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Bupropion Synthesis Essay

Stereochemistry in Drug Action

Jonathan McConathy, Ph.D. and Michael J. Owens, Ph.D.

From the Laboratory of Neuropsychopharmacology, Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, Ga.

Corresponding author and reprints: Michael J. Owens, Ph.D., Laboratory of Neuropsychopharmacology, Department of Psychiatry & Behavioral Sciences, 1639 Pierce Dr., Ste. 4000, Emory University School of Medicine, Atlanta, GA 30322 (ude.yrome@snewom :liam-e).

Author information ►Article notes ►Copyright and License information ►

Received 2003 Mar; Accepted 2003 Apr 25.

Copyright © 2003, Physicians Postgraduate Press, Inc.

Prim Care Companion J Clin Psychiatry. 2003; 5(2): 70–73.

This article has been cited by other articles in PMC.

Abstract

The importance of stereochemistry in drug action is gaining greater attention in medical practice, and a basic knowledge of the subject will be necessary for clinicians to make informed decisions regarding the use of single-enantiomer drugs. Many of the drugs currently used in psychiatric practice are mixtures of enantiomers. For some therapeutics, single-enantiomer formulations can provide greater selectivities for their biological targets, improved therapeutic indices, and/or better pharmacokinetics than a mixture of enantiomers. This article reviews the nomenclature for describing stereochemistry and enantiomers, emphasizes the potential biological and pharmacologic differences between the 2 enantiomers of a drug, and highlights the clinical experience with single enantiomers of the selective serotonin reuptake inhibitors fluoxetine and citalopram. In some cases, both a mixture of enantiomers and a single-enantiomer formulation of a drug will be available simultaneously. In these cases, familiarity with stereochemistry and its pharmacologic implications will aid the practicing physician to provide optimal pharmacotherapy to his or her patients.

CHIRALITY AND ENANTIOMERS

This section contains the basics needed to understand chiral drugs. Undergraduate textbooks in chemistry are good resources for a more thorough discussion of chirality and enantiomers. The most important point is that chiral drugs have 2 structurally similar forms that can behave very differently in biological systems due to their different shapes in 3-dimensional space. These 2 possible forms are termed enantiomers, and the 2 enantiomers of a given chiral drug should be considered 2 different drugs. This topic is discussed further in the next section.

Chirality is formally defined as the geometric property of a rigid object (like a molecule or drug) of not being superimposable with its mirror image. Molecules that can be superimposed on their mirror images are achiral (not chiral). Chirality is a property of matter found throughout biological systems, from the basic building blocks of life such as amino acids, carbohydrates, and lipids to the layout of the human body. Chirality is often illustrated with the idea of left- and right-handedness: a left hand and right hand are mirror images of each other but are not superimposable. The 2 mirror images of a chiral molecule are termed enantiomers. Like hands, enantiomers come in pairs. Both molecules of an enantiomer pair have the same chemical composition and can be drawn the same way in 2 dimensions (e.g., a drug structure on a package insert), but in chiral environments such as the receptors and enzymes in the body, they can behave differently. A racemate (often called a racemic mixture) is a mixture of equal amounts of both enantiomers of a chiral drug. Chirality in drugs most often arises from a carbon atom attached to 4 different groups, but there can be other sources of chirality as well. Single enantiomers are sometimes referred to as single isomers or stereoisomers. These terms can also apply to achiral drugs and molecules and do not indicate that a single enantiomer is present. For example, molecules that are isomers of each other share the same stoichiometric molecular formula but may have very different structures. However, many discussions of chiral drugs use the terms enantiomer, single isomer, and/or single stereoisomer interchangeably.

The 2 enantiomers of a chiral drug are best identified on the basis of their absolute configuration or their optical rotation. Other designations such as D and L (note the upper case) are used for sugars and amino acids but are specific to these molecules and are not generally applicable to other compounds. The terms d, or dextro, and l, or levo, are considered obsolete and should be avoided. Instead, the R/S system for absolute configuration and the +/− system for optical rotation should be used. The absolute configuration at a chiral center is designated as R or S to unambiguously describe the 3-dimensional structure of the molecule. R is from the Latin rectus and means to the right or clockwise, and S is from the Latin sinister for to the left or counterclockwise. There are precise rules based on atomic number and mass for determining whether a particular chiral center has an R or S configuration. A chiral drug may have more than one chiral center, and in such cases it is necessary to assign an absolute configuration to each chiral center. Optical rotation is often used because it is easier to determine experimentally than absolute configuration, but it does not provide information about the absolute configuration of an enantiomer. For a given enantiomer pair, one enantiomer can be designated (+) and the other as (−) on the basis of the direction they rotate polarized light. Optical rotations have also been described as dextrorotatory for (+) and levorotatory for (−). Racemates can be designated as (R,S) or (±).

CHIRAL DRUGS IN BIOLOGICAL SYSTEMS

Enantiomers of a chiral drug have identical physical and chemical properties in an achiral environment. In a chiral environment, one enantiomer may display different chemical and pharmacologic behavior than the other enantiomer. Because living systems are themselves chiral, each of the enantiomers of a chiral drug can behave very differently in vivo. In other words, the R-enantiomer of a drug will not necessarily behave the same way as the S-enantiomer of the same drug when taken by a patient. For a given chiral drug, it is appropriate to consider the 2 enantiomers as 2 separate drugs with different properties unless proven otherwise.

The difference between 2 enantiomers of a drug is illustrated in Figure 1 using a hypothetical interaction between a chiral drug and its chiral binding site. In this case, one enantiomer is biologically active while the other enantiomer is not. The portions of the drug labeled A, B, and C must interact with the corresponding regions of the binding site labeled a, b, and c for the drug to have its pharmacologic effect. The active enantiomer of the drug has a 3-dimensional structure that can be aligned with the binding site to allow A to interact with a, B to interact with b, and C to interact with c. In contrast, the inactive enantiomer cannot bind in the same way no matter how it is rotated in space. Although the inactive enantiomer possesses all of the same groups A, B, C, and D as the active enantiomer, they cannot all be simultaneously aligned with the corresponding regions of the binding site.

Figure 1.

The Hypothetical Interaction Between the 2 Enantiomers of a Chiral Drug and Its Binding Sitea

This difference in 3-dimensional structure prevents the inactive enantiomer from having a biological effect at this binding site. In some cases, the portion of a molecule containing the chiral center(s) may be in a region that does not play a role in the molecule's ability to interact with its target. In these instances, the individual enantiomers may display very similar or even equivalent pharmacology at their target site. Even in these cases, the enantiomers may differ in their metabolic profiles as well as their affinities for other receptors, transporters, or enzymes.

IMPORTANCE OF CHIRALITY IN DRUGS

Approximately 50% of marketed drugs are chiral, and of these approximately 50% are mixtures of enantiomers rather than single enantiomers.1 In this section, the potential advantages of using single enantiomers of chiral drugs are discussed and some specific examples of single-enantiomer drugs currently on the market are given. Single-enantiomer drugs will become increasingly more available to the practicing physician, and both the single-enantiomer form and the mixture of enantiomers of a given drug may be available at the same time. In these cases, it is critical to distinguish the single enantiomer from the racemic form because they may differ in their dosages, efficacies, side effect profiles, or even indicated use. It is also important to realize that the safety and efficacy data for a drug evaluated as a mixture of enantiomers are still valid. The introduction of a single-enantiomer preparation of a drug previously approved as a mixture of enantiomers does not necessitate that the single enantiomer should become the standard of care. The decision to use a single enantiomer versus a mixture of enantiomers of a particular drug should be made on the basis of the data from clinical trials and clinical experience.

The 2 enantiomers of a chiral drug may differ significantly in their bioavailability, rate of metabolism, metabolites, excretion, potency and selectivity for receptors, transporters and/or enzymes, and toxicity. The use of single-enantiomer drugs can potentially lead to simpler and more selective pharmacologic profiles, improved therapeutic indices, simpler pharmacokinetics due to different rates of metabolism of the different enantiomers, and decreased drug interactions. For example, one enantiomer may be responsible for the therapeutic effects of a drug whereas the other enantiomer is inactive and/or contributes to undesirable effects. In such a case, use of the single enantiomer would provide a superior medication and may be preferred over the racemic form of the drug. Single-enantiomer formulations of (S)-albuterol, a β2-adrenergic receptor agonist for treatment of asthma, and (S)-omeprazole, a proton pump inhibitor for treatment of gastroesophageal reflux, have been shown to be superior to their racemic formulations in clinical trials.2 In other cases, however, both enantiomers of a chiral drug may contribute to the therapeutic effects, and the use of a single enantiomer may be less effective or even less safe than the racemic form. For example, the (−)-enantiomer of sotalol has both β-blocker and antiarrhythmic activity, whereas the (+)-enantiomer has antiarrhythmic properties but lacks β-adrenergic antagonism.3,4 In addition, the R-enantiomer of fluoxetine, at its highest administered dose, led to statistically significant prolongation of cardiac repolarization in phase II studies; the studies were subsequently stopped.5

Currently, there is no regulatory mandate in the United States or Europe to develop new drugs exclusively as single enantiomers. The U.S. Food and Drug Administration (FDA) policy regarding single enantiomers was published in 1992. This statement is available at the FDA Web site at www.fda.gov/cder/guidance/stereo.htm. The FDA leaves the decision to pursue a racemic or a single-enantiomer formulation of a new drug to its developers, but the choice of a racemic versus a single-enantiomer formulation must be justified. Although both racemic and single-enantiomer drugs will continue to be developed, a higher proportion of single enantiomers are being submitted for new drug approval.6

Although many psychotropic drugs are either achiral (e.g., fluvoxamine, nefazodone) or are already marketed as single enantiomers (e.g., sertraline, paroxetine, escitalopram), a number of antidepressants are currently marketed as racemates, including bupropion, citalopram, fluoxetine, tranylcypromine, trimipramine, and venlafaxine. Other drugs often used in psychiatric practice including zopiclone, methylphenidate, and some phenothiazines are also available as racemates. Of these, single-enantiomer formulations are being developed for bupropion and zopiclone. Dexmethylphenidate (d-methylphenidate) has also been introduced recently. Selected racemic drugs used in psychiatric practice are listed in Table 1. An instructive comparison can be made between the development of the single-enantiomer formulations of citalopram and fluoxetine. In both cases, one enantiomer appeared to have superior in vivo properties, and clinical trials were conducted to determine the safety and efficacy of (S)-citalopram and (R)-fluoxetine.

Table 1.

Selected Racemic Drugs Currently Used in Psychiatric Practice

In the case of citalopram, the S-enantiomer is primarily responsible for antagonism of serotonin reuptake while the R-enantiomer is 30-fold less potent.7 In clinical trials, both racemic (R,S)-citalopram (marketed as Celexa) and (S)-citalopram (marketed as Lexapro) were significantly better than placebo for improving depression.8–11 The early data suggest that (S)-citalopram has greater efficacy than (R,S)-citalopram at doses predicted to be equivalent as well as equal efficacy to (R,S)-citalopram at a dose that produces fewer side effects.12,13 Overall, (S)-citalopram appears to have advantages over racemic citalopram and is a good example of the potential benefits of single-enantiomer drugs. However, there is currently no evidence that patients with major depression who are responding well to therapy with R,S-citalopram benefit from switching to S-citalopram.

In contrast, the attempt to develop a single-enantiomer formulation of fluoxetine for the treatment of depression was unsuccessful. While (R)-fluoxetine and (S)-fluoxetine are similarly effective at blocking serotonin reuptake, they are metabolized differently.5 The use of the R-enantiomer was expected to result in less variable plasma levels of fluoxetine and its active metabolites than observed with racemic fluoxetine. Additionally, (R)-fluoxetine and its metabolites inhibit CYP2D6, a cytochrome P450 system enzyme, to a lesser extent than (S)-fluoxetine and its metabolites.14 As mentioned, in phase II studies of (R)-fluoxetine, the highest dose led to statistically significant prolongation of cardiac repolarization, and the studies were stopped.5 Although racemic fluoxetine has been shown to be a safe and effective antidepressant for over 15 years, the (R)-enantiomer formulation was not viable due to safety concerns. The experience with (S)-citalopram and (R)-fluoxetine highlight the potential differences between enantiomers of a given chiral drug and the need to consider single-enantiomer formulations of a previously racemic drug on a case-by-case basis.

SUMMARY

The increasing availability of single-enantiomer drugs promises to provide clinicians with safer, better-tolerated, and more efficacious medications for treating patients. It is incumbent upon the practicing physician to be familiar with the basic characteristics of chiral pharmaceuticals discussed in this article. In particular, each enantiomer of a given chiral drug may have its own particular pharmacologic profile, and a single-enantiomer formulation of a drug may possess different properties than the racemic formulation of the same drug. When both a single-enantiomer and a racemic formulation of a drug are available, the information from clinical trials and clinical experience should be used to decide which formulation is most appropriate.

Drug names: albuterol (Ventolin, Proventil, and others), bupropion (Wellbutrin and others), citalopram (Celexa), dexmethylphenidate (Focalin), escitalopram (Lexapro), fluoxetine (Prozac and others), fluvoxamine (Luvox and others), methylphenidate (Ritalin, Concerta, and others), nefazodone (Serzone), omeprazole (Prilosec and others), paroxetine (Paxil), sertraline (Zoloft), tranylcypromine (Parnate), trimipramine (Surmontil), venlafaxine (Effexor).

Footnotes

Supported by an unrestricted grant from Forest Laboratories (Dr. Owens).

Dr. Owens has received grant/research support from Forest, Cypress Bioscience, GlaxoSmithKline, and Pfizer.

REFERENCES

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  • Kato R, Ikeda N, and Yabek S. et al. Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics. J Am Coll Cardiol. 1986 7:116–125. [PubMed]
  • Advani SV, Singh BN. Pharmacodynamic, pharmacokinetic and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol. Drugs. 1995;49:664–679.[PubMed]
  • DeVane CL, Boulton DW. Great expectations in stereochemistry: focus on antidepressants. CNS Spectrums. 2002;7:28–33.[PubMed]
  • Rouhi AM. Chiral business. Chem Eng News. 2003;81(18):45–55.
  • Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50:345–350.[PubMed]
  • Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry. 2002;63:331–336.[PubMed]
  • Lepola UM, Loft H, and Reines EH. Escitalopram: efficacious and well tolerated in depression management in primary care. In: New Research Abstracts of the 154th Annual Meeting of the American Psychiatric Association. 5–10May2001 New Orleans, La. Abstract NR431:117.
  • Montgomery SA, Loft H, and Sanchez C. et al. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol. 2001 88:282–286. [PubMed]
  • Wade AJ, Lemming OM, Hedegaard KB. Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol. 2002;17:95–102.[PubMed]
  • Owens MJ, Rosenbaum JF. Escitalopram: a second-generation SSRI. CNS Spectrums. 2002;7:34–39.[PubMed]
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  • Stevens JC, Wrighton SA. Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. J Pharmacol Exp Ther. 1993;266:964–971.[PubMed]

Articles from Primary Care Companion to The Journal of Clinical Psychiatry are provided here courtesy of Physicians Postgraduate Press, Inc.

MODIFIED RELEASE FORMULATIONS OF A BUPROPION SALT

RELATED APPLICATIONS

[001] The present application claims priority from United States provisional application

60/693,906 filed June 27, 2005, the contents of which is incorporated by reference in their entirety.

FIELD OF THE INVENTION

[002] There is a need for dosage forms comprising a pharmaceutically acceptable salt of bupropion that is more stable than bupropion hydrochloride. Accordingly, the present invention relates to dosage forms comprising an effective amount of a pharmaceutically acceptable salt of bupropion that is more stable than bupropion hydrochloride. The present invention also relates to the use of such dosage forms for the treatment of one or more conditions in a subject suitable for treatment by bupropion or pharmaceutically acceptable salts thereof such as depression, nicotine addiction and obesity.

BACKGROUND

[003] 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 (±)-l-(3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-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.

[004] 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®)).

[005] 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, suitably with 6 or more hours in between doses. For patients requiring more than 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 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.

[006] In general, patient compliance is a problem with medications that require a multiple dosing regimen and is especially problematic with depressed individuals. While sustained release formulations have simplified the dosing regimen and increased patient compliance, there is still room for further simplifying the dosing regimen and further improving patient adherence to the dosing regimen. The development of an approved stable once daily modified-release bupropion formulation would be an advance in the art.

[007] The selection of a suitable salt for a drug candidate is recognized as an important step in the preclinical phase of drug development; however, the scientific literature on this topic is rather limited. Changing the salt form of a drug is a recognized means of modifying its chemical and biological properties without modifying its structure. As yet, there is. no reliable way of predicting exactly what effect changing the salt form of an active drug will have on its biological activity. A decision to change the salt form at a later stage introduces the need to repeat toxicological, formulation and stability tests, with obvious implications for the overall development and production time for the new pharmaceutical product.

[008] In general, a few of the factors that should be considered during a salt selection include:

What is the effect of the salt on the chemical stability of the drug substance and the drug product? Does the salt form a hydrate? What is the solubility of the salt and is it appropriate for in vivo administration? What is the quality of the salt with regard to processing, issues with scale up, safety, etc.?

[009] According to the Chemical Abstracts Registry® Database, the only salts of bupropion that have been previously reported are the hydrochloride (HCl), (2Z)-2-butenedioate, (2E)-2- butenedioate, methane sulfonate, formic acid, 2-hydroxy-l,2,3-propanetricarboxylate, phosphate and trifluoromethanesulfonate salts.

[010] There is a need for a once daily formulation of a pharmaceutically acceptable salt of bupropion with enhanced stability.

SUMMARY

[011] The present invention relates to dosage forms comprising an effective amount of a pharmaceutically acceptable salt of bupropion (bupropion hydrobromide) which is more stable than bupropion hydrochloride. In particular such bupropion compositions are more stable than otherwise equivalent bupropion hydrochloride compositions when stored for at least 3 months and/or at least 6 months at 40 degrees C and 75% relative humidity ("accelerated storage conditions") as evidenced by a reduced amount of at least one moiety characteristic of bupropion degradation and/or exhibit less fluctuation or reduction in potency after being stored for at least 3 months and/or at least 6 months under accelerated storage conditions relative to an otherwise similar bupropion hydrochloride composition as evidenced e.g., by less fluctuation in the in vitro dissolution profile in at least one dissolution medium over a 24 hour period.

[012] The present invention also relates to the use of such more stable bupropion hydrobromide dosage forms for the treatment of one or more conditions in a subject.

[013] The dosage forms of the present invention comprise a compound of formula I (bupropion hydrobromide):

and pharmaceutically acceptable carriers, excipients and/or diluents, said composition having greater stability than a corresponding pharmaceutical composition comprising bupropion hydrochloride and pharmaceutically acceptable carriers, excipients and/or diluents. [014] In other embodiments of the present invention, the bupropion salt can be in the form of its anhydrous, hydrated, and solvated forms, in the form of prodrugs, and in the individually optically active enantiomers of the bupropion salt, such as for examle (+)-bupropion and (-)- bupropion. Suitable pharmaceutically acceptable salts of bupropion for use in the present invention are more stable than bupropion hydrochloride. Suitable salts of bupropion also include for example, pharmaceutically acceptable acid addition salts. In certain embodiments, the acid addition salt of bupropion can be indirectly obtained by the separate addition of bupropion and an acid to the core formulation.

[015] Another embodiment of the present invention contemplates the use of bupropion hydrobromide to prepare a medicament to treat a condition which can benefit from administration of bupropion, wherein said medicament has greater stability than a corresponding medicament comprising bupropion hydrochloride. Herein enhanced stability means that the salt or a composition containing is more stable after being stored for at least 3 months and/or 6 months at 40 degrees C and 75 % relative humidity (accelerated storage conditions) as evidenced by a lesser amount of at least one moiety characteristic of bupropion degradation and/or a reduction or fluctuation in potency evidenced e.g., by a greater fluctuation in the in vitro dissolution profile over at least a 12 or a 24 hour period in at least one dissolution medium relative and under the same conditions to an otherwise equivalent bupropion hydrobromide compostion stored for the same length of time under the same accelerated storage conditions. [016] As discussed infra and generally known in the art appropriate dissolution medium and appropropriate conditions for assaying the dissolution characteristics of pharmaceutical dosage forms such as tablets are well known in the art and are contained in the United States Pharmacopoiea and its Eoropean or Japanese counterparts and include by way of example dissolution in USP Type 1 apparatus (Rotating Basket Method) in 900 ml water; 0.1 N HCl; 0.1N HCl + 0.1% Cetrimide; USP bufffer pH 1.5; Acetate buffer pH 4.5; Phosphate Buffer pH

6.5; or Phosphate Buffer pH 7.4 at 75 RPM at 37 degrees C +/- 0.5 degrees C.

[017] Additionally, other disolution media include USP-3 media and USP-3 dissolution conditions i.e., SGF pH 1.2; Acetate buffer pH 4.5 and Phosphate Buffer pH 6.8.

[018] In another embodiment of the present invention, the dosage forms comprising bupropion hydrobromide can be used to treat a condition which can benefit from administration of bupropion such as depression, seasonal effective disorder, smoking cessation or obesity.

[019] Another embodiment of the present invention contemplates the use of bupropion hydrobromide to prepare a modifϊed-release tablet of bupropion hydrobromide with enhanced stability. The tablets of the present invention, comprising bupropion hydrobromide, have unexpected enhanced stability compared to the prior art bupropion hydrochloride tablets.

[020] In another embodiment the present invention contemplates the use of bupropion hydrobromide to produce once-daily administrable tablets or other dosage forms that are bioequivalent to Welbutrin™ or Zyban/Wellbutrin™ SR tablets as defined by FDA criteria when administered once daily to a subject in need thereof. In particular at least one of the Tmax,

Cmax, and AUC profile are within 80-125% of Wellbutrin™- and Zyban™/Wellbutrin™ when administerd once daily to a subject in need thereof. Preferably, these formulatuions also will be free of any significant food effect.

[021] In addition the present invention provides bupropion hydrobromide dosage forms containing at least one coating, e.g., tablets, which are resistant to dose dumping in high alcohol, e.g., 40% ethanol, because of the presence of an appropriate coating, i.e., a SmartCoat.™

[022] Another embodiment of the present invention further contemplates a method of preparing a medicament for the treatment of a condition which can benefit from the administration of bupropion comprising bringing an effective amount of bupropion hydrobromide into contact with one or more pharmaceutically acceptable carriers, diluents and/or excipients.

[023] Another embodiment of the present invention contemplates a method of treating a condition which can benefit from the administration of bupropion comprising administering an effective amount of bupropion hydrobromide to a subject. For example, such conditions which can benefit from administration of bupropion hydrobromide include but are not limited to depression, including seasonal effective disorder, cognitive symptoms in depression, bipolar depression, post partum depression, minor depression, lack of energy in depression, suicidal depression, anxiety disorders, generalized anxiety disorder, social anxiety disorder, obsessive compulsive disorder, post traumatic stress disorder (PTSD), panic disorder, disorders requiring a stimulant effect, attention deficit/hyperactiviy disorder (ADHD), narcolepsy, hypersomnia, substance-abuse disorders, stimulant dependence, marijuana dependence, nicotine dependence, obesity, female and male sexual dysfunction such as premature ejaculation, premenstrual syndrome, premenstrual dysphoric disorder, neuropathic pain, fibromyalgia, diabetic neuropathy, viral infection, sleep apnea, sleep disorders and migraines. The conditions may be focused on different demographic populations, such as reproductive related mood disorders, specific age population disorders and specific ethnic population disorders.

[024] According to an aspect of the invention, there is provided a composition for administration to a subject in need of treatment for a condition. The composition comprises a pharmaceutically effective amount of a bupropion salt that is more stable than bupropion hydrochloride as defined herein. In addition, the composition is more stable than a corresponding composition comprising bupropion hydrochloride.

[025] The present invention includes both oral and non-oral bupropion hydrobromide containing medicaments. Prior to the present invention medicaments containing bupropion hydrobromide were unavailabe Particularly, the invention embraces compositions suitable for topical, injectable, inhalation and other modes of administration. Typically the medicaments of the present invention are orally administrable.

[026] In particular the invention includes extended release formulations. In another aspect,, the present invention includes delayed release formulations. Further, the present invention embraces enhanced absorption formulations.

[027] In a particular embodiment, the inventive compositions include controlled release matrix tablet formulations.

[028] In a more particular implementation of the invention, a bupropion medicament composition according to the invention may comprise (i) a core that includes bupropion hydrobromide, a binder and a lubricant; and (ii) a control releasing coat substantially surrounding said core; wherein said composition provides controlled release of said bupropion hydrobromide. Such composition optionally may comprise one or more additional coatings surrounding the core and/or the control releasing coat such as moisture barrier coats, enteric coats or coatings that affect the physical integrity and/or appearance of the bupropion The binder can be selected from known pharmaceutical binders such as polyvinyl alcohol. The lubricant also can be selected from known pharmaceutical lubricants such as glyceryl behenate. The control releasing coat can include a water-insoluble polymer, a water-soluble polymer, and optionally a plasticizer. The water-insoluble polymer can be selected from a range of water insoluble polymers useful in extended release pharmaceutical compositions such as ethylcellulose. The water-soluble polymer can be selected from a variety of water-soluble polymers useful in extended release pharmaceutical compositions such as polyvinylpyrrolidone. The plasticizer if present can be selected from a range of known plasticizers such as mixtures of polyethylene glycol 4000 and dibutyl sebacate. These compositions include once-daily administrable compositions that are bioequivalent to Wellbutrin™ or Zyban™/Wellbutrin™ SR tablets when administered once- daily to a subject in need thereof.may be bioequivalent. These compositions optionally may not exhibit a food effect and/or may be resistan to dose dumping in the prersence of high alcohol concentrations (i.e., 40% by weight of ethanol).

[029] In a more particular implementation of the invention , the subject bupropion composition comprises (i) a core that includes bupropion hydrobromide, a binder and a lubricant; and (ϋ) a control releasing coat substantially surrounding said core; wherein said control releasing coat includes an aqueous dispersion of a neutral ester copolymer without any functional groups, a polyglycol having a melting point greater than 550C, and one or more pharmaceutically acceptable excipients, wherein said coat is coated onto said core and cured at a temperature at least equal to of greater than the melting point of the polyglycol. Optionally, this medicament may comprise one or more additional coatings surrounding the core and/or control-release coating such as moisture barrier coats, enteric coats, coats that preclude dose dumping in specific media such as alcohol, and coatings that affect the physical stability or integrity of the medicament and/or its physical appearance.

[030] In a particular implementation of the invention, the subject bupropion composition comprises multiparticulates.

[031] In a particular implementation of the invention, the subject bupropion composition comprises a second drug. The second drug can be any drug which may be administered in combination with the subject bupropion salt such as other anti-depressants, SSRFs, anti-anxiety agents, etc. The invention embraces drug combinations wherein the second drug may elicit a synergistic benefit on bupropion efficacy as well as non-synergistic drug combinations. In particular the invention embraces bupropion hydrobromide compositions wherein the second drug is citalopram, escitalopram and/or venlafaxine.

[032] According to another aspect of the invention, there is provided a method of using a composition according to any of the foregoing claims for treatment in a subject in need of such administration. This includes in particular the treatment of depression, obesity and abuse disorders such as nicotine addiction and smoking cessation. In an exemplary embodiments such treatments comprise once-daily dosage regimens.

[033] According to another aspect of the invention, there is provided a use of bupropion hydrobromide to prepare a medicament to treat conditions which benefit from administration of bupropion, wherein said medicament has greater stability than a corresponding medicament comprising bupropion hydrochloride.

[034] In accordance with one aspect of the present invention, there is provided a controlled release tablet, comprising (i) a core comprising an effective amount of a bupropion hydrobromide, a binder, a lubricant; and (ii) a control-releasing coat surrounding said core; and optionally (iii) a moisture barrier surrounding said control-releasing coat or the core; and; wherein the extended release tablet exhibits a dissolution profile such that after 2 hours, no more than 20% of the bupropion hydrobromide content is released, for example in certain embodiments 2% to 18%, 4% to 8%, or 5% of the bupropion hydrobromide content is released after 2 hours; after 4 hours, 15% to 45% of the bupropion hydrobromide content is released, for example in certain embodiments 21% to 37%, 28% to 34%, or 32% of the bupropion hydrobromide content is released after 4 hours; after 8 hours, 40% to 90% of the bupropion hydrobromide content is released, for example in certain embodiments 60% to 85%, 68% to 74%, or 74% of the bupropion hydrobromide content is released after 8 hours; and after 16 hours no less than 80% of the bupropion hydrobromide content is released, for example in certain embodiments not less than 93%, not less than 96%, or not less than 99% of the bupropion hydrobromide content is released after 16 hours; and wherein the bupropion hydrobromide salt contained insaid extended release tablet has greater stability than a tablet having the same composition with the exception that bupropion hydrobromide is replaced with bupropion hydrochloride.

[035] In another aspect the composition exhibits a dissolution profile such that after 2 hours not more than 40% of the bupropion hydrobromide is released, e.g., 33%, after 4 hours from 40- 75%, e.g., 59% of the bupropion hydrobromide is released, after 8 hours not less than 75% of the bupropion hydrobromide is released, e.g., 91%, and after 16 hours not less than 85% of the bupropion hydrobromide is released, e.g., 97%. These medicaments will typically comprise 50- 500 mg of bupropion hydrobromide. In exemplary embodiments diosclosed herein the medicament contain 174 mg or 348 mg of bupropion hydrobromide.

[036] In accordance with another aspect of the present invention, there is provided an enhanced-absorption tablet, comprising (i) a core comprising an effective amount of bupropion hydrobromide, a binder, a lubricant; and (ii) a control-releasing coat surrounding said core; and wherein the enhanced absorption tablet exhibits a dissolution profile such that after 2 hours, no more than 25% of the bupropion hydrobromide content is released, for example in certain embodiments 10% to 20% of the bupropion hydrobromide content is released after 2 hours; after 4 hours, 25% to 55% of the bupropion hydrobromide content is released, for example in certain embodiments 30% to 50%, of the bupropion hydrobromide content is released after 4 hours; after 8 hours, more than 60% of the bupropion hydrobromide content is released, for example in certain embodiments 70% to 90% of the bupropion hydrobromide content is released after 8 hours; and after 16 hours more than 70% of the bupropion hydrobromide content is released, for example in certain embodiments more than 80% of the bupropion hydrobromide content is released after 16 hours; and wherein said extended release tablet has greater stability than a tablet having the same composition with the exception that bupropion hydrobromide is replaced with bupropion hydrochloride. This composition optionally may further comprise one or more additional coats surrounding the core and/or control-release coat.

[037] In an exemplary embodiment this composition may comprise a dissolution profile such that after 2 hours not more than 40% of bupropion hydrobromide is released therefrom, e.g., 33%; after 4 hours 40-75% of bupropion hydrobromide is released therefreom, e.g., 59%, after 8 hours not less than 75% of bupropion hydrobromide is released therefrom, e.g., 91%, and after 16 hours not less than 85% of bupropion hydrobromide is released therefrom, e.g., 97%. [038] In accordance with a further aspect of the invention there is provided a salt of bupropion and polymorphic forms thereof having enhanced stability wherein the salt is hydrobromide, and wherein enhanced stability refers to the reduced formation of at least one degradation product characteristic of bupropion degradation and/or the increased retention of potency as evidenced e.g., by a reduced fluctuation in the in vitro dissolution profile in at least one dissolution medium relative to an otherwise equivalent formulation containing bupropion hydrochloridewhen the formulations containing these bupropion salts are stored for prolonged time periods under equivalent conditions. In particular enhanced stability referes to bupropion hydrobromide compositions that are less subject to degradation than an otherwise equivalent bupropion hydrochloride composition when stored under accelerated storage conditions, i.e., 40 degrees C at 75% relative humidity for at least 3 months, and/or for at least 6 months or longer and/or which exhibits less fluctuation or reduction in potency as evidence by a reduced fluctuation in the in vitro dissolution profile in at least one dissolution medium wherein dissolution is effected under the same conditions after the bupropion hydrobromide and bupropion hydrochloride compositions are stored for at least 3 months and/or at least 6 months at 40 degrees C and 75% relative humidity. In the present invention, as described infra, degradation is assayed based on the amount of at least one compound characteristic of bupropion degration.

[039] More particularly, the present invention embraces enhancede absorption tablets comprising (i) a core comprising an effective amount of bupropion HBr, a binder, a lubricant: and (ii) a control-releasing coat surrounding said core; wherein the enhanced absorption tablet exhibits a dissolution profile such that after 2 hours no more than 40% bupropion is released,

(e.g, 33%); after 4 hours 40-75% bupropion is released (e.g., 59%), after 8 hours at least 75% is released (e.g., 91%); and after 16 hours at least 85% is released (e.g, 97%)

[040] As discussed infra, in vitro dissolution of bupropion from controlled or extended release formulations according to the invention can be determined by methods well known to those skilled in the pharmaceutical art. Suitable methods are contained in the United States

Pharmacopoiea (USP) as well as European and Japanese counterpats of the USP and are exemplified infra. This includes by way of example effecting dissolution in a USP 1 apparatus

(Rotating Type Basket Method) in 900 ml water, 0.1N HCl, 0.1N HCl + 0.1% Cetrimide, USP

Buffer pH 1.5, Acetate Buffer pH 6.5 or Phosphate Buffer pH 7.4 at 75 RPM at 37 degrees C +/-

0.5 degrees C or by effecting dissolution using a USP3 dissolution medium such as SGF having a pH 1.2; acetate buffer having a pH of 4.5 or phosphate buffer having a pH of 6.8.

BRIEF DESCRIPTION OF THE DRAWINGS

[041] Figure 1 shows a DVS profile for bupropion hydrobromide (HBr).

[042] Figure 2 shows DVS isotherm data for bupropion HBr. [043] Figure 3 is a bar graph showing the results of stability testing on the bupropion salts mixed with excipients in closed vials over 20 days at 40°C/75% relative humidity (RH). [044] Figure 4 is a bar graph showing the potency of the bupropion salts mixed with excipients after storage in closed vials over 20 days at 40°C/75%RH compared to their initial potency. [045] Figure 5 is a bar graph showing the potency of the bupropion salts mixed with excipients and water after storage in closed vials over 32 days at 4O0C compared to their initial potency. [046] Figure 6 is a bar graph showing the potency of the bupropion salts mixed with excipients, water, isopropyl alcohol and ethanol after storage in closed vials over 32 days at 4O0C compared to their initial potency.

[047] Figure 7 is a bar graph showing the potency of the bupropion salts mixed with excipients, isopropyl alcohol and ethanol after storage in closed vials over 32 days at 400C compared to their initial potency.

[048] Figure 8 is a bar graph showing the % impurities for the bupropion salts mixed with excipients and treated for 32 days in closed vials and spiked with water.

[049] Figure 9 is a bar graph showing the % impurities for the bupropion salts mixed with excipients and treated for 32 days in closed vials ans spiked with water, isopropyl alcohol (IPA) and ethanol (EtOH).

[050] Figure 10 is a bar graph showing the % impurities for the bupropion salts mixed with excipients and treated for 32 days in closed vials and spiked with isopropyl alcohol (IPA) and ethanol (EtOH).

[051] Figure 11 is a flow chart showing the overall process for the development of bupropion

HBr XL tablets.

[052] Figure 12 is a flow chart demonstrating the granulation process of the bupropion HBr XL and EA tablets.

[053] Figure 13 is a flow chart showing the overall tabletting process of bupropion HBr XL.

[054] Figure 14 is a flow chart showing the overall coating process of bupropion HBr XL.

[055] Figure 15 is a dissolution profile of the 4kp, 6-7kp and 9-10kp tablets, comparing the effects of hardness on dissolution in the study on Batch BUP-HBr-XL-009-5.

[056] Figure 16 is a dissolution profile of the 348mg Bupropion HBr cores which have been compressed using 9mm tooling in the study on Batch BUP-HBr-XL-009-5. [057] Figure 17 is a dissolution profile of the 348mg Bupropion HBr cores which have been compressed using 10mm tooling in the study on Batch BUP-HB r-XL-009-5.

[058] Figure 18 is a dissolution profile comparison of the 9mm and 10mm diameter 348mg

Bupropion HBr cores in the study on Batch BUP-HBr-XL-009-5.

[059] Figure 19 is a dissolution profile of the 174mg in the study on Batch BUP-HBr-XL-021-

5.

[060] Figure 20 is a dissolution profile of BUP-HBr-XL-348mg-013-5 (28mg, 30mg, 32mg and

34 mg weight gains).

[061] Figure 21 is a dissolution profile of BUP-HBr-XL-348mg-013-5 (5mg, 6mg, and 7mg weight gains).

[062] Figure 22 is a dissolution profile of BUP-HBr-XL-348mg-018-5 (26mg, 28mg, 30mg and

32 mg weight gains).

[063] Figure 23 is a dissolution profile of BUP-HBr-XL-348mg-018-5 (7mg weight gain).

[064] Figure 24 is a dissolution profile of BUP-HBr-XL- 174mg-022-5 (22mg, 24mg, 28mg and

30 mg weight gains).

[065] Figure 25 is a dissolution profile of BUP-HBr-XL- 174mg-022-5 (5mg, 6mg, and 7mg weight gains).

[066] Figure 26 is a dissolution profile of BUP-HBr-XL-348mg-023-5 (26mg, 28mg, 30mg and

32mg weight gains).

[067] Figure 27 is a dissolution profile of BUP-HBr-XL-348mg-025-5 (26mg, 28mg, 30mg, and 32mg mg weight gains).

[068] Figure 28 is a dissolution profile of BUP-HBr-XL-348mg-025-5 (5mg, 6mg, and 7mg weight gains).

[069] Figure 29 is a dissolution profile of BUP-HBr-XL-348mg-026-5 (26mg, 28mg, 30mg, and 32mg weight gains).

[070] Figure 30 is a dissolution profile of BUP-HBr-XL- 174mg-027-5 (22mg, 24mg, and 26mg weight gains).

[071] Figure 31 is a dissolution profile of BUP-HBr-XL- 174mg-027-5 (4mg, 5mg, 6mg, and

7mg weight gains).

[072] Figure 32 is a flow chart showing the overall process for the development of bupropion

HBr EA tablets. [073] Figure 33 is a flow chart demonstrating the granulation process of the bupropion HBr EA tablets.

[074] Figure 34 is a flow chart showing the compression process of the 300 mg and 150 mg bupropion HBr EA Tablets.

[075] Figure 35 is a flow chart showing the coating process of 150 mg and 300 mg bupropion

HBr EA Tablets with an Ethocel ™ Coating.

[076] Figure 36 is a dissolution profile of the of tablet cores at different hardness levels (4kp, 6-

7kp and 9kp) in the study on Batch BUP-HBr-XL-016-5.

[077] Figure 37 is a dissolution profile of the 300mg Bupropion HBr EACores in the study on

Batch BUP-HBr-XL-016-5.

[078] Figure 38 is a dissolution profile of the 150mg Bupropion HBr Cores in the study on

Batch BUP-HBr-XL-016-5.

[079] Figure 39 is a dissolution profile of BUP-HBr-EA-300mg-001-5 (44mg, 46mg, 48mg,

50mg 52mg, and 54mg weight gains).

[080] Figure 40 is a comparative USP3 dissolution profile of Bupropion HBr 300mg EA

Tablets with 52mg weight gain to the in vivo and the in vitro profiles of the target (Bupropion

HCl 300mg).

[081] Figure 41 is a dissolution profile of BUP-HBr-EA- 150mg-002-5 (18mg, 20mg, 22mg,

24mg, 26mg, 28mg, 30mg, 32mg, 34mg and 36mg weight gains).

[082] Figure 42 is a dissolution profile of BUP-HBr-EA-3OOmg-OO3-5 (44mg, 46mg, 48mg,

50mg, 52mg, and 54mg weight gains).

[083] Figure 43 is a dissolution profile of BUP-HBr-EA-300mg-004-5 (44mg, 46mg, 48mg,

50mg, 52mg, and 54mg weight gains).

[084] Figure 44 is a dissolution profile of BUP-HBr-EA-300mg-005-5 (44mg, 46mg, 48mg,

50mg, 52mg, and 54mg weight gains).

[085] Figure 45 is a dissolution profile of BUP-HBr-EA- 150mg-006-5 (24mg, 28mg, 32mg,

34mg and 36mg weight gains).

[086] Figure 46 is a comparative USP3 dissolution profile of bupropion HBr 150mg EA

Tablets with 24 and 34mg weight gains to the in vivo and the in vitro profiles of the target

(bupropion HCl 300mg). [087] Figure 47 is a bar graph showing the % impurities for the bupropion HCl XL 300mg and bupropion HBr 348mg EC coated tablets at 4O0C and 75% relative humidity.

[088] Figure 48 is a bar graph showing the % impurities for the bupropion HCl 300mg

(Wellbutrin XL) and bupropion HBr 348mg XL final tablets at 4O0C and 75% relative humidity.

[089] Figure 49 contains bar graphs showing the % of 3-CBA formed in forced degradation studies of bupropion hydrochloride (HCl) vs. bupropion HBr in the presence of excipients.

[090] Figure 50 contains bar graphs showing the % of 852U77 formed in forced degradation studies of bupropion HCl vs. bupropion HBr in the presence of excipients.

[091] Figure 51 contains bar graphs showing the % of 20U78 formed in forced degradation studies of bupropion HCl vs. bupropion HBr in the presence of excipients.

[092] Figure 52 contains bar graphs showing the % of 827U76 formed in forced degradation studies of bupropion HCl vs. bupropion HBr in the presence of excipients.

[093] Figure 53 is a graph showing the loss of API in a thermal gravimetric analysis (TGA) experiment at 1000C of bupropion HCl vs. bupropion HBr.

[094] Figure 54 is a graph showing . the relative powder X-ray diffraction (PXRD) for bupropion hydrobromide polymorphic form I.

[095] Figure 55 is a graph showing the differential scanning calorimetry (DSC) profile of bupropion hydrobromide polymorphic form I.

[096] Figure 56 is a graph showing the relative PXRD for bupropion hydrobromide polymorphic form II.

[097] Figure 57 is a graph showing the DSC profile of bupropion hydrobromide polymorphic form H

[098] Figure 58 is a graph showing the relative PXRD for bupropion hydrobromide polymorphic form HI.

[099] Figure 59 is a graph showing the DSC profile of bupropion hydrobromide polymorphic form IE.

[0100] Figure 60 is a graph of the relative PXRD of a sample of bupropion hydrobromide polymorphic form I after 6 months under the ICH (International Conference on Harmonisation of

Technical Requirements for Registration of Pharmaceuticals for Human Use) conditions (400C,

75%R.H.). [0101] Figure 61 is a graph of the PXRD of a sample of bupropion hydrobromide polymorphic form π after 1 month under ICH conditions (400C, 75%R.H.).

[0102] Figure 62 is a graph of the PXRD of a sample of bupropion hydrobromide polymorphic form m after 1 month under ICH conditions (4O0C, 75%R.H.).

[0103] Figure 63 contains the results of stability studies for Bupropion HBr XL 174 mg core

(Lot # Bup-HBr-XL-004-5 core; Bupropion HBr XL 348 mg core (Lot # Bup-HBr-XL-009-5 core; Bupropion HCl XL 150 mg core (Lot # 05E056) and Bupropion HCl XL 300 mg core (Lot

# O5D38O) initially, after 10 days open and closed, and after 20 days open and closed. The % of impurities 3-CBZ, 852U77, 20U78dihi, 827U76 are shown therein.

[0104] Figure 64 and Figure 65 respectively contain stability data for bupropion 348 mg HBr XL tablets (Lot # Bup-HBr-XL-348-025-5) and Bupropion HBr EA 300 mg tablets (Lot # Bup-HBr-

EA-300-001-5 initially and after 3 months, 6 months, 9 months and 12 months under accelerated storage conditions (40 degrees C and 75% relative humidity). The assay tested for amount of impurities 3-CBA, 852U77, 20U78/diluent, 827U76, and also compared the dissolution profiles and appearance thereof.

[0105] Figure 66 compares the dissolution profiles and in vitro drug release of Bupropion HBr

XL 348 mg tablets (final) Lot # Buρ-HBr-XL-012-5, Wellbutrin XL 300 mg tablets final (Lot #

05Al 16), Bupropion HBr XL 348 mg tablets ECl) Lot # Bup-HBr-XL-012-5 (EC 32mg wg), and

Wellbutrin XL 300 mg tablets (ECl) (Lot # 05D047) in different USP-3 media (SGF pH 1.2,

Acetate Buffer pH 4.5, and Phosphate Buffer pH 6.8 over a period of 16 hours.

[0106] Figure 67 compares the dissolution profiles and drug release for Bupropion HBr 348 mg

Lot # 05E304 in different USP-3 media (SGF pH 1.2, Acetate Buffer pH 4.5, Phosphate Buffer

SIF pH 6.8) over a period of 16 hours and further compares this release profile against the release profile for Bup 300 XL Target (01L238) in vivo and BUP 300XL Target (01L238) in vitro in USP-3 media.

[0107] Figure 68 contains comparative dissolution profiles for Bupropion HBr XL 348 mg and

Wellbutrin XL (final and EC) in USP-3 media (pH 1.2 SGF, pH 4.5 acetate buffer and pH 6.8 phosphate buffer over a period of 16 hours.

DEFINΓΓIONS [0108] The term "bupropion salt" herein has its ordinary meaning and includes any salt of bupropion.

[0109] The term "buropion salt that is more stable than bupropion hydrochloride"refers to a bupropion salt or a composition containing that is less subject to degradation than an otherwise equivalent bupropion hydrochloride salt or composition containing when stored for at least 3 months, 4 months, 5 months, and/or at least 6 months under accelerated storage conditions (40 degrees C, and 75% relative humidity), and/or when stored for at least 3, 4, 5 and/or 6 months under accelerated storage conditions (40 degrees C and 75% relative humidity) and/or which exhibits less of a reduction or fluctuation in potency as eviddenced by less fluctuation in the in vitro dissolution profile in at least one dissolution medium relative to an otherwise similar bupropion hydrochloride composition wherein dissolution is effected under the same conditions after these compositions are stored for at least 3, 4, 5, or 6 months at 40 degrees C at 75% relative humidity. Particularly, bupropion hydrobromide salts and polymorphs thereof may result in bupropion formuulations that exhibit dissolution profiles over time that are less subject to fluctuation when stored under accelerated storage conditions for prolonged time periods, i.e., at least 3 , 4, 5, or 6 months at 40 degrees C and 75% relative humidity.

[0110] The term "active", "active agent", "active pharmaceutical agent", "active drug" or "drug" as used herein means any active pharmaceutical ingredient ("API"), including its pharmaceutically acceptable salts (e.g. the hydrochloride salts, the hydrobromide salts, the hydroiodide salts, and the saccharinate salts), as well as in the anhydrous, hydrated, and solvated forms, in the form of prodrugs, and in the individually optically active enantiomers of the API as well as polymorphs of the API.

[0111] The term "dose dumping" herein refers to the rapid release of a drug from a medicament under certain conditions such as solvent conditions e.g., high (40%) ethanol. [0112] The term "other drug" or "second drug" as used herein means a drug other than bupropion, including but not limited to anti-depression agents, other neuropsychiatric drugs, vasodilators, anti-anxiety agents, appetite modulators, sleep modulating drugs, SSRIs, anti-viral agents, anti-pain agents, anti-migraine agents, antiinflammatories (both steroidal and nonsteroidal) and more particularly may include citalopram, escitalopram, venlafaxine, clozapine, melperone, amperozide, iloperidone, risperidone, quetiapene, olanzapine, ziprasidone, aripiprazole, reboxetine, Viagra®, sertraline, paroxetine, fluoxetine, gabapentin, valproic acid, amitriptyline, lofepramine, fluvoxamine, imipramine, mirtazapine, nefazodone, nortriptyline, SAM-E, combinations thereof, and their pharmaceutically acceptable salts (e.g. the hydrochloride salts, the hydrobromide salts, the hydroiodide salts, and the saccharinate salts), as well as in the anhydrous, hydrated, and solvated forms, in the form of prodrugs, and in the individually optically active enantiomers of the drug.

[0113] The term "formulation" or "composition" as used herein refers to the drug in combination with pharmaceutically acceptable carriers and additional inert ingredients. This includes orally administrable formulations as well as formulations administrable by other means. [0114] The term "dosage form" as used herein is defined to mean a pharmaceutical preparation in which doses of active drug are included.

[0115] "Modified release dosage forms" as used herein is as defined by the United States

Pharmacopoeia (USP) as those whose drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional, immediate release or uncoated normal matrix dosage forms. The rate of release of the active drug from a modified release dosage form is controlled by features of the dosage form and/or in combination with physiologic or environmental conditions rather than by physiologic or environmental conditions alone. The modified release dosage forms of the invention can be contrasted to conventional, immediate release, or uncoated normal matrix dosage forms which typically produce large maximum/minimum plasma drug concentrations (Cmax/Cmin) due to rapid absorption of the drug into the body (i.e., in vivo, relative to the drug's therapeutic index; i.e., the ratio of the maximum drug concentration needed to produce and maintain a desirable pharmacological response). In conventional, immediate release or uncoated normal matrix dosage forms, the drug content is released into the gastrointestinal tract within a short period of time, and plasma drug levels peak shortly after dosing. The design of conventional, immediate release or uncoated normal matrix dosage forms is generally based on getting the fastest possible rate of drug release, and therefore absorbed, often at the risk of creating undesirable dose related side effects. The modified release dosage forms of the invention, on the other hand, improve the therapeutic value of the active drug by reducing the ratio of the maximum/minimum plasma drug concentration (Cmax/Cmin) while maintaining drug plasma levels within the therapeutic window. The modified release dosage forms of the invention attempt to deliver therapeutically effective amount of bupropion salt and combinations thereof as a once-daily dose so that the ratio Cmax/Cmin in the plasma at steady state is less than the therapeutic index, and to maintain drug levels at constant effective levels to provide a therapeutic benefit over a 24-hour period. The modified release dosage forms of the invention, therefore, avoid large peak-to-trough fluctuations normally seen with conventional or immediate release dosage forms and can provide a substantially flat serum concentration curve throughout the therapeutic period. Modified- release dosage forms can be designed to provide a quick increase in the plasma concentration of the bupropion salt which remains substantially constant within the therapeutic range of bupropion salt for at least a 24-hour period. Alternatively, modified-release dosage forms can be designed to provide a quick increase in the plasma concentration of the bupropion salt, which although may not remain constant, declines at rate such that the plasma concentration remains within the therapeutic range for at least a 12 hour and desirably at least a 24-hour period. [0116] The modified release dosage forms of the invention can be constructed in many forms known to one of ordinary skill in the drug delivery arts and described in the prior art such as for example, "modified release matrix dosage forms", "normal release matrix dosage forms" coated with at least one "control-releasing coat", "osmotic dosage forms", "multiparticulate dosage forms", and "gastric retention dosage forms". The USP considers that the terms controlled release, prolonged release and sustained release are interchangeable. Accordingly, the terms "modified-release", controlled-release", "control-releasing", "rate-controlled release", "prolonged-release", and "sustained-release" are used interchangeably herein. For the discussion herein, the definition of the term "modified-release" encompasses the scope of the definitions for the terms "extended release", "enhanced-absorption", "controlled release", and "delayed release".

[0117] "Controlled release dosage forms" or "control-releasing dosage forms", or dosage forms which exhibit a "controlled release" of the bupropion salt as used herein is defined to mean dosage forms administered once-or twice-daily that release the bupropion salt at a controlled rate and provide plasma concentrations of the bupropion salt that remain controlled with time within the therapeutic range of the bupropion salt over a 12 or 24-hour period. "Controlled release" or "control releasing" is defined to mean release of the drug gradually or in a controlled manner per unit time. For example, the controlled rate can be a constant rate providing plasma concentrations of the bupropion salt that remain invariant with time within the therapeutic range of the bupropion salt over at least a 12 or 24-hour period. [0118] "Sustained-release dosage forms" or dosage forms which exhibit a "sustained-release" of the bupropion salt as used herein is defined to mean dosage forms administered once-daily that provide a release of the bupropion salt sufficient to provide a therapeutic dose soon after administration, and then a gradual release over an extended period of time such that the sustained-release dosage form provides therapeutic benefit over a 12 or 24-hour period. [0119] "Extended-or sustained-release dosage forms" or dosage forms which exhibit an "extended or sustained release" of the bupropion salt as used herein is defined to include dosage forms administered once-or twice-daily that release the bupropion salt slowly, so that plasma concentrations of the bupropion salt are maintained at a therapeutic level for an extended period of time such that the extended or sustained-release dosage form provides therapeutic benefit over a 12 or 24-hour period.

[0120] "Prolonged-release dosage forms" or dosage forms which exhibit a "prolonged release" of the bupropion salt as used herein is defined to mean dosage forms administered once daily which provide for absorption of the bupropion salt over a longer period of time than from a conventional, immediate release or uncoated normal release matrix dosage form and which provide therapeutic benefit over at least a 12 hour and more typically at least a 24-hour period. [0121] "Delayed-release dosage forms" or dosage forms which exhibit a "delayed release" of the bupropion salt as used herein is defined to mean dosage forms administered once-daily that do not effectively release drug immediately following administration but at a later time. Delayed- release dosage forms provide a time delay prior to the commencement of drug-absorption. This time delay is referred to as "lag time" and should not be confused with "onset time" which represents latency, that is, the time required for the drug to reach minimum effective concentration.

[0122] "Enhanced absorption dosage forms" or dosage forms which exhibit an "enhanced absorption" of the bupropion salt as used herein is defined to mean dosage forms that when exposed to like conditions, will show higher release and/or more aborption of the burpopion base as compared to other dosage forms with the same or higher amount of bupropion base. The same therapeutic effect can be achieved with less bupropion base in the enhanced absorption dosage form as compared to other dosage forms.

[0123] The term "controlled release matrix" as used herein is defined to mean a dosage form in which the bupropion salt and combinations thereof is dispersed within a matrix, which matrix can be either insoluble, soluble, or a combination thereof. Controlled release matrix dosage forms of the insoluble type are also referred to as "insoluble polymer matrices", "swellable matrices", or "lipid matrices" depending on the components that make up the matrix. Controlled release matrix dosage forms of the soluble type are also referred to as "hydrophilic colloid matrices", "erodible matrices", or "reservoir systems". Controlled release matrix dosage -forms of the invention refer to dosage forms comprising an insoluble matrix, a soluble matrix or a combination of insoluble and soluble matrices in which the rate of release is slower than that of an uncoated non-matrix conventional or immediate release dosage forms or uncoated "normal release matrix" dosage forms. Controlled release matrix dosage forms can be coated with a "control-releasing coat" to further slow the release of the bupropion salt from the controlled release matrix dosage form. Such coated controlled release matrix dosage forms can exhibit "modified-release", controlled-release", "sustained-release", "extended-release", "prolonged- release", "delayed-release" or combinations thereof of the bupropion salt. [0124] The term "normal release matrix" as used herein is defined to mean dosage forms in which the bupropion salt and combinations thereof is dispersed within a matrix, which matrix can be either insoluble, soluble, or combinations thereof but constructed such that the release of the bupropion salt mimics the release rate of an uncoated non-matrix conventional or immediate release dosage form comprising the bupropion salt. The release rate from normal release matrix dosage forms can be slowed down or modified in conjunction with a "control releasing coat". [0125] A "control releasing coat" or "controlled release coat" as used herein is defined to mean a functional coat which can for example comprise at least one pH independent polymer, pH dependent (such as for example enteric or reverse enteric types) polymer, soluble polymer, insoluble polymer, lipids, lipidic materials or combinations thereof which when applied onto a dosage form can slow (for example when applied to a normal release matrix dosage form), further slow (for example when applied to a controlled release matrix dosage form) or modify the rate of release of the bupropion salt when applied to an uncoated dosage form. For example, the control releasing coat can be designed such that when the control releasing coat is applied to a dosage form, the dosage form in conjunction with the control releasing coat can exhibit the release of the bupropion salt, such as for example, as a "modified-release", "controlled-release", "sustained-release", "extended-release", "delayed-release", "prolonged-release" or combinations thereof. The "control releasing coat" can optionally comprise additional materials that can alter the functionality of the control releasing coat.

[0126] The term "moisture barrier" as used herein is one, which impedes or retards the absorption of moisture. It is known that bupropion salts are hygroscopic and, as such, are susceptible to decomposition over time under high humidity conditions. The proportion of the components of the moisture barrier and the amount of the moisture barrier optionally applied onto the control-releasing coat or onto the core is typically such that the moisture barrier does not fall within the USP definition and requirement for an enteric coat. Suitably, the moisture barrier is comprised of an enteric and/or acrylic polymer, suitably an acrylic polymer, optionally a plasticizer, and a permeation enhancer. The permeation enhancer is a hydrophilic substance, which allows water to enter without physical disruption of the coating. The moisture barrier may additionally contain other conventional inert excipients, which may improve processing of the extended-release formulation described herein.

[0127] The term "medicament" as used herein refers to all possible oral and non-oral dosage forms, including but not limited to, all modified release dosage forms, osmosis controlled release systems, erosion controlled release systems, dissolution controlled release systems, diffusion controlled release systems, matrix tablets, enteric coated tablets, single and double coated tablets (including the extended release and enhanced absorption tablets as described herein), capsules, minitablets, caplets, coated beads, granules, spheroids, pellets, microparticles, suspensions, topicals such as transdermal and transmucoasal compositions and delivery systems (containing or not containing matrices), injectables, and inhalable compositions.

[0128] The term "enhanced stability", "greater stability", "increased stability" or "more stable" as used herein when referring to a bupropion salt (bupropion HBr) means that the bupropion salt ( bupropion hydrobromide), and compositions, formulations or medicaments comprising the bupropion salt, when exposed to like conditions, i.e, when stored for at least 3 months under accelerated storage conditions (40 degrees C, 75% relative humidity) and/or when stored for at least 3,4,5 and/or 6 months or a year or more under accelerated storage conditions (40 degrees C, 75% relative humidity) show less degradation as determined by the formation of less of at least one degradation product than an otherwise similar composition containing bupropion HCl.. Additionally enhanced stability or greater stability or increased stability of a bupropion salt (relative to bupropion HCl) includes bupropion HBr compositions which exhibit more consistent dissolution profiles and therefore potency, compared to an otherwise similar bupropion hydrochloride formulation after being stored for at least 3, 4, 5 and/or 6 months under the same accelerated storage conditions of 40 degrees C and 75% relative humidity. [0129] By "less degradation" it is meant any measurable decrease in the amount of at least one impurity characteristic of bupropion degradation or any measurable difference in the retention of potency relative to an otherwise similar bupropion HCl composition after being stored for at least 3, 4, 5 and/or 6 months or longer, e.g, one or two years under the afore-identified accelerated storage conditions. The "degradation products" include those listed on page 281 of the 26th edition of the USP and any other degradation products that may appear as peaks on a chromatogram during the assay that are characteristic of bupropion degradation. [0130] As used herein "total impurities" mean all degradation products resulting from the degradation of bupropion hydrobromide. The "degradation products" include those listed on page 281 of the 26th edition of the USP and any other degradation products that may appear as peaks on a chromatogram during the assay.

[0131] The term "plasticizer" as used herein includes any compounds capable of plasticizing or softening a polymer or a binder used in the present invention. The use of plasticizers is optional, and can be included in the dosage form to modify the properties and characteristics of the polymers used in the coat(s) or core of the dosage form for convenient processing during manufacture of the coat(s) and/or the core of the dosage form. Once the coat(s) and/or core has been manufactured, certain plasticizers can function to increase the hydrophilicity of the coat(s) and/or the core of the dosage form in the environment of use. During manufacture of the coat(s) and/or core, the plasticizer can lower the melting temperature or glass transition temperature (softening point temperature) of the polymer or binder. Plasticizers can broaden the average molecular weight of a polymer in which they are included thereby lowering its glass transition temperature or softening point. Plasticizers also can reduce the viscosity of a polymer. Plasticizers can impart some particularly advantageous physical properties to the dosage forms of the invention.

[0132] The term "moiety" as used herein is defined to mean the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), of the molecule, responsible for the physiological or pharmacological action of the drug substance. [0133] The term "microparticle", as used herein refers to a drug formulation in discrete particulate form, and is interchangeable with the terms "microspheres", "spherical particles", "microcapsules", "particles", "multiparticulates", "granules", "spheroids", beads" and "pellets". [0134] The term "core" as used here in is defined to mean any structure that is surrounded by a wall, membrane, or coating. The wall, membrane, or coating can be a functional or nonfunctional coating.

[0135] The term "tablet" as used herein refers to a single dosage form, i.e. the single entity containing the active pharmaceutical agent that is administered to the subject. , The term "tablet" also includes a tablet that may be the combination of one or more "minitablets". [0136] The term "osmosis" as used herein refers to the flow of a solvent through a selectively- permeable membrane from a region of high solvent potential to a region of low solvent potential. The selectively-permeable membrane must be permeable to the solvent, but not to the solute, resulting in a pressure gradient across the membrane.

[0137] The term "osmotic dosage form", "osmotic delivery device", "modified release osmotic dosage form" or "controlled release osmotic dosage form" as used herein is defined to mean dosage forms which forcibly dispense the bupropion salt all or in part by pressure created by osmosis or by a combination of osmosis and diffusion of fluid into a dosage form which forces the bupropion salt to be dispensed from the osmotic dosage form. The term "osmotic dosage form", "osmotic delivery device", "modified release osmotic dosage form", or "controlled release osmotic dosage form" also encompasses such forms that can be coated with a "control releasing coat".

[0138] The terms "osmagent", "osmotic agent", "osmotically effective solute", "osmotic enhancer" "osmotically effective compounds", "osmotic solutes", or "osmotic fluid imbibing agents" are all used interchangeably herein and define any material that increases the osmotic pressure of the core, thus, increasing the hydrostatic pressure inside the osmotic dosage form. The osmagent can be either soluble or swellable and totally or partially solubilized. The osmagent can be the bupropion salt.

[0139] The term "pharmaceutically acceptable" means compatible with the treatment of subjects, in particular, humans.

[0140] The term "subject" or "patient" as used herein means all members of the animal kingdom, in particular, humans. [0141] The term "effective amount" as used herein means a "pharmaceutically effective amount". A "pharmaceutically effective amount" is the amount or quantity of the bupropion salt or polymorph or anantiomer thereof which is sufficient to elicit an appreciable biological response when administered to a patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient and the nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

[0142] As used herein, and as well understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, dirninishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.

"Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0143] "Palliating" a disease or disorder means that the extent and/or undesirable clinical manifestations of a disorder or a disease state are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.

[0144] The term "a" or "an" as used herein means "one" or "one or more".

The term "about" or "approximately" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviations, per practice in the art.

Where particular values are described in the application and claims, unless otherwise stated, the term "about" means within an acceptable error range for the particular value.

[0145] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about" Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0146] Other terms are defined as they appear in the following description and should be construed in the context with which they appear.

DETAILED DESCRIPTION

[0147] There is a need for dosage forms comprising a pharmaceutically acceptable salt of bupropion that are more stable than otherwise similar compositions containing bupropion hydrochloride. Accordingly, the present invention relates to dosage forms comprising an effective amount of bupropion hydrobromide that are more stable than bupropion hydrochloride. Also, the invention encompasses polmorphs thereof and specific purified enantiomeric forms thereof. The present invention also relates to the use of such dosage forms for the treatment of one or more conditions in a subject suitable for treatment by bupropion or pharmaceutically acceptable salts thereof such as depression, obesity, smoking cessation, and other conditions treatable with bupropion such as are disclosed herein.

Formulations

[0148] The present invention encompasses any medicament containing a pharmaceutically effective amount of a stable bupropion salt according to the invention, i.e., bupropion hydrobromide. This includes both oral and non-orally administrable medicaments such as topicals, injectables, aerosols and other inhalable medicaments. Particularly such medicament compositions include orally administrable modified release dosage form containing the bupropion salt. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

[0149] "Dosage form" as used herein, means a pharmaceutical preparation that comprises an effective amount of a bupropion salt that is more stable than bupropion hydrochloride. In at least one embodiment the bupropion salt is bupropion hydrobromide.

A "solid dosage form" as used herein, means a dosage form that is neither liquid nor gaseous. Dosage forms include solid dosage forms, such as tablets, powders, microparticles, capsules, suppositories, sachets, troches, patches and losenges as well as liquid suspensions and elixirs. Capsule dosages contain the solid composition within a capsule that can be made of gelatin or other conventional encapsulating material.

[0150] The modified release dosage forms contemplated in the present invention can be multiparticulate or monolithic. For example, those skilled in the pharmaceutical art and the design of medicaments are aware of modified release matricies conventionally used in oral pharmaceutical compositions adopted for modified release and means for their preparation. Examples of modified release formulations are disclosed in United States Patents 5,591,452 and 5,965,161.

[0151] A modified release formulation containing the bupropion salt according to the present invention can be coated with one or more functional or non-functional coatings. Examples of functional coatings include controlled release polymeric coatings (i.e. control releasing coats), moisture barrier coatings, enteric polymeric coatings, and the like. Non-functional coatings are coatings that do not affect drug release, but which affect other properties; such as the enhancement of the chemical, biological or physical stability characteristics, or the enhancement of the physical appearance of the formulation.

[0152] In at least one embodiment of the present invention the controlled release polymeric coating (or control-releasing coat) comprises an acrylic polymer. Suitable acrylic polymers include but are not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic add), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. [0153] In at least one embodiment polymerizable quaternary ammonium compounds are employed in the control releasing coat, of which non-limiting examples include quaternized aminoalkyl esters and aminoalkyl amides of acrylic acid and methacrylic acid, for example β- methacryl-oxyethyl-trimethyl-ammonium methosulfate, β-acryloxy-propyl-trimethyl-ammonium chloride, and trimethylaminomethyl-methacrylamide methosulfate. The quaternary ammonium atom can also be part of a heterocycle, as in methacryloxyethylmethyl-morpholiniom chloride or the corresponding piperidinium salt, or it can be joined to an acrylic acid group or a methacrylic acid group by way of a group containing hetero atoms, such as a polyglycol ether group. Further suitable polymerizable quaternary ammonium compounds include quaternized vinyl-substituted nitrogen heterocycles such as methyl-vinyl pyridinium salts, vinyl esters of quaternized amino carboxylic acids, styryltrialkyl ammonium salts, and the like. Other polymerizable quaternary ammonium compounds useful in the present invention include acryl- and methacryl- oxyethyltrimethyl-ammonium chloride and methosulfate, benzyldimethylammoniumethyl- methacrylate chloride, diethylmethylammoniumethyl-acrylate and -methacrylate methosulfate, N-trimethylammoniumpropylmethacrylamide chloride, and N-trimethylammonium-2,2- dimethylpropyl- 1 -methacrylate chloride.

[0154] In at least one embodiment the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers (such as those sold under the Trade Mark Eudragit® RS and RL) are described in National Formulary (NF) XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In order to obtain a desirable dissolution profile for a given therapeutically active agent, such as bupropion hydrobromide, two or more ammonio methacrylate copolymers having differing physical properties can be incorporated. For example, it is known that by changing the molar ratio of the quaternary ammonium groups to the neutral (meth)acrylic esters, the permeability properties of the resultant coating can be modified.

[0155] In other embodiments of the present invention, the control releasing coat further includes a polymer whose permeability is pH dependent, such as anionic polymers synthesized from methacrylic acid and methacrylic acid methyl ester. Such polymers are commercially available, e.g., from Rohm Pharma GmbH under the tradename Eudragit® L and Eudragit® S. The ratio of free carboxyl groups to the esters is known to be 1:1 in Eudragit® L and 1:2 in Eudragit® S. Eudragit® L is insoluble in acids and pure water, but becomes increasingly permeable above pH 5.0. Eudragit® S is similar, except that it becomes increasingly permeable above pH 7. The hydrophobic acrylic polymer coatings can also include a polymer which is cationic in character based on dimethylaminoethyl methacrylate and neutral methacrylic acid esters (such as Eudragit® E, commercially available from Rohm Pharma). The hydrophobic acrylic polymer coatings of the present invention can further include a neutral copolymer based on poly (meth)acrylates, such as Eudragit® NE (NE=neutral ester), commercially available from Rohm Pharma. Eudragit® NE 3OD lacquer films are insoluble in water and digestive fluids, but permeable and swellable. [0156] In at least one other embodiment of the invention, the control releasing coat comprises a dispersion of poly (ethylacrylate, methyl methacrylate) 2:1 (Kollicoat® EMM 30 D, BASF). [0157] In at least one other embodiment of the invention, the control releasing coat comprises a polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate such as Kollicoat® SR30D (BASF). The dissolution profile can by altered by changing the relative amounts of different acrylic resin lacquers included in the coating. Also, by changing the molar ratio of polymerizable permeability-enhancing agent (e.g., the quaternary ammonium compounds) to the neutral (meth)acrylic esters, the permeability properties (and thus the dissolution profile) of the resultant coating can be modified.

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