JP2011140510A - Modified-release tablet of bupropion hydrochloride - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a modified-release tablet of a pharmaceutically permissible salt of bupropion, preferably bupropion hydrochloride. <P>SOLUTION: This modified-release tablet of bupropion hydrochloride includes (i) a core containing an effective amount of bupropion hydrochloride, a binder and a lubricant, (ii) a controlled-release coat enclosing the core and (iii) a moisture-barrior layer enclosing the coat, and is biologically equivalent to Wellbutrin (R) or Zyban (R)/Wellbutrin (R) SR tablet. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a modified release tablet of pharmaceutically acceptable salt of bupropion, preferably bupropion hydrochloride.

  Bupropion is an antidepressant that is chemically unrelated to tricyclic drugs, tetracyclic drugs, selective serotonin reuptake inhibitors (SSRIs), or other known antidepressants. This drug is similar to a psychostimulant in terms of its neurochemical and behavioral profile in vivo, but it does ensure a stimulant effect in humans at clinically prescribed doses. Does not occur. Its structure is very similar to that of diethylpropion and is related to phenylethylamine. Bupropion is named (±) -1- (3-chlorophenyl) -2-[(1,1-dimethylethyl) amino] -1-propanone hydrochloride and is represented by its generic name amphetamon hydrochloride. Bupropion hydrochloride is marketed as an immediate release form (Wellbutrin®) and a sustained release form (Wellbutrin® SR and Zyban®). Wellbutrin® SR and Zyban® are both chemically and pharmaceutically identical.

  Little is known about the neurochemical mechanism of bupropion's antidepressant effect. Bupropion does not inhibit monoamine oxidase. Bupropion affects the chemicals in the brain that nerves use to send messages to each other. These chemical messengers are called neurotransmitters. Neurotransmitters released by nerves are taken up again by nerves that release them for reuse (this is called reuptake). Many experts believe that depression is caused by an imbalance in the amount of neurotransmitter released. Bupropion functions by inhibiting reuptake of the neurotransmitters dopamine, serotonin, and norepinephrine, and its action is made more dopamine made available to transmit messages to other nerves, It is thought to result in serotonin and norepinephrine. Thus, bupropion is unique in that its main effect is on dopamine, and the effect is SSRI (eg, paroxetine (Paxil®), fluoxetine (Prozac®), sertraline. (Zoloft®)) or a tricyclic antidepressant or TCA (eg, amitriptyline (Eravir®), imipramine (tofuranyl®), desipramine (Norpramine®)) Not.

  Wellbutrin® and Wellbutrin® SR are used for the management of depression. Zyban® is approved as an aid for patients who want to quit smoking. Wellbutrin®, an immediate release formulation of bupropion, is administered 3 times a day, preferably 6 hours or more between doses. For patients who need more than 300 mg bupropion per day, each dose should not exceed 150 mg. This requires administration of the tablet at least 4 times a day with at least 4 hours between administrations. Immediate release formulations result in more than 75% release of bupropion into the dissolution medium in about 45 minutes, one of the main side effects of bupropion being seizure occurrence, Seems to be strongly related to the immediate release of bupropion into the system. Therefore, sustained release products have been developed to avoid the occurrence of seizures. The sustained release product is administered twice a day.

  In general, patient compliance is a problem associated with medication that requires a multi-dose regimen, and is especially problematic for those with depression. While sustained release formulations have simplified dosing regimens and increased patient compliance, there is still room to further simplify dosing formulations and further improve patient compliance with dosing formulations. The development of an approved stable once daily modified release bupropion formulation would be an advance in the art.

  A sustained release tablet form of bupropion has been reported in the prior art. U.S. Pat. No. 4,687,660 is in the form of a core and a coating, the core comprising bupropion hydrochloride, one or more excipients, and optionally an osmotic enhancing agent. A coating comprising a water-insoluble, water-permeable film-forming polymer (such as cellulose acetate), and a pore-forming agent (such as fine lactose and sodium carbonate), and optionally Disclosed are tablets containing so-called water permeability promoters (such as polyethylene glycol) and optionally also a plasticizer.

  US Pat. Nos. 5,358,970 and 5,427,798 describe sustained release formulations of bupropion hydrochloride based on matrix technology. The term matrix refers to a tablet in which the drug is embedded in an excipient that makes a non-disintegrating core called a matrix. Drug diffusion occurs through this core. Because bupropion hydrochloride is unstable, the products described in the above two patents require a stabilizer to obtain sufficient stability. This stabilizer is an acidic compound, preferably cysteine hydrochloride. The main drawback of matrix systems is that they generally exhibit a primary release profile. That is, drug particles on the surface of the tablet are first eluted and the drug is released rapidly. Thereafter, the drug particles are eluted in order of increasing distance from the surface of the tablet, and are released to the outside of the tablet by diffusion in the pores. Thus, the diffusion distance of the drug will increase as the release process proceeds. It is usually preferred to obtain a zero order or near zero order release profile rather than a first order release profile. A zero order release system provides a constant rate of drug release over a defined time. Primarily, this system is used for drugs with a short half-life so that a constant blood concentration of the active drug compound can be maintained with fewer doses.

  US Pat. No. 6,589,553 and International Publication No. WO 02/062299 describe a once-daily capsule formulation with two populations of coated pellets, each releasing bupropion hydrochloride at different pH. ing. One population of pellets is coated to release the drug at a pH corresponding to about 4.8 or less. Release of drug from this population of pellets is expected to occur in the upper gastrointestinal tract. The other population of pellets is coated to release the drug at a pH of 7 or higher. Release of bupropion from this population is expected to occur in the lower gastrointestinal tract. In the example shown, the relative bioavailability of bupropion to Zyban was only 40% for the Cmax ratio and only 80% for the AUC0-inf ratio. In another example shown, the relative bioavailability of bupropion to Zyban was only 48% and 59% for Cmax and AUC0-inf. In addition, this reference describes the introduction of a third population of uncoated active pellets and is said to result in further modification and improvement of bupropion release. Based on the mean plasma concentration-time profiles shown in FIGS. 3 and 4 of these references, it is easy to introduce an uncoated active pellet into a once-daily bioequivalent formulation. Is not clear (the reference product is Zeiban®). Neither of the two references gives any drug stability data.

  US Pat. No. 6,033,686 discloses a core consisting essentially of bupropion hydrochloride, a binder and a lubricant, and a water-insoluble and water-permeable film-forming polymer, plasticizer and water-soluble A controlled release tablet comprising a coating comprising a polymer, no stabilizer and no pore former. The product derived from this' 686 patent is a product twice a day.

  US Pat. Nos. 6,096,341 and 6,143,327 both relate to delayed release formulations of bupropion hydrochloride. US Pat. No. 6,096,341 consists essentially of a core consisting of bupropion hydrochloride, a binder and a lubricant, and essentially consists of a water-insoluble and water-permeable film-forming polymer, a plasticizer and a water-soluble polymer. And a controlled release tablet without a stabilizer and without a pore former. US Pat. No. 6,143,327 discloses a core consisting essentially of bupropion hydrochloride, a binder and a lubricant, and a control consisting essentially of a water-insoluble and water-permeable film-forming polymer, a plasticizer and a water-soluble polymer. A controlled-release tablet comprising a control-releasing coating and a second coat consisting essentially of a methacrylic polymer and a plasticizer, free of stabilizers and free of pore formers. ing. However, the formulation described in US Pat. No. 6,143,327 does not meet FDA guidelines for bioequivalence (see Example 8 herein).

U.S. Pat. No. 4,687,660 US Pat. No. 5,358,970 US Pat. No. 5,427,798 US Pat. No. 6,589,553 International Publication WO02 / 062299 US Pat. No. 6,033,686 US Pat. No. 6,096,341 US Pat. No. 6,143,327

  At present, there are no approved commercial stable once-daily dosage forms of bupropion dosage forms. Accordingly, there is a need for a stable once-daily dosage form of a bioequivalent formulation of bupropion or a pharmaceutically acceptable salt thereof.

(Definition)
“Modified release dosage form” is defined by the USP as a dosage form whose drug release characteristics with respect to time and / or location are selected to achieve a therapeutic or convenience objective not provided by conventional forms. . Extended-release dosage forms allow for halving the number of doses or improving patient compliance or treatment performance. The USP considers terms such as controlled release, long term release and sustained release to be compatible with extended release. Thus, “modified-release”, “controlled-release”, “prolonged-release”, “extended-release”, and “sustained-release”. The term “)” is used interchangeably herein.

  The term “pharmaceutically acceptable salt of bupropion” includes salts that are physiologically tolerated by a patient. Usually, such salts are prepared from inorganic acids or bases and / or organic acids or bases. Examples of such acids and bases are well known to those skilled in the art. Although the present invention specifically contemplates the use of bupropion hydrochloride, the use of other pharmaceutically acceptable salts is within the scope of the present invention. As used herein, the term “effective amount” means “pharmaceutically effective amount”. A “pharmaceutically effective amount” is the amount or quantity of a pharmaceutically acceptable salt of bupropion that is sufficient to elicit an apparent biological response when administered to a patient. Of course, the exact therapeutic amount will depend on the age and condition of the patient and the nature of the condition being treated and will be at the ultimate judgment of the attending physician.

  As used herein, the term “moisture barrier” is a barrier that prevents or delays moisture absorption. Since bupropion hydrochloride is extremely hygroscopic, it is known to be relatively unstable and susceptible to degradation particularly with time under high humidity conditions. The proportion of moisture barrier components and the amount of moisture barrier applied over the controlled release coat ensures that the moisture barrier is not included in USP definitions and requirements for enteric coats. The moisture barrier preferably comprises an enteric and / or acrylic polymer, preferably an acrylic polymer, optionally a plasticizer, and a penetration enhancer. Penetration enhancers are hydrophilic substances that allow water to enter without physical destruction of the coating. The moisture barrier may further contain other conventional inert excipients and may improve the processing of the modified release formulations described herein.

  As used herein, “total impurities” means all degradation products resulting from the degradation of bupropion hydrochloride. “Degradation products” include degradation products listed on page 281 of USP 26th edition and other degradation products that may appear as peaks on the chromatogram during the assay.

  The modified release tablets of the present invention are bioequivalent to Wellbutrin® or Zaiban® / Wellbutrin® SR tablets. The term “biologically equivalent” is used in a pharmaceutical equivalent or pharmaceutical substitute at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed test. It means that there is no significant difference in the rate and extent at which the active ingredient or moiety becomes available. Where there is an intentional difference in rate (eg, in certain extended release dosage forms), certain pharmaceutical equivalents or alternatives may make active ingredients or portions from each product available at the site of drug action If there is no significant difference, it is considered biologically equivalent. This is intentional and reflects the difference in the rate at which an active ingredient or part becomes available at the site of drug action, and is reflected in the proposed labeling, which is essentially essential for achieving effective in vivo drug concentrations through chronic use. Only applies if there is no difference and it is considered medically unimportant for the drug.

2 is a graph illustrating the dissolution profile for 150 mg dose strength bupropion hydrochloride modified release tablets with three different release rates according to an embodiment of the present invention. 2 is a graph illustrating the dissolution profile for a 300 mg dose strength bupropion hydrochloride modified release tablet with three different release rates according to an embodiment of the present invention. Relative sensitivity factor in 150 mg dose strength bupropion hydrochloride modified release tablets according to an embodiment of the present invention stored in HDPE bottles (7 ct, 40 cc and 30 ct, 100 cc) at 25 ° C. ± 2 ° C./60% RH ± 5% RH It is a graph which illustrates the statistical analysis about the total impurity content correct | amended by (RRF). Relative sensitivity factor in 300 mg dose strength bupropion hydrochloride modified release tablets according to an embodiment of the present invention stored in HDPE bottles (7 ct, 40 cc and 30 ct, 100 cc) at 25 ° C. ± 2 ° C./60% RH ± 5% RH It is a graph which illustrates the statistical analysis about the total impurity content correct | amended by (RRF). Mean plasma bupropion concentration in a dose strength equivalence study after administration of 2 × 150 mg (qd) and 1 × 300 mg (qd) dose strength modified release bupropion hydrochloride tablets according to an embodiment of the present invention. It is a graph to illustrate. Mean plasma hydroxybupropion concentration in a dose strength equivalence study after administration of 2 × 150 mg (qd) and 1 × 300 mg (qd) dose strength modified release bupropion hydrochloride tablets according to certain embodiments of the invention FIG. Mean plasma bupropion threonine in a dose strength equivalence study after administration of 2 × 150 mg (qd) and 1 × 300 mg (qd) dose strength modified release bupropion hydrochloride tablets according to certain embodiments of the invention It is a graph which illustrates alcohol concentration. Mean plasma bupropion erythroamino in dose strength equivalence studies after administration of 2 × 150 mg (qd) and 1 × 300 mg (qd) dose strength modified release bupropion hydrochloride tablets according to certain embodiments of the invention It is a graph which illustrates alcohol concentration. 2 is a graph illustrating the effect of food on mean plasma bupropion concentration after a single dose of a 150 mg dose strength modified release bupropion hydrochloride tablet according to an embodiment of the invention. 4B is a graph comparing the mean plasma bupropion concentration shown in FIG. 4A with the mean plasma bupropion concentration after a single dose of 150 mg Zyban® tablets of the prior art. The mean plasma hydroxybupropion concentration after a single dose of 150 mg dose strength modified-release bupropion hydrochloride tablet according to an embodiment of the present invention is the average plasma hydroxybupropion concentration after a single dose of prior art 150 mg Zyban® tablet. It is a graph compared with. Average plasma bupropion threoaminoalcohol concentration after a single administration of a 150 mg dose strength modified release bupropion hydrochloride tablet according to an embodiment of the present invention was obtained as a mean plasma hydroxy after a single administration of a prior art 150 mg Zyban® tablet. It is a graph compared with a bupropion density | concentration. Average plasma bupropion erythroaminoalcohol concentration after a single dose of 150 mg dose strength modified-release bupropion hydrochloride tablet according to an embodiment of the present invention was determined as the mean plasma hydroxy after a single dose of prior art 150 mg Zyban® tablet. It is a graph compared with a bupropion density | concentration. 2 is a graph illustrating the effect of food on the mean plasma bupropion concentration of a single-dose once daily 300 mg dose strength modified release bupropion hydrochloride tablet according to an embodiment of the invention. 2 is a graph illustrating the effect of food on the mean plasma hydroxybupropion concentration of modified release bupropion hydrochloride tablets at a single once-dose 300 mg dose strength according to an embodiment of the present invention. 1 is a graph illustrating the effect of food on mean plasma bupropion threoaminoalcohol concentration of a single once-dose 300 mg dose strength modified release bupropion hydrochloride tablet according to an embodiment of the invention. 1 is a graph illustrating the effect of food on mean plasma bupropion threoaminoalcohol concentration of a single once-dose 300 mg dose strength modified release bupropion hydrochloride tablet according to an embodiment of the invention. 2 is a graph illustrating mean steady state plasma bupropion concentration after multiple administrations of 300 mg release modified bupropion hydrochloride tablets once daily according to an embodiment of the invention when administered to a patient in a fasted state. 5B is a graph comparing the average steady state plasma bupropion concentration shown in FIG. 5A with the average steady state plasma bupropion concentration after multiple doses of prior art Wellbutrin® tablets in the fasted state. Average steady state plasma hydroxybupropion concentration after multiple administrations of 300 mg once daily modified release bupropion hydrochloride tablets according to an embodiment of the present invention when administered to a patient in a fasted state, FIG. 6 is a graph comparing mean steady state plasma hydroxybupropion concentration after multiple doses of Trin® tablets. Average steady-state plasma bupropion threoaminoalcohol concentration after multiple administrations of 300 mg once daily modified release bupropion hydrochloride tablets according to an embodiment of the present invention when administered to a patient in a fasted state was determined according to the prior art in a fasted state. FIG. 2 is a graph comparing the average steady state plasma bupropion threoamino alcohol concentration after multiple doses of the Wellbutrin® tablets. Average steady state plasma bupropion erythroaminoalcohol concentration after multiple administrations of 300 mg once daily modified release bupropion hydrochloride tablets according to an embodiment of the present invention when administered to a patient in a fasted state is compared to the prior art in the fasted state. 2 is a graph comparing the average steady state plasma bupropion erythroaminoalcohol concentration after multiple doses of the Wellbutrin® tablets. 2 is a graph illustrating the mean steady state plasma bupropion concentration after multiple doses of 300 mg once daily modified release bupropion hydrochloride tablets according to certain embodiments of the invention under fasting conditions. The average steady-state plasma bupropion concentration shown in FIG. 7A was calculated as the average steady-state plasma bupropion concentration after multiple administrations of the prior art 150 mg (bid) Zyban® tablets under fasting conditions. It is a graph to compare. Mean steady state plasma hydroxybupropion concentration after multiple doses of 300 mg once daily modified release bupropion hydrochloride tablets according to an embodiment of the present invention under fasting conditions was compared to 150 mg (bi. d.) Graph comparing the mean steady-state plasma hydroxybupropion concentration after multiple doses of Zyban® tablets. Mean steady state plasma bupropion threoaminoalcohol concentration after multiple administrations of 300 mg once daily modified release bupropion hydrochloride tablets according to certain embodiments of the present invention under fasting conditions was compared to the prior art 150 mg (b. id) is a graph comparing the mean steady state plasma bupropion threoaminoalcohol concentration after multiple administrations of Zyban® tablets. The average steady state plasma bupropion erythroamino alcohol concentration after multiple administrations of 300 mg once daily modified release bupropion hydrochloride tablets according to certain embodiments of the present invention under fasting conditions was compared to the prior art 150 mg (b. id) is a graph comparing the mean steady state plasma bupropion erythroaminoalcohol concentration after multiple doses of Zyban® tablets.

(Summary of Invention)
The present invention relates to a modified release tablet of pharmaceutically acceptable salt of bupropion, preferably bupropion hydrochloride. The advantage of the modified release tablet of the present invention that is not obtainable by the prior art commercially available Wellbutrin® or Zyban® / Wellbutrin® SR tablets is that the modified release tablets are administered once a day. It allows formulation and is bioequivalent to commercially available prior art tablets and shows no dietary effects.

  According to one aspect of the present invention, (i) a core comprising an effective amount of a pharmaceutically acceptable salt of bupropion, a binder, a lubricant; (ii) a controlled release coat surrounding the core; and (iii) ) A controlled release tablet comprising a moisture barrier layer surrounding the controlled release coat, which is bioequivalent and, after about 2 hours, not more than about 20% of the bupropion hydrochloride content, preferably about 2% to About 18%, more preferably about 4% to about 8%, most preferably about 5% is released, and after about 4 hours, about 15% to about 45%, preferably about 21% to about bupropion hydrochloride content. About 37%, more preferably about 28% to about 34%, most preferably about 32% are released, and after about 8 hours, about 40% to about 90%, preferably about 60% to about bupropion hydrochloride content. About 85%, more preferably about 68% to about 7 %, Most preferably about 74% released, and after about 16 hours, about 80% or more of the bupropion hydrochloride content, preferably about 93% or more, more preferably about 96% or more, most preferably about 99% or more. A modified release tablet is provided that exhibits an elution profile such that is released.

  In one embodiment, the moisture barrier is 10% less than the total amount of drug released when placed in 0.1N HCl for 1 hour as required for enteric coated tablets by USP testing. Not exceeding, does not serve as an enteric coat, defined as 75% or more of the drug released in 45 minutes in pH 6.8 buffer.

  In one embodiment of the invention, the pharmaceutically acceptable salt of bupropion is present at least about 94% by weight of the dry core weight. The modified release tablet of the present invention preferably contains from about 50 mg to about 450 mg of bupropion hydrochloride. Most preferably, the tablets of the present invention contain about 150 mg or 300 mg of bupropion hydrochloride.

  In another embodiment of the present invention, the amount of binder is preferably present from about 1% to about 6%, more preferably about 3% by weight of the dry core weight. The binder is preferably polyvinyl alcohol.

  In another embodiment of the invention, the lubricant is present preferably from about 1% to about 6%, more preferably about 3% by weight of the dry core weight. Lubricants useful for the tablets of the present invention may be selected from the group consisting of glyceryl behenate, stearic acid, hydrogenated vegetable oils, and any combination thereof. A preferred lubricant is glyceryl behenate.

  In another embodiment of the invention, the controlled release coat consists essentially of a water insoluble and water permeable film-forming polymer, the amount present being from about 35% to about 60% by weight of the controlled release coat dry weight. % May change. The amount of water-insoluble and water-permeable film-forming polymer is present at about 50% by weight of the controlled release coat dry weight for a 150 mg dose and about 45% by weight of the controlled release coat dry weight for a 300 mg dose. It is preferable. The water insoluble and water permeable film-forming polymer may be selected from the group consisting of cellulose ethers, cellulose esters, polyvinyl alcohol, and any combination thereof. A preferred water-insoluble and water permeable film-forming polymer is ethylcellulose, which may be selected from the group consisting of ethylcellulose grade PR100, ethylcellulose grade PR20, and any combination thereof. A preferred water insoluble and water permeable film forming polymer is ethyl cellulose grade PR100.

  In another embodiment of the invention, the amount of plasticizer is present from about 6% to about 30%, more preferably about 12% by weight of the controlled release coat dry weight. Useful plasticizers for the tablets of the present invention may be selected from the group consisting of polyols, organic esters, oils / glycerides and any combination thereof. A preferred plasticizer is polyethylene glycol 1450.

  In another embodiment of the invention, the amount of water soluble polymer present may vary from about 25% to about 50% by weight of the controlled release coat dry weight. The water soluble polymer is preferably present at about 43% by weight of the controlled release coat. The water soluble polymer may be selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, and any combination thereof. A preferred water soluble polymer is polyvinylpyrrolidone.

  In another embodiment of the present invention, the ratio of water insoluble and water permeable film forming polymer: plasticizer: water soluble polymer for the 150 mg modified release bupropion hydrochloride tablet of the present invention is from about 3: 1: 4 to about 5. The ratio may vary from 1: 3, with a preferred ratio of 4: 1: 3.

  In another embodiment of the invention, the ratio of water insoluble and water permeable film forming polymer: plasticizer: water soluble polymer for the 300 mg modified release bupropion hydrochloride tablet of the invention is from about 7: 2: 6 to about 19 : 5: 18, and a preferred ratio is 13: 4: 12.

  In another embodiment of the present invention, the weight gain after coating the tablet core with a controlled release coat may vary from 3% to about 30% of the dry tablet core weight. For a 150 mg dose of the modified release tablet of the present invention, the increased weight may vary from about 13% to about 16% of the dry tablet core weight, with a preferred weight increase being about 15% of the dry tablet core weight. is there. For the 300 mg dose modified release tablet of the present invention, the weight increased after application of the controlled release coat may vary from about 8% to about 10% of the dry tablet core weight, with a 9% weight increase being preferred.

  In another embodiment of the present invention, the moisture barrier comprises an enteric and / or acrylic polymer, a plasticizer and a penetration enhancer and is present in a ratio of about 13: 2: 5. The enteric and / or acrylic polymer is preferably an acrylic polymer, and is preferably a methacrylic acid copolymer commercially available as Eudragit® L30D-55. The amount of methacrylic acid copolymer present may vary from about 30% to about 90% by weight of the moisture barrier dry weight, but is preferably present at about 66% of the moisture barrier dry weight.

  In another embodiment of the invention, the plasticizer may be selected from the group consisting of polyols, organic esters, oils / glycerides, and any combination thereof. A preferred plasticizer for use in the moisture barrier is a combination of polyol and organic ester. The preferred polyol in the combination is polyethylene glycol 1450, in which case triethyl citrate is the preferred organic ester. The ratio of organic ester to polyol is preferably 1: 2. The plasticizer is preferably present from about 1% to about 30%, more preferably about 10% by weight of the moisture barrier dry weight.

  In another embodiment of the present invention, the penetration enhancer is a hydrophilic substance, silicon dioxide, colloidal silicon, lactose, hydrophilic polymer, sodium chloride, aluminum oxide, colloidal aluminum oxide, silica, microcrystalline cellulose. And a group consisting of any combination thereof. The penetration enhancer is preferably silicon dioxide and is present from about 20% to about 40%, more preferably about 25% by weight of the moisture barrier dry weight.

  In another embodiment of the present invention, the moisture barrier layer has a weight that increases after application of the moisture barrier layer, preferably about 6% or less of the tablet dry weight for both the 150 mg and 300 mg dose modified release tablets of the present invention. Is applied to about 2.5% or less.

  In another embodiment of the invention, the modified release tablet of the invention is at least about 95%, preferably at least about at least about bupropion hydrochloride after about 12 months storage at 25 ° C. ± 2 ° C./60% RH ± 5% RH. Provide stable bupropion hydrochloride formulations where 97.5%, even 98.5%, or even 99% remain stable.

  In another embodiment of the invention, the modified release tablet of the invention is at least about 95%, preferably at least 97% of bupropion hydrochloride after about 18 months storage at 25 ° C. ± 2 ° C./60% RH ± 5% RH. Provide stable bupropion hydrochloride formulations such that .5%, even 98.5%, and even 99% remain stable.

  In another embodiment of the invention, the modified release bupropion hydrochloride tablets of the invention are bioequivalent to Wellbutrin® or Zyban® / Wellbutrin® SR tablets, Does not show the effect of.

In another embodiment of the present invention, the moisture barrier layer substantially hinders or delays the absorption of moisture into the tablet, thereby increasing the stability of bupropion hydrochloride.
(Detailed description of the invention)
The invention described herein is a core comprising a pharmaceutically acceptable salt of bupropion and a conventional excipient, surrounded by a controlled release coat that controls the release of the pharmaceutically acceptable salt of bupropion. And a controlled release tablet having a core and a moisture barrier layer surrounding a controlled release coat. The modified release tablets of the present invention are bioequivalent.
1. Core 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 active drug present may vary from about 50% to about 90% by weight of the tablet dry weight, 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 contains bupropion hydrochloride in an amount that can vary from about 50 mg to about 450 mg. This tablet preferably contains 150 mg or 300 mg of bupropion hydrochloride. For 150 mg dose tablets, bupropion hydrochloride is about 78% by weight of the tablet dry weight. For a 300 mg dose, the amount of bupropion hydrochloride is present at about 83% by weight of the tablet dry weight. In both the 150 mg and 300 mg dose bupropion hydrochloride modified release tablets of the present invention, the amount of bupropion hydrochloride is present at about 94% by weight of the dry core for each dose.

  A binder (sometimes called a sticking agent) is added to the drug-filler mixture to ensure that granules and tablets can be formed with the required mechanical strength. The binder can be used in various ways: (1) as a dry powder mixed with other ingredients before wet agglomeration, (2) as a granulating liquid during wet granulation, And (3) can be added to the formulation as a dry powder that is mixed with other ingredients prior to compression. In this form, the binder is called a dry binder. In general, solution binders are considered to be most effective, and thus solution binders are the most common method of incorporating binders into granules. The binder used herein takes the form of a solution binder. Non-limiting examples of binders useful for the core include modified starch, gelatin, polyvinyl pyrrolidone, cellulose derivatives such as hydroxypropyl methylcellulose (HPMC) and hydroxypropylcellulose (HPC) and polyvinyl alcohol. Water-soluble polymers such as The amount of binder present is about 0.5% to about 15% by weight of the tablet dry weight, preferably about 1% to about 6% by weight of the tablet dry weight, most preferably about 3% by weight of the tablet dry weight. % May change. For both 150 mg and 300 mg dose tablets, the amount of binder is preferably present from about 1% to about 6% by weight of each dry core weight, more preferably about 3% by weight of each dry core weight. There is. A preferred binder is polyvinyl alcohol.

  A lubricant is added to the pharmaceutical formulation to reduce friction between the solid and the die wall to ensure that tablet formation and ejection occurs. High friction during tableting can cause a range of problems including poor tablet quality (capping or even disintegration of tablets during discharge, and vertical scratch marks on the tablet edges), discontinuing production There is even a thing. Accordingly, a lubricant is added to almost all tablet formulations, including the bupropion hydrochloride tablet formulations described herein. Non-limiting examples of lubricants useful for the core include glyceryl behenate, stearic acid, hydrogenated vegetable oils (hydrogenated cottonseed oil (Sterotex®), hydrogenated soybean oil (Sterotex®) HM), and hydrogenated soybean oil & castor wax (such as Sterotex® K), stearyl alcohol, leucine and polyethylene glycol (MW 4000 or higher). The lubricant is preferably glyceryl behenate. The amount of lubricant present is about 1% to about 5% by weight of the tablet dry weight, preferably about 2% to about 3% by weight of the tablet dry weight, most preferably about 2.5% of the tablet dry weight. It may vary from wt%. In both the 150 mg and 300 mg dose modified release tablets of the present invention, the lubricant is about 2.5% by weight of the dry tablet weight, preferably about 1% to about 6% of the dry core weight for both doses. % By weight, more preferably about 3% by weight of the dry core weight.

  At this stage, the core formulation is an immediate release formulation, resulting in 100% elution of bupropion hydrochloride within 1 hour (data not shown). Ideally, the core comprises only an effective pharmaceutical amount of a pharmaceutically acceptable salt of bupropion, a binder, preferably polyvinyl alcohol, and a lubricant, preferably glyceryl behenate. However, if necessary, additional inert excipients consistent with the objectives of the present invention may be added to the core formulation. Additional inert excipients may be added to facilitate the preparation of the final modified release bupropion hydrochloride dosage forms described herein and / or improve patient acceptance. Additional inert excipients are well known to those skilled in the art and can be found in the relevant literature, such as the Handbook of Pharmaceutical Excipients. Non-limiting examples of such excipients include spray dried lactose, sorbitol, mannitol, and any cellulose derivative.

  Granules that are compressed to form the core of the modified release tablet of the invention described herein are preferably produced by a wet granulation process. Basically, wet granulation involves mixing the powder (active drug) in the presence of a liquid (solution binder) as usual and then drying. In order to form granules that are finally compressed into a tablet core, bupropion hydrochloride is first preferably mixed with a solution binder, for example in a fluid bed granulator from Glatt (Germany) or Aeromatic (Switzerland). Such a fluidized bed granulator is preferred, but is not necessarily limited thereto, and is granulated by a granulator.

  The binder, preferably polyvinyl alcohol, is first dissolved or dispersed in a suitable solvent, preferably water. The solution binder is then sprayed onto the drug in a granulator, preferably a fluid bed granulator. Alternatively, granulation can be performed in a conventional or high shear mixer. If necessary, additional inert excipients such as fillers can be mixed with bupropion hydrochloride prior to the granulation step.

Subsequently, the formed granules are dried and then sieved before combining the granules with the lubricant. The dried granules are preferably screened through a 1.4 mm mesh screen. The sieved granules are then combined with a lubricant and, if necessary, other additional inert excipients that would improve the processing of the modified release tablets of the invention. Mixing of the granules with the lubricant and, if necessary, optionally additional inert excipients such as glidants can be done in a V blender or other suitable mixing equipment. Glidants improve the flowability of the powder. This is particularly important during high production rate tablet production and direct compression. However, since the requirements for obtaining sufficient flow are high, glidants are often added to the granulation before tableting. Subsequently, the blended granules are compressed into tablets, the subsequent ones are called tablet cores. Tablet cores can be obtained through the use of standard techniques and equipment well known to those skilled in the art. The tablet core is ideally obtained by a rotary press (also called a multi-station press) fitted with suitable punches, but this is not necessarily so.
2. Tablet coating The tablet core is coated in two stages. The controlled release coating is applied directly onto the surface of the tablet core and serves to control the release of the pharmaceutically acceptable salt of bupropion. The moisture barrier is applied directly on the surface of the controlled release coat and interferes with or delays moisture absorption.
2.1 Controlled Release Coat The controlled release coat is a semipermeable coat comprising a water insoluble, water permeable film forming polymer, a plasticizer and a water soluble polymer.

  Non-limiting examples of water-insoluble, water-permeable film-forming polymers useful for controlled release coats include cellulose ethers, cellulose esters, and polyvinyl alcohol. A preferred water-insoluble, water-permeable film-forming polymer is ethyl cellulose, which can be selected from the group consisting of ethyl cellulose grade PR100, ethyl cellulose grade PR20, and any combination thereof. Ethyl cellulose grade PR100 is a preferred water-insoluble, water-permeable film-forming polymer. The amount of the water-insoluble, water-permeable film-forming polymer may vary from about 1% to about 8% by weight of the tablet dry weight, preferably from about 2% to about 6% by weight of the tablet dry weight. For the 150 mg dose bupropion hydrochloride modified release tablet of the present invention, the amount of water insoluble, water permeable film forming polymer may vary from about 3% to about 6% by weight of the tablet dry weight. The amount of water-insoluble, water-permeable film-forming polymer is preferably present at about 6.3% by weight of the tablet dry weight. With respect to the controlled release coat itself, the amount of water insoluble, water permeable film forming polymer may vary from about 35% to about 60% by weight of the controlled release coat dry weight. The amount of water-insoluble, water-permeable film-forming polymer is preferably present at about 50% by weight of the controlled release coat dry weight. For the 300 mg dose bupropion hydrochloride modified release tablet of the present invention, the amount of water insoluble, water permeable film forming polymer may vary from about 2% to about 5% by weight of the tablet dry weight. The amount of water-insoluble, water-permeable film-forming polymer is preferably present at about 3.6% by weight of the tablet dry weight. With respect to the controlled release coat itself, the water insoluble, water permeable film forming polymer is present at about 45% by weight of the controlled release coat dry weight.

Generally, a plasticizer is added to the film coating formulation to alter the physical properties of the polymer to make it more effective. The amount and choice of plasticizer contributes to the hardness of the tablet and can even affect its dissolution or disintegration properties, as well as its physical and chemical stability. One important property of the plasticizer is its ability to reduce the brittleness of the coating by imparting elasticity and flexibility to the coating. Non-limiting examples of plasticizers useful for the controlled release coat described herein include polyols such as polyethylene glycols of various molecular weights, organic esters such as diethyl phthalate or triethyl citrate, fractionated coconut oil Or an oil / triglyceride such as castor oil. The amount of plasticizer for the controlled release coat may vary from about 0.5% to about 2% by weight of the tablet dry weight. A preferred plasticizer is polyethylene glycol 1450. For the 150 mg dose bupropion hydrochloride modified release tablet of the present invention, the amount of plasticizer present in the controlled release coat may vary from about 1% to about 1.5% by weight of the tablet dry weight. The amount of plasticizer is preferably present at about 1.5% by weight of the tablet dry weight. For the 300 mg dose bupropion hydrochloride modified release tablet of the present invention, the amount of plasticizer present may vary from about 0.5% to about 2% by weight of the tablet dry weight. For both 150 mg and 300 mg dosage forms, the plasticizer is preferably present from about 6% to about 30% by weight of the controlled release coat dry weight, more preferably about 12% by weight of the controlled release coat dry weight. .

  Non-limiting examples of water soluble polymers useful for controlled release coats include polyvinylpyrrolidone, hydroxypropylmethylcellulose and hydroxypropylcellulose. A preferred water soluble polymer is polyvinylpyrrolidone, the amount of which may vary from about 1.5% to about 6% by weight of the tablet dry weight. With respect to the controlled release coat itself, the amount of water soluble polymer present may vary from about 25% to about 55% by weight of the controlled release coat dry weight. For a 150 mg dose of the bupropion hydrochloride modified release tablet of the present invention, the amount of water soluble polymer present is from about 3% to about 5% by weight of the tablet dry weight or from about 25% by weight of the controlled release coat dry weight. It may vary from about 50% by weight. For a 300 mg dose of the bupropion hydrochloride modified release tablet of the present invention, the amount of water soluble polymer present may vary from about 2% to about 5% of the tablet dry weight and about 43% of the controlled release coat dry weight. Good.

  For a 150 mg dose of the inventive modified release bupropion hydrochloride tablet described herein, the ratio of water insoluble and water permeable film forming polymer: plasticizer: water soluble polymer is from about 3: 1: 4 to about 5 1: 3 may be changed. A preferred ratio is about 4: 1: 3. For a 300 mg dose of the inventive controlled release bupropion hydrochloride tablet described herein, the ratio of water insoluble and water permeable film forming polymer: plasticizer: water soluble polymer is about 7: 2: 6 to about 19 : 5: 18 may be changed. A preferred ratio is about 13: 4: 12.

  In general, the preparation and application of a controlled release coat is as follows. A water insoluble and water permeable film forming polymer, preferably ethyl cellulose, and a plasticizer, preferably polyethylene glycol 1450, are dissolved in an organic solvent such as a mixture of ethyl alcohol and isopropyl alcohol. Next, a plasticizer, preferably polyvinyl pyrrolidone, is added until a uniform mixture is obtained. The resulting controlled release coating solution is then sprayed onto the tablet core using a tablet coater, fluid bed apparatus or other suitable coating apparatus known in the art until the desired weight gain is obtained. Subsequently, the tablet core coated with the controlled release coat is dried and a moisture barrier layer is applied.

  One skilled in the art will appreciate that by controlling permeability, the release of bupropion hydrochloride and / or the amount of coating applied to the tablet core can be controlled. The permeability of the controlled release coat can be varied by changing the water-insoluble and water-permeable film-forming polymer: plasticizer: water-soluble polymer ratio and / or the amount of coating applied to the tablet core. In general, a longer amount of water-insoluble, water-permeable film-forming polymer provides a more extended release. The addition of other excipients to the tablet core may also change the permeability of the controlled release coat. For example, if it is desirable for the tablet core to further include a swelling agent, the pressure on the less flexible coat by the swelling agent will rupture the coat, thus increasing the amount of plasticizer in the controlled release coat and making the coat more flexible Must be. Furthermore, the ratio of water-insoluble and water-permeable film-forming polymer and water-soluble polymer must also be varied depending on whether a faster elution and / or release profile or a slower elution and / or release profile is desired.

Depending on the desired dissolution or in vivo release profile, the weight gain after coating the tablet core with a controlled release coat may vary from about 3% to about 30% of the weight of the dry tablet core. For the 150 mg dose modified release bupropion hydrochloride tablet of the present invention, the weight gain may vary from about 13% to about 16% of the weight of the dry tablet core. The weight gain is preferably about 15% of the weight of the dry tablet core. For the 300 mg dose-release modified bupropion hydrochloride tablets of the present invention, the weight gain may vary from about 8% to about 10% of the weight of the dry tablet core. The weight increase is preferably about 9% of the weight of the dry tablet core.
2.2 Moisture-proof layer The moisture-proof layer is applied directly on the controlled release coat and contains enteric and / or acrylic polymers, penetration enhancers and optionally plasticizers.

  The enteric polymer is preferably an acrylic polymer. The acrylic polymer is methacrylic acid copolymer type C (poly (methacrylic acid, methyl methacrylate) 1: commercially available under the trade name Eudragit® (eg Eudragit L30D-55) 1: 1] is preferable. The methacrylic acid copolymer is present in an amount that 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 a 150 mg dose of the modified release bupropion hydrochloride tablet of the present invention, the methacrylic acid copolymer may vary from about 2% to about 3% of the tablet dry weight. The amount of methacrylic acid copolymer is preferably present at about 2.5% of the tablet dry weight. With respect to the moisture barrier itself, the amount of methacrylic acid copolymer is preferably present from about 30% to about 90% by weight of the moisture barrier dry weight, more preferably about 66% by weight of the moisture barrier dry weight. For a 300 mg dose of the modified release bupropion hydrochloride tablet of the present invention, the amount of methacrylic acid copolymer may vary from about 1.5% to about 3% of the tablet dry weight. The amount of methacrylic acid copolymer is preferably present at about 2% by weight of the tablet dry weight. With respect to the coating itself, the methacrylic acid copolymer is preferably about 30% to about 90% by weight of the moisture barrier dry weight, more preferably about 66% of the moisture barrier dry weight for the 300 mg dose modified release tablet of the present invention. % Exists.

It is known in the art that plasticizers are required due to the tendency of methacrylic acid copolymers to become brittle. Non-limiting examples of plasticizers useful for the controlled release coat described herein include polyols such as polyethylene glycols of various molecular weights, organic esters such as diethyl phthalate or triethyl citrate, fractionated coconut oil Or an oil / glyceride such as castor oil. A preferred plasticizer is a combination of triethyl citrate and polyethylene glycol 1450. The ratio of triethyl citrate to polyethylene glycol 1450 is about 1: 2. The plasticizer is present in an amount that may vary from about 0.2% to about 0.5%, preferably from about 0.2% to about 0.4% of the tablet dry weight. The plasticizer is present at about 0.35% of the tablet dry weight for a 150 mg tablet and from about 0.2% to about 0.4% of the tablet dry weight for a 300 mg tablet. With respect to the moisture barrier itself, the plasticizer is preferably about 1% to about 30% by weight of the moisture barrier dry weight, more preferably moisture resistant, for both 150 mg and 300 mg modified release bupropion hydrochloride tablets of the invention. About 10% of the layer dry weight is present. It is well known in the art that excipients used in tablets are subcategorized into various groups depending on the intended primary function. However, one excipient can affect the properties of a drug or tablet as a whole in a series of ways, and thus many substances used in tablet formulations can be described as multi-functional. . That is, the polyethylene glycol 1450 used in the combination of plasticizers for the moisture-proof layer not only increases the hydrophilicity of the moisture-proof layer, but also serves as a flow promoter.

  In addition to polyethylene glycol 1450, the penetration enhancer also serves as a glidant and increases the hydrophilicity of the moisture barrier. The penetration enhancer is a hydrophilic substance, the group consisting of silicon dioxide, colloidal silicon, lactose, hydrophilic polymer, sodium chloride, aluminum oxide, colloidal aluminum oxide, silica, microcrystalline cellulose and any combination thereof You can choose from. Silicon dioxide is a preferred penetration enhancer. The amount of penetration enhancer present may vary from about 0.5% to about 1% by weight of the tablet dry weight and is about 25% by weight of the moisture barrier dry weight. For the 150 mg dose modified bupropion hydrochloride tablet of the present invention, the penetration enhancer is about 0.9% of the tablet dry weight and about 20% to about 40% by weight of the moisture barrier dry weight, preferably about 25%. % Present. In the case of the 300 mg dose modified release bupropion hydrochloride tablet of the present invention, the penetration enhancer may vary from about 0.5% to about 1% by weight of the tablet dry weight, preferably about 20% of the moisture barrier dry weight. It is present in an amount present from weight percent to about 40 weight percent, preferably about 25 weight percent.

  The ratio of methacrylic acid copolymer: plasticizer: penetration enhancer is preferably about 13: 2: 5.

  In general, the preparation and application of the moisture barrier process is as follows. First, a plasticizer, preferably a combination of polyethylene glycol 1450 and triethyl citrate, is added to water and the mixture is mixed to homogeneity. The methacrylic acid copolymer, preferably Eudragit® L30D-55, is then screened and added to the plasticizer mixture and mixed to homogeneity. In another container, a penetration enhancer, preferably silicon dioxide, is dissolved in water until a uniform mixture is obtained. The mixture of plasticizer and methacrylic acid copolymer is then mixed with the penetration enhancer solution and mixed until uniform. The resulting moisture barrier solution is then coated with a controlled release coat using a tablet coater, fluid bed apparatus or other suitable coating equipment known in the art until the desired weight gain is obtained. Spray onto the core. Subsequently, the tablets coated with a moisture barrier are dried and packaged.

  The moisture barrier is a controlled release coated tablet such that the weight gain is no more than about 6%, preferably no more than about 2.5% of the tablet dry weight of both the 150 mg and 300 mg modified release bupropion hydrochloride tablets of the present invention. Applied to the core. The amount of moisture barrier applied does not make the bupropion hydrochloride modified release tablets described herein resistant to gastric juice and does not significantly affect drug release characteristics.

  The moisture barrier used herein does not serve as an enteric coat. Even if the methacrylic acid copolymer, Eudragit® L30D-55 is mentioned and used in enteric coating formulations in the art, its functionality depends on the formulation and on the amount of material applied. To do. As is known in the art, enteric coatings are applied when the drug is destroyed or inactivated by gastric juice, or when the drug can irritate the gastric mucosa. . To meet the enteric coat requirements, the test described in USP (Method A or B) eluted at least 6 out of 6 experiments after 2 hours in acidic medium (0.1 N HCl). It stipulates that the active drug does not exceed 10% and more than 75% is eluted in 45 minutes at pH 6.8. Although bupropion hydrochloride is not adversely affected in acidic media and does not irritate the gastric mucosa, the moisture barrier does not meet this requirement for the following reasons. (1) A weight increase of about 6% to about 8% based on dry polymer per dose unit is recommended for obtaining enteric integrity in films containing Eudragit® L30D-55. The amount of Eudragit® L30D-55 solid applied onto the controlled release tablet core is 6% or less, preferably 2.5% or less. (2) If enteric preservation is required, the dissolution test on the final product (ie tablet core coated with a moisture barrier) at the 2 hour time point will not specify a limit of 20% or less. (3) Analytical tests performed on the final two-layer coated product indicate that the product does not meet all test requirements as an enteric coating product as defined by the USP test method. Since the moisture barrier is applied directly on the controlled release coat, a test was conducted to determine whether the moisture barrier applied directly on the immediate release tablet core served as an enteric coat. The test shows that in 0.1N HCl, more than 40% of bupropion hydrochloride is released from the tablet core after 1 hour, so that a moisture barrier applied directly on the immediate release tablet core is included in the USP definition for enteric coats. (See Example 2). In addition, the functionality of the moisture barrier is a tablet core individually coated with a controlled release coat and moisture barrier for 10 days under accelerated conditions (40 ° C. ± 2 ° C./75% RH ± 5% RH) in an open glass pan. This was confirmed by measuring the water content using the Karl Fischer (KF) test (see Example 2). The results show that the moisture content for tablet cores coated with controlled release is higher than tablet cores coated with a moisture barrier. Cumulatively, these data demonstrate the functionality of the moisture barrier as a coat that substantially impedes or delays the absorption of moisture rather than as an enteric coat as defined by USP.

  The tablet of the present invention provides extended release of bupropion hydrochloride despite the absence of a pore former in the formulation. Further, after about 2 hours, the above preparation has about 20% or less of the bupropion hydrochloride content, preferably about 2% to about 18%, more preferably about 4% to about 8%, and most preferably about 5%. After about 4 hours, about 20% to about 45%, preferably about 21% to about 37%, more preferably about 28% to about 34%, most preferably about 32% of the bupropion hydrochloride content is released. After about 8 hours, about 40% to about 90%, preferably about 60% to about 85%, more preferably about 68% to about 74%, most preferably about 74% of the bupropion hydrochloride content. A stable hydrochloric acid that is released and after about 16 hours, more than about 80%, preferably more than about 93%, more preferably more than about 96%, most preferably more than about 99% of the bupropion hydrochloride content is released. Provide bupropion formulation

  The favorable effect of the formulations described herein on the stability of modified release bupropion hydrochloride tablets is 6 months under accelerated conditions (40 ° C. ± 2 ° C./75% RH ± 5% RH), as well as 25 ° C. ± 2 ° C. This is evident in studies conducted to assess total impurities present in 150 mg or 300 mg dosage forms through long term stability at 12 months and 18 months at 60% RH ± 5% RH. The stability test showed a decrease in the value of all impurities in the tablet (compared to Wellbutrin SR).

For example, for both the 150 mg and 300 mg dose strength modified release tablets of the present invention, in 7 count, 40 cc and 30 count, 100 cc HDPE bottles, all impurities present were 25 ° C. ± 2 ° C./60% RH ± 5 Not more than about 2.5% by weight of the amount of bupropion hydrochloride in the tablet, preferably not more than about 1.5%, most preferably not more than about 0.6%, through long-term stability in% RH for at least 12 months Don't be. In 18 months long-term stability at 25 ° C. ± 2 ° C./60% RH ± 5% RH, the total impurities present is less than about 2.5% by weight of the amount of bupropion hydrochloride in the tablet, preferably in the tablet It should be no more than about 1.5%, most preferably no more than about 0.7% by weight of the amount of bupropion hydrochloride. That is, modified release bupropion hydrochloride tablets according to the present invention are stored for 12 or 18 months for long-term stability under humidity and temperature conditions normally encountered in pharmacies and drug cabinets, ie, room temperature and 35-60% humidity. Later, it contains at least about 95% w / w of undegraded bupropion hydrochloride, more preferably at least 98%, and even at least 99%. That is, when used in pharmaceutical preparations such as tablets, for example, at least 95% of its potency, preferably at least 95% of its potency after 1 year storage at room temperature (15 ° C to 25 ° C) at 35-60% humidity At least 98% and even at least 99% will still be retained. For example, at the time of preparation, if the tablet initially contains 300 mg bupropion hydrochloride (signed amount), after 1 year storage, at least 285 mg bupropion hydrochloride, preferably 294 mg or more will remain in the tablet.

When stored under accelerated conditions for at least 6 months in a 7 count, 40 cc HDPE bottle configuration, the total amount of KF water content and bupropion hydrochloride impurities for 150 mg dose strength tablets of the present invention should not be less than about 1% Don't be. The same bottle and tablet arrangement for a 300 mg dose strength stored under the same acceleration conditions has a KF water content of about 1% or less and a total impurity of about 0.6% or less for at least 6 months. There must be. 150 mg tablets stored in a 30 count, 100 cc HDPE bottle configuration should have a KF moisture content of no more than about 1% and a total impurity of no more than about 1.2% when stored under accelerated conditions for at least 6 months Don't be. A 300 mg dose strength tablet stored in the same configuration under the same time and under the same conditions should have a KF moisture content of about 1% or less and a total impurity of about 0.8% or less. When stored in an open glass dish, the KF moisture content of the 300 mg dose strength modified release tablet of the present invention is less than about 0.8% after 3 days, preferably 0 after 10 days when stored under accelerated conditions. Must be less than 45%. When stored in a tightly sealed glass bottle, the KF water content should be no more than 0.45% after 3 days, preferably no more than about 0.4% after 10 days.
(Example)
The following examples are intended to illustrate the present invention and are not intended to limit the scope of the invention.
Example 1
1. Modified Release Tablets Three different core formulations were prepared as shown in Table 1 for each of the 150 mg and 300 mg modified release bupropion hydrochloride tablets.

  First, water is heated to 60 ± 5 ° C. Next, the binder (polyvinyl alcohol) is uniformly dissolved in the water, passed through a 0.7 mm mesh screen, and cooled to about 30 ° C. or less. Bupropion hydrochloride is placed in the upper spray chamber of a fluidized bed apparatus, such as, for example, a Glatt GPCG1 fluidized bed granulator. Spray the binder solution (ie polyvinyl alcohol solution) onto bupropion hydrochloride according to the manufacturing process parameters shown in Table 2.

  Once granulation is complete, the granules are dried and the temperature is allowed to cool below about 35 ° C. Next, the bupropion hydrochloride granules are passed through a 1.4 mm mesh sieve.

  A lubricant (glyceryl behenate) is mixed with the sieved granules in a V-blender until the mixture is uniform. The resulting mixture is tableted into a tablet core using a rotary tableting machine (Manesty Unipress), but with a 150 mg tablet core, the average hardness is about 8 Sc to about 25 Sc and the average thickness is about 3.9 mm to about 4 0.5 mm, with a 300 mg tablet core having an average hardness of about 12 Sc to about 33 Sc and an average thickness of about 4.8 mm to about 5.4 mm. The friability of the tablet core for both dose strengths is 0.8% or less. The tablet core is then coated with a controlled release coating agent as shown in Table 3.

  A plasticizer (polyethylene glycol 1450) is added to a part of the mixed liquid of modified ethyl alcohol and isopropyl alcohol, and then a water-insoluble and water-permeable film-forming polymer (ethyl cellulose 100) is added. Once mixed, the water soluble polymer is gradually added to the above mixture to avoid large particles or agglomeration. Mix solution to homogenize. Next, the remainder of the mixture of denatured ethyl alcohol and isopropyl alcohol is added to the coating agent mixture, and mixing is continued until a uniform solution is obtained. The coating agent solution is passed through DeBee Homogenizer (nozzle size 7, process pressure 8500 ± 2000 psi and back pressure 1000 ± 250 psi). The uniform coating solution is then sprayed onto the tablet core according to the process parameters shown in Table 4 in a tablet coater (O'Hara 36 Side Vent).

  The tablet core coating with the controlled release coating solution is about 24 mg (wet coat width of about 22 to about 26 mg) and about 29 mg (wet coat width of about 27 to about 31 mg) for 150 mg and 300 mg tablet cores, respectively. ) Continue until the increase is achieved. Once the desired weight gain is achieved, the coating is stopped and the coated tablet core is dried with an inlet air temperature of about 35 ± 2 ° C. and a pan speed of about 2 rpm. Next, the dried and cooled coated tablet core is coated with the moisture-proof layer formulation shown in Table 5.

  The plasticizer combination is preferably polyethylene glycol 1450 and triethyl citrate, but first this is dissolved in a portion of purified water and mixed uniformly. While mixing the plasticizer solution, the methacrylic acid copolymer is preferably Eudragit® L30D-55, which is placed in a separate container through a 0.3 mm mesh screen. The plasticizer solution is then added to the methacrylic acid copolymer and mixed until a uniform solution is obtained. While mixing the methacrylic acid copolymer / plasticizer solution, the penetration enhancer is preferably silicon dioxide, but this is dissolved in the remainder of the purified water and the suspension is homogenized by a high speed shear mixer. Mix until. The moisture barrier final solution is obtained by mixing the penetration enhancer solution with the methacrylic acid copolymer / plasticizer solution. The uniform moisture barrier solution is then sprayed onto the controlled release coated tablet core in a pan coating apparatus according to the process parameters shown in Table 6.

  The moisture barrier is about 7 mg (wet-coated tablet range is about 6.3 to about 7.7 mg) and about 10.5 mg (wet-coated tablet range is about 9 for 150 mg and 300 mg dose modified release tablets, respectively. 0.5-11.5 mg) until applied. Once the desired weight gain is achieved, the coating is stopped and the coated tablets are dried with an inlet air temperature of about 35 ± 2 ° C. and a pan speed set to 2 rpm.

  Finally, the coated tablets are imprinted with an appropriate display using a tablet stamping machine (Print International) with an appropriate black ink, for example Opacode® S-1-8090 black ink. .

  Dissolution profiles were determined under the following dissolution conditions for three doses of 150 mg and 300 mg each.

Test solution: 900 mL of 0.1N hydrochloric acid
Test method: US Pharmacopeia Type I device (150 mg dose) / US Pharmacopeia Type II device (300 mg dose), 75 rpm, temperature 37 ° C.
The results are shown in Table 7 as the average release rate of the total content of bupropion hydrochloride in the coated tablet.

The average dissolution profiles for three different modified release bupropion hydrochloride tablets at 150 mg and 300 mg are shown in FIGS. 1A and 1B, respectively. For all subsequent testing and manufacturing, formulations C and C ′ were selected for 150 mg and 300 mg dosage forms.
2. Stability of modified release tablet formulation The formulation does not contain a stabilizer. In order to determine the stability of bupropion hydrochloride in the absence of stabilizer, stability tests were performed under both accelerated and long term conditions. Acceleration conditions were 6 months at 40 ° C. ± 2 ° C./75% RH ± 5% RH, and long term conditions were 12 and 18 months at 25 ° C. ± 2 ° C./60% RH ± 5% RH. At the end of the predetermined period, the tablets were analyzed by HPLC for impurities produced by the decomposition of bupropion hydrochloride. Degradation products included all listed peaks in the United States Pharmacopeia (26th edition, page 281) and any other peaks that appeared on the chromatogram. The results of stability analysis under both accelerated and long term conditions for both 150 mg and 300 mg dosage forms are shown in Tables 8, 9 and 10.

Stability data up to 48 months was evaluated by statistically effective analysis for each dose strength of modified release tablets. Effective plots are shown in FIGS. 2A and 2B. By projecting and evaluating the upper limit of the confidence interval over 48 months, a “data driven” standard was derived.
Example 2
1. The moisture barrier is not enteric coated The purpose of this study was to show that the modified release bupropion hydrochloride tablets of the present invention were not enteric coated. The modified release formulation is based on a tablet core containing bupropion hydrochloride, a binder, and a lubricant. The tablet core is coated with a controlled release coat, which has the function of controlling the release of bupropion hydrochloride. The controlled release coated tablet core is subsequently coated with a moisture barrier, which substantially hinders or retards the absorption of moisture.

  In order to evaluate the integrity of the tablets, drug release was measured spectrophotometrically by a two-step dissolution method using the US Pharmacopoeia enteric coating dissolution test method B (75 rpm by basket method). . The results of the test are shown in Tables 11 and 12.

  At acidic pH (0.1N hydrochloric acid), about 7% bupropion hydrochloride is released within 2 hours. However, at pH 6.8, about 21% bupropion hydrochloride is released within 1 hour. Thus, the modified release tablets of the present invention have an individual value of dissolved active pharmaceutical ingredient not exceeding 10% after 2 hours in acidic test solution (0.1N hydrochloric acid) in a buffer solution of pH 6.8. Does not meet US Pharmacopoeia enteric coated tablet requirement of at least 75% per minute.

  The function of the moisture barrier as a non-enteric coat was further demonstrated by a 150 mg tablet core coated directly with the moisture barrier. Table 13 shows that the dissolution results (first 2 hours in acidic test solution) do not meet US Pharmacopoeia enteric coated tablet requirements.

Test solution: 900 mL of 0.1N hydrochloric acid
Test method: US Pharmacopoeia Type I device, 75 rpm, temperature 37 ° C

The buffer test was not performed due to the high release in the acidic test solution.
2. The moisture barrier layer functions to substantially hinder or delay moisture absorption.

  The function of the moisture barrier as a coat that substantially impedes or retards moisture absorption was confirmed by determining the water content with the Karl-Ficher method in a controlled release coated tablet core or moisture barrier coated tablet core for a 300 mg tablet core. . The preparation of the preparation is the same as described in Example 1. Each coated tablet was placed separately on an open glass dish under accelerated conditions (40 ° C. ± 2 ° C./75% RH ± 5% RH) for 10 days. As shown in Table 14, the moisture content of the controlled release coated tablet core was higher than the moisture barrier coated tablet core.

The data shown in Tables 13 and 14 indicate that the moisture barrier does not function as an enteric coat as defined by the US Pharmacopoeia. Instead, the data shows the function of the moisture barrier as a coat, which substantially impedes or retards water absorption.
Example 3
The purpose of this study was to examine the equivalence of dose strength in the following test to 150 mg and 300 mg product strength of bupropion hydrochloride modified release tablets under fasting conditions. Two strength (150 mg and 300 mg) binary, crossed, open-label, single dose, fasted dose strength equivalence studies of the bupropion hydrochloride modified release tablets of the present invention were performed. The modified release tablet of the present invention was administered once a day to non-smoking healthy male and female subjects.

  The study design was a 2 period, 2 treatment, 1 dose, crossover design under fasting conditions. The study period was divided by a 3 week washout period. A total of 36 subjects (19 men and 17 women) were registered in the study, of which 35 subjects (19 men and 16 women) completed the study. The subjects were treated as follows.

  A) Oral administration of 2 150 mg tablets of controlled release bupropion hydrochloride of the invention once daily with 240 mL of room temperature water after an overnight fast of at least 10 hours.

  B) After an overnight fast of at least 10 hours, one 300 mg tablet of modified release bupropion hydrochloride of the present invention is orally administered once daily with 240 mL of room temperature water.

  Bupropion and its metabolites hydroxybupropion, bupropion threo amino alcohol, and erythro amino alcohol over a period of 120 hours after administration of two 150 mg dosage forms once a day and one 300 mg dosage form once a day Graphs of mean plasma concentration (ng / ml) profiles are shown in FIGS.

  Tables 15a-d provide the mean (± SD) pharmacokinetic data for bupropion after administration of two 150 mg dose strength tablets once a day or 300 mg dose strength tablets once a day.

  Relative to fasting conditions for AUC0-inf, AUC0-t, and Cmax converted using natural logarithm (150 mg 2 tablets (once a day) vs. 300 mg 1 tablet (once a day)) , Bupropion and its metabolites are summarized in Table 16.

The data show that in the modified release tablets of the invention described herein and in Example 1, both 150 mg dose strength tablets administered twice daily and 300 mg dose strength tablets administered once daily are bupropion. And its pharmacokinetic parameters for its metabolites are mutually equivalent.
Example 4
Comparative bioavailability study of quaternary, crossed, open-label, single-dose fasting and dietary effects on 150 mg tablets of bupropion hydrochloride modified release and Zyban® 150 mg tablets described herein and in Example 1 This was conducted in non-smoking healthy male and female subjects. This study was designed to evaluate the rate and extent of absorption of bupropion in fed and fasted states after administration of the 150 mg dose strength bupropion hydrochloride modified release tablet described herein and in Example 1. . In parallel, the study also assessed the rate and extent of bupropion absorption after administration of 150 mg dose strength Zyban® tablets in the fed and fasted state.

  The study design followed a 2 period, 2 treatment, 1 dose, crossover design under fasted and fed conditions. The study period was divided by a 2-week washout period. A total of 35 subjects (24 men and 11 women) were enrolled in the study, of which 32 subjects (22 men and 10 women) completed the study. The subjects were treated as follows.

A) Under fasting conditions, 150 mg of the modified release bupropion hydrochloride tablet of the present invention once a day,
B) Under fed conditions, 150 mg of the modified release bupropion hydrochloride tablet of the present invention once a day,
C) 150 mg of Zyban® tablets once a day under fasting conditions and D) 150 mg of Zyban® tablets once a day under fed conditions.

  Bupropion and its metabolites hydroxybupropion, bupropion threo amino acid for 72 hours after administration of 150 mg 1 modified release tablet of the present invention once daily and Zyban® dosage form 150 mg once daily Graphs of the mean plasma concentration (ng / ml) profiles of alcohol and erythro amino alcohol are shown in FIGS.

  Table 17 shows the pharmacokinetics for bupropion after administration of 150 mg dose strength modified release tablets of the present invention or 150 mg dose strength prior art commercial product Zyban® tablets under fasting and feeding conditions. The mean (± SD) of experimental data is provided for bupropion and its metabolites.

  Relative to AUC0-inf, AUC0-t, and Cmax converted using natural logarithm under both fasting and fasting conditions (release-controlled tablet of the present invention fasting vs fasting) bioavailability analysis results, bupropion And its metabolites are summarized in Table 18.

The data in Table 18 shows that the bioavailability of bupropion and its metabolites does not show a dietary effect. That is, the modified release tablets of the invention containing bupropion hydrochloride are bioequivalent in the presence or absence of food and in the fasted versus fed state, AUC0-inf (and AUC0- The fact that 90% CI of the geometric mean ratio to t) and Cmax is within 80-125% of the FDA recommended range.
Example 5
Comparative bioavailability study of the effects of a binary, crossed, open-label, single-dose diet on the 300 mg dose strength bupropion hydrochloride modified release tablet of the present invention in non-smoking healthy male and female subjects.

  The study was designed to evaluate the effect of food on the rate and extent of absorption of the 300 mg dose strength modified bupropion hydrochloride modified release tablet of the present invention once a day under one dose condition. The study design followed a two-period, two-treatment, one-dose, crossover design under fasting and feeding conditions. The study period was divided by a 2-week washout period. A total of 36 subjects (26 men and 10 women) were registered in the study, of which 32 subjects (23 men and 9 women) completed the study. Subjects received the following:

  A) One modified release tablet 300 mg after 10 hours of fasting.

  B) One 300 mg modified release tablet after complete consumption of a high fat breakfast.

  Bupropion and its metabolites hydroxybupropion, bupropion threo-type amino alcohol, and erythro-type amino alcohol over a period of 120 hours after administration of 300 mg tablet of the present invention once a day under conditions of feeding and fasting Graphs of mean plasma concentration (ng / ml) profiles are shown in FIGS.

  Table 19 provides the mean (± SD) pharmacokinetic data for bupropion and its metabolites after administration of the 300 mg dose strength modified release tablets of the present invention under fed and fasted conditions.

  The results of relative (fasting vs fasting) bioavailability analysis for AUC0-inf, AUC0-t, and Cmax converted using natural logarithms are shown for bupropion and its metabolites under both fasting and fasting conditions. To summarize.

The data in Table 20 show that the bioavailability of bupropion and its metabolites from the 300 mg dose strength modified release bupropion hydrochloride tablet of the present invention does not show a dietary effect, and AUC0-inf (and suitably AUC0- The fact that 90% CI of the geometric mean ratio to t) and Cmax is within 80-125% of the FDA recommended range in the fed versus fasted state.
Example 6
Comparison of Binary, Crossed, Steady State, Multiple Dose, Unblinded, Fasting for the Bupropion Hydrochloride 300 mg Modified Release Tablets of the Invention Once Daily vs. Immediate Release Wellbutrin® 100 mg Tablets Three Daily Bioavailability studies were conducted in normal healthy non-smoking male and female subjects. This test shows that the 300 mg dose strength modified release tablet of the present invention once a day bioavailability compared to the prior art commercial immediate release Wellbutrin® tablet 3 times a day, steady state, fasting Designed to compare and evaluate under conditions.

  The study was designed as a 2 period, 2 treatment, dose escalation, multiple dose, crossover study under fasting conditions, with a 2 week washout period between the 2 study periods. A total of 40 subjects (27 men, 13 women) were registered in the study, of which 30 subjects (22 men, 8 women) completed the study. Subjects were given the following medication regimen:

  A) Wellbutrin® 100 mg tablets are administered at room temperature after an overnight fast of at least 10 hours at 0.0 am (starting at 7 am) on days 1, 2, and 3 (twice a day). Orally administered with 240 ml of water. In addition, a second wellbutrin (registered trademark) 100 mg tablet was administered to all the subjects together with 240 mL of room temperature water after fasting for 1 hour at 12.0 hours. One 300 mg dose strength bupropion hydrochloride modified release tablet of the present invention was administered to subjects with 240 ml of room temperature water at 0.0 hours (starting at 7:00 am) on days 4-13, after an overnight fast of at least 10 hours. Administered.

  B) Wellbutrin® 100 mg tablets were administered at room temperature after an overnight fast of at least 10 hours at 0.0 (starting at 7 am) on days 1, 2, and 3 (twice a day). Orally administered with 240 ml of water. A second Wellbutrin® 100 mg tablet was administered to all subjects with 240 ml of room temperature water at 12.0 hours after fasting for at least 1 hour. One wellbutrin® 100 mg tablet was administered to subjects with 240 ml of room temperature water at 00:00 (starting at 7:00 am) on days 4-13 after a fasting of at least 10 hours overnight. A second wellbutrin® 100 mg tablet was then administered to all subjects at 6.0 hours after a fast of at least 1 hour with 240 ml of room temperature water. A third Wellbutrin® 100 mg tablet was administered to all subjects with 240 ml of room temperature water at 12.0 hours after fasting for at least 1 hour.

  Bupropion and its metabolites hydroxybupropion, bupropionthreo aminoalcohol, and erythro aminoalcohol after administration of one 300 mg modified release tablet of the present invention once a day and three wellbutrin® 100 mg tablets Graphs of mean plasma concentration (ng / ml) profiles over the duration of this study are shown in FIGS.

  Table 21 shows the pharmacokinetic data for bupropion after administration of the 300 mg dose strength modified release tablet of the present invention once daily or prior art marketed Wellbutrin® 100 mg tablet three times daily. Provide the mean (± SD).

  The results of a relative (invented modified release tablet vs. Wellbutrin®) bioavailability analysis for AUC0-τ and Cmax for bupropion and its metabolites converted using natural logarithm are summarized in Table 22.

The data in Tables 21 and 22 show that the 300 mg dose strength modified release tablet of the present invention once daily is bioequivalent to the 100 mg dose immediate release Wellbutrin® three times daily. Indicates that there is.
Example 7
Comparative bioavailability studies in binary, steady state, crossed, open-label, multiple dose, fasted for 150 mg Zaiban® formulation, a prior art commercial product of 300 mg modified release bupropion hydrochloride tablet of the present invention. This was conducted in non-smoking healthy male and female subjects. The study was designed to compare the once-daily bioavailability of the 300 mg dosage form of the modified release bupropion hydrochloride tablet of the present invention to the prior art commercial product Zyban® tablet 150 mg twice a day.

The study design followed a 2 period, 2 treatment, multiple dose, crossover design under fasting conditions. The study period was divided by a 2-week washout period. A total of 54 subjects (40 men and 14 women) were registered in the study, of which 49 subjects (37 men and 12 women) completed the study. Subjects were administered 150 mg of Zyban® tablets once a day from day 1 to day 3 of the study. On days 4-17, the following was followed.
A) 300 mg of the modified release bupropion hydrochloride tablet of the present invention once a day.
B) 150 mg of Zyban® tablets twice a day.

  Bupropion and its metabolites hydroxybupropion and bupropion threo-type amino alcohol after administration of 300 mg 1 tablet of the present invention once a day and 150 mg 2 tablets of Zyban (registered trademark) twice a day under fasting conditions And graphs of mean plasma concentration (ng / ml) profiles over the test period for erythro amino alcohols are shown in FIGS.

  Table 23 shows the pharmacokinetic data for bupropion after the 300 mg dose strength modified release tablet of the present invention was administered once a day or 150 mg of the prior art commercial Zaiban® tablet twice a day. Provide the mean (± SD).

  The results of a relative (invented modified release tablet of the invention vs. Zyban®) bioavailability analysis for AUC0-τ, Cmax and Cmin converted using natural logarithms are summarized in Table 24 for bupropion and its metabolites. .

The data in Tables 23 and 24 show that one controlled dose bupropion hydrochloride tablet 300 mg (once a day) dose strength of the present invention is a prior art commercial product sustained release Zyban® tablet 150 mg per day 2 Indicates biologically equivalent to times.
Example 8 (comparative example)
150 mg and 300 mg formulations of bupropion hydrochloride were prepared as taught in US Pat. No. 6,143,327 to evaluate pharmacokinetic parameters and relative bioavailability data for bioequivalence. . Table 25 shows the ratio of the components used in the core, first layer, and second layer coat formulations.

  The tablets were made in the same manner as taught in US Pat. No. 6,143,327.

  Bupropion hydrochloride tablets (150 mg, 2 tablets once a day) vs. commercial Zaiban® sustained release tablets (150 mg, 1 tablet twice a day) and Welve manufactured according to Patent '327 (“Patent' 327 formulation”) A three-way, multi-dose, open-label, fasted, preliminary comparative bioavailability study on Trin® tablets (3 times daily) was conducted in healthy and non-smoking male healthy volunteers. The purpose of this study was to determine the relative bioavailability of 327 formulation bupropion hydrochloride 150 mg (150 mg 2 tablets once a day), Zyban® sustained release tablets (150 mg 1 tablet 2 times a day) It was to evaluate under fasting conditions at one dose or steady state as compared to Trin® 100 mg tablets (1 tablet of 100 mg 3 times a day).

  Table 26 shows the mean (± SD) plasma concentration (ng / ml) -time profile for bupropion under one dose condition.

  Table 27 provides the mean (± SD) pharmacokinetic data for bupropion after administration of the tablets shown in Table 25.

  The results of the relative bioavailability analysis for AUC0-24 (ng · hour / ml) and Cmax (ng / ml) shown in Table 27 converted using the natural algorithm are summarized in Table 28.

  Table 29 shows the mean (± SD) steady state plasma concentration-time profile (ng / ml) for bupropion of the tablet composition shown in Table 25.

  Table 30 shows the mean (± SD) pharmacokinetic data for bupropion under steady state after tablet administration as shown in Table 25.

  The results of the relative bioavailability analysis for AUC0-24 (ng · hour / ml) and Cmax (ng / ml) shown in Table 30 converted using the natural algorithm are summarized in Table 31.

  Pharmacokinetic and relative bioavailability data show that 90% CI for the formulation taught in Patent '327 is in the FDA recommended 80% to 125% range, making the product comparable to biology. Indicates that it does not fit. Thus, the data show that the '327 formulation is not bioequivalent to the commercially available Zyban® / sustained release Wellbutrin® or Wellbutrin® tablets.

Claims (1)

(I) a core comprising an effective amount of a pharmaceutically acceptable salt of bupropion, and a conventional excipient;
(Ii) a first controlled release coat surrounding the core;
(Iii) a controlled release tablet comprising a moisture barrier layer surrounding the first controlled release coat,
Bioequivalent, about 20% or less of the bupropion content is released after about 2 hours, about 15% to about 45% of the bupropion content is released after about 4 hours, and about 8 hours The modified release tablet exhibiting an elution profile such that about 40% to about 90% of the bupropion content is released later, and about 80% or more of the bupropion content is released after about 16 hours.

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