.5 hours after ingestion of the composition, and with a second peak between 4 and 6 hours after ingestion of the composition. Alternatively, the composition may have an in vivo serum profile that reaches a therapeutically effective level fairly rapidly (1-3 hours) and them continues to increase more slowly up to a maximum serum level between 4 hours and 7 hours after ingestion.
In one aspect, the compositions have in vivo serum profiles bioequivalent to the profiles of compositions described in the Examples and shown in the Figures. In particular aspect, the in vivo serum profile of the composition is bioequivalent to the in vivo serum profile of ADDERALL XR (e.g., under fasted conditions). In other embodiments, the compositions have one or more partial AUCs (e.g., AUC0-4, AUC0-5, AUC4-12, AUC5-12, AUC5-t (AUC5-last)1, AUC0-24, and/or AUC0-∞) which meet the bioequivalence conditions of the compositions described in the Examples (e.g., ADDERALL XR) and shown in the Figures. In another embodiment, the composition, in the presence of ethanol, provides that the recipient of the composition is exposed to a reduced amount of amphetamines compared to ADDERALL XR. 1(AUC5-last)=AUC5-t=the area under the plasma concentrate time curve for the time between 5 hours after ingestion to the last data point collected.
The invention also provides for methods of treating various conditions such as Attention-Deficit Disorder or ADHD, fatigue, obesity or imparting alertness, by administering an effective amount of the compositions described herein. In one embodiment, the amount of drug delivered to the subject is between about 2 mg/24 hours to about 60 mg/24 hours. In another embodiment, the amount of drug delivered to the subject is about 5 mg/24 hours to about 30 mg/24 hours. In particular embodiments, the effective amount is 0.5 mg/kg/day to 1.5 mg/kg/day, 0.25 mg/kg/day to 0.5 mg/kg/day, or 0.28/kg/day to 0.4 mg/kg/day. The composition may be administered once-a-day as a single or multiple unit dose. This invention is preferred for a subject suffering from dysphagia.
The invention also relates to methods of reducing the effects of an elevated exposure of a subject to ADHD effective agents (e.g., amphetamines). For example, when the compositions are administered substantially contemporaneously with ethanol, such that the subject is exposed to a reduced amount of amphetamines compared to administering ADDERALL XR to a subject substantially contemporaneously with ethanol.
The invention also provides for various methods of making the compositions. In one embodiment, the method involves (a) loading a plurality of resin particles with at least one ADHD effective agent (e.g., at least one amphetamine, methylphenidate) to form drug-resin particles; (b) coating a subset of the drug-resin particles with a triggered-release coating to form coated drug-resin particles; and (c) combining uncoated drug-resin particles with the subset of coated drug-resin particles in a pharmaceutical composition. In another embodiment, the method involves (a) loading a plurality of resin particles with an ADHD effective agent (e.g., methylphenidate) to form drug-resin particles; (b) coating drug-resin particles with an extended release coating (e.g., ethyl cellulose) to form extended release coated drug-resin particles; (c) further coating the extended release coated drug-resin particles with a delayed release coating (e.g., triggered-release coating) to form extended release/delayed release coated drug-resin particles; and (d) combining loaded, but uncoated drug-resin particles with the extended release/delayed release coated drug-resin particles in a pharmaceutical composition.
In another embodiment, the composition, wherein, for in vivo pharmacokinetic parameters of the composition, one or more in vivo pharmacokinetic parameters selected from the group consisting of Cmax, AUC0-5, AUC5-12, AUC5-24, AUC5-t (AUC5-last), AUC0-12, AUC0-24, AUC0-t, and AUC0-∞ have a 90% confidence interval with upper and lower bounds within a range from 90%-115% of the value of the same parameter(s) for a bioequivalent reference composition (e.g., ADDERALL XR).



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts an exemplary process for loading amphetamines onto resin particles.
FIG. 2 shows the dissolution profile of the composition described in Example 4.
FIG. 3 shows the dissolution profile of the composition described in Example 5.
FIG. 4 shows the dissolution profile of the composition described in Example 6.
FIG. 5 shows the dissolution profile of the composition described in Example 7.
FIG. 6 shows the dissolution profile of the composition described in Example 8.
FIG. 7 shows the dissolution profile of the composition described in Example 9.
FIG. 8 shows the results of a pH study on different coated resins described in Example 10.
FIG. 9 shows the plasma concentrations of amphetamine released from two different amphetamine formulations compared to ADDERALL XR (i.e., the reference formulation) in the pig study described in Example 12.
FIGS. 10A and 10B shows the plasma concentrations of exemplary amphetamine formulations compared to ADDERALL XR (i.e., the reference formulation) with alcohol and without alcohol as described in Example 13A. FIG. 10A shows the results of d-amphetamine. FIG. 10B shows the results of l-amphetamine.
FIG. 11 shows in vitro release profiles of ADDERALL XR (i.e., the reference formulation) with the addition of 0%, 20%, and 40% alcohol as described in Example 13B.
FIG. 12 shows the in vitro release profiles of the drug sample similar to that in Example 6 with the addition of 0%, 20%, and 40% alcohol as described in Example 13B.
FIG. 13 shows the amount of drug released over a range of pHs for three different lots of the delayed release product described in Example 6.
FIGS. 14A and 14B show the mean d-amphetamine concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), and Reference Product (Treatment C), as described in Example 15.
FIGS. 15A and 15B show the mean l-amphetamine concentration-time profiles after administration of test formulation #1 (Treatment A), test formulation #2 (Treatment B), and reference product (Treatment C), as described in Example 15.
FIG. 16 shows the mean d-amphetamine concentration-time profiles after administration of the ODT formulation and Reference Product (ADDERALL XR), as described in Example 16.
FIG. 17 shows the mean l-amphetamine concentration-time profiles after administration of the ODT formulation and Reference Product (ADDERALL XR), as described in Example 16.
FIG. 18 shows the mean d-amphetamine concentration-time profiles after administration of the suspension formulation and Reference Product (ADDERALL XR), as described in Example 16.
FIG. 19 shows the mean l-amphetamine concentration-time profiles after administration of the suspension formulation and Reference Product (ADDERALL XR), as described in Example 16.
FIGS. 20A and 20B show the mean d-methylphenidate concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), and Reference Product (Treatment C), as described in Example 18.
FIGS. 21A and 21B show the mean l-methylphenidate concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), and Reference Product (Treatment C), as described in Example 18.
FIGS. 22A and 22B show the mean total methylphenidate (d+1) concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), and Reference Product (Treatment C), as described in Example 18.
FIG. 23 shows the mean d-amphetamine and l-amphetamine plasma concentrations following administration of ADDERALL XR 20 mg (8 am) and ADDERALL (immediate-release) 10 mg twice daily (8 am and noon) in the fed state as reported in the prior art.
FIG. 24 shows the mean plasma concentrations following administration of immediate release methylphenidate and METADATE CD formulations as reported in the prior art.
FIGS. 25A-25C show in vitro release profiles of METADATE CD (i.e., the reference drug) with the addition of 0%, 5%, 10%, 20%, and 40% alcohol (FIG. 25A), the in vitro release profiles of a formulation similar to those formulations described in Example 17 with the addition of 0%, 5%, 10%, 20%, and 40% alcohol (FIG. 25B), and the in vitro release profiles of METADATE CD and a formulation similar to those described in Example 17 with the addition of 0%, 5%, 10%, 20%, and 40% alcohol (FIG. 25C).
FIG. 26 shows the dissolution profile of compositions A and B described in Example 17.
FIGS. 27A and 27B show the mean methylphenidate (d+l) concentration-time profiles after administration of Formulation #102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B), as described in Example 20.
FIGS. 28A and 28B show the mean d-methylphenidate concentration-time profiles after administration of Formulation #102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B), as described in Example 20.
FIGS. 29A and 29B show the mean l-methylphenidate concentration-time profiles after administration of Formulation #102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B), as described in Example 20.
FIGS. 30A and 30B show the mean d-amphetamine concentration-time profiles after administration of test formulation-fed (Treatment A) and test formulation-fasted (Treatment B), as described in Example 21.
FIGS. 31A and 31B show the mean l-amphetamine concentration-time profiles after administration of test formulation-fed (Treatment A) and test formulation-fasted (Treatment B), as described in Example 21.
FIGS. 32A and 32B show the mean d-amphetamine concentration-time profiles after administration of controlled release ODT with Deionized Water (0% Ethanol Solution) (Treatment A), 4% ethanol (Treatment B), 20% ethanol (Treatment C) and 40% ethanol (Treatment D) on linear (upper panel) and semi-logarithmic (lower panel) scales, as described in Example 22.
FIGS. 33A and 33B shows the mean l-amphetamine concentration-time profiles after administration of controlled release ODT with Deionized Water (0% Ethanol Solution) (Treatment A), 4% ethanol (Treatment B), 20% ethanol (Treatment C) and 40% ethanol (Treatment D) on linear (upper panel) and semi-logarithmic (lower panel) scales, as described in Example 22.
FIGS. 34A and 34B mean d-amphetamine concentration-time profiles after administration of amphetamine-containing ODT for Group 1 (Ages 6-7), Group 2 (Ages 8-9), and Group 3 (Ages 10-12), as described in Example 23.
FIGS. 35A and 35B mean d-amphetamine concentration-time profiles after administration of amphetamine-containing ODT for Group 1 (Ages 6-7), Group 2 (Ages 8-9), and Group 3 (Ages 10-12), as described in Example 23.
FIGS. 36A and 36B show the mean d-amphetamine concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), Test Formulation #3 (Treatment C), and the Reference Product (Treatment D), as described in Example 24.
FIGS. 37A and 37B show the mean l-amphetamine concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), Test Formulation #3 (Treatment C), and the Reference Product (Treatment D), as described in Example 24.
FIG. 38: Mean d-Amphetamine Concentration-Time Profiles after Administration of Suspension under Fasted Conditions (Treatment A), Suspension under Fed Conditions (Treatment B), and the Reference Product under Fed Conditions (Treatment C).
FIG. 39: Mean l-Amphetamine Concentration-Time Profiles after Administration of Suspension under Fasted Conditions (Treatment A), Suspension under Fed Conditions (Treatment B), and the Reference Product under Fed Conditions (Treatment C)



DETAILED DESCRIPTION OF THE INVENTION
The invention provides for various dosage forms comprising drug-resin particles that provide an effective treatment over a prolonged period of time. The invention provides pharmaceutical compositions such as liquid drug suspensions, chewable compositions, or orally disintegrating compositions comprising at least one plurality of drug-resin particles comprising a delayed-release coating. The invention also provides for methods of making pharmaceutical compositions and methods of treatment using these pharmaceutical compositions.
For example, the invention provides for such pharmaceutical compositions in which (i) the rate of appearance of the drug (e.g., at least one amphetamine) in a dissolution medium is increasing during a time period from a first time point through to a second time point, wherein the first time point is at least one hour after the composition is introduced into the dissolution medium; and/or (ii) the composition achieves an ascending plasma concentration of the drug (e.g., at least one amphetamine) after a therapeutically effective level is reached (e.g., one, two, three hours after ingestion of the composition).
The inventors have also observed that, when monitoring the release of the compositions of the invention and a reference listed ADHD effective agent (e.g., amphetamine, methylphenidate) in vivo, contemporaneous consumption of alcohol and drug affected both the rate and amount of ADHD effective agent appearing in the subject's circulation. Consequently, alcohol consumption by a patient being treated for ADHD can substantially increase the patient's level of exposure to ADHD effective agent (e.g., amphetamine, methylphenidate). The compositions of this invention help control the exposure, by reducing dose dumping.
Definitions
As used herein, a “drug-resin particle” is a drug-containing ion-exchange resin particle in which there is an ionic bond between the drug and the ion-exchange resin particle.
As used herein, an “ADHD effective agent” is any agent effective to treat ADHD or ADD in any patient population (e.g., children, adolescents, adults), wherein the agent includes stimulants such as amphetamine, lisdexamphetamine, methylphenidate, and their optical isomers; non-stimulants such as atomoxetine, guanfacine, and clonidine; antidepressants such as bupropion; anti-hypertussives such as gaunfacine and clonidine, derivatives thereof, or any combination that comprises at least one of these agents. As discussed herein, ADHD effective agents may also be used in the effective treatment of other conditions such as fatigue, obesity and for imparting alertness.
As used herein, “controlled release” means the time course of drug appearance in medium surrounding the composition is modified compared to an immediate release composition. Controlled release encompasses “delayed release” and “extended release” formulations.
As used herein, “delayed release” means that appearance of drug in the medium surrounding the composition occurs after a time lapse. An example of a delayed release coating is a triggered-release coating.
As used herein, a “triggered-release coating” is a coating that degrades as a result of a triggering event, where the triggering event is a change in the physiological environment of surrounding the triggered-release coating. Triggering events include, but are not limited to, a pH change which occurs upon transit from one stage to another stage in a subject's GI tract, an enzyme secreted in a particular region in a subject's GI tract, or enzymatic presence in digestion.
As used herein, “extended release” means that the rate of release is slower than the rate for an immediate release or delayed release composition from the initial point of release.
As used herein, “immediate release” means the initial period during which drug is released from the composition that does not involve delayed or extended release but may include taste-masking.
As used herein, a “subject” means any animal, but is preferably a mammal, such as, for example, a human.
As used herein, “dose dumping” means the premature and/or accelerated release of a drug. Dose dumping could produce adverse effects or toxicity due to exposure of the patient to higher levels of the drug.
As used herein, “substantially free of dextroamphetamine saccharate and/or amphetamine asparate” means little to no dextroamphetamine saccharate and/or amphetamine asparate is present. Thus, while trace amounts of dextroamphetamine saccharate and/or amphetamine asparate may be included, therapeutically effective levels of dextroamphetamine saccharate and/or amphetamine asparate are excluded.
As used herein, “substantially free of soluble anions” means little to no soluble anions may be included. Thus, while trace amounts of soluble anions may be included, these trace amounts will affect the release of the drug by no more than 5%, preferably no more than 2%. Particularly, the trace amounts will affect the release of the drug by no more than 5%, preferably no more than 2%, during the first half hour after ingestion of the drug or after introduction of the drug to a dissolution assay.
As used herein, “substantially contemporaneously with ethanol” means ingesting (or introducing) a substance containing ethanol (e.g., beer, wine, hard liquor) within 5, 10, 15, 30, 45, 60, 75, 90, or 120 minutes before or after ingesting (or introducing) a composition of the invention.
As used herein, “substantially all,” in the context of drug release, means 90% or more.
As used herein, “substantially similar” parameters have values within −20%/+25% of each other.
Bioavailability
Measures of bioavailability well known in the art include the area under the plasma concentration-time curve (AUC), the concentration maximum (Cmax), and the time to Cmax (Tmax).
AUC is a measurement of the area under the plasma concentration-time curve, and is representative of the amount of drug absorbed following administration of a single dose of a drug (see Remington: The Science and Practice of Pharmacy, (Alfonso R. Gennaro ed. 2000), page 999).
Cmax is the maximum plasma concentration achieved after oral drug administration (see Remington, page 999). An oral drug administration results in at least one Cmax, but may result in more than one “peak plasma concentration” or “plasma concentration peak” (for example, following the administration of a pulsed dose formulation).
Tmax is the amount of time necessary to achieve the Cmax after oral drug administration, and is related to the rate of absorption of a drug (see Remington, page 999).
Bioequivalence is the absence of a significantly different rate and extent of absorption in the availability of the active ingredient when administered at the same dose under similar conditions. Bioequivalence can be measured by pharmacokinetic parameters such as, for example, AUC and Cmax. According to the FDA, two products are bioequivalent if the 90% confidence intervals of the relative mean AUC, Cmax, and Tmax of the test formulation are within 80% to 125% (−20%/+25%) of the reference formulation drug when administered in the fasting state. In a particular embodiment, bioequivalence may be established by comparing a test drug to a reference drug by comparing partial AUCs (e.g., over statistically or clinically relevant time intervals). This bioequivalence measure based partial AUCs may be used alone or in combination with the bioequivalence measure discussed above.
As used herein, a dissolution profile is “statistically similar” to another profile if the f2 similarity factor calculated for the two profiles is greater than or equal to 50. (See Moore and Flanner, Pharm. Tech. 20: 64-74, 1996).
Drug-containing Resin Particles
The invention provides for various dosage forms comprising drug-containing ion-exchange resin particles. These particles generally comprise at least one ADHD effective agent (e.g., at least one amphetamine, methylphenidate) bound to particles of an ion-exchange resin to provide a drug-resin complex. This complex may be coated with (i) a delayed release coating (e.g., triggered-release coating); (ii) an extended release coating (e.g., a water-permeable diffusion barrier coating that is insoluble in gastrointestinal fluids (and water) thereby providing a controllable extended release of drug under conditions encountered in the gastrointestinal tract); or (iii) both (i) and (ii). The drug-resins may also include a slow-dissolve polymer coating. Alternatively, the drug-resin particles are uncoated, i.e., omit a delayed release coating (e.g., triggered-release coating) and/or other coating (e.g., water-permeable diffusion barrier coating).
Resins
Ion-exchange resins suitable for use in the preparations and methods described herein are water-insoluble and comprise an indigestible organic and/or inorganic matrix containing covalently bound functional groups that are ionic or capable of being ionized under the appropriate conditions of pH. The organic matrix may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, sulfonated styrene, sulfonated divinylbenzene), or partially synthetic (e.g., modified cellulose and dextrans). The inorganic matrix preferably comprises silica gel modified by the addition of ionic groups. Covalently bound ionic groups may be strongly acidic (e.g., sulfonic acid, phosphoric acid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g., primary amine), weakly basic (e.g. quaternary ammonium), or a combination of acidic and basic groups. In general, the types of ion-exchangers suitable for use in ion-exchange chromatography and for such applications as deionization of water are suitable for use in the controlled release of drug preparations. Suitable ion exchange resins are also sold under the trade names AMBERLITE and Dowex. Such ion-exchangers are described by H. F. Walton in “Principles of Ion Exchange” (pp. 312-343) and “Techniques and Applications of Ion-Exchange Chromatography” (pp. 344-361) in Chromatography. (E. Heftmann, editor), Van Nostrand Reinhold Company, New York (1975), incorporated herein by reference. Exemplary ion-exchange resins that can be used in the present invention have exchange capacities below about 6 milliequivalents (meq)/gram and preferably below about 5.5 meq/gram.
Typically, the size of the ion-exchange particles is from about 30 microns to about 500 microns, preferably the particle size is within the range of about 40 micron to about 150 micron for liquid dosage forms, although particles up to about 1,000 micron can be used for solid dosage forms, e.g., tablets and capsules. Particle sizes substantially below the lower limit are difficult to handle in all steps of the processing. Commercially-available ion-exchange resins having an irregular shape and larger diameters up to about 200 micron are gritty in liquid dosage forms. Moreover, it is believed that the increased distance that a displacing ion must travel in its diffusion into these large particles, and the increased distance the displaced drug must travel in its diffusion out of these large particles, cause a measurable but not readily controlled prolongation of release, even when the drug-resin complexes are uncoated. Release of drug from uncoated drug-resin complexes with particle sizes in the approximate range of 40 micron to 150 micron is relatively rapid in the appropriate environment. Satisfactory control of the release from such complexes is achieved almost exclusively by applying a diffusion barrier coating.
Both regularly and irregularly shaped particles may be used as resins. Regularly shaped particles are those particles that substantially conform to geometric shapes, such as spherical, elliptical, cylindrical and the like, which are exemplified by Dow XYS-40010.00 and Dow XYS-40013.00 (The Dow Chemical Company). Irregularly shaped particles are all particles not considered to be regularly shaped, such as particles with amorphous shapes and particles with increased surface areas due to surface channels or distortions. Irregularly shaped ion-exchange resins of this type are exemplified by AMBERLITE IRP-69 (Rohm and Haas). Two of the preferred resins of this invention are AMBERLITE IRP-69 and Dow XYS-40010.00. Both are sulfonated polymers composed of polystyrene cross-linked with 8% of divinylbenzene, with an ion-exchange capacity of about 4.5 to 5.5 meq/g of dry resin (Na+-form). Their essential difference is in physical form. AMBERLITE IRP-69 consists of irregularly-shaped particles with a size range of 47 micron to 149 micron produced by milling the parent large-sized spheres of AMBERLITE® IRP-120. The Dow XYS-40010.00 product consists of spherical particles with a size range of 45 micron to 150 micron. Another useful exchange resin, Dow XYS-40013.00, is a polymer composed of polystyrene cross-linked with 8% of divinylbenzene and functionalized with a quaternary ammonium group; its exchange capacity is normally within the range of approximately 3 to 4 meq/g of dry resin.
The following U.S. Patents and Publications describe resins suitable for use in the preparations and methods described herein: U.S. Pat. Nos. 4,221,778; 4,996,047; and 5,980,882; U.S. Publication Nos. 2003/0099711; 2006/0193877; 2007/0059270; 2007/01400983; 2007/0148239; and 2009/0011027. The disclosure of each of these patents and publications is incorporated by reference herein in their entireties.
Drugs
Drugs that are suitable for the invention may be acidic, basic or amphoteric. Basic drugs that can be used in the present invention include amphetamine and methylphenidate. Drugs which may be used in the invention include ADHD effective agents such as amphetamine, dextroamphetamine, levoamphetamine, lisdexamphetamine, methylphenidate, dexmethylphenidate, atomoxetine, guanfacine, clonidine, and bupropion. In preferred embodiments, the drug is a stimulant such as amphetamine and methylphenidate.
Drug-resin Complexes
Binding of drug to resin can be accomplished using methods known in the art. Indeed, one of ordinary skill in the art can easily determine the appropriate method depending upon the drug. Typically four general reactions are used for a basic drug, these are: (a) resin (Na+-form) plus drug (salt form); (b) resin (Na+-form) plus drug (as free base); (c) resin (H+-form) plus drug (salt form); and (d) resin (H+-form) plus drug (as free base). All of these reactions except (d) have cationic by-products and these by-products, by competing with the cationic drug for binding sites on the resin, reduce the amount of drug bound at equilibrium. For basic drugs, stoichiometric binding of drug to resin is accomplished only through reaction (d).
Typically, the ion-exchange resin, in the form indicated by the chosen reaction, is placed in an aqueous solution of the chosen form of drug and agitated. The drug-resin complex thus formed is collected and washed with deionized or purified water to ensure removal of any unbound drug. The complexes are then dried.
Uncoated drug-resin complexes rapidly release the drug in the subject, such as, for example, in the gastrointestinal tract. To delay the release of drug from the drug-resin complex, the complex may be coated as described below.
The amount of drug that can be loaded onto a resin will typically range from about 1% to about 80%, preferably about 15% to about 60%, by weight of the loaded drug-resin particles. A skilled artisan with little or no experimentation can readily determine the optimum loading for any drug resin complex. In a preferred embodiment, loadings of about 30% to about 60% by weight of the drug-resin particles can be employed.
Those of skill in the art will appreciate that certain drugs will have an affinity for particular types of resins. The inventors have determined that the loading levels of amphetamine are suitable on strongly acidic cation exchange resins such as AMBERLITE IRP-64 and AMBERLITE IRP-69 resins. Resins useful in the invention with modification of the API are strong base anion exchange resins (e.g., DUOLITETM AP143) and weak acid cation exchange resins (e.g., AMBERLITE IRP-88).
Amphetamine resin complexes can be formed using any amphetamine salt, since the salt counter-ion is replaced by the ion exchange resin, and release of the drug is controlled by coating and ionic bonding, rather than differential solubility of the salts. In a preferred mode, resin particles are loaded using a single salt of racemic amphetamine and a single salt of dextroamphetamine.
The following U.S. Patents and Publications describe preparations and methods suitable for drug-resin complexes described herein: U.S. Pat. Nos. 4,221,778; 4,996,047; and 5,980,882; U.S. Publication Nos. 2003/0099711; 2006/0193877; 2007/0059270; 2007/01400983; 2007/0148239; and 2009/0011027. The disclosure of each of these patents and publications is incorporated by reference herein in their entireties.
Impregnation
Drug-resin particles can be impregnated with a humectant substantially as described in U.S. Pat. No. 4,221,778. The humectant can be added as an ingredient in the resin drug complexation step or, preferably, the particles can be treated with the humectant after complexing. This treatment helps particles retain their geometry, and enables the effective application of diffusion barrier coatings to such particles. One preferred humectant is polyethylene glycol, a hydrophilic agent. Other effective humectant agents include, for example, propylene glycol, lactose, methylcellulose, hydroxypropylmethylcellulose, sugar alcohols such as sorbitol, mannitol, polyvinylpyrrolidone, carboxypolymethylene, xanthan gum, propylene glycol, alginate and combinations of these agents. The humectant may be added in an amount of up to about 50 parts per 100 parts by weight of the resin or 50 to 150 parts per 100 parts of the resin; such humectant levels have been found to be effective. Preferably, the humectant (solvating agent) is added in an amount of about 75 to about 100 parts per 100 parts of resin.
Coatings
Coating layers can provide immediate release, delayed release, pulsed release, or extended release of drug from the drug-resin particle. Immediate release of the drug from the immediate-release layer can be achieved by any of various methods known in the art. One example is the use of a very thin layer or coating which by virtue of its thinness is quickly penetrated by gastric fluid allowing rapid leaching of the drug. Another example is by incorporating the drug in a mixture that includes a supporting binder or other inert material that dissolves readily in gastric fluid, releasing the drug as the material dissolves. A third is the use of a supporting binder or other inert material that rapidly disintegrates upon contact with gastric fluid, with both the material and the drug quickly dispersing into the fluid as small particles. Examples of materials that rapidly disintegrate and disperse are lactose and microcrystalline cellulose.
The following U.S. Patents and Publications describe coating materials suitable for use in the preparations and methods described herein: U.S. Pat. Nos. 4,221,778; 4,996,047; and 5,980,882; U.S. Publication Nos. 2003/0099711; 2006/0193877; 2007/0059270; 2007/01400983; 2007/0148239; US 2007/0264323; and 2009/0011027. The disclosure of each of these patents and publications is incorporated by reference herein in their entireties.
Diffusion Barrier Coating
Loaded particles may be coated with a diffusion barrier comprising a water-permeable, film-forming polymer. Any coating procedure which provides a contiguous coating on each particle of drug-resin complex without significant agglomeration of particles may be used. Coatings may be applied with a fluid-bed coating apparatus having the Wurster configuration. Measurements of particle size distribution can be done before and after coating to show that agglomeration of particles is acceptable.
The polymer may be any of a large number of natural or synthetic film-formers used singly, or in admixture with each other, and optionally in admixture with plasticizers, pigments and other substances to alter the characteristics of the coating. In general, the diffusion barrier coating should be insoluble or slowly soluble in water and permeable to water. Additional examples of coating polymers are described by R. C. Rowe in Materials Used in Pharmaceutical Formulation (A. T. Florence, editor), Blackwell Scientific Publications, Oxford, 1-36 (1984), incorporated by reference herein.
Preferably, the diffusion barrier is ethyl cellulose, for example, an ethyl cellulose having the content of ethoxyl group from 44 to 47.5%, preferably from 45 to 46.5%. In embodiments of the present invention, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic polymer will further improve the physical properties of the film. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it may be necessary to add plasticizer to the ethylcellulose before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after routine experimentation with the particular coating solution and method of application.
Examples of suitable plasticizers for ethylcellulose include water insoluble plasticizers such a dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. A plasticizer such as Durkex 500 vegetable oil may also be incorporated to improve the film forming property. In one alternative, it is desirable to incorporate a water-soluble substance, such as methyl cellulose, to alter the permeability of the coating.
The diffusion barrier coating materials can be applied as an aqueous suspension. One commercially available aqueous dispersion of ethylcellulose is Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® is typically prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is preferable to intimately mix the Aquacoat® with a suitable plasticizer prior to use.
Another aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). This product is typically prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (e.g., dibutyl sebacate), and stabilizer (e.g., oleic acid) may be prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates.
Another alternative coating material is a mixture of an insoluble, film-forming polymer and a water soluble pore former or polymer, i.e., refers to a two-component system. One preferred water soluble polymer is methyl cellulose, which may be used in a two-component system with ethylcellulose.
Another alternative coating material is a mixture of two insoluble, film-forming polymers; for example polyvinyl acetate phthalate (PVAP) and ethylcellulose. Another alternative coating material is polyvinylpyrrolidone (PVP), polyvinylalcohol, polyvinylacetate and mixtures thereof.
Typically, the water-permeable, film-forming polymer comprises from about 1% to about 60% by weight of the drug-resin complex, and preferably from about 20% to about 50% by weight of the dry resin. In terms of coat thickness, preferably, the diffusion barrier coat thickness is at least 5 microns and more preferably, the diffusion barrier coat thickness is from about 10 microns to about 50 microns. Optimum coat weight and coat thickness may be determined for each drug-resin complex and generally depend on the drug release characteristics of the resin for a particular drug. For example, to achieve drug release times within about 1 hour to about 4 hours, the drug-resin complex may be coated with a light coat weight. A light coat weight is a coat weight present in the amount of about 10% to about 20% by weight of the dry resin. To achieve drug release times from about 6 hours to 10 hours, a medium coat weight may be used, i.e. a coat weight present in the amount of 30% to about 35% by weight. To achieve drug release times for about 12 hours, a heavy coat weight may be used, i.e. a coat weight of about 40% to 50% by weight of the dry resin.
Triggered-release Coatings
A water-soluble barrier comprises a pharmaceutically acceptable polymer such as, for example, methylcellulose (dissolves in cold water), hydroxypropylmethylcellulose (HPMC), hydroxyethlycellulose (HEC), acrylic acid ester, cellulose acetate phthalate, HEC phthalate, HPMC phthalate, hydroxypropyl cellulose (HPC), polyethylene glycol, polyvinyl alcohol, xanthan gum, carbomer, carrageenan, zooglan or other cellulosic polymers, or mixtures of polymers. Drugs mixed with one or more of these polymers, or covered by a layer of the polymer, will not be released until the polymer dissolves or degrades.
Triggered-release coatings are degraded as a result of a triggering event. Triggering events may be pH dependent or pH independent. A pH dependent coating is activated to release drug within a known pH range, which typically is matched to the local pH of the environment where delayed release is desired. Exemplary pH dependent coatings include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate (PVAP), carboxymethylethylcellulose, co-polymerized methacrylic acid/acrylic acid ethyl esters, co-polymerized methacrylic acid/methacrylic acid methyl esters such as, for instance, materials known under the trade name EUDRAGIT L12.5, L100, or EUDRAGIT S12.5, S100 or similar compounds. Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g., EUDRAGIT L 30D-55, EUDRAGIT L100-55, EUDRAGIT S100, EUDRAGIT preparation 4110D (Rohm Pharma); AQUATERIC, AQUACOAT CPD 30 (FMC); KOLLICOAT MAE 30D and. 30DP (BASF); or EASTACRYL 30D (Eastman Chemical). Aqueous colloidal polymer dispersions or re-dispersions can be also applied, e.g. EUDRAGIT® L 30D-55, EUDRAGIT L100-55, EUDRAGIT S100, EUDRAGIT preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT CPD 30 (FMC); KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).
A pH independent coating includes materials susceptible to enzymatic activation. Exemplary triggered-release coatings include cross-linked gelatin, polylactic acid, cellophane, plastarch material, polycaprolactone, polyglycolide, poly-3-hydroxybutyrate, zein, materials susceptible to enzymatic activation by azo-reductases in intestinal bacteria, and materials susceptible to degradation in the colon.
The invention provides for combinations of triggered-release coatings and diffusion barrier coatings. For example, the invention provides for drug-resin particles that include a diffusion barrier coating such as ethylcellulose which is overcoated with a triggered-release coating (or vice versa, i.e., the triggered-release coating is overcoated with a diffusion barrier coating). This multicoated particle provides for a delayed release (via the triggered-release coating) followed by an immediate or extended release (via the diffusion barrier coating).
Dosage Forms
The invention provides for pharmaceutical compositions comprising various pluralities of drug-resin particles in which the pharmaceutical composition is, for example, a liquid, a chewable composition, or an orally disintegrating solid. Alternatively, pharmaceutical compositions according to this invention may be prepared in capsules or by standard tableting methods. For example, the invention provides for such pharmaceutical compositions in which (i) the rate of appearance of the drug (e.g., at least one amphetamine) in a dissolution medium is increasing during a time period from a first time point through to a second time point, wherein the first time point is at least one hour after the composition is introduced into the dissolution medium; and/or (ii) the composition achieves an ascending plasma concentration of the drug (e.g., at least one amphetamine) after a therapeutic effective level is reached (e.g., one, two, three hours after ingestion of the composition).
In any of the dosage forms described herein, the drug may be at least one of an amphetamine or dextroamphetamine, or methylphenidate. In some preferred modes, both amphetamine or dextroamphetamine are present.
Liquid Drug Suspensions
The invention provides for liquid oral dosage forms. These dosage forms have distinct advantages over prior art solid dosage forms including dosage flexibility and ease of swallowing. Liquid dosage forms are especially preferred for pediatric use.
Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, and flavoring agents. Liquid forms, such as syrups and suspensions, preferably contain from about 1% to about 50%, and more preferably from about 1% to about 25%, and most preferably from about 3% to about 10%, of the drug-resin complex. Other optional ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants and the like to provide a palatable and pleasant looking final product; acidulants, for example, citric acid, ascorbic acid, or malic acid and the like to adjust pH; antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene; and preservatives, for example, methyl or propyl paraben or sodium benzoate, to prolong and enhance shelf life.
In preparing the liquid oral dosage forms, the coated drug-resin complexes are incorporated into an aqueous-based orally acceptable pharmaceutical carrier consistent with conventional pharmaceutical practices. An “aqueous-based orally acceptable pharmaceutical carrier” is one wherein the entire or predominant solvent content is water. Typical carriers include simple aqueous solutions, syrups, dispersions and suspensions, and aqueous based emulsions such as the oil-in-water type. Preferably, the carrier is a suspension of the pharmaceutical composition in an aqueous vehicle containing a suitable suspending agent. Suitable suspending agents include Avicel RC-591 (a microcrystalline cellulose/sodium carboxymethyl cellulose mixture available from FMC), guar gum and the like. Such suspending agents are well known to those skilled in the art. While the amount of water in the compositions of this invention can vary over quite a wide range depending upon the total weight and volume of the drug-resin complex and other optional non-active ingredients, the total water content, based on the weight of the final composition, will generally range from about 20 to about 75%, and, preferably, from about 20 to about 40%, by weight/volume.
Although water itself may make up the entire carrier, typical liquid formulations may contain a co-solvent, for example, propylene glycol, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients, such as flavoring oils and the like, into the composition. In general, therefore, the compositions of this embodiment preferably contain from about 5 to about 25 volume/volume percent and, most preferably, from about 10 to about 20 volume/volume percent, of the co-solvent.
Orally Disintegrating and Chewable Dosage Forms
The invention also provides for compositions and methods of making orally disintegrating or chewable, controlled-release formulations. In particular, the invention provides for orally disintegrating and chewable dosage forms comprising the various pluralities of drug-resin particles described herein Like liquid dosage forms, orally disintegrating and chewable dosage forms have distinct advantages over prior art solid dosage forms including ease of ingestion. Methods of preparing orally disintegrating and chewable dosage forms with drug-resins are known in the art. See U.S. Publication No. 2007/0092553, which is hereby incorporated by reference in its entirety.
Drug Release Profiles
The invention provides for compositions having various drug (e.g., ADHD effective agent) release profiles. In particular, the compositions may be administered in the morning and have therapeutically effective activity throughout the course of the day. For example, in one embodiment, the composition is administered to a child during breakfast (i.e., before school starts) and, by the time school starts, the ADHD effective agent (e.g., amphetamine, methylphenidate) will begin having a therapeutic effect on the child. The composition will continue to be therapeutically effective throughout the day including the mid-afternoon, when children tend to be fatigued. As such, the compositions described herein have an escalating in vivo serum profile.
In some embodiments, the invention provides for compositions in which the rate of appearance of the ADHD effective agent (e.g., at least one amphetamine) in a dissolution medium increases after a period of decrease in the rate of appearance of the drug in the dissolution medium. The compositions typically contain an immediate release and delayed release portion. The immediate release portion, in an in vitro dissolution assay, contributes to an initial release of ADHD effective agent (e.g., 30-60%) within an initial time period (e.g., 0.5, 1, 1.5, 2, or 2.25 hours from when the composition is introduced into the dissolution medium). After the initial increase amount of ADHD effective agent in the dissolution, due to the immediate release portion, the release rate of ADHD effective agent will decrease or level off. After this decrease or leveling off, typically the delayed release portion will release and the amount of ADHD effective agent released increases until, e.g., 80% or more of the ADHD effective agent is released. It will be appreciated that the first and second time points will vary depending on the ADHD effective agent, coatings used, and ratio of immediate and delayed release drug-resin particles.
In a particular embodiment, 40-45% of the drug (e.g., ADHD effective agent such as at least one amphetamine) is released within the first 45 minutes after the drug-resin particles are introduced into a dissolution assay, followed by a period of substantially no drug release from 45 minutes to 2 hours, and concluding with period of from 2 to 8 hours in which substantially all of the remaining ADHD effective agent is released from 2 to 8 hours. In another embodiment, 40-45% of the drug (e.g., ADHD effective agent such as at least one amphetamine) is released within the first 45 minutes after the drug-resin particles are introduced into a dissolution assay, 45-50% of the drug is released within 45 minutes to 2 hours, and 50-100% of the drug is released within 2 to 8 hours. In another embodiment, the delayed release coating releases substantially all of the one or more pharmaceutically active ADHD effective agents (e.g., amphetamines) coated with the delayed release coating within about 60 minutes after initiation of the delayed release. In yet another embodiment, 30-33% of the drug (e.g., ADHD effective agent such as methylphenidate) is released the first 30 minutes after the drug-resin particles are introduced into a dissolution assay, 34-42% of the drug is released within 30 minutes to 2 hours, 40-80% of the drug is released within 2 to 4 hours and 80-100% of the drug is released within 4 to 24 hours. For any of these embodiments, the conditions of the dissolution assay may be an initial dissolution medium of 0.1 N HCL, and after 2 hours, the medium is adjusted to a pH which triggers the triggered release coating, e.g., pH of  ̃6.8; and dissolution testing is performed using a USP Apparatus 2. In other embodiments, the pH is adjusted to e.g., pH 6.8, 7, etc.
The invention also provides for compositions in which the composition achieves an ascending plasma concentration of the drug (e.g., at least one amphetamine during a time period) after a therapeutically effective level is reached. Typically, a therapeutically effective level is reached within one, two, three, four, or five hours after ingestion of the composition. Sometime after the therapeutically effective level is reached, the plasma concentration of drug increases due to additional release of drug from the drug-resin complex in the composition to a peak drug concentration level. In some individuals, clearance of drug will result in a decrease in plasma level between these two releases, resulting in two successive peak drug levels. In others, the timing of the two releases is close enough that no decrease is observed. As a result, the in vivo plasma concentration profile is preferably bimodal with two peaks. For example, the first peak may be achieved, between 1 to 3, 1 to 2.5, or 1 to 2 hours after ingestion of the composition. The second peak may be achieved 4 to 7, 4 to 6, or 4 to 5 hours after ingestion of the composition. The first or second peak may be the Cmax. Alternatively, the composition may have an in vivo serum profile that reaches a therapeutically effective level fairly rapidly (1-3 hours) and them continues to increase more slowly up to a maximum serum level between 4 hours and 7 hours after ingestion. It will be appreciated that the therapeutic and peak drug concentration level will vary depending on the subject, drug, coatings used, and ratio of immediate and delayed release drug-resin particles.
The compositions of the invention may include at least one plurality of drug-resin particles coated with a triggered-release coating. In a particular embodiment, the invention provides for a first plurality of uncoated drug-resin particles and a second plurality of drug-resin particles being coated with a triggered-release coating. In another embodiment, the invention provides for a first plurality of uncoated drug-resin particles, a second plurality of drug-resin particles being coated with a triggered-release coating, and a third plurality of drug-resin particles being coated with a diffusion barrier coating. In another embodiment, the composition is a liquid dosage form and includes at least one plurality of drug-resin particles being coated with a triggered-release coating accompanied by unbound drug in solution.
Any of the diffusion barrier coatings or triggered-release coatings described herein may be used in any of the dosage forms described herein. For example, the some embodiments, the triggered-release coating is EUDRAGIT L100 or EUDRAGIT L100-55. In some embodiments, the triggered-release coating may have an overcoat (e.g., HPMC).
In other embodiments, the drug-resin particles may comprise both a triggered-release and a diffusion barrier coating. For example, the triggered-release coating may cover (i.e., overcoat) the diffusion barrier coating. In one embodiment, the diffusion barrier coating is ethylcellulose and the triggered-release coating is polyvinyl acetate phthalate (PVAP).
The invention provides pharmaceutical compositions comprising various mixtures of immediate release drug-resin particles (e.g., uncoated drug-resin particles) and delayed release drug-resin particles (e.g., triggered-release coated drug-resin particles). In one embodiment, the pharmaceutical composition comprises 20%-50% of immediate release drug-resin particles and 50-80% of delayed release drug-resin particles. In a particular embodiment, the composition comprises 40%-50% of immediate release drug-resin particles and 50%-60% of delayed release drug-resin particles. In a specific embodiment, the pharmaceutical composition comprises 45% of immediate release drug-resin particles and 55% of delayed release drug-resin particles. In another embodiment, the composition comprises 20%-30% of immediate release drug-resin particles and 70%-80% of delayed release drug-resin particles. In a specific embodiment, the pharmaceutical composition comprises 25% of immediate release drug-resin particles and 75% of delayed release drug-resin particles. As shown in the Examples, the percentage of uncoated and coated particles, as well as the types and percentages of coatings, effects the release profiles of the drug (e.g., at least one amphetamine).
The Examples provide in vitro dissolution and in vivo serum profiles for exemplary compositions of the inventions. These compositions (and their profiles) are encompassed within the invention. It will be understood that complete and partial profiles (e.g., partial AUCs) of the compositions set forth and described in the Examples are encompassed within the invention.
In one embodiment, the invention provides for administering an effective amount of a ADHD effective agent (e.g., at least one amphetamine such as a mixture of levo-amphetamine and dextroamphetamine). The effective dosage may range from 3.13 mg of amphetamine calculated as free base (equivalent to 5 mg of mixed amphetamine salts found in ADDERALL XR) to 18.8 mg of amphetamine calculated as free base (equivalent to 30 mg of mixed amphetamine salts found in ADDERALL XR). The amphetamine provided is preferably a mixture of 75% dextroamphetamine and 25% levoamphetamine. A delivery of about 2 mg/24 hours to about 60 mg/24 hours of the compositions of the invention, and more preferably from about 5 mg/24 hours to about 30 mg/24 hours, is typically needed to achieve a therapeutically effective dose in a patient (based on mixed amphetamine salts in ADDERALL XR). In particular embodiments, children 6-12 years old may take 10-30 mg/day (e.g., 0.5 mg/kg/day to 1.5 mg/kg/day), adolescents 13-17 years old may take 10-20 mg/day (0.25 mg/kg/day to 0.5 mg/kg/day), and adults may take 20 mg/day (0.28/kg/day to 0.4 mg/kg/day) (based on a mixed amphetamine salt in ADDERALL XR).
In another embodiment, the invention provides for administering an effective amount of methylphenidate. In one embodiment, the effective dosage ranges from 8.7 mg of methylphenidate base (equivalent to 10 mg of methylphenidate HCl) to 52.2 mg of methylphenidate base (equivalent to 60 mg of methylphenidate HCl). In another embodiment, the effective dosage is 26.1 mg of methylphenidate base (equivalent to 30 mg of methylphenidate HCl). A delivery of about 10 mg/24 hours to about 60 mg/24 hours of the compositions of the invention, and more preferably from about 20 mg/24 hours to about 40 mg/24 hours, is typically needed to achieve a therapeutically effective dose in a patient (based on methylphenidate HCl).
The compositions may be administered once-a-day (e.g., in a single unit or multiple unit compositions) in an amount that provides a therapeutic benefit equivalent to multiple doses of immediate release dosages.
The invention also provides for unit doses and packaging comprising unit dosages. For example, the invention provides for individually packaged liquid drug suspensions (e.g., 5, 10, 15, 30, or 60 ml), or the equivalent amount of drug as a chewable compositions or orally disintegrating dosage forms described herein. Methods of preparing unit dosage forms are known in the art.
It will be understood that the various aspects described herein may be combined. For example, the invention provides for a pharmaceutical composition comprising a first plurality of drug-resin particles being uncoated and a second plurality of drug-resin particles being coated with a triggered-release coating, wherein the drug is an ADHD effective agent (e.g., at least one amphetamine, methylphenidate) and the resin is IRP-64, IRP-69, IRP-88, or AP143.
Methods of Making Dosage Forms
The invention provides for methods of making the pharmaceutical compositions described herein. In one embodiment, the method comprises (a) loading a plurality of resin particles with at least one ADHD effective agent (e.g., at least one amphetamine, methylphenidate) to form drug-resin particles; (b) coating a subset of the loaded drug-resin particles with a delayed release coating (e.g., triggered-release coating) to form coated drug-resin particles; and (c) combining a subset of loaded, uncoated drug-resin particles with coated drug-resin particles in a pharmaceutical composition. In another embodiment, the method comprises (a) loading a plurality of resin particles with at least one ADHD effective agent (e.g., at least one amphetamine, methylphenidate) to form drug-resin particles; (b) coating drug-resin particles with a delayed release coating (e.g., triggered-release coating) to form coated drug-resin particles; and (c) combining said drug-resin particles with said coated drug-resin particles in a pharmaceutical composition.
In another embodiment, the method involves (a) loading a plurality of resin particles with an ADHD effective agent (e.g., methylphenidate) to form drug-resin particles; (b) coating drug-resin particles with an extended release coating (e.g., ethyl cellulose) to form extended release coated drug-resin particles; (c) further coating the extended release coated drug-resin particles with a delayed release coating (e.g., triggered-release coating) to form extended release/delayed release coated drug-resin particles; and (d) combining loaded, but uncoated drug-resin particles with the extended release/delayed release coated drug-resin particles in a pharmaceutical composition. In an alternative embodiment, a delayed release coating is applied to the loaded drug-resin particles to form delayed release coated drug-resin particles, and the extended release coating is then applied to the delayed release coated drug-resin particles.
The compositions made by the methods described herein may comprise various pluralities of drug-resin particles with the profiles described herein. For example, the composition may comprise pluralities of drug-resin particles such that (i) the rate of appearance of the drug (e.g., at least one amphetamine) in a dissolution medium is increasing during a time period from a first time point through to a second time point, wherein the first time point is at least one hour after the composition is introduced into the dissolution medium; and/or (ii) the composition achieves an ascending plasma concentration of the drug (e.g., at least one amphetamine) after a therapeutic effective level is reached (e.g., one, two, three hours after ingestion of the composition).
Methods of loading drugs onto resin particles are generally known in the art. The invention provides for methods of loading ADHD effective agents (e.g., at least one amphetamine, methylphenidate) onto resin particles (e.g., IRP-69, IRP-64, IRP-88, AP143). An exemplary method of loading is depicted in FIG. 1 and described in Example 1. In another embodiment, the composition comprises drug-resin particles comprise a mixture of l- and d-amphetamine (e.g., 25% l-amphetamine and 75% d-amphetamine), wherein each enantiomer is loaded onto a separate resin and the separately loaded resins are combined to form drug-resin particles. Alternatively, l- and d-amphetamine are mixed together in the desired ratio (e.g., 25% l-amphetamine and 75% d-amphetamine) and the mixed amphetamines are then loaded onto resins to form drug-resin particles.
Methods of coating drug-resin particles are also generally known in the art. The invention provides for various coating solutions and combinations of coatings (e.g., triggered-release coating such as EUDRAGIT L100, and a combination of EUDRAGIT 100 with HPMC). Example 2 provides an exemplary coating process and Examples 4-9 provide exemplary compositions with different coatings. Coatings may be applied using methods known in the art, such as with a fluid-bed coating apparatus having the Wurster configuration.
In alternative embodiments, the invention provides for methods of making orally disintegrating and chewable dosage forms comprising the various pluralities described herein. Methods of preparing orally disintegrating and chewable dosage forms with drug-resins are known in the art. See U.S. Publication No. 2007/0092553, which is hereby incorporated by reference in its entirety.
It will be understood that the various aspects described herein may be combined. For example, the invention provides for a pharmaceutical composition comprising a first plurality of drug-resin particles being uncoated and a second plurality of drug-resin particles being coated with a triggered-release coating, wherein the drug is at least one amphetamine or methylphenidate and the resin is IRP-64, IRP-69, IRP-88, AP143.
Methods of Treatment
The invention provides for various methods of treatment using the dosage forms described herein. In a particular embodiment, the invention provides for methods of treating ADD or ADHD, fatigue, obesity, or for imparting alertness, comprising administering an effective amount of any of the compositions described herein (e.g., a composition comprising at least one plurality of drug-resin particles being uncoated and at least one plurality of drug-resin particles coated with a delayed release coating such as a triggered-release coating, where the drug is at least one ADHD effective agent and the composition is, for example, a liquid, a chewable composition, or an orally disintegrating solid). In a preferred method, the individual being treated suffers from dysphagia.
It will be understood that the various aspects described herein may be combined. For example, the invention provides for methods of treating ADD or ADHD comprising administering an effective amount of a pharmaceutical composition comprising a first plurality of drug-resin particles being uncoated and a second plurality of drug-resin particles being coated with a triggered-release coating, wherein the drug is at least one amphetamine or methylphenidate and the resin is IRP-64, IRP-69, IRP-88, AP143.
Methods of Reducing Exposure of Amphetamines
The inventors have observed that, when the compositions described herein are administered to a subject substantially contemporaneously with ethanol, the subject has a reduced exposure level of an ADHD effective agent (e.g., amphetamines) compared to administering a reference listed drug (e.g., ADDERALL XR) to a subject substantially contemporaneously with ethanol. In particular embodiments, the exposure of amphetamines are reduced within 1.0, 1.5, 2.0, 2.5, and/or 3.0 hours after ingestion of the composition and ethanol. As such, the invention relates to methods of reducing exposure of amphetamines and, in particular, reduced exposure levels as compared to ADDERALL XR. The reduction in exposure is detectable; and assays for detecting exposure levels and comparing exposure levels are known in the art.
The inventors also observed that, when the compositions described herein are introduced into a dissolution medium substantially contemporaneously with ethanol, dose dumping of an ADHD effective agent (e.g., amphetamines) is reduced compared to introducing a reference listed drug (e.g., ADDERALL XR) into the same dissolution medium substantially contemporaneously with ethanol. As such, the invention relates to methods of reducing dose dumping of amphetamines in vitro and, in particular, reduced dose dumping as compared to ADDERALL XR. The reduction in dose dumping is detectable; and assays for detecting dose dumping levels and comparing such levels are known in the art. For example, cumulative release in vitro may be measured for the initial portion of the release curve, e.g., the first 0.5, 1, 1.5, 2, or 3 hours. Dose dumping may be evaluated from a partial area under the curve measurement to a relevant time point.
Dosage Forms Bioequivalent To A Target Product
The invention provides for dosage forms, methods of making dosage forms, and methods of administering dosage forms (e.g., for the conditions described herein such as ADHD) that are bioequivalent to a target product. In various embodiments, the invention provides for dosage forms (e.g., a liquid drug suspension, orally disintegrating tablet) that are bioequivalent to the in vivo serum profile of ADDERALL XR, or METADATE CD methods of making such dosage forms, and methods of treatment (as described herein) using such dosage forms. In particular embodiments, the compositions have complete and/or partial profiles (e.g., partial AUCs) that are bioequivalent to the profiles of ADDERALL XR or METADATE CD. Examples 16 and 17 describe such compositions. For example, the invention encompasses compositions that, when administered to a human, produce a mean plasma concentration profile which has any one of AUC0-3, AUC0-4, AUC0-5, AUC0-tmax, AUC4-12, AUC5-12, AUCtmax-12, AUC5-24, AUCtmax-24, AUC5-t, AUCtmax-t AUC0-24 and/or AUC0-∞ (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and/or 13 AUC values) that is/are bioequivalent to the corresponding profiles of ADDERALL XR or METADATE CD.
U.S. Pat. Nos. 6,322,819 and 6,605,300, which are hereby incorporated by reference in their entirety, provide release profiles and plasma concentrations of ADDERALL XR. See also FIG. 23.
In another embodiment, the invention provides for dosage forms (e.g., orally disintegrating tablet) that are statistically similar and/or have partial AUCs with 90% confidence intervals that are within 80-125% of METADATE CD. For example, Example 18 describes compositions in which d-methylphenidate and total methylphenidate (d+1) are statistically similar and/or have AUClast and AUCinf with 90% confidence intervals that are within 80-125% of METADATE CD; but which does not have Tmax that is substantially similar.
EXAMPLES
The following examples describe various compositions encompassed within the invention and their corresponding dissolution and in vivo serum profiles. These examples are not intended to limit the invention in any way.
Example 1
Loading the Resin Particles with Drug
The invention relates pharmaceutical compositions comprising drug-resin particles and the methods of making these compositions. This example provides an exemplary method of loading amphetamines onto resin particles. FIG. 1 depicts this loading method.
In a kettle, amphetamine sulfate and dextroamphetamine sulfate are mixed in purified water until fully dissolved. AMBERLITE IRP 69 resins are added to the kettle and mixed. The solution is filtered through a 20 μm filter (Grade 54), then again through a 8 μm filter (Grade 540). The loaded resinate is collected on the filter paper during each filtration.
In a kettle, polyethylene glycol is mixed in purified water until fully dissolved. After it is completely dissolved, the loaded resinate is added, and the solution is mixed until uniform. The solution is filtered through a 20 μm filter (Grade 54), then again through a 8 μm filter (Grade 540). The loaded resinate/PEG is collected on the filter paper during each filtration.
The loaded resinate/PEG is dried in an oven until Loss on Drying is between 3% and 7%. The dried material is screened through a 100-mesh and 325-mesh screen.
The material that passed through the 100-mesh screen, but did not pass through the 325-mesh screen, is collected. This material is used as the uncoated delayed release resinate. Alternatively, this material could be used as a substitute immediate release resinate.
The material that did not pass through the 100-mesh screen is milled using a Fitzmill (with knives forward and a 50-mesh screen). This material is added together with the material that passed through the 325-mesh screen to become the immediate release resinate. These two materials are blended together.
Example 2
Coating Drug-resin Particles
The pharmaceutical compositions of the invention may comprise a coated and uncoated plurality of drug-resin particles. The coated drug-resin particles provide the delayed or triggered-release portion of the composition. This example provides an exemplary method of preparing a polymer coating for the coated drug-resin particles.
A clean, stainless steel container is pre-weighed. Acetone and ethanol are added to the container. Plasticizer is then added to the container and mixed until dispersed. A coating polymer such as HPMC, is slowly added to the container while mixing. The polymer solution is continuously stirred for at least an hour and until all of the solids are dissolved. This coating solution is continuously stirred during the coating process. The loaded resinate of Example 1 may be coated (e.g., in a wurster coater) with this coating solution to prepare coated drug-resin complexes.
Example 3
Loading Resin Particles with Drug and Coating the Drug-resin Particles
The methods of Examples 1 and 2 may be combined to prepare the pharmaceutical compositions of the invention. In particular, drug-resin particles may be prepared using the method of Example 1, and those drug-resin particles to be used as the delayed release portion of the composition may be coated with a polymer coating prepared by the method of Example 2. The particles may be dried and mixed in a V-blender. The specific ratio of immediate release and delayed release particles may vary as described below.
Once the resin particles are loaded, coated, and mixed, the resulting drug-resin particles may be used in any suitable dosage form (e.g., suspension, chewable composition, orally disintegrating composition, capsule, tablet, etc.).
Example 4
Orally Disintegrating Tablet with 45% IR and 55% DR (Formula A)
An orally disintegrating tablet was formulated with 45% of the amphetamine from immediate release resin complex and 55% of the amphetamine from a delayed release resin complex. A hydroxypropyl methylcellulose (HPMC) coating overlays the delayed released resin complex. The formula is presented below in Table 1.







TABLE 1





ODT amphetamine formulation with 45% IR and 55% DR with HPMC Overcoat
















IR —34.17% base assay & DR —6.26% base assay: These values will be variable.






Dissolution Method

Dissolution Parameters:
Dissolution testing is carried out using a USP Apparatus 2 with cannulas and cannula filters (Quality Lab Accessories, Porus Micron full flow filters 20 micron); paddle speed—100 rpm; kettle size—1000 mL; temperature—37.0±0.5° C.; filter—25 mm 0.45 um PVDF w/GMF; syringe—B-D10 mL Luer-Lok.
Dissolution Media:
The medium for the dissolution assay is 900 mL of 0.1N HCl for the first hour; after 2 hour time point  ̃100 mL of potassium phosphate/sodium hydroxide solution is added to bring to pH  ̃6.8.
The sample is weighed and is placed into the corresponding kettle, and the dissolution timing started.
Sampling pull times are 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours. For each sample pull time and each kettle, 10 mL of sample are pulled into a B-D 10 mL Luer-Lok syringe and returned to the kettles before the sample pull to flush out the cannula from the prior pulls. 2 ml are then pulled for filtration and placed into an HPLC vial. Non-media replacement and volume changes from the two media changes are calculated.
Dissolution Profile:
The amount of drug in the filtrate at each time point is determined by HPLC, and the percentage released from the drug-resin is plotted in FIG. 2.
The same profile was obtained without the use of the HPMC overcoat.
Example 5
Orally Disintegrating Tablet with 30% IR and 70% DR (Formula B)
An orally disintegrating tablet was formulated with 30% of the amphetamine from immediate release resin complex and 70% of the amphetamine from a delayed release resin complex. An HPMC coating overlays the delayed released resin complex. The formula is presented in Table 2.







TABLE 2





ODT amphetamine formulation with 30% IR and 70% DR with HPMC Overcoat
















IR —34.17% base assay & DR—6.26% base assay: These values will be variable.






The dissolution method is performed as described in the previous Example, except that sample pull times are 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, and 6.0 hours.
Dissolution Profile:
The amount of drug in the filtrate at each time point is determined by HPLC, and the percentage released from the drug-resin is plotted in FIG. 3.
The same profile was obtained without the use of the HPMC overcoat.
Example 6
Orally Disintegrating Tablet with 45% IR and 55% DR (Formula C)
An orally disintegrating tablet was formulated with 45% of the amphetamine from immediate release resin complex and 55% of the amphetamine from a delayed release resin complex. This formulation did not include an HPMC overcoat. The formula is presented in Table 3.







TABLE 3





ODT amphetamine formulation with 45% IR and 55% DR
















IR —34.17% base assay & DR—8.53% base assay: (These values will be variable.)






The dissolution method is performed as described in Example 4, except that sample pull times are 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours.
Dissolution Profile:
The amount of drug in the filtrate at each time point is determined by HPLC, and the percentage released from the drug-resin is plotted in FIG. 4.
Example 7
Suspension with 50% IR and 50% DR (Formula A1)
A suspension was formulated with 50% of the amphetamine from immediate release resin complex and 50% of the amphetamine from a delayed release resin complex. The resin was IRP-69. The delayed release resin complexes coated with 15% TEC, and 70% EUDRAGIT L100. The formulation is presented in Table 4.







TABLE 4







Suspension amphetamine formulation with 50% IR and 50% DR













Amount per



Ingredient
Application
15 ml















Purified Water
Diluent
7.9
g



Ascorbic Acid
pH
6.00
mg



Propylene Glycol
Solvent
525.00
mg



Methylparaben
Preservative
12.00
mg



Propylparaben
Preservative
1.50
mg



Polysorbate 80
Surfactant
15.00
mg



Xanthan Gum
Suspending Agent
90.00
mg



Vegetable (Corn) Oil
Viscosity Agent
30.00
mg



Amphetamine
Active Resin
27.57
mg



Uncoated Resin






Amphetamine
Active Resin
76.19
mg



Coated Resin






Sucrose
Sweetener
2250.00
mg



High Fructose Corn Syrup
Sweetener
6750.00
mg









The dissolution method was performed as described in Example 4, except that the samples were pulled at different time points: 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, and 6.0 hours.
Dissolution Profile:
The amount of drug in the filtrate at each time point was determined by HPLC, and the percentage released from the drug-resin is plotted in FIG. 5 and reflected below.












Leakage












2 W
2 W



Initial
AMB1
ASL2









30 Mins (% Release): @ 2 Hours











47.9
56.8
60.3









(% Release): Profile (% Release)












Hours
51.5
67.2
72.4















0.5
47.9
56.8
60.3



1
51.5
66.7
70.5



1.5
52.2
66.1
72.5



2
52.8
67.2
72.4



2.5
93.4
100.2
97.8



3
94.9
99.9
97.8



4
95.6
100.1
98.1



6

102.5
98.2





1Two weeks under ambient conditions.


2Two weeks under accelerated shelf life conditions.






Example 8
ODT with 50% IR and 50% DR (Formula D)
An orally disintegrating tablet was formulated with 50% of the amphetamine from immediate release resin complex and 50% of the amphetamine from a delayed release resin complex. This formulation was similar to Examples 4-6 and is reflected in Table 5. The resin was IRP-69. The delayed release coated resin comprised 15% TEC, and 70% EUDRAGIT L100.







TABLE 5







ODT amphetamine formulation with 50% IR and 50% DR.













Amount per



Ingredient
Application
tablet






Amphetamine Resin IR
Active Resin I
38.10 mg




(Assay -16.9%)




Amphetamine Resin DR
Active Resin II
13.79 mg




(Assay -46.7%)




Ludiflash
Compressing
371.11 mg 




Agent




Croscarmellose Sodium
Disintegrant
22.50 mg



Magnesium Stearate
Lubricant
 4.50 mg









The dissolution method was performed as described in Example 4, except that the samples were pulled at different time points.
Dissolution Profile:
The amount of drug in the filtrate at each time point was determined by HPLC, and the percentage released from the drug-resin is plotted in FIG. 6 and reflected below.













Profile (% Release)




Hours


















0.5
50.5



1
51.0



1.5
51.5



2
52.4



2.5
85.3



3
96.0



4
96.9









Example 9
ODT with 35% IR and 65% DR (Formula E)
An orally disintegrating tablet was formulated with 35% of the amphetamine from immediate release resin complex and 65% of the amphetamine from a delayed release resin complex. This formulation was similar to Examples 4-6 and is reflected in Table 6. Unlike these examples, however, the resin was an IRP-64 resin. The delayed release coated resin comprised 15% HPMC, 15% TEC, and 110% EUDRAGIT L100.







TABLE 6







ODT amphetamine formulation with 35%


IR and 65% DR with HPMC Overcoat













Amount per



Ingredient
Application
tablet















Amphetamine Resin DR
Active Resin I
128.8
mg1




(Assay -6.5%)





Amphetamine Resin IR
Active Resin II
7.07
mg2




(Assay -63.73%)





Ludiflash
Compressing
287.13
mg




Agent





Croscarmellose Sodium
Disintegrant
22.50
mg



Magnesium Stearate
Lubricant
4.50
mg









The dissolution method was performed as described in Example 4, except that the samples were pulled at different time points.
Dissolution Profile
The amount of drug in the filtrate at each time point was determined by HPLC, and the percentage released from the drug-resin is plotted in FIG. 7 and reflected below.













Profile (% Release)




Hours


















0.5
47.6



1
52.4



1.5
56



2
58.2



2.5
81.8



3
88.9



4
93.4



24
108.3









Example 10
pH study
A pH study was also conducted to compare a control and four different coated drug-resin particles prepared according to the methods described in Examples 1 and 2 for the following coatings and resins: (1) 70% EUDRAGIT L100/IRP69; (2) 110% EUDRAGIT L100/IRP 64; (3) 40% EUDRAGIT L100-55/IRP 69; (4) 70% EUDRAGIT L100-55/IRP 64.
pH Study Protocol:
The medium for the dissolution assay is 0.1N HCl. pH change buffer described in the previous examples is added, drop wise, until a pH of 2.0, 3.0, 4.0, 5.0, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, and 6.5 is reached. At each pH point, 2 mL of sample was removed and then pH change buffer solution is added to adjust pH to next pH target. The next sample is taken 10 minutes after adjusted pH.
Varying the coating and the resin composition shifted the release curve as shown in FIG. 8. EUDRAGIT L100 and IRP69 gave results closest to the pH for release observed with ADDERALL XR.
Example 11
Pig Study Using Pharmaceutical Compositions
This study is an open-label, random order, crossover comparison study of three test formulations (two tablets and one liquid suspension) and the currently marketed reference drug (ADDERALL XR). In vivo studies are performed using pigs. A total of 12 animals are initially assigned to study (3 males per group×4 groups). All animals are fasted overnight prior to dosing and through the first 4 hours of blood sample collection (total fasting time not to exceed 24 hours). Water is available ad libitum. Animals are dosed on days 1, 4, 8, and 15).
Phase 1: Each animal in Groups 1 and 2 receives a 2 tablet dose of the appropriate test article formulation as outlined in the study design in Table 7 below. Each animal in Group 4 receives a 1 capsule dose of the reference formulation as outlined in Table 7. A balling gun may be used, if appropriate, to facilitate dosing. Whether animals are hand-dosed or a balling gun is used for dosing, a subsequent 10 mL tap water rinse is administered orally following dosing. Each animal in Group 3 receives a single oral gavage (PO) dose of the appropriate test article formulation as outlined in the study design table below. The dosing syringes are weighed when loaded with the test formulation and then again following dose administration for each animal (i.e. loaded and delivered syringe weights). Oral gavage dosing formulations will be continuously stirred throughout dosing. The gavage tube should be rinsed with approximately 10 mL of tap water following dosing (prior to removal of the gavage tube).
Phase 2: Following a washout at least 3 days, each animal in Groups 2 and 3 receives a 2 tablet dose of the appropriate test article formulation as outlined in Table 7. Each animal in Group 1 receives a 1 capsule dose of the reference formulation as outlined in Table 7. A balling gun may be used, if appropriate, to facilitate dosing. Whether animals are hand-dosed or a balling gun is used for dosing, a subsequent 10 mL tap water rinse is administered orally following dosing. Each animal in Group 4 receives a single oral gavage (PO) dose of the appropriate test article formulation as outlined in the study design table below. The dosing syringes should be weighed when loaded and then again following dose administration for each animal (i.e. loaded and delivered syringe weights). Oral gavage dosing formulations should be continuously stirred throughout dosing. The gavage tube should be rinsed with approximately 10 mL of tap water following dosing (prior to removal of the gavage tube).
Phase 3: Following a washout of at least 3 days, each animal in Groups 3 and 4 receives a 2 tablet dose of the appropriate test article formulation as outlined in Table 7. Each animal in Group 2 receives a 1 capsule dose of the reference formulation as outlined in Table 7. A balling gun may be used, if appropriate, to facilitate dosing. Whether animals are hand-dosed or a balling gun is used for dosing, a subsequent 10 mL tap water rinse is administered orally following dosing. Each animal in Group 1 receives a single oral gavage (PO) dose of the appropriate test article formulation as outlined in the study design table below. The dosing syringes are weighed when loaded and then again following dose administration for each animal (i.e. loaded and delivered syringe weights). Oral gavage dosing formulations are continuously stirred throughout dosing. The gavage tube is rinsed with approximately 10 mL of tap water following dosing (prior to removal of the gavage tube).
Phase 4: Following a washout of at least 3 days, each animal in Groups 1 and 4 receives a 2 tablet dose of the appropriate test article formulation as outlined in Table 7. Each animal in Group 3 receives a 1 capsule dose of the reference formulation as outlined in Table 7. A balling gun may be used, if appropriate, to facilitate dosing. Whether animals are hand-dosed or a balling gun is used for dosing, a subsequent 10 mL tap water rinse is administered orally following dosing. Each animal in Group 2 receives a single oral gavage (PO) dose of the appropriate test article formulation as outlined in the study design table below. The dosing syringes are weighed when and then again following dose administration for each animal (i.e. loaded and delivered syringe weights). Oral gavage dosing formulations are continuously stirred throughout dosing. The gavage tube is rinsed with approximately 10 mL of tap water following dosing (prior to removal of the gavage tube).







TABLE 7







Pig study design.















Number of
Dose
Dose Level
Dose Volume/
Matrix


Group
Test Article
Males*
Route
(mg)
Amount
Collected










PHASE 1













1
Neos 2
3
Oral, tablet
30
2 tablets
BloodE



Formulation #1



(15 mg/tablet)



2
Neos 2 Formulation #2
3
Oral, tablet
30
2 tablets
BloodE







(15 mg/tablet)



3
Neos 2 Formulation #3
3
PO, Liquid
30
15 mL
BloodE





suspension





4
Reference Drug
3
Oral,
30
1 capsule
BloodE



(ADDERALL XR)

capsule

(30 mg/capsule)




Formulation












PHASE 2













1
Reference Drug
3
Oral,
30
1 capsule
BloodE



(ADDERALL XR)

capsule

(30 mg/capsule)




Formulation







2
Neos 2
3
Oral, tablet
30
2 tablets
BloodE



Formulation #1



(15 mg/tablet)



3
Neos 2 Formulation #2
3
Oral, tablet
30
2 tablets
BloodE







(15 mg/tablet)



4
Neos 2 Formulation #3
3
PO, Liquid
30
15 mL
BloodE





suspension










PHASE 3













1
Neos 2 Formulation #3
3
PO, Liquid
30
15 mL
BloodE





suspension





2
Reference Drug
3
Oral,
30
1 capsule
BloodE



(ADDERALL XR)

capsule

(30 mg/capsule)




Formulation







3
Neos 2
3
Oral, tablet
30
2 tablets
BloodE



Formulation #1



(15 mg/tablet)



4
Neos 2 Formulation #2
3
Oral, tablet
30
2 tablets
BloodE







(15 mg/tablet)








PHASE 4













1
Neos 2
3
Oral, tablet
30
2 tablets
BloodE



Formulation #2



(15 mg/tablet)



2
Neos 2 Formulation #3
3
PO, Liquid
30
15 mL
BloodE





suspension





3
Reference
3
Oral,
30
1 capsule
BloodE



(ADDERALL XR)

capsule

(30 mg/capsule)




Formulation







4
Neos 2
3
Oral, tablet
30
2 tablets
BloodE



Formulation #1



(15 mg/tablet)





DReference Formulation is a Marketed Product. All capsules and tablets will be used as received.


EBlood samples will be collected predose and at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 16, and 24 hours postdose.


*The same animals will be used for each phase following a washout of at least 3 days.






For each phase, blood samples (approximately 2 mL/sample) are collected from the thoracic inlet (jugular vein, or other suitable vein) predose and at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 16, and 24 hours postdose and placed into tubes containing K2EDTA. All blood samples are placed on an ice block (or wet ice) following collection. The samples are centrifuged and the resulting plasma is separated and stored frozen at approximately −70° C. until analyzed (following separation; the plasma may be initially placed on dry ice prior to being stored in the −70° C. freezer). Any clotted samples should be noted.
Plasma samples are analyzed for amphetamine over the range of 0.1 ng/mL to 200 ng/mL. Control plasma procured from a commercial source is used for all analyses. Each analysis batch includes duplicate calibration samples (one set run at beginning of batch and one at the end of batch) with a minimum of 6 non-zero levels, and duplicate QC samples prepared at 4 concentration levels. The calibration and QC samples are prepared from separate stocks. Acceptance criteria for each batch is that at least 75% of individual calibration points and 62.5% of the QC samples must be within +/−30% of the target concentration.
Example 12
In vivo Study
Drug samples from Examples 4 and 5 were administered to pigs as described in Example 11. Capsules of ADDERALL XR were administered as controls under the same conditions.
Results of the pig study are depicted in FIG. 9. Outliers were excluded. FIG. 9 shows the plasma concentrations of drug released from the formulas in Examples 4 and 5 compared to ADDERALL XR (i.e., the reference formulation). The relative amounts of coated and uncoated particles differed between Examples 4 and 5; both compositions showed two peaks in the in vivo release profile, but with the composition having relatively more coated particles, the Tmax for both peaks is later, and the Cmax for the second peak is higher. Thus, the skilled person can adjust the relative Cmax and AUC for each of the two peaks by adjusting the relative amounts of coated and uncoated drug-resin particles in the composition.
Example 13
Ethanol Study
A. In Vivo Study
The effects of ethanol were also tested. In vivo studies were carried out using drug samples similar to that from Example 6 administered to pigs as described in Example 11. The drug formulations were administered to pigs as described in Example 11, except that alcohol (240 ml of 20% ethanol) was also administered to the pigs contemporaneously. Capsules of ADDERALL XR were administered under the same conditions as controls.
Results of the pig study are depicted in FIGS. 10A and 10B. Outliers were excluded. FIGS. 3A and 3B show the plasma concentrations of drug released from the resin formulas similar to that in Example 6 compared to ADDERALL XR (i.e., the reference formulation) and IR mixed amphetamines in the presence and absence of alcohol. The figures show (1) an increased exposure of amphetamines in the presence of alcohol; and (2) in the present of ethanol, formulations of the invention have a significantly reduced exposure level of amphetamines as compared to ADDERALL XR as demonstrated by comparison between the curves shown.
Often drugs products exhibit dose dumping in the presence of ethanol. This is one of the reason that the FDA asks for ethanol interaction studies on controlled release formulations. If a drug product showed dose dumping, all of the drug that is to be administered over time would become immediately available and adverse events could be seen. In contrast, the graph clearly shows that the integrity of the controlled release mechanism remains intact and two peaks can be distinguished. The first peak being the immediate release portion and the second peak being the still intact delayed release portion. The increased exposure, approximately 3 times the area under the curve (AUC), for both peaks is due to another physiological effect in the presence of ethanol such as impairment of the liver metabolism by the ethanol and thus lower first pass metabolism of the drug in the liver or other mechanism resulting in greater than expected blood levels for a given dose.
B. In Vitro Study
In vitro dissolution studies using amphetamine compositions in the presence or absence of ethanol were also carried out. Drug compositions to be tested were introduced into USP dissolution Apparatus 2 as described above, except that the media started with alcoholic 0.1N HCl and samples were taken at different time points. FIG. 11 shows the release profiles of the ADDERALL XR reference formulation with 0%, 20%, and 40% ethanol. These results demonstrate that the addition of 20% or 40% ethanol substantially increases the amount of drug released in the reference formulation, i.e., there is a substantial increase in drug released through dose dumping in the presence of ethanol. This dose dumping may exacerbate the exposure of the subject to amphetamines which increases in vivo approximately 3 times in the presence of ethanol.
FIG. 12 shows the release profiles of the drug sample similar to that from Example 6 with 0%, 20%, and 40% ethanol. These results demonstrate that the addition 20% ethanol does not substantially increase the amount of drug released. Moreover, the addition of 40% ethanol increases the amount of drug released but to a lesser extent than in the reference formulation. As such, the ethanol study's results show that, in the presence of ethanol, the formulations of the invention have a reduced exposure level of amphetamines as compared to the reference formulation. This prevents or substantially reduces the likelihood of dose dumping when the formulations of the invention and ethanol are ingested by a subject.
Example 14
pH Study
A pH study was also conducted on the compositions administered to the pigs in Example 13. The dissolution and pH protocols are the same as described in Example 10. The results of the pH study on three different lots of the delayed release particles from Example 6 are depicted in FIG. 13.
Example 15
Human Pharmacokinetic Study Using ODT Pharmaceutical Compositions
This example describes a single-dose, open-label, randomized, three-period, three-treatment crossover study comparing the rate of absorption and oral bioavailability of two controlled release ODT preparations of mixed amphetamine polistirex (equivalent to 30 mg mixed amphetamines) to an equivalent 30 mg oral dose of the commercially available reference product, ADDERALL XR, (Shire US Inc.) following an overnight fast of at least 10 hours. Subjects were randomly assigned to a treatment sequence and received three, separate single-dose administrations of study medication, one treatment per period, according to the randomization schedule. Dosing days were separated by a washout period of at least 7 days.
Subjects received each of the treatments listed below during the three treatment periods:
Treatment A: Test Formulation #1 (mixed amphetamine resins) controlled-release ODT. Test Formulation #1 is substantially similar to Formula C in Example 6. Dose=1× mixed amphetamine polistirex ODT equivalent to 30 mg mixed amphetamine salts.
Treatment B: Test Formulation #2 (mixed amphetamine resins) controlled-release ODT. Test Formulation #2 is substantially similar to Formula C in Example 6. Dose=1× mixed amphetamine polistirex ODT equivalent to 30 mg mixed amphetamine salts
Treatment C: Reference Product ADDERALL XR Shire US, Inc. Dose=1×30 mg capsule
Clinical Procedures Summary
During each study period, 4 mL blood samples were obtained prior to each dosing and following each dose at selected times through 60 hours post-dose. A total of 60 pharmacokinetic blood samples were collected from each subject, 20 samples in each study period. In addition, blood was drawn and urine was collected for clinical laboratory testing at screening and study exit.
In each study period, subjects were admitted to the study unit in the evening prior to the scheduled dose. Subjects were confined to the research center during each study period until completion of the 36-hour blood collection and other study procedures. Subjects returned to the study unit for outpatient pharmacokinetic blood samples at 48 and 60 hours. Thirty-three (33) of the 36 subjects enrolled completed the study.
Procedures for Collecting Samples for Pharmacokinetic Analysis
Blood samples (1×4 mL) were collected in vacutainer tubes containing K2-EDTA as a preservative at pre-dose (0) and at 1.0, 2.0, 3.0, 4.0, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 9.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0, and 60.0 hours after dosing.
Bioanalytical Summary
Plasma samples were analyzed for d-amphetamine and l-amphetamine by a third party laboratory using a validated LC MS MS procedure. The method was validated for a range of 0.500 to 80.0 ng/mL for d-amphetamine and 0.200 to 32.0 ng/mL for 1-amphetamine, based on the analysis of 0.150 mL of human EDTA plasma.
Pharmacokinetic Analysis
Concentration time data were analyzed by noncompartmental methods in WinNonlin. Concentration time data that were below the limit of quantification (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”. Full precision concentration data (not rounded to three significant figures) and actual sample times were used for all pharmacokinetic and statistical analyses.
The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λ2), terminal half-life (T1⁄2), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), and area under the plasma concentration time curve from time-zero extrapolated to infinity (AUCinf). Secondary pharmacokinetic endpoints included partial AUCs. The following partial AUCs were calculated using the linear trapezoidal method: AUC0-4, AUC4-12, and AUC0-24.
Analysis of variance (ANOVA) and the Schuirmann's two one sided t test procedures at the 5% significance level were applied to the log-transformed pharmacokinetic exposure parameters, Cmax, AUClast, and AUCinf. The 90% confidence interval for the ratio of the geometric means (Test/Reference) was calculated. Bioequivalence was declared if the lower and upper confidence intervals of the log-transformed parameters were within 80% to 125%. Comparisons of partial AUC0-4, AUC4-12, and AUC0-24 across treatments were performed as supportive evidence of equivalence.
Results
Data from 33 subjects who completed the study were included in the pharmacokinetic and statistical analyses. Mean concentration-time data are shown in FIGS. 14 and 15. Results of the pharmacokinetic and statistical analyses are shown below in Tables 8 through 11.
The results show that the d- and l-amphetamine enantiomers of Test Formulations #1 and #2 were bioequivalent to the Reference Product. In particular, nearly all of the partial AUCs (AUC4-12 and AUC0-24) of the d- and l-amphetamine enantiomers of Test Formulations #1 and #2 were bioequivalent to the Reference Product.
FIGS. 14A and 14B show the mean d-amphetamine concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), and Reference Product (Treatment C).
FIGS. 15A and 15B show the mean l-amphetamine concentration-time profiles after administration of test formulation #1 (Treatment A), test formulation #2 (Treatment B), and reference product (Treatment C).







TABLE 8







Statistical analysis of the log-transformed systemic exposure parameters of


d-amphetamine comparing Test Formulation #1 (Treatment A) to the Reference Product


(Treatment C).












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
44.5370
45.9975
96.82
94.62
99.08
1.0000
5.61


ln(AUC0-4)
85.9326
100.9418
85.13
78.30
92.56
0.9965
20.54


ln(AUC4-12)
290.8805
294.3597
98.82
96.85
100.82
1.0000
4.89


ln(AUC0-24)
613.2608
631.8461
97.06
94.84
99.32
1.0000
5.61


ln(AUClast)
825.7531
843.4700
97.90
94.99
100.90
1.0000
7.34


ln(AUCinf)
848.3149
866.4947
97.90
94.73
101.18
1.0000
7.88





aGeometric Mean for the Test Formulation #1 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


Note:


T1/2 and parameters based on extrapolation could not be calculated for all subjects; statistical analysis is based on n = 33 for Cmax, AUC0-4, AUC4-12, AUC0-24, AUClast, and n = 32 for AUCinf













TABLE 9







Statistical analysis of the log-transformed systemic exposure


parameters of d-amphetamine comparing Test Formulation #2


(Treatment B) to the Reference Product (Treatment C).












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
45.2664
45.9975
98.41
96.17
100.70
1.0000
5.61


ln(AUC0-4)
80.8609
100.9418
80.11
73.68
87.09
0.9965
20.54


ln(AUC4-12)
295.5819
294.3597
100.42
98.42
102.45
1.0000
4.89


ln(AUC0-24)
616.5054
631.8461
97.57
95.35
99.85
1.0000
5.61


ln(AUClast)
830.7075
843.4700
98.49
95.56
101.50
1.0000
7.34


ln(AUCinf)
851.1774
866.4947
98.23
95.05
101.52
1.0000
7.88





aGeometric Mean for the Test Formulation #2 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


Note:


T1/2 and parameters based on extrapolation could not be calculated for all subjects; statistical analysis is based on n = 33 for Cmax, AUC0-4, AUC4-12, AUC0-24, AUClast, and n = 32 for AUCinf













TABLE 10







Statistical analysis of the log-transformed systemic exposure


parameters of l-amphetamine comparing Test Formulation #1


(Treatment A) to the Reference Product (Treatment C).












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
14.2494
14.1857
100.45
98.07
102.89
1.0000
5.85


ln(AUC0-4)
26.3537
30.0286
87.76
80.53
95.64
0.9951
21.14


ln(AUC4-12)
95.1124
93.0132
102.26
100.09
104.47
1.0000
5.20


ln(AUC0-24)
204.9113
203.7331
100.58
98.07
103.15
1.0000
6.14


ln(AUClast)
295.5590
290.6272
101.70
98.33
105.18
1.0000
8.21


ln(AUCinf)
312.0976
307.0441
101.65
97.80
105.64
1.0000
9.24





aGeometric Mean for the Test Formulation #1 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


Note:


T1/2 and parameters based on extrapolation could not be calculated for all subjects; statistical analysis is based on n = 33 for Cmax, AUC0-4, AUC4-12, AUC0-24, AUClast, and n = 32 for AUCinf













TABLE 11







Statistical analysis of the log-transformed systemic exposure


parameters of l-amphetamine comparing Test Formulation #2


(Treatment B) to the Reference Product (Treatment C).












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
14.6051
14.1857
102.96
100.51
105.46
1.0000
5.85


ln(AUC0-4)
24.9270
30.0286
83.01
76.17
90.46
0.9951
21.14


ln(AUC4-12)
96.8135
93.0132
104.09
101.88
106.34
1.0000
5.20


ln(AUC0-24)
206.6684
203.7331
101.44
98.91
104.03
1.0000
6.14


ln(AUClast)
297.5544
290.6272
102.38
98.99
105.89
1.0000
8.21


ln(AUCinf)
313.3883
307.0441
102.07
98.21
106.07
1.0000
9.24





aGeometric Mean for the Test Formulation #2 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


Note:


T1/2 and parameters based on extrapolation could not be calculated for all subjects; statistical analysis is based on n = 33 for Cmax, AUC0-4, AUC4-12, AUC0-24, AUClast, and n = 32 for AUCinf






Example 16
Human Pharmacokinetic Study Comparing ODT to Suspension Formulations
This example compared the rate of absorption and oral bioavailability of a controlled release ODT preparation of mixed amphetamine polistirex (equivalent to 30 mg mixed amphetamine salts) and a controlled release liquid suspension of mixed amphetamine polistirex (equivalent to 30 mg mixed amphetamine salts) to an equivalent 30 mg oral dose of the commercially available reference product, ADDERALL XR (Shire US Inc.) following an overnight fast of at least 10 hours. Subjects were randomly assigned to a treatment sequence and received three separate single-dose administrations of study medication, one treatment per period, according to the randomization schedule as described in the previous Example. Dosing days were separated by a washout period of at least 7 days.
Subjects received each of the treatments listed below during the three treatment periods:
Treatment A: Test Formulation #3 (mixed amphetamine resins) controlled-release ODT. Dose=1× mixed amphetamine polistirex ODT equivalent to 30 mg mixed amphetamine salts.
Treatment B: Test Formulation #4 (mixed amphetamine resins) controlled-release suspension. Dose=1× mixed amphetamine polistirex suspension equivalent to 30 mg mixed amphetamine salts.
Treatment C: Reference Product ADDERALL XR, Shire US, Inc. Dose=1×30 mg capsule.







TABLE 12







Test Formulation #3 (ODT amphetamine with 45% IR and 55% DR)


IR Resin - 34.08% base assay & DR Resin - 7.28%


base assay: These values will be variable










Formula #3




(45% active from IR Resin &




55% active from DR Resin)












mg/dose
Notes
%













Uncoated (IR) AMP Resin
24.82

3.76


Amphetamine (base)
4.23




Dextroamphetamine (base)
4.23




AMBERLITE IRP069 Resin
13.88




Polyethylene Glycol
1.24




Purified Water
1.24




Coated (DR) AMP Resin
142.03

21.52


Amphetamine (base)
5.17




Dextroamphetamine (base)
5.17




AMBERLITE IRP069 Resin
16.96




Polyethylene Glycol
1.52




Purified Water
1.52




EUDRAGIT L100
97.21




Triethyl Citrate
14.48




Prosolv ODT
323.20

48.97


Crospovidone
105.60

16.00


Flavorings
65.35

9.75


Total
660.00 mg

100%
















TABLE 13







Test Formulation #4 (Suspension amphetamine with 45% IR and 55% DR)


IR Resin - 34.08% base assay & DR Resin - 7.28% base assay:









Formula #4



(45% active from IR Resin &



55% active from DR Resin)











mg per 15 mL





dose
Notes
%














Uncoated (IR) AMP Resin
24.82


0.14


Amphetamine (base)
4.23





Dextroamphetamine (base)
4.23





AMBERLITE IRP069 Resin
13.88





Polyethylene Glycol
1.24





Purified Water
1.24





Coated (DR) AMP Resin
142.03


0.79


Amphetamine (base)
5.17





Dextroamphetamine (base)
5.17





AMBERLITE IRP069 Resin
16.96





Polyethylene Glycol
1.52





Purified Water
1.52





EUDRAGIT L100
97.21





Triethyl Citrate
14.48





Purified Water
8123.2

Each 15 mL dose
45.13


Ascorbic Acid
6.00

of suspension is
0.03


Propylene Glycol
525.00

equivalent to
2.92


Preservative
3.75

18 grams at the
0.03


Polysorbate 80
15.00

theoretical
0.08


Xanthan Gum
90.00

suspension
0.50


Vegetable Oil
30.00

specific
0.17


Color & Flavor
40.20

gravity of 1.2.
<0.23


Sucrose
2250.00


12.50


High Fructose Corn Syrup
6750.00


37.50


Total
18,000.00
mg

100%









Administration, data collection and analysis were carried out as described in the previous Example. Data from subjects who completed the study were included in the pharmacokinetic and statistical analyses. Mean concentration-time data are shown in FIGS. 16-19. Results of the pharmacokinetic and statistical analyses are shown below in Tables 14 through 17.







TABLE 14







Statistical Analysis of Human Bioequivalence Studies: ODT Data (D-


Isomer)











Mean
Ratio (%)
90% CI












Dependent Variable
Test
Ref
(Test/Ref)
Lower
Upper















ln(Cmax)
44.5
46.0
96.7
94.6
99.1


ln(AUC0-4)
85.9
100.9
85.1
78.3
92.6


ln(AUC0-5)
126.3
46.0 (?)
87.7
82.1
93.7


ln(AUC4-12)
290.9
294.4
98.8
96.9
100.8


ln(AUC5-12)
250.5
251.6
99.5
97.3
101.8


ln(AUC0-24)
613.3
631.8
97.1
94.8
99.3


ln(AUClast)
825.8
843.5
97.9
95.0
100.9


ln(AUCinf)
848.3
866.5
97.9
94.7
101.2


Tmax
5.26
4.53
















TABLE 15







Statistical Analysis of Human Bioequivalence Studies: ODT Data (L-


Isomer)











Mean
Ratio (%)
90% CI












Dependent Variable
Test
Ref
(Test/Ref)
Lower
Upper















ln(Cmax)
14.2
14.2
100.5
98.1
102.9


ln(AUC0-4)
26.4
30.0
87.8
80.5
95.6


ln(AUC0-5)
39.2
43.2
90.7
84.6
97.1


ln(AUC4-12)
95.1
93.0
102.3
100.1
104.5


ln(AUC5-12)
82.3
79.9
103.0
100.5
105.5


ln(AUC0-24)
204.9
203.7
100.6
98.1
103.2


ln(AUClast)
295.6
290.6
101.7
98.3
105.2


ln(AUCinf)
312.1
307.0
101.7
97.8
105.6


Tmax
5.70
4.59
















TABLE 16







Statistical Analysis of Human Bioequivalence Studies: Suspension Data


(D-Isomer)











Mean
Ratio (%)
90% CI












Dependent Variable
Test
Ref
(Test/Ref)
Lower
Upper















ln(Cmax)
46.3
49.1
94.2
91.4
97.0


ln(AUC0-4)
104.7
107.4
97.5
88.7
107.0


ln(AUC0-5)
148.6
152.4
97.5
90.7
104.9


ln(AUC4-12)
300.4
313.8
95.7
92.7
98.9


ln(AUC5-12)
256.9
269.1
95.5
92.1
98.9


ln(AUC0-24)
651.8
680.2
95.8
92.6
99.2


ln(AUClast)
861.2
904.5
95.2
91.0
99.6


ln(AUCinf)
892.8
935.4
95.4
91.0
100.1


Tmax
4.61
4.96
















TABLE 17







Statistical Analysis of Human Bioequivalence Studies: Suspension


Data (L-Isomer)











Mean
Ratio (%)
90% CI












Dependent Variable
Test
Ref
(Test/Ref)
Lower
Upper















ln(Cmax)
14.6
14.8
98.9
96.3
101.6


ln(AUC0-4)
31.8
31.6
100.8
91.6
110.8


ln(AUC0-5)
45.7
45.2
101.1
93.8
108.9


ln(AUC4-12)
96.8
97.1
99.7
96.4
103.2


ln(AUC5-12)
83.2
83.6
99.5
95.9
103.2


ln(AUC0-24)
215.2
215.5
99.9
96.3
103.6


ln(AUClast)
304.8
306.8
99.3
94.6
104.4


ln(AUCinf)
325.3
327.0
99.5
94.0
105.2


Tmax
5.09
5.27









Example 17
Orally Disintegrating Tablet with 25% IR and 75% ER/DR
An orally disintegrating tablet was formulated with 25% of methylphenidate from immediate release resin complex and 75% of the methylphenidate from an extended release (ER)/delayed release (DR) resin complex. In the ER/DR coating, ethylcellulose overlays EUDRAGIT. The formula is presented below.







TABLE 18







ODT methylphenidate Formulation A with 25% IR and 75% ER/DR.


IR Resin - 36.98% base assay & ER/DR Resin - 13.11% base assay:


These values are variable









Formula A (25% active from



IR Resin & 75% active from ER/DR Resin)











mg/dose
Notes
%














Uncoated (IR) MPH Resin
17.65

The 17.65 mg/dose quantity is the
2.67


Methylphenidate (base)
6.525

actual amount of IR resin (at a



AMBERLITE IRP069 Resin
10.24

36.98% assay value) that



Polyethylene Glycol
0.441

goes into each tablet.



Purified Water
0.441

The values in the gray area are the






quantities of each material that






compromise the IR material.



Coated (ER/DR) MPH Resin
149.37

The 149.37 mg/dose quantity is
22.63


Methylphenidate (base)
19.575

the actual amount of ER/DR resin



AMBERLITE IRP069 Resin
30.72

(at a 13.11% assay value)



Polyethylene Glycol
1.32

that goes into each tablet.



Purified Water
1.32

The IR resin material was used to



Ethylcellulose N-10
11.505

make the 149.37 mg/dose ER/DR



EUDRAGIT L100
73.37

material.



Triethyl Citrate
11.56

The values in the gray area are the






quantities of each material that






compromise the ER/DR material.



Prosolv ODT
369.83

The Prosolv ODT quantity will
56.03


Crospovidone
66.00

be variable to account for the variable
10.00


Sucralose Powder
23.00

assay value of the IR and DR resin
3.48


Citric Acid
10.00


1.52


Flavor & Color
17.55


2.66


Magnesium Stearate
6.60


1.00


Total
660.00
mg

100%
















TABLE 19







ODT methylphenidate Formulation B with 25% IR and 75% ER/DR.


IR Resin - 36.98% base assay & ER/DR Resin - 12.77% base assay:


These values are variable.









Formula B (25% active from



IR Resin & 75% active from ER/DR Resin)












mg/dose

Notes
%














Uncoated (IR) MPH Resin
17.65

The 17.65 mg/dose quantity is the
2.67


Methylphenidate (base)
6.525

actual amount of IR resin (at a



AMBERLITE IRP069 Resin
10.24

36.98% assay value) that



Polyethylene Glycol
0.441

goes into each tablet.



Purified Water
0.441

The values in the gray area are the






quantities of each material that






compromise the IR material.



Coated (ER/DR) MPH Resin
153.32

The 153.32 mg/dose quantity is
23.23


Methylphenidate (base)
19.575

the actual amount of ER/DR resin



AMBERLITE IRP069 Resin
30.72

(at a 12.77% assay value)



Polyethylene Glycol
1.32

that goes into each tablet.



Purified Water
1.32

The IR resin material was used to



Ethylcellulose N-10
13.13

make the 153.32 mg/dose ER/DR



EUDRAGIT L100
75.31

material.



Triethyl Citrate
11.945

The values in the gray area are the






quantities of each material that






compromise the ER/DR material.



Prosolv ODT
365.88

The Prosolv ODT quantity will
55.44


Crospovidone
66.00

be variable to account for the variable
10.00


Sucralose Powder
23.00

assay value of the IR and DR resin.
3.48


Citric Acid
10.00


1.52


Flavor & Color
17.55


2.66


Magnesium Stearate
6.60


1.00


Total
660.00
mg

100%









These formulas are exactly the same except for the level of actual ethylcellulose coating (as determined by assay). Formula “A” has 18.6% ethylcellulose coating and “B” has 20.7%. These are the calculated coating levels of ethylcellulose prior to the EUDRAGIT coating.
Dissolution Method
Dissolution testing is carried out using an Apparatus 2 with cannulas and cannula filters (Quality Lab Accessories, Porus Micron full flow filters 20 micron); paddle speed—100 rpm; kettle size—1000 mL; temperature—37.0±0.5° C.; filter—25 mm 0.45 um PTFE; syringe—B-D10 mL Luer-Lok.
Dissolution Media:
The medium for the dissolution assay is 900 mL of 0.1N HCl for the first hour; after 2 hour time point  ̃100 mL of potassium phosphate/sodium hydroxide solution is added to bring to pH  ̃6.8.
The sample is weighed and is placed into the corresponding kettle, and the dissolution timing started.
Sampling pull times are 30 minutes, 2 hours, 4 hours and 8 hours. For each sample pull time and each kettle, 10 mL of sample are pulled into a B-D 10 mL Luer-Lok syringe and returned to the kettles before the sample pull to flush out the cannula from the prior pulls. 4 ml are then pulled for filtration, discarding the first 2 ml to waste and the remaining sample into an HPLC vial. Non-media replacement and volume changes from the two media changes are calculated.
Dissolution Profile:
The amount of drug in the filtrate at each time point is determined by HPLC, and the percentage released from Formulae A and B, respectively, are shown below and in FIG. 26.














Profile



Hours
(% Release)















Formula A Profile










0.5
31%



2
39%



4
79%



8
87%



24
87%







Formula B Profile










0.5
32%



2
41%



4
80%



8
90%



24
90%









Example 18
Human Pharmacokinetic Study Using ODT Pharmaceutical Compositions
This example describes a single-dose, open-label, randomized, three-period, three-treatment crossover study comparing the rate of absorption and oral bioavailability of two controlled release ODT preparations of methylphenidate polistirex (equivalent to 60 mg methylphenidate) to an equivalent 60 mg oral dose of the commercially available reference product, METADATE CD, (UCB, Inc.) following an overnight fast of at least 10 hours. Subjects were randomly assigned to a treatment sequence and received three, separate single-dose administrations of study medication, one treatment per period, according to the randomization schedule. Dosing days were separated by a washout period of at least 7 days.
Subjects received each of the treatments listed below during the three treatment periods:
Treatment A: Test Formulation #1 (methylphenidate resins) controlled-release ODT. Test Formulation #1 is substantially similar to the formulation A described in Example 17. Dose=2× methylphenidate polistirex ODT containing 26.1 mg methylphenidate base, equivalent to 60 mg methylphenidate HCl.
Treatment B: Test Formulation #2 (methylphenidate resins) controlled-release ODT. Test Formulation #2 is substantially similar to the formulation B described in Example 17. Dose=2× methylphenidate polistirex ODT containing 26.1 mg methylphenidate base, equivalent to 60 mg methylphenidate HCl.
Treatment C: Reference Product METADATE CD UCB, Inc. Dose=1×60 mg capsule
Clinical Procedures Summary
During each study period, 6 mL blood samples were obtained prior to each dosing and following each dose at selected times through 36 hours post-dose. A total of 63 pharmacokinetic blood samples were collected from each subject, 21 samples in each study period. In addition, blood was drawn and urine was collected for clinical laboratory testing at screening and study exit.
In each study period, subjects were admitted to the study unit in the evening prior to the scheduled dose. Subjects were confined to the research center during each study period until completion of the 24-hour blood collection and other study procedures. Subjects returned to the study unit for outpatient pharmacokinetic blood samples at 36 hours. Thirty-eight (38) of the 42 subjects enrolled completed the study.
Procedures for Collecting Samples for Pharmacokinetic Analysis
Blood samples (1×6 mL) were collected in vacutainer tubes containing K2-EDTA as a preservative at pre-dose (0) and at 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 10.0, 12.0, 18.0, 24.0, and 36.0 hours after dosing.
Bioanalytical Summary
Plasma samples were analyzed for d-methylphenidate and l-methylphenidate by a third party laboratory using a validated LC-MS-MS procedure. The method was validated for a range of 0.250 to 50.0 ng/mL for d-methylphenidate and 0.0100 to 2.00 ng/mL for 1-methylphenidate, based on the analysis of 0.100 mL of human EDTA plasma.
Pharmacokinetic Analysis
Concentration time data were analyzed by noncompartmental methods in WinNonlin. Concentration time data that were below the limit of quantification (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”. Full precision concentration data (not rounded to three significant figures) and actual sample times were used for all pharmacokinetic and statistical analyses.
The following pharmacokinetic parameters were calculated for d-methylphenidate, l-methylphenidate, and total methylphenidate (d+1): peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λ2), terminal half-life (T1⁄2), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), and area under the plasma concentration time curve from time-zero extrapolated to infinity (AUCinf). Secondary pharmacokinetic endpoints included partial AUCs. The following partial AUCs were calculated using the linear trapezoidal method: AUC0-3, AUC0-max (AUC0-5), AUCtmax-24 (AUC5-24), AUC0-24, and AUCtmax-tlast.
Test Formulations #1 and #2 were compared to the reference product. Analysis of variance (ANOVA) and the Schuirmann's two one sided t test procedures at the 5% significance level were applied to the log-transformed pharmacokinetic exposure parameters, Cmax, AUClast, and AUCinf d-methylphenidate, l-methylphenidate, and total methylphenidate (d+1). The 90% confidence interval for the ratio of the geometric means (Test/Reference) was calculated. Bioequivalence was declared if the lower and upper confidence intervals of the log-transformed parameters were within 80% to 125%. mComparisons of partial AUCs, AUC0-3, AUC0-tmax (AUC0-5), AUCtmax-24 (AUC5-24), AUC0-24, and AUCtmax-tlast across treatments were performed as supportive evidence of equivalence.
Results
Data from 38 subjects who completed the study were included in the pharmacokinetic and statistical analyses.
FIGS. 20A and 20B show the mean linear and log d-methylphenidate concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), and Reference Product (Treatment C).
FIGS. 21A and 21B show the mean linear and log l-methylphenidate concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), and Reference Product (Treatment C).
FIGS. 22A and 22B show the mean linear and log total methylphenidate (d+1) concentration-time profiles after administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), and Reference Product (Treatment C).







TABLE 20







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of d-Methylphenidate Comparing Test Formulation 1


(Treatment A) to the Reference Product (Treatment C)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
20.1714
16.3095
123.68
117.21
130.50
1.0000
14.10


ln(AUC0-3)
20.5344
23.7682
86.39
79.10
94.36
0.9935
23.36


ln(AUC0-tmax)d
50.1624
50.0850
100.15
93.53
107.25
0.9998
18.03


ln(AUCtmax-24)d
103.8409
95.3024
108.96
104.11
114.04
1.0000
11.94


ln(AUC0-24)
156.7217
146.3987
107.05
103.73
110.48
1.0000
8.25


ln(AUCtmax-tlast)d
104.3909
100.4459
103.93
98.76
109.37
1.0000
13.39


ln(AUClast)
157.4500
151.7064
103.79
100.26
107.44
1.0000
9.05


ln(AUCinf)
161.1557
157.9722
102.02
98.78
105.35
1.0000
8.43





aGeometric Mean for the Test Formulation 1 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


dThe median Tmax of the Reference Product (5.00 hr) was used













TABLE 21







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of d-Methylphenidate Comparing Test Formulation 2


(Treatment B) to the Reference Product (Treatment C).












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
20.4113
16.3095
125.15
118.62
132.04
1.0000
14.10


ln(AUC0-3)
21.7843
23.7682
91.65
83.92
100.10
0.9936
23.36


ln(AUC0-tmax)d
51.9061
50.0850
103.64
96.79
110.97
0.9998
18.03


ln(AUCtmax-24)d
105.8856
95.3024
111.10
106.16
116.27
1.0000
11.94


ln(AUC0-24)
160.7525
146.3987
109.80
106.40
113.31
1.0000
8.25


ln(AUCtmax-tlast)d
106.3546
100.4459
105.88
100.62
111.42
1.0000
13.39


ln(AUClast)
161.3617
151.7064
106.36
102.75
110.10
1.0000
9.05


ln(AUCinf)
165.4229
157.9722
104.72
101.40
108.14
1.0000
8.43





aGeometric Mean for the Test Formulation 2 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


dThe median Tmax of the Reference Product (5.00 hr) was used













TABLE 22







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of l-Methylphenidate Comparing Test Formulation 1


(Treatment A) to the Reference Product (Treatment C).












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %





ln(Cmax)
0.4471
0.2224
201.01
167.90
240.64
0.6550
49.75


ln(AUC0-3)
0.6292
0.2691
233.82
198.86
274.92
0.7346
44.29


ln(AUC0-tmax)d
1.0739
0.5281
203.35
175.47
235.66
0.8024
40.01


ln(AUCtmax-24)d
0.9649
0.7668
125.84
108.56
145.87
0.8013
40.08


ln(AUC0-24)
2.1909
1.3404
163.45
143.93
185.62
0.8936
34.18


ln(AUCtmax-tlast)d
0.8821
0.7435
118.64
101.75
138.33
0.7736
41.81


ln(AUClast)
2.1125
1.3231
159.66
140.14
181.90
0.8801
35.09


ln(AUCinf)
2.2098
1.5598
141.68
122.06
164.44
0.7952
40.46





aGeometric Mean for the Test Formulation 1 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


dThe median Tmax of the Reference Product (5.00 hr) was used













TABLE 23







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of l-Methyphenidate Comparing Test Formulation 2


(Treatment B) to the Reference Product (Treatment C)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %





ln(Cmax)
0.5092
0.2224
228.93
191.26
274.02
0.6557
49.75


ln(AUC0-3)
0.6798
0.2691
252.63
214.89
296.99
0.7354
44.29


ln(AUC0-tmax)d
1.1261
0.5281
213.23
184.02
247.07
0.8031
40.01


ln(AUCtmax-24)d
1.1095
0.7668
144.70
124.85
167.70
0.8021
40.08


ln(AUC0-24)
2.4426
1.3404
182.23
160.49
206.92
0.8942
34.18


ln(AUCtmax-tlast)d
1.0239
0.7435
137.71
118.13
160.55
0.7744
41.81


ln(AUClast)
2.3641
1.3231
178.68
156.86
203.54
0.8807
35.09


ln(AUCinf)
2.4774
1.5598
158.83
136.87
184.32
0.7959
40.46





aGeometric Mean for the Test Formulation 2 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


dThe median Tmax of the Reference Product (5.00 hr) was used













TABLE 24







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of Total Methylphenidate (d + l) Comparing Test


Formulation 1 (Treatment A) to the Reference Product (Treatment C)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
20.6080
16.5477
124.54
117.98
131.46
1.0000
14.21


ln(AUC0-3)
21.2961
24.1188
88.30
80.92
96.35
0.9943
23.10


ln(AUC0-tmax)d
51.4307
50.7312
101.38
94.67
108.56
0.9998
18.02


ln(AUCtmax-24)d
105.0763
96.2603
109.16
104.30
114.24
1.0000
11.94


ln(AUC0-24)
159.2597
148.0008
107.61
104.29
111.03
1.0000
8.20


ln(AUCtmax-tlast)d
105.6235
102.0912
103.46
98.33
108.86
1.0000
13.35


ln(AUClast)
159.9855
153.9687
103.91
100.39
107.55
1.0000
9.03


ln(AUCinf)
163.6833
159.5401
102.60
99.37
105.93
1.0000
8.36





aGeometric Mean for the Test Formulation 1 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


dThe median Tmax of the Reference Product (5.00 hr) was used













TABLE 25







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of


Total Methylphenidate (d + l) Comparing Test Formulation 2


(Treatment B) to the Reference Product (Treatment C).












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
20.8467
16.5477
125.98
119.35
132.97
1.0000
14.21


ln(AUC0-3)
22.5591
24.1188
93.53
85.73
102.05
0.9944
23.10


ln(AUC0-tmax)d
53.1774
50.7312
104.82
97.90
112.24
0.9998
18.02


ln(AUCtmax-24)d
107.4905
96.2603
111.67
106.70
116.86
1.0000
11.94


ln(AUC0-24)
163.6952
148.0008
110.60
107.20
114.12
1.0000
8.20


ln(AUCtmax-tlast)d
108.1238
102.0912
105.91
100.66
111.43
1.0000
13.35


ln(AUClast)
164.4747
153.9687
106.82
103.21
110.57
1.0000
9.03


ln(AUCinf)
168.3659
159.5401
105.53
102.22
108.95
1.0000
8.36





aGeometric Mean for the Test Formulation 2 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


dThe median Tmax of the Reference Product (5.00 hr) was used






Conclusions

Based on Cmax, the peak exposure to d-methylphenidate is higher after administration of Test Formulations 1 and 2 relative to that after METADATE CD and the 90% confidence intervals about the ratios for Cmax (Test Formulation 1/Reference and Test Formulation 2/Reference) are not within the 80% to 125% range necessary to establish traditional bioequivalence. However, based on AUClast and AUCinf, the overall systemic exposure to d-methylphenidate after administration of Test Formulations 1 and 2 is comparable to that after METADATE CD and the 90% confidence intervals about the ratios for AUClast and AUCinf are within the 80% to 125% range, indicating no significant difference in bioavailability. Except for AUC0-3 after Test Formulation 1 (ratio: 86.39%; 90% confidence interval: 79.10%-94.36%), the 90% confidence intervals about the Test/Reference ratios for all partial AUCs are within the 80% to 125% range, indicating comparable early systemic exposure through Tmax (5.00 hr) and 24 hours after Test Formulations 1 and 2 relative to METADATE CD.
Based on Cmax, AUClast, and AUCinf, peak and overall systemic exposure to l-methylphenidate is higher after administration of Test Formulations 1 and 2 relative to that after METADATE CD and the 90% confidence intervals about the Test/Reference ratios (Test Formulation 1/Reference and Test Formulation 2/Reference) are not within the 80% to 125% range necessary to establish traditional bioequivalence. Similarly, based on partial AUCs, early systemic exposure to l-methylphenidate is higher after administration of Test Formulations 1 and 2 relative to that after METADATE CD and the 90% confidence intervals about the Test/Reference ratios for all partial AUCs are not within the 80% to 125% range.
Based on AUClast and AUCinf, the overall systemic exposure to total methylphenidate (d+l) after administration of Test Formulations 1 and 2 is comparable to that after METADATE CD and the 90% confidence intervals about the ratios for AUClast and AUCinf are within the 80% to 125% range, indicating no significant difference in bioavailability. In addition, the 90% confidence intervals about the Test/Reference ratios for all partial AUCs are within the 80% to 125% range, indicating comparable early systemic exposure through 3 hours, Tmax (5.00 hr), and 24 hours after Test Formulations 1 and 2 relative to METADATE CD.
Example 19
Ethanol Study
In vitro dissolution studies using methylphenidate compositions in the presence or absence of ethanol were also carried out. One 60 mg capsule of METADATE CD, and separately, two (30 mg) tablets of a formulation similar to Example 17, were introduced into USP dissolution Apparatus 2. The dissolution media started with alcoholic 0.1N HCl with various amounts of ethanol (0%, 5%, 10%, 20%, and 40%). Appropriate amounts of pH change buffer were added to the media at 2 hours (after the sample was introduced) to make the pH of the media to 6.8. Samples were taken at different time points. The results are shown in FIG. 25A (METADATE CD), 25B (test formulation) and 25C (METADATE CD and test formulation).
FIG. 25A shows that the addition of 40% ethanol substantially increases the amount of drug released in the reference formulation, i.e., there is a substantial increase in drug released through dose dumping in the presence of ethanol.
FIG. 25B shows that the addition 40% ethanol increases the amount of drug released but to a lesser extent than in the reference formulation. As such, the ethanol study's results show that, in the presence of ethanol, the formulations of the invention have a reduced exposure level of methylphenidate as compared to the reference formulation. This prevents or substantially reduces the likelihood of dose dumping when the formulations of the invention and ethanol are ingested by a subject.
Example 20
Food-effect Study of an Extended Release Methylphenidate ODT Formulation in Healthy Subjects
This example describes a single-dose, open-label, randomized, two-period crossover study that assessed the effect of food on the rate of absorption and oral bioavailability of a single dose (two ODTs) of a methylphenidate extended release ODT (equivalent to 60 mg methylphenidate HCl), under fed and fasted conditions.
Subjects in both treatment conditions fasted overnight for at least 10 hours. Subjects in the fed condition were dosed 5 minutes after completing consumption of a Food and Drug Administration (FDA) standard high-calorie, high-fat breakfast meal. Consumption of the FDA standard high-calorie, high-fat breakfast began 30 minutes prior to dosing. Subjects in the fasted condition continued to fast up until the time that they were dosed. Each drug administration was separated by a washout period of 7 days.
Subjects were administered a single 2 ODT dose of each of the treatments in a randomized, sequenced fashion. Immediately prior to dose, each subject was given 60 mL of room temperature water in a cup and instructed to swish the water around in the mouth and to spit it out in order to wet the mouth.
Treatment A (Fasted): Test Formulation #102 (shown below) was orally administered following a 10-hour overnight fast. Dose=2× methylphenidate polistirex ODT containing 26.1 mg methylphenidate base Formulation #102, equivalent to 60 mg of methylphenidate HCl.
Treatment B (Fed): Test Formulation #102 (shown below) was orally administered following a 10-hour overnight fast and consumption of an FDA standard high-fat, high-calorie breakfast beginning 30 minutes prior to dose. Dose=2× methylphenidate polistirex ODT, each containing 26.1 mg methylphenidate base Formulation #102; this dose is equivalent to 60 mg of methylphenidate HCl.
The subjects fasted for 4 hours thereafter. Standard meals were provided at approximately 4 and 10 hours after drug administration and at appropriate times thereafter.
Except for the 60 mL mouth rinse given immediately prior to each dose (and which the subjects spit out), no water was allowed for 1 hour prior through 1 hour after dose. Each subject was required to drink approximately 360 mL of fluid with each snack or meal administered during confinement after dosing on Day 1. Each subject was required to drink 120 mL of water at approximately 1, 2, and 3 hours after dose administration. Subjects were provided approximately 700 mL of water that was required to be consumed between lunch and snack administrations during confinement on Day 1. After snack administration on Day 1, water was allowed ad lib.







TABLE 26







ODT methylphenidate Formulation #102 with 25% IR and 75% ER/DR


IR Resin - 36.97% base assay & ER/DR Resin - 12.88% base assay









Formulation #102 (25% active from



IR Resin & 75% active from ER/DR Resin)












mg/dose

Notes
%














Uncoated (IR) MPH Resin
17.65

The 17.65 mg/dose quantity is the
2.67


Methylphenidate (base)
6.525

actual amount of IR resin (at a



AMBERLITE IRP069 Resin + Water
11.08

36.97% assay value) that



Polyethylene Glycol
0.045

goes into each tablet.






The values in the gray area are the






quantities of each material that






compromise the IR material.



Coated (ER/DR) MPH Resin
151.98

The 151.98 mg/dose quantity is the
23.03


Methylphenidate (base)
19.575

actual amount of ER/DR resin (at a



AMBERLITE IRP069 Resin + Water
32.04

12.88% assay value) that



Polyethylene Glycol
0.38

goes into each tablet.



Ethylcellulose N-10
12.00

The IR resin material was used to



EUDRAGIT L100
75.94

make the 151.98 mg/dose ER/DR



Triethyl Citrate
12.045

material.






The values in the gray area are the






quantities of each material that






compromise the ER/DR material.



Prosolv ODT
367.22

The Prosolv ODT quantity will
55.64


Crospovidone
66.00

be variable to account for the variable
10.00


Sucralose Powder
23.00

assay value of the IR and DR resin.
3.48


Citric Acid
10.00


1.52


Flavor & Color
17.55


2.66


Magnesium Stearate
6.60


1.00


Total
660.00
mg

100%









Data collection and analysis were carried out as similarly as described above. Twenty-three (23) of the 24 subjects enrolled completed the study. Data from 23 subjects were included in the pharmacokinetic and statistical analyses Mean concentration-time data are shown in FIGS. 27-29. Results of the pharmacokinetic and statistical analysis are shown below in Tables 27 through 29.
Results:
FIGS. 27A and 27B show the mean methylphenidate (d+l) concentration-time profiles after administration of Formulation #102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B).
FIGS. 28A and 28B mean d-methylphenidate concentration-time profiles after administration of Formulation #102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B).
FIGS. 29A and 29B mean l-methylphenidate concentration-time profiles after administration of Formulation #102-Fasted (Treatment A) and Formulation #102-Fed (Treatment B).







TABLE 27







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of


Methylphenidate (d + l)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
22.4817
25.9799
86.53
80.52
93.00
0.9992
14.25


ln(AUClast)
229.2966
205.8759
111.38
106.74
116.21
1.0000
8.38


ln(AUCinf)
237.5598
211.0504
112.56
108.18
117.11
1.0000
7.82





aGeometric Mean for Formulation #102-Fed (Test) and Formulation #102-Fasted (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 28







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of


d-Methylphenidate












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
22.1811
25.5705
86.74
80.74
93.20
0.9992
14.20


ln(AUClast)
226.7299
203.5182
111.41
106.79
116.22
1.0000
8.34


ln(AUCinf)
234.9939
208.7056
112.60
108.24
117.13
1.0000
7.78





aGeometric Mean for Formulation #102-Fed (Test) and Formulation #102-Fasted (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 29







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of


l-Methylphenidate












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
0.3806
0.4171
91.25
74.52
111.73
0.5695
41.51


ln(AUClast)
2.1957
1.9338
113.54
99.76
129.23
0.8869
25.90


ln(AUCinf)
2.3594
2.0529
114.93
100.74
131.12
0.8768
26.40





aGeometric Mean for Formulation #102-Fed (Test) and Formulation #102-Fasted (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval






Conclusions

There were no unusual or unexpected adverse events (AEs) related to the study medication. In general, the AE profile was consistent with the mechanism of action for this drug.
The 90% confidence intervals for comparing the log-transformed exposure parameters ln(Cmax), ln(AUClast), and ln(AUCinf) were within the accepted 80% to 125% limits for the a priori designated endpoint, methylphenidate (d+l).
Therefore, the presence of food did not significantly alter methylphenidate (d+l) exposure following the administration of methlyphenidate-polistirex formulated as ODT (equivalent to 60 mg methylphenidate HCl) under fasting and fed conditions.
Example 21
The Effect of Food on the Pharmacokinetics of a Controlled Release Amphetamine ODT in Healthy Subjects
This example describes a single-dose, open-label, randomized, two-period, two-treatment crossover study that assessed the effect of food on the rate of absorption and oral bioavailability of a controlled release ODT preparations of mixed amphetamine polistirex (equivalent to 30 mg mixed amphetamines), under fed and fasted conditions.
The protocol was the same as described in Example 20, except subjects received treatment listed below during the two treatment periods:
Treatment A (Fed Conditions): Test Formulation #1002A (mixed amphetamine resins) controlled-release ODT (shown below). Dose=1× mixed amphetamine polistirex ODT equivalent to 30 mg mixed amphetamine salts.
Treatment B (Fasted Conditions): Test Formulation #1002A (mixed amphetamine resins) controlled-release ODT (shown below). Dose=1× mixed amphetamine polistirex ODT equivalent to 30 mg mixed amphetamine salts.







TABLE 30







ODT amphetamine formulation with 45% IR and 55% DR


IR Resin - 34.08% base assay & DR Resin - 7.28% base assay









Formula #1002A



(45% active from IR Resin & 55% active from DR Resin)












mg/dose

Notes
%














Uncoated (IR) AMP Resin
24.8

The 24.8 mg/dose quantity is the
3.76


Amphetamine (base)
4.23

actual amount of IR resin (at a 34.08%



Dextroamphetamine (base)
4.23

assay value) that goes into each tablet.



AMBERLITE IRP069 Resin + Water
16.34

The values in the gray area are the






quantities of each material that






compromise the IR material.



Coated (DR) AMP Resin
142.0

The 142.0 mg/dose quantity is the
21.52


Amphetamine (base)
5.17

actual amount of DR resin (at an 7.28%



Dextroamphetamine (base)
5.17

assay value) that goes into each tablet.



AMBERLITE IRP069 Resin + Water
23.75

The IR resin material was used to make



Humectant
0.32

the 142.0 mg/dose DR material.



EUDRAGIT L100
93.72

The values in the gray area are the



Plasticizer
13.87

quantities of each material that






compromise the DR material.



Prosolv ODT
323.3

The Prosolv ODT quantity will
48.98


Crospovidone
105.6

be variable to account for the variable
16.00


Sucralose Powder
20.3

assay value of the IR and DR resin.
3.08


Citric Acid
22.5


3.41


Color and Flavor
14.9


2.26


Magnesium Stearate
6.6


1.00


Total
660.00
mg

100%









Data collection and analysis were carried out similarly as described above. All 16 subjects enrolled completed the study. Data from the 16 subjects were included in the pharmacokinetic and statistical analyses. Mean concentration-time data are shown in FIGS. 30 and 31. Results of the pharmacokinetic and statistical analysis are shown below in Tables 31 and 32.
Results







TABLE 31







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of


d-amphetamine Comparing Test Formulation-Fed (Treatment A) to Test Formulation-Fasted


(Treatment B)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Fed
Fasted
(Fed/Fasted)
Lower
Upper
Power
CV %

















ln(Cmax)
40.8357
47.6112
85.77
81.34
90.44
1.0000
8.54


ln(AUClast)
886.6801
962.1617
92.16
88.40
96.07
1.0000
6.68


ln(AUCinf)
941.2440
1018.5933
92.41
88.11
96.91
1.0000
7.35





aGeometric Mean for the Test Formulation-Fed and Test Formulation-Fasted based on Least Squares Mean of log-transformed parameter values


bRatio(%) = Geometric Mean (Fed)/Geometric Mean (Fasted)


c90% Confidence Interval


Note:


T1/2 and parameters based on extrapolation could not be calculated for all subjects; statistical analysis is based on n = 16 for Cmax, AUClast and n = 15 for AUCinf













TABLE 32







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of


l-amphetamine Comparing Test Formulation-Fed (Treatment A) to Test Formulation-Fasted


(Treatment B)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Fed
Fasted
(Fed/Fasted)
Lower
Upper
Power
CV %

















ln(Cmax)
12.8378
14.8236
86.60
82.37
91.06
1.0000
8.07


ln(AUClast)
312.5311
342.9993
91.12
86.84
95.61
1.0000
7.74


ln(AUCinf)
346.2042
378.5080
91.47
86.33
96.91
0.9999
8.94





aGeometric Mean for the Test Formulation-Fed and Test Formulation-Fasted based on Least Squares Mean of log-transformed parameter values


bRatio(%) = Geometric Mean (Fed)/Geometric Mean (Fasted)


c90% Confidence Interval


Note:


T1/2 and parameters based on extrapolation could not be calculated for all subjects; statistical analysis is based on n = 16 for Cmax, AUClast and n = 15 for AUCinf






Conclusions

There were no unusual or unexpected adverse events related to the study medication. Study exit clinical laboratory, ECG, and physical examination evaluations were completed with no clinically significant findings. The 90% confidence intervals for comparing the maximum exposure, based on ln(Cmax), are within 80% to 125% for both d- and l-amphetamine. The 90% confidence intervals for comparing total systemic exposure, based on ln(AUClast) and ln(AUCinf), are within 80% to 125% for both d- and l-amphetamine. On the other hand, Tmax values were statistically different for the two treatments.
These data confirm that the extended-release characteristics of ODT containing amphetamine polistirex were maintained in the presence of a high-fat meal, and that a high-fat meal does not have a significant effect on the rate of absorption or oral bioavailability of mixed amphetamine resins in controlled-release ODT.
Example 22
The Effect of Alcohol on the Pharmacokinetics of a Controlled Release Amphetamine ODT in Healthy Subjects
This example describes a single-dose, open-label, randomized, four-period, four-treatment, four-sequence crossover study that assessed the effect of varying concentrations of alcohol on the rate of absorption and oral bioavailability of a controlled release ODT preparation of mixed amphetamine polistirex (equivalent to 30 mg mixed amphetamines), in healthy adults.
Subjects fasted overnight for at least 10 hours, but were administered intravenous (IV) fluids continuously from approximately 10 hours predose to approximately 2 hours predose. The subjects received dose administrations of a controlled-release ODT preparation of amphetamines followed by varying concentrations of alcohol. Subjects were assigned to one of two cohorts (Group 1 or Group 2), randomly assigned to a treatment sequence, and received four, separate single-dose administrations of study medication, one treatment per period, according to the randomization schedule. Dosing days were separated by a washout period of at least 14 days. Subjects were divided into two groups of 16.
Subjects received the treatments listed below during the four treatment periods:
Treatment A: Test Formulation #1002A (described in Example 21) controlled-release ODT followed by 240 mL of deionized water (0% ethanol).
Treatment B: Test Formulation #1002A (described in Example 21) controlled-release ODT followed by 240 mL of 4% ethanol solution.
Treatment C: Test Formulation #1002A (described in Example 21) controlled-release ODT followed by 240 mL of 20% ethanol solution
Treatment D: Test Formulation #1002A (described in Example 21) controlled-release ODT followed by 240 mL of 40% ethanol solution.
Subjects were given a single oral dose of the formulation followed by varying amounts of alcohol at a pre-specified time in each period, after a 10 hour overnight fast that was preceded by a standard meal. The subjects fasted for 4 hours thereafter. Water was allowed ad lib during the study except for 1 hour prior through 1 hour post-dose. Standard meals were provided at approximately 4 and 10 hours after drug administration and at appropriate times thereafter.
The water and/or alcohol solution was administered following confirmation that the ODT formulation had completely disintegrated. The deionized water and/or alcohol solution was consumed within 30 minutes.
Data collection and analysis were carried out as similarly as described above. Twenty seven (27) of the 32 subjects enrolled completed the study. Data from 32 subjects who completed at least one study period were included in the pharmacokinetic and statistical analyses. Mean concentration-time data are showing in FIGS. 32 and 33. Results of the pharmacokinetic and statistical analysis are shown below in Tables 33 through 38.
Results
FIGS. 32A and 32B show mean d-amphetamine concentration-time profiles after administration of controlled Release ODT with Deionized Water (0% Ethanol Solution) (Treatment A), 4% ethanol (Treatment B), 20% ethanol (Treatment C) and 40% ethanol (Treatment D) on linear (upper panel) and semi-logarithmic (lower panel) scales.
FIGS. 33A and 33B show mean l-amphetamine concentration-time profiles after administration of controlled Release ODT with Deionized Water (0% Ethanol Solution) (Treatment A), 4% ethanol (Treatment B), 20% ethanol (Treatment C) and 40% ethanol (Treatment D) on linear (upper panel) and semi-logarithmic (lower panel) scales.







TABLE 33







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of d-amphetamine Comparing Formula #1002A +


4% Ethanol (Treatment B) to Formula #1002A +


Deionized Water (0% Ethanol Solution) (Treatment A)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
42.6047
41.6151
102.38
98.11
106.83
1.0000
9.88


ln(AUClast)
880.9005
854.9740
103.03
97.48
108.90
1.0000
12.88


ln(AUCinf)GRP1
1000.2608
931.5954
107.37
102.69
112.27
1.0000
6.96


ln(AUCinf)GRP2
909.5489
865.2939
105.11
100.49
109.95
1.0000
7.39





aGeometric Mean for Formula #1002A + 4% Ethanol (Test) Formula #1002A + Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


GRP1/GRP2= Group 1/Group 2













TABLE 34







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of d-amphetamine Comparing Formula #1002A +


20% Ethanol (Treatment C) to Formula #1002A +


Deionized Water (0% Ethanol Solution) (Treatment A)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
40.0621
41.6151
96.27
92.21
100.51
1.0000
9.88


ln(AUClast)
841.7095
854.9740
98.45
93.08
104.13
1.0000
12.88


ln(AUCinf)GRP1
895.8201
931.5954
96.16
91.85
100.67
1.0000
6.96


ln(AUCinf)GRP2
916.3051
865.2939
105.90
101.24
110.77
1.0000
7.39





aGeometric Mean for Formula #1002A + 20% Ethanol (Test) and Formula #1002A + Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


GRP1/GRP2= Group 1/Group 2













TABLE 35







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters of


d-amphetamine Comparing Formula #1002A + 40% Ethanol (Treatment D)


to Formula #1002A + Deionized Water (0% Ethanol Solution) (Treatment A)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
39.5057
41.6151
94.93
90.88
99.17
1.0000
9.88


ln(AUClast)
848.9149
854.9740
99.29
93.81
105.10
1.0000
12.88


ln(AUCinf)GRP1
908.1250
931.5954
97.48
93.18
101.98
1.0000
6.96


ln(AUCinf)GRP2
868.8805
865.2939
100.41
95.91
105.13
1.0000
7.39





aGeometric Mean for Formula #1002A + 40% Ethanol (Test) and Formula #1002A + Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


GRP1/GRP2= Group 1/Group 2













TABLE 36







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters


of l-amphetamine Comparing Formula #1002A + 4% Ethanol (Treatment


B) to Formula #1002A + Deionized Water (0% Ethanol Solution) (Treatment A)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
13.6773
13.3098
102.76
98.64
107.05
1.0000
9.50


ln(AUClast)
316.6826
307.3284
103.04
96.77
109.73
1.0000
14.63


ln(AUCinf) GRP1
379.7166
345.8712
109.79
103.92
115.98
1.0000
8.56


ln(AUCinf) GRP2
342.6777
325.5756
105.25
100.16
110.60
1.000
8.15





aGeometric Mean for Formula #1002A + 4% Ethanol (Test) and Formula #1002A + Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


GRP1/GRP2 = Group 1/Group 2













TABLE 37







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters


of l-amphetamine Comparing Formula #1002A + 20% Ethanol (Treatment


C) to Formula #1002A + Deionized Water (0% Ethanol Solution) (Treatment A)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
12.9647
13.3098
97.41
93.45
101.53
1.0000
9.50


ln(AUClast)
301.3609
307.3284
98.06
92.01
104.50
1.0000
14.63


ln(AUCinf) GRP1
333.1404
345.8712
96.32
91.03
101.91
1.000
8.56


ln(AUCinf) GRP2
346.3956
325.5756
106.39
101.25
111.80
1.0000
8.15





aGeometric Mean for Formula #1002A + 20% Ethanol (Test) and Formula #1002A + Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


GRP1/GRP2 = Group 1/Group 2













TABLE 38







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters


of l-amphetamine Comparing Formula #1002A + 40% Ethanol (Treatment


D) to Formula #1002A + Deionized Water (0% Ethanol Solution) (Treatment A)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
12.6112
13.3098
94.75
90.86
98.81
1.0000
9.50


ln(AUClast)
306.0284
307.3284
99.58
93.36
106.21
1.0000
14.63


ln(AUCinf) GRP1
337.9262
345.8712
97.70
92.43
103.27
1.0000
8.56


ln(AUCinf) GRP2
328.1746
325.5756
100.80
95.83
106.03
1.0000
8.15





aGeometric Mean for Formula #1002A + 40% Ethanol (Test) and Formula #1002A + Deionized Water (0% Ethanol Solution) (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval


GRP1/GRP2 = Group 1/Group 2






Conclusions:

The 90% confidence intervals for comparing the maximum exposure to d-amphetamine and l-amphetamine, based on ln(Cmax), are within the accepted 80% to 125% limits across all comparisons
The 90% confidence intervals for comparing total systemic exposure to d-amphetamine and l-amphetamine, based on ln(AUClast) and ln(AUCinf), are within the accepted 80% to 125% limits across all comparisons.
Therefore, varying concentrations of alcohol (4%-40% ethanol solution) did not significantly alter the rate and extent of absorption of Formula #1002A amphetamine polistirex (equivalent to 30 mg mixed amphetamine salts), in healthy subjects. The results of this study indicate that the controlled-release properties of formulations according to this invention are maintained in the presence of alcohol.
Example 23
Human Pharmacokinetic Study of a Controlled Release Amphetamine ODT Under Fasted Conditions in Children with ADHD
This example describes a single-dose, open-label, single-period, one-treatment study to determine the pharmacokinetic profile of a controlled release ODT preparation of mixed amphetamine polistirex (equivalent to 30 mg mixed amphetamines), in children (6-12 years old). Subjects were children diagnosed with ADHD, and 28 enrolled children were divided into three cohorts (6 of 6-7 years, 11 of 8-9 years, and 11 of 10-12 years).
Following a 10-hour overnight fast, subjects received 1 dose of Test Formulation #1002A (described in Example 21). This dose was administered without water (other than a small mouth rinse (which was not ingested) prior to drug administration) and allowed to disintegrate on the tongue. After dosing, no food was allowed until 4 hours post-dose. No water was to be consumed for 1 hour prior through 1 hour post-dose.
Subjects remained in the research center until completion of the 12-hour blood sampling for the study period and returned for outpatient visits at approximately 24 (Visit 3), 36 (Visit 4), and 48 hours (Visit 5) post-dose in the study period. After the final plasma sample was collected, subjects were permitted to resume taking their usual dose of amphetamines. The final safety visit took place 2 days after dosing as part of Visit 5 (Day 7).
During the study period, 3 mL blood samples were obtained prior to dosing and following the dose at selected times through 48 hours post-dose. Data collection and analysis were carried out as described above. The following PK parameters were determined:

    
    
        λZ: The elimination rate constant (λZ) was calculated as the negative of the slope of the terminal log-linear segment of the plasma concentration-time curve; the range of data to be used was determined by visual inspection of a semi-logarithmic plot of concentration versus time.
        CL/F: Oral clearance (CL/F) was calculated as:

CL/F=D/AUCinf,

    
    


 where D was the administered dose.

    
    
        Vz/F: Volume of distribution in the terminal phase after oral administration (Vz/F) was calculated as:

Vz/F=(CL/F)/λZ. 

Results

    
    


Data from 28 enrolled subjects who completed the study were included in the pharmacokinetic and statistical analyses. Mean concentration-time data are showing in FIGS. 34 and 35. Results of the pharmacokinetic and statistical analysis are shown below in Tables 39 and 40.
FIGS. 34A and 34B mean d-amphetamine Concentration-Time Profiles after Administration of Formula #1002A ODT for Group 1 (Ages 6-7), Group 2 (Ages 8-9), and Group 3 (Ages 10-12).
FIGS. 35A and 35B show mean l-amphetamine Concentration-Time Profiles after Administration of Formula #1002A ODT for Group 1 (Ages 6-7), Group 2 (Ages 8-9), and Group 3 (Ages 10-12).







TABLE 39







Statistical Analysis of Weight-Normalized Clearance and Volume


of Distribution of d-amphetamine. Supplied as Formula #1002A













Target Confidence




95% Confidence
Interval Range



Geo-
Interval
60%-140%















metric
Lower
Upper
Lower
Upper


Parameter
n
Mean
Bound
Bound
Bound
Bound












Age Group 1 (6-7 yrs):













Vz/F (L/kg)
6
10.08
8.448
11.95
6.048
14.11


CL/F (L/h/kg)
6
0.7619
0.6682
0.8648
0.4571
1.067









Age Group 2 (8-9 yrs):













Vz/F (L/kg)
11
9.177
8.284
10.28
5.506
12.85


CL/F (L/h/kg)
11
0.7117
0.6371
0.8057
0.4270
0.9964









Age Group 3 (10-12 yrs):













Vz/F (L/kg)
11
8.678
8.064
9.396
5.207
12.15


CL/F (L/h/kg)
11
0.6094
0.5349
0.7106
0.3656
0.8532





Note:


Target confidence interval range was calculated by multiplying the geometric mean by 0.6 for the 60% lower bound and 1.4 for the 140% upper bound.


Abbreviations: CL/F = oral clearance; CR = controlled release; h = hour; MAR = mixed amphetamine resin; ODT = oral disintegrating tablet; Vz/F = volume of distribution in the terminal phase after oral administration; yrs = years.













TABLE 40







Statistical Analysis of Weight-Normalized Clearance and Volume


of Distribution of l-amphetamine Supplied as Formula #1002A













Target Confidence




95% Confidence
Interval Range



Geo-
Interval
60%-140%















metric
Lower
Upper
Lower
Upper


Parameter
n
Mean
Bound
Bound
Bound
Bound












Age Group 1 (6-7 yrs):













Vz/F (L/kg)
6
32.68
26.72
39.63
19.61
45.75


CL/F (L/h/kg)
6
2.137
1.840
2.466
1.282
2.992









Age Group 2 (8-9 yrs):













Vz/F (L/kg)
11
29.63
26.46
33.65
17.78
41.48


CL/F (L/h/kg)
11
2.019
1.778
2.335
1.211
2.827









Age Group 3 (10-12 yrs):













Vz/F (L/kg)
11
28.35
26.23
30.84
17.01
39.69


CL/F (L/h/kg)
11
1.712
1.497
2.001
1.027
2.397





Note:


Target confidence interval range was calculated by multiplying the geometric mean by 0.6 for the 60% lower bound and 1.4 for the 140% upper bound.


Abbreviations: CL/F = oral clearance; CR = controlled release; h = hour; MAR = mixed amphetamine resin; ODT = oral disintegrating tablet; Vz/F = volume of distribution in the terminal phase after oral administration; yrs = years.






Conclusions:

There were no unusual or unexpected adverse effects (AEs) related to the study medication. There were no deaths, SAEs, or discontinuations. In general, the nature of the TEAEs reported was consistent with the mechanism of action for these study medications.
An age-related trend in mean maximum and total d-amphetamine and l-amphetamine exposure was observed; as age increased, mean amphetamine exposure decreased. Weight did not appear to be a prominent factor in the observed downward age-related trend in amphetamine exposure.
Mean weight-normalized CL/F and Vz/F values for d-amphetamine and l-amphetamine decreased slightly with an increase in age. Mean T1/2 was similar across age groups. Additionally, the geometric means and 95% CIs calculated for d-amphetamine and l-amphetamine CL/F and Vz/F were within the target range of 60% to 140% for each age group.
Example 24
Human Pharmacokinetic Study Using Amphetamine Liquid Formulations and ADDERALL XR Under Fasted Conditions
This was a single-dose, open-label, randomized, four-period, four-treatment crossover study that compared the rate of absorption and oral bioavailability of three different amphetamine controlled-release liquid suspensions (equivalent to 30 mg mixed amphetamine salts/15 mL) to an equivalent 30 mg dose of ADDERALL XR capsule, in healthy subjects.
All doses were administered after an overnight fast of at least 10 hours. Each dose administration was separated by a washout period of at least 7 days.
Subjects received the treatments listed below during the four treatment periods:
Treatment A: Test Formulation #1005A controlled-release liquid (shown below). Dose=1×15 mL of suspension. This dose was administered orally without water.
Treatment B: Test Formulation #1005B controlled-release liquid (shown below). Dose=1×15 mL of suspension. This dose was administered orally without water.
Treatment C: Test Formulation #1005C controlled-release liquid (shown below). Dose=1×15 mL of suspension. This dose was administered orally without water.
Treatment D (Reference Product): ADDERALL XR Shire US, Inc. Dose=1×30 mg capsule. This dose was administered orally with 60 mL (2 fl. oz.) of water.







TABLE 41







Test Formulation #1005A (suspension amphetamine with 45% IR and 55% DR)


IR Resin - 36.05% base assay & DR Resin - 7.82% base assay









Formula 1005A



(45% active from IR Resin & 55% active from DR Resin)











mg per





15 mL dose
Notes
%














Uncoated (IR) AMP Resin
23.5

The 23.5 mg/dose quantity is the
0.145


Amphetamine (base)
4.23

actual amount of IR resin (at a 36.05%



Dextroamphetamine (base)
4.23

assay value) that goes into each 15 mL



AMBERLITE IRP069 Resin + Water
15.04

dose.






The values in the gray area are the






quantities of each material that






compromise the IR material.



Coated (DR) AMP Resin
132.2

The 132.2 mg/dose quantity is the
0.816


Amphetamine (base)
5.17

actual amount of DR resin (at an 7.82%



Dextroamphetamine (base)
5.17

assay value) that goes into each 15 mL



AMBERLITE IRP069 Resin + Water
21.98

dose.



Humectant
0.34

The IR resin material was used to make



EUDRAGIT L100
86.74

the 132.2 mg/dose DR material.



Plasticizer
12.84

The values in the gray area are the






quantities of each material that






compromise the DR material.



Purified Water
9839.55

Each 15 mL dose of liquid suspension
60.74


Citric Acid
5.10

is equivalent to 16.2 grams at the
0.03


Propylene Glycol
577.50

theoretical specific gravity of 1.08.
3.56


Preservative
8.55


0.05


Xanthan Gum
116.25


0.72


Vegetable Oil
33.00


0.20


Maltitol Syrup
5400.00


33.33


Flavor and Color
4.35


<0.39


Total
16,200.0
mg

100%
















TABLE 42







Test Formulation #1005B (suspension amphetamine with 45% IR and 55% DR)


IR Resin - 36.05% base assay & DR Resin - 7.82% base assay









Formula #1005B



(45% active from IR Resin & 55% active from DR Resin)











mg per





15 mL dose
Notes
%














Uncoated (IR) AMP Resin
23.5

The 23.5 mg/dose quantity is the
0.145


Amphetamine (base)
4.23

actual amount of IR resin (at a 36.05%



Dextroamphetamine (base)
4.23

assay value) that goes into each 15 mL



AMBERLITE IRP069 Resin + Water
15.04

dose.






The values in the gray area are the






quantities of each material that






compromise the IR material.



Coated (DR) AMP Resin
132.2

The 132.2 mg/dose quantity is the
0.816


Amphetamine (base)
5.17

actual amount of DR resin (at an 7.82%



Dextroamphetamine (base)
5.17

assay value) that goes into each 15 mL



AMBERLITE IRP069 Resin + Water
21.98

dose.



Humectant
0.34

The IR resin material was used to make



EUDRAGIT L100
86.74

the 132.2 mg/dose DR material.



Plasticizer
12.84

The values in the gray area are the






quantities of each material that






compromise the DR material.



Purified Water
11,227.05

Each 15 mL dose of liquid suspension
69.30


Citric Acid
5.10

is equivalent to 16.2 grams at the
0.03


Propylene Glycol
577.50

theoretical specific gravity of 1.08.
3.56


Preservative
8.55


0.05


Xanthan Gum
116.25


0.72


Vegetable Oil
33.00


0.20


70% Sorbitol Solution
4012.5


24.77


Flavor and Color
64.35


<0.39


Total
16,200.0
mg

100%
















TABLE 43







Test Formulation #1005C (suspension amphetamine with 45% IR and 55% DR)


IR Resin - 36.05% base assay & DR Resin - 7.82% base assay









Formula #1005C



(45% active from IR Resin & 55% active from DR Resin)











mg per





15 mL dose
Notes
%














Uncoated (IR) AMP Resin
23.5

The 23.5 mg/dose quantity is the
0.145


Amphetamine (base)
4.23

actual amount of IR resin (at a 36.05%



Dextroamphetamine (base)
4.23

assay value) that goes into each 15 mL



AMBERLITE IRP069 Resin + Water
15.04

dose.






The values in the gray area are the






quantities of each material that






compromise the IR material.



Coated (DR) AMP Resin
132.2

The 132.2 mg/dose quantity is the
0.816


Amphetamine (base)
5.17

actual amount of DR resin (at an 7.82%



Dextroamphetamine (base)
5.17

assay value) that goes into each 15 mL



AMBERLITE IRP069 Resin + Water
21.98

dose.



Humectant
0.34

The IR resin material was used to make



EUDRAGIT L100
86.74

the 132.2 mg/dose DR material.



Plasticizer
12.84

The values in the gray area are the






quantities of each material that






compromise the DR material.



Purified Water
11,201.55

Each 15 mL dose of liquid suspension
69.15


Citric Acid
5.10

is equivalent to 16.2 grams at the
0.03


Propylene Glycol
577.50

theoretical specific gravity of 1.08.
3.56


Preservative
8.55


0.05


Xanthan Gum
116.25


0.72


Vegetable Oil
33.00


0.20


Sodium Polystyrene Sulfonate
25.5


0.16


Maltitol Syrup
4012.5


24.77


Flavor and Color
64.35


<0.39


Total
16,200.0
mg

100%









Data collection and analysis were carried out as similarly described above. 44 subjects participated in the study with 39 subjects completing all four study periods, and 42 subjects completing at least one test period and the reference period of the study. Data for the 42 subjects were included in the pharmacokinetic and statistical analyses. Mean concentration-time data are showing in FIGS. 36 and 37. Results of the pharmacokinetic and statistical analysis are shown below in Tables 44 through 49.
FIGS. 36A and 36B show mean d-amphetamine Concentration-Time Profiles after Administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), Test Formulation #3 (Treatment C), and the Reference Product (Treatment D).
FIGS. 37A and 37B show mean l-amphetamine Concentration-Time Profiles after Administration of Test Formulation #1 (Treatment A), Test Formulation #2 (Treatment B), Test Formulation #3 (Treatment C), and the Reference Product (Treatment D).







TABLE 44







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of d-amphetamine Comparing Test Formulation #1 (Treatment


A) to the Reference Product (Treatment D)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
50.1580
49.5786
101.17
99.16
103.22
1.0000
5.43


ln(AUC0-5)
130.5315
153.2270
85.19
79.53
91.25
0.9997
18.76


ln(AUC5-12)
287.7548
272.5554
105.58
103.05
108.16
1.0000
6.56


ln(AUC5-last)
823.1422
791.92221
103.94
100.64
107.35
1.0000
8.75


ln(AUC0-24)
696.5164
696.4442
100.01
98.18
101.88
1.0000
5.01


ln(AUClast)
958.9738
951.6525
100.77
98.40
103.19
1.0000
6.45


ln(AUCinf)
1001.0534
995.6153
100.55
97.95
103.21
1.0000
7.10





aGeometric Mean for Test Formulation #1 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 45







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of d-amphetamine Comparing Test Formulation #2 (Treatment


B) to the Reference Product (Treatment D)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
50.0963
49.3574
101.50
99.82
103.20
1.0000
4.42


ln(AUC0-5)
135.9603
152.6483
89.07
84.05
94.38
1.0000
15.45


ln(AUC5-12)
286.6888
271.5835
105.56
103.52
107.64
1.0000
5.18


ln(AUC5-last)
821.7640
789.8344
104.04
100.69
107.51
1.0000
8.71


ln(AUC0-24)
699.0396
694.7072
100.62
98.59
102.70
1.0000
5.41


ln(AUClast)
960.8482
949.2052
101.23
98.63
103.90
1.0000
6.91


ln(AUCinf)
1003.0198
993.2407
100.98
98.07
103.99
1.0000
7.79





aGeometric Mean for Test Formulation #2 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 46







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of d-amphetamine Comparing Test Formulation #3 (Treatment


C) to the Reference Product (Treatment D)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
50.7295
49.3066
102.89
100.35
105.49
1.0000
6.51


ln(AUC0-5)
136.5321
152.7544
89.38
84.81
94.20
1.0000
13.75


ln(AUC5-12)
289.7260
271.3370
106.78
105.26
108.31
1.0000
3.72


ln(AUC5-last)
829.3721
787.7095
105.29
102.81
107.83
1.0000
6.22


ln(AUC0-24)
705.8156
693.9269
101.71
99.85
103.61
1.0000
4.82


ln(AUClast)
970.1670
947.3535
102.41
100.17
104.69
1.0000
5.76


ln(AUCinf)
1015.0619
991.6597
102.36
99.66
105.13
1.0000
6.96





aGeometric Mean for Test Formulation #3 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 47







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of l-amphetamine Comparing Test Formulation #1 (Treatment


A) to the Reference Product (Treatment D)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
15.6903
14.9321
105.08
102.81
107.40
1.0000
5.92


ln(AUC0-5)
39.6019
45.0296
87.95
81.98
94.35
0.9996
19.20


ln(AUC5-12)
92.7020
85.1083
108.92
106.39
111.52
1.0000
6.39


ln(AUC5-last)
302.9169
283.7188
106.77
103.27
110.38
1.0000
9.03


ln(AUC0-24)
230.3610
222.7249
103.43
101.39
105.51
1.0000
5.40


ln(AUClast)
344.2092
330.7995
104.05
101.35
106.83
1.0000
7.14


ln(AUCinf)
373.9861
360.6700
103.69
100.39
107.10
1.0000
8.78





aGeometric Mean for Test Formulation #1 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 48







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of l-amphetamine Comparing Test Formulation #2 (Treatment


B) to the Reference Product (Treatment D)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
15.6747
14.8460
105.58
103.86
107.33
1.0000
4.36


ln(AUC0-5)
41.2088
44.8276
91.93
86.65
97.52
1.0000
15.75


ln(AUC5-12)
92.3827
84.8244
108.91
106.73
111.14
1.0000
5.37


ln(AUC5-last)
303.6696
283.1073
107.26
103.43
111.24
1.0000
9.66


ln(AUC0-24)
231.4482
222.2016
104.16
101.78
106.59
1.0000
6.12


ln(AUClast)
345.8479
330.0470
104.79
101.67
108.00
1.0000
8.02


ln(AUCinf)
375.9631
360.0332
104.42
100.75
108.23
1.0000
9.51





aGeometric Mean for Test Formulation #2 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 49







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of l-amphetamine Comparing Test Formulation #3 (Treatment


C) to the Reference Product (Treatment D)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
16.0082
14.8077
108.11
105.08
111.23
1.0000
7.42


ln(AUC0-5)
41.4033
44.8626
92.29
87.52
97.32
1.0000
13.89


ln(AUC5-12)
93.3817
84.7844
110.14
108.48
111.83
1.0000
3.97


ln(AUC5-last)
305.8158
282.5814
108.22
105.23
111.30
1.0000
7.32


ln(AUC0-24)
233.5886
222.0427
105.20
103.03
107.41
1.0000
5.42


ln(AUClast)
348.6608
329.6149
105.78
103.04
108.59
1.0000
6.85


ln(AUCinf)
380.0816
359.7935
105.64
101.93
109.48
1.0000
9.32





aGeometric Mean for Test Formulation #3 (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval






Conclusions

There were no unusual or unexpected adverse events related to the study medication. The 90% confidence interval for comparing the maximum exposure, based on ln(Cmax), is within the accepted 80% to 125% limits for all comparisons and analytes.
The 90% confidence intervals for comparing total systemic exposure, based on ln(AUClast) and ln(AUCinf), are within the accepted 80% to 125% limits for all comparisons and analytes.
With the exception of the log-transformed AUC0-5 Test Formulation #1005A vs. reference comparison for d-amphetamine, all log-transformed partial AUC parameters were within the accepted 80% to 125% range across all treatment comparisons and analytes. The lower bound of the 90% confidence interval for the log-transformed AUC0-5 Test Formulation #1005A vs. reference comparison was 79.53%, slightly below 80% for d-amphetamine.
Therefore, Test Formulations #1005B and #1005C (equivalent to 30 mg mixed amphetamine salts/15 mL) are bioequivalent to ADDERALL XR under fasted conditions.
Test Formulation #1005A (equivalent to 30 mg mixed amphetamine salts/15 mL) is bioequivalent to ADDERALL XR under fasted conditions based on standard bioequivalence metrics (Cmax, AUClast, AUCinf) and additional metrics such as AUC5-12, AUC5-last, and AUC0-24; bioequilvance criteria were not met for AUC0-5 for d-amphetamine.
Example 25
Rate Of Absorption And Oral Bioavailability Of Mixed Amphetaminers In Oral Liquid Suspension Compared To The Commercially Available Reference Product, Adderall XR
This was an open-label, single-dose, 3-treatment, 3-period, randomized, crossover study to assess the effect of food on the rate of absorption and oral bioavailability of mixed amphetamines on ion exchange resin in oral liquid suspension. The oral liquid suspension is similar to the suspension described in Example 24. Subjects were randomly assigned to a treatment sequence and received three separate single-dose administrations of study medication, one treatment per period, according to the randomization schedule. Dosing days were separated by a washout period of at least 7 days. Subjects received each of the treatments listed below during the three treatment periods:
Treatment A: Test Formulation 25A, an Oral Liquid suspension (equivalent to 30 mg mixed amphetamine salts/15 mL) was administered under fasted conditions; Dose=1×15 mL liquid oral suspension.
Treatment B: Test Formulation 25B, an Oral Liquid Suspension (equivalent to 30 mg mixed amphetamine salts/15 mL) was administered under fed conditions; Dose=1×15 mL liquid oral suspension.
Treatment C: Reference Product 25C, an Adderall XR® administered under fed conditions; Dose=1×30 mg capsule.
In each study period, subjects were admitted to the study unit in the evening prior to the scheduled dose. Subjects were confined to the research center during each study period until completion of the 36-hour blood collection and other study procedures. Subjects returned to the study unit for outpatient pharmacokinetic blood samples at 48 and 60 hours.
Procedures for Collecting Samples for Pharmacokinetic Analysis
Blood samples (1×4 mL) were collected and analyzed for d- and l-amphetamine. Samples were analyzed as described above. The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λz), terminal half-life (T1/2), area under the concentration-time curve from time-zero to 5.00 hours (AUCO5), area under the concentration-time curve from 5.00 hours to the time of the last quantifiable concentration (AUC5-last), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), and area under the plasma concentration time curve from time-zero extrapolated to infinity (AUCinf).
To assess the bioequivalence for Treatment B (fed) vs. Adderall XR (Treatment C, fed), an analysis of variance (ANOVA) model and the two one-sided t-tests procedure was performed on the log-transformed pharmacokinetic parameters Cmax, AUC0-5, AUC5-last, and AUC, for d- and l-amphetamine across treatments. Bioequivalence was demonstrated if the 90% confidence intervals were within the accepted limits of 80.00 to 125.00%.
To assess the effect of food on the rate and extent of absorption of Treatment B (fed) vs. Treatment A (fast), an analysis of variance (ANOVA) model and the two one-sided t-tests procedure was performed on the log-transformed pharmacokinetic parameters Cmax, AUClast, and AUC, for d- and l-amphetamine across treatments. No significant food effect was demonstrated if the 90% confidence intervals were within the accepted limits of 80.00 to 125.00%.
Results
Data from 29 subjects were included in the pharmacokinetic and statistical analyses. Mean concentration-time data are shown in FIGS. 38 and 39. Results of the pharmacokinetic and statistical analyses are shown below in Tables 50 through 53.
Conclusions
Bioequivalence Assessment (Treatment B, (Fed) Vs. Adderall XR (Treatment C, (Fed))
The 90% confidence interval for comparing the maximum exposure, based on ln(Cmax), is within the accepted 80% to 125% limits for d- and l-amphetamine. The 90% confidence intervals for comparing late and total systemic exposure, based on ln(AUC5-last) and ln(AUCinf), are within the accepted 80% to 125% limits for d- and l-amphetamine. The 90% confidence intervals for comparing early systemic exposure, based on ln(AUC0-5) are not within the accepted 80% to 125% limits for either d- and l-amphetamine. Therefore, a formulation of mixed amphetamine resin Oral Liquid Suspension (equivalent to 30 mg mixed amphetamine salts/15 mL) is not bioequivalent to the reference listed drug product (RLD) Adderall XR under fed conditions. Rather, formulating amphetamines in a suspension of drug-resin particles maintains an early onset of amphetamine effect, even when taken with meals.
Food Effect Assessment (Treatment B, Fed) Vs. (Treatment a, Fast))
The 90% confidence interval for comparing the maximum exposure, based on ln(Cmax), is within the accepted 80% to 125% limits for d- and l-amphetamine. The 90% confidence intervals for comparing total systemic exposure, based on ln(AUClast) and ln(AUCinf), are within the accepted 80% to 125% limits for d- and l-amphetamine. Therefore, no significant food effect was demonstrated for the formulations of Oral Liquid Suspension containing mixed amphetamines on resin particles (equivalent to 30 mg mixed amphetamine salts/15 mL). Such suspensions provide amphetamine exposure levels that more closely resemble the fasted state, even when taken with meals.







TABLE 50







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters


of d-Amphetamine Comparing Fed Conditions (Treatment B) to the


Reference Product under Fed Conditions (Treatment C)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
45.2535
41.6470
108.66
103.14
114.47
1.0000
11.66


ln(AUC0-5)
125.0648
72.1095
173.44
145.51
206.73
0.6764
40.70


ln(AUC5-last)
773.0222
757.8067
102.01
97.59
106.63
1.0000
9.90


ln(AUCinf)
945.7804
866.6134
109.14
104.84
113.61
1.0000
8.97





aGeometric Mean for Treatment B, Fed (Test) and Reference Product-Fed (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 51







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of d-Amphetamine Comparing Fed Conditions (Treatment


B) to Fasted Conditions (Treatment A)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
45.3087
51.0913
88.68
85.41
92.08
1.0000
8.40


ln(AUClast)
909.6180
942.7716
96.48
93.20
99.89
1.0000
7.74


ln(AUCinf)
945.6631
977.1454
96.78
93.30
100.39
1.0000
8.19





aGeometric Mean for Treatment B, Fed (Test) and Treatment A Fasted (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 52







Statistical Analysis of the Log-Transformed Systemic Exposure Parameters


of l-Amphetamine Comparing Fed Conditions (Treatment B) to the


Reference Product under Fed Conditions (Treatment C)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
14.3840
12.5275
114.82
109.16
120.78
1.0000
11.32


ln(AUC0-5)
38.7444
20.9999
184.50
154.35
220.53
0.6642
41.41


ln(AUC5-last)
281.9542
258.7635
108.96
103.88
114.29
1.0000
10.68


ln(AUCinf)
349.4520
301.4583
115.92
110.57
121.53
1.0000
10.56





aGeometric Mean for Treatment B, Fed (Test) and Reference Product-Fed (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval













TABLE 53







Statistical Analysis of the Log-Transformed Systemic Exposure


Parameters of l-Amphetamine Comparing Fed Conditions (Treatment


B) to Fasted Conditions (Treatment A)












Dependent
Geometric Meana
Ratio (%)b
90% CIc

ANOVA














Variable
Test
Ref
(Test/Ref)
Lower
Upper
Power
CV %

















ln(Cmax)
14.3990
16.0658
89.63
86.43
92.94
1.0000
8.11


ln(AUClast)
324.6557
338.2024
95.99
92.54
99.58
1.0000
8.19


ln(AUCinf)
349.3468
361.6533
96.60
92.75
100.61
1.0000
9.09





aGeometric Mean for Treatment B, Fed (Test) and Treatment A, Fasted (Ref) based on Least Squares Mean of log-transformed parameter values


bRatio (%) = Geometric Mean (Test)/Geometric Mean (Ref)


c90% Confidence Interval






All documents (e.g., patents and published patent applications) mentioned in this specification are hereby incorporated by reference in their entirety.

## Claims

1. A pharmaceutical composition comprising amphetamines complexed with ion-exchange resin particles to form drug-resin particles, wherein 30 to 50% by weight of said amphetamines are present in a first plurality of immediate release drug-resin particles and 50 to 70% by weight of said amphetamines are present in a second plurality of drug-resin particles that are coated with a delayed release coating.

2. The composition of claim 1, wherein the second plurality of drug resin particles comprises a triggered-release coating triggered by a pH change.

3. The composition of claim 2, wherein the triggered-release coating is cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, co-polymerized methacrylic acid/ acrylic acid ethyl esters, or mixtures thereof.

4. The composition of claim 1, wherein the resin particles are strong acidic cation exchange resins, selected from the group consisting of polistirex, polacrilex, cholestyramine, polacrilin or mixtures thereof.

5. The composition of claim 1, wherein 40%-50% by weight of said amphetamines are present in the first plurality of drug-resin particles and 50%-60% by weight of said amphetamines are present in the second plurality of drug-resin particles.

6. The composition of claim 5, wherein about 45% by weight of said amphetamines are present in the first plurality of drug-resin particles and about 55% by weight of said amphetamines are present in the second plurality of drug-resin particles.

7. The composition of claim 1, wherein the composition is a liquid suspension, chewable composition, or an orally disintegrating tablet composition.

8. The composition of claim 1, wherein said amphetamines in said drug-resin particles comprise 25% levo-amphetamine and 75% dextro-amphetamine.

9. The composition of claim 1, wherein the amount of said amphetamines is 2-60 mg.

10. The composition of claim 1, wherein 40-45% of said amphetamines are released within the first 45 minutes after the drug-resin particles are introduced into an in vitro dissolution assay, followed by a period of substantially no amphetamine release from 45 minutes to 2 hours, and concluding with period of from 2 to 8 hours during which substantially all of the remaining amphetamines are released, wherein the conditions of the dissolution assay are an initial dissolution medium of 0.1 N HCL, and after 2 hours, the medium is adjusted to a pH of about 6.8; and the dissolution assay is performed using a USP Apparatus 2.

11. The composition of claim 1, wherein the delayed release coating releases substantially all of the amphetamines in the second plurality of drug-resin particles within about 60 minutes after initiation of the delayed release.

12. A pharmaceutical composition comprising amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein a mammal receiving said composition, in the presence of ethanol, is exposed to a reduced amount of amphetamines compared to when said mammal receives a composition without resin particles particles in the presence of ethanol, said composition comprising a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate.

13. The composition of claim 1, wherein the amount of said amphetamines is equivalent to the total amount of amphetamines present in a 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg reference composition without resin particles which comprises a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate.

14. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein said composition is an orally disintegrating tablet and is effective to provide a mean plasma concentration profile in human ADHD patients which has the following AUC and Cmax values for a 30 mg total dose, or respective AUC and Cmax values directly proportional thereto for a total dose other than 30 mg:
(a) an AUC0-4 of 85.8 ng hr/mL −20% /+25% and a Cmax of 44.5 ng/mL −20% /+25% for dextroamphetamine and/or an AUC0-4 of 26.3 ng hr/mL −20% /+25% and a Cmax of 14.2 ng/mL −20% /+25% for levoamphetamine;
(b) an AUC0-5 of 126.3 ng hr/mL −20% /+25% and a Cmax of 44.5 ng/mL −20% /+25% for dextroamphetamine and/or an AUC0-5 of 39.1 ng hr/mL −20% /+25% and a Cmax of 14.2 ng/mL−20% /+25% for levoamphetamine;
(c) an AUC4-12 of 291 ng hr/mL −20% /+25% and a Cmax of 44.5 ng/mL −20% /+25% for dextroamphetamine and/or an AUC4-12 of 95.1 ng hr/mL −20% /+25% and a Cmax of 14.2 ng/mL −20% /+25% for levoamphetamine;
(d) an AUC5-12 of 250.5 ng hr/mL −20% /+25% and a Cmax of 44.5 ng/mL −20% /+25% for dextroamphetamine and/or an AUC5-12 of 82.3 ng hr/mL −20% /+25% and a Cmax of 14.2 ng/mL −20% /+25% for levoamphetamine; and/or
(e) an AUC0-24 of 613.3 ng hr/mL −20% /+25% and a Cmax of 44.5 ng/mL −20% /+25% for dextroamphetamine and/or an AUC0-24of 204.9 ng hr/mL −20% /+25% and a Cmax of 14.2 ng/mL −20% /+25% for levoamphetamine.

15. A pharmaceutical composition comprising a mixture of dextro- and levo-amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein said composition is a liquid suspension and is effective to provide a mean plasma concentration profile in human ADHD patients which has the following AUC and Cmax values for a 30 mg total dose, or respective AUC and Cmax values directly proportional thereto for a total dose other than 30 mg:
(a) an AUC0-4 of 104.7 ng hr/mL −20% /+25% and a Cmax of 46.3 ng/mL −20% /+25% for dextroamphetamine and/or an AUC0-4 of 31.8 ng hr/mL −20% /+25% and a Cmax of 14.6 ng/mL −20% /+25% for levoamphetamine;
(b) an AUC0-5 of 148.6 ng hr/mL −20% /+25% and a Cmax of 46.3 ng/mL −20% /+25% for dextroamphetamine and/or an AUC0-5 of 45.7 ng hr/mL −20% /+25% and a Cmax of 14.6 ng/mL −20% /+25% for levoamphetamine; and/or
(c) an AUC4-12 , of 300.3 ng hr/mL −20% /+25% and a Cmax of 46.3 ng/mL −20% /+25% for dextroamphetamine and/or an AUC4-12 , of 96.8 ng hr/mL −20% /+25% and a Cmax of 14.6 ng/mL −20% /+25% for levoamphetamine.

16. A pharmaceutical composition comprising amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein said composition, when containing about a total amphetamine dose of 30 mg, will produce in a human, a mean plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC0-∞) of about 1140 to about 1240 for total amphetamines.

17. A pharmaceutical composition comprising dextro-amphetamines, levo-amphetamines, or a racemic mixture thereof complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein one or more in vivo pharmacokinetic parameters of the composition selected from the group consisting of Cmax, AUC0-5, AUC5-12, AUC5-24, AUC5-t, AUC0-12, AUC0-24, AUC0-t,and AUC0-∞have a 90% confidence interval with upper and lower bounds within a range from 90%-115% of the value of the same parameter(s) for a bioequivalent reference composition.

18. A pharmaceutical composition comprising amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating, wherein said composition is a liquid suspension and a human receiving said composition substantially contemporaneously with food is exposed to an increased amount of amphetamines in the first 4 hours compared to a human receiving a reference composition comprising a mixture of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate.

19. A pharmaceutical composition comprising amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein about 50% by weight of said amphetamines are present in a first plurality of immediate release drug-resin particles and about 50% by weight of said amphetamines are present in a second plurality of drug-resin particles that are coated with a delayed release coating.

20. A pharmaceutical composition comprising amphetamines complexed with ion-exchange resin particles to form drug resin particles, wherein said composition comprises a first plurality of immediate release drug-resin particles and a second plurality of drug-resin particles that are coated with a delayed release coating and wherein said composition has an in vivo fasted serum profile with a first and second peak wherein said first peak occurs between 1 and 3 hours after ingestion of the composition and said second peak occurs between 4 and 7 hours after ingestion and is the Cmax.

21. The composition of claim 1, wherein said amphetamines comprise a mixture of dextro-and levo-amphetamines.