Pharmaceutical dosage forms for treating neurological and psychiatric conditions

Abstract

This disclosure relates to dosage forms comprising: 1) about 100-110 mg, about 104-106 mg, or about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of dextromethorphan; and 2) about 25-35 mg, about 29-31 mg, about 30 mg, about 40-50 mg, about 44-46 mg, or about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan. In some embodiments, a dosage form as described herein is free of a Compound I and Compound II. In some embodiments, a dosage form may contain 0.5 ng to 750 ng of Compound I, 0.5 ng to 750 ng of Compound II, or a combination thereof. These dosage forms may be used to treat various neurological and psychiatric conditions, including major depressive disorder, agitation associated with Alzheimer's disease, and nicotine addiction.

Description

[0001] PCT APPLICATION 134061-00001369 PHARMACEUTICAL DOSAGE FORMS FOR TREATING NEUROLOGICAL AND PSYCHIATRIC CONDITIONS

[0002] Inventor: Herriot Tabuteau

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 719,699, filed November 13, 2024, which is incorporated by reference herein in its entirety.

[0005] SUMMARY

[0006] Some embodiments include a dosage form comprising: 1) about 100 mg to about 110 mg of bupropion hydrochloride, or about 195 mg to about 205 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion; and 2) about 25 mg to about 35 mg, about 40 mg to about 50 mg, or about 90 mg to about 100 mg of dextromethorphan hydrobromide (e.g., dextromethorphan hydrobromide monohydrate), or a molar equivalent amount of the free base form or another salt form of dextromethorphan. In some embodiments, the dosage form is substantially free from Compound I and / or Compound II. In some embodiments, the dosage form further comprises 0.5 ng to 1500 ng of Compound I, 0.5 ng to 1500 ng of Compound II, or a combination thereof.

[0007] Some embodiments include a method of treating major depressive disorder, comprising administering a dosage form described herein to a human patient in need thereof.

[0008] Some embodiments include a method of treating agitation associated with Alzheimer's disease, comprising administering a dosage form described herein to a human patient in need thereof.

[0009] Some embodiments include a method of treating nicotine addiction, comprising administering a dosage form described herein to a human patient in need thereof.

[0010] DETAILED DESCRIPTION

[0011] Pharmaceutical formulation development presents significant challenges and inherent unpredictability, particularly when combining two active pharmaceutical ingredients (APIs) with unique mechanisms of action, different chemical and physical stabilities, and distinct release profiles. The complexity arises from the need to achieve precise control over the dissolution and release kinetics of each API while maintaining their individual therapeutic PCT APPLICATION 134061-00001369 efficacy and stability. When formulating dual-API systems, formulators must navigate the intricate interplay between excipient compatibility, drug-drug interactions, and the competing requirements for different release mechanisms, such as immediate release for one API (e.g., a dextromethorphan as described herein) and sustained release for another (e.g., a bupropion as described herein). The unpredictable nature of these formulations stems from the numerous variables that can influence drug release, including particle size distribution, polymorphic forms, moisture content, compression forces, and the potential for unexpected chemical or physical interactions between the APIs and excipients. Furthermore, achieving the desired release profiles from the tablet formulation often requires extensive experimentation with different coating systems, matrix materials / excipients, and manufacturing parameters, where minor changes can lead to dramatically different dissolution behaviors. The challenge is compounded by the need to ensure that the formulation remains stable throughout its shelf life while maintaining consistent bioavailability and therapeutic performance, making the development process both timeintensive and highly unpredictable despite advances in formulation science.

[0012] Disclosed herein is a novel bilayer tablet comprising bupropion (e.g., bupropion hydrochloride) and dextromethorphan (e.g., dextromethorphan hydrobromide or dextromethorphan hydrobromide monohydrate). Both active pharmaceutical agents have potential to exhibit chemical instability in the presence of moisture and / or certain excipients. Solutions to these formulation challenges are described herein.

[0013] As mentioned above, this disclosure relates to administration of a combination of: 1) about 100-110 mg, about 104-106 mg, about 105 mg, about 195-205 mg, about 200-202 mg, or about 201.6 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion; and 2) about 25-35 mg, about 29-31 mg, about 30 mg, about 40-50 mg, about 44-46 mg, about 45 mg, about 90-100 mg, about 95-96 mg, or about 95.5 mg of dextromethorphan hydrobromide (e.g., dextromethorphan hydrobromide monohydrate), or a molar equivalent amount of the free base form or another salt form of dextromethorphan.

[0014] This combination is referred to for convenience herein as the "subject combination." In every instance where the subject combination is referred to herein, the combination of 105 mg of bupropion hydrochloride and 30 mg of dextromethorphan hydrobromide PCT APPLICATION 134061-00001369 monohydrate, the combination of 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide monohydrate, and the combination of 201.6 mg of bupropion hydrochloride and 95.5 mg of dextromethorphan hydrobromide monohydrate are specifically contemplated.

[0015] Some embodiments include Compound I and / or Compound II, or compositions comprising Compound I and / or Compound II. These compounds may be useful, for example, as analytical standards for assessing the purity of pharmaceutical compounds.

[0016]

[0017] Compound II Dextromethorphan hydrobromide is an uncompetitive NMDA receptor antagonist and a sigma-1 receptor agonist.

[0018] The chemical name of dextromethorphan hydrobromide is morphinan, 3-methoxy-17-methyl-, (9a, 13a, 14a), hydrobromide monohydrate. Dextromethorphan hydrobromide has the empirical formula Ci8H25NO»HBr»H2O and a molecular weight of 370.33. The structural formula is:

[0019]

[0020] Dextromethorphan hydrobromide powder is white or almost white, crystalline, and sparingly soluble in water.

[0021] Bupropion hydrochloride is an aminoketone and CYP4502D6 inhibitor. PCT APPLICATION 134061-00001369 The chemical name of bupropion hydrochloride is: (±)-l-(3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-propanone hydrochloride. Bupropion hydrochloride has the empirical formula CisHisCINO’HCI and a molecular weight of 276.2. The structural formula is:

[0022]

[0023] Bupropion hydrochloride powder is white and highly soluble in water.

[0024] Unless otherwise indicated, any reference to a compound herein, such as dextromethorphan, bupropion, Compound I, or Compound II, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; deuterium modified compounds, such as deuterium modified dextromethorphan; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

[0025] The subject combination may be contained in an oral dosage form, including a tablet, such as an extended-release tablet. In some embodiments, the subject combination is contained in a dosage form for oral administration and is available as round bilayer tablets. In some embodiments, the subject combination is contained in a dosage form for oral administration and is available as round bilayer tablet that comprises one extended-release layer and one immediate release layer. In some embodiments, the extended-release layer comprises a bupropion (e.g., bupropion hydrochloride) and the immediate release layer comprises a dextromethorphan (e.g., dextromethorphan hydrobromide monohydrate).

[0026] In some embodiments, a tablet containing the subject combination contains 45 mg of dextromethorphan hydrobromide monohydrate in an immediate-release formulation. In some embodiments, a tablet of the subject combination contains 105 mg of bupropion hydrochloride in an extended-release formulation. In some embodiments, a tablet of the subject combination contains 45 mg of dextromethorphan hydrobromide monohydrate in an PCT APPLICATION 134061-00001369 immediate-release formulation and 105 mg of bupropion hydrochloride in an extended-release formulation.

[0027] In some embodiments, a tablet containing the subject combination contains 30 mg of dextromethorphan hydrobromide monohydrate in an immediate-release formulation. In some embodiments, a tablet of the subject combination contains 105 mg of bupropion hydrochloride in an extended-release formulation. In some embodiments, a tablet of the subject combination contains 30 mg of dextromethorphan hydrobromide monohydrate in an immediate-release formulation and 105 mg of bupropion hydrochloride in an extended-release formulation.

[0028] In some embodiments, a dosage form, such as a tablet is free from Compound I. In some embodiments, a dosage form, such as a tablet, contains about 0.5-1000 ng, 0.5-50 ng, 50-100 ng, 100-150 ng, 150-200 ng, 200-250 ng, 250-300 ng, 300-350 ng, 350-400 ng, 400-450 ng, 450-500 ng, 500-550 ng, 550-600 ng, 600-650 ng, 650-700 ng, 700-750 ng, 750-800 ng, 800-850 ng, 850-900 ng, 900-950 ng, 950-1,000 ng, 1,000-1,050 ng, 1,050-1,100 ng, 1,100-1,150 ng, 1,150-1,200 ng, 1,200-1,250 ng, 1,250-1,300 ng, 1,300-1,350 ng, 1,350-1,400 ng, 1,400-1,450 ng, 1,450-1,500 ng, 0.5-250 ng, 250-500 ng, 500-750, ng, 750-1,000 ng, 1,000-1,250 ng, 1,250-1,500 ng, 0.5-300 ng, 300-600 ng, 600-900 ng, 900-1,200 ng, or 1,200-1,500 ng of Compound I.

[0029] In some embodiments, a dosage form, such as a tablet is free from Compound II. In some embodiments, a dosage form, such as a tablet, contains about 0.5-1000 ng, 0.5-50 ng, 50-100 ng, 100-150 ng, 150-200 ng, 200-250 ng, 250-300 ng, 300-350 ng, 350-400 ng, 400-450 ng, 450-500 ng, 500-550 ng, 550-600 ng, 600-650 ng, 650-700 ng, 700-750 ng, 750-800 ng, 800-850 ng, 850-900 ng, 900-950 ng, 950-1,000 ng, 1,000-1,050 ng, 1,050-1,100 ng, 1,100-1,150 ng, 1,150-1,200 ng, 1,200-1,250 ng, 1,250-1,300 ng, 1,300-1,350 ng, 1,350-1,400 ng, 1,400-1,450 ng, 1,450-1,500 ng, 0.5-250 ng, 250-500 ng, 500-750, ng, 750-1,000 ng, 1,000-1,250 ng, 1,250-1,500 ng, 0.5-300 ng, 300-600 ng, 600-900 ng, 900-1,200 ng, or 1,200-1,500 ng of Compound II.

[0030] In some embodiments, a dosage form, such as a tablet, is free from Compound I and Compound II. PCT APPLICATION 134061-00001369 In some embodiments, a tablet containing the subject combination contains cysteine. In some embodiments, a tablet containing the subject combination contains cysteine hydrochloride. In some embodiments, a tablet containing the subject combination contains L-cysteine hydrochloride monohydrate. In some embodiments, a tablet containing the subject combination contains carbomer homopolymer. In some embodiments, a tablet containing the subject combination contains microcrystalline cellulose. In some embodiments, a tablet containing the subject combination contains colloidal silicon dioxide. In some embodiments, a tablet containing the subject combination contains polyvinylpolypyrrolidone (crospovidone). In some embodiments, a tablet containing the subject combination contains hydroxypropyl methylcellulose. In some embodiments, a tablet containing the subject combination contains stearic acid. In some embodiments, a tablet containing the subject combination contains magnesium stearate. In some embodiments, a tablet containing the subject combination contains stearic acid and magnesium stearate.

[0031] In some embodiments, a tablet containing the subject combination contains the following inactive ingredients: L-cysteine hydrochloride monohydrate, carbomer homopolymer (e.g., Carbopol 971A), microcrystalline cellulose, colloidal silicon dioxide, polyvinylpolypyrrolidone (crospovidone), stearic acid, and magnesium stearate.

[0032] In some embodiments, a tablet containing the subject combination contains the following inactive ingredients: L-cysteine hydrochloride monohydrate, carbomer homopolymer, hydroxypropyl methylcellulose, microcrystalline cellulose, colloidal silicon dioxide, polyvinylpolypyrrolidone (crospovidone), stearic acid, and magnesium stearate.

[0033] The pharmaceutical composition may include any suitable amount of cysteine (e.g., L-cysteine), such as about 30-100 mg, about 30-40 mg, about 40-50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 60-65 mg, about 65-70 mg, or about 67 mg of the cysteine, such as L-cysteine hydrochloride, another salt form of L-cysteine, or the neutral or zwitterionic form of L-cysteine. Cysteine in these amounts may be helpful in stabilizing bupropion in the presence of other excipients. The cysteine may be in the form of a hydrate of cysteine. For example, the cysteine may be in the form of cysteine hydrochloride monohydrate or L-cysteine hydrochloride monohydrate.

[0034] The pharmaceutical composition or dosage form may further comprise a sustained release or controlled release polymer, such as a crosslinked or uncross linked acrylate PCT APPLICATION 134061-00001369 polymer or copolymer (e.g., a carbomer copolymerType A such as Carbopol 971P), a cellulose derivative, such as methylcellulose, etc. In some embodiments, the controlled release polymer is about 1-40%, about 1-5%, about 5-10%, about 10-15%, about 15-20%, about 20-30%, about 30-40%, about 11-13%, or about 12% of the weight of the pharmaceutical composition. In some embodiments, the controlled release polymer is about 0.1-20%, about 0.1-2%, about 2-4%, about 4-6%, about 6-8%, about 8-10%, about 10-15%, about 15-20%, or about 7% of the weight of the dosage form. In some embodiments, the controlled release polymer is about 8% of the weight of the dosage form. In some embodiments, the controlled release polymer is about 9% of the weight of the dosage form. In some embodiments, the controlled release polymer is about 10% of the weight of the dosage form. In some embodiments, the controlled release polymer is about 11% of the weight of the dosage form. In some embodiments, the controlled release polymer is about 12% of the weight of the dosage form.

[0035] The pharmaceutical composition or dosage form may further comprise a filler such as microcrystalline cellulose. In some embodiments, the filler may be about 20-60%, about 20-30%, about 30-40%, about 40-50%, or about 50-60% of the weight of the pharmaceutical composition orthe dosage form. In some embodiments, the filler may be about 5-10%, about 10-15%, or about 15-20% of the weight of the pharmaceutical composition or the dosage form.

[0036] The pharmaceutical composition or dosage form may further comprise a lubricant such as magnesium stearate. In some embodiments, the lubricant is about 0.1-10%, about 0.1-2%, about 2-4%, about 4-6%, about 6-8%, or about 8-10% of the weight of the pharmaceutical composition or the dosage form. In some embodiments, the lubricant is about 0.1-5%, about 0.1-3%, about 0.5-3%, about 0.5-2%, about 0.5-1.5%, or about 1-1.5% of the weight of the pharmaceutical composition or the dosage form.

[0037] The pharmaceutical composition or dosage form may further comprise a second lubricant such as stearic acid. In some embodiments, the second lubricant is about 0.1-10%, about 0.1-2%, about 2-4%, about 4-6%, about 6-8%, or about 8-10% of the weight of the pharmaceutical composition orthe dosage form. In some embodiments, the second lubricant is about 0.1-5%, about 0.1-3%, about 0.5-3%, about 0.5-2%, about 0.5-1.5%, or about 1-1.5% of the weight of the pharmaceutical composition or the dosage form. PCT APPLICATION 134061-00001369 In some embodiments, the pharmaceutical composition or dosage form comprises more than one lubricant such as magnesium stearate and stearic acid. In some embodiments, the total lubricant in the tablet is about 0.1-10%, about 0.1-2%, about 2-3%, about 2-4%, about 4-6%, about 6-8%, or about 8-10% of the weight of the pharmaceutical composition or the dosage form.

[0038] The dosage form may be formulated for any suitable route of administration, such as oral administration.

[0039] Dosage forms, such as solid dosage forms, e.g., capsules, tablets, or pills, for oral administration may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a sweetening agent such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring. When the dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as a coating, for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially nontoxic in the amounts employed.

[0040] In some embodiments, the subject dosage form comprises active ingredients comprising dextromethorphan hydrobromide or dextromethorphan hydrobromide monohydrate, bupropion hydrochloride, as well as excipients. The excipients may comprise an acidifier, release controlling polymer, filler, disintegrant, lubricant, and glidant. The excipients may comprise cysteine (e.g., L-cysteine hydrochloride monohydrate), a carbomer homopolymer such as Carbopol 971P, microcrystalline cellulose such as Avicel PH 101 and / or Avicel PH102, colloidal silicon dioxide, magnesium stearate, a crospovidone such as crospovidone ultra (e.g., NF / PH.EUR / JP (Type A)), stearic acid, or a combination thereof. In some embodiments, the subject dosage form may be in a solid dosage form. In some embodiments, the solid dosage form may be a tablet (e.g., a bilayer tablet). In some embodiments, the tablet may include a film coating. In some embodiments, the film coating of the tablet may include a high-performance moisture barrier film coating, such as Opadry AMB II Beige (e.g., Opadry AMB II 88A170009 Beige) and / or Opadry AMB II White (e.g., Opadry AMB II 88A180040 White). PCT APPLICATION 134061-00001369 Opadry AMB II White is a film coating system that contains a polymer, plasticizer, and pigments like titanium dioxide. Opadry AMB II 88A180040 White is a high-performance aqueous moisture barrier film coating. These coatings, moreover, are a PVA-based immediate release system without polyethylene glycol (PEG), which offers increased moisture protection for oral solid dosage forms to promote stability in environmental humidity. Opadry AMB II 88A170009 Beige is also a high-performance moisture barrier film coating and a PVA-based release system without PEG, offering increased moisture protection.

[0041] Crospovidone ultra is a synthetic, insoluble, but rapidly swellable, crosslinked homopolymer of N-vinyl-2-pyrrolidone that enhances dissolution of poorly soluble drugs and provides rapid disintegration and dissolution to an oral solid-dosage form. In some embodiments, the Crospovidone ultra comprises less than 100 ppm peroxide. In some embodiments, the Crospovidone ultra comprises less than 50 ppm peroxide. In some embodiments, the Crospovidone ultra comprises a maximum of 30 ppm peroxide.

[0042] Carbopol 971P is a type of carbomer homopolymer comprising poly (acrylic acid). It is a lightly crosslinked polymer with long rheology. Carbopol 971P may be used for extended / controlled release tablets such as tablets containing the subject dosage form comprising dextromethorphan and bupropion, oral liquids and suspension, and bioadhesive formulations.

[0043] In some embodiments, the dosage form described herein is a bilayer tablet comprising bupropion, or pharmaceutical acceptable salt thereof, and dextromethorphan, or pharmaceutical acceptable salt thereof. Such a bilayer tablet comprising a dextromethorphan and a bupropion may offer many advantages, such as higher stability and higher purity of the active agents. This increased API stability and purity, in turn, results in a drug product with higher stability and purity.

[0044] In some embodiments, a bilayer tablet containing the subject dosage form described herein comprising a bupropion and a dextromethorphan may be structured in such a way that bupropion (such as bupropion hydrochloride), and a dextromethorphan (such as dextromethorphan hydrobromide monohydrate), are in separate layers of the bilayer tablet.

[0045] In some embodiments, a bilayer tablet containing the subject dosage form comprising a bupropion and a dextromethorphan may be structured in such a way that the controlling PCT APPLICATION 134061-00001369 releasing polymer, such as carbopol 971P, and the bupropion (such as bupropion hydrochloride), are in the same layer of the bilayer tablet.

[0046] In some embodiments, a bilayer tablet containing the subject dosage form comprising a bupropion and a dextromethorphan may be structured in such a way that the bupropion (e.g., bupropion hydrochloride) and cysteine (e.g., L-cysteine hydrochloride monohydrate) are in the same layer of the bilayer tablet and the dextromethorphan (e.g., dextromethorphan hydrobromide monohydrate) is in a separate layer of the bilayer tablet.

[0047] In some embodiments, a bilayer tablet containing the subject dosage form comprising bupropion, or pharmaceutical acceptable salt thereof, and dextromethorphan, or pharmaceutical acceptable salt thereof, may be structured in such a way that a lubricant, such as steric acid and the dextromethorphan (such as dextromethorphan hydrobromide monohydrate), are in the same layer of the bilayer tablet.

[0048] Dosage Form 1

[0049] Layer 1

[0050]

[0051] Layer 2

[0052]

[0053] PCT APPLICATION 134061-00001369

[0054]

[0055] In some embodiments, dosage Form 1 is stable for at least 30 months. In some embodiments, dosage Form 1 is stable for at least 50 months. In some embodiments, dosage Form 1 is stable for at least 60 months.

[0056] Dosage Form 2

[0057]

[0058] Layer 2

[0059]

[0060] PCT APPLICATION 134061-00001369

[0061] In some embodiments, dosage Form 2 is stable for at least 30 months. In some embodiments, dosage Form 2 is stable for at least 50 months. In some embodiments, dosage Form 2 is stable for at least 60 months.

[0062] Dosage Form 3

[0063] Layer 1

[0064]

[0065] Layer 2

[0066]

[0067] In some embodiments, dosage Form 3 is stable for at least 30 months. In some embodiments, dosage Form 3 is stable for at least 50 months. In some embodiments, dosage Form 3 is stable for at least 60 months.

[0068] These dosage forms may have improved stability, so the dosage form may be stored for at least 30 months, at least 38 months, at least 40 months, at least 45 months, at least 50 months, at least 54 months, at least 60 months, about 30-120 months, about 38-120 months, about 40-120 months, about 45-120 months, about 50-120 months, about 54-120 months, PCT APPLICATION 134061-00001369 about 60-120 months, about 30-60 months, about 38-60 months, about 40-60 months, about 45-60 months, about 50-60 months, or about 54-60 months.

[0069] In some embodiments, e.g., for treatment of major depressive disorder, the starting dosage of the subject combination is 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride in one tablet that is administered once daily in the morning. In some embodiments, after 3 days, the dosage is increased to one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily, e.g., given at least 8 hours apart. In some embodiments, no more than two doses containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride are administered in the same day.

[0070] In some embodiments, e.g., for the treatment of agitation associated with Alzheimer's disease, the starting dosage of the subject combination is 30 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride in one tablet that is administered once daily in the morning. In some embodiments, on the first day of the second week, the dosage is increased to one tablet (or one dosage form containing 30 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily, e.g., given at least 8 hours apart. In some embodiments, on the first day of the third week, the dosage is increased to one tablet (or one dosage form containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) twice daily, e.g., given at least 8 hours apart. In some embodiments, no more than two doses containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride are administered in the same day.

[0071] In some embodiments, such as for the treatment of agitation associated with dementia due to Alzheimer's disease, the dosage form may be present in a pharmaceutical product, such as a blister pack. Such a pharmaceutical product may comprise 21 units of a dosage form comprising about 30 mg of dextromethorphan hydrobromide monohydrate, or a molar equivalent amount of the free base form or another salt form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion. In some embodiments, the product contains instructions to administer one unit of the dosage form once a day for 7 consecutive days, and then administer one unit of the dosage form twice a day for 7 consecutive days. In some embodiments, the product contains instructions to administer one unit of a second dosage PCT APPLICATION 134061-00001369 form twice a day for 7 or 14 consecutive days, wherein the second dosage form comprises about 45 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion. In some embodiments, the product contains instructions to continue to administer one unit of the second dosage form twice a day as a target or maintenance dose. In some embodiments, the pharmaceutical product comprises a blister pack, and each unit of the dosage form is contained in the blister pack.

[0072] In some embodiments, e.g., for the treatment of nicotine addiction or to improve smoking cessation, 95.5 mg of dextromethorphan hydrobromide and 201.6 mg of bupropion hydrochloride in one tablet that is administered once daily, e.g., in the morning.

[0073] The subject combination may be administered orally with or without food. In some embodiments, the tablets are swallowed whole, and not crushed, divided, or chewed.

[0074] In some embodiments, the human patient experiences a reduction from baseline in total MADRS score in the human patient for administering the subject combination that is more than the patient would experience if a placebo were administered. The human patient taking the subject combination may experience the greater reduction in MADRS score than taking a placebo at, for example, after 1 week of administration, after 2 weeks of administration, after 3 weeks of administration, after 4 weeks of administration, after 5 weeks of administration, after 6 weeks of administration, or at other times.

[0075] In the subject combination, bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan, when co-administered with bupropion, displays nonlinear pharmacokinetics at steady state, with greater than dose-proportional changes in AUC and Cmax for varying doses of dextromethorphan hydrobromide monohydrate (30 to 60 mg) and less than dose-proportional changes for varying doses of bupropion hydrochloride (75 to 150 mg).

[0076] Steady state plasma concentrations of dextromethorphan and bupropion when given as the subject combination are achieved within 8 days. The accumulation ratios for dextromethorphan at steady state are about 20 and about 32, respectively based on Cmax and PCT APPLICATION 134061-00001369 AUCo -12. The accumulation ratios for bupropion at steady state are 1.1 and 1.5, respectively based on Cmax and AUCo-12.

[0077] After administration of the subject combination, the median Tmax of dextromethorphan is about 3 hours and the median Tmax of bupropion is about 2 hours. The Cmax of hydroxybupropion metabolite occurs approximately 3 hours post-dose and is approximately 14 times the peak level of bupropion. The AUCo-12 hydroxybupropion is about 19 times that of bupropion. The Cmaxof the erythrohydroxybupropion and threohydroxybupropion metabolites occurs approximately 4 hours post-dose and is approximately equal to and about 5 times that of bupropion, respectively. The AUCo-12 values of erythrohydroxybupropion and threohydroxybupropion are about 1.2 and about 7 times that of bupropion, respectively.

[0078] The subject combination can be taken with or without food. Dextromethorphan Cmax and AUCo-12 were unchanged and decreased by 14%, respectively, and bupropion Cmax and AUCo-12 were increased by 3% and 6%, respectively, when the subject combination was administered with food.

[0079] The plasma protein binding of dextromethorphan is approximately 60-70% and that of bupropion is 84%. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion; whereas the extent of protein binding of the threohydroxybupropion metabolite is about half that seen with bupropion.

[0080] Following 8 days of administration of the subject combination in extensive metabolizers, the mean elimination half-life of dextromethorphan was increased approximately 3-fold to about 22 hours, as compared to dextromethorphan given without bupropion.

[0081] The mean elimination half-life of dextromethorphan and bupropion was 22 hours and 15 hours, respectively. The apparent elimination half-life of hydroxybupropion, erythrohydroxybupropion and threohydroxybupropion metabolites were approximately 35, 44 and 33 hours, respectively.

[0082] The subject combination may be used for adjunctive treatment of major depressive disorder or depression. PCT APPLICATION 134061-00001369 In addition to major depressive disorder, the subject combination may be used to treat other diseases in conditions in the patient populations or circumstances described herein. For example, the subject combination may be used to treat pain or a neurological disorder. Examples of neurological disorders that may be treated with the subject combination include, but are not limited to: affective disorders, psychiatric disorders, cerebral function disorders, movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0083] Affective disorders that may be treated by the subject combination include, but are not limited to, depression, major depression, treatment resistant depression, treatment resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic conditions, obsessive-compulsive disorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

[0084] Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts, or attempts, and / or self-deprecation. Physical symptoms of depression may include insomnia, anorexia, appetite loss, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive issues, and / or abnormal hormonal circadian rhythms.

[0085] Psychiatric disorders that may be treated by the subject combination, include, but are not limited to, anxiety disorders, including but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease. PCT APPLICATION 134061-00001369 Alzheimer's disease may also be referred to as dementia of the Alzheimer's type. Other neurobehavioral symptoms of Alzheimer's disease that may be treated include disinhibition and apathy.

[0086] Agitation in Alzheimer's disease occurs as the disease progresses. Agitation may present itself as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking.

[0087] Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, and behavioral and psychological symptoms including agitation. AD is the most common form of dementia and afflicts an estimated 6 million individuals in the United States, a number that is anticipated to increase to approximately 14 million by 2050. Agitation is reported in up to 70% of patients with AD and is characterized by emotional distress, aggressive behaviors, disruptive irritability, and disinhibition. Managing agitation is a priority in AD. Agitation in patients with AD has been associated with increased caregiver burden, decreased functioning, accelerated cognitive decline, earlier nursing home placement, and increased mortality. There are currently no therapies approved by the FDA for the treatment of agitation in patients with AD.

[0088] Neurobehavioral symptoms have been known to appear during dementia and may be treated by the combination. Caregivers or families may feel more overwhelmed by patients' behavioral / psychological symptoms than by their cognitive impairment. Common forms of the syndrome are Alzheimer's disease, vascular dementia, dementia with Lewy bodies (abnormal aggregates of protein that develop inside nerve cells), and a group of diseases that contribute to frontotemporal dementia (degeneration of the frontal lobe of the brain). The symptoms that dementia patients have are similar to those of psychiatric disorders, but some are slightly different from each other. Neurobehavioral symptoms associated with dementia include depression, apathy, agitation, disinhibition, hallucinations, delusions, psychosis, impulsiveness, aggressiveness, compulsion, excessive sex drive, and personality disorders. PCT APPLICATION 134061-00001369 Neurobehavioral symptoms such as disinhibition may also be found in other conditions such as traumatic brain injury.

[0089] Agitation in patients with Alzheimer's disease may be assessed using the Cohen Mansfield Agitation Inventory or CMAI. The CMAI assesses various behaviors including, Hitting (including self), Kicking, Grabbing onto people, Pushing, Throwing things, Biting, Scratching, Spitting, Hurting self or others, Tearing things or destroying property, Making physical sexual advances, Pacing, aimless wandering, Inappropriate dress or disrobing, Trying to get to a different place, Intentional falling, Eating / drinking inappropriate substances, Handling things inappropriately, Hiding things, Hoarding things, Performing repetitive mannerisms, General restlessness, Screaming , Making verbal sexual advances, Cursing or verbal aggression, Repetitive sentences or questions, Strange noises (weird laughter or crying), Complaining, Negativism, Constant unwarranted request for attention or help.

[0090] Schizophrenia may be treated by the combination including positive symptoms and / or negative symptoms of schizophrenia, or residual symptoms of schizophrenia. Other conditions that may be treated include intermittent explosive disorder.

[0091] Cerebral function disorders that may be treated by the subject combination include, but are not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer's type dementia, memory loss, amnesia / amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia. Cerebral function disorders also include disorders caused by cerebrovascular diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders.

[0092] Substance addiction abuse that may be treated by the subject combination includes, but is not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and / or pipes, e-cigarettes or vaping, and addiction to chewing tobacco. PCT APPLICATION 134061-00001369 Movement disorders that may be treated by the subject combination include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, Huntington's disease chorea, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and Wilson's disease.

[0093] Dementias that may be treated bythe subject combination include, butare not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

[0094] Motor neuron diseases that may be treated by the subject combination include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sach's disease, Sandhoff disease, and hereditary spastic paraplegia.

[0095] Neurodegenerative diseases that may be treated the subject combination include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barre syndrome, and spastic paraplesia.

[0096] Seizure disorders that may be treated by the subject combination include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile seizures; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsia partialis continua; generalized seizures including, but not limited to, PCT APPLICATION 134061-00001369 generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0097] Types of headaches that may be treated by the subject combination include, but are not limited to, migraine, tension, and cluster headaches.

[0098] Other neurological disorders that may be treated by the subject combination include, Rett Syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0099] In some embodiments, the subject combination may be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar affect, depression (including treatment resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett's syndrome, seizures, cough (including chronic cough), etc.

[0100] In some embodiments, the subject combination may be administered orally to relieve musculoskeletal pain including low back pain, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, etc.

[0101] In some embodiments, the subject combination may be administered to relieve inflammatory pain including musculoskeletal pain, arthritis pain, and complex regional pain syndrome.

[0102] Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritis pain include pain associated with osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, peri-articular disorders, neuropathic arthropathies PCT APPLICATION 134061-00001369 including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.

[0103] In some embodiments, the subject combination is used to treat chronic musculoskeletal pain.

[0104] In some embodiments, the subject composition may be administered to relieve complex regional pain syndrome, such as complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-I I), CRPS-NOS, or another type of CRPS. CRPS is a type of inflammatory pain. CRPS can also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in a limb that can be accompanied by edema, and autonomic, motor, and sensory changes.

[0105] In some embodiments, the subject composition may be administered orally to relieve neuropathic pain.

[0106] Examples of neuropathic pain include pain due to diabetic peripheral neuropathy or diabetic peripheral neuropathic pain, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, pain due to multiple sclerosis, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy, and radio- or chemo-therapy associated neuropathy, etc.

[0107] In some embodiments, the subject composition may be administered to relieve fibromyalgia.

[0108] The term "treating" or "treatment" includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.

[0109] Example 1

[0110] Carbopol 971P and BUP are more suitable in the same layer of a bi layer tablet

[0111] It is important to find a release controlling polymer that (1) provides extended or sustained release of bupropion, or pharmaceutically acceptable salt thereof, and (2) exhibits compatibility with the bupropion (e.g., bupropion hydrochloride) and other excipients. For this purpose, an excipient compatibility study was designed to test compatibility of multiple PCT APPLICATION 134061-00001369 release controlling polymers with bupropion hydrochloride. In the study, five release controlling polymers including sodium carboxymethylcellulose 7MF PH, hydroxypropylcellulose JXF, hydroxyethylcellulose 250HHX, methylcellulose A4M, and Carbopol 971P were tested. Among them, methocel A4M and Carbopol 971P appeared to have the least incompatibility as shown in summary Table A below. The level of impurities at each time point compared to initial (t=0) was used as an indication of compatibility. The higher total RS (related substance) correlates with larger amounts of impurities, which in turn means increased instability observed for the resulting mixture of the polymer and bupropion hydrochloride at various temperatures (25 °C -50 °C), various humidity levels of 60-75% relative humidity (RH), and at various timepoints of T = 0, 2 weeks, 4 weeks, and 8 weeks. These results indicate that Carbopol 971P is more compatible with bupropion hydrochloride than the other release controlling polymers tested. The mixture of Carbopol 971P and bupropion hydrochloride at T = 0 to 8 weeks exhibits the lowest total RS (i.e., the least amount of impurities) at accelerated conditions, such as high temperature and / or high humidity (e.g., compare the stability data at 40°C / 75 %RH and 50°C for Methylcellulose A4M (entry 5) and Carbomer 971P (entry 6) in Table A). Thus, Carbopol 971P exhibits good stability when combined with bupropion hydrochloride. PCT APPLICATION 134061-00001369 Table A. Excipient compatibility data for bupropion hydrochloride

[0112] >

[0113] < <

[0114] <

[0115] <

[0116] <

[0117]

[0118] *LOQ means Limit of Quantitation.

[0119] As discussed below, several experiments in the compatibility study showed that Carbopol 971P, a controlling release polymer carbomer homopolymer, was compatible with bupropion hydrochloride but not compatible with dextromethorphan (e.g., dextromethorphan hydrobromide monohydrate).

[0120] In an excipient compatibility study, several excipients were used fortablets comprising 105 mg of bupropion and 45 mg of dextromethorphan hydrobromide (bupropion ("BU") HCI 105 mg / dextromethorphan ("DM") hydrobromide monohydrate HBr 45 mg) formulation. PCT APPLICATION 134061-00001369 Other ratios of Bup HCI / DM HBr monohydrate to excipients were also explored. In the study, for example, it was discovered that the controlling release polymer carbomer homopolymer, such as Carbopol 971P, was not compatible with dextromethorphan. It was observed that at T=0, the release polymer or agent Carbopol 971P exhibited lumps with dextromethorphan hydrobromide monohydrate in the binary mixture. However, no lumps were observed with Carbopol 971P and bupropion hydrochloride mixture. These results indicate that Carbopol 971P is not compatible with dextromethorphan hydrobromide monohydrate, while exhibiting compatibility with bupropion hydrochloride. Thus, a bilayer tablet described herewith can solve this problem where a bupropion and a dextromethorphan are formulated in separate layers, and Carbopol 971P is formulated in the same layer as bupropion.

[0121] Additionally, dextromethorphan hydrobromide monohydrate with Carbopol 971P at 1:1 and 1:3 ratios by weight showed an increase in the unknown impurities and total RS (related substance) at T=0, having assay value of about 95.3% to 86% respectively, with the amount of dextromethorphan significantly decreased with increased amount of Carbopol 971P. However, in the same study, at T=0, bupropion hydrochloride and cysteine with Carbopol 971P at 1:1 and 1:3 ratios by weight showed relatively high assay values of 100.6% and 97.6% respectively, with minimal decease in the amount of bupropion with increase of Carbopol 971P. As comparison, both dextromethorphan hydrobromide monohydrate and bupropion hydrochloride at T=0 have high assay value of 100.6% and 101.5% respectively. The results are summarized in Table B below. These results indicate that mixing Carbopol 971P and dextromethorphan hydrobromide together even at T=0 is not stable. Thus, this is further evidence that Carbopol 971P is not compatible with dextromethorphan. PCT APPLICATION 134061-00001369 Table B. Results for Potency assay at T=0 for mixtures comprising bupropion or dextromethorphan

[0122]

[0123] *DM is dextromethorphan, DM HBR is dextromethorphan hydrobromide monohydrate. BUP HCI is bupropion hydrochloride, CYS is cysteine hydrochloride. L-CYS is L-cysteine hydrochloride monohydrate.

[0124] Moreover in a separate blend compatibility study, in the presence of Carbopol 971P, bupropion hydrochloride with cysteine (e.g., L-cysteine hydrochloride monohydrate) were stable as evidenced by the low total RS corresponding to low impurity, at various temperatures (25 °C -40 °C), various humidity level of 60-75% RH, and various timepoints of T=0, 2 weeks, 4 weeks, and 8 weeks. The results are summarized in Table C below. PCT APPLICATION 134061-00001369 Table C. Blend compatibility study for mixtures comprising Bupropion*

[0125] <

[0126]

[0127] * BUP HCI is bupropion hydrochloride. Cys HCI is L-cysteine HCI monohydrate. The ratio of bupropion hydrochloride to cysteine hydrochloride is the molar ratio. In this experiment, for compatibility study, the ratio is weight ratio, while for blend study, the ratio is molar ratio.

[0128] The above results indicate that Carbopol 971P may be in the same layer with bupropion hydrochloride due to good stability, but cannot be combined with dextromethorphan due to instability. To solve this problem, disclosed herein is a bilayer tablet comprising a bupropion and a dextromethorphan, wherein the bupropion and the dextromethorphan are in separate layers.

[0129] BUP and Cys are more suitable in same layer of a bilayer tablet

[0130] Bupropion hydrochloride can be unstable in the presence of certain excipients and may need to be stabilized with an acid when formulated into an oral dosage form such as a tablet. For acidifiers, both L-cysteine hydrochloride monohydrate and ascorbic acid were tested in a blend compatibility study with bupropion hydrochloride in the presence of various release controlling polymers. In the study, it was found that cysteine hydrochloride provided significantly higher stability than the ascorbic acid, and bupropion HCI and cysteine in the presence of Carbopol 971P was very stable as shown above in Table C. Thus, it is necessary to formulate bupropion HCI and the cysteine in the same layer of the bilayer tablet described herein.

[0131] An additional formulation study showed that combining dextromethorphan hydrobromide with L-cysteine hydrochloride monohydrate resulted in instability. In this study, it was found that dextromethorphan hydrobromide with L-cysteine hydrochloride monohydrate at 1:1 ratio by weight showed unknown impurities and around 6.87 percent in PCT APPLICATION 134061-00001369 total RS at T=12 weeks, 40 °C, 75% RH in closed cap condition as shown in Table D below. This result indicates that the mixture of dextromethorphan hydrobromide monohydrate and L-Cysteine hydrochloride monohydrate is not stable compared with dextromethorphan hydrobromide monohydrate alone.

[0132] Table D. Results for Potency assay, RS, individual known and unknown impurities with DM HBr monohydrate and excipients at T=12 weeks, 40°C / 75%RH in Closed Cap condition.

[0133] <

[0134]

[0135] Add itiona lly, in a separate study, a quaternary mixture containing bupropion hydrochloride and L-cysteine hydrochloride monohydrate (1.6:1 by weight), dextromethorphan hydrobromide monohydrate, and Opadry AMB II WHITE 88A180040 is not stable as compared with another quaternary mixture containing bupropion hydrochloride and L-Cysteine hydrochloride monohydrate (1.6:1 by weight, corresponding to molar ratio of 1:1), Carbomer, and Opadry AMB II WHITE 88A180040 at 40 °C / 75% RH in closed cap condition. The former quaternary mixture containing the dextromethorphan had 39.9% of total RS, while the later quaternary mixture without the dextromethorphan had only 0.14% total RS at 12 weeks. The result is summarized in Table E below. Additionally, the former quaternary mixture also showed high amount 39.71% of dextromethorphan-related unknown impurities under high temperature (40 °C) and humidity (75% RH) conditions at 12 weeks in a closed cap condition, indicating a potential incompatibility of dextromethorphan hydrobromide monohydrate with L-cysteine hydrochloride monohydrate and / or carbomer. PCT APPLICATION 134061-00001369 On the other hand, in a separate blend compatibility study shown above in Table C, in presence of Carbopol 971P, the mixture of bupropion hydrochloride and cysteine hydrochloride monohydrate are stable with low total RS (low impurity) at various temperatures (25 °C -40 °C), various humidity level of 60-75% RH, and various timepoints of T=0, 2 weeks, 4 weeks, and 8 weeks for both molar ratios of 1:0.5 and 1:2 for bupropion hydrochloride to cysteine hydrochloride monohydrate.

[0136] The above results indicate that bupropion HCI and the cysteine; or bupropion HCI, the cysteine, and Carbopol 971P; can be co-formulated in the same layer, while dextromethorphan HBr monohydrate and the cysteine cannot be combined in the same layer, of a bilayer tablet comprising a bupropion and a dextromethorphan, wherein the bupropion and the dextromethorphan are in separate layers. PCT APPLICATION 134061-00001369 Table E. Excipient Compatibility Studies for Bupropion HCI mixtures at t= 0, 4, 8 and 12 weeks.

[0137] ""

[0138]

[0139] PCT APPLICATION 134061-00001369 Stearic acid and BUP / Cys are more suitable in separate layers of a bilayer tablet

[0140] As discussed above, the two APIs (i.e., bupropion and dextromethorphan) are not compatible for combination. While a bilayer tablet may solve this problem as each API can be in its own layer, new challenges arise regarding excipient selection for each layer of the bilayer tablet. Tables A-E above show the challenges in selecting the release controlling polymer and L-cysteine HCI monohydrate. Such challenges can also arise for other excipients.

[0141] In the same compatibility study described above, wherein several excipients were used for tablets comprising 105 mg of bupropion HCI and 45 mg of dextromethorphan hydrobromide monohydrate (Bup HCI 105 mg / DM HBr monohydrate 45 mg) formulation, little lumps were observed in the mixture of stearic acid with bupropion hydrochloride and L-cysteine hydrochloride monohydrate, indicating that stearic acid is not compatible with bupropion.

[0142] Thus, stearic acid is more suitable to be in a separate layer from bupropion in a bilayer tablet comprising a bupropion and a dextromethorphan, wherein the bupropion and the dextromethorphan are in separate layers.

[0143] Coating

[0144] A bilayer tablet comprising bupropion (e.g., bupropion hydrochloride) and dextromethorphan (e.g., dextromethorphan hydrobromide monohydrate) may be coated to further enhance the stability of the bilayer tablet by resisting moisture and peroxide formation. Based on the formulation study, the film coat of the bilayer tablet may include Opadry AMB II Beige, such as Opadry AMB II 88A170009 Beige, and / or Opadry AMB II White, such as Opadry AMB II 88A180040 White.

[0145] A stability study at accelerated conditions with a bilayer tablet coated with Opadry II was conducted. The bilayer tablet containing 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide monohydrate and excipients. The test results showed that at 40 °C and 75% RH, at 3 months, the assay value for the bupropion and the dextromethorphan are 95.4% and 91.2% of original samples respectively determined by PCT APPLICATION 134061-00001369 HPLC. The total impurities at 40 °C and 75% RH, at 3 months, was only 0.14%. These results indicate that the coated bilayer tablets are stable in the tested period of 3 months at high temperature and high humidity.

[0146] Furthermore, the Bup HCI 105 mg / DM HBr monohydrate 45 mg registration batch (containing a coated bilayer tablet comprising 105 mg of bupropion hydrochloride and 45 mg of dextromethorphan hydrobromide monohydrate and excipients) has an established 60-month shelf life.

[0147] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as amounts, percentage, and so forth used in the specification and claims are to be understood in all instances as indicating both the exact values as shown and as being modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. 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.

[0148] Use of the term "comprising" or "comprises" herein also contemplates that use of "consisting essentially of," "consists essentially of," "consisting of," or "consists of" in its place.

[0149] Affirmative recitation of an element anywhere herein should be understood to contemplate both including and excluding that element.

[0150] The terms "a," "an," "the" and similar referents used in the context of describing the embodiments (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to PCT APPLICATION 134061-00001369 better illuminate the embodiments and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims.

[0151] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from a group, for reasons of convenience and / or to expedite prosecution. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups if used in the appended claims.

[0152] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend forthe claimed embodiments to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

[0153] In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

PCT APPLICATION 134061-00001369 CLAIMS1. A dosage form comprising: 1) about 100 mg to about 110 mg of bupropion hydrochloride, or about 195 mg to about 205 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion; and 2) about 25 mg to about 35 mg, about 40 mg to about 50 mg, or about 90 mg to about 100 mg of dextromethorphan hydrobromide monohydrate, or a molar equivalent amount of the free base form or another salt form of dextromethorphan.

2. The dosage form of claim 1, wherein the dosage form has been stored for at least 38 months.

3. The dosage form of claim 1, further comprising:a. 0.5 ng to 1500 ng of Compound Ib. 0.5 ng to 1500 ng of Compound IIc. a combination thereof.

4. The dosage form of claim 1, 2, or 3, comprising about 30 mg of dextromethorphan hydrobromide monohydrate, or a molar equivalent amount of the free base form or another salt form of dextromethorphan.

5. The dosage form of claim 1, 2, or 3, comprising about 45 mg of dextromethorphan hydrobromide monohydrate, or a molar equivalent amount of the free base form or another salt form of dextromethorphan.PCT APPLICATION 134061-00001369 6. The dosage form of claim 1, 2, 3, 4, or 5 comprising about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion.

7. The dosage form of claim 1, 2, 3, 4, 5, or 6 comprising 0.5 ng to 750 ng of Compound I.

8. The dosage form of claim 1, 2, 3, 4, 5, 6, or 7, comprising 0.5 ng to 750 ng of Compound II.

9. The dosage form of claim 1, comprising about 95.5 mg of dextromethorphan hydrobromide monohydrate, or a molar equivalent amount of the free base form or another salt form of dextromethorphan.

10. The dosage form of claim 1 or 9, comprising about 201.6 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion.

11. The dosage form of claim 9 or 10, comprising 0.5 ng to 1500 ng of Compound I and 0.5 ng to 1500 ng of Compound II.

12. A dosage form comprising an extended-release layer and an immediate release layer, wherein the extended -release layer comprises:and the immediate release layer comprises:PCT APPLICATION 134061-0000136913. A dosage form comprising an extended-release layer and an immediate release layer, wherein the extended -release layer comprises:and the immediate release layer comprises:

14. The dosage form claim 12, comprising 30 mg of dextromethorphan hydrobromide monohydrate, or a molar equivalent amount of the free base form or another salt form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion.

15. The dosage form claim 12, comprising 45 mg of dextromethorphan hydrobromide monohydrate, or a molar equivalent amount of the free base form or another salt form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion.PCT APPLICATION 134061-00001369 16. The dosage form claims 12 or 13, wherein the dosage form is stable for at least 3 months.

17. A pharmaceutical product comprising 21 units of a dosage form, wherein the dosage form comprises about 30 mg of dextromethorphan hydrobromide monohydrate, or a molar equivalent amount of the free base form or another salt form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion.

18. The pharmaceutical product of claim 17, wherein the pharmaceutical product contains instructions to administer one unit of the dosage form once a day for 7 consecutive days, and then administer one unit of the dosage form twice a day for 7 consecutive days.

19. The pharmaceutical product of claim 17 or 18, wherein each unit of the dosage form is contained in a blister pack.

20. A method of treating major depressive disorder, comprising administering a dosage form of claim 1-8, 13, or 15-16 to a human patient in need thereof.

21. A method of treating agitation associated with Alzheimer's disease, comprising administering a dosage form of any one of claims 1 to 19 to a human patient in need thereof.

22. The method of claim 21, wherein, in the first 14 days that the dosage form is administered, the dosage form is administered from a pharmaceutical product comprising 21 units of the dosage form, wherein each unit of the dosage form comprises about 30 mg of dextromethorphan hydrobromide, or a molar equivalent amount of the free base form or another salt form of dextromethorphan, and about 105 mg of bupropion hydrochloride, or a molar equivalent amount of the free base form or another salt form of bupropion.

23. The method of claim 22, wherein one unit of the dosage form is administered once a day for 7 consecutive days, and then one unit of the dosage form is administered twice a day for 7 consecutive days.

24. The method of claim 21 or 22, wherein each unit of the dosage form is contained in a blister pack.PCT APPLICATION 134061-00001369 25. A method of treating nicotine addiction, comprising administering a dosage form of claim 1, 9, 10, or 11 to a human patient in need thereof.

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