Source: http://www.google.com/patents/US7537784?dq=inassignee:integral+inassignee:peripherals
Timestamp: 2016-07-30 02:08:36
Document Index: 482437427

Matched Legal Cases: ['art 150', 'art 150', 'art 150', 'art 150', 'art 150', 'art 150', 'art 150', 'art 150', 'art 150', 'art 150', 'art 150']

Patent US7537784 - Modified release tablet of bupropion hydrochloride - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsA modified-release tablet of bupropion hydrochloride comprising (i) a core comprising an effective amount of bupropion hydrochloride, a binder, a lubricant; and (ii) a control releasing coat surrounding said core; and (iii) a moisture barrier surrounding said control releasing coat, wherein the modified-release...http://www.google.com/patents/US7537784?utm_source=gb-gplus-sharePatent US7537784 - Modified release tablet of bupropion hydrochlorideAdvanced Patent SearchPublication numberUS7537784 B2Publication typeGrantApplication numberUS 11/451,496Publication dateMay 26, 2009Filing dateJun 13, 2006Priority dateAug 8, 2003Fee statusPaidAlso published asCA2524300A1, CA2524300C, CN1819821A, CN1819821B, DE60330909D1, EP1575565A1, EP1575565A4, EP1575565B1, US20050238718, US20060228415, WO2005016318A1Publication number11451496, 451496, US 7537784 B2, US 7537784B2, US-B2-7537784, US7537784 B2, US7537784B2InventorsWerner Oberegger, Okponanabofa Eradiri, Fang Zhou, Paul MaesOriginal AssigneeBiovail Laboratories International SrlExport CitationBiBTeX, EndNote, RefManPatent Citations (100), Non-Patent Citations (7), Classifications (24), Legal Events (11) External Links: USPTO, USPTO Assignment, EspacenetModified release tablet of bupropion hydrochloride
US 7537784 B2Abstract
A modified-release tablet of bupropion hydrochloride comprising (i) a core comprising an effective amount of bupropion hydrochloride, a binder, a lubricant; and (ii) a control releasing coat surrounding said core; and (iii) a moisture barrier surrounding said control releasing coat, wherein the modified-release tablet is bioequivalent to Wellbutrin� or Zyban�/Wellbutrin�SR tablets.
(i) a core comprising an effective amount of bupropion hydrochloride, polyvinyl alcohol, and glyceryl behenate, wherein said bupropion hydrochloride is present in an amount of at least about 94% by weight of the core dry weight, said polyvinyl alcohol is present in an amount of about 3% by weight of the core dry weight, and said glyceryl behenate is present in an amount of about 3% by weight of each core dry weight;
(ii) a control-releasing coat completely surrounding and contacting said core, said control-releasing coat comprising ethyl cellulose grade PR 100, polyethylene glycol 1450, and polyvinylpyrrolidone, wherein said ethyl cellulose grade PR 100 is present in an amount of from about 45% to about 50% by weight of the control-releasing coating dry weight, said polyethylene glycol 1450 is present in an amount of about 12% by weight of the control-releasing coating dry weight, and said polyvinylpyrrolidone is present in an amount of from about 25% to about 50% of the control-releasing coat dry weight, wherein the amount of said control-releasing coat applied is from about 9% to about 15% by weight of the dry tablet core; and
(iii) a moisture barrier surrounding said control-releasing coat, said moisture barrier comprising methacrylic acid copolymer, polyethylene glycol 1450, triethyl citrate and silicon dioxide, wherein said methacrylic acid copolymer is present in an amount of about 66% by weight of said moisture barrier dry weight, said polyethylene glycol 1450 and triethyl citrate is present in an amount of about 10% by weight of said moisture barrier dry weight in a proportion of 1 part triethyl citrate to 2 parts polyethylene glycol 1450, and said silicon dioxide is present in an amount of about 25% by weight of said moisture barrier dry weight, wherein the amount of the said moisture barrier applied is no more than about 2.5% of the tablet dry weight,
wherein the tablet provides an extended-release of the bupropion hydrochloride such that after about 2 hours about 5% of the bupropion hydrochloride content is released, after about 4 hours about 32% of the bupropion hydrochloride content is released, after about 8 hours about 74% of the bupropion hydrochloride content is released and after about 16 hours no less than about 99% of the bupropion hydrochloride content is released,
and wherein the ratio of the ethyl cellulose grade PR 100:polyethylene glycol 1450:polyvinylpyrrolidone is from about 3:1:4 to about 5:1:3.
2. The modified release tablet of claim 1 wherein said modified-release tablet provides a Cmax of bupropion in the blood plasma at between about 3 hours and about 8 hours (Tmax) after administration in the fasted state.
3. The modified-release tablet of claim 1 wherein said modified-release tablet provides a Cmax of bupropion ranging from about 60 ng/ml to about 280 ng/ml in the blood plasma at about 5 hours (Tmax) after administration of a once daily 300 mg dose of said modified-release bupropion hydrochloride tablet or a 2�150 mg dose once daily of said modified-release bupropion hydrochloride tablet in the fasted state.
4. The modified-release tablet of claim 1 wherein said modified-release tablet exhibits an AUC(0-t) for bupropion from about 800 ng.hr/ml to about 2850 ng.hr/ml after administration of a once daily 300 mg dose of said modified-release bupropion hydrochloride tablet or a 2�150 mg dose once daily of said modified-release bupropion hydrochloride tablet in the fasted state.
5. The modified-release tablet of claim 1 wherein said modified-release tablet exhibits an AUC(0-inf) for bupropion from about 840 ng.hr/ml to about 3000 ng.hr/ml after administration of a once daily 300 mg dose of said modified-release bupropion hydrochloride tablet or a 2�150 mg dose once daily of said modified-release bupropion hydrochloride tablet in the fasted state.
6. The modified-release tablet of claim 1 which when administered in a once-daily bupropion treatment regimen to a patient in need of treatment provides a Cmax for bupropion ranging from about 60 ng/ml to about 280 ng/ml at between 3 hours and 8 hours (Tmax) and an AUC(0-t) for bupropion ranging from about 800 ng.hr/ml to about 2850 ng.hr/ml.
7. The modified-release tablet of claim 1 wherein the moisture content of said modified-release tablet is no more than about 0.4 % in said tablet when stored at 40� C.�2� C./75% RH�5% RH in an open dish after about 10 days.
8. The modified-release tablet of claim 1 wherein the moisture content of said modified-release tablet is no more than about 1% in said tablet when stored at 40� C.�2� C./75% RH�5% RH after storage for about 6 months.
9. The modified-release tablet of claim 1 wherein said modified-release tablet contains at least about 95% undegraded bupropion hydrochloride after storage for 12 months at about 25� C.�2� C./60% RH�5% RH.
10. The modified-release tablet of claim 1 wherein said modified-release tablet contains at least about 95% undegraded bupropion hydrochloride after storage for 18 months at about 25� C.�2� C./60% RH�5% RH.
11. The modified-release tablet of claim 1, wherein said tablet contains 150 mg of bupropion hydrochloride.
12. The modified-release tablet of claim 1, wherein said tablet contains 300 mg of bupropion hydrochloride.
13. The modified release tablet of claim 1 which does not exhibit any food effects.
14. A method of treating depression in a patient in need thereof comprising administering to the patient the modified-release tablet of claim 1.
15. The method of claim 14 wherein said modified-release tablet contains a 300 mg dose.
16. The method of claim 14 wherein said modified-release tablet contains a 150 mg dose. Description
Bupropion is an antidepressant chemically unrelated to tricyclics, tetracyclics, selective serotonin re-uptake inhibitors (SSRIs), or other known antidepressant agents. The drug resembles a psycho stimulant in terms of its neurochemical and behavioral profiles in vivo, but it does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Its structure closely resembles that of diethylpropion and it is related to phenylethylamines. It is designated as (�)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride and by its generic name amfebutamone hydrochloride. Bupropion hydrochloride is commercially available as an immediate release form (Wellbutrin�) and a sustained release form (Wellbutrin� SR and Zyban�). Both Wellbutrin� SR and Zyban� are chemically and pharmaceutically identical.
The neurochemical mechanism of the antidepressant effect of bupropion is not well known. Bupropion does not inhibit monoamine oxidase. Bupropion affects chemicals within the brain that nerves use to send messages to each other. These chemical messengers are called neurotransmitters. The neurotransmitters that are released by nerves are taken up again by the nerves that release them for reuse (This is referred to as reuptake). Many experts believe that depression is caused by an imbalance among the amounts of neurotransmitters that are released. It is believed that bupropion works by inhibiting the reuptake of the neurotransmitters dopamine, serotonin, and norepinephrine, an action which results in more dopamine, serotonin, and norepinephrine made available to transmit messages to other nerves. Accordingly, bupropion is unique in that its major effect is on dopamine, an effect, which is not shared by the SSRIs (e.g. paroxetine (Paxil�), fluoxetine (Prozac�), sertraline (Zoloft�)) or the tricyclic antidepressants or TCAs (e.g. amitriptyline (Elavil�), imipramine (Tofranil�), desipramine (Norpramin�)).
Wellbutrin� and Wellbutrin� SR are used for the management of depression. Zyban� has been approved as an aid to patients wanting to quit smoking. Wellbutrin�, the immediate release formulation of bupropion, is dosed three times a day, preferably with 6 or more hours in between doses. For patients requiring more that 300 mg bupropion a day, each dose should not exceed 150 mg. This requires administration of the tablets at least 4 times a day with at least 4 hours in between doses. The immediate release formulation results in more than a 75% release of the bupropion into the dissolution media in about 45 minutes, and one of the major side effects of bupropion has been the incidence of seizures, which in part appears to be strongly associated with the immediate release of the bupropion into the system. Accordingly, sustained release products were developed to avoid the incidence of seizures. The sustained release products are dosed twice daily.
U.S. Pat. No. 6,589,553 and International Publication No. WO 02/062299 purportedly describes a once daily capsule formulation with two populations of coated pellets, each of which release bupropion hydrochloride at a different pH. One population of pellets is coated to release the drug at a pH corresponding to about 4.8 and lower. The release of the drug from this population of pellets is expected to occur in the upper GI tract. The other population of pellets is coated to release the drug at a pH of 7 and above. The release of bupropion from this population is expected to occur in the lower GI tract. In one example shown, the relative bioavailability of bupropion to Zyban� was only 40% in terms of Cmax ratio and only 80% in terms of AUC0-inf ratio. In another example shown, the relative bioavailability of bupropion to Zyban� was only 48% and 59% in terms of Cmax and AUC0-inf. The references further describe the introduction of a third population of uncoated active pellets, which purportedly result in a further modification and improvement of the bupropion release. Based on the mean plasma concentration-time profile shown in FIGS. 3 and 4 of these references it is not readily apparent that the introduction of the uncoated active pellets would result in a once daily bioequivalent formulation (reference product is Zyban�). Also, neither one of the two references present any drug stability data.
The modified-release tablets of the invention comprising are bioequivalent to Wellbutrin� or Zyban�/Wellbutrin�SR tablets. The term “bioequivalent” means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Where there is an intentional difference in rate (e.g., in certain extended release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action. This applies only if the difference in the rate at which the active ingredient or moiety becomes available at the site of drug action is intentional and is reflected in the proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.
The present invention relates to a modified-release tablet of a pharmaceutically acceptable salt of bupropion, preferably bupropion hydrochloride. The advantage of the modified-release tablets of the invention not afforded by the prior art commercially available Wellbutrin� or Zyban�/Wellbutrin� SR tablets is that the modified-release tablets allow for a once daily administration regimen, is bioequivalent to the commercially available prior art tablets and do not exhibit a food effect.
In another embodiment off the present invention, the moisture barrier comprises an enteric and/or acrylic polymer, a plasticizer and a permeation enhancer and is present in a ratio of about 13:2:5. The enteric and/or acrylic polymer is preferably an acrylic polymer, which in turn is preferably a methacrylic acid copolymer available commercially as Eudragit� L 30 D-55. Although the amount of methacrylic acid copolymer present may vary from about 30% to about 90% by weight of the moisture barrier dry weight, it is preferable that the amount of the methacrylic acid copolymer is present at about 66% of the moisture barrier dry weight.
In another embodiment of the present invention, the modified-release tablet of the invention provides for a stable bupropion hydrochloride formulation such that at least about 95% and preferably at least about 97.5% and even 98.5% or even 99% of the bupropion hydrochloride remains stable after about 12 months storage at 25� C.�2� C./60% RH�5% RH.
In another embodiment of the present invention, the modified-release tablet of the invention provides for a stable bupropion hydrochloride formulation such that at least about 95% and preferably at least about 97.5% and even 98.5% or even 99% of the bupropion hydrochloride remains stable after about 18 months storage at 25� C.�2� C./60% RH�5% RH
In another embodiment of the present invention, the modified-release bupropion hydrochloride tablets of the invention are bioequivalent to either Wellbutrin� or Zyban�/Wellbutrin� SR tablets and do not exhibit a food effect.
FIG. 2A is a graph illustrating the statistical analysis for Relative Response Factors (RRF) corrected total impurities content in the 150 mg dosage strength bupropion hydrochloride modified-release tablets according to an embodiment of the invention stored at 25� C.�2� C./60% RH�5% RH in HDPE bottles (7 ct, 40 cc and 30 ct, 100 cc).
FIG. 2B is a graph illustrating the statistical analysis for Relative Response Factors (RRF) corrected total impurities content in the 300 mg dosage strength bupropion hydrochloride modified-release tablets according to an embodiment of the invention stored at 25� C.�2� C./60% RH�5% RH in HDPE bottles (7 ct, 40 cc and 30 ct, 100 cc).
FIG. 3A is a graph illustrating the mean plasma bupropion concentrations of a dosage strength equivalency study after administration of 2�150 mg (q.d.) and 1�300 mg (q.d.) dosage strength modified-release bupropion hydrochloride tablets according to an embodiment of the invention.
FIG. 3B is a graph illustrating the mean plasma hydroxybupropion concentrations of a dosage strength equivalency study after administration of 2�150 mg (q.d.) and 1�300 mg (q.d.) dosage strength modified-release bupropion hydrochloride tablets according to an embodiment of the invention.
FIG. 3C is a graph illustrating the mean plasma bupropion threoamino alcohol concentrations of a dosage strength equivalency study after administration of 2�150 mg (q.d.) and 1�300 mg (q.d.) dosage strength modified-release bupropion hydrochloride tablets according to an embodiment of the invention.
FIG. 3D is a graph illustrating the mean plasma bupropion erythroamino alcohol concentrations of a dosage strength equivalency study after administration of 2�150 mg (q.d.) and 1�300 mg (q.d.) dosage strength modified-release bupropion hydrochloride tablets according to an embodiment of the invention.
FIG. 4B is a graph comparing the mean plasma bupropion concentrations shown in FIG. 4A with the mean plasma bupropion concentrations after a single dose administration of the prior art 150 mg Zyban� tablet.
FIG. 4C is a graph comparing the mean plasma hydroxybupropion concentrations after a single dose administration of a 150 mg dosage strength modified-release bupropion hydrochloride tablet according to an embodiment of the invention with the mean plasma hydroxybupropion concentrations after a single dose administration of the prior art 150 mg Zyban� tablet.
FIG. 4D is a graph comparing the mean plasma bupropion threoamino alcohol concentrations after a single dose administration of a 150 mg dosage strength modified-release bupropion hydrochloride tablet according to an embodiment of the invention with the mean plasma hydroxybupropion concentrations after a single dose administration of the prior art 150 mg Zyban� tablet.
FIG. 4E is a graph comparing the mean plasma bupropion erythroamino alcohol concentrations after a single dose administration of a 150 mg dosage strength modified-release bupropion hydrochloride tablet according to an embodiment of the invention with the mean plasma hydroxybupropion concentrations after a single dose administration of the prior art 150 mg Zyban� tablet.
FIG. 6B is a graph comparing the mean steady state blood plasma bupropion concentrations shown in FIG. 5A with the mean steady state plasma bupropion concentrations after multiple dosing of the prior art Wellbutrin� tablet in the fasted state.
FIG. 6C is a graph comparing the mean steady state blood plasma hydroxybupropion concentrations after multiple dosing of a once daily 300 mg modified-release bupropion hydrochloride tablet according to an embodiment of the invention when administered to a patient in the fasted state with the mean steady state plasma hydroxybupropion concentrations after multiple dosing of the prior art Wellbutrin� tablet in the fasted state.
FIG. 6D is a graph comparing the mean steady state blood plasma bupropion threoamino alcohol concentrations after multiple dosing of a once daily 300 mg modified-release bupropion hydrochloride tablet according to an embodiment of the invention when administered to a patient in the fasted state with the mean steady state plasma bupropion threoamino alcohol concentrations after multiple dosing of the prior art Wellbutrin� tablet in the fasted state.
FIG. 6E is a graph comparing the mean steady state blood plasma bupropion erythroamino alcohol concentrations after multiple dosing of a once daily 300 mg modified-release bupropion hydrochloride tablet according to an embodiment of the invention when administered to a patient in the fasted state with the mean steady state plasma bupropion erythroamino alcohol concentrations after multiple dosing of the prior art Wellbutrin� tablet in the fasted state.
FIG. 7B is a graph comparing the mean steady state blood plasma bupropion concentrations shown in FIG. 7A with the mean steady state blood plasma bupropion concentrations after multiple dosing of the prior art 150 mg (b.i.d.) Zyban� tablets under fasted conditions.
FIG. 7C is a graph comparing the mean steady state blood plasma hydroxybupropion concentrations after multiple dosing of a once daily 300 mg modified-release bupropion hydrochloride tablet according to an embodiment of the invention under fasted conditions with the mean steady state blood plasma hydroxybupropion concentrations after multiple dosing of the prior art 150 mg (b.i.d.) Zyban� tablets under fasted conditions.
FIG. 7D is a graph comparing the mean steady state blood plasma bupropion threoamino alcohol concentrations after multiple dosing of a once daily 300 mg modified-release bupropion hydrochloride tablet according to an embodiment of the invention under fasted conditions with the mean steady state blood plasma bupropion threoamino alcohol concentrations after multiple dosing of the prior art 150 mg (b.i.d.) Zyban� tablets under fasted conditions.
FIG. 7E is a graph comparing the mean steady state blood plasma bupropion erythroamino alcohol concentrations after multiple dosing of a once daily 300 mg modified-release bupropion hydrochloride tablet according to an embodiment of the invention under fasted conditions with the mean steady state blood plasma bupropion erythroamino alcohol concentrations after multiple dosing of the prior art 150 mg (b.i.d.) Zyban� tablets under fasted conditions.
The core of the modified-release tablet comprises an effective amount of a pharmaceutically acceptable salt of bupropion, a binder, and a lubricant and may contain other conventional inert excipients. The amount of the active drug present may vary in an amount from about 50% to about 90% by weight of the tablet dry weight, and preferably from about 70% to about 90% by weight of the tablet dry weight. The pharmaceutically acceptable salt of bupropion is preferably bupropion hydrochloride. The tablet comprises an amount of bupropion hydrochloride that can vary from about 50 mg to about 450 mg. Preferably, the tablet comprises 150 mg or 300 mg of bupropion hydrochloride. For a 150 mg dose tablet the bupropion hydrochloride is about 78% by weight of the tablet dry weight. For the 300 mg dose, the amount of bupropion hydrochloride is present at about 83% by weight of the tablet dry weight. For both the 150 mg and 300 mg dose bupropion hydrochloride modified-release tablets of the invention, the amount of bupropion hydrochloride is present at about 94% by weight of the dry core for each dose.
Lubricants are added to pharmaceutical formulations to ensure that tablet formation and ejection can occur with low friction between the solid and the die wall. High friction during tabletting can cause a series of problems, including inadequate tablet quality (capping or even fragmentation of tablets during ejection, and vertical scratches on tablet edges) and may even stop production. Accordingly, lubricants are added to almost all tablet formulations including the bupropion hydrochloride tablet formulation described herein. Non-limiting examples of lubricants useful for the core include glyceryl behenate, stearic acid, hydrogenated vegetable oils (such as hydrogenated cottonseed oil (Sterotex�), hydrogenated soybean oil (Sterotex� (HM) and hydrogenated soybean oil & castor wax (Sterotex� K), stearyl alcohol, leucine and polyethylene glycol (MW 4000 and higher). The lubricant is preferably glyceryl behenate. The amount lubricant present may vary from about 1% to about 5% by weight of the tablet dry weight, preferably from about 2% to about 3% by weight of the tablet dry weight, and most preferably about 2.5% by weight of the tablet dry weight. For the 150 mg and 300 mg dose modified-release tablets of the invention the lubricant is present at about 2.5% by weight of the tablet dry weight and preferably from about 1% to about 6% by weight of the dry core weight and more preferably at about 3% by weight of the dry core weight for both dosages.
The enteric polymer is preferably an acrylic polymer. The acrylic polymer is preferably a methacrylic acid copolymer type C [poly(methacrylic acid, methyl methacrylate) 1:1] available commercially under the trade name Eudragit� (e.g. Eudragit L 30 D-55). The methacrylic acid copolymer is present in an amount, which may vary from about 1% to about 3% of the tablet dry weight and from about 55% to about 70% of the moisture barrier dry weight. For the 150 mg dose of the modified-release bupropion hydrochloride tablet of the invention, the methacrylic acid copolymer may vary from about 2% to about 3% of the tablet dry weight. Preferably, the amount of the methacrylic acid copolymer is present at about 2.5% of the tablet dry weight. With respect to the moisture barrier itself, the amount of the methacrylic acid copolymer is present preferably from about 30% to about 90% by weight of the moisture barrier dry weight and more preferably at about 66% of the moisture barrier dry weight. For the 300 mg dose of the modified-release bupropion hydrochloride tablet of the invention, the amount of the methacrylic acid copolymer may vary from about 1.5% to about 3% of the tablet dry weight. Preferably, the amount of methacrylic acid copolymer is present at about 2% by weight of the tablet dry weight. With respect to the coating itself, the methacrylic acid copolymer is present preferably from about 30% to about 90% of the moisture barrier dry weight and more preferably at about 66% of the moisture barrier dry weight for the 300 mg dose modified-release tablet of the invention.
Generally, the preparation and application of the moisture barrier process is as follows. The plasticizer, preferably a combination of polyethylene glycol 1450 and triethyl citrate, is first added to water and the mixture mixed to homogeneity. The methacrylic acid co-polymer, preferably Eudragit� L 30 D-55, is next sieved and added to the plasticizer mixture and mixed to homogeneity. In a separate container the permeation enhancer, preferably silicon dioxide is dissolved in water until a homogeneous mixture is achieved. The plasticizer and methacrylic acid copolymer mixture is then combined with the permeation enhancer solution and mixed to homogeneity. The resulting moisture barrier solution is then sprayed onto the tablet cores coated with the control-releasing coat using a tablet coater, fluidized bed apparatus or any other suitable coating apparatus known in the art until the desired weight gain is achieved. The tablets coated with the moisture barrier are subsequently dried prior to packaging.
The moisture barrier as used herein does not function as an enteric coat. Even though the methacrylic acid copolymer, Eudragit� L 30 D-55, is referenced and is used in enteric coating formulations in the art, its functionality is formulation dependent and on the quantity of the material applied. As is known in the art, an enteric coating is applied where a drug may be destroyed or inactivated by gastric juice or where the drug may irritate the gastric mucosa. To meet the requirements for an enteric coat, the test as described in the USP (method A or B) stipulates that after 2 hours in acidic media (0.1N HCl), no individual values of at least six experiments exceed 10% of the active drug dissolved and not less than 75% dissolved at 45 minutes in pH 6.8. The moisture barrier does not meet this requirement for the following reasons even though the bupropion hydrochloride is not negatively affected in acidic media nor is it irritating the gastric mucosa: (1) to obtain enteric integrity with a film containing Eudragit� L 30 D-55, a weight gain of between about 6% to about 8% based on the dry polymer per dosage unit is recommended. The amount of Eudragit� L 30 D-55 solid applied onto the control-releasing coated tablet cores is no more than 6% and preferably no more than 2.5%, (2) if enteric integrity would be required, the dissolution test for the finished product (i.e., the moisture barrier coated tablet cores) at the 2 hour time point would not stipulate a limit of no more than 20%, and (3) analytical tests performed on the final two coat product indicate that the product does not meet all the test requirements as an enteric coated product as defined by USP test methods. Since the moisture barrier is applied directly onto the control release coat, tests were conducted to determine if the moisture barrier applied directly onto the immediate release tablet cores function as an enteric coat. Tests show that after 1 hour more than 40% of the bupropion hydrochloride is released from the tablet cores in 0.1 N HCl and hence does not fall within the definition of the USP for an enteric coat (see Example 2). The functionality of the moisture barrier was also confirmed by determining the moisture content using the Karl-Fischer (KF) test of the individually coated control releasing and moisture barrier coated tablet cores under accelerated conditions (40� C.�2� C./75% RH�5% RH) in an open glass dish for 10 days (see Example 2). The results show that moisture content for the control-releasing coated tablet cores is higher than for the moisture barrier coated tablet cores. Cumulatively these data establish the functionality of the moisture barrier as a coat, which substantially impedes or retards the absorption of moisture and not as an enteric coat as defined by the USP.
The positive impact on stability of the modified-release bupropion hydrochloride tablet of the formulation described herein is evident in the tests performed to evaluate the total impurities present in either the 150 mg or 300 mg dosage forms through 6 months under accelerated conditions (40� C.�2� C./75% RH�5% RH) as well as through 12 months and 18 months of long-term stability at 25� C.�2� C./60% RH�5% RH. The stability tests showed reduced values (relative to Wellbutrin SR) in total impurities in tablets.
In 7 count, 40 cc and 30 count, 100 cc HDPE bottles for both the 150 mg and 300 mg dosage strength modified-release tablets of the invention for example, the total impurities present should be no more than about 2.5% by weight of the amount of bupropion hydrochloride in the tablet, preferably no more that about 1.5%, and most preferably no more that about 0.6% through at least 12 months of long-term stability at 25� C.+2� C./60% RH�5% RH. At 18 months of long-term-stability at 25� C.�2� C./60% RH�5% RH, the total impurities present should be no more than about 2.5% by weight of the amount of bupropion hydrochloride in the tablet, preferably no more than about 1.5%, and most preferably no more than about 0.7% by weight of the amount of bupropion hydrochloride in the tablet. Thus, the modified-release bupropion hydrochloride tablet according to the present invention contains at least about 95% w/w and more preferably at least 98% or even at least 99% of undegraded bupropion hydrochloride after storage for 12 or 18 months of long-term stability under the humidity and temperature conditions usually encountered in pharmacies and medicine cabinets i.e. room temperature and 35-60% humidity. Thus, when used in a pharmaceutical preparation for example, a tablet, it will still retain at least 95% of its potency and preferably at least 98% or even 99% of its potency after one year of storage at room temperature (15�-25� C.) at 35-60% humidity. For example if the tablet initially contains 300 mg bupropion hydrochloride (labeled amount) at time of preparation, after one-year storage at least 285 mg of bupropion hydrochloride and preferably at least 294 mg or more will remain in the tablet.
(mg/%)1 (mg/%)
(mg/%)
150/81.1 150/82.4 150/79 300/79
300/87.6 300/83.5
Binder2 5.3/2.86
5.3/2.9 5.3/2.8 10.6/2.8
10.6/3.1 10.6/2.95
Lubricant3 4.7/2.54
4.7/2.58
4.7/2.46
9.4/2.48
9.4/2.74 9.4/2.61
Purified water4 *
160/86.48
160/87.91
160/83.77
320/84.43
320/93.47
320/89.02
The water is first heated to 60�5� C. The binder (polyvinyl alcohol) is next dissolved in the water to homogeneity and then passed through a 0.7 mm mesh screen and allowed to cool to a temperature of no more than about 30� C. Bupropion hydrochloride is placed in the top spraying chamber of a fluidized bed apparatus, such as for example a Glatt GPCG1 fluidized bed apparatus. The solution binder (i.e., the polyvinyl alcohol solution) is sprayed onto the bupropion hydrochloride, with the in-process parameters shown in Table 2:
Pump flow rate (g/min)
50� C.-70� C.
30� C.-50� C.
Spraying pressure (Bar)
Once the granulation is completed, the granules are allowed to dry and then cooled to a temperature of no more than about 35� C. The bupropion hydrochloride granules are then passed through a 1.4 mm mesh sieve.
(mg/%1)
Water-insoluble water-
10.26/5.55 5.63/3.1 12/6.28
19/5.01
6.71/1.96
13.05/3.63
polymer2 Water soluble polymer3 5.64/3.05
7.5/4.1
9/4.7
18.06/4.77 6.37/1.86
12.40/3.45
Plasticizer4 2.1/1.14
1.88/1.03
5.16/1.36
1.82/0.53
3.55/0.99
Alcohol 95%5 Isopropyl Alcohol 99%5 *
Dry weight of control-
18/9.73
15/8.24
24/12.56
42.22/11.14
14.9/4.35
29/8.07
2Ethylcellulose 100 (Ethocel �)
3Polyvinylpyrrolidone (Kollidon � 90F)
4Polyethylene Glycol 1450 (Carbowax �)
The plasticizer (polyethylene glycol 1450) followed by the water-insoluble water permeable film-forming polymer (ethylcellulose 100) is added to a portion of a mixture of the denatured ethyl alcohol and the isopropyl alcohol. Once mixed, the water-soluble polymer is gradually added to the above mixture to avoid large particles or clumping. The solution is mixed to homogeneity. The remainder of the denatured ethyl alcohol and isopropyl alcohol is then added to the coating mixture and mixing is continued until a homogeneous solution is achieved. The coating solution is then passed through a DeBee Homogenizer (nozzle size 7, process pressure at 8500�2000 psi and back pressure at 1000�250 psi). The homogenized coating solution is then sprayed onto the tablet cores in a tablet coater (O'Hara 36 Side Vent) with the process parameters shown in Table 4:
150 mg tablet cores
300 mg tablet cores
Pan Speed (rpm)
Inlet Air Temperature (� C.)
300 � 60 30 � 60
Spray Rate (g/min)
Atomizing Air Pressure (psi)
Pattern Air Pressure (psi)
Coating of the tablet cores with the control-releasing coat solution is continued until a weight gain of about 24 mg (wet coating range of about 22 to about 26 mg) and a weight gain of about 29 mg (wet coating range of about 27 to about 31 mg) is achieved for the 150 mg and 300 mg tablet cores respectively. Once the desired weight gain is reached, the coating is stopped and the coated tablet cores are dried at an inlet air temperature of about 35�2� C. with a pan speed set at about 2 rpm. The dried and cooled coated tablet cores are next coated with the moisture barrier formulation shown in Table 5:
Methacrylic Acid Co-
4.59/2.48
4.59/2.52
4.59/2.40
10.99/2.9 4.88/1.42
6.86/1.91
Polymer2 Plasticizer Combination
(D = 0.46
(D = 1.1
(D = 0.49
(D = 0.69
(D + E)3 E = 0.23)
E = 0.23)
E = 0.56)
E = 0.25)
E = 0.35)
0.69/0.38
0.69/0.36
0.74/0.21
1.04/0.29
Permeation enhancer4 1.72/0.93
1.72/0.95
1.72/0.90
4.11/1.08
1.83/0.53
2.57/0.71
Purified Water5 *
Dry weight of moisture
7/3.85
7/3.66
16.76/4.42 7.45/2.18
10.47/2.91 barrier
2poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit � L 30 D-55)
3D = Polyethylene Glycol 1450 (Carbowax �), E = Triethyl Citrate
4Silicon Dioxide (Syloid � 244)
The plasticizer combination, preferably polyethylene glycol 1450 and triethyl citrate, are first dissolved in a portion of the purified water and mixed to homogeneity. While the plasticizer solution is being mixed, the methacrylic acid copolymer, preferably Eudragit� L 30 D-55, is passed through a 0.3 mm mesh screen in a separate container. The plasticizer solution is next added to the methacrylic acid copolymer and mixed until a homogenous solution is achieved. While the methacrylic acid copolymer/plasticizer solution is being mixed, the permeation enhancer, preferably, silicon dioxide, is dissolved in the remainder of the water and mixed with a high shear mixer until the suspension is homogenous. The final moisture barrier solution is obtained by mixing the permeation enhancer solution with the methacrylic acid copolymer/plasticizer mixture. The homogenized moisture barrier solution is then sprayed onto the control release coated tablet cores in a coating pan with the process parameters as shown in Table 6:
The moisture barrier is applied until a weight gain of about 7 mg (wet coating tablet range of about 6.3 to about 7.7 mg) and about 10.5 mg (wet coating tablet range of about 9.5-11.5 mg) is achieved for the 150 mg and 300 mg dose modified release tablets respectively. Once the desired weight gain is reached, the coating is stopped and the coated tablets are dried at an inlet air temperature of about 35�2� C. with a pan speed set at about 2 rpm.
Medium: 900 ml, 0.1N HCl Method: USP Type I Apparatus (150 mg dose)/USP Type II Apparatus (300 mg dose), at 75 rpm and 37� C. The results are presented in Table 7 as the mean percent release of the total bupropion hydrochloride content in the coated tablets:
The formulations are free of a stabilizer. To determine the stability of the bupropion hydrochloride in the absence of stabilizer, stability tests were conducted both under accelerated conditions over 6 months at 40� C.�2� C./75% RH�5% RH and under long-term conditions over 12 and 18 months at 25� C.�2� C./60% RH�5% RH. At the end of the specified time period, the tablets were analyzed for impurities resulting from the degradation of bupropion hydrochloride by HPLC. The degradation products included those listed in the USP (26th edition, pg 281) and any other peaks that appeared on the chromatogram. The results of the stability analysis under both accelerated and long-term condition for both the 150 mg and 300 mg dosage forms is shown in Tables 8, 9 and 10:
Accelerated Conditions (40� C. � 2� C./75 � 5% RH)
150 mg1 300 mg1 Time
Moisture2 Impurities3 Moisture2 Impurities3 Moisture2 Impurities3 Moisture2 Impurities3 1
18 months of long-term stability
Medium: 900 ml 0.1 N HCl Method: USP Apparatus type I at 75 rpm at 37� C. TABLE 13
% Bupropion Hydrochloride dissolved
The functionality of the moisture barrier as a coat which substantially impedes or retards the absorption of moisture was confirmed by determining the Karl-Fischer moisture content of either control-releasing coated tablet cores or moisture barrier coated tablet cores for the 300 mg tablet cores. The preparation for the formulations is as described in Example 1. The respective coated tablets were placed separately under accelerated conditions (40� C.�2� C./75% RH�5% RH) in an open glass dish for 10 days. As shown in Table 14, the moisture content for the control-releasing coated tablet cores are higher than for the moisture barrier coated tablet cores.
Control-releasing Coated Tablet
Moisture barrier Coated Tablet Cores
A) 2�150 mg q.d. modified-release bupropion hydrochloride tablets of the invention administered orally with 240 mL of ambient temperature water following an overnight fast of at least 10 hours.
B) 1�300 mg q.d. modified-release bupropion hydrochloride tablets of the invention administered orally with 240 mL of ambient temperature water following an overnight fast of at least 10 hours.
The graphical mean plasma-concentration (ng/ml) profiles of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol, and erythroamino alcohol over a 120-hour time period after administration of the 2�150 mg once daily and the 1�300 mg once daily dosage forms are shown in FIGS. 3A-D respectively.
Tables 15a-d provide the mean (�SD) pharmacokinetic data for bupropion following administration of the 2�150 mg dosage strength tablet administered once daily or the 300 mg dosage strength tablet administered once daily:
Bupropion HCl 2 � 150 mg
Bupropion HCl 1 �
300 mg Modified-
1648.85 � 475.34
1676.61 � 474.09
1702.69 � 489.30
1728.34 � 478.43
150.11 � 37.22
146.88 � 47.61
4.99 � 0.76
5.20 � 0.88
22.70 � 7.42
21.84 � 7.35
0.036 � 0.017
0.037 � 0.018
22.28 � 5.50
22.92 � 5.50
HCl � 300 mg
Tablets of the
The relative (2�150 mg (q.d.) vs. 1�300 mg (q.d.)) bioavailability analysis results for AUC0-inf, AUC0-t, and Cmax, transformed using the natural logarithm under fasting conditions is summarized in Table 16 for bupropion and its metabolites:
Intra-Subject
AUC0-t 93.96%-102.76%
94.42%-106.07%
AUC0-inf 93.97%-102.88%
94.23%-105.81%
Cmax 97.77%-110.30%
97.76%-108.17%
AUC0-t 96.66%-109.16%
96.83%-110.30%
AUC0-inf 94.87%-108.57%
97.09%-110.89%
Cmax 100.06%-114.03% 106.82%
99.41%-111.26%
A four-way, crossover, open-label, single-dose, fasting and food-effect comparative bioavailability study of bupropion hydrochloride modified-release 150 mg tablets as described herein and in Example 1 and Zyban� 150 mg tablets in normal healthy non-smoking male and female subjects were conducted. This study was designed to evaluate the rate and extent of absorption of bupropion in the fed and fasted state after administration of 150 mg dosage strength bupropion hydrochloride modified-release tablets as described herein and in Example 1. In parallel, the rate and extent of absorption of bupropion in the fed and fasted state after administration of 150 mg dosage strength Zyban� tablets was also evaluated in this study.
C) 150 mg q.d. Zyban� tablets under fasting conditions, and
D) 150 mg q.d. Zyban� tablets under fed conditions.
The graphical mean plasma-concentration (ng/ml) profiles of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol, and erythroamino alcohol over a 72-hour time period after administration of the 1�150 mg once daily modified-release tablets of the invention and the 1�150 mg once daily dosage form of Zyban� are shown in FIGS. 4A-E.
Table 17 provides the mean (�SD) pharmacokinetic data for bupropion following administration of the 150 mg dosage strength modified-release tablets of the invention or the commercially available prior art Zyban� tablets under fasting and fed conditions for bupropion and its metabolites:
Release Tablets of
Zyban � 150 mg
825.1787
882.1834
840.5866
1002.9491
864.56 � 259.86
918.59 � 271.21
881.48 � 270.64
1048.50 � 306.63 (30.06)
886.1622*
926.4870*
884.2148*
1043.8802*
923.43 � 263.01
966.18 � 290.02
929.01 � 291.01
1092.41 � 326.05 (28.48)
78.2884
73.1637
92.1115
124.3873
81.78 � 24.47
75.75 � 19.77
96.96 � 31.38
128.81 � 32.03 (29.93)
Tmax (hours)†
5.13 � 1.13
6.59 � 2.18
3.04 � 0.77
3.88 � 1.01
t1/2 (hours)†
18.17 � 6.35*
19.26 � 6.77*
19.88 � 5.91*
19.48 � 5.45*
Kel (hour−1)†
0.044 � 0.018*
0.041 � 0.017*
0.039 � 0.017*
0.039 � 0.015*
(41.996)
(38.386)
MRT0-inf (hours)†
4.81 � 2.38*
5.18 � 2.99*
4.69 � 2.25*
4.34 � 2.00*
10745.045 10939.113 11514.933 12975.263 12611.91 � 8151.69 12604.70 � 7739.11 12976.49 � 6817.46 14679.97 � 8184.51 (64.63)
11209.310 11383.270 11910.790 13397.186* 13034.17 � 8207.41 13049.55 � 7933.08 13344.28 � 6863.47 15129.56 � 8370.60 (62.97)
(60.79)
222.2716
230.4191
294.8008
301.9918
245.61 � 119.94
252.46 � 112.93
316.89 � 125.90
325.85 � 131.69
15.22 � 6.14 15.38 � 4.35 6.04 � 1.18
7.19 � 2.91
25.19 � 5.90 25.26 � 5.98 25.37 � 6.14 25.68 � 5.70*
0.029 � 0.007
0.029 � 0.008
0.028 � 0.006*
5.78 � 4.17
5.78 � 3.20
4.84 � 2.22
4.01 � 1.87*
M/P ratio†
3.851 � 1.097
4.029 � 1.210
3.874 � 1.214
4.556 � 1.360
4223.4179
4397.5375
4376.0423
5042.7155
4686.42 � 2736.63
4969.37 � 3229.17
4832.84 � 2671.85
5478.16 � 2694.10
(64.98)
4466.6770
4702.2669
4644.3189
5346.5138
5006.42 � 3088.85
5360.00 � 3691.31
5147.80 � 2897.63
5853.85 � 3083.18*
81.8673
87.4966
107.2111
124.7860
88.43 � 37.68
93.97 � 36.82
112.12 � 34.64 130.65 � 40.68 (42.61)
10.03 � 3.62 11.94 � 3.39 5.76 � 1.02
5.38 � 0.95
49.27 � 14.83
50.94 � 15.39
51.44 � 14.06
52.82 � 14.82*
0.014 � 0.004
0.014 � 0.004*
15.81 � 12.98
17.89 � 13.50
16.52 � 12.41
18.23 � 14.02*
(82.07)
615.3554
662.8840
666.6066
766.3201
675.24 � 321.49
722.75 � 341.87
716.66 � 300.64
823.24 � 320.87
711.3752
754.6092
750.7705
839.2428
768.15 � 333.66
816.35 � 372.52
802.32 � 315.77
893.65 � 330.20*
13.6946
14.6158
17.2653
18.1560
14.17 � 3.85 15.04 � 3.56 17.55 � 3.23 18.50 � 3.84 (27.14)
15.57 � 4.65 14.88 � 3.09 6.85 � 1.92
7.88 � 3.83
29.14 � 8.77 30.39 � 10.17
29.69 � 9.37 31.38 � 10.74*
0.026 � 0.007
0.025 � 0.008
0.026 � 0.009
0.024 � 0.007*
17.10 � 6.30 16.94 � 9.04 15.10 � 5.65 15.09 � 6.62*
†Expressed as Arithmetic Mean � SD (% CV)
Subject CV
AUC0-t 101.74%-112.23%
106.852%
95.30%-109.76%
16.971%
AUC0-inf 100.18%-109.60%
104.788%
10.533%
95.48%-108.95%
101.993%
15.844%
Cmax 86.58%-100.13%
93.107%
17.470%
97.20%-111.36%
104.043%
16.336%
AUC0-t 98.77%-109.74%
104.108%
12.646%
101.02%-114.99%
107.780%
15.564%
AUC0-inf 100.03%-110.79%
105.274%
12.269%
100.49%-112.09%
106.132%
13.127%
Cmax 100.41%-113.77%
106.884%
14.998%
101.23%-112.49%
106.712%
12.662%
A) 1�300 mg modified-release tablet after a 1 hour fast.
B) 1�300 mg modified-release tablet after complete intake of a high fat breakfast.
The graphical mean plasma-concentration (ng/ml) profiles of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol, and erythroamino alcohol over a 120-hour time period after administration of the 1�300 mg once daily modified-release tablets of the invention under fed and fasting conditions are shown in FIGS. 5A-D respectively.
Table 19 provides mean (�SD) pharmacokinetic data for bupropion and its metabolites following administration of the 300 mg dosage strength modified-release tablets of the invention under fasting and fed conditions:
1775.45 � 530.77
1628.38 � 511.15
AUC0-inf 1832.54 � 548.50
1678.36 � 521.18
138.36 � 42.35
151.35 � 48.87
Tmax (hour)
6.16 � 1.84
5.16 � 0.86
21.76 � 5.85
21.21 � 6.17
0.035 � 0.011
0.036 � 0.012
MRT (hour)
22.56 � 4.60
21.58 � 4.23
19733.51 � 9411.52
18938.84 � 8387.21
AUC0-inf 20886.13 � 10230.69
19852.73 � 9049.54
449.05 � 181.73
409.79 � 154.84
14.32 � 3.18
13.71 � 5.15
24.11 � 5.21
23.95 � 4.84
42.03 � 7.60
41.08 � 6.13
10.5919 � 3.8325
11.3178 � 4.6281
9769.69 � 6136.11
9032.19 � 6595.77
AUC0-inf 13280.57 � 9398.23
11696.29 � 9018.00
208.39 � 98.15
182.52 � 99.62
12.26 � 3.36
9.94 � 4.84
55.09 � 17.66
55.25 � 20.72
79.10 � 25.10
78.60 � 28.28
6.9435 � 3.8129
6.6417 � 3.4215
1803.45 � 693.19
1634.56 � 741.60
AUC0-inf 2116.01 � 1026.23
1867.74 � 971.96
35.80 � 9.13
31.03 � 9.97
14.74 � 2.71
14.16 � 3.85
35.23 � 12.03
33.89 � 11.02
0.022 � 0.006
57.78 � 17.49
54.75 � 14.45
1.1322 � 0.3876
1.0947 � 0.3952
AUC0-t 104.00%-116.57%
96.27%-111.84%
AUC0-inf 104.18%-116.49%
97.03%-112.72%
Cmax 84.49%-100.86%
103.44%-116.91%
AUC0-t 104.31%-121.18%
104.06%-123.56%
AUC0-inf 104.15%-125.65%
105.26%-126.61%
Cmax 110.61%-124.96%
110.14%-126.40%
117.99%
A two-way, crossover, steady state, multiple-dose, open-label, fasting, comparative bioavailability study of a once-daily bupropion hydrochloride 300 mg modified-release tablet of the invention versus the immediate release thrice daily Wellbutrin� 100 mg tablets in normal healthy non-smoking male and female subjects was conducted. This study was designed to evaluate the bioavailability of a once daily 300 mg dosage strength of the modified-release tablets of the invention relative to the commercially available prior art thrice daily immediate release Wellbutrin� tablets under steady-state, fasting conditions.
A) Wellbutrin� 100 mg tablets were administered orally at 0.0 hours (starting at 7:00 AM) on Days 1, 2, and 3 (b.i.d.) with 240 ml of ambient temperature water following an overnight fast of at least 10 hours. All subjects also received a second dose of 1 Wellbutrin� 100 mg tablets at 12.0 hours with 240 ml of ambient temperature water after a fast of at least 1 hour. On days 4-13, subjects received one 300 mg dosage strength bupropion hydrochloride modified-release tablet of the invention at 0.0 hours (starting at 7: AM) with 240 ml of ambient temperature water following an overnight fast of at least 10 hours.
B) Wellbutrin� 100 mg tablets were administered orally at 0.0 hours (starting at 7:00 AM) on Days 1, 2, and 3 (b.i.d.) with 240 ml of ambient temperature water following an overnight fast of at least 10 hours. All subjects also received a second dose of 1 Wellbutrin� 100 mg tablet at 12.0 hours with 240 ml of ambient temperature water after a fast of at least 1 hour. On days 4-13, subjects received 1 Wellbutrin� 100 mg tablet at 0.0 hours (starting at 7:00 AM) with 240 ml of ambient temperature water, following an overnight fast of at least 10 hours. All subjects then received a second dose of 1 Wellbutrin� 100 mg tablet at 6.0 hours with 240 ml of ambient temperature water following a fast of at least 1 hour. All subjects also received a third dose of 1 Wellbutrin� 100 mg tablet at 12.0 hours with 240 ml of ambient temperature water, following a fast of at least 1 hour.
The graphical mean plasma-concentration (ng/ml) profiles of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol, and erythroamino alcohol over the study period after administration of the 1�300 mg once daily modified-release tablets of the invention and the Wellbutrin� 3�100 mg tablets are shown in FIGS. 6A-E respectively.
Table 21 provides the mean (�SD) pharmacokinetic data for bupropion following administration of the once daily 300 mg dosage strength modified-release tablet of the invention or the thrice-daily commercially available prior art Wellbutrin� 100 mg tablet:
Wellbutrin � 100 mg
AUC0-τ (ng � hr/mL)
1612.04 � 490.27 1791.98 � 483.43 Cmax (ng/mL)
167.50 � 46.56 175.40 � 56.03 Cmin (ng/mL)
27.64 � 10.73
34.06 � 12.49
4.90 � 0.89
1.60 � 0.58
Degree of Fluctuation
212.56 � 39.42 189.98 � 38.99 (%)
67.17 � 20.43
74.67 � 20.14
Degree of Swing (%)
554.59 � 193.21
439.58 � 141.64
12.92 � 5.31 12.61 � 5.11 Hydroxybupropion
20824.77 � 7423.56 22456.08 � 6889.20 Cmax (ng/mL)
1095.64 � 385.06 1156.34 � 339.34 Cmin (ng/mL)
722.23 � 281.76
800.90 � 262.97
7.30 � 2.45
2.47 � 0.83
44.34 � 16.57
40.78 � 31.24
867.70 � 309.32
935.67 � 287.05
54.65 � 22.48
49.19 � 40.60
7.01 � 1.84
6.91 � 1.81
10987.88 � 3193.09 12051.42 � 3107.48 Cmax (ng/mL)
585.36 � 155.83
629.81 � 138.84
364.42 � 122.60
415.71 � 122.32
7.83 � 2.15
2.49 � 0.81
50.47 � 17.22
45.25 � 21.80
457.83 � 133.05
502.14 � 129.48
65.68 � 26.11
56.34 � 29.48
1.39 � 0.44
1.36 � 0.43
2145.70 � 615.22 2353.73 � 645.40 Cmax (ng/mL)
109.07 � 29.98 119.37 � 26.82 Cmin (ng/mL)
76.51 � 25.69
85.59 � 26.63
8.37 � 2.04
2.40 � 0.66
38.11 � 15.25
38.90 � 33.91
89.40 � 25.63
98.07 � 26.89
46.04 � 20.70
46.18 � 43.72
The relative (modified-release tablets of the invention v. Wellbutrin�) bioavailability analysis results for AUC0-τ and Cmax for bupropion and its metabolites transformed using the natural logarithm is summarized in Table 22:
AUC0-τ 86.14%-92.64%
87.00%-95.42%
Cmax 91.08%-103.00%
85.98%-99.90%
AUC0-τ 87.17%-94.21%
87.32%-94.66%
Cmax 87.42%-97.28%
84.84%-95.89%
The data in Tables 21 and 22 show that a 300 mg dosage strength modified-release tablet of the invention administered once daily is bioequivalent to the 100 mg dosage strength immediate release Wellbutrin� administered thrice daily.
A two-way, steady state, crossover, open-label, multiple-dose, fasting, comparative bioavailability study of the 300 mg modified-release bupropion hydrochloride tablets of the invention versus the commercially available prior art 150 mg Zyban� product in normal healthy non-smoking male and female subjects was carried out. The study was designed to compare the bioavailability of the 300 mg q.d. dosage form of the modified-release bupropion hydrochloride tablets of the invention against the commercially available prior art 150 mg b.i.d. Zyban� tablets.
The study design followed a 2-period, 2-treatment, multiple-dose crossover design under fasting conditions. The study periods were separated by a 2-week washout interval. A total of 54 subjects (40 Male, 14 Female) were enrolled in the study of which 49 of the subjects (37 Male, 12 Female) completed the study. Subjects were administered 150 mg q.d. Zyban� tablets from days 1-3 of the study. Days 4-17 were followed by:
B) 1.50 mg b.i.d. Zyban� tablets.
The graphical mean plasma-concentration (ng/ml) profiles of bupropion and its metabolites hydroxybupropion, bupropion threoamino alcohol, and erytlroamino alcohol over the study period after administration of the 1�300 mg once daily modified-release tablets of the invention and the 2�150 mg (b.i.d.) Zyban� tablets under fasting conditions are shown in FIGS. 7A-E respectively.
Table 23 provides the mean (�SD) pharmacokinetic data for bupropion following administration of the once daily 300 mg dosage strength modified-release tablet of the invention or the commercially available prior art 150 mg b.i.d. Zyban� tablet:
Modified Release Bupropion
HCl Tablets of the Invention
1412.4767
1561.9651
1464.21
1617.72
143.9693
135.9517
23.1224
25.3277
Degree of Swing (%)*
Cave (ng/mL)*
MRT (hours)*
19688.697
21984.655
21255.88
23792.58
1035.5625
1114.0976
1200.37
669.3453
775.6489
MRT(hours)*
M/P Ratio*
9040.7734
110398.325
9638.64
11100.02
494.6250
542.8864
285.9451
339.2713
1784.5115
2033.8788
1875.33
92.4622
101.5651
61.3442
The relative (modified-release tablets of the invention v. Zyban�) bioavailability analysis results for AUC0-t, Cmax and Cmin transformed using the natural logarithm for bupropion and its metabolites is summarized in Table 24:
AUC0-τ 87.19%-93.93%
85.87%-93.26%
Cmax 99.25%-113.46%
89.02%-97.00%
Cmin 85.77%-97.00%
82.22%-90.34%
AUC0-τ 83.91%-90.09%
84.48%-91.09%
Cmax 86.76%-95.78%
86.95%-95.44%
Cmin 80.45%-88.16%
81.61%-89.60%
The data in Tables 23 and 24 show that a 300 mg (q.d.) dosage strength modified-release bupropion hydrochloride tablet of the invention is bioequivalent to the 150 mg b.i.d sustained-release commercially available prior art Zyban� tablet.
Binder1 5.30
Lubricant2 4.70
Purified Water3 110.00
Total core weight
Water-insoluble water
polymer4 Water-soluble polymer5 4.70
Plasticizer6 2.34
Ethyl Alcohol3 190.00
Isopropyl Alcohol 99%3 10.00
Total dry first coat
Copolymer7 Glidant8 2.30
Plasticizer9 2.25
Purified water3 48.00
Total dry second coat
4Ethyl cellulose 100 Premium (Ethocel �)
5Polyvinylpyrrolidone (Kollidon � 90F)
6Polyethylene Glycol 1450 (Carbowax �)
7poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit � L 30 D-55)
9Silicon Dioxide (Syloid � 244)
A pilot three-way multiple-dose open-label fasting comparative bioavailability study of bupropion hydrochloride tablets (2�150 mg q.d.) made according to the '327 patent (the ‘327 patent formulation’) versus the commercially available Zyban� sustained-release tablets (1�150 mg b.i.d.) and Wellbutrin� tablets (t.i.d.) in normal healthy smoking and non-smoking male volunteers was conducted. The purpose of the study was to evaluate the relative bioavailability of bupropion hydrochloride 150 mg of the 327 formulation (2�150 mg q.d.) relative to Zyban� 150 mg sustained-release tablets (1�150 mg b.i.d) and Wellbutrin� 100 mg tablets (1�100 mg t.i.d.) under single dose or steady-state fasting conditions.
Table 26 shows the mean (�SD) plasma concentration-time profiles for bupropion (ng/ml) under single dose conditions:
2 � 150 mg (q.d.)
Wellbutrin � tablet
tablet of the ′327
150 mg SR tablets
100 mg (3 � 100 mg
patent (A)
(1 � 150 mg b.i.d.) (B)
t.i.d) (C)
11.71 � 3.55 8.25 � 2.74
30.01 � 17.82
11.08 � 2.90 53.87 � 14.58
113.91 � 40.96 2.0
12.95 � 4.38 75.96 � 13.83
104.04 � 20.62 4.0
60.60 � 24.59
83.71 � 12.49 58.45 � 12.90
45.92 � 10.65
98.23 � 31.28
64.03 � 13.95
85.54 � 80.91
104.45 � 39.11 8.0
82.63 � 23.84
41.69 � 7.81 ND
76.79 � 15.73
50.28 � 15.09
59.47 � 18.45
21.50 � 4.50 110.38 � 71.29 13.0
51.03 � 34.38
120.69 � 32.81 14.0
84.04 � 41.74
75.30 � 20.36
86.15 � 37.20
58.53 � 15.44
32.46 � 9.52 55.48 � 13.29
33.45 � 7.40 24.0
20.21 � 5.28 27.81 � 7.77 24.14 � 6.03 Table 27 provides the mean (�SD) pharmacokinetic data for bupropion following administration of the tablets shown in Table 25:
Wellbutrin �
AUC0-24 1154.65 � 244.28
1301.05 � 214.94
1622.89 � 318.02
103.77 � 28.13
112.68 � 37.06
163.10 � 56.84
6.40 � 1.88
11.07 � 5.85
6.87 � 5.60
The relative bioavailability analysis results for AUC0-24 (ng�hr/ml), and Cmax (ng/ml) shown in Table 27, transformed using the natural algorithm is summarized in Table 28:
AUC0-24 Cmax Ratio of
78%-99%
78%-111%
63%-80%
54%-76%
Table 29 shows the mean (�SD) steady-state plasma concentration-time profiles for bupropion (ng/ml) for the tablet composition shown in Table 25:
Zyban 150 mg SR
(q.d.) tablet
tablets (1 � 150 mg
of the ′327 patent
t.i.d)
20.21 � 5.28 27.81 � 7.77 24.14 � 6.03 0.0
22.22 � 5.80 34.12 � 8.51 27.11 � 8.31 0.0
21.58 � 6.21 32.70 � 9.94 27.33 � 8.79 0.0
23.44 � 8.31 31.96 � 8.83 28.71 � 11.05
21.47 � 7.06 64.22 � 18.93
112.09 � 29.65 2.0
24.37 � 8.77 90.76 � 18.63
116.66 � 27.01 4.0
87.61 � 36.30
94.97 � 19.30
61.94 � 16.35
49.43 � 13.56
101.39 � 25.48 73.35 � 17.94
85.34 � 52.23
112.05 � 46.38 8.0
77.06 � 16.40
52.56 � 11.74
87.11 � 23.77
55.49 � 17.50
58.88 � 16.23
31.23 � 9.05 115.93 � 53.59 13.0
58.01 � 21.81
117.74 � 39.87 14.0
105.36 � 42.68 ND
74.33 � 17.77
93.55 � 23.49
60.45 � 14.56
34.69 � 8.82 65.80 � 14.61
39.86 � 12.55
23.30 � 6.75 33.15 � 9.39 29.49 � 10.09
8.80 � 4.20
12.02 � 4.84 11.11 � 4.68 72.0
4.61 � 2.60
5.75 � 3.06
5.59 � 2.75
2.25 � 1.82
3.03 � 2.01
2.35 � 1.45
1.01 � 1.12
1.43 � 1.44
1.35 � 1.53
Table 30 shows the mean (�SD) pharmacokinetic data for bupropion under steady state conditions following administration of the tablets shown in Table 25:
327 formulation
AUC0-24 1251.45 � 257.24
1554.77 � 293.70
1728.31 � 374.54
112.24 � 26.42
119.77 � 27.76
156.19 � 32.27
5.33 � 1.23
11.47 � 5.04
9.00 � 4.14
The relative bioavailability analysis results for AUC0-24 (ng�hr/ml), and Cmax (ng/ml) shown in Table 30, transformed using the natural algorithm is summarized in Table 31:
AUC(0-24) Cmax Ratio of
71%-91%
82%-108%
64%-82%
62%-82%
The pharmacokinetic and relative bioavailability data show that the 90% CI for the formulation as taught in the '327 patent does not fall within the FDA suggested 80%-125% range for a product to be bioequivalent. Accordingly, the data show that the '327 patent formulation is not bioequivalent to the commercially available Zyban�/Wellbutrin� SR or Wellbutrin� tablets.
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