# Patent

## Title
Sustained release of guaifenesin combination drugs

## Abstract

The invention relates to a novel pharmaceutical sustained release formulation of guaifenesin and pseudoephedrine. The formulation may comprise a hydrophilic polymer, preferably a hydroxypropyl methylcellulose, and a water-insoluble polymer, preferably an acrylic resin, in a ratio range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to-one (4:1) by weight. This formulation capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject. The invention also relates to a modified release product which has two portions: a first portion having an immediate release formulation of guaifenesin and a second portion having a sustained release formulation of guaifenesin, wherein one or both portions further comprises pseudoephedrine. The modified release product has a maximum guaifenesin serum concentration equivalent to that of an immediate release guaifenesin tablet, and is capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. patent application Ser. No. 10/121,706 which was filed on Apr. 15, 2002 now U.S. Pat. No. 6,955,821 which is a continuation-in-part of U.S. patent application Ser. No. 09/559,542, now U.S. Pat. No. 6,372,252 which was filed on Apr. 28, 2000 and issued on Apr. 16, 2002 both of which are hereby incorporated in their entirety by reference.


BACKGROUND OF THE INVENTION
The invention is directed to a sustained release formulation for oral administration comprising combinations of guaifenesin and optionally at least one additional drug and methods of manufacture thereof. In particular, the invention is directed to a sustained release formulation which maintains a therapeutically effective blood concentration of guaifenesin and optionally the additional drug for a duration of about twelve hours. The invention further relates to combinations which demonstrate a maximum serum concentration equivalent to an immediate release tablet, while maintaining therapeutically effective blood concentration for about twelve hours.
Sustained release pharmaceutical formulations provide a significant advantage over immediate release formulations to both clinicians and their patients. Sustained release dosage forms provide for fewer daily dose administrations than their immediate release counterparts. For example, a standard dosage regimen for a 400 mg immediate release drug with a short half-life, such as guaifenesin, requires administration three times within twelve hours to maintain adequate bioavailability to achieve the desired therapeutic effect. This results in a series of three serum concentration profiles in the patient showing a rapid increase of drug followed by a similar rapid decrease. As a result, patients are provided with only a short window of the appropriate blood concentration of the medicament for optimum therapy. A 1200 mg sustained release dosage form, on the other hand, may require administration once every twelve hours to achieve therapeutic effect. Sustained release dosage forms generally control the rate of drug absorption, to avoid excessive drug absorption while maintaining effective blood concentration of the drug to provide a patient with a consistent therapeutic effect over an extended duration of time.
Besides reducing the frequency of dosing and providing a more consistent therapeutic effect, sustained release dosage forms generally help reduce side effects caused by a drug. Because sustained release dosage forms deliver the drug in slow, incremental amounts versus the cyclic high and low concentrations of immediate release formulations, it is easier for a patient's body to digest the drug, thereby avoiding undesirable side-effects. For patients who self-administer therapies, sustained release dosage forms generally result in greater compliance due to the lower frequency of dosing, lower quantity of dosage units to be consumed, and reduced undesired side-effects.
Generally, sustained release formulations contain drug particles mixed with or covered by a polymer material, or blend of materials, which is resistant to degradation or disintegration in the stomach and/or in the intestine for a selected period of time. Release of the drug may occur by leeching, erosion, rupture, diffusion or similar actions depending upon the nature of the polymer material or polymer blend used.
Conventionally, pharmaceutical manufacturers have used hydrophilic hydrocolloid gelling polymers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, or Pullulan to formulate sustained release tablets or capsules. These polymers first form a gel when exposed to an aqueous environment of low pH thereby slowly diffusing the active medicament which is contained within the polymer matrix. When the gel enters a higher pH environment such as that found in the intestines, however, it dissolves resulting in a less controlled drug release. To provide better sustained release properties in higher pH environments, some pharmaceutical manufacturers use polymers which dissolve only at higher pHs, such as acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, and hydroxypropyl methylcellulose phthalate, either alone or in combination with hydrophilic polymers.
Generally, these formulations are prepared by combining the medicament with a finely divided powder of the hydrophilic polymer, or the hydrophilic and water-insoluble polymers. These ingredients are mixed and granulated with water or an organic solvent and the granulation is dried. The dry granulation is then usually further blended with various pharmaceutical additives and compressed into tablets.
Although these types of formulations have been successfully used to manufacture dosage forms which demonstrate sustained release properties, these formulations generally do not have the desired release profile or serum concentration of medicament over an extended period of time. These sustained release formulations generally result in a delay in the appearance of drug in the blood stream, thereby delaying therapeutic effect. Additionally, when the drug does appear, its maximum serum concentration (Cmax) is lower than the maximum concentration required for the most effective therapeutic result. Furthermore, most formulations which claim twelve hour potency release almost all of their drug within six to eight hours, making the formulation less therapeutically effective towards the end of the twelve hour period. To prevent blood serum concentrations of drug from falling below a therapeutically effective level (Cmin) at extended time periods, many manufacturers increase the drug strength of the dosage form. The increase in drug strength, however, results in a concomitant increase in side-effects.
Other pharmaceutical manufacturers have made tablets and capsules containing a combination of an immediate release formulation and a sustained release formulation to improve the release profile of certain sustained release dosage forms. Although this solution improves the Cmax and length of time before the drug appears in the blood stream in some formulations, the extended therapeutic effect is not improved.
Furthermore, medicaments have different solubility properties and pH dependencies which affect dissolution rate and bioavailability. Bioavailability can also be affected by a number of factors such as the amounts and types of adjuvants used, the granulation process, compression forces (in tablet manufacturing), surface area available for dissolution and environmental factors such as agitation in the stomach and the presence or absence of food. Due to these numerous factors, specific formulations play an important role in the preparation of prolonged action solid dosage forms, particularly in the preparation of solid dosage forms which achieve appropriate bioavailability for optimum therapeutic effect.
Guaifenesin, 3-(2-methoxyphenoxy)-1,2-propanediol, is an expectorant which increases respiratory tract fluid secretions and helps to loosen phlegm. By reducing the viscosity of secretions, guaifenesin increases the efficiency of a cough reflex and of ciliary action in removing accumulated secretions from trachea and bronchi. Guaifenesin is readily absorbed from the intestinal tract and is rapidly metabolized and excreted in urine. guaifenesin has a typical plasma half-life of approximately one hour. The rapid metabolism and excretion of guaifenesin provides only a short window of therapeutic effectiveness when immediate release dosage is used.
Pseudoephedrine hydrochloride is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory effects. At the recommended oral dose, it has little or no pressor effect in normotensive adults. Pseudoephedrine has been shown to have a mean elimination half-life of 4-6 hours.
The need exists for a sustained release dosage form of guaifenesin alone and in combinations which are capable of sustaining therapeutic effective for extended periods of time. Further the need exists for sustained release dosage forms of guaifenesin alone and in combination which results in a Cmax equivalent to that of an immediate release formulation, appears in the blood stream as quickly as an immediate release formulation, and sustains the therapeutic effect.
SUMMARY OF THE INVENTION
The invention relates to strategies and designs in formulations of modified release guaifenesin and guaifenesin combination dosage forms. This invention provides sustained release pharmaceutical formulation comprising guaifenesin and at least one additional drug. The sustained release formulation (SR) may comprise a combination of at least one hydrophilic polymer and at least one water-insoluble polymer. The total weight ratio of hydrophilic polymer to water-insoluble polymer may be in a range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably in a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to-one (4:1). When a tablet comprising the sustained release formulation is exposed to an aqueous medium of low pH, such as that found in the stomach, the polymer combination gels causing guaifenesin and the drug(s) to diffuse from the gel. When the tablet passes to the intestines where an aqueous medium of higher pH is present, the gel begins to dissolve, thereby releasing guaifenesin and/or the drug(s) in controlled amounts. The tablet is capable of releasing therapeutically effective amounts of guaifenesin over an extended period, e.g. twelve or more hours and at least one additional drug immediately, over an extended period, or both.
This invention also encompasses a modified release composition which comprises two portions (e.g. a bi-layer tablet, or capsule), an immediate release formulation (IR) and a sustained release formulation (SR). Each formulation comprises a specific quantity of guaifenesin and may optionally contain at least one additional drug. The immediate release formulation is formulated to dissolve in aqueous acidic medium, such as that found in the stomach, to quickly release guaifenesin contained within the portion, and optionally quickly release the at least one additional drug. The sustained release portion may comprise a combination of hydrophilic polymer and a water-insoluble polymer in a ratio range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably from about two-to-one (2:1) to about four-to-one (4:1). Likewise, the sustained release portion may also contain the additional drug(s).
The invention also relates to sustained release preparations of the type described above in the form of capsules having beads or granules of both immediate release formulation and beads or granules of sustained release formulation. The beads may comprise a mixture of discrete beads each having only one of the SR or IR formulations or may comprise beads containing both SR and IR formulations associated in a single bead, or combinations of the foregoing. Alternatively, the sustained release formulation may comprise a core that is coated by a layer of the immediate release formulation to form a single tablet. For purpose of illustration only, the invention will be described in detail in the context of the bi-layered tablet embodiment. It should be understood that for either the immediate release and/or the sustained release portion the guaifenesin and optionally the additional drug may be mixed within the same matrix portion or comprise separate release portions which are then either compressed or mixed for capsules (e.g. comprise separate beads or granules) etc.
A bi-layer tablet demonstrates a maximum serum concentration (Cmax) and time of availability in the blood stream that are equivalent to an immediate release tablet. The bi-layer tablet also provides sustained release of guaifenesin over about a twelve hour period from one dose. The bi-layer tablet further maintains serum concentration levels of guaifenesin at a therapeutically effective level for about a twelve hour period without an increase in dosage strength. As the bi-layer tablet may also contain at least one additional drug, the additional drug can be formulated within the sustained release formulation, immediate release formulation, or both. In one embodiment, the bi-layer tablet maintains serum concentration levels of at least one additional drug at a therapeutically effective level for about a twelve hour period without an increase in dosage strength.
In another embodiment, the tablets and capsules of the invention provide a Cmin which is above the necessary therapeutically effective level for a period of 10 hours, more preferably 12 or more hours. In a more preferred embodiment, a tablet or capsule of the invention provides the above describe Cmin characteristics and provides the necessary Cmax to mimic a immediate release product to obtain symptom relief. In a more preferred embodiment, the delivery system provides the above describe Cmin characteristics and provides the necessary Cmax to mimic a immediate release product to obtain symptom relief within a substantially similar Tmax period to a immediate release profile.
In another embodiment of the invention, the delivery system provides a Cmax which does not result in a equivalent Cmax of an immediate release product but does provide a Cmax which is therapeutically effect to relieve systems while reducing the likelihood of side effects due to an increased Cmax.
The invention also relates to methods of manufacturing sustained release formulations and bi-layer tablets. An example of a manufacturing method for a sustained release formulation comprises mixing a hydrophilic polymer and active ingredients in a mixer, adding water to the mixture and continuing to mix and chop, drying the mixture to obtain hydrophilic polymer encapsulated granules, milling and screening the resulting granulation, and blending it with various pharmaceutical additives, additional hydrophilic polymer, and water insoluble polymer. The formulation may then be tableted and may further be film coated with a protective coating which rapidly dissolves or disperses in gastric juices.
An example of a bi-layer tablet manufacturing method comprises blending a quantity of guaifenesin and optionally, at least one drug with various excipients, colorants, and/or other pharmaceutical additives to form an immediate release formulation, separately blending another quantity of guaifenesin and optionally at least one drug with a hydrophilic polymer, a water-insoluble polymer, and various excipients, colorants, and/or other pharmaceutical additives to form a sustained release formulation, and compressing a quantity of the immediate release formulation with a quantity of the sustained release formulation to form a bi-layer tablet. The tablet may then optionally be coated with a protective coating which rapidly dissolves or disperses in gastric juices.
Other objects, advantages and embodiments of the invention are described below and will be obvious from this description and practice of the invention.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a flow diagram depicting steps in a wet granulation method for manufacturing the sustained release formulation.
FIG. 2 is a flow diagram depicting steps in a dry granulation method for manufacturing the sustained release formulation.
FIG. 3 is a flow diagram depicting steps in a method for manufacturing the bi-layer tablet.
FIG. 4 is a graph demonstrating the dissolution profiles of tablets comprising two different sustained release formulations.
FIG. 5 is a graph demonstrating the dissolution profiles of a commercially available immediate release dosage form and two sustained release dosage forms of guaifenesin.
FIG. 6 is a graph demonstrating the plasma concentration of guaifenesin over time in healthy human volunteers who were dosed with three different guaifenesin formulations; a commercial immediate release formulation, and two different sustained release formulations (Lot 7B-32 and Lot 7B-31).
FIG. 7 is a graph demonstrating the plasma concentration of guaifenesin over time in healthy human volunteers from a commercially available immediate release tablet, a non-layered modified release tablet of the invention, and two bi-layered modified release tablets of the invention (one comprising 600 mg of immediate release formulation and 600 mg of sustained release formulation and the other one comprising 400 mg of immediate release formulation and 800 mg of sustained release formulation).
FIG. 8 is a graph demonstrating the dissolution profiles of four sustained release tablets: one tablet is non-layered, comprising 1200 mg of sustained release formulation; another tablet is bi-layered, comprising 600 mg of sustained release formulation and 600 mg of immediate release formulation; another tablet is bi-layered, comprising 800 mg of sustained release formulation and 400 mg of immediate release formulation; and yet another tablet is bi-layered comprising 1000 mg of sustained release formulation and 200 mg of immediate release formulation.
FIG. 9 is a graph demonstrating the plasma concentration of guaifenesin over an averaged 12 hour interval (taken from 11 twelve hour intervals over 5.5 days) in healthy human volunteers from an immediate release tablet and a bi-layered modified release tablet of the invention.
FIG. 10 is a graph demonstrating the plasma concentration of guaifenesin over time (the last twelve hour interval of the 11 twelve hour intervals described above) in healthy human volunteers from an immediate release tablet and a bi-layered modified release tablet of the invention.
FIG. 11 is a graph demonstrating the averaged plasma concentration of guaifenesin over a 16 hour period in 27 healthy human volunteers from 600 mg bi-layered modified release tablets of the invention administered to fasting volunteers, 1200 mg bi-layered modified release tablets of the invention administered to fasting volunteers, and 1200 mg bi-layered modified release tablets of the invention administered to volunteers who had been fed a high fat meal.
FIG. 12 is a graph demonstrating the dissolution profile of dextromethorphan HBr as measured by three different batches of a 1200 mg guaifenesin −60 mg dextromethorphan tablet over a 12 hour period as measured by the weight percentage of dextromethorphan HBr dissolved over time.
FIG. 13 is a graph demonstrating the plasma concentration of guaifenesin following the administration of 1200 mg guaifenesin and 60 mg dextromethorphan HBr to volunteers separately and in formulations of the invention.
FIG. 14 is a graph demonstrating the plasma concentrations of dextromethorphan HBr following the administration of 1200 mg guaifenesin and 60 mg dextromethorphan HBr to volunteers in three different formulations.
FIG. 15 is a graph demonstrating the plasma concentrations of the metabolite dextrorphan following the administration of 1200 mg guaifenesin and 60 mg dextromethorphan HBr to volunteers in three different formulations.
FIG. 16 is a graph demonstrating the dissolution profile of pseudoephedrine HCl in three different batches of a 1200 mg guaifenesin-120 mg pseudoephedrine HCl tablet formulation over a 12 hour period as measured by the percent pseudoephedrine HCl dissolved over time.
FIG. 17 is a graph demonstrating the plasma concentration of guaifenesin following the administration of 1200 mg guaifenesin and 120 mg pseudoephedrine HCl to volunteers separately and in formulations of the invention.
FIG. 18 is a graph demonstrating the plasma concentration of pseudoephedrine HCl following the administration of 1200 mg guaifenesin and 120 mg pseudoephedrine HCl to volunteers in three different formulations.
FIG. 19 is a graph demonstrating the plasma concentration of three different 1200 mg guaifenesin dosages in groups A, B, and C of example 12.
FIG. 20 is a graph demonstrating the plasma concentration of three different 120 mg pseudoephedrine dosages in groups A, B, and C of example 12.
FIG. 21 is a graph demonstrating the plasma concentration of three different 1200 mg guaifenesin dosages for treatments A, B, and C of example 13.
FIG. 20 is a graph demonstrating the plasma concentration of three different 120 mg pseudoephedrine dosages for treatments A, B, and C of example 13.
FIG. 21 depicts guaifenesin concentrations of various formulations and dosage strength.
FIG. 22 depicts pseudoephedrine plasma concentrations following administration of two different dose strengths of pseudoephedrine, as well as, different formulations.
FIG. 23 depicts guaifenesin concentrations following administration of 1200 mg of guaifenesin with 120 mg pseudoephedrine hydrochloride in two different formulations following a high-fat meal.
FIG. 24 depicts pseudoephedrine concentrations following administration of 1200 mg of guaifenesin with 120 mg pseudoephedrine hydrochloride in two different formulations following a high-fat meal.
FIG. 25 depicts steady-state guaifenesin plasma concentrations following administration of 11 doses of 120 mg pseudoephedrine with 1200 mg of guaifenesin in two different formulations.
FIG. 26 depicts steady-state pseudoephedrine plasma concentrations following administration of 11 doses of 120 mg pseudoephedrine with 1200 mg of guaifenesin in two different formulations.
FIG. 27 depicts guaifenesin plasma concentrations following administration of 1200 mg of guaifenesin with and without the co-administration of 120 mg of pseudoephedrine.
FIG. 28 depicts pseudoephedrine plasma concentrations following administration of 120 mg of pseudoephedrine with and without the co-administration of 1200 mg of guaifenesin.
FIG. 29 depicts guaifenesin plasma concentrations following administration of an experimental 1200 mg guaifenesin-120 mg pseudoephedrine formulation to volunteers under fed and fasted conditions.
FIG. 30 depicts pseudoephedrine plasma concentrations following administration of an experimental 1200 mg guaifenesin-120 mg pseudoephedrine formulation to volunteers under fed and fasted conditions.
FIG. 31 depicts guaifenesin dissolution profiles for various batches associated with the studies.
FIG. 32 depicts pseudoephedrine dissolution profiles for various batches associated with the studies.
FIG. 33 depicts a process flow diagram for the manufacture of guaifenesin DC (95%).
FIG. 34 depicts a process flow diagram for a guaifenesin/pseudoephedrine product (1200/120 mg) tablets.
FIG. 35 depicts a process flow diagram for guaifenesin/pseudoephedrine product (600/60 mg) tablets.



DETAILED DESCRIPTION OF THE INVENTION
The invention relates to sustained release formulations of guaifenesin. In a preferred embodiment, the formulations also comprise at least one additional drug in immediate release form, sustained release form, or both. Each formulation comprises a specific quantity of guaifenesin and may optionally contain at least one additional drug. The immediate release formulation is formulated to dissolve in aqueous acidic medium, such as that found in the stomach, to provide rapid release of the guaifenesin and optionally the at least one additional drug. In a preferred embodiment, the sustained release formulation comprises a combination of a hydrophilic polymer and a water-insoluble polymer in a ratio range of about one-to-one (1:1) to about nine-to-one (9:1), more preferably a range of about three-to-two (3:2) to about six-to-one (6:1), and most preferably in a range of about two-to-one (2:1) to about four-to-one (4:1).
In a preferred embodiment the hydrophilic polymers are selected from acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, methylcellulose, hydroxomethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose, agar, pectin, carrageen, alginates, carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharides, and modified starch derivatives. In a more preferred embodiment the hydrophilic polymers are selected from cellulose ethers. In a most preferred embodiment the hydrophilic polymers are selected from hydroxypropyl methylcelluloses such as Methocel (E10M). Preferred total amounts of the hydrophilic polymer include more than 0.5% and less than 10% by weight for a 1200 mg tablet. More preferably hydrophilic polymer amounts includes more than 1.0% and less than 7.0%, more than 2% and less than 6.0%. These amounts include the hydrophilic polymer in the Guaifenesin DC described below. The hydrophilic polymer added separately to form the release-delaying matrix is preferably from about 0.5% to 4.0% and more preferably from about 1.0% to 2.0%. It should be recognized that these amounts may be proportionally present in a 600 mg tablet or any desired formulation strength.
In a preferred embodiment the water-insoluble polymers are selected from polyacrylic acids, acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate. In a more preferred embodiment the water-insoluble polymers are selected from acrylic resins. In a most preferred embodiment the water-insoluble polymers are selected from Carbomer acrylic resins such as Carbomer 934P. Preferred amounts of the water-insoluble polymer include more than about 0.5% and less than about 2.5% by weight for a 1200 mg tablet. More preferably hydrophilic polymer amounts includes more than about 0.75% and less than about 1.5%, and most preferably more than about 0.9% and less than 1.25%. It should be recognized that these amounts may be proportionally present in a 600 mg tablet or any desired formulation strength.
The invention also relates to sustained release preparations of the type described above in the form of bi-layered tablets or capsules having a combination of beads or granules of immediate release formulation and beads or granules of sustained release formulation. Alternatively, the sustained release formulation may comprise a core that is coated by a layer of immediate release formulation to form a single tablet. For purpose of illustration only, the invention will be described in detail in the context of the bi-layered tablet embodiment. When the embodiment is a bi-layered tablet, the tablet is made of two portions: one portion comprising a sustained release formulation and a second portion comprising an immediate release formulation. In a preferred embodiment, the at least one additional drug can be present within the sustained release formulation, the immediate release formulation, or both depending upon the desired effect.
For instance, in a preferred embodiment of the present invention has the following ingredients and proportions in the sustained release layer (mg/tablet): 1052.6 mg Guaifenesin DC (95%) [1000.0 mg of Guaifenesin, USP and 52.6 mg of hydroxypropyl methylcellulose, USP]; 120.0 mg Pseudoephedrine HCL, USP; 30.0 mg hydroxypropyl methylcellulose, USP [Methocel E10M, USP]; 15.0 mg Carbomer 934P, NF [Carbopol 974P]; 0.4 mg FD&C Red #40 Aluminum Lake (14-16%); and 10.0 mg magnesium stearate, NF for a total sustained release weight of 1228.0 mg. In a preferred embodiment the immediate release layer has the following proportions: 210.5 mg Guaifenesin DC (95%) [200.0 mg of guaifenesin, USP and 10.5 mg of hydroxypropyl methylcellulose, USP]; 117.5 mg of microcrystalline cellulose, NF [Avicel PH102]; 30.0 mg of sodium starch glycolate, NF [EXPLOTAB]; and 1.0 mg magnesium stearate, NF for a total immediate release weight of 359.0 mg.
In another preferred embodiment a 1200 mg Guaifenesin/120 mg Pseudoephedrine Tablet has the following ingredients and proportions:















Representative
Representative



Amount
Batch (kg)1
Batch (kg)1


Component
(mg/tablet)
IR Layer
SR Layer


















Guaifenesin DC (95%)2
1263.1
280.00
947.376


Hydroxypropyl
30.0
N/A
27.000


methylcellulose





(Methocel TM)





Pseudoephedrine
120.0
N/A
108.0


hydrochloride





Microcrystalline
117.50
156.28
N/A


cellulose





Sodium starch glycolate
30.0
39.90
N/A


Carbomer 934P
15.0
N/A
13.500


Magnesium stearate
11.0
1.33
9.000


FD&C Red
0.4
N/A
0.360


(14-16%)





#40 Aluminum





Lake





Water, purified
N/A3
N/A3
N/A3


Total Weight
1587.0
477.51
1105.236





1Based on batch size of 900,000 tablets


2Guaifenesin direct compression used in the manufacturing process consists of 95% Guaifenesin, USP, 5% hydroxpropyl methylcellulose, USP (Methocel TM E10M) granulated with Purified water, USP (49.21 Kg).


3Water is removed during processing of Guaifenesin DC 95%.






In another preferred embodiment a 600 mg Guaifenesin/60 mg Pseudoephedrine Tablet has the following ingredients and proportions:















Representative
Representative



Amount
Batch (kg)1
Batch (kg)1


Component
(mg/tablet)
IR Layer
SR Layer


















Guaifenesin DC (95%)2
631.55
280.00
947.376


Hydroxypropyl
15.0
N/A
27.000


methylcellulose





(Methocel TM)





Pseudoephedrine
60.0
N/A
108.0


hydrochloride,





USP





Microcrystalline
58.75
156.28
N/A


cellulose





Sodium starch glycolate
15.0
39.90
N/A


Carbomer 934P
7.5
N/A
13.500


Magnesium stearate
5.50
1.33
9.000


D&C Yellow #6
0.8
N/A
1.440


Aluminum Lake





(15-18%)





Water, purified
N/A3
N/A3
N/A3


Total Weight
794.1
477.51
1106.316





1 Based on batch size of 1,800,000 tablets


2 guaifenesin direct compression used in the manufacturing process consists of 95% guaifenesin, USP, 5% hydroxpropyl methylcellulose, USP (Methocel TM E10M) granulated with purified water, USP (49.21 Kg).


3 Water is removed during processing of Guaifenesin DC 95%.






In another example, a 1200 mg Guaifenesin/120 mg Pseudoephedrine Tablet may also have the following properties:













Description
1200 mg bi-layer tablet


Average Tablet Weight
1587.0 mg ± 3% (1539.4 mg-1634.6 mg)


Tablet Thickness
0.321′′-0.341′′


Tablet Hardness
25-45 SCU


Friability
NMT 0.8%


Loss on Drying
NMT 2.0%


(moisture)
NMT 31.74 mg/unit dose


Assay-guaifenesin
1140.0-1260.0 mg/tablet



(95.0-105.0%)


Assay-Pseudoephedrine
116.6 to 128.4 mg/tablet


hydrochloride
(93.0-107.0%)


Guaifenesin
The retention time of the peak obtained


Identification A
from the Assay preparation matches



that of the Standard preparation.


Guaifenesin
A deep-cherry red to purpose color is produced.


(Identification B)



Pseudoephedrine
The retention time of the peak obtained


hydrochloride
from the Assay preparation matches


Identification A
that of the Standard preparation


Pseudoephedrine
The IR spectrum matches that of the standard


hydrochloride
in the 2510 cm−1 to 2400 range cm−1.


Identification B



Dose Uniformity
% RSD NMT 6.0% (% RSD NMT 7.8%



for Level II) All individual values



between 85.0-115.0%



(For Level II, one value is allowed



outside 85.0-115.0%, but



none outside 75.0-125.0%)


Dissolution:
 1 Hour: NMT 45%


Guaifenesin
 2 Hour: 36-56%



 6 Hour: 61-81%



12 Hour: NLT 85%


Dissolution:
 1 Hour: NMT 53%


Pseudoephedrine
 2 Hour: 48-68%


hydrochloride
 6 Hour: NLT 75%



12 Hour: NLT 85%









In another example, a 600 mg Guaifenesin/60 mg Pseudoephedrine Tablet may also have the following properties:













Description
600 mg bi-layer tablet


Average Tablet Weight
794.1 mg ± 3% (766.4 mg-821.8 mg)


Tablet Thickness
0.247′′-0.262′′


Tablet Hardness
17-32 SCU


Friability
NMT 0.8%


Loss on Drying
NMT 2.0%


(moisture)
NMT 15.88 mg/unit dose


Assay-Guaifenesin
570.0-630.0 mg/tablet (95.0-105.0%)


Assay-Pseudoephedrine
58.2 to 61.8 mg/tablet


hydrochloride
(93.0-107.0%)


Guaifenesin
The retention time of the peak


Identification A
obtained from the Assay preparation



matches that of the



Standard preparation.


Guaifenesin
A deep-cherry red to purpose


Identification B
color is produced.


Pseudoephedrine
The retention time of the peak


hydrochloride
obtained from the Assay


Identification A
preparation matches that of



the Standard preparation.


Pseudoephedrine
The IR spectrum matches that of the


hydrochloride
standard in the 2510 cm−1 to


Identification B
2400 range cm−1.


Dose Uniformity
% RSD NMT 6.0% (% RSD NMT 7.8%



for Level II) All individual values



between 85.0-115.0%



(For Level II, one value is



allowed outside 85.0-115.0%, but none



outside 75.0-125.0%)


Dissolution:
 1 Hour: NMT 48%


Guaifenesin
 2 Hour: 41-61%



 6 Hour: 73-93%



12 Hour: NLT 90%


Dissolution:
 1 Hour: NMT 58%


Pseudoephedrine
 2 Hour: 56-76%


hydrochloride
 6 Hour: NLT 80%



12 Hour: NLT 85%









Embodiments of the invention, include a SCU that is preferably less than 43, more preferably less than 41, more preferably less than 38, more preferably less than 37, and more preferably between 32 and 35. SCU is also preferably greater than 21, more preferably greater than 24, more preferably greater than 28, and more preferably greater than 31.
The weight of 10 bi-layer tablets (1200 mg/120 mg) is preferably less than 16.4 g, more preferably less than 16.35 g, more preferably less than 16.29 g, more preferably less than 16.22 g, more preferably less than 16.16 g, more preferably less than 16.10 g, more preferably less than 16.04 g, and more preferably between 15.71 g and 16.03 g. The weight of 10 bi-layer tablets is also preferably greater than 15.35 g, more preferably greater than 15.40 g, more preferably greater than 15.46 g, more preferably greater than 15.53 g, more preferably greater than 15.59 g, more preferably greater than 15.65 g.
Other embodiments and characteristics of the invention are describe in further detail below.
Sustained Release Formulation
In one embodiment of the invention, a sustained release formulation comprises guaifenesin and optionally at least one drug both mixed with a polymer blend which comprises at least one hydrophilic polymer and at least one water-insoluble polymer. In a further embodiment, the sustained release formulation may comprise a combination of guaifenesin and at least one additional drug, wherein the additional drug may be selected from, but is not limited to, an antitussive such as dextromethorphan hydrobromide, codeine, hydrocodone, a decongestant such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride or ephedrine, an antihistamine such as chlorpheniramine maleate, brompheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, and clemastine fumerate, an analgesic such as aspirin, ibuprofen, naprosin, and acetaminophen, or combinations thereof. Preferably, the drug is dextromethorphan hydrobromide, pseudoephedrine hydrochloride, or a combination thereof.
The sustained release matrix utilizes polymers as described below to achieve the required delay release profile in vivo. To obtain the release profile proper mixing and formulation is required. For instance, too much hydrophilic polymer will result in too quick of a release and not allow for 12 hour relief while too much hydrophobic polymer will result in inadequate Cmax for relief of symptoms. Therefore, the selection of polymers, the amounts utilized in total and the amount utilized in comparison to each other provide a matrix which is then formulated according to the below methods to provide the appropriate release profile.
Hydrophilic polymers suitable for use in the sustained release formulation include: one or more natural or partially or totally synthetic hydrophilic gums such as acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, modified cellulosic substances such as methylcellulose, hydroxomethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxymethylcellulose; proteinaceous substances such as agar, pectin, carrageen, and alginates; and other hydrophilic polymers such as carboxypolymethylene, gelatin, casein, zein, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives, and other hydrophilic polymers known to those of skill in the art or a combination of such polymers.
These hydrophilic polymers gel and dissolve slowly in aqueous acidic media thereby allowing the guaifenesin and at least one drug to diffuse from the gel in the stomach. When the gel reaches the intestines, where the guaifenesin and the drug are fairly absorbable, it dissolves in controlled quantities in the higher pH medium to allow sustained release of guaifenesin and at least one drug throughout the digestive tract. Preferred hydrophilic polymers are the hydroxypropyl methylcelluloses such as those manufactured by The Dow Chemical Company and known as Methocel ethers. In one preferred embodiment of a sustained release formulation the hydrophilic polymer is a Methocel ether known as Methocel E10M.
Water-insoluble polymers which are suitable for use in the sustained release formulation are polymers which generally do not dissolve in solutions of a pH below 5, and dissolve more slowly in basic solutions than the hydrophilic polymer. Because the polymer is insoluble in low pH environments such as those found in gastric fluid, it aids in retarding drug release in those regions. Likewise, because the polymer dissolves more slowly in solutions of higher pH than hydrophilic polymers, it aids in retarding drug release throughout the intestines. This overall delayed release results in a more uniform serum concentration of guaifenesin.
The water-insoluble polymers suitable for use in this invention include for example: polyacrylic acids, acrylic resins, acrylic latex dispersions, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and other polymers common to those of skill in the art. In a preferred embodiment, a sustained release formulation comprises the acrylic resin Carbopol 974P supplied by BF Goodrich.
A sustained release formulation of invention may further comprise pharmaceutical additives including, but not limited to: lubricants such as magnesium stearate, calcium stearate, zinc stearate, powdered stearic acid, hydrogenated vegetable oils, talc, polyethylene glycol, and mineral oil; colorants; binders such as sucrose, lactose, gelatin, starch paste, acacia, tragacanth, povidone polyethylene glycol, Pullulan and corn syrup; glidants such as colloidal silicon dioxide and talc; surface active agents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, triethanolamine, polyoxyethylene sorbitan, poloxalkol, and quarternary ammonium salts; preservatives and stabilizers; excipients such as lactose, mannitol, glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, chloride, sulfate and phosphate salts of potassium, sodium, and magnesium; and/or any other pharmaceutical additives known to those of skill in the art. Colorants include, but are not limited to, Emerald Green Lake, FD&C Red No. 40, FD&C Yellow No. 6, D&C Yellow No. 10, or FD&C Blue No. 1 and other various certified color additives (See 21 CFR, Part 74). In one preferred embodiment, a sustained release formulation further comprises magnesium stearate and Emerald Green Lake. In another preferred embodiment, a sustained release formulation further comprises magnesium stearate and FD&C Blue No. 1 Aluminum Lake Dye.
In another embodiment the sustained release formulation comprises at least two drugs, one of which is guaifenesin, at least one hydrophilic polymer, at least one water-insoluble polymer, and at least one pharmaceutical additive which permits dissolution of drugs in a therapeutically effective profile for an extended period of time. It is preferred that the drug profile provide a therapeutically effective profile for greater than 10 hours, more preferably greater than 12 hours, and most preferably greater than 14 hours. In a preferred embodiment, a sustained release formulation comprises from about 75% to about 95% guaifenesin by weight, from about 1% to about 15% by weight of an additional drug, from about 0.5% to about 10% hydroxypropyl methylcellulose, from about 0.5% to about 2.5% acrylic resin, from about 0.4% to about 1.5% magnesium stearate, and from about 0.01% to about 1% colorant by weight. In a more preferred embodiment, a sustained release formulation comprises from about 75% to about 80% guaifenesin by weight, from about 3% to about 10% by weight of an additional drug, from about 3% to about 6% hydroxypropyl methylcellulose, from about 1% to about 1.5% acrylic resin, from about 0.7% to about 1% magnesium stearate, and from about 0.03% to about 0.13% colorant by weight.
The sustained release formulation controls the release of guaifenesin and optionally at least one additional drug into the digestive tract over an extended period of time resulting in an improved profile when compared to immediate release combinations. guaifenesin solubility is effected by the pH of the environment in which it is present (i.e. stomach versus intestinal tract). In a more acidic environment, such as the stomach, guaifenesin is less soluble while in a higher pH environment, such as the intestines, guaifenesin is readily soluble. The pH changes throughout the digestive tract effect the dissolution rate of guaifenesin and are partially determinate of the concentrations of guaifenesin attained in the blood and tissues.
To maintain a blood concentration of guaifenesin which provides good therapeutic effect, the release, or dissolution, of guaifenesin from a formulation matrix is preferably retarded and/or controlled through the intestines. The hydrophilic and water-insoluble polymers of the sustained release formulation gel when exposed to media of low pH. This gel matrix allows the sustained release drugs, e.g. guaifenesin alone or in combination with a second drug to diffuse at a controlled rate when exposed to a higher pH environment.
When using drugs approved by the Food and Drug Administration (FDA), the sustained release formulation may be formulated to mimic the blood serum profile of guaifenesin and optionally the additional drug(s) as described in the clinical documents filed with the FDA or as required by the FDA. In other words, the sustained release formulation releases at least one additional drug at a similar rate to the commercially available formulation, thereby providing a therapeutically effective amount of the additional drug.
In a preferred embodiment, a sustained release formulation comprises a hydrophilic polymer and a water-insoluble polymer in a ratio of about one-to-one (1:1) to about nine-to-one (9:1), more preferably the range is about three-to-two (3:2) to about six-to-one (6:1), and most preferably the range of hydrophilic polymer to water-insoluble polymer is about two-to-one (2:1) to about four-to-one (4:1). In another embodiment, the sustained release formulation comprises not more than about 10% hydrophilic polymer, preferably, not more than 6%, and in a more preferred embodiment, the sustained release formulation also comprises not more than 2.5% of the water-insoluble polymer by weight. In another preferred embodiment, the water-hydrophilic polymer is hydroxypropyl methylcellulose and the water-insoluble polymer is acrylic resin. The ratios result in a serum concentration profile of guaifenesin that provides an optimal therapeutic concentration for about twelve hours.
A sustained release formulation may be manufactured according to any appropriate method known to those of skill in the art of pharmaceutical manufacture. In one embodiment, guaifenesin and a hydrophilic polymer may be mixed in a mixer with an aliquot of water to form a wet granulation. The granulation may be dried to obtain hydrophilic polymer encapsulated granules of guaifenesin. The resulting granulation may be milled, screened, then blended with various pharmaceutical additives, water insoluble polymer, and additional hydrophilic polymer. The formulation may then tableted and may further be film coated with a protective coating which rapidly dissolves or disperses in gastric juices.
In a preferred embodiment the method of preparing a sustained release formulation comprises loading approximately 126 kg of guaifenesin and about 2 kg of Methocel E10M into a high shear mixer. The Methocel E10M and guaifenesin may be mixed for about seven minutes at a mixing speed of about 150 RPM and a chopper speed of about 2000 RPM. The mixing and chopping speeds may then be increased to about 200 RPM and 3000 RPM respectively for about five minutes while about 49 kg of water are added to the mixer contents. The mixer may be run for two additional minutes to complete granulation. In a further preferred embodiment, the shut off for the mixer load is set to 21 kilowatts.
The wet granulation may be emptied into a fluid bed bowl and placed into a fluid bed dryer set to a dryer air flow of 900 CFM and an inlet temperature of about 50° C. to about 55° C. until the outlet temperature increases at a rate of 1° C. per minute. The air flow may then be decreased to 600 CFM, and the inlet temperature may be decreased to 43° C. until the granulation is dried to a moisture content of no more than 0.5%. In another preferred embodiment, the outlet temperature is set to a cut-off of 48° C. In yet another preferred embodiment, an agitator in the fluid bed bowl may be run intermittently during drying. The dried granulation may be passed through a mill fitted with a suitable screen size so that not more than about 30% of the resulting granulation comes through a 100 mesh screen and not more than about 10% of the resulting granulation is retained on a 10 mesh screen. In one preferred embodiment, the dried granulation may be passed through a mill fitted with a 0.109′′ size screen at a mill speed of about 500 to about 1500 RPM and a screw feed rate of about 35 to about 45 RPM. The resulting screened granulation is about 95% guaifenesin and is called G Guaifenesin DC. (Direct Compressed) herein after. Screened granulation may be transferred to a 10 cubic foot V blender, combined with about another 0.6 kg of Methocel E10M, about 0.3 kg of a colorant such as Emerald Green Lake or FD&C BLUE No. 1, about 0.7 kg of magnesium stearate, and about 1.3 kg of Carbopol 974P. The combination may be blended for about three minutes.
In another preferred embodiment the method of preparing a sustained release formulation comprises loading about 101 kg to about 150 kg of guaifenesin, about 4.5 kg to about 18 kg of the additional drug, about 4.5 kg to about 5 kg of Methocel E10M, about 1.5 kg to about 2.25 kg of Carbopol® 974P, and about 40 g to about 240 g of colorant into a high shear mixer. If at this time water is to be added, then about 1 kg to about 1.5 kg of magnesium stearate is added as well. The ingredients may be mixed for about ten to about 12 minutes at a mixing speed of about 150 RPM and a chopper speed of about 2000 RPM. The mixing and chopping speeds may then be increased to about 200 RPM and 3000 RPM, respectively, for about five minutes while optionally about 29 kg of water are added to the mixer contents. If no water is added, then from about 1 kg to about 1.5 kg of magnesium stearate can be added at this time. The mixer may be run for ten additional minutes to complete granulation. In a further preferred embodiment, the shut off for the mixer load is set to 21 kilowatts.
The wet granulation may be emptied into a fluid bed bowl and placed into a fluid bed dryer set to a dryer air flow of 900 CFM and an inlet temperature of about 38° C. to about 48° C. until the outlet temperature increases at a rate of 1° C. per minute. The air flow may then be decreased to 600 CFM, and the inlet temperature may be decreased to 43° C. until the granulation is dried to a moisture content of no more than 0.5%. In another preferred embodiment, the outlet temperature is set to a cut-off of 48° C. In yet another preferred embodiment, an agitator in the fluid bed bowl may be run intermittently during drying. The dried granulation may be passed through a mill fitted with a suitable screen size so that not more than about 30% of the resulting granulation comes through a 100 mesh screen and not more than about 10% of the resulting granulation is retained on a 10 mesh screen. In one preferred embodiment, the dried granulation may be passed through a mill fitted with a size screen of about 0.190′′ to about 0.125′′ at a mill speed of about 500 to about 1500 RPM and a screw feed rate of about 35 to about 45 RPM.
The resulting formulations may further be compressed on a tablet compressor machine using tooling to form tablets. The tablets may be any appropriate weight, size, and shape depending on the desired dosage strength of tablet. In one embodiment, these tablets may further be loaded into a coating pan and film coated with Opadry Y-S-3-714 (supplied by Colorcon, Inc.) and air dried in the pan.
In another embodiment, the method of preparing a sustained release formulation comprises blending the drugs, hydrophilic polymer, water insoluble polymer, and any pharmaceutical additives. The resulting blend may then be compressed into tablets and, if desired, film coated with a protective coating which rapidly dissolves or disperses in gastric juices. In a preferred embodiment of such a method, about 126 kg of Guaifenesin DC. (about 95% purity), about 2.6 kg of Methocel E10M, about 1.3 kg of Carbopol 974P and about 0.333 kg of a colorant such as Emerald Green Lake or FD&C. BLUE No. 1 may be loaded into a 10 cubic foot V Blender. The ingredients may be blended for about 20 minutes at which time about 0.6 kg of magnesium stearate may be added to the blended ingredients. This mixture may be blended for about another 10 minutes. The resulting formulation may further be compressed on a tablet compressor machine using tooling to form tablets. The tablets may be any appropriate weight, size, and shape depending on the desired dosage strength of the tablet. These tablets may further be loaded into a coating pan and film coated with Opadry Y-S-3-714 (supplied by Colorcon, Inc.) and air dried in the pan.
One embodiment of the invention uses the following general methods of manufacturing. To make the Guaifenesin DC. (95%) intermediate granulation is conducted. The granulator is charged with purified water USP. The guaifenesin USP is added into the granulator. Next the hydroxypropyl methylcelluose USP (Methocel El OM) is added. The guaifenesin intermediate is dried with the air inlet temperature set about 5° C., until the air outlet temperature reached approximately 48° C. A sample may then be taken for in-process control testing (moisture analysis). After the material reaches the target moisture level, discharge the blend and proceed to milling. The dried granulation is then added to the milling machine and the milling process initiated. Again a sample may be taken for in-process control testing (moisture and sieve analysis). The milled material is collected into tared fiber drums, double-lined with plastic bags and containing a desiccant pouch between the inner and outer plastic bags, then transferred to blending. The batches are blended in a 60-cu. foot blender for at least 10 minutes. Again, a sample may be taken for in-process control testing (description, moisture, blend assay and sieve analysis). The final sieve analysis for milled Guaifenesin DC preferably will be as follows: not more than about 2 to 10% retained on a 10-mesh screen (2.00 mm), not less than about 50 to 60% retained on the 20-mesh through 100-mesh screens (150 μm), not less than about 4 to 6% will pass through a 100-mesh screen, and not more than about 15-20% will pass through a 140-mesh screen (106 μm). When at least 50%, and preferably at least 60% of the Guaifenesin DC has a particle size in the range of from about 2 mm to about 150 μm, this facilitates both processability and achievement of the desired in vivo release profiles for the single entity and combination drugs described herein. The final Guaifenesin DC (95%) granulation is collected into tared fiber drums, double-lined with double-lined with plastic bags and containing a desiccant pouch between the inner and outer plastic bags.
In one embodiment the immediate release layer is produced according to the following general procedures. The released components, Guaifenesin DC (95%) and microcrystalline cellulose, NF (Avicel® PH102), are weighed and blended in a PK V-blender for about 20 minutes. Then sodium starch glycolate, NF (Explotab®), is added to the blender and blend for about 10 minutes. Next magnesium stereate, NF, is added to the blender and blended for approximately an additional 10 minutes. Sample may then be taken for in-process control testing (description, blend assay and sieve analysis).
In one embodiment the sustained release layer is produced according to the following general procedures. The released components, Guaifenesin DC (95%) and pseudoephedrine HCl, USP, previously screened through a No. 20 screen, are weighed and blended for ten minutes with hydroxypropyl methylcellulose, USP (Methocel E10M), Carbomer 934P and the appropriate colorant (FD & C. Red No. 40 aluminum lake dye for 1200 mg guaifenesin/120 mg pseudoephedrine HCl tablets or FD & C Yellow No. 6 aluminum lake dye for 600 mg guaifenesin/60 mg pseudoephedrine HCl tablets). Next, an additional amounts of Guaifenesin DC (95%), previously screened through a No. 10 screen, is added and blended for about ten minutes. Then magnesium stereate, NF, previously screened through a No. 20 screen, is added and blended for about ten minutes. Again, samples may be taken for in-process control testing (description, sieve analysis, and blend assay for both guaifenesin and pseudoephedrine HCl). Tablet Compression involved loading each blend (IR and SR) into its respective hopper on the bi-layer tablet compressor and then compressed according to the described parameters.
Tablets comprising a sustained release formulation were prepared and tested for both in vitro and in vivo release characteristics as described in Examples 1, 2, and 3 below. In the in vitro testing, the dissolution rates of these tablets were compared against modified release tablets formulated without acrylic resin (Example 1), and three commercially available tablets, one being an immediate release formulation and the other two being modified release formulations. Tablets comprising the sustained release formulation demonstrated a slower, more controlled release of guaifenesin over a twelve hour period than any of the other tablets (see e.g., Example 1 and 2, and FIGS. 4 and 5).
In the in vivo testing, serum concentrations of subjects taking tablets comprising the sustained release formulation were compared with serum concentrations of subjects taking immediate release guaifenesin tablets and modified release guaifenesin tablets formulated without acrylic resin (see Example 3 and FIG. 6). Tablets comprising the sustained release formulation demonstrated improved sustained release and therapeutic concentration over an extended time period compared to the other two formulations. Additionally, in the subjects taking tablets comprising the sustained release formulation, it took longer for guaifenesin to appear in the blood stream and the maximum guaifenesin serum concentration (Cmax) was less than half that of the subjects who took the immediate release tablets.
Modified Release Formulation
To improve the Cmax and guaifenesin appearance speed in patients while maintaining therapeutic effect for about twelve hours, a portion of a sustained release formulation as described above may be combined with a portion of an immediate release formulation in a modified release product. In a preferred embodiment, at least one additional drug can be present within the sustained release formulation, the immediate release formulation, or both depending upon the desired effect. When using drugs approved by the Food and Drug Administration (FDA), the sustained release formulation, immediate release formulation, or both may be formulated to mimic the blood serum profile of the additional drug as described in the clinical documents filed with the FDA or as required by the FDA. In other words, the sustained and/or immediate release formulations of the modified release formulation may release the at least one additional drug at a similar rate to the commercially available formulation, thereby providing a therapeutically effective amount of the additional drug.
The modified release formulation can be in the form of bi-layered tablets, capsules having a combination of beads or granules of immediate release formulation and sustained release formulation, or a tablet wherein the sustained release formulation comprises a core that is coated by a layer of the immediate release formulation. For purpose of illustration only, the invention will be described in detail in the context of the bi-layered tablet embodiment.
The immediate release formulation may comprise guaifenesin and various pharmaceutical additives such as lubricants, colorants, binders, glidants, surface active agents, preservatives, stabilizers, as described above and/or any other pharmaceutical additives known to those of skill in the art. In one embodiment, the immediate release layer comprises at least one drug. In another embodiment, the immediate release layer comprises at least two drugs. In a more preferred embodiment, an immediate release formulation comprises guaifenesin, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate. In another more preferred embodiment, an immediate release formulation comprises guaifenesin, at least one additional drug, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, and magnesium stearate. In yet another preferred embodiment, an immediate release formulation may comprise about 47% to about 58% guaifenesin, about 32% to about 42% microcrystalline cellulose, about 3% to about 8% sodium starch glycolate, and about 0.3% to about 0.5% magnesium stearate by weight. In yet another preferred embodiment, an immediate release formulation comprises about 47% to about 58% guaifenesin, about 3% to about 5% of at least one additional drug, about 32% to about 42% microcrystalline cellulose, about 2% to about 5% hydroxypropyl methylcellulose, about 3% to about 8% sodium starch glycolate, and about 0.3% to about 0.5% magnesium stearate by weight.
The bi-layer tablet may be manufactured according to any method known to those of skill in the art. The resulting tablet comprises the two portions compressed against one another so that the face of each portion is exposed as either the top or bottom of the tablet, or the resulting tablet may comprise the sustained release portion in the center coated by the immediate release portion so that only the immediate release portion is exposed. In a preferred embodiment, a bi-layer tablet comprises the two portions compressed against one another so that the face of each portion is exposed.
In a preferred method of manufacturing the bi-layer tablets, a sustained release formulation is prepared according to either a wet granulation or dry granulation method as described above. The immediate release formulation may be prepared by simply blending the guaifenesin with any pharmaceutical additives. If at least one additional drug is present, then water may be added to the formulation, as described above. In a further preferred embodiment, appropriate quantities of Guaifenesin DC, microcrystalline cellulose, and sodium starch glycolate are blended in a 10 cubic foot blender for about twenty minutes. An appropriate quantity of magnesium stearate is then added to the ingredients and blended for about ten more minutes to make an immediate release formulation. Portions of the sustained release formulation and immediate release formulation are then compressed by a tablet compressor machine capable of forming bi-layer tablets. In one embodiment, these tablets may further be coated with a protective film which rapidly disintegrated or dissolves in gastric juices.
The tablets may be made with any ratio of guaifenesin to at least one additional drug which results in a blood profile demonstrating appropriate therapeutic effect over extended time periods. As discussed above, the additional drug may be present in an amount sufficient to mimic the blood serum profile of the commercially available formulation of the drug and not to exceed the maximum dose approved by the FDA for the treatment, prevention, or amelioration of a particular illness or disease. In one embodiment, the ratio of total guaifenesin to at least one additional drug is about 1:1 to about 20:1 by weight, preferably, the ratio is about 2:1 to about 15:1 by weight, and more preferably, the ratio of guaifenesin to at least one additional drug is about 8:1 to about 12:1 by weight. When present in the immediate release layer, the amount of the at least one additional drug should be sufficient to match the drug release profile of the additional drug within the sustained release profile.
In a preferred embodiment, the tablets are made with any ratio of guaifenesin to pseudoephedrine which results in a blood profile demonstrating appropriate therapeutic effect over extended time periods. As discussed above, the pseudoephedrine is present in an amount sufficient to mimic the blood serum profile of the commercially available formulation of the drug and not to exceed the maximum dose approved by the FDA for the treatment, prevention, or amelioration of a particular illness or disease. In one embodiment, the ratio of total guaifenesin to pseudoephedrine is about 1:1 to about 20:1 by weight, preferably, the ratio is about 2:1 to about 15:1 by weight, and more preferably, the ratio of guaifenesin to pseudoephedrine is about 8:1 to about 12:1 by weight. In another embodiment the pseudoephedrine is only present in the immediate release layer.
The tablets may be made with any ratio of sustained release to immediate release formulation which results in a blood profile demonstrating appropriate therapeutic effect over extended time periods. In one embodiment, the bi-layer tablets comprise guaifenesin distributed within the sustained release formulation and the immediate release formulation wherein the ratio of guaifenesin in the SR to guaifenesin in the IR is about 1:1 to about 15:1 by weight, preferably the ratio is about 3:2 to about 11:1, and more preferably, the ratio of guaifenesin distributed within the sustained release formulation and the immediate release formulation is about 5:1 to about 9:1 by weight, respectively. For example, in a 1200 mg bi-layer modified release guaifenesin tablet, there may be about 200 mg of guaifenesin in the immediate release layer and about 1000 mg of guaifenesin in the sustained release layer.
The tablets may be made with at least one additional drug only within the sustained release formulation or with the additional drug only in the immediate release formulation. Optionally, the tablets may be made with at least one additional drug distributed within the sustained release formulation and the immediate release formulation. In one embodiment, the bi-layer tablets comprise an additional drug distributed within the sustained release formulation and immediate release formulation wherein the ratio of additional drug in the SR to additional drug in the IR is about 1:1 to about 19:1 by weight, preferably the ratio is about 3:2 to about 9:1, and more preferably the ratio is about 3:1 to about 4:1 by weight, respectively.
In one preferred embodiment of manufacturing a 1200 mg bi-layer sustained release guaifenesin tablet, about 105 kg of Guaifenesin DC, about 2.5 kg of Methocel E10M, about 1.25 kg of Carbopol 974P, and about 0.333 kg of Emerald Green Lake or FD&C Blue No. 1 in a 10 cubic foot P.K. blender for about twenty minutes. About 0.6 kg of magnesium stearate may then be added and blending continued for about another ten minutes to prepare the sustained release formulation. Approximately 21 kg of Guaifenesin DC, approximately 11.75 kg of microcrystalline cellulose, and approximately 3 kg of sodium starch glycolate may be blended in a 3 cubic foot P.K. blender for about twenty minutes. Approximately 0.1 kg of magnesium stearate may then be added and blending continued for about another ten minutes to prepare the immediate release formulation. The two formulations may then be compressed to make bi-layer tablets wherein about 75% of each tablet may be sustained release formulation and about 25% of each tablet may be immediate release formulation. The tablets may be any dosage strength, size, or shape. In a preferred embodiment, 1200 mg tablets are round and about 5⁄8 inch in diameter, about 0.28 inch-0.31 inch in thickness, weigh about 1.46 grams and have a hardness range of about 15-40 SCU. In another preferred embodiment, 600 mg tablets are round and about 1⁄2 inch in diameter, about 0.218 inch-0.230 inch in thickness, weigh about 0.729 grams and have a hardness range of about 12-30 SCU.
In another preferred embodiment of manufacturing a 1200 mg bi-layer sustained release guaifenesin tablet, about 101 kg of Guaifenesin DC, about 4.5 kg of at least one additional drug such as dextromethorphan, about 5 kg of Methocel E10M, about 1.5 kg of Carbopol 974P, and about 0.04 kg of FD&C Blue No. 1 are blended in a 10 cubic foot Day mixer for about twelve minutes. Thereafter, about 29 kg of water is added and the mixture is blended for an additional 10 minutes, followed by drying. About 1 kg of magnesium stearate may then be added and blending continued for about another ten minutes to prepare the sustained release formulation. About 45.6 kg of GUAIFENESIN, about 3.6 kg of at least one additional drug such as dextromethorphan, about 40.32 kg of microcrystalline cellulose, and approximately 3 kg of sodium starch glycolate are blended in a 3 cubic foot Day mixer for about 12 minutes. Thereafter, about 36 kg of water is added and the mixture is blended for an additional 10 minutes, followed by drying. About 0.48 kg of magnesium stearate may then be added and blending continued for about another ten minutes to prepare the immediate release formulation. The two formulations may then be compressed to make bi-layer tablets wherein about 75% of each tablet may be sustained release formulation and about 25% of each tablet may be immediate release formulation. The tablets may be any dosage strength, size, or shape. In a preferred embodiment, 1200 mg tablets are round and about 5⁄8 inch in diameter, about 0.31 inch-0.34 inch in thickness, weigh about 15.3 grams and have a hardness range of about 15-35 SCU. In another preferred embodiment, 600 mg tablets are round and about 1⁄2 inch in diameter, about 0.22 inch-0.26 inch in thickness, weigh about 7.65 grams and have a hardness range of about 15-65 SCU.
The immediate release portion of the bi-layer tablet is formulated to dissolve in aqueous media of low pH, such as that found in the stomach, to quickly release the guaifenesin contained within the portion. This results in rapid bioavailability of a high concentration of guaifenesin. As demonstrated in Example 6 and FIGS. 9 and 10 below, the immediate release portion of the bi-layer tablet results in a maximum serum concentration (Cmax) and time of maximum serum concentration (Tmax) equivalent to the Cmax obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period.
The sustained release portion gels when exposed to media of low pH allowing the sustained release portion of the tablet to be passed into the intestinal tract. In the intestines, the gelled sustained release portion is exposed to a higher pH environment, causing the gel to slowly dissolve, thereby allowing guaifenesin to diffuse and dissolve out of the gelled matrix. This results in controlled bioavailability over an extended time period (i.e. eight to twelve or more hours) causing the tablet to provide extended therapeutic effect. As shown in Example 6 and FIGS. 9 and 10, the half-life of the modified release bi-layer tablet is increased to more than 3 hours and the tablet has an AUCinf (the area under a plasma concentration versus time curve from time 0 to infinity) of greater than 8000 hr-ng/mL.
As demonstrated in Example 7 and FIG. 11, the bi-layer tablets of the invention had a further surprising result in that a 600 mg tablet had a Tmax equivalent to that of a 1200 mg and a Cmax and AUCinf approximately half of a 1200 mg tablet. Thus, without adjusting or changing the composition of the sustained release formulation or bi-layer tablet, a lower dosage strength guaifenesin tablet of the invention exhibits a plasma concentration profile that is approximately directly proportional to that of a higher dosage strength guaifenesin tablet. As further demonstrated in Example 7 and FIG. 11, the bi-layer tablets resulted in that the Cmax and AUCinf of a 1200 mg tablet administered to volunteers who had been fasting and the Cmax and AUCinf of a 1200 mg tablet administered to volunteers who had consumed a high fat meal were approximately equivalent. Thus, a bi-layer tablet of the invention demonstrates a reduced food effect, being approximately equally effective when administered to a patient on an empty or full stomach. Similar results were obtained for combination formulations for instance as described in Examples 8-17.
Several combination formulations were also compared to commercial drugs for bioavailability. For instance, Example 8 shows three batches of the 1200 mg guaifenesin/60 mg dextromethorphan HBr which were dissolved to determine the amount of dextromethorphan HBr released over time. Generally, the formulations had 1200 mg of guaifenesin and 60 mg dextromethorphan HBr and were studied over a 12 hour period. The released amount of dextromethorphan HBr was determined as a weight percent of dissolved dextromethorphan in contrast to the total weight of dextromethorphan prior to dissolution. After 1 hour about 46% to 47% of the dextromethorphan had dissolved. After 2 hours the about 59% to 60% had dissolved, after 6 hours 73% to 76% had dissolved, and after 12 hours about 86% to 89% by weight of the dextromethorphan had dissolved. Thus, the formulations of the invention reproducibly release dextromethorphan over time. (see, FIG. 12). While, example 9, for instance demonstrates the in vivo bioavailability of a sustained release guaifenesin with dextromethorphan.
Various combination guaifenesin/pseudoephedrine compositions were also examined to determine their dissolution rates and bioavailability. Examples 10 and 11, provide a formulations of guaifenesin and pseudoephedrine in the sustained release portion of a bi-layered tablet. Results demonstrated that combining the drugs into a single tablet according to methods of the invention did not effect their dissolution profile or their in vivo release profile.
The two prototype lots of example 12 showed similar in vitro release to market MucinexTM and Sudafed®. In particular, Formulation B (lot PB01-K61) produced optimal bioavailability for both guaifenesin and pseudoephedrine and was therefore used in subsequent bioavailability studies.
Example 13 compared combination products for guaifenesin/pseudoephedrine HCL) of 1200/120 mg strength, Formulation B(lot PB01-M65A2) and of 600/60 mg strength, Formulation C(lot PB01-A12A) to commercial MucinexTM and Sudafed® 12 Hour. The 1200/120 mg strength showed bioequivalence for ratios of both Cmax and AUCinf with a 90% confidence interval, which is contained in the 80-125% range. Further, the 600/60 mg strength demonstrated proportional dosage pharmacokinetics.
Example 14 compared reference MucinexTM and Sudafed® 12 Hour to a 1200/120 mg strength test formulation (lot PB01-M65A3) for steady-state bioavailability in a 11 day twice-daily dose regime. The test formulation was bioequivalent (within the 80-125% range with a 90% confidence interval) when compared to the reference formulation. Therefore, for both guaifenesin and pseudoephedrine, the steady state for Cmax and AUCss were bioequivalent.
Examples 15 and 17 compared the effect of a high fat meal for both reference formulations and combination formulations of the invention. The test formulation (lot PB01-M65) was not bioequivalent with regard to Cmax for guaifenesin but was for the pseudoephedrine portion when compared to the reference. However, the AUCinf was bioequivalent for both guaifenesin and pseudoephedrine within the 80-125% range.
Example 16 compared single-dose relative bioavailability and interaction potential of guaifenesin and pseudoephedrine administered as MucinexTM and Sudafed® 12 Hour alone or in combination. The results demonstrate that the pharmacokinetics of guaifenesin and pseudoephedrine are unaffected with regard to both AUCinf and Cmax in the presence or absence of one another (ratios within 80-125%). This further confirms the results of the other examples which demonstrate bioequivalence for the combination formulations of the invention.
These studies demonstrate the compositions of the invention provide systemic levels of drug over a 12-hour period. Additionally, the studies demonstrate the bioequivalence of the combination formulations.
Comparison to FDA Approved Drugs
When using drugs approved by the Food and Drug Administration (FDA), the sustained release formulation alone or in combination with an immediate release component may be formulated to mimic the blood serum profile of guaifenesin and optionally the additional drug(s) as described in the clinical documents filed with the FDA or as required by the FDA. This information may be found at http://www.fda.gov/cder/foi/nda/2002/21-282_Mucinex.htm which is hereby incorporated by reference in its entirety. For instance, a single dose 400 mg immediate release tablet has a Cmax of 2,463±1033, a Tmax of 0.5, an AUC0-12 8,382±3,282, an AUCinf 8,529±3,362, and a T1/2 of 0.78±0.09. Alternatively, multiple doses of a 400 mg immediate release tablet has a Cmax of 2,278±791, a Tmax of 0.5, an AUC0-12 7,751±2,697, Cmin0 112±52, and a Cmin12 137±98. Preferably, the formulations result in a maximum serum concentration (Cmax) and/or time of maximum serum concentration (Tmax) equivalent to the Cmax obtained when the first of three doses of a standard immediate release formulation having one third the amount of guaifenesin is dosed every four hours over a 12 hour period. In other words, the sustained release formulation releases both the guaifenesin and at least one additional drug at a similar rate to the commercially available formulation, thereby providing a therapeutically effective amount of both drugs. Alternatively, the parameters may be calculated through any of the following or combinations thereof: Cmax, Cmin, Tmax, AUCinf, AUC0-1, AUCss and T1/2. Unless otherwise specified, all reference to AUC0-t in the specification and claims shall refer to data which corresponds to a time (t) of 24 hours. The parameters may also be calculated from in vivo studies such as those presented herein where equivalence is determined from the mean and a 80-125% range with a 90% confidence level and/or one standard deviation from the mean. FIGS. 31 and 32 demonstrate specification ranges for various batch compositions of the invention.
Additionally the Cmax for either guaifenesin, the additional drug(s) or both is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the Cmax for guaifenesin is preferably greater than 640 ng/mL, more preferably 800 ng/mL, more preferably 1000 ng/mL, and most preferably 1250 ng/mL depending on the formulation. The high end of the Cmax for guaifenesin is preferably less than 3750 ng/mL, more preferably 3000 ng/mL, more preferably 2750 ng/mL, and most preferably 2500 ng/mL depending on the formulation. For a 1200 mg tablet the range is preferably between 1000 ng/mL and 3750 ng/mL, 1200 ng/mL and 3500 ng/mL, 1350 ng/mL and 3000 ng/mL, and 1450 ng/mL and 2750 ng/mL. For a 600 mg tablet the range is preferably between 320 ng/mL and 1875 ng/mL, 400 ng/mL and 1500 ng/mL, 500 ng/mL and 1375 ng/mL, and 625 ng/mL and 1250 ng/mL.
Alternatively, the low end of the Cmax for pseudoephedrine is preferably greater than 150 ng/mL, more preferably 175 ng/mL, more preferably 200 ng/mL, and most preferably 250 ng/mL depending on the formulation. The high end of the Cmax for pseudoephedrine is preferably less than 500 ng/mL, more preferably 450 ng/mL, more preferably 400 ng/mL, and most preferably 375 ng/mL depending on the formulation. For a 120 mg tablet the range is preferably between 150 ng/mL and 500 ng/mL, 175 ng/mL and 500 ng/mL, 200 ng/mL and 450 ng/mL, 250 ng/mL and 400 ng/mL, and 300 ng/mL and 375 ng/mL. For a 60 mg tablet the range is preferably between 75 ng/mL and 250 ng/mL, 88 ng/mL and 250 ng/mL, 100 ng/mL and 225 ng/mL, 125 ng/mL and 200 ng/mL, and 150 ng/mL and 188 ng/mL.
The Cmin is another aspect which is often not met by various extended release drugs found on the market. Formulations of the invention provide a Cmin which maintains it therapeutic effectiveness for a period of at least 10 hours, more preferably 12 hours and most preferably 14 or more hours. Additionally the Cmin for either guaifenesin, the additional drug(s) or both is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the Cmin for guaifenesin is preferably greater than 40 ng/mL, more preferably 50 ng/mL, more preferably 60 ng/mL, and most preferably 70 ng/mL depending on the formulation. The high end of the Cmin for guaifenesin is preferably less than 200 ng/mL, more preferably 175 ng/mL, more preferably 150 ng/mL, and most preferably 125 ng/mL depending on the formulation. The Cmin range for either a 1200 or a 600 mg tablet may be selected from 50 ng/mL and 150 ng/mL, 50 ng/mL and 125 ng/mL, 60 ng/mL, 125 ng/mL, 70 ng/mL and 125 ng/mL, 80 ng/mL and 125 ng/mL, between 35 ng/mL and 75 ng/mL, 40 ng/mL and 70 ng/mL, 45 ng/mL and 65 ng/mL, and 50 ng/mL and 60 ng/mL.
Alternatively, the low end of the Cmin for pseudoephedrine is preferably greater than 75 ng/mL, more preferably 100 ng/mL, more preferably 125 ng/mL, and most preferably 150 ng/mL depending on the formulation. The high end of the Cmin for pseudoephedrine is preferably less than 300 ng/mL, more preferably 250 ng/mL, more preferably 225 ng/mL, and most preferably 200 ng/mL depending on the formulation. The Cmin range for either a 120 mg or 60 mg tablet may be selected from 75 ng/mL and 300 ng/mL, 100 ng/mL and 250 ng/mL, 125 ng/mL and 225 ng/mL, 150 ng/mL and 200 ng/mL.
Formulations of the invention provide a Tmax for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the Tmax for guaifenesin is preferably greater than 0.6 hours, more preferably 0.8 hours, more preferably 0.9 hours, more preferably 1.0 hours, and most preferably 1.1 hours depending on the formulation. The high end of the Tmax for guaifenesin is preferably less than 3.0 hours, more preferably 2.5 hours, more preferably 2.25 hours, and most preferably 2 hours depending on the formulation. The Tmax range may also be selected from between 0.6 hours and 3.0 hours, 0.8 hours and 2.5 hours, 0.9 hours and 2.25 hours, 1.0 hours and 2 hours, and 1.1 hours and 2 hours.
Alternatively, the low end of the Tmax for pseudoephedrine is preferably greater than 3.75 hours, more preferably 4.0 hours, more preferably 4.25 hours, more preferably 4.5 hours, and most preferably 4.75 hours depending on the formulation. The high end of the Tmax for pseudoephedrine is preferably less than 9.0 hours, more preferably 8.5 hours, more preferably 8.0 hours, and most preferably 7.5 hours depending on the formulation. The Tmax range may also be selected from between 3.75 hours and 9.0 hours, 4.0 hours and 8.5 hours, 4.25 hours and 8.0 hours, 4.5 hours and 7.5 hours, and 4.75 hours and 7.5 hours.
Formulations of the invention provide a AUCinf for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the AUCinf for guaifenesin is preferably greater than 4,000 hr-ng/mL, more preferably 5,000 hr-ng/mL, more preferably 5,500 hr-ng/mL, and most preferably 6,000 hr-ng/mL depending on the formulation. The high end of the AUCinf for guaifenesin is preferably less than 12,500 hr-ng/mL, more preferably 10,000 hr-ng/mL, more preferably 9,500 hr-ng/mL, and most preferably 9,000 hr-ng/mL depending on the formulation. For a 1200 mg tablet the AUCinf range may be selected from between 4,000 hr-ng/mL and 12,500 hr-ng/mL, 5,000 hr-ng/mL and 10,000 hr-ng/mL, 5,500 hr-ng/mL and 9,500 hr-ng/mL, and 6,000 hr-ng/mL and 9,000 hr-ng/mL. For a 600 mg tablet the AUCinf range may be selected from between 2,000 hr-ng/mL and 6,250 hr-ng/mL, 2,500 hr-ng/mL and 5,000 hr-ng/mL, 2,250 hr-ng/mL and 4,750 hr-ng/mL, and 3,000 hr-ng/mL and 4,500 hr-ng/mL.
Alternatively, the low end of the AUCinf for pseudoephedrine is preferably greater than 2,500 hr-ng/mL, more preferably 2,800 hr-ng/mL, more preferably 3,500 hr-ng/mL, and most preferably 3,750 hr-ng/mL depending on the formulation. The high end of the AUCinf for pseudoephedrine is preferably less than 6,000 hr-ng/mL, more preferably 5,800 hr-ng/mL, more preferably 5,500 hr-ng/mL, and most preferably 5,000 hr-ng/mL depending on the formulation. For a 120 mg tablet the AUCinf may be selected from between 2,500 hr-ng/mL and 6,000 hr-ng/mL, 2,800 hr-ng/mL and 5,800 hr-ng/mL, 3,500 hr-ng/mL and 5,500 hr-ng/mL, and 3,750 hr-ng/mL and 5,000 hr-ng/mL. For a 60 mg tablet the AUCinf may be selected from between 1,250 hr-ng/mL and 3,000 hr-ng/mL, 1,400 hr-ng/mL and 2,900 hr-ng/mL, 1,750 hr-ng/mL and 2,750 hr-ng/mL, and 1,875 hr-ng/mL and 2,500 hr-ng/mL.
Formulations of the invention provide a AUC0-t for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the AUC0-t for guaifenesin is preferably greater than 3,200 hr-ng/mL, more preferably 3,700 hr-ng/mL, more preferably 4,000 hr-ng/mL, and most preferably 4,500 hr-ng/mL depending on the formulation. The high end of the AUC0-t for guaifenesin is preferably less than 11,250 hr-ng/mL, more preferably 10,500 hr-ng/mL, more preferably 9,500 hr-ng/mL, more preferably 9,000 hr-ng/mL, and most preferably 8,500 hr-ng/mL depending on the formulation. For a 1200 mg tablet the AUC0-t may be selected from between 3,200 hr-ng/mL and 11,250 hr-ng/mL, 3,700 hr-ng/mL and 10,500 hr-ng/mL, 4,000 hr-ng/mL and 9,500 hr-ng/mL, 4,250 hr-ng/mL and 9,000 hr-ng/mL, and 4,500 hr-ng/mL and 8,500 hr-ng/mL. For a 600 mg tablet the AUC0-t may be selected from between 1,600 hr-ng/mL and 5,625 hr-ng/mL, 1,850 hr-ng/mL and 5,250 hr-ng/mL, 2,000 hr-ng/mL and 4,750 hr-ng/mL, 2,125 hr-ng/mL and 4,500 hr-ng/mL, and 2,250 hr-ng/mL and 4,250 hr-ng/mL.
Alternatively, the low end of the AUC0-t for pseudoephedrine is preferably greater than 2,000 hr-ng/mL, more preferably 2,200 hr-ng/mL, more preferably 2,500 hr-ng/mL, and most preferably 2,800 hr-ng/mL depending on the formulation. The high end of the AUC0-t for pseudoephedrine is preferably less than 6,000 hr-ng/mL, more preferably 5,750 hr-ng/mL, more preferably 5,500 hr-ng/mL, more preferably 5,250 hr-ng/mL, and most preferably 5,000 hr-ng/mL depending on the formulation. For a 120 mg tablet the AUC0-t may be selected from between 2,000 hr-ng/mL and 6,000 hr-ng/mL, 2,200 hr-ng/mL and 5,750 hr-ng/mL, 2,500 hr-ng/mL and 5,500 hr-ng/mL, 2,700 hr-ng/mL and 5,250 hr-ng/mL, and 2,800 hr-ng/mL and 5,000 hr-ng/mL. For a 60 mg tablet the AUC0-t may be selected from between 1,000 hr-ng/mL and 3,000 hr-ng/mL, 1,100 hr-ng/mL and 2,875 hr-ng/mL, 1,250 hr-ng/mL and 2,750 hr-ng/mL, 1,350 hr-ng/mL and 2,625 hr-ng/mL, and 1,400 hr-ng/mL and 2,500 hr-ng/mL.
Formulations of the invention provide a AUCss for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the AUCss for guaifenesin is preferably greater than 5000 hr-ng/mL, more preferably 5600 hr-ng/mL, more preferably 6000 hr-ng/mL, and most preferably 6500 hr-ng/mL depending on the formulation. The high end of the AUCss for guaifenesin is preferably less than 9000 hr-ng/mL, more preferably 8750 hr-ng/mL, more preferably 8250 hr-ng/mL, and most preferably 8000 hr-ng/mL depending on the formulation. The AUCss for a 1200 mg tablet may be selected from between 5000 hr-ng/mL and 9000 hr-ng/nL, 5600 hr-ng/mL and 8750 hr-ng/mL, 6000 hr-ng/mL and 8000 hr-ng/mL, and 6500 hr-ng/mL and 8250 hr-ng/mL. The AUCss for a 600 mg tablet may be selected from between 2,500 hr-ng/mL and 4,500 hr-ng/mL, 2,800 hr-ng/mL and 4,375 hr-ng/mL, 3,000 hr-ng/mL and 4,000 hr-ng/mL, and 3,250 hr-ng/mL and 4,125 hr-ng/mL.
Alternatively, the low end of the AUCss for pseudoephedrine is preferably greater than 2,100 hr-ng/mL, more preferably 2,400 hr-ng/mL, more preferably 2,650 hr-ng/mL, and most preferably 2,800 hr-ng/mL depending on the formulation. The high end of the AUCss for pseudoephedrine is preferably less than 5,500 hr-ng/mL, more preferably 5,000 hr-ng/mL, more preferably 4,500 hr-ng/mL, and most preferably 4,000 hr-ng/mL depending on the formulation. The AUCss for a 120 mg tablet may be selected from between 2,100 hr-ng/mL and 5,500 hr-ng/mL, 2,400 hr-ng/mL and 5,000 hr-ng/mL, 2,650 hr-ng/mL and 4,500 hr-ng/mL, and 2,800 hr-ng/mL 4,000 hr-ng/mL. The AUCss for a 60 mg tablet may be selected from between 1,050 hr-ng/mL and 2,250 hr-ng/mL, 1,200 hr-ng/mL and 2,500 hr-ng/mL, 1,325 hr-ng/mL and 2,250 hr-ng/mL, and 1,400 hr-ng/mL 2,000 hr-ng/mL.
Formulations of the invention provide a T1/2 for either guaifenesin, the additional drug(s) or both which is preferably between 80% and 125% of the FDA approved mean, more preferably between 90% and 115%, and most preferably between 95% and 115%. These ranges do not have to adjust commensurately, that is to say the mean may for instance preferably be between 90% and 125% of the FDA mean depending on the formulation. Alternatively, the low end of the T1/2 for guaifenesin is preferably greater than 0.7 hours, more preferably 0.9 hours, more preferably 1.1 hours, more preferably 1.3 hours, and most preferably 1.4 hours depending on the formulation. The high end of the T1/2 for guaifenesin is preferably less than 7.25 hours, more preferably 6.0 hours, more preferably 5.0 hours, and most preferably 3.5 hours depending on the formulation. The T1/2 for a 1200 mg tablet may be selected from between 0.7 hours and 7.25 hours, 0.9 hours and 6.0 hours, 1.1 hours and 5.0 hours, 1.3 hours and 3.5 hours, and 1.4 hours and 3.5 hours. The T1/2 for a 600 mg tablet may be selected from between 0.35 hours and 3.63 hours, 0.45 hours and 3.0 hours, 0.55 hours and 2.5 hours, 0.65 hours and 1.75 hours, and 0.70 hours and 1.75 hours.
Alternatively, the low end of the T1/2 for pseudoephedrine is preferably greater than 3.2 hours, more preferably 3.6 hours, more preferably 4.0 hours, more preferably 4.2 hours, and most preferably 4.5 hours depending on the formulation. The high end of the T1/2 for pseudoephedrine is preferably less than 8.0 hours, more preferably 7.5 hours, more preferably 7.0 hours, and most preferably 6.25 hours depending on the formulation. The T1/2 for a 120 mg tablet may be selected from between 3.2 hours and 8.0 hours, 3.6 hours and 7.5 hours, 4.0 hours and 7.0 hours, 4.2 hours and 6.25 hours, and 4.5 hours and 6.25 hours. The T1/2 for a 60 mg tablet may be selected from between 1.60 hours and 4.0 hours, 1.80 hours and 3.75 hours, 2.0 hours and 3.5 hours, 2.1 hours and 3.13 hours, and 2.25 hours and 3.13 hours.
Examples of other sustained release/immediate release formulations with and without additional drugs are discussed further in the examples which follow.
EXAMPLES
The invention is further defined by reference to the following examples describing in detail the compositions and methods of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention.
For the in vivo study portions, the following general procedures were used for sample analysis unless otherwise indicated. Blood samples (5-10 mLs with sodium heparin as anticoagulant) were taken prior to dosing and at specific intervals after dosing. (typically between 12 and 16 hours). All blood samples were chilled and centrifuged within 30 minutes of being drawn. The plasma was separated, transferred to a polypropylene tube, frozen at −20° C. or below and stored frozen until being shipped for drug analysis. The plasma samples were then analyzed by a fully validated HPLC method. This resulting plasma concentration v. time data was subjected to pharmacokinetic analysis using non-compartmental analysis with Winnonlin 1.5.
When necessary, volunteers were then given at least a seven day washout period (where no guaifenesin was administered to them under the study) prior to being crossed-over to the next treatment group. Generally, the subjects weighed within 15% of their Ideal Body Weight as defined by the 1983 Metropolitan Life chart.
Example 1
A batch of sustained release guaifenesin tablets, LotNo. 7LB-31FC, with the following composition was prepared:













Components
Weight per Tablet








Guaifenesin DC
 1260 mg



Methocel E10M
  30 mg



Emerald Green Lake
   4 mg



Magnesium Stearate
 6.8 mg



Opadry Y-S-3-7413
13.01 mg









Another batch of sustained release guaifenesin tablets, Lot No. 7LB-32FC, with the following composition was prepared:













Components
Weight per Tablet








Guaifenesin DC
1260 mg



Methocel E10M
  30 mg



Carbopol 974P
  15 mg



Emerald Green Lake
   4 mg



Magnesium Stearate
 6.8 mg



Opadry Y-S-3-7413
13.16 mg









Six tablets from Lot 7LB-31FC and six tablets from Lot 7LB-32FC were tested for in vitro guaifenesin release using an Acid/Base dissolution (slightly modified USP 23/NF 18 <711> Drug Release using Apparatus 2). Six dissolution vessels of a USP calibrated Hanson dissolution bath, equipped with shafts and paddles, were filled with 675 mL of 0.1N hydrochorlic acid at 37.0° C. The bath and vessels were maintained at a temperature of 37.0±0.5° C. throughout the 12 hour dissolution test. The paddles were set to rotate at 50 RPM and slowly lowered into the vessels. One tablet of lot 7LB-31 was then dropped into each vessel.
At the one hour and two hour intervals of testing, 5 mL samples of dissolution solution were withdrawn from each vessel and filtered through a 10 micron polyethylene filter into glass HPLC vials. Immediately after the two hour samples were withdrawn, 225 mL of 0.2M sodium phosphate tribasic was added to each vessel to increase the solution pH to about 6.8. The dissolution was run for ten additional hours, 2.0 mL samples being withdrawn from each vessel at the four, eight, 10, and 12 hour intervals. The filtered samples were then run on an HPLC to determine percent guaifenesin released.
The same dissolution testing procedure was performed for lot 7LB-32 FC. The lots gave dissolution profiles shown below and depicted in FIG. 4. Lot 7LB-31


















Vessel









No.
1 hr.
2 hr.
4 hr.
8 hr.
10 hr.
12 hr.























1
26
38
55
77
84
88



2
27
39
54
75
81
86



3
22
37
50
73
78
85



4
23
33
47
64
73
79



5
25
36
52
75
81
86



6
24
35
49
74
81
87



Average
24.5
36.3
51.2
73.0
79.7
85.2









Lot 7LB-32FC



















Vessel









No.
1 hr.
2 hr.
4 hr.
8 hr.
10 hr.
12 hr.























1
25
36
42
54
59
64.0



2
24
35
42
55
61
66



3
26
38
45
59
65
69



4
24
35
42
54
60
65



5
24
36
43
54
59
64



6
23
34
38
50
55
59



Average
24.3
35.7
42.0
54.3
59.8
64.5









Both formulations demonstrated sustained release of guaifenesin over a 12 hour period. Lot 7LB-32FC demonstrated identical release properties to Lot 7LB-31FC in 0.1N HCl. In buffered solution, however, Lot 7LB-32FC, the lot comprising a 2:1 ratio of Methocel E10M to Carbopol 974P, demonstrated a statistically slower release than lot 7LB-31FC, comprising Methocel E10M and no Carbopol 974P. A slower release rate in vitro translates to a slower, more controlled release with longer drug action in vivo—a favorable characteristic for pharmaceutical products containing a high concentration of an active ingredient with a short half-life (e.g. guaifenesin).
Example 2
A dissolution study was run to compare dissolution profiles of lots 7LB-32FC and 7LB-31FC with currently available guaifenesin dosage forms. One immediate release tablet, ORGANIDIN NR, and two sustained release tablets, HUMIBID L.A. and DURATUSS, were subjected to the same dissolution study as described for lots 7LB-31FC and 7LB-32FC in Example 1 above. The following is a summary of the results which are also depicted in FIG. 5.














Organidin NR





% guaifenesin
Humibid LA
Duratuss



released
% guaifenesin released
% guaifenesin released


















 1 hr.
100
36
24


 2 hr.
103
51
35


 4 hr.
104
72
47


 8 hr.
103
91
75


10 hr.
103
96
86


12 hr.
105
100
92









The immediate release Organidin released 100% of guaifenesin content within the first hour of dissolution. The two commercial sustained release dosage forms demonstrated a slower release of guaifenesin. However, both the Humibid LA and Duratuss released guaifenesin more rapidly than either Lot 7LB-31FC or 7LB-32FC, particularly after the eight hour interval. Both Humibid LA and Duratuss would, therefore, exhibit a faster rate of release and thus a shorter lived therapeutic effect in vivo.
Example 3
The in vivo behavior of sustained release tablets of Lot 7LB-31FC and Lot 7LB-32FC from Example 1 were compared to the in vivo behavior of an immediate release formulation (Organidin NR). The open-label study involved 9 healthy volunteers averaging 38±11.01 years of age with a range of 23 years to 55 years of age. The subjects weighed 175.56±24.22 lbs. with a range of 143 to 210 lbs. One subject was female and the remainder were male. Each subject received either one 1200 mg dose of 7LB-31FC, 7LB-32FC or a commercial 400 mg immediate release tablet (every four hours for 3 doses).
The results of the pharmacokinetic parameters analysis are described below and depicted in FIG. 6.


















Tmax
Cmax
AUC0-12

AUCinf


Subject
Formulation
(hr.)
(ng/mL)
(hr-ng/mL)
T1/2 (hrs.)
(hr-ng/mL)





















1
7LB-31FC
2.00
827.02
4817.20
4.64
6339.25


2
7LB-31FC
1.50
834.65
4695.89
2.71
5291.71


3
7LB-31FC
1.50
802.44
4142.14
3.44
4728.33


4
7LB-32FC
0.75
625.48
3034.31
5.78
5134.35


5
7LB-32FC
1.00
1052.00
5872.46
5.99
8298.33


6
7LB-32FC
2.00
1372.00
7924.35
5.53
9557.78


7
Organidin NR
0.50
2140.00
6921.94
0.86
7009.68


8
Organidin NR
4.25
18.17.00
6598.26
0.73
6674.65


9
Organidin NR
0.50
2831.00
9389.76
0.81
9570.91


Mean
7LB-31FC
1.67
821.37
4551.74
3.59
5453.10


Mean
7LB-32FC
1.25
1016.49
5610.37
5.77
7663.49


Mean
Organidin NR
1.75
2262.67
7636.65
0.80
7751.74


Ratio (%)
7LB-31FC/IR
95.43
36.30
59.60
448.27
70.35


Ratio (%)
7LB-32FC/IR
71.43
44.92
73.47
718.92
98.86









Subjects given the 1200 mg formulation 7LB-32FC reached maximum plasma guaifenesin concentrations of 1016 ng/mL in 1.25 hours and had an AUCinf of 7663 hr-ng/mL. The subjects given formulation 7LB-31FC reached maximum plasma guaifenesin concentrations of 821 ng/mL in 1.67 hours and had an AUCinf of 5453 hr-ng/mL. The subjects given the immediate release formulation, Organidin NR, reached maximum plasma guaifenesin concentrations of 2263 ng/mL in 1.75 hours (2 subjects peaked at 0.5 hours after the first dose and the third peaked at 0.25 hours after the second dose at 4 hours) and had an AUCinf of 7752 hr-ng/mL. The two controlled release formulations demonstrated sustained release in that their half-lives were longer, 5.77 hours for the 7LB-32FC and 3.59 hours for the 7LB-31 FC compared to 0.8 hours for the immediate release formulation, Organidin NR.
Both formulations 7LB-32FC (with both Methocel E10M and Carbopol 974P) and 7LB-31FC (with Methocel E10M only) control the release of guaifenesin from the tablet compared to the immediate release Organidin NR. Formulation 7LB-32FC, the formulation containing a 6:1 ratio of Methocel E10M to Carbopol 974P, had the longest half life at 5.77 hours with the largest AUCinf between the two sustained release formulation. However, both sustained release formulations have a Cmax less than half of the Cmax of the immediate release Organidin NR.
Example 4
Three different sustained release tablet lots of guaifenesin alone were prepared: i) Formulation I-1200 mg SR; ii) Formulation II-400 mg IR and 800 mg SR; and iii) Formulation III-600 mg IR and 600 mg SR.
Non-Layered Tablet (Sustained Release)












Formulation I










Components
Weight per Tablet






Guaifenesin DC
 1260 mg



Methocel E10M
  40 mg



Carbopol 974P
  20 mg



Emerald Green Lake
   4 mg



Magnesium Stearate
 6.8 mg









Bi-Layered Tablets (Sustained Release and Immediate Release)











Immediate release layer










Formulation II
Formulation III


Components
Weight per Tablet
Weight per Tablet





Guaifenesin DC
421 mg
630.8 mg


Microcrystalline Cellulose
 40 mg
  353 mg


(Avicel)




Sodium Starch Glycolate
 60 mg
 90.1 mg


(Explotab)




Magnesium Stearate
 2 mg
   3 mg



















Sustained release layer












Formulation II
Formulation III



Components
Weight per Tablet
Weight per Tablet






Guaifenesin DC
 842 mg
630.8 mg



Methocel E10M
  27 mg
  40 mg



Carbopol 974P
13.5 mg
  20 mg



Emerald Green Lake
  3 mg
   4 mg



Magnesium Stearate
 4.5 mg
 6.8 mg









The in vivo behavior of each of the three sustained release tablets and a commercial immediate release formulation (Organidin NR) were compared. The open-label study involved 15 healthy volunteers averaging 31.67±11.89 years of age with a range of 20 years to 51 years of age. The subjects weighed 162.00±25.05 lbs. with a range of 123 to 212 lbs. All 15 subjects were administered 400 mg of the immediate release formulation every 4 hours for a total of 12 hours in on one day. On another day, 5 subjects were administered Sustained Formulation I, another 5 subjects were administered Sustained Formulation II, and yet another 5 subjects were administered Sustained Formulation III.
The results of the pharmacokinetic parameters analysis are described below and depicted in FIG. 7.




















AUC0-12






Tmax
Cmax
(hr-
T1/2
AUCinf



Formulation
(hr.)
(ng/mL)
ng/mL)
(hrs.)
(hr-ng/mL)







Mean
Organidin NR
0.90
2609.40
8768.40
1.28
9082.78


Mean
Formulation I
2.30
1631.40
5549.30
2.88
6044.93


Mean
Formulation II
2.30
2415.40
7304.38
1.48
7509.78


Mean
Formulation III
1.95
2938.00
8904.62
2.05
9161.03









Sustained Formulations II and III exhibited a Cmax more comparable to the immediate release formulation and an increased AUCinf from that of the non-layered Sustained Formulation I. The half-lives of both Sustained Formulation II and III were reduced from the half-life of Sustained Formulation I. These bi-layer tablets, however, showed an improved serum concentration of guaifenesin and an increased overall concentration with time.
Example 5
A dissolution study was run to compare dissolution profiles of Formulation I, Formulation II and Formulation III prepared as defined in Example 4 above, and Formulation IV, a bi-layer tablet lot with 200 mg IR and 1000 mg SR prepared with the following composition:










Immediate release layer











Formulation IV



Components
Weight per Tablet






Guaifenesin DC
211 mg



Microcrystalline Cellulose
118 mg



(Avicel)




Sodium Starch Glycolate
 30 mg



(Explotab)




Magnesium Stearate
 1 mg



















Sustained release layer











Formulation IV



Components
Weight per Tablet






Guaifenesin DC
 1053 mg 



Methocel E10M
 25 mg



Carbopol 974P
12.5 mg 



Emerald Green Lake
3.3 mg



Magnesium Stearate
5.7 mg









The following is a summary of the results which are also depicted in FIG. 8.



















Formulation



Formulation I
Formulation II
Formulation III
IV



% released
% released
% released
% released



















1 hr.
22
45
38
29


2 hr.
34
54
46
38


4 hr.
43
65
56
48


6 hr.
50
70
61
53


8 hr.
58
73
66
60


10 hr. 
62
78
70
66


12 hr. 
66
81
75
71









Formulation I, the non bi-layered tablet, demonstrated the slowest release of guaifenesin. Formulation II and Formulation III had the fastest rates of release and would, therefore, exhibit a faster rate of release and thus a shorter lived therapeutic effect in vivo. Formulation IV has a rate of release which was faster than Formulation I, comprising no immediate release blend, but slower than Formulation II and Formulation III, both comprising more immediate release blend than Formulation IV.
Example 6
The in vivo behavior of Formulation IV bi-layered tablets, prepared as described above in Example 5, was compared to an immediate release formulation (Organidin NR). The open-label, multiple dose, randomized, 2-way crossover study involved 26 healthy volunteers averaging 31.31±9.81 years of age with a range of 19 years to 50 years of age. The subjects weighed 166.77±29.83 lbs. The subjects were placed into one of two treatment groups. Group 1 received Formulation IV tablet with 240 mL of water after an overnight fast every 12 hours for 5 days and a single dose on day 6. Group 2 received 400 mg of Organidin NR (2×200 mg tablets) with 240 mL of water every 4 hours for 5 days and one 400 mg dose every four hours for a total of 3 doses on day 6.
Blood samples (5 mL with sodium heparin as anticoagulant) were taken prior to dosing on days 1, 4, 5, and 6. On Day 1, additional blood samples (5 mL with sodium heparin as anticoagulant) were also obtained at 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10. 11, and 12 hours after the initial dose. On Day 6, additional blood samples (5 mL with sodium heparin as anticoagulant) were also obtained at 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 4.75, 5, 5.5, 6, 7, 8, 8.5, 8.75, 9, 9.5, 10, 11, 12, 14, 16, and 24 hours after the initial dose.
The results of the pharmacokinetic parameters analysis are below.










Averaged Testing - 11 Twelve-Hour Intervals

















AUC0-12






Tmax
Cmax
(hr-
T1/2
AUCinf



Formulation
(hr.)
(ng/mL)
ng/mL)
(hrs.)
(hr-ng/mL)





Mean
Organidin NR
1.69
2463.20
8381.93
0.78
8528.51


Mean
Formulation IV
1.05
2111.38
7875.68
3.31
8686.08









The results of the testing are depicted in FIG. 9.











Steady State Testing

















AUC0-12






Tmax
Cmax
(hr-
T1/2
AUCinf



Formulation
(hr.)
(ng/mL)
ng/mL)
(hrs.)
(hr-ng/mL)





Mean
Organidin NR
2.03
2278.20
7751.23
0.88
7962.14


Mean
Formulation IV
0.86
2349.6
8202.47
3.61
9259.24









The results of the testing are depicted in FIG. 10.
The 200/1000 mg bi-layered tablet exhibited a Cmax and a AUCinf equivalent to that of the immediate release blend, a short Tmax and an extended half-life. Thus, a bi-layered tablet with 200 mg guaifenesin in the immediate release formulation and 1000 mg of guaifenesin in the sustained release formulation results in a tablet which delivers a high serum concentration in a short period of time, yet maintains an effective concentration of guaifenesin in the blood stream for a full twelve hours.
Example 7
A study was performed to examine the relative bioavailability of two different dosage strengths of modified release guaifenesin formulations of the invention as well as the effect of food on the relative bioavailability of a guaifenesin formulation of the invention in normal, healthy male and/or female volunteers. Two batches of guaifenesin bi-layer tablets, one 600 mg and one 1200 mg, were prepared.










Immediate release layer










600 mg Tablet
1200 mg Tablet



Weight per
Weight per


Components
200,000 Tablets
100,000 Tablets





Guaifenesin DC
21.05 kg
21.05 kg


Microcrystalline Cellulose
11.75 kg
11.75 kg


(Avicel PH102)




Sodium Starch Glycolate
 3.00 kg
 3.00 kg


(Explotab)




Magnesium Stearate
 0.10 kg
 0.10 kg



















Sustained release layer










600 mg Tablet
1200 mg Tablet



Weight per
Weight per


Components
200,000 Tablets
100,000 Tablets





Guaifenesin DC
105.27 kg 
105.27 kg 


Hydroxypropyl Methyl
2.50 kg
2.50 kg


Cellulose (Methocel E10M)




Carbomer (Carbopol 974P)
1.25 kg
1.25 kg


FD&C Blue No. 1
0.33 kg
0.33 kg


Aluminum Lake Dye




Magnesium Stearate
0.57 kg
0.57 kg









The 600 mg and 1200 mg tablets were similarly prepared, the with the exception of the number of tablets produced from the amount of materials used.
The in vivo behaviors of a 600 mg tablet administered to volunteers in the fasting state (about 10 hours pre-dose until about 4 hours after dosing), the 1200 mg tablet administered to volunteers in the fasting state (about 10 hours pre-dose until about 4 hours after dosing), and the 1200 mg tablet administered to volunteers after a high fat meal (consumed within 30 minutes of dosing) were compared. The open-label study involved 27 healthy volunteers between the ages of 18 and 55. The 27 volunteers were divided into 3 treatment groups, 9 receiving the 600 mg tablet, 9 receiving the 1200 mg tablet while fasting, and 9 receiving a 1200 mg tablet after consuming a high fat meal for Period 1 of the trial. After completion of Period 1, the volunteers were crossed-over for Period 2 (e.g. so that the 9 volunteers who had been receiving the 600 mg tablet in Period 1 received the 1200 mg tablet while fasting in Period 2). After completion of Period 2, the volunteers were crossed-over again into their 3rd and final treatment group (i.e. the 9 volunteers who received the 1200 mg tablet while fasting in Period 2 and the 600 mg tablet while fasting in Period 1 received the 1200 mg tablet after consumption of a high fat meal in Period 3). Each volunteer was administered one dose of the appropriate tablet and then monitored over a 16 hour period.
Blood samples were taken about one hour prior to dosing and at specific intervals up to 16 hours after dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 hours). The results of the pharmacokinetic parameters analysis are described below and in FIG. 11.




















AUC0-12

AUCinf




Tmax
Cmax
(hr-
T1/2
(hr-



Formulation
(hr.)
(ng/mL)
ng/mL)
(hrs.)
ng/mL)







Mean
 600 mg Fasted
0.81
1074.26
3623.03
2.33
3676.23


Mean
1200 mg Fasted
0.94
1948.62
7483.20
3.33
7912.61


Mean
1200 mg Fed
2.18
1988.08
7424.20
0.91
7425.29









The 600 mg tablet demonstrated a serum profile approximately directly proportional to the serum profile of the 1200 mg tablet. The Cmax of the 600 mg tablet was about 55% that of the 1200 mg tablet. The AUC0-12 of the 600 mg tablet was about 48% that of the 1200 mg tablet and the AUCinf of the 600 mg tablet was about 46% that of the 1200 mg. improved serum concentration of guaifenesin and an increased overall concentration with time, their half-life was compromised.
The 1200 mg tablet demonstrated that the bi-layer tablets of the invention greatly reduce the food effect in bioavailability and serum concentration of guaifenesin. The Cmax of the 1200 mg tablet administered after a high fat meal (fed tablet) was about 102% of the Cmax of the 1200 mg tablet administered after fasting (fasted tablet). The AUCO0-12 of the 1200 mg fed tablet was about 99% that of the fasted tablet and the AUCinf of the 1200 mg fed tablet was about 94% that of the fasted tablet.
Example 8
In an example of a combination drug formulation, two batches of guaifenesin/dextromethorphan HBr bi-layer tablets were prepared: i) 600 mg/30 mg dextromethorphan and ii) 1200 mg/60 mg. In the 30 mg dextromethorphan tablet 7.5 mg was within the immediate release layer and 22.5 mg within the sustained release layer. The 60 mg dextromethorphan tablet comprised double the dextromethorphan respectively.










Sustained release layer










600 mg/30 mg
1200 mg/60 mg



Weight per 200,000
Weight per 100,000


Components
tablets (kg)
tablets (kg)












Guaifenesin, USP
101.00
101.00


Dextromethorphan HBr
4.50
4.50


Carbopol 974P, NF
1.50
5.00


Microcrystalline Cellulose
5.00
1.50


(Methocel E10M)




D&C Yellow No. 10
0.04
0.04


Aluminum Lake (14-18%)




Magnesium Stearate
1.00
1.0



















Immediate release layer










600 mg/30 mg
1200 mg/60 mg



Weight per 480,000
Weight per 240,000


Components
tablets (kg)
tablets (kg)












Guaifenesin, USP
45.60
45.60


Dextromethorphan HBr
3.60
3.60


Sodium Starch Glycolate,
3.60
3.60


NF (Explotab)




Microcrystalline Cellulose
40.32
40.32


(Avicel PH102)




Methocel E10M, USP
2.40
2.40


Magnesium Stearate, NF
0.48
0.48









The following is a summary of 1200 mg guaifenesin/60 mg dextromethorphan HBr Dissolution Rate for three different batches also depicted in FIG. 12.














PB01-H30 (clinical batch)
PB01-H43
PB01-H44



% released
% released
% released


















1 hr
46
47
47


2 hr
59
60
61


6 hr
73
74
76


12 hr 
86
87
89









The in vivo behavior of the 1200 mg guaifenesin, dextromethorphan HBr, studied by measuring the plasma concentration of guaifenesin, dextromethorphan HBr, and the metabolite dextrorphan. FIGS. 13-15 illustrate the plasma concentration for each drug or metabolite in two formulations, Formulation B and Formulation C, during a 24 hour period. Immediately after administration the plasma concentration of guaifenesin peaks in about an hour, followed by a gradual plasma concentration decrease over 24 hours. Immediately after administration, guaifenesin plasma concentration never decreased to less than 200 ng/mL over 12 hours. Thereafter, guaifenesin plasma concentration gradually decreased over the next 12 hours. Plasma concentration of dextromethorphan HBr peaks at about 6 hours at about 12 ng/mL and the concentration is maintained for the following 19 hours.
Formulations B and C of FIG. 13, exhibited guaifenesin release profiles similar to the reference formulation. The reference formulation for FIG. 13 was Formulation IV of Example 5. Formulation B comprised 77% guaifenesin by weight, 3.8% by weight dextromethorphan, 9.1% by weight microcrystalline cellulose, 1.9% by weight Methocel E10M, and 0.9% Carbopol® 974P. Formulation C comprised 76.5% by weight guaifenesin, 3.8% by weight dextromethorphan, 9.7% by weight microcrystalline cellulose, 1.9% by weight Methocel E10M, and 0.9% by weight Carbopol® 974P. Formulations B and C exhibited similar behavior and had a guaifenesin release profile similar to the reference formulation. Accordingly, the combination formulations of the invention did not interfere with the release of guaifenesin. In particular, after 12 hours Formulation C released a greater dose of guaifenesin than the reference formulation.
Formulations B and C of FIG. 13 were compared against a reference consisting of an extended release formulation of dextromethorphan commercially available under the name Delsym sold by Celltech. The comparison was carried out to determine the behavior of guaifenesin-dextromethorphan formulations of the invention as compared to separately administered combination formulations of dextromethorphan. Formulations B and C had longer dextromethorphan release profiles than the reference, as shown in FIG. 14. Additionally, the combined formulations of the inventions had no detrimental effect upon the release profile of dextromethorphan.
Another method to monitor dextromethorphan plasma concentrations is to measure the plasma concentration of the metabolite dextrorphan. The plasma concentration of dextrorphan metabolite of the reference formulation and Formulations B and C of FIG. 14 were plotted in FIG. 15. Generally, the formulations exhibited similar dextrorphan concentrations, with Formula C exhibiting the highest dextrorphan concentration after 12 hours. FIG. 15 demonstrates that the formulations of the invention containing guaifenesin do not inhibit the release of dextromethorphan, as determined by measuring the presence of the metabolite dextrorphan.
Example 9
A study was performed to examine the relative bioavailability of a sustained release guaifenesin with dextromethorphan formulation of the invention with normal, healthy male and/or female volunteers. A batch of guaifenesin and dextromethorphan bi-layer tablet, 1200 mg, was prepared according to the composition described above for Example 8.
The in vivo behaviors of the 1200 mg tablet administered to volunteers in the fasting state (about 10 hours pre-dose until about 4 hours after dosing) was determined. The open-label study involved 29 healthy volunteers between the ages of 18 and 55. The 29 volunteers were divided into two treatment groups half receiving the 1200 mg tablet while fasting for Period 1 of the trial. Each volunteer was administered one dose of the appropriate tablet and then monitored over a 16 hour period.
Blood samples (7 mL with sodium heparin as anticoagulant) were taken about one hour prior to dosing and at specific intervals up to 16 hours after dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 hours). The results of the pharmacokinetic parameters analysis for guaifenesin include a Tmax of 1.48 hr, Cmax (ng/mL) of 2196, AUC0-12 (hr-ng/mL) of 8702, T1/2 of 1.32 hrs., and an AUCinf (hr-ng/mL) of 8732.5. The results of the pharmacokinetic parameters analysis for dextromethorphan include a Tmax of 5.0 hrs, Cmax (pg/mL) of 5157, AUCO0-12 (hr-pg/mL) of 74209, T1/2 of 7.93 hrs., and an AUCinf (hr-pg/mL) of 75016.
Example 10
In another example of a combination formulation, two batches of guaifenesin-pseudoephedrine HCl bi-layer tablets, one 600 mg and one 1200 mg, were prepared in the following amounts.










Sustained release layer










600 mg/60 mg
1200 mg/120 mg



Weight per
Weight per



300,000 tablets
150,000 tablets


Components
(kg)
(kg)












Guaifenesin DC (95%)
157.90
157.89


Pseudoephedrine HCl
18.0
18.00


Hydroxypropyl
4.50
4.50


Methylcellulose (Methocel




E10M)




Carbopol 974P, NF
2.25
2.25


FD&C Yellow No. 6
0.24
0.06


Aluminum Lake (15-18%)




Magnesium Stearate
1.50
1.50



















Immediate release layer










600 mg/60 mg
1200 mg/120 mg



Weight per 300,000
Weight per 150,000


Components
tablets (kg)
tablets (kg)












Guaifenesin DC (95%)
39.476
39.476


Microcrystalline Cellulose
22.028
22.028


(Avicel PH102)




Sodium Starch Glycolate
5.626
5.626


Magnesium Stearate, NF
0.188
0.188









The following is a summary of 1200 mg guaifenesin/120 mg pseudoephedrine dissolution rates also depicted in FIG. 16.














PB01-M65





(clinical batch)
PB01-M68
PB01-M71



% released
% released
% released




















1 hr
45
44
43



2 hr
60
59
58



6 hr
89
87
82



12 hr 
97
98
96









The in vivo behavior of the 1200 mg guaifenesin and 120 mg pseudoephedrine tablet was studied by measuring the plasma concentration of guaifenesin, and pseudoephedrine HCl. The three batches of the 1200 mg guaifenesin/120 mg pseudoephedrine HCl formulation were dissolved to determine the amount of pseudoephedrine HCl released over time. Generally, the formulations had 1200 mg of guaifenesin and 120 mg pseudoephedrine HCl and were studied over a 12 hour period. The released amount of pseudoephedrine HCl was determined as a weight percent of dissolved pseudoephedrine HCl in contrast to the total weight of pseudoephedrine HCl prior to dissolution. After 1 hour about 43% to 45% of the pseudoephedrine HCl had dissolved. After 2 hours the about 58% to 60% dissolved, after 6 hours 82% to 89% had dissolved, and after 12 hours about 96% to 97% by weight of the pseudoephedrine HCl had dissolved. (See FIG. 16).
Three formulations of guaifenesin, two containing an additional drug, pseudoephedrine, were compared to determine whether an additional drug affects the release profile of guaifenesin. FIGS. 17-18 illustrate the plasma concentration for each drug (Formulation B and Formulation C) during a 24 hour period. Immediately after administration the plasma concentration of guaifenesin peaks in about an hour, followed by a gradual plasma concentration decrease over 24 hours. Immediately after administration, guaifenesin plasma concentration never decreased below 200 ng/mL over 12 hours. Thereafter, guaifenesin plasma concentration gradually decreased over the next 12 hours. Plasma concentration of pseudoephedrine HCl peaked at about 6 hours and gradually decreased over the next 18 hours. The plasma concentration of pseudoephedrine HCl never decreased to less than 50 ng/mL after 30 minutes of administration.
In FIG. 17, the reference formulation included formulation IV of Example 5 and a separate Sudafed® 12 hour formulation available from Pfizer Inc. 201 Tabor Road, Morris Plains, N.J., 07950. The reference formulation was compared to Formulation B and Formulation C of the invention. Formulation B comprised a sustained release formulation having 86% by weight Guaifenesin DC, 9.8% by weight pseudoephedrine HCl, 2.4% by weight hydroxypropyl methylcellulose, and 1.2% by weight Carbopol® 974P, and an immediate release formulation having 52% by weight Guaifenesin DC and 39% by weight microcrystalline cellulose by weight. Formulation C comprised 77% by weight Guaifenesin DC, 7.7% by weight pseudoephedrine, 9% by weight microcrystalline cellulose, 1.8% by weight Methocel E10M, and 0.9% by weight Carbopol® 974P. Formulations B and C exhibited similar behavior to separately administered formulations, thus demonstrating that formulations of the invention did not interfere with the profile release of pseudoephedrine.
The plasma concentration for pseudoephedrine HCl was studied to determine whether the formulations of the invention interfered with the release profile of pseudoephedrine. The pseudoephedrine plasma concentrations for the formulations of FIG. 17 were plotted over a 24 hour period. As illustrated in FIG. 18, Formulations B and C of FIG. 17 exhibited higher pseudoephedrine concentrations than the reference formulation. Thus, the combined formulations of the invention release pseudoephedrine in comparable or better release profiles than formulations containing pseudoephedrine alone.
Example 11
A study was performed to examine the relative bioavailability of sustained release guaifenesin with pseudoephedrine formulations of the invention in normal, volunteers. A batch of guaifenesin and pseudoephedrine bi-layer tablets, 1200 mg, was prepared according to the composition described above for Example 10.
The in vivo behaviors of a 1200 mg tablet administered to volunteers in the fasting state (about 10 hours pre-dose until about 4 hours after dosing) were compared. The open-label study involved 29 healthy volunteers between the ages of 18 and 55. The 29 volunteers were divided into two treatment groups, half receiving the 1200 mg tablet while fasting for Period 1 of the trial. Each volunteer was administered one dose of the appropriate tablet and then monitored over a 16 hour period.
Blood samples (7 mL with sodium heparin as anticoagulant) were taken about one hour prior to dosing and at specific intervals up to 16 hours after dosing (at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 hours). The results of the pharmacokinetic parameters analysis for guaifenesin include a Tmax of 1.48 hr, Cmax (ng/mL) of 2196, AUC0-12 (hr-ng/mL) of 8702, T1/2 of 1.32 hrs., and an AUCinf (hr-ng/mL) of 8732.5. The results of the pharmacokinetic parameters analysis for pseudoephedrine include a Tmax of 6 hrs, Cmax (ng/mL) of 300, AUC0-12 (hr-ng/mL) of 4201, T1/2 of 5.98 hrs., and an AUCinf (hr-ng/mL) of 4709.
Example 12
Guaifenesin and pseudoephedrine sustained release formulations were compared to commercial controlled release guaifenesin and pseudoephedrine products in healthy volunteers in an open label, single dose, randomized, 3-way crossover study in 15 subjects.
The subjects were randomized and placed into one of three treatment groups. Group A was given Formulation A, one 1200 mg controlled release guaifenesin product (Mucinex) plus a 120 mg controlled release pseudoephedrine hydrochloride product (Sudafed-12 Hour) with 240 mL of water after an overnight fast. Group B received Formulation B (lot PB01-K61), an experimental controlled release tablet containing 1200 mg guaifenesin and 120 mg of pseudoephedrine hydrochloride with 240 mL of water after an overnight fast. Group C received Formulation C (lotCB00-01A), another experimental controlled release tablet containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water after an overnight fast. There was at least a 7-day washout between doses.
The volunteers averaged 26.4±10.57 years of age (Mean±Standard Deviation) with a range of 18 years to 50 years of age. They were 66.93±4.37 inches tall with a range of 60 to 74 inches. They weighed 160.87±26.22 pounds with a range of 118 to 222 pounds. Seven were male (47%) and eight female (53%). Ten (67%) of the subjects had a large frame size, three (20%) had a medium frame and two (13%) had a small frame. Thirteen volunteers (87%) were Caucasian and two (13%) were Multiracial. Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose.
Subjects given 1200 mg of guaifenesin as guaifenesin ER (reference) reached a Cmax of 1847 ng/mL in 0.78 hours and had an AUCinf of 7302 hr-ng/mL. Subjects given 1200 mg guaifenesin as Formulation B reached a Cmax of 1784 ng/mL (103% of that of the reference) in 0.82 hour (113% of that of the reference) and had an AUCinf of 7602 hr-ng/mL (109% of that of the reference). Subjects given 1200 mg guaifenesin as Formulation C reached a Cmax of 1154 ng/mL (65% of that of the reference) in 1.22 hours (179% of that of the reference) and had an AUCinf of 7128 hr-ng/mL (100% of that of the reference).
Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed-12 Hour (reference) reached a Cmax of 300 ng/mL (mean±standard deviation) in 6 hours and had an AUCinf of 4710 hr-ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as Formulation B reached a Cmax of 285 ng/mL (99% of that of the reference) in 6 hours (101% of that of the reference) and had an AUCinf of 4449 hr-ng/mL (100% of that of the reference). Subjects given 120 mg pseudoephedrine hydrochloride as Formulation C reached a Cmax of 256 ng/mL (86% of that of the reference) in 8 hours (151% of that of the reference) and had an AUCinf of 4444 hr-ng/mL (97% of that of the reference).
The plasma concentrations of guaifenesin are depicted in FIG. 19. The resulting pharmacokinetic data is shown in Tables 1 through 4. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex were 1847±686.6 ng/mL and occurred in 0.78±0.28 hours. The resulting area under the plasma concentration vs. time curve (AUCinf was 7302±2866.4 hr-ng/mL. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Formulation B were 1784±549.9 ng/mL (102.93%±36.57% of that of the reference formulation) and occurred in 0.82±0.27 hours (112.78%±43.29% that of the reference formulation). The resulting AUCinf was 7602±2492.8 hr-ng/mL (108.67%±23.93% of that of the reference formulation). The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Formulation C were 1154±523.3 ng/mL (64.56%±28.03% of that of the reference formulation) and occurred in 1.22±0.45 hours (178.9%±100.64% that of the reference formulation). The resulting AUCinf was 7128±3166.0 hr ng/mL(99.81%±34.23% of that of the reference formulation).







TABLE 1







Guaifenesin Pharmacokinetic Variables Following


the Administration of 1200 mg Guaifenesin as


Mucinex along with Sudafed 12 Hour to Normal Volunteers
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1847
0.78
7143
7302
3.60
188.98


Median
1530
0.75
5776
5863
3.21
204.68


Standard
686.63
0.28
2793.41
2866.39
2.05
74.55


Deviation








Standard
183.51
0.08
746.57
766.08
0.55
19.92


Error








% CV
37.18
35.92
39.11
39.26
56.94
39.45


Maximum
1847
0.78
7143
7302
3.60
188.98


Minimum
1530
0.75
5776
5863
3.21
204.68
















TABLE 2







Guaifenesin Pharmacokinetic Variables Following


the Administration of 1200 mg Guaifenesin and 120 mg


Pseudoephedrine Hydrochloride as Formulation B to


Normal Volunteers
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1784
0.82
7557
7602
1.59
172.56


Median
1730
0.75
7297
7349
1.35
163.30


Standard
549.90
0.27
2487.33
2492.75
0.59
49.49


Deviation








Standard
146.97
0.07
664.77
666.22
0.16
13.23


Error








% CV
30.82
33.67
32.91
32.79
37.09
28.68


Maximum
1800
0.75
5818
5842
1.35
205.42


Minimum
1120
0.5
4952
4979
1.14
241.01
















TABLE 3







Guaifenesin Pharmacokinetic Variables Following


the Administration of 1200 mg Guaifenesin and 120 mg


Pseudoephedrine Hydrochloride as Formulation C to


Normal Volunteers
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1154
1.22
6989
7128
2.40
202.57


Median
1050
1.00
6291
6314
2.38
190.05


Standard
523.29
0.45
3078.23
3165.98
1.06
89.63


Deviation








Standard
139.86
0.12
822.69
846.14
0.28
23.96


Error








% CV
45.35
37.14
44.04
44.41
44.30
44.25


Maximum
612
0.75
3157
3205
1.25
374.38


Minimum
781
0.75
4902
4949
2.49
242.46
















TABLE 4







Ratio of Guaifenesin Pharmacokinetic Variables Following


the Administration of 1200 mg Guaifenesin and 120 mg


Pseudoephedrine Hydrochloride as Formulation B


Compared to that of the Reference Formulation to


Normal Volunteers (%)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
102.93
112.78
110.31
108.67
66.51
95.42


Median
90.59
100.00
102.28
100.45
50.76
99.55


Standard
36.57
43.29
23.94
23.93
65.61
16.90


Deviation








Standard
9.77
11.57
6.40
6.40
17.53
4.52


Error








% CV
35.53
38.38
21.70
22.02
98.64
17.72


Maximum
165.14
75
122.87
121.60
83.97
82.24


Minimum
80
50
87.60
84.93
17.70
117.75









The plasma concentrations of pseudoephedrine are depicted in FIG. 20. The resulting pharmacokinetic data is shown in Tables 5 through 9. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed-12 Hour (reference) were 300.3±91.44 ng/mL and occurred in 6±1.69 hours. The resulting AUCinf was 4710±1394.5 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Formulation B were 285.3±53.28 ng/mL (99.3 1%±20.39% of that of the reference formulation) and occurred in 5.80±2.40 hours (101.11%±41.77% of that of the reference formulation). The resulting AUCinf was 4449±1079.6 hr-ng/mL (99.87%±26.40% of that of the reference formulation). The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Formulation C were 256.4±80.7 ng/mL (86.37%±14.38% of that of the reference formulation) and occurred in 8.27±2.71 hours (5 1.11%±73.25% of that of the reference formulation). The resulting AUCinf was 4444±1212.1 hr-ng/mL (96.78%±17.90% of that of the reference formulation).







TABLE 5







Pseudoephedrine Pharmacokinetic Variables Following


the Administration of 120 mg Pseudoephedrine


Hydrochloride as Sudafed-12 Hour along with 1200 mg


Guaifenesin as Mucinex to Normal Volunteers
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
300.27
6.00
4201.62
4709.88
5.98
22.93


Median
287.00
6.00
4042.53
4601.31
5.19
21.37


Standard
91.44
1.69
1182.92
1394.49
1.68
7.77


Deviation








Standard
24.44
0.45
316.15
372.69
0.45
2.08


Error








% CV
30.45
28.17
28.15
29.61
28.01
33.87


Maximum
523
8
6518.45
7137.33
10.18
38.94


Minimum
183
4
2419.97
2524.37
4.29
13.77
















TABLE 6







Pseudoephedrine Pharmacokinetic Variables Following


the Administration of 120 mg Pseudoephedrine


Hydrochloride and 1200 mg Guaifenesin as


Formulation B to Normal Volunteers
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
285.33
5.80
4080.27
4448.85
5.40
23.41


Median
269.00
6.00
3985.05
4463.18
5.21
22.03


Standard
53.28
2.40
946.92
1079.61
1.01
6.06


Deviation








Standard
14.24
0.64
253.07
288.54
0.27
1.62


Error








% CV
18.67
41.32
23.21
24.27
18.64
25.88


Maximum
387
10
6003.14
6799.07
7.44
37.40


Minimum
215
2
2381.18
2628.19
3.85
14.46
















TABLE 7







Pseudoephedrine Pharmacokinetic Variables Following


the Administration of 120 mg Pseudoephedrine


Hydrochloride and 1200 mg Guaifenesin


as Formulation C to Normal Volunteers
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
256.40
8.27
4008.32
4444.09
5.39
23.85


Median
226.00
10.00
3888.93
4266.92
5.15
23.04


Standard
80.71
2.71
1084.90
1212.13
1.10
7.16


Deviation








Standard
21.57
0.72
289.95
323.96
0.29
1.91


Error








% CV
31.48
32.80
27.07
27.28
20.41
30.03


Maximum
448
10
6200.18
6756.67
8.66
40.05


Minimum
162
2
2360.01
2454.79
4.09
14.55
















TABLE 8







Ratio of Pseudoephedrine Pharmacokinetic Variables


Following the Administration of 120 mg Pseudoephedrine


Hydrochloride and 1200 mg Guaifenesin as Formulation B


Compared to that of the Reference Formulation to


Normal Volunteers (%)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
99.31
101.11
101.58
99.87
93.38
109.24


Median
94.74
100.00
104.95
101.63
90.66
98.40


Standard
20.39
41.77
24.96
26.40
17.54
40.60


Deviation








Standard
5.45
11.16
6.67
7.06
4.69
10.85


Error








% CV
20.53
41.31
24.57
26.44
18.79
37.13


Maximum
140.40
200
139.07
144.72
120.84
234.43


Minimum
65.97
25
50.46
42.66
60.12
69.10
















TABLE 9







Ratio of Pseudoephedrine Pharmacokinetic Variables


Following the Administration of 120 mg Pseudoephedrine


Hydrochloride and 1200 mg Guaifenesin as Formulation C


Compared to that of the Reference Formulation to


Normal Volunteers (%)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
86.37
151.11
96.79
96.78
93.98
107.04


Median
85.66
133.33
98.75
99.37
96.77
100.63


Standard
14.38
73.25
14.24
17.90
21.06
22.01


Deviation








Standard
3.84
19.58
3.80
4.78
5.63
5.88


Error








% CV
16.65
48.48
14.71
18.49
22.41
20.56


Maximum
115.30
250
126.82
132.10
129.45
153.94


Minimum
62.60
50
75.98
64.96
51.20
75.70









The data indicates that both formulations produce optimum guaifenesin bioavailability (although Formulation B appears to more closely match the reference) and Formulation B produces optimal pseudoephedrine bioavailability.
Example 13
The bioavailability of a sustained release combination formulation of 1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride was used to examine the dose proportionality of Pseudoephedrine normal volunteers compared to reference guaifenesin and Pseudoephedrine Hydrochloride in an open label, single dose, randomized, 3-way crossover study with 36 subjects. The example also demonstrates the dose proportionality of pseudoephedrine.
The subjects were randomized and placed into one of three treatment groups. Group I received Treatment A, a 1200 controlled release guaifenesin product (Mucinex) plus a 120 mg controlled release pseudoephedrine product (Sudafed® 12 Hour) with 240 mL of water after an overnight fast (Reference). Group 2 received Treatment B(PB01-M65A2), an experimental controlled release formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water after an overnight fast (test). Group 3 received Treatment C(PB01-A12A), an experimental controlled release formulation containing 600 mg guaifenesin and 60 mg pseudoephedrine with 240 mL of water after an overnight fast.
The volunteers averaged 23.06±7.05 years of age (Mean±Standard Deviation) with a range of 18 years to 48 years of age. They were 70.58±3.08 inches tall with a range of 64 to 75 inches. They weighed 167.42±26.14 pounds with a range of 114 to 229 pounds. Twenty-four were male (67%) and twelve female (33%). Sixteen (44%) of the subjects had a large frame size, thirteen (36%) had a medium frame and seven (19%) had a small frame. Thirty-two volunteers (89%) were Caucasian, three (8%) were Black and one (3%) Multiracial. Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose (the total blood loss for guaifenesin and pseudoephedrine analysis will be 450 mL).
Subjects given 1200 mg of guaifenesin as Mucinex and 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour (Treatment A, Reference) reached a Cmax of 1940 ng/mL in 0.77 hours and had an AUCinf of 8061 hr-ng/mL. Subjects given 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride as Treatment B (Test) reached a Cmax of 1813 ng/mL (98% of that of the reference) in 1.04 hour (140% of that of the reference) and had an AUC0-∞ of 8124 hr ng/mL (101% of that of the reference). Subjects given 600 mg guaifenesin and 60 mg pseudoephedrine hydrochloride as Treatment C reached a Cmax of 920 ng/mL (54% of that of the reference) in 0.99 hours (116% of that of the reference) and had an AUCinf of 3565 hr-ng/mL (46% of that of the reference).
Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour and 1200 mg guaifenesin as Mucinex (Treatment A, Reference) reached a mean Cmax of 250 ng/mL in 6 hours and had an AUCinf of 3847 hr-ng/mL. Subjects given 120 mg pseudoephedrine and 1200 mg guaifenesin as an experimental formulation (Treatment B, Test) reached a of 263 ng/mL (107% of that of the reference) in 5 hours (85% of that of the reference) and had an AUCinf of 3884 hr-ng/mL (103% of that of the reference). Subjects given 60 mg pseudoephedrine hydrochloride and 600 mg guaifenesin in an experimental formulation (Treatment C) reached a Cmax of 141 ng/mL (54% of that of Formulation B) in 5 hours (100% of that of Formulation B) and had an AUCinf of 1968 hr-ng/mL (50% of that of Formulation B).
Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre-dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose. Bioequivalence was examined between the test (Treatment B—guaifenesin or pseudoephedrine hydrochloride experimental formulation) and the reference (Treatment A—guaifenesin or pseudoephedrine hydrochloride reference formulations) groups. The dose response relationship was also examined between the test (Treatment B—guaifenesin or pseudoephedrine hydrochloride experimental formulation) and the reference (Treatment C—guaifenesin or pseudoephedrine hydrochloride reference formulations) groups.
The plasma concentrations of guaifenesin is depicted in FIG. 21. The resulting pharmacokinetic data is shown in Tables 10 through 14. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex and 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour were 1940±889 ng/mL and occurred in 0.77±0.22 hours. The resulting area under the plasma concentration vs. time curve (AUCinf was 8061±3329 hr-ng/mL. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Treatment B were 1813±900 ng/mL (98.1%±35.8% of that of the reference formulation) and occurred in 1.04±0.49 hours (140%±65.3% that of the reference formulation). The resulting AUCinf was 8124±3677 hr-ng/mL (101%±19.3% of that of the reference formulation). The maximum plasma concentrations of guaifenesin following a 600 mg oral dose as Treatment C were 920±481 ng/mL (54.3%±20.2% of that of the reference formulation) and occurred in 0.99±0.46 hours (116%±78.7% that of the reference formulation). The resulting AUCinf was 3565±1442 hr-ng/mL (45.6%±10.2% of that of the reference formulation).







TABLE 10







Guaifenesin Pharmacokinetic Variables Following the


Administration of 1200 mg guaifenesin Mucinex along with


Sudafed 12 Hour to Normal Volunteers (%)
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1847
0.78
7143
7302
3.60
188.98


Median
1530
0.75
5776
5863
3.21
204.68


Standard
686.63
0.28
2793.41
2866.39
2.05
74.55


Deviation








Standard
183.51
0.08
746.57
766.08
0.55
19.92


Error








% CV
37.18
35.92
39.11
39.26
56.94
39.45


Maximum
1847
0.78
7143
7302
3.60
188.98


Minimum
1530
0.75
5776
5863
3.21
204.68
















TABLE 11







Guaifenesin Pharmacokinetic Variables Following the


Administration of 1200 mg guaifenesin and 120 mg


Pseudoephedrine Hydrochloride as an Experimental


Formulation to Normal Volunteers (Treatment B, Test)
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1813
1.04
8002
8124
2.21
175


Median
1530
0.75
7036
7083
1.99
169


Standard
900
0.49
3677
3677
1.19
68.2


Deviation








Standard
154
0.08
631
631
0.20
11.7


Error








% CV
49.6
46.9
45.9
45.3
53.9
38.9
















TABLE 12







Guaifenesin Pharmacokinetic Variables Following the


Administration of 600 mg Guaifenesin and 60 mg


Pseudoephedrine Hydrochloride to Normal Volunteers


(Treatment C)
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
920
0.99
3529
3565
1.76
192


Median
721
0.75
3078
3098
1.47
194


Standard
481
0.46
1437
1442
0.92
66.5


Deviation








Standard
81.3
0.08
243
244
0.16
11.2


Error








% CV
52.3
46.0
40.7
40.4
52.4
34.5
















TABLE 13







Ratio of Guaifenesin Pharmacokinetic Variables Following


the Administration of 1200 mg Guaifenesin and 120 mg


Pseudoephedrine Hydrochloride as Formulation B Compared


to that of the Reference Formulation (Treatment A) to


Normal Volunteers (%)
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
98.1
140
104
101
66.2
103


Median
96.8
133
106
100
53.1
99.5


Standard
35.8
65.3
20.3
19.3
42.0
24.2


Deviation








Standard
6.14
11.2
3.48
3.31
7.20
4.16


Error








% CV
36.5
46.5
19.5
19.1
63.4
23.5
















TABLE 14







Ratio of Guaifenesin Pharmacokinetic Variables Following


the Administration of 600 mg Guaifenesin and 60 mg


Pseudoephedrine Hydrochloride (Treatment C) Compared


to that of (Treatment B) to Normal Volunteers (%)
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
54.3
116
45.9
45.6
97.0
114


Median
48.8
100
43.9
44.0
86.1
114


Standard
20.2
78.7
10.6
10.2
61.6
23.2


Deviation








Standard
3.47
13.50
1.82
1.75
10.57
3.98


Error








% CV
37.3
67.9
23.1
22.4
63.5
20.3









The plasma concentrations of pseudoephedrine are depicted in FIG. 22. The resulting pharmacokinetic data is shown in Tables 15 through 19. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed® 12 Hour and 1200 mg guaifenesin as Mucinex (Treatment A, Reference) were 250±53.4 ng/mL and occurred in 6.29±1.76 hours. The resulting AUCinf was 3847±910 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as an experimental formulation (Treatment B) were 263±58.5 ng/mL (107%±18.9% of that of the reference formulation) and occurred in 5.11±1.78 hours (85.2%±31.5% of that of the reference formulation). The resulting AUCinf was 3884±911 hr-ng/mL (103%±20.2% of that of the reference formulation). The maximum plasma concentrations of pseudoephedrine following a 60 mg oral dose as an experimental formulation (Treatment C) were 141±30.3 ng/mL (53.5%±6.52% of that of Formulation B) and occurred in 4.94±1.60 hours (99.5%±25.9% of that of Formulation B). The resulting AUCinf was 1968±477 hr-ng/mL (50.5%±8.77% of that of Formulation B).







TABLE 15







Pseudoephedrine Pharmacokinetic Parameters Following the


Administration of 120 mg Pseudoephedrine Hydrochloride


as Sudafed ® 12 Hour and 1200 mg Guaifenesin as


Mucinex to Normal Volunteers (Treatment A)
















AUC0-t
AUCinf





Cmax

(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
Tmax (hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
250
6.29
3479
3847
5.75
27.1


Median
252
6
3381
3652
5.42
26.9


Standard
53.4
1.76
805
910
1.02
7.11


Deviation








Standard
9.16
0.30
138
156
0.18
1.22


Error








% CV
21.3
28.0
23.2
23.7
17.8
26.2
















TABLE 16







Pseudoephedrine Pharmacokinetic Following the


Administration 120 mg Pseudoephedrine Hydrochloride


and 1200 mg Guaifenesin in an Experimental


Formulation to Normal Volunteers (Treatment B)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
263
5.11
3591
3884
5.22
26.7


Median
257
4.00
3507
3824
5.19
25.7


Standard
58.5
1.78
824
911
0.89
6.23


Deviation








Standard
10.0
0.31
141
156
0.15
1.07


Error








% CV
22.3
34.8
23.0
23.5
16.9
23.3
















TABLE 17







Pseudoephedrine Pharmacokinetic Parameters Following


the Administration of 60 mg Pseudoephedrine


Hydrochloride and 600 mg Guaifenesin in an Experimental


Formulation to Normal Volunteers (Treatment C)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
141
4.94
1781
1968
5.57
26.5


Median
134
4.00
1696
1855
5.38
26.5


Standard
30.3
1.60
445
477
1.02
6.58


Deviation








Standard
5.12
0.27
75.1
80.6
0.17
1.11


Error








% CV
21.5
32.4
25.0
24.2
18.4
24.9
















TABLE 18







Ratio of the Pseudoephedrine Pharmacokinetic Parameters


Following the Administration of 120 mg Pseudoephedrine


Hydrochloride and 1200 mg Guaifenesin as an Experimental


Formulation (Treatment B) Compared to that Following the


Administration of 120 mg Pseudoephedrine Hydrochloride


as Sudafed ® 12 Hour and 120 mg Guaifenesin


as Mucinex (Treatment A) (%)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
107
85.2
105
103
92.1
101


Median
106
75.0
102
101
93.7
98.7


Standard
18.9
31.5
19.39
20.16
15.19
22.03


Deviation








Standard
3.24
5.41
3.33
3.46
2.61
3.78


Error








% CV
17.7
37.0
18.4
19.5
16.5
21.8
















TABLE 19







Ratio of Pseudoephedrine Pharmacokinetic Parameters


Following the Administration of 60 mg Pseudoephedrine


Hydrochloride and 600 mg Guaifenesin as an Experimental


Formulation (Treatment C) Relative to that Following the


Administration of 120 mg Pseudoephedrine Hydrochloride


and 1200 mg Guaifenesin in an Experimental Formulation


(Treatment B) (%)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
53.5
99.5
49.1
50.5
108
102


Median
52.6
100
46.7
48.0
105
104


Standard
6.52
25.9
7.80
8.77
17.4
16.2


Deviation








Standard
1.12
4.44
1.34
1.50
2.98
2.78


Error








% CV
12.2
26.0
15.9
17.4
16.2
15.9









In conclusion, the experimental formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride is bioequivalent to the reference formulations given is separate doses. In addition the pharmacokinetics of guaifenesin and pseudoephedrine are linear over the range studied.
Example 14
The effects of a high fat meal on the bioavailability of a combination formulation were tested. The bioavailability of a 1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride formulation volunteers was compared to reference drug bioavailability in an open-label, single-dose, randomized, 2-way-crossover study using 36 subjects.
The subjects were randomized and placed into one of two treatment groups. Group 1 received a 1200-mg controlled-release guaifenesin product (Mucinex) and 120 mg pseudoephedrine hydrochloride (Sudafed® 12 Hour) with 240 mL of water, 30 minutes after the beginning of the consumption of a high-fat breakfast (Reference). Group 2 received an experimental formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water, 30 minutes after the beginning of the consumption of a high-fat breakfast (Test)(PB01-M65A3).
Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose (the total blood loss for guaifenesin and pseudoephedrine analysis was 300 mL).
Subjects given 1200 mg of guaifenesin as Mucinex (Reference) reached a Cmax of 2207 ng/mL in 1.85 hours and had an AUCinf of 8067 hr-ng/mL. Subjects given 1200 mg guaifenesin as an experimental formulation (Treatment B) reached a of 1649 ng/mL (79% of that of the Reference) in 1.84 hour (118% of that of the Reference) and had an AUCinf of 7663 hr-ng/mL (93% of that of the Reference).
Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour (Reference) reached a Cmax of 268 ng/mL in 6.38 hours and had an AUCinf of 3636 hr-ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as an experimental formulation (Treatment B) reached a Cmax of 274 ng/mL (103% of that of the Reference) in 4.80 hours (76.5% of that of the Reference) and had an AUCinf of 3528 hr-ng/mL (96.5% of that of the Reference).
Additionally, bioequivalence data was examined between the Test group (Treatment B—1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental formulation) and the Reference group (Treatment A—the reference 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride formulations).
The plasma concentrations of guaifenesin are depicted in FIG. 23. The resulting pharmacokinetic data are shown in Tables 20 through 22. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex were 2207±952 ng/mL and occurred in 1.85±1.06 hours. The resulting area under the plasma concentration vs. time curve (AUCinf was 8067±2663 hr-ng/mL. The maximum plasma concentrations of guaifenesin following a 1200-mg oral dose as an experimental formulation (Treatment B) was 1649±690 ng/mL (79%±31.5% of the Reference formulation) and occurred in 1.84±0.818 hours (118%±68.8% of the Reference formulation). The resulting AUCinf was 7663±2864 hr-ng/mL (93%±17.6% of that of the Reference formulation).







TABLE 20







guaifenesin Pharmacokinetic Parameters Following


the Administration of 1200 mg Guaifenesin as Mucinex


Along with 120 mg Pseudoephedrine Hydrochloride


as Sudafed ® 12 Hour to Normal Volunteers


Following the Consumption of a High-Fat


Meal (Treatment A, Reference)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
2207
1.85
8049
8067
1.22
168


Median
2140
1.50
8160
8196
0.983
146


Standard
952
1.06
2666
2663
0.621
64.4


Deviation








Standard
166
0.184
464
464
0.108
11.2


Error








% CV
43.2
57.2
33.1
33.0
51.1
38.3
















TABLE 21







Guaifenesin Pharmacokinetic Parameters Following


the Administration of 1200 mg Guaifenesin and 120 mg


Pseudoephedrine Hydrochloride in an Experimental


Formulation to Normal Volunteers Following the


Consumption of a High-Fat Meal (Treatment B, Test)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1649
1.84
7611
7663
1.40
181


Median
1580
2.00
7474
7485
1.07
160


Standard
690
0.818
2816
2864
0.793
77.6


Deviation








Standard
118
0.140
483
491
0.136
13.3


Error








% CV
41.9
44.4
37.0
37.4
56.6
42.9
















TABLE 22







Ratio of Guaifenesin Pharmacokinetic Parameters


Following the Administration of 1200 mg Guaifenesin


and 120 mg Pseudoephedrine Hydrochloride in an


Experimental Formulation Compared to those of


Treatment A (Reference) to Normal Volunteers


Following the Consumption of a High-Fat Meal (%)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
79
118
93
93
135
109.9


Median
73
100
91
91
99
109.8


Standard
31.5
68.8
17.5
17.6
97.1
16.8


Deviation








Standard
5.57
12.2
3.09
3.12
17.2
2.96


Error








% CV
39.8
58.3
18.8
18.9
72.0
15.3









The plasma concentrations of pseudoephedrine are depicted in FIG. 24. The resulting pharmacokinetic data are shown in Tables 23 through 25. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed® 12 Hour (Reference) was 268±69.7 ng/mL and occurred in 6.38±1.26 hours. The resulting AUCinf was 3636±940 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as an experimental formulation (Treatment B) was 274±72.3 ng/mL (103%±10.3% of that of the Reference formulation) and occurred in 4.80±1.28 hours (76.5%±23.1% of that of the Reference formulation). The resulting AUCinf was 3528±962 hr-ng/mL (96.5%±11.7% of that of the Reference formulation).







TABLE 23







Pseudoephedrine Pharmacokinetic Parameters Following


the Administration of 120 mg Pseudoephedrine Hydrochloride


as Sudafed ® 12 Hour Along with 1200 mg Guaifenesin


as Mucinex to Normal Volunteers Following the


Consumption of a High-Fat Meal (Treatment A, Reference)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
268
6.38
3362
3636
5.28
28.8


Median
249
6.00
3238
3545
4.97
27.7


Standard
69.7
1.26
847
940
1.08
7.55


Deviation








Standard
12.1
0.219
147
164
0.188
1.31


Error








% CV
26.03
19.67
25.18
25.86
20.42
26.19
















TABLE 24







Pseudoephedrine Pharmacokinetic Parameters Following


the Administration of 120 mg of Pseudoephedrine Hydrochloride


and 1200 mg Guaifenesin in an Experimental Formulation


to Normal Volunteers Following the Consumption of a


High-Fat Meal (Treatment B, Test)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
274
4.80
3273
3528
5.26
30.0


Median
268
4.00
3198
3448
5.31
28.5


Standard
72.3
1.28
876
962
1.02
8.48


Deviation








Standard
12.2
0.216
148
163
0.172
1.43


Error








% CV
26.4
26.6
26.8
27.3
19.4
28.3
















TABLE 25







Ratio of Pseudoephedrine Pharmacokinetic Parameters


Following the Administration of 120 mg Pseudoephedrine


Hydrochloride and 1200 mg Guaifenesin in


an Experimental Formulation Compared to those of


Treament A (Reference) to Normal Volunteers Following


the Consumption of a High-Fat Meal (%)


















AUC0-t
AUCinf






Cmax
Tmax
(hr-
(hr-
Half-life
Clearance



Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)


















Mean
103
76.5
96.5
96.5
101
105



Median
103
66.7
95.7
94.2
99.5
106



Standard
10.3
23.1
10.6
11.7
17.9
12.6



Deviation









Standard
1.82
4.09
1.88
2.06
3.17
2.23



Error









% CV
10.0
30.3
11.0
12.1
17.7
12.0









The rate of absorption of guaifenesin from the experimental formulation, as assessed by Cmax is not bioequivalent to the test formulation in the presence of a high fat meal with a 95% confidence interval between 67.9% to 81.8%. The extent of absorption of guaifenesin from the experimental tablet, as assessed by AUCinf is equivalent to the test formulation in the presence of a high fat meal.
In conclusion, the rate of guaifenesin absorption from the experimental formulation is not bioequivalent to the Reference formulations; whereas the extent of guaifenesin absorption is bioequivalent to the Reference formulation in the presence of a high-fat meal. The rate and extent of pseudoephedrine absorption from the experimental formulation are bioequivalent to the Reference formulation in the presence of a high-fat meal.
Example 15
A combination guaifenesin and Pseudoephedrine formulation was tested for steady state pharmacokinetics as compared to references in an open-label, multiple-dose, randomized, 2-way-crossover study using 36 subjects. The subjects were randomly placed into one of two treatment groups. Group 1 received a 1200 mg controlled-release guaifenesin product (Mucinex) plus a 120 mg controlled-release pseudoephedrine product (Sudafed® 12 Hour) with 240 mL of water after an overnight fast and again 12 hours later for 11 doses (Reference). Group 2 received an experimental controlled-release formulation comprising 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water after an overnight fast and again 12 hours later for 11 doses (Test)(PB01-M65).
Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose blood sample before the AM dose on Days 1, 4, 5 and 6. On Day 6 additional blood samples (5 mL, sodium heparin anticoagulant) were also obtained at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours after the last dose (total blood loss for guaifenesin determination was 380 mL).
The subjects given 1200 mg guaifenesin, as Mucinex every 12 hours for 11 doses, reached a maximum steady-state plasma guaifenesin concentration of 1960 ng/mL at 0.81 hours after the last dose (120.81 hours after the first dose). The mean AUCss was 7209 hr-ng/mL and the mean Cmin was 52 ng/mL. Those subjects given 1200 mg guaifenesin, as an experimental formulation every 12 hours for 11 doses, reached a maximum steady-state plasma guaifenesin concentration of 1983 ng/mL (103% of the Reference formulation) at 0.96 hours after the last dose (120.96 hours after the first dose, 100% of that of the Reference formulation). The mean AUCss was 8183 hr-ng/mL (114% of that of the Reference formulation) and the mean Cmin was 117 ng/mL.
At steady state, the subjects given 120 mg pseudoephedrine hydrochloride, as Sudafed(® 12 Hour, every 12 hours for 11 doses, reached a steady-state maximum plasma pseudoephedrine concentration of 361 ng/mL at 4.89 hours after the last dose (124.89 hours after the first dose). The mean AUCss was 3528 hr-ng/mL and the mean Cmin was 182 ng/mL. Those subjects, when given the 120 mg pseudoephedrine hydrochloride as an experimental formulation, reached a steady-state maximum plasma pseudoephedrine concentration of 365 ng/mL (103% of that of the Reference) 4.10 hours after the last dose (124.10 hours after the first dose, 99.4% of that of the Reference). The mean AUCss was 3550 hr-ng/mL (102% of that of the Reference) and the mean Cmin was 173 ng/mL.
The mean plasma concentrations of guaifenesin are depicted in FIG. 25. The resulting pharmacokinetic data are shown in Tables 26 through 28. At steady state, the subjects given 1200 mg guaifenesin every 12 hours, as Reference Mucinex for 11 doses, reached a steady-state maximum plasma guaifenesin concentration of 1960±859 ng/mL (Mean±Standard Deviation) in 0.81 hours±0.305 hour after the last dose (120.81 hours after the first dose) and the steady-state AUC (AUCss) was 7209±3746 hr-ng/mL. At steady state, the subjects given 1200 mg guaifenesin every 12 hours, as an experimental tablet formulation for 11 doses, reached a steady-state maximum plasma guaifenesin concentration of 1983±1019 ng/mL (103%±29.6% of the Reference Mucinex) in 0.96 hours±0.645 hour after the last dose (120.96 hours after the first dose, 100%±0.494%). The AUCss was 8183±5141 hr-ng/mL (114%±27.0%).







TABLE 26







Guaifenesin Steady-State Pharmacokinetic Parameters


Following the Administration of 11 Doses of 1200 mg


guaifenesin as Mucinex and 120 mg Pseudoephedrine


Hydrochloride as Sudafed ® 12 Hour to Normal


Volunteers - Treatment A (Reference)













AUCSS
Cmin
Cmax
Tmax
CAVERAGE


Subject
(hr-ng/mL)
(ng/mL)
(ng/mL)
(hr)
(ng/mL















Mean
7209
52.0
1960
120.81
604


Median
6554
28.3
1850
120.75
547


Standard
3746
48.1
859
0.305
311


Deviation


Standard
633
8.13
145
0.052
52.6


Error


% CV
52.0
92.5
43.8
0.253
51.5
















TABLE 27







guaifenesin Steady-State Pharmacokinetic Parameters Following the


Administration of 11 Doses of 1200 mg guaifenesin and 120 mg


Pseudoephedrine Hydrochloride in an Experimental Formulation to


Normal Volunteers - Treatment B (Test)













AUCSS
Cmin
Cmax
Tmax
CAVERAGE


Subject
(hr-ng/mL)
(ng/mL)
(ng/mL)
(hr)
(ng/mL















Mean
8183
117
1983
120.96
686


Median
6769
100
1750
120.75
564


Standard
5141
87.2
1019
0.645
431


Deviation


Standard
869
14.7
172
0.109
72.8


Error


% CV
62.8
74.5
51.4
0.533
62.7
















TABLE 28







Ratio of Guaifenesin Steady-State Pharmacokinetic Parameters


Following the Administration of 11 Doses of 1200 mg Guaifenesin and


120 mg Pseudoephedrine Hydrochloride in an Experimental Formulation


Compared to Reference Formulations to Normal Volunteers (%)












Subject
AUCSS
Cmin
Cmax
Tmax
CAVERAGE















Mean
114
550
103
100
114


Median
116
261
104
100
113


Standard
27.0
712
29.6
0.494
26.4


Deviation


Standard
4.57
120
5.01
0.084
4.46


Error


% CV
23.7
129
28.6
0.494
23.2









The mean plasma concentration of Pseudoephedrine are shown in FIG. 26. The resulting pharmacokinetic data are shown in Tables 29 through 31. At steady state, the subjects given 120 mg pseudoephedrine hydrochloride, as Sudafed® 12 Hour, every 12 hours for 11 doses, reached a steady-state maximum plasma pseudoephedrine concentration of 361±77.7 ng/mL in 4.89 hours±2.14 hour after the last dose (124.89 hours after the first dose). The AUCss was 3528±862 hr-ng/mL. At steady state, the subjects given 120 mg pseudoephedrine hydrochloride every 12 hours, as an experimental tablet formulation for 11 doses, reached a steady-state maximum plasma pseudoephedrine concentration of 365±83.3 ng/mL (103%±2 1.4% of the Reference Sudafed 12-Hour) in 4.10 hours±1.85 hours after the last dose (124.10 hours after the first dose, 99.4%±2.09%). The AUCss was 3550±898 hr-ng/mL (102%±19.6%).







TABLE 29







Pseudoephedrine Steady-State Pharmacokinetic


Parameters Following the Administration of 11 Doses


of 120 mg Pseudoephedrine Hydrochloride as Sudafed ®


12 Hour and 1200 mg Guaifenesin as Mucinex to Normal


Volunteers - Treatment A (Reference)













AUCSS
Cmin
Cmax
Tmax
CAVERAGE


Subject
(hr-ng/mL)
(ng/mL)
(ng/mL)
(hr)
(ng/mL















Mean
3528
182
361
124.89
294


Median
3462
164
362
124.00
288


Standard
862
66.4
77.7
2.14
71.9


Deviation


Standard
146
11.2
13.1
0.361
12.1


Error


% CV
24.4
36.5
21.5
1.71
24.4
















TABLE 30







Pseudoephedrine Steady-State Pharmacokinetic Parameters


Following the Administration of 11 Doses of 120 mg


Pseudoephedrine Hydrochloride and 1200 mg Guaifenesin


in an Experimental Formulation to Normal


Volunteers - Treatment B (Test)















AUCSS
Cmin
Cmax
Tmax
CAVERAGE



Subject
(hr-ng/mL)
(ng/mL)
(ng/mL)
(hr)
(ng/mL


















Mean
3550
173
365
124.10
296



Median
3399
170
350
124.00
283



Standard
898
55.2
83.3
1.85
74.8



Deviation



Standard
152
9.34
14.1
0.313
12.7



Error



% CV
25.3
32.0
22.8
1.49
25.3

















TABLE 31







Ratio of Pseudoephedrine Steady-State Pharmacokinetic


Parameters Following the Administration of 11 Doses of


120 mg Pseudoephedrine Hydrochloride and 1200 mg


Gaifenesin in an Experimental Formulation Compared


to Reference Formulations to Normal Volunteers (%)














Subject
AUCSS
Cmin
Cmax
Tmax
CAVERAGE


















Mean
102
100
103
99.4
102



Median
99.6
102
100
99.2
100



Standard
19.6
28.0
21.4
2.09
19.6



Deviation



Standard
3.31
4.73
3.62
0.354
3.31



Error



% CV
19.1
27.9
20.8
2.11
19.1










In conclusion, the experimental tablet formulation was bioequivalent to the Reference formulations at steady state. The experimental formulation is bioequivalent to the Reference formulations in terms of both Cmax and AUCss for guaifenesin and pseudoephedrine hydrochloride.
Example 16
In another study drug interaction potential for combination drugs was examined. The interaction potential for 1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride was compared to reference in an open label, single dose, randomized, 3-way crossover study using 36 subjects.
The subjects were randomized and placed into one of three treatment groups. roup A received a 1200 mg controlled release guaifenesin product (Mucinex) with 240 mL of room-temperature water after an overnight fast. Group B received a 120 mg controlled release pseudoephedrine product (Sudafed® 12 Hour) with 240 mL of room-temperature water after an overnight fast. Group C received a 1200 mg guaifenesin product (Mucinex) and 120 mg pseudoephedrine hydrochloride (Sudafed® 12 Hour) with 240 mL of room-temperature water after an overnight fast.
Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose (the total blood loss for guaifenesin and pseudoephedrine analysis was—450 mL).
Subjects given 1200 mg of guaifenesin as Mucinex (Treatment A, Reference) reached a Cmax of 2009 ng/mL in 0.89 hours and had an AUCinf of 8138 hr-ng/mL. Subjects given 1200 mg guaifenesin as Mucinex along with 120 mg Pseudoephedrine hydrochloride as Sudafed® 12 Hour (Treatment C, Test) reached a Cmax of 1989 ng/mL (102% of that of the reference) in 0.84 hour (104% of that of the reference) and had an AUCinf of 8052 hr-ng/mL (100% of that of the reference).
Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour (Treatment B, Reference) reached a Cmax of 296 ng/mL in 6 hours and had an AUCinf of 4505 hr ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as Sudafed® 12 Hour, along with 1200 mg guaifenesin as Mucinex (Treatment C, Test) reached a C of 289 ng/mL (98% of that of the reference) in 6 hours (101% of that of the reference) and had an AUCinf of 4396 hr-ng/mL (98% of that of the reference).
The plasma concentrations of guaifenesin are depicted in FIG. 27. The resulting pharmacokinetic data is shown in Tables 38 through 41. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex (Treatment A, Reference) were 2009±819.2 ng/mL and occurred in 0.89±0.42 hours. The resulting area under the plasma concentration vs. time curve (AUCinf was 8138±3253 hr-ng/mL. The maximum plasma concentrations of guaifenesin following a 1200 mg oral dose as Mucinex along with 120 mg pseudoephedrine hydrochloride (Treatment C, Test) were 1989±863 ng/mL (102.33%±31.40% of that of the reference formulation) and occurred in 0.84±0.31 hours (103.94%±35.38% that of the reference formulation). The resulting AUCinf was 8052±3344 hr-ng/mL (100.06%±18.09% of that of the reference formulation).







TABLE 38







Gaifenesin Pharmacokinetic Parameters Following


the Administration of 1200 mg Gaifenesin to Normal


Volunteers (Treatment A)
















AUC0–t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
2009
0.89
7921
8138
4.00
172.13


Median
1695
0.75
7063.8
7284.17
2.82
164.87


Standard
819.22
0.42
3196.53
3253.39
5.58
70.19


Deviation


Standard
138.47
0.07
540.31
549.92
0.94
11.87


Error


% CV
40.77
46.79
40.35
39.98
139.48
40.78
















TABLE 39







Gaifenesin Pharmacokinetic Parameters Following


the Administration of 1200 mg Gaifenesin Along with


120 mg Pseudoephedrine Hydrochloride to Normal


Volunteers (Treatment C)
















AUC0–t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1989
0.84
7923
8052
3.41
175.45


Median
1770
0.75
6689
6745
3.33
177.93


Standard
863.36
0.31
3337
3344
1.72
71.07


Deviation


Standard
145.93
0.05
564.04
565.25
0.29
12.01


Error


% CV
43.41
36.37
42.12
41.53
50.56
40.51
















TABLE 40







Ratio of Gaifenesin Pharmacokinetic Parameters


Following the Administration of 1200 mg Gaifenesin


Along with 120 mg Pseudoephedrine Hydrochloride


Compared to 1200 mg Gaifenesin Alone to


Normal Volunteers (%)
















AUC0–t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
102.33
103.94
100.87
100.06
128.38
103.47


Median
95.79
100
103.14
101.71
107.41
98.32


Standard
31.40
35.38
18.01
18.09
79.38
20.60


Deviation


Standard
5.31
5.98
3.05
3.06
13.42
3.48


Error


% CV
30.69
34.04
17.86
18.08
61.83
19.91
















TABLE 41







Psuedoephedrine Pharmacokinetic Parameters Following the


Administration of 120 mg Pseudoephedrine Hydrochloride to Normal


Volunteers (Treatment B)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
295.8
6.17
4024
4505
6.05
23.66


Median
297.5
6
3823
4430
5.81
22.20


Standard
73.25
1.92
1047
1250
1.44
7.24


Deviation


Standard
12.38
0.32
177
211
0.24
1.22


Error


% CV
24.76
31.13
26.02
27.75
23.83
30.60









The plasma concentrations of pseudoephedrine are depicted in FIG. 28. The resulting pharmacokinetic data is shown in Tables 42 through 43. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed® 12 Hour (Treatment B, Reference) were 295.8±73.25 ng/mL and occurred in 6.17±1.92 hours. The resulting AUCinf was 4505±1250 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following a 120 mg oral dose as Sudafed® 12 Hour along with 1200 mg guaifenesin as Mucinex (Treatment C, Test) were 289.3±77.61 ng/mL (98.41%±12.77% of that of the reference formulation) and occurred in 5.75±1.54 hours (100.74%±38.65% of that of the reference formulation). The resulting AUCinf was 4396±1347 hr-ng/mL (98.40%±15.24% of that of the reference formulation).







TABLE 42







Pseudoephedrine Pharmacokinetic Following the Administration of


120 mg Pseudoephedrine Hydrochloride Along with 1200 mg guaifenesin


to Normal Volunteers (Treatment C)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
289.33
5.75
3925
4396
6.04
24.30


Median
286
6
3932
4247
5.63
23.16


Standard
77.61
1.54
1089
1347
1.38
6.95


Deviation


Standard
13.12
0.26
184
228
0.23
1.17


Error


% CV
26.82
26.74
27.75
30.65
22.79
28.60
















TABLE 43







Ratio of Pseudoephedrine Pharmacokinetic Parameters


Following the Administration of 120 mg Along with 1200 mg


Gaifenesin Hydrochloride Compared to 120 mg


Pseudoephedrine Alone to Normal Volunteers (%)
















AUC0–t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
98.41
100.74
98.22
98.40
103.30
103.99


Median
98.40
100
96.90
97.91
97.46
102.14


Standard
12.77
38.65
13.15
15.24
30.44
15.96


Deviation


Standard
2.16
6.53
2.22
2.58
5.14
2.70


Error


% CV
12.97
38.36
13.39
15.49
29.47
15.35









In conclusion, the pharmacokinetics of guaifenesin and pseudoephedrine hydrochloride are unaffected by the presence or absence of one another.
Example 17
In another experiment the effect of a high-fat on the bioavailability of an of the combination of 1200 mg guaifenesin and 120 mg Pseudoephedrine Hydrochloride in normal healthy volunteers was again compared to reference drug in an open-label, single-dose, randomized, 2-way-crossover study using 36 subjects.
The subjects were randomized and placed into one of two treatment groups. Each treatment group was fasted overnight. Treatment A received an experimental formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water (Reference). Treatment B received an experimental controlled-release formulation containing 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride with 240 mL of water, 30 minutes after the beginning of the consumption of a high-fat breakfast (Test).
Blood (10 mL, sodium heparin anticoagulant) was obtained at the following times: Pre dose, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 24 hours post dose (the total blood loss for guaifenesin and pseudoephedrine analysis was 300 mL). Subjects given 1200 mg of guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental formulation following an overnight fast (Treatment A, Reference) reached a plasma guaifenesin Cmax of 1857 ng/mL in 1.06 hours and had an AUCinf of 8142 hr-ng/mL. Subjects given 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental formulation after the consumption of a high-fat meal (Treatment B, Test) reached a plasma guaifenesin Cmax of 1364 ng/mL (79.3% of that of the Reference) in 2.06 hour (238% of that of the Reference) and had an AUCinf of 7469 hr-ng/mL (94.1% of that of the Reference).
Subjects given 120 mg pseudoephedrine hydrochloride as an experimental formulation after an overnight fast (Treatment A, Reference) reached a plasma pseudoephedrine Cmax of 283 ng/mL in 4.6 hours and had an AUCinf of 3746 hr-ng/mL. Subjects given 120 mg pseudoephedrine hydrochloride as an experimental formulation following the consumption of a high-fat meal (Treatment B, Test) reached a plasma pseudoephedrine Cmax of 301 ng/mL (108% of that of the Reference) in 5.77 hours (137% of that of the Reference) and had an AUCinf of 3660 hr-ng/mL (99% of that of the Reference).
The plasma concentrations of guaifenesin are depicted in FIG. 29. The resulting pharmacokinetic data are shown in Tables 44 through 46. The maximum plasma concentrations of guaifenesin following 1200 mg guaifenesin and 120 mg pseudoephedrine hydrochloride after an overnight fast were 1857±838 ng/mL (Mean±Standard Deviation) and occurred in 1.06±0.582 hours. The resulting area under the plasma concentration vs. time curve (AUCinf was 8142±3500 hr-ng/mL. The maximum plasma concentrations of guaifenesin, following 1200 mg oral guaifenesin and 120 mg pseudoephedrine hydrochloride as an experimental formulation following the consumption of a high-fat meal (Treatment B, Test), were 1364±691 ng/mL (79.3%±34.7% of that of the Reference formulation) and occurred in 2.06±1.16 hours (23 8%±157% that of the Reference formulation). The resulting AUCinf was 7469±3217 hr-ng/mL (94.1%±23.1% of that of the Reference formulation).







TABLE 44







Gaifenesin Pharmacokinetic Parameters Following


the Administration of 1200 mg Gaifenesin and 120 mg


Pseudoephedrine Hydrochloride in an Experimental


Formulation to Normal Volunteers After an Overnight


Fast (Treatment A, Reference)
















AUC0–t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1857
1.06
8091
8142
1.82
18.0


Median
1830
0.750
8228
8244
1.68
14.6


Standard
838
0.582
3501
3500
0.702
8.46


Deviation


Standard
144
0.100
600
600
0.120
1.45


Error


% CV
45
55.0
43.3
43.0
38.6
47.0
















TABLE 45







Gaifenesin Pharmacokinetic Parameters Following


the Administration of 1200 mg Gaifenesin and 120 mg


Pseudoephedrine Hydrochloride in an Experimental


Formulation to Normal Volunteers After the Consumption


of a High-Fat Meal (Treatment B, Test)
















AUC0–t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
1364
2.06
7403
7469
1.39
18.9


Median
1190
2.00
6842
6857
1.12
17.5


Standard
691
1.16
3185
3217
0.833
7.80


Deviation


Standard
119
0.200
546
552
0.143
1.34


Error


% CV
50.7
56.6
43.0
43.1
60.0
41.2
















TABLE 46







Ratio of Gaifenesin Pharmacokinetic Parameters Following


the Administration of 1200 mg Gaifenesin and 120 mg


Pseudoephedrine Hydrochloride in an Experimental


Formulation Following the Consumption of a High-Fat


Meal (Treatment B, Test) Compared to that After an


Overnight Fast (Treatment A, Reference) to Normal


Volunteers (%)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
79.3
238
94.0
94.1
87.2
112


Median
71.4
200
89.7
89.6
68.1
112


Standard
34.7
157
23.4
23.1
53.2
24.5


Deviation








Standard
6.04
27.4
4.07
4.02
9.27
4.26


Error








% CV
43.8
66.1
24.8
24.6
61.1
21.9









The resulting pharmacokinetic data are shown in Tables 47 through 49. The maximum plasma concentrations of pseudoephedrine following a 120 mg pseudoephedrine hydrochloride and 1200 mg guaifenesin, in an experimental formulation after an overnight fast (Treatment A, Reference), were 283±79.6 ng/mL and occurred in 4.60±1.56 hours. The resulting AUCinf was 3746±997 hr-ng/mL. The maximum plasma concentrations of pseudoephedrine following 120 mg pseudoephedrine hydrochloride and 1200 mg guaifenesin, in an experimental formulation following the consumption of a high-fat meal (Treatment B, Test), were 301±80.4 ng/mL (108%±18.5% of that of the Reference formulation) and occurred in 5.77±1.78 hours (137%±6 1.9% of that of the Reference formulation). The resulting AUCinf was 3660±963 hr-ng/mL (99.0%±20.1% of that of the Reference formulation).







TABLE 47







Pseudoephedrine Pharmacokinetic Parameters Following


the Administration of 120 mg of Pseudoephedrine


Hydrochloride and 1200 Gaifenesin in an Experimental


Formulation to Normal Volunteers After an Overnight Fast


(Treatment A, Reference)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
283
4.60
3477
3746
5.01
28.2


Median
266
4.00
3374
3552
4.94
27.7


Standard
79.6
1.56
884
997
1.06
8.03


Deviation








Standard
13.7
0.267
152
171
0.182
1.38


Error








% CV
28.2
33.8
25.4
26.6
21.2
28.5
















TABLE 48







Pseudoephedrine Pharmacokinetic Parameters Following


the Administration of 120 mg of Pseudoephedrine


Hydrochloride and 1200 mg guaifenesin in an


Experimental Formulation to Normal Volunteers After


Consumption of a High-Fat Meal (Treatment B, Test)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
301
5.77
3403
3660
4.64
28.8


Median
292
6.00
3152
3455
4.45
28.5


Standard
80.4
1.78
915
963
1.05
7.91


Deviation








Standard
13.8
0.306
157
165
0.180
1.36


Error








% CV
26.7
30.9
26.9
26.3
22.6
27.5
















TABLE 49







Ratio of Pseudoephedrine Pharmacokinetic Parameters


Following the Administration of 120 mg Pseudoephedrine


Hydrochloride and 1200 mg guaifenesin in an Experimental


Formulation After the Consumption of a High-Fat Meal


(Treatment B, Test) Compared to that After an Overnight


Fast (Treatment A, Reference) to Normal Volunteers (%)
















AUC0-t
AUCinf





Cmax
Tmax
(hr-
(hr-
Half-life
Clearance


Subject
(ng/mL)
(hr)
ng/mL)
ng/mL)
(hr)
(L/hr)
















Mean
108
137
98.9
99.0
93.7
105


Median
109
133
96.9
95.9
88.4
104


Standard
18.5
61.9
20.8
20.1
17.1
20.2


Deviation








Standard
3.22
10.8
3.62
3.50
2.97
3.52


Error








% CV
17.1
45.2
21.0
20.3
18.2
19.3









The rate of absorption of guaifenesin from the experimental formulation, as assessed by Cmax is not bioequivalent to the Test formulation in the presence of a high-fat meal. The extent of absorption of guaifenesin from the experimental tablet, as assessed by AUCinf, is equivalent to the Test formulation in the presence of a high-fat meal.
The rate and extent of pseudoephedrine absorption from the experimental formulation was bioequivalent to the Reference formulation in the presence of a high-fat meal.
In conclusion, the rate of guaifenesin absorption from the experimental formulation is not bioequivalent to the Reference formulation; whereas the extent of guaifenesin absorption is bioequivalent to the Reference formulation in the presence of a high-fat meal. The rate and extent of pseudoephedrine absorption from the experimental formulation are bioequivalent to the Reference formulation in the presence of a high-fat meal.
Other embodiments and uses of the invention will be apparent to those of skill in the art from consideration of the specification and practice of the invention disclosed herein. The specification and examples should be considered exemplary only with the true scope and spirit of the invention indicated by the following claims. As will be easily understood by those of skill in the art, variations and modifications of each of the disclosed embodiments can be easily made within the scope of this invention as defined by the following claims.

## Claims

1. A drug product comprising guaifenesin and pseudoephedrine and having two portions,
wherein a first portion comprises guaifenesin in an immediate release form, which releases guaifenesin in a human's stomach, and a second portion comprises guaifenesin in a sustained release form,
wherein the drug product contains 1200 mg of guaifenesin and provides a mean Cmax and at least one of a mean AUCinf and a mean AUC0-12 for guaifenesin under fasted conditions based on single-dose administration that are from 80% to 125% of the mean Cmax and at least one of the mean AUCinf and the mean AUC0-12 for guaifenesin provided by a bi-layer tablet containing 1200 mg of guaifenesin and having an immediate release layer consisting essentially of about 210.5 mg of guaifenesin dc, about 117.5 mg of microcrystalline cellulose, about 30 mg of sodium starch glycolate, and about 1 mg of magnesium stearate, and a sustained release layer consisting essentially of about 1052.7 mg of guaifenesin dc, about 25 mg of hydroxypropyl methyl cellulose, about 12.5 mg of carbomer 934P, about 5.7 mg of magnesium stearate, and a colorant, and
wherein guaifenesin is absorbed into bloodstream such that the drug product can be appropriately dosed once in a 12-hour period.

2. The drug product according to claim 1, wherein the mean Cmax and at least one of the mean AUCinf and the mean AUC0-12 for guaifenesin provided by the drug product are from 80% to 125% of the mean Cmax and at least one of the mean AUCinf and the mean AUC0-12 for guaifenesin provided by the bi-layer tablet at a 90% confidence interval.

3. The drug product according to claim 1, which contains 120 mg of pseudoephedrine.

4. The drug product according to claim 1, wherein the first and second portions are discrete.

5. A drug product comprising guaifenesin and pseudoephedrine and having two portions,
wherein a first portion comprises guaifenesin in an immediate release form, which releases guaifenesin in a human subject's stomach, and a second portion comprises guaifenesin in a sustained release form,
wherein the drug product contains 600 mg of guaifenesin and provides a mean Cmax and at least one of a mean AUCinf and a mean AUC0-12 for guaifenesin under fasted conditions based on single-dose administration that are from 80% to 125% of the mean Cmax and at least one of the mean AUCinf and the mean AUC0-12 for guaifenesin provided by a bi-layer tablet containing 600 mg of guaifenesin and having an immediate release layer consisting essentially of about 105.25 mg of guaifenesin dc, about 58.75 mg of microcrystalline cellulose, about 15 mg of sodium starch glycolate, and about 0.5 mg of magnesium stearate, and a sustained release layer consisting essentially of about 526.35 mg of guaifenesin dc, about 12.5 mg of hydroxypropyl methyl cellulose, about 6.25 mg of carbomer 934P, about 2.85 mg of magnesium stearate, and a colorant, and
wherein guaifenesin is absorbed into bloodstream such that the drug product can be appropriately dosed once in a 12-hour period.

6. The drug product according to claim 5, wherein the mean Cmax and at least on of the mean AUCinf and the mean AUC0-12 for guaifenesin provided by the drug product are from 80% to 125% of the mean Cmax and at least one of the mean AUCinf and the mean AUC0-12 for guaifenesin provided by the bi-layer tablet at a 90% confidence interval.

7. The drug product according to claim 5, which contains 60 mg of pseudoephedrine.

8. The drug product according to claim 5, wherein the first and second portions are discrete.