Combination Therapeutic Methods

Abstract

The present disclosure provides methods of combination therapy using bupropion and / or its metabolites, and zonisamide or other similar anticonvulsant or GABAergic agents, optionally further in combination with one or more nicotine substitutes or replacements, to promote smoking cessation, reduce cravings for combustible tobacco products, treat dependence, addiction, or withdrawal associated with combustible tobacco products, and / or facilitate a smoker's switch from combustible tobacco products to a nicotine substitute or replacement, such as an e-cigarette.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 187,001, filed May 11, 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] In various embodiments, the present disclosure generally relates to methods for promoting smoking cessation and / or switching from combustible tobacco products to a nicotine substitute or replacement.

[0003] background Smoking is a major health hazard in our society. It is considered the number one preventable cause of death in the United States, with more than 500,000 deaths annually from smoking-related diseases. According to the United States Surgeon General's 2010 report, the major smoking-related diseases (including cancer, heart, and lung disease) are related to the inhalation of combustion products of combusted tobacco, not nicotine itself. Furthermore, smoking not only affects the health of smokers, but also increases the health risks of non-smokers. Therefore, it is of great public interest to quit smoking or to promote the switch to non-combustible nicotine products. Despite various developments in this field, it remains difficult to quit smoking. Summary of the Invention

[0004] In various embodiments, the present disclosure provides novel therapeutic methods for promoting smoking cessation and / or switching from smoking combustible tobacco products to one or more nicotine substitutes or replacements described herein. In a broad aspect, the present disclosure provides methods of using bupropion and / or its metabolites, and zonisamide or other similar anticonvulsant or GABAergic agents, optionally in combination with one or more nicotine substitutes or replacements, to promote smoking cessation, reduce cravings for combustible tobacco products, and / or improve avoidance effects from combustible tobacco products, treat dependence, addiction, or withdrawal associated with combustible tobacco products, and / or promote a smoker's switch from combustible tobacco products to a nicotine substitute or replacement, such as an e-cigarette.

[0005] The present disclosure is based in part on the discovery that combination treatment of smokers with bupropion and zonisamide facilitates the switch of smokers from smoking combustible tobacco products to nicotine substitutes or replacements (in the examples, e-cigarettes) and helps smokers achieve and maintain abstinence from smoking combustible tobacco products. The present disclosure shows that the smoking cessation benefits achieved by the combination therapy can be maintained for a long period of time, with clinical results showing that approximately one-third of participants maintained abstinence from smoking for 8-11 weeks after the target switch date. In addition, it was found that administration of zonisamide appears to reduce the incidence of adverse events associated with bupropion, such as insomnia, which is favorable for the dosing schedule and is expected to lead to better compliance. In light of these clinical results, the methods described herein can provide many advantages over existing methods for facilitating smoking cessation and / or facilitating the switch from combustible tobacco products to nicotine substitutes or replacements, such as e-cigarettes. Certain aspects of the clinical results have also been published, see Drug and Alcohol Dependence, 234:109346 (2022), which is incorporated by reference in its entirety.

[0006] In some embodiments, the present disclosure provides: [1] A therapeutic method for promoting smoking cessation in a subject, the method comprising administering to the subject a) bupropion or hydroxybupropion, b) an anticonvulsant or GABAergic agent, and optionally c) a nicotine replacement or substitution. [2] The method of [1], comprising administering to the subject a daily dose of bupropion in the range of about 150 mg to about 450 mg, for example, about 300 mg to about 450 mg. [3] The method of [2], wherein the bupropion is administered in a controlled release formulation, such as a sustained or extended release formulation, formulated for once-daily or twice-daily administration. [4] The method of [2], wherein the bupropion is administered in the form of an immediate release formulation. [5] The method according to any one of [2] to [4], wherein the bupropion is administered orally. [6] The method according to any one of [2] to [5], wherein the bupropion is administered to the subject once a day or twice a day. [7] The method according to any one of [2] to [6], wherein the bupropion is administered in the form of a pharma- ceutically acceptable salt. [8] The method according to any one of [2] to [7], comprising administering the bupropion to the subject in the morning. [9] The method according to any one of [2] to [8], comprising administering the bupropion to the subject in the evening.

[10] The method according to any one of [1] to [9], wherein the anticonvulsant or GABAergic agent is zonisamide.

[11] The method of

[10] , comprising administering zonisamide to the subject at a daily dose in the range of about 25 mg to about 400 mg, for example, about 25 mg to about 100 mg, about 50 mg to about 100 mg, etc., preferably, wherein zonisamide is administered orally.

[12] The method of

[10] or

[11] , comprising administering zonisamide simultaneously with bupropion, e.g., administering a dosage form containing both zonisamide and bupropion as active ingredients, or administering separate dosage forms each containing zonisamide and bupropion simultaneously.

[13] The method according to

[10] or

[11] , comprising administering zonisamide and bupropion sequentially in any order.

[14] The method according to any one of

[10] to

[13] , wherein the zonisamide is administered in an amount effective to reduce one or more adverse effects associated with bupropion or hydroxybupropion.

[15] The method according to any one of

[10] to

[14] , wherein the zonisamide is administered in an amount effective to reduce the incidence of insomnia and / or agitation without increasing the incidence of somnolence or fatigue.

[16] The method according to any one of

[10] to

[15] , wherein the zonisamide is administered in an amount effective for reducing the incidence of seizures.

[17] The method according to any one of

[10] to

[16] , wherein the zonisamide is administered in an amount effective to enhance the smoking cessation effect of bupropion.

[18] The method according to any one of

[10] to

[17] , wherein the subject is not administered a nicotine replacement or substitution.

[19] The method according to any one of

[10] to

[17] , comprising administering to the subject a nicotine replacement or substitution.

[20] The method of

[19] , wherein the nicotine substitute or replacement is an e-cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, and / or a nicotine inhaler (including nicotine salt inhalers, such as Philip Morris International's Platform 3 products).

[21] The method according to

[19] , wherein the nicotine replacement or substitution is a reduced-risk tobacco product.

[22] The method of

[21] , wherein the reduced risk tobacco product is a smokeless tobacco product, such as chewing tobacco, or a non-combustible tobacco product, such as Heat Not Burn (e.g., IQOS by Philip Morris International).

[23] The method according to any one of [1] to

[22] , wherein the subject does not require treatment for obesity.

[24] The method according to any one of [1] to

[23] , wherein the subject is a smoker who uses both electronic cigarettes and combustible cigarettes before the treatment.

[25] The method according to any one of [1] to

[24] , wherein the subject smokes at least 10 commercially available cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to the treatment.

[26] The method according to any one of [1] to

[25] , wherein the subject has a breath CO reading of at least 10 ppm prior to the treatment.

[27] A method according to any one of [1] to

[26] , which reduces the subject's daily consumption of combustible tobacco.

[28] The method according to any one of [1] to

[27] , wherein the subject's exhaled CO level is reduced by 20% or more (e.g., about 50%) compared to baseline, and / or urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) is reduced by 20% or more (e.g., about 50%) compared to baseline.

[29] A method according to any one of [1] to

[28] , which reduces the subject's craving for combustible tobacco, e.g., reduces the subject's average per-item craving score to 4 or less on a 7-point Schiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale) and / or does not increase the subject's average per-item craving score by more than 1 point on a 7-point Schiffman-Jarvik Withdrawal Scale (or more than 10 points on a 100-point visual analog scale).

[30] The method according to any one of [1] to

[29] , wherein the subject achieves abstinence from smoking combustible tobacco.

[31] A method of treatment for encouraging a smoker to switch from combustible cigarettes to an e-cigarette or other nicotine substitute or replacement, the method comprising administering to the smoker a) bupropion or hydroxybupropion, and b) an anticonvulsant or a GABAergic agent.

[32] The method of

[31] , comprising administering to the smoker a daily dose of bupropion in the range of about 150 mg to about 450 mg, for example, about 300 mg to about 450 mg.

[33] The method of

[32] , wherein the bupropion is administered in a controlled release formulation, such as a sustained or extended release formulation, formulated for once-daily or twice-daily administration.

[34] The method of

[33] , wherein the bupropion is administered in the form of an immediate release formulation.

[35] The method according to any one of

[32] to

[34] , wherein the bupropion is administered orally.

[36] The method according to any one of

[32] to

[35] , wherein the bupropion is administered to the smoker once a day or twice a day.

[37] The method according to any one of

[32] to

[36] , wherein the bupropion is administered in the form of a pharma- ceutically acceptable salt.

[38] The method according to any one of

[32] to

[37] , comprising administering the bupropion to the smoker in the morning.

[39] The method according to any one of

[32] to

[38] , comprising administering the bupropion to the smoker in the evening.

[40] The method according to any one of

[31] to

[39] , wherein the anticonvulsant or GABAergic agent is zonisamide.

[41] The method of

[40] , which comprises administering zonisamide at a daily dose in the range of about 25 mg to about 400 mg, for example, about 25 mg to about 100 mg, about 50 mg to about 100 mg, etc., wherein preferably zonisamide is administered orally.

[42] The method of

[40] or

[41] , comprising administering zonisamide simultaneously with bupropion, e.g., administering a dosage form containing both zonisamide and bupropion as active ingredients, or administering separate dosage forms each containing zonisamide and bupropion simultaneously.

[43] The method according to

[40] or

[41] , comprising administering zonisamide and bupropion sequentially in any order.

[44] The method according to any one of

[40] to

[43] , wherein the zonisamide is administered in an amount effective to reduce one or more adverse effects associated with bupropion or hydroxybupropion.

[45] The method according to any one of

[40] to

[44] , wherein the zonisamide is administered in an amount effective to reduce the incidence of insomnia and / or agitation without increasing the incidence of somnolence or fatigue.

[46] The method according to any one of

[40] to

[45] , wherein the zonisamide is administered in an amount effective to reduce the incidence of seizures.

[47] The method according to any one of

[40] to

[46] , wherein the zonisamide is administered in an amount effective to enhance the smoking cessation effect of bupropion.

[48] ​​A method according to any one of

[31] to

[47] , for encouraging the smoker to switch from combustible cigarettes to electronic cigarettes.

[49] The method of any one of

[31] to

[47] for encouraging the smoker to switch from combustible cigarettes to a nicotine substitute or replacement selected from electronic cigarettes, nicotine patches, nicotine gum, nicotine lozenges, nicotine pouches, nasal spray nicotine, dissolvable nicotine products, sublingual nicotine tablets, nicotine inhalers (including nicotine salt inhalers, such as Philip Morris International's Platform 3 products), and reduced-risk tobacco products, e.g., smokeless tobacco such as chewing tobacco, or non-combustible tobacco products such as Heat Not Burn (e.g., Philip Morris International's IQOS).

[50] The method according to any one of

[31] to

[49] , wherein the smoker does not require treatment for obesity.

[51] The method according to any one of

[31] to

[50] , wherein the smoker is a smoker who uses both electronic cigarettes and combustible cigarettes prior to the treatment.

[52] The method according to any one of

[31] to

[51] , wherein the smoker smokes at least 10 commercially available cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to the treatment.

[53] The method of any one of

[31] to

[52] , wherein the smoker has a breath CO reading of at least 10 ppm prior to the treatment.

[54] The method according to any one of

[31] to

[53] , which reduces the smoker's daily consumption of combustible tobacco.

[55] The method according to any one of

[31] to

[54] , wherein the smoker's breath CO level is reduced by 20% or more (e.g., about 50%) compared to baseline, and / or urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) is reduced by 20% or more (e.g., about 50%) compared to baseline.

[56] A method according to any one of

[31] to

[55] , which reduces the smoker's craving for combustible tobacco, e.g., reduces the subject's average per-item craving score to 4 or less on a 7-point Schiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale) and / or does not increase the subject's average per-item craving score by more than 1 point on a 7-point Schiffman-Jarvik Withdrawal Scale (or more than 10 points on a 100-point visual analog scale).

[57] The method according to any one of

[31] to

[56] , wherein the smoker achieves abstinence from smoking combustible tobacco.

[58] A method of treatment for reducing cravings for combustible tobacco in a subject, comprising administering to the subject: a) bupropion or hydroxybupropion; b) an anticonvulsant or GABAergic agent; and optionally c) a nicotine substitute or replacement.

[59] The method of

[58] , comprising administering to the subject a daily dose of bupropion in the range of about 150 mg to about 450 mg, for example, about 300 mg to about 450 mg.

[60] The method of

[59] , wherein the bupropion is administered in a controlled release formulation, such as a sustained or extended release formulation, formulated for once-daily or twice-daily administration.

[61] The method of

[59] , wherein the bupropion is administered in the form of an immediate release formulation.

[62] The method according to any one of

[59] to

[61] , wherein the bupropion is administered orally.

[63] The method according to any one of

[59] to

[62] , wherein the bupropion is administered to the subject once a day or twice a day.

[64] The method according to any one of

[59] to

[63] , wherein the bupropion is administered in the form of a pharma- ceutically acceptable salt.

[65] The method according to any one of

[59] to

[64] , comprising administering the bupropion to the subject in the morning.

[66] The method according to any one of

[59] to

[65] , comprising administering the bupropion to the subject in the evening.

[67] The method according to any one of

[58] to

[66] , wherein the anticonvulsant or GABAergic agent is zonisamide.

[68] The method of

[67] , comprising administering zonisamide to the subject at a daily dose in the range of about 25 mg to about 400 mg, such as about 25 mg to about 100 mg, about 50 mg to about 100 mg, etc., preferably wherein zonisamide is administered orally.

[69] The method of

[67] or

[68] , comprising administering zonisamide simultaneously with bupropion, e.g., administering a dosage form containing both zonisamide and bupropion as active ingredients, or administering separate dosage forms each containing zonisamide and bupropion simultaneously.

[70] The method according to

[67] or

[68] , comprising administering zonisamide and bupropion sequentially in any order.

[71] The method according to any one of

[67] to

[70] , wherein the zonisamide is administered in an amount effective to reduce one or more adverse effects associated with bupropion or hydroxybupropion.

[72] The method according to any one of

[67] to

[71] , wherein the zonisamide is administered in an amount effective to reduce the incidence of insomnia and / or agitation without increasing the incidence of somnolence or fatigue.

[73] The method according to any one of

[67] to

[72] , wherein the zonisamide is administered in an amount effective to reduce the incidence of seizures.

[74] The method according to any one of

[67] to

[73] , wherein the zonisamide is administered in an amount effective to enhance the smoking cessation effect of bupropion.

[75] The method according to any one of

[67] to

[74] , wherein the subject is not administered a nicotine replacement or substitution.

[76] The method according to any one of

[67] to

[74] , comprising administering to the subject a nicotine replacement or substitution.

[77] The method of

[76] , wherein the nicotine substitute or replacement is an e-cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, and / or a nicotine inhaler (including nicotine salt inhalers, such as Philip Morris International's Platform 3 products).

[78] The method according to

[76] , wherein the nicotine replacement or substitution is a reduced-risk tobacco product.

[79] The method of

[78] , wherein the reduced risk tobacco product is a smokeless tobacco product, such as chewing tobacco, or a non-combustible tobacco product, such as Heat Not Burn (e.g., IQOS by Philip Morris International).

[80] The method according to any one of

[58] to

[79] , wherein the subject does not require treatment for obesity.

[81] The method according to any one of

[58] to

[80] , wherein the subject is a smoker who uses both electronic cigarettes and combustible cigarettes before the treatment.

[82] The method according to any one of

[58] to

[81] , wherein the subject smokes at least 10 commercially available cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to the treatment.

[83] The method of any one of

[58] to

[82] , wherein the subject has a breath CO reading of at least 10 ppm prior to the treatment.

[84] A method according to any one of

[58] to

[83] , which reduces the subject's daily consumption of combustible tobacco.

[85] The method according to any one of

[58] to

[84] , wherein the subject's exhaled CO level is reduced by 20% or more (e.g., about 50%) compared to baseline, and / or urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) is reduced by 20% or more (e.g., about 50%) compared to baseline.

[86] A method according to any one of

[58] to

[85] , wherein the subject's mean item-by-item craving score is reduced to 4 or less on a 7-point Shiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale).

[87] A method according to any one of

[58] to

[86] , wherein the subject's mean craving score for each item does not increase by more than 1 point on a 7-point Shiffman-Jarvik Withdrawal Scale (or by more than 10 points on a 100-point visual analog scale).

[88] The method according to any one of

[58] to

[87] , wherein the subject achieves abstinence from smoking combustible tobacco.

[89] A method for treating dependence, addiction, or withdrawal associated with combustible tobacco in a subject, comprising administering to the subject a) bupropion or hydroxybupropion, b) an anticonvulsant or GABAergic agent, and optionally c) a nicotine replacement or substitution.

[90] The method of

[89] , comprising administering to the subject a daily dose of bupropion in the range of about 150 mg to about 450 mg, e.g., about 300 mg to about 450 mg.

[91] The method of

[90] , wherein the bupropion is administered in a controlled release formulation, such as a sustained or extended release formulation, formulated for once-daily or twice-daily administration.

[92] The method of

[90] , wherein the bupropion is administered in the form of an immediate release formulation.

[93] The method according to any one of

[90] to

[92] , wherein the bupropion is administered orally.

[94] The method according to any one of

[90] to

[93] , wherein the bupropion is administered to the subject once a day or twice a day.

[95] The method according to any one of

[90] to

[94] , wherein the bupropion is administered in the form of a pharma- ceutically acceptable salt.

[96] The method according to any one of

[90] to

[95] , comprising administering the bupropion to the subject in the morning.

[97] The method according to any one of

[90] to

[96] , comprising administering the bupropion to the subject in the evening.

[98] The method according to any one of

[89] to

[97] , wherein the anticonvulsant or GABAergic agent is zonisamide.

[99] The method of

[98] , comprising administering zonisamide to the subject at a daily dose in the range of about 25 mg to about 400 mg, e.g., about 25 mg to about 100 mg, about 50 mg to about 100 mg, etc., preferably wherein zonisamide is administered orally.

[0100] The method of

[98] or

[99] , comprising administering zonisamide simultaneously with bupropion, e.g., administering a dosage form containing both zonisamide and bupropion as active ingredients, or administering separate dosage forms each containing zonisamide and bupropion simultaneously.

[0101] The method of

[98] or

[99] , comprising administering zonisamide and bupropion sequentially in any order.

[0102] The method according to any one of

[98] to

[0101] , wherein the zonisamide is administered in an amount effective to reduce one or more adverse effects associated with bupropion or hydroxybupropion.

[0103] The method according to any one of

[98] to

[0102] , wherein the zonisamide is administered in an amount effective to reduce the incidence of insomnia and / or agitation without increasing the incidence of somnolence or fatigue.

[0104] The method according to any one of

[98] to

[0103] , wherein the zonisamide is administered in an amount effective to reduce the incidence of seizures.

[0105] The method according to any one of

[98] to

[0104] , wherein the zonisamide is administered in an amount effective to enhance the smoking cessation effect of bupropion.

[0106] The method according to any one of

[98] to

[0105] , wherein the subject is not administered a nicotine replacement or substitution.

[0107] A method according to any one of

[98] to

[0105] , comprising administering to the subject a nicotine substitute or replacement.

[0108] The method of claim 0107, wherein the nicotine substitute or replacement is an electronic cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, and / or a nicotine inhaler (including nicotine salt inhalers, such as Philip Morris International's Platform 3 products).

[0109] The method of claim 0107, wherein the nicotine substitute or replacement is a reduced-risk tobacco product.

[0110] The method of claim 0109, wherein the reduced risk tobacco product is a smokeless tobacco product such as chewing tobacco, or a non-combustible tobacco product such as Heat Not Burn (e.g., IQOS by Philip Morris International).

[0111] The method according to any one of

[89] to

[0110] , wherein the subject does not require treatment for obesity.

[0112] The method according to any one of

[89] to

[0111] , wherein the subject is a smoker who uses both electronic cigarettes and combustible cigarettes before the treatment.

[0113] The method according to any one of

[89] to

[0112] , wherein the subject smokes at least 10 commercially available cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to the treatment.

[0114] The method according to any one of

[89] to

[0113] , wherein the subject has a breath CO reading of at least 10 ppm prior to the treatment.

[0115] A method according to any one of

[89] to

[0114] , which reduces the subject's daily consumption of combustible tobacco.

[0116] The method according to any one of

[89] to

[0115] , wherein the subject's exhaled CO level is reduced by 20% or more (e.g., about 50%) compared to baseline, and / or urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) is reduced by 20% or more (e.g., about 50%) compared to baseline.

[0117] A method according to any one of

[89] to

[0116] , which reduces the subject's craving for combustible tobacco, for example by reducing the subject's average per-item craving score to 4 or less on a 7-point Schiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale) and / or by not increasing the subject's average per-item craving score by more than 1 point on a 7-point Schiffman-Jarvik Withdrawal Scale (or more than 10 points on a 100-point visual analog scale).

[0118] The method according to any one of

[89] to

[0117] , wherein the subject achieves abstinence from smoking combustible tobacco.

[0119] A method for reducing the rewarding effects (e.g., satisfaction, taste enjoyment, increased attention, reduced irritability) and / or increasing the avoidance effects (e.g., nausea, dizziness) of smoking a combustible tobacco product, such as a combustible cigarette, in a subject, comprising administering to the subject a) bupropion or hydroxybupropion, b) an anticonvulsant or GABAergic agent, and optionally c) a nicotine substitute or replacement.

[0120] The method of

[0119] , comprising administering to the subject a daily dose of bupropion in the range of about 150 mg to about 450 mg, for example, about 300 mg to about 450 mg.

[0121] The method of claim 1, wherein the bupropion is administered in the form of a controlled release formulation, such as a sustained release or extended release formulation, formulated for once-daily or twice-daily administration.

[0122] The method of claim 0120, wherein the bupropion is administered in the form of an immediate release formulation.

[0123] The method according to any one of

[0120] to

[0122] , wherein the bupropion is administered orally.

[0124] The method according to any one of

[0120] to

[0123] , wherein the bupropion is administered to the subject once a day or twice a day.

[0125] The method according to any one of

[0120] to

[0124] , wherein the bupropion is administered in the form of a pharma- ceutically acceptable salt.

[0126] The method according to any one of

[0120] to

[0125] , comprising administering the bupropion to the subject in the morning.

[0127] The method according to any one of

[0120] to

[0126] , comprising administering the bupropion to the subject in the evening.

[0128] The method according to any one of

[0119] to

[0127] , wherein the anticonvulsant or GABAergic agent is zonisamide.

[0129] The method of claim 0128, comprising administering zonisamide to the subject at a daily dose in the range of about 25 mg to about 400 mg, for example, about 25 mg to about 100 mg, about 50 mg to about 100 mg, etc., preferably, wherein zonisamide is administered orally.

[0130] The method described in

[0128] or

[0129] , which includes administering zonisamide simultaneously with bupropion, for example, administering a dosage form containing both zonisamide and bupropion as active ingredients, or administering separate dosage forms each containing zonisamide and bupropion simultaneously.

[0131] The method described in

[0128] or

[0129] , which comprises administering zonisamide and bupropion sequentially in any order.

[0132] The method according to any one of

[0128] to

[0131] , wherein the zonisamide is administered in an amount effective to reduce one or more adverse effects associated with bupropion or hydroxybupropion.

[0133] The method according to any one of

[0128] to

[0132] , wherein the zonisamide is administered in an amount effective to reduce the incidence of insomnia and / or agitation without increasing the incidence of somnolence or fatigue.

[0134] The method according to any one of

[0128] to

[0133] , wherein the zonisamide is administered in an amount effective to reduce the incidence of seizures.

[0135] The method according to any one of

[0128] to

[0134] , wherein the zonisamide is administered in an amount effective to enhance the smoking cessation effect of bupropion.

[0136] The method according to any one of

[0128] to

[0135] , wherein the subject is not administered a nicotine replacement or substitution.

[0137] A method according to any one of

[0128] to

[0135] , comprising administering a nicotine replacement or substitution to a subject.

[0138] The method of claim 0137, wherein the nicotine substitute or replacement is an electronic cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, and / or a nicotine inhaler (including nicotine salt inhalers, such as Philip Morris International's Platform 3 products).

[0139] The method of claim 0137, wherein the nicotine substitute or replacement is a reduced-risk tobacco product.

[0140] The method of claim 0139, wherein the reduced risk tobacco product is a smokeless tobacco product such as chewing tobacco, or a non-combustible tobacco product such as Heat Not Burn (e.g., IQOS by Philip Morris International).

[0141] The method according to any one of

[0119] to

[0140] , wherein the subject does not require treatment for obesity.

[0142] The method according to any one of

[0119] to

[0141] , wherein the subject is a smoker who uses both electronic cigarettes and combustible cigarettes prior to the treatment.

[0143] The method according to any one of

[0119] to

[0142] , wherein the subject smokes at least 10 commercially available cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to the treatment.

[0144] The method according to any one of

[0119] to

[0143] , wherein the subject has a breath CO reading of at least 10 ppm prior to the treatment.

[0145] A method according to any one of

[0119] to

[0144] , which reduces the subject's daily consumption of combustible tobacco.

[0146] The method according to any one of

[0119] to

[0145] , wherein the subject's exhaled CO level is reduced by 20% or more (e.g., about 50%) compared to baseline, and / or urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) is reduced by 20% or more (e.g., about 50%) compared to baseline.

[0147] A method according to any one of

[0119] to

[0146] , which reduces the subject's craving for combustible tobacco, for example by reducing the subject's average per-item craving score to 4 or less on a 7-point Schiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale) and / or by not increasing the subject's average per-item craving score by more than 1 point on a 7-point Schiffman-Jarvik Withdrawal Scale (or more than 10 points on a 100-point visual analog scale).

[0148] The method according to any one of

[0119] to

[0147] , wherein the subject achieves abstinence from smoking combustible tobacco.

[0149] 1. A kit comprising: a) one or more daily doses of bupropion, each comprising an extended release formulation comprising from about 150 mg to about 450 mg of bupropion; b) one or more daily doses of zonisamide, each comprising a pharmaceutical composition comprising from about 25 mg to about 400 mg of zonisamide; and, optionally, c) a nicotine substitute or replacement.

[0150] The kit described in

[0149] , wherein the extended release formulation is formulated for once-daily administration.

[0007] It is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. [Brief description of the drawings]

[0008] [Figure 1]Example 1 shows the overall study design of an open-label study investigating the effect of a combination of zonisamide and bupropion on the switching process from combustible cigarettes (CC) to an electronic nicotine delivery system ("ENDS"), which in this Example 1 is an e-cigarette. [Diagram 2] FIG. 1 shows a graph of mean (±standard error) exhaled carbon monoxide levels (CO) in ppm, a quantitative marker of tobacco smoke inhalation, for study participants in Example 1, 11 weeks after the target "switch-over" date, with average data calculated based on the same set of subjects at each time point. [Figure 3-1] 1 shows the Shiffman-Jarvik scale questionnaire used in the study of Example 1. [Figure 3-2] 1 shows the Shiffman-Jarvik scale questionnaire used in the study of Example 1. [Figure 3-3] 1 shows the Shiffman-Jarvik scale questionnaire used in the study of Example 1. [Figure 4A-1] 1 shows the modified Smoking Effects Questionnaire used in the study of Example 1. [Figure 4A-2] 1 shows the modified Smoking Effects Questionnaire used in the study of Example 1. [Figure 4B-1] 1 shows the modified e-cigarette smoking effects questionnaire used in the study of Example 1. [Figure 4B-2] 1 shows the modified e-cigarette smoking effects questionnaire used in the study of Example 1. [Diagram 5] Graphs depicting change in craving for combustible cigarettes (CC) assessed in sessions conducted over a 13-week period (assessments began after the screening session (S1), not shown). Points represent the mean (± standard error) of data from the same participants (N=22) reporting in all sessions, with ratings of 1 ("not at all"), 2 ("not at all"), 3 ("a little bit"), 4 ("somewhat"), 5 ("very much"), 6 ("very much"), and 7 ("extremely likely"). [Figure 6] Graphs showing change in ratings of reward / avoidance effects of combustible cigarettes (CC) and ENDS assessed in sessions conducted over 13 weeks (assessment began after the screening session (S1) - not shown). Points represent the mean (± standard error) of data from the same participants (N=10 abstinent and N=16 non-abstinent) reporting in all sessions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present disclosure generally relates to combination therapies using bupropion and / or its metabolites and zonisamide or other similar anticonvulsant or GABAergic agents, for example, to promote smoking cessation and / or promote switching from smoking combustible tobacco products to a nicotine replacement or substitution.

[0010] Zonisamide is a US FDA approved drug with antiepileptic indications, with daily doses typically ranging from 100 mg / day to 600 mg / day. See, e.g., Renu Kadian; Anil Kumar, In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020, available at www.ncbi.nlm.nih.gov / books / NBK507903. It has multiple mechanisms of action, including inhibiting activation of voltage-gated sodium channels at therapeutic levels. In addition, zonisamide also inhibits glutamate-mediated neurotransmission and enhances inhibitory GABAergic and serotonergic neurotransmission (see, e.g., Biton V. Clin Neuropharmacol. 2007; 30(4): 230-240, and Leppik IE. Seizure. 2004; 13 Suppl 1: S5-9; discussion S10). It also enhances dopamine levels in the striatum, which may theoretically help replace the desired effects of addictive drugs, such as nicotine, which also increases striatal dopamine.Zonisamide has been shown to reduce and limit free smoking while at the same time alleviating cravings for cigarettes.It has also been shown to reduce irritability, restlessness, and impatience during smoking abstinence, Dunn KE,et al.Nicotine Tob Res Off J Soc Res Nicotine Tob.2016;18(5):1171-1179.

[0011] Bupropion inhibits the reuptake of both noradrenaline and dopamine. The drug has been approved as an antidepressant for over 20 years. The U.S. Food and Drug Administration (FDA) approved the use of bupropion in smoking cessation in 1997. It is only one of two non-nicotine preparations currently approved by the FDA for this purpose, Wilkes S. Int J Chron Obstruct Pulmon Dis. 2008;3(1):45-53. A combination of bupropion and zonisamide is being studied as a treatment for weight loss in obese adults. The usual dose of bupropion for smoking cessation is 150 mg once daily for 3 days, followed by 300 mg once daily for 7 to 12 weeks. The maximum prescribed dose of bupropion is 450 mg / day, which is the maximum dose for treating major depression and attention deficit hyperactivity disorder in adults.

[0012] There is additional evidence for the combination of zonisamide / bupropion that potential side effects of each drug can be offset by each other. For example, bupropion is associated with side effects of agitation and insomnia, while zonisamide has sedative effects. Conversely, zonisamide's side effects include sedation, which is expected to be partially offset by the stimulant effects of bupropion. The combination of bupropion and zonisamide has been shown to be well tolerated in a study of weight loss caused by this drug combination, Gadde KM,et al.J Clin Psychiatry.2007;68(8):1226-1229. Some of the common side effects reported for empathic treatment (bupropion SR and zonisamide SR) in terms of weight loss were insomnia, nausea, and headache. See, for example, www.tesofensine-information.com / empatic.html.

[0013] Smoking cessation In some embodiments, the present disclosure provides various methods of treatment related to cessation of smoking combustible tobacco products, and in particular, related to cessation of smoking combustible tobacco products.

[0014] Some embodiments of the present disclosure relate to a method for promoting smoking cessation in a subject, comprising administering to the subject a) bupropion or hydroxybupropion, b) an anticonvulsant or GABAergic agent, and optionally c) a nicotine substitute or replacement. As used herein, a method for "promoting smoking cessation" should be understood to include any method that helps a person to stop or reduce smoking combustible tobacco or to stop or reduce the use of combustible tobacco products, reduce craving for combustible tobacco products, reduce relapse to heavy smoking during withdrawal or once smoking abstinence has been achieved, and / or alleviate various symptoms of smoking withdrawal syndrome. In some embodiments, a method for "promoting smoking cessation" also includes a method for reducing the rewarding effect of combustible tobacco use and / or increasing the avoidance effect associated with combustible tobacco use. In any of the embodiments described herein, unless otherwise specified or otherwise contrary by context, the combustible tobacco product may be a combustible tobacco.

[0015] In some embodiments, the present disclosure also provides a method of reducing a subject's craving for combustible tobacco products, such as cigarettes, comprising administering to the subject a) bupropion or hydroxybupropion, b) an anticonvulsant or GABAergic agent, and optionally c) a nicotine substitute or replacement. In some embodiments, reducing a subject's craving for combustible tobacco products, such as cigarettes, comprises reducing the subject's average craving score per item to 4 or less on a 7-point Shiffman-Jarvik withdrawal scale (or less than 50 on a 100-point visual analog scale). Typically, during the process of smoking cessation, a smoker's craving score tends to increase compared to baseline levels. Thus, reducing a smoker's craving also includes preventing or reducing an increase in the smoker's craving score. For example, in some embodiments, reducing a subject's craving for combustible tobacco products, such as cigarettes, includes not increasing the subject's average per-item craving score by more than 1 point based on a 7-point score on the Schiffman-Jarvik Withdrawal Scale (or by more than 10 points on a 100-point visual analog scale); for example, the subject's craving score may be maintained or decreased compared to baseline, or the subject's craving score may increase by less than 1 point above baseline. The version of the Schiffman-Jarvik Withdrawal Scale used in the study described below (see FIG. 3) consists of 33 7-point items that are used to determine scores for five subscales (i.e., craving, psychological, physical, stimulant / sedative, and appetite symptoms), and a total withdrawal score. The maximum possible score on each of the five Schiffman-Jarvik Withdrawal Scale subscale items is 7, and the highest possible total score for the craving scale is 42, while the maximum average score per item is 7. In each case, higher scores indicate more severe withdrawal. As used herein, for the sake of clarity, unless otherwise specified or clearly contrary from the context, references to subscale scores of the Shiffman-Jarvik Withdrawal Scale, e.g., craving scores, will be understood to refer to the average score per item, with a maximum score of 7.

[0016] In some embodiments, the disclosure further provides a method of treating dependence, addiction, or withdrawal associated with combustible tobacco products, such as cigarettes, in a subject, comprising administering to the subject a) bupropion or hydroxybupropion, b) an anticonvulsant or GABAergic agent, and optionally c) a nicotine substitute or replacement.

[0017] In some embodiments, the disclosure further provides a method of reducing the rewarding effects (e.g., satisfaction, taste enjoyment, increased attention, decreased irritability) of smoking a combustible tobacco product, such as a combustible cigarette, in a subject and / or increasing the avoidance effects (e.g., nausea, dizziness) of smoking, comprising administering to the subject a) bupropion or hydroxybupropion; b) an anticonvulsant or GABAergic agent; and optionally c) a nicotine substitute or replacement.

[0018] A variety of subjects are suitable for treatment with the methods described herein. Typically, the subject desires to quit smoking combustible cigarettes. In some embodiments, the subject is a smoker who uses both e-cigarettes and combustible cigarettes prior to treatment. In some embodiments, the subject smokes at least 10 commercial cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to treatment. In some embodiments, the subject has a breath CO reading of at least 10 ppm prior to treatment. In some embodiments, the subject does not require treatment for obesity.

[0019] The methods herein can also typically be characterized by a predetermined therapeutic effect. For example, in some embodiments, the methods described herein can reduce the subject's daily consumption of combustible cigarettes, e.g., compared to daily consumption before treatment, and the number of combustible cigarettes is reduced by 20% or more, or 50% or more, and up to 100%. In some embodiments, the subject achieves abstinence from combustible cigarettes. In some embodiments, the methods described herein can reduce the subject's breath CO level by 20% or more (e.g., about 50%) compared to baseline (i.e., breath CO level before treatment). For example, in some embodiments, the methods can reduce the subject's breath CO level to less than 5 ppm. In some embodiments, the methods described herein can reduce the subject's urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) level by 20% or more (e.g., about 50%) compared to baseline. In some embodiments, the methods described herein can reduce the subject's craving for combustible cigarettes. For example, in some embodiments, treated subjects can achieve a mean craving score per item of 4 or less on a 7-point Schiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale). In some embodiments, treated subjects' mean craving score per item does not increase by more than 1 point on a 7-point Schiffman-Jarvik Withdrawal Scale (or more than 10 points on a 100-point visual analog scale). In any of the embodiments described herein, unless otherwise specified by context or to the contrary, the therapeutic benefits described herein can be achieved and / or maintained during and thereafter the treatment period, e.g., after 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months of treatment. In any of the embodiments described herein, unless otherwise specified by context or to the contrary, the methods described herein can be characterized by a reduction in adverse effects associated with bupropion or hydroxybupropion.For example, in some embodiments, the methods described herein can be characterized by a reduced incidence of insomnia and / or agitation compared to treatment with bupropion alone. In some embodiments, the methods described herein may also be characterized by a reduced incidence of seizures. The therapeutic effects described herein may be achieved by using an effective dosing regimen of bupropion or hydroxybupropion and an anticonvulsant or GABAergic agent, typically in combination with the optional use of a nicotine replacement or substitution.

[0020] Typically, the methods described herein include administering to the subject a pharmaceutical composition comprising an effective amount of bupropion. In some embodiments, the methods may include administering to the subject a pharmaceutical composition comprising an effective amount of bupropion's active metabolite, hydroxybupropion (6-hydroxybupropion), or administering to the subject a pharmaceutical composition comprising an effective amount of one or more prodrugs of hydroxybupropion. Bupropion useful in the methods described herein is not particularly limited to a particular form. For example, bupropion in its free form or a pharma-ceutically acceptable salt, e.g., HCl salt, can be used in the methods described herein. For clarity, amounts of bupropion, such as daily doses, referred to herein should be understood to be the equivalent amount of bupropion hydrochloride. Bupropion is typically present as a racemic mixture, such as in products sold under the trade names Wellbutrin® or Zyban®. Formulations of bupropion suitable for the methods described herein include any of those described herein.

[0021] The anticonvulsant or GABAergic agent that can be administered to the subject for the methods described herein is also not particularly limited. However, in a preferred embodiment, the anticonvulsant or GABAergic agent is zonisamide. Other anticonvulsants or GABAergic agents that act similarly to zonisamide (e.g., have a similar mechanism of action or otherwise have a similar pharmacological effect) can also be used in the methods described herein. Like bupropion, zonisamide useful in the methods described herein is also not particularly limited to any particular form. For example, zonisamide in its free form, or a pharmacologic acceptable salt, such as sodium salt, may be used in the methods described herein. The amount of zonisamide, such as the daily dose referred to herein, should be understood as the equivalent amount of zonisamide in its free form. The formulation of zonisamide suitable for the methods described herein includes any of those described herein.

[0022] Typically, nicotine substitutes or replacements are also administered (e.g., self-administered) to the subject in the methods described herein. However, in some embodiments, the methods described herein do not include administering nicotine substitutes or replacements. When administered, suitable nicotine substitutes or replacements are not particularly limited and broadly include any product that can deliver nicotine to the subject user in a non-combustible manner. Non-limiting nicotine substitutes or replacements useful in the methods described herein include any of those described herein.

[0023] Switching to nicotine replacement or substitution According to the US Surgeon General (2010 report), the major smoking-related diseases (including cancer, heart, and lung disease) are related to the inhalation of the combustion products of combusted tobacco, not nicotine itself. Therefore, less toxic forms of nicotine delivery, such as e-cigarettes, may open the way to reduced harm for smokers who are unable or unwilling to give up nicotine addiction. A significant proportion of smokers who use e-cigarettes continue to smoke combustible cigarettes ("dual use"), weakening the potential beneficial effects on disease risk. It is therefore important to consider strategies to improve the complete switch from combustible cigarettes to e-cigarettes. Dual users find their preferred cigarette the most difficult to give up, and studies have shown that it is cigarettes smoked after meals. Jarvik M,et al.J Behav Med.1993;16(4):413-422.

[0024] As demonstrated in the clinical trials herein, treating smokers with a combination of bupropion and zonisamide can facilitate smokers switching from smoking combustible cigarettes to a nicotine replacement or substitution (e.g., e-cigarettes) and help smokers achieve and maintain abstinence from smoking combustible cigarettes.

[0025] In some embodiments, the disclosure provides a method of treatment for encouraging a smoker to switch from combustible cigarettes to e-cigarettes and / or other nicotine substitutes or replacements, comprising administering to the smoker a) bupropion or hydroxybupropion and b) an anticonvulsant or a GABAergic agent. In some embodiments, the method is for encouraging a smoker to switch from combustible cigarettes to e-cigarettes. In some embodiments, the method is for encouraging a smoker to switch from combustible cigarettes to nicotine substitutes or replacements (e.g., any of those described herein). For example, in some embodiments, the method is for encouraging a smoker to switch from combustible cigarettes to one or more nicotine substitutes or replacements selected from e-cigarettes, nicotine patches, nicotine gums, nicotine lozenges, nicotine pouches, nasal spray nicotine, dissolvable nicotine products, sublingual nicotine tablets, nicotine inhalers (including nicotine salt inhalers, such as Philip Morris International's Platform 3 products), and reduced-risk tobacco products, smokeless tobacco (e.g., chewing tobacco), or non-combustible tobacco products, such as Heat Not Burn (e.g., IQOS, Philip Morris International). In such methods, the smoker is typically not restricted to the use of one or more nicotine substitutes or replacements.

[0026] Smokers suitable for treatment with the methods described herein are not particularly limited. Typically, the smoker desires to stop smoking combustible cigarettes. In some embodiments, the smoker uses both e-cigarettes and combustible cigarettes prior to treatment. In some embodiments, the smoker smokes at least 10 commercial cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to treatment. In some embodiments, the smoker has a breath CO reading of at least 10 ppm prior to treatment. In some embodiments, the smoker does not require treatment for obesity.

[0027] The methods herein can also typically be characterized by a predetermined therapeutic effect. For example, in some embodiments, the methods described herein can reduce a smoker's daily consumption of combustible cigarettes, e.g., compared to daily consumption before treatment, where the number of combustible cigarettes is reduced by 20% or more, or 50% or more, and up to 100%. In some embodiments, the smoker achieves abstinence from combustible cigarettes. In some embodiments, the methods described herein can reduce a smoker's breath CO level by 20% or more (e.g., about 50%) compared to baseline (i.e., breath CO level before treatment). For example, in some embodiments, the methods can reduce a smoker's breath CO level to less than 5 ppm. In some embodiments, the methods described herein can reduce a smoker's urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) level by 20% or more (e.g., about 50%) compared to baseline. In some embodiments, the methods described herein can reduce a smoker's craving for combustible cigarettes. For example, in some embodiments, treated smokers can achieve a mean craving score per item of 4 or less on a 7-point Schiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale). In some embodiments, treated subjects' mean craving scores per item do not increase by more than 1 point on a 7-point Schiffman-Jarvik Withdrawal Scale (or more than 10 points on a 100-point visual analog scale). In any of the embodiments described herein, unless otherwise specified by context or to the contrary, the therapeutic benefits described herein can be achieved and / or maintained during and thereafter the treatment period, e.g., after 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months of treatment. In any of the embodiments described herein, unless otherwise specified by context or to the contrary, the methods described herein can be characterized by a reduction in adverse effects associated with bupropion or hydroxybupropion.For example, in some embodiments, the methods described herein can be characterized by a reduced incidence of insomnia and / or agitation compared to treatment with bupropion alone. In some embodiments, the methods described herein can also be characterized by a reduced incidence of seizures compared to treatment with bupropion alone. The therapeutic effects described herein can typically be achieved by using an effective dosing regimen of bupropion or hydroxybupropion and an anticonvulsant or GABAergic agent, including dosage amounts, types of formulations, etc., including any of those described herein.

[0028] Typically, the method for promoting switching comprises administering to the smoker a pharmaceutical composition comprising an effective amount of bupropion. In some embodiments, the method may comprise administering to the smoker a pharmaceutical composition comprising an effective amount of bupropion, an active metabolite of hydroxybupropion (6-hydroxybupropion), or administering to the smoker a pharmaceutical composition comprising an effective amount of one or more prodrugs of hydroxybupropion. Bupropion useful in the methods described herein is not particularly limited to a particular form. For example, bupropion in its free form or a pharma-ceutically acceptable salt, e.g., an HCl salt, can be used in the methods described herein. Bupropion typically exists as a racemic mixture, such as in products sold under the trade names Wellbutrin®, or Zyban®. Formulations of bupropion suitable for the methods for promoting switching include any of those described herein.

[0029] The anticonvulsant or GABAergic agent that can be administered to a smoker for the method of promoting switching is also not particularly limited. However, in a preferred embodiment, the anticonvulsant or GABAergic agent is zonisamide. Other anticonvulsants or GABAergic agents that act similarly to zonisamide can also be used in the method. As with bupropion, zonisamide that is useful in the method described herein is also not particularly limited to a particular form. For example, zonisamide in its free form or a pharma- ceutical acceptable salt, such as sodium salt, can be used in the method described herein. Formulations of zonisamide suitable for the method of promoting smoking cessation include any of those described herein.

[0030] Bupropion and Zonisamide Dosage Regimen Combination treatment with bupropion and zonisamide for the methods described herein is not limited to any particular dosing regimen, which may typically be adjusted as necessary to achieve one or more of the desired therapeutic effects described herein.

[0031] Generally, the daily dose of bupropion for the methods described herein (e.g., any of those described herein, e.g., those set forth in the Summary of the Invention section, [1] to

[0148] , as the case may be) is in the range of about 100 mg to about 450 mg, e.g., about 150 mg, about 300 mg, about 450 mg, or any range between the recited values, e.g., about 150 mg to about 450 mg, or about 300 mg to about 450 mg. The daily dose of bupropion is generally administered orally to the subject. Bupropion is typically administered as its pharma- ceutically acceptable salt, such as the hydrochloride (HCl salt) or hydrobromide (HBr salt). Bupropion may be administered in an immediate release formulation, or in a controlled release formulation, such as a sustained or extended release formulation.

[0032] Bupropion formulations suitable for the methods described herein include those known in the art, including any of the formulations approved by the U.S. Food and Drug Administration (FDA) or equivalent agencies outside the United States, such as extended-release APLENZIN® tablets (174 mg, 348 mg, or 522 mg of bupropion hydrobromide), ZYBAN® (bupropion hydrochloride) extended-release tablets, FORFIVO® XL tablets (450 mg of bupropion hydrochloride), WELLBUTRIN® tablets (75 mg or 100 mg of bupropion hydrochloride), WELLBUTRIN® SR extended-release tablets (100 mg, 150 mg, or 200 mg of bupropion hydrochloride), WELLBUTRIN® XL extended-release tablets (150 mg or 300 mg of bupropion hydrochloride), or generic bioequivalents approved by the FDA for any of the foregoing. Non-limiting bupropion formulations suitable for the methods described herein include those described in U.S. Pat. Nos. 5,427,798, 6,096,341, 6,143,327, 6,905,708, 7,579,380, and 8,932,628, the contents of each of which are incorporated herein by reference in their entirety.

[0033] In some embodiments, bupropion is administered in a sustained release formulation. Typically, the "sustained release" bupropion formulations described herein include dosage forms characterized in that the sustained release dosage form is capable of releasing bupropion in a single dose to provide a plasma concentration of bupropion and / or bupropion metabolite(s) that is maintained at a therapeutic level over a period of time to provide a therapeutic effect (e.g., smoking cessation) for a period of about 6 hours or more, preferably about 12 hours or more. Typically, the sustained release bupropion dosage forms herein are formulated for a twice-daily dosing regimen. In some embodiments, the sustained release bupropion dosage form may be a tablet comprising bupropion hydrochloride and a release-controlling polymer, such as hydroxypropylmethylcellulose or hydroxypropylcellulose, such as those described in U.S. Pat. No. 5,427,798, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the extended release bupropion dosage form may be a tablet containing about 150 mg of bupropion hydrochloride and having the following inactive ingredients: carnauba wax, cysteine ​​hydrochloride, hydroxypropyl-methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, titanium dioxide, and having a pharmacokinetic profile suitable for twice daily dosing. In some embodiments, the extended release bupropion dosage form may be ZYBAN® (bupropion hydrochloride) extended release tablets, or generic bioequivalents thereof.

[0034] In some embodiments, bupropion is administered in an extended release dosage form. Typically, the "extended release" bupropion dosage forms herein include dosage forms characterized in that the extended release dosage form can release bupropion in a single dose to provide a plasma concentration of bupropion and / or bupropion metabolite(s) that is maintained at a therapeutic level over a period of time to provide a therapeutic effect (e.g., smoking cessation) for a period of about 12 hours or more, preferably about 24 hours or more. Typically, the extended release bupropion formulations herein are formulated for a once-daily dosing regimen. In some embodiments, the extended release bupropion dosage form may be a tablet comprising a core of bupropion hydrochloride, a film coating comprising ethylcellulose, and a second coating comprising a methacrylic acid copolymer, such as those described in U.S. Pat. No. 6,143,327, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the extended release bupropion dosage form may be a tablet containing about 150 mg or 300 mg of bupropion hydrochloride and having the following inactive ingredients: ethylcellulose, glyceryl behenate, methacrylic acid copolymer dispersion, polyvinyl alcohol, polyethylene glycol, povidone, silicon dioxide, and triethyl citrate, with a pharmacokinetic profile suitable for once-daily administration. In some embodiments, the extended release bupropion formulation may be WELLBUTRIN® XL sustained release tablets, or a common bioequivalent thereof.

[0035] As will be appreciated by one of skill in the art, the daily dose and dosing regimen of bupropion for the methods described herein (e.g., any of those described herein, e.g., those set forth in the Summary of the Invention section, [1] to

[0148] , as the case may be) may be adjusted along with the dosing regimen of zonisamide for efficacy and safety profile, as well as convenience.

[0036] For example, in some preferred embodiments, bupropion is administered once daily at a daily dose of about 300 mg to about 450 mg, e.g., about 300 mg, using an extended release formulation having a pharmacokinetic / pharmacodynamic profile suitable for such once daily administration (e.g., WELLBUTRIN® XL extended release tablets, or generic bioequivalents thereof). In some embodiments, bupropion can be administered once daily in the morning. In some embodiments, bupropion can also be administered once daily in the evening, e.g., several hours (e.g., 4 or 5 hours) before sleep. In some embodiments, administration of bupropion may be combined with simultaneous or substantially simultaneous administration of an anticonvulsant or GABAergic agent, preferably zonisamide. In some embodiments, administration of bupropion may also be administered to the subject before or after administration of the anticonvulsant or GABAergic agent. Typically, the dose of the anticonvulsant or GABAergic agent, preferably zonisamide, provides a suitable pharmacokinetic profile such that side effects associated with administration of bupropion extended release formulations, such as, for example, insomnia, can be reduced, minimized, or eliminated.

[0037] In some embodiments, bupropion may also be administered twice daily at a daily dose of about 300 mg to about 450 mg, e.g., about 300 mg, using a sustained release formulation with a pharmacokinetic / pharmacodynamic profile suitable for twice daily administration, such as ZYBAN® (bupropion hydrochloride), or its generic bioequivalents. In such embodiments, the daily dose of bupropion is typically administered in two equivalent doses, one in the morning and one in the evening, e.g., several hours (e.g., 8 hours) after the first administration. In some embodiments, one or both of the administrations may be combined with the simultaneous or substantially simultaneous administration of an anticonvulsant or GABAergic agent, preferably zonisamide. In some embodiments, one or both of the administrations may also be administered to the subject before or after administration of the anticonvulsant or GABAergic agent. Typically, the dose of the anticonvulsant or GABAergic agent, preferably zonisamide, provides a suitable pharmacokinetic profile such that side effects associated with administration of a bupropion sustained release formulation, such as, for example, insomnia, may be reduced, minimized, or eliminated.

[0038] In some embodiments, bupropion may also be administered as an immediate release formulation, for example, to achieve acute prevention against smoking relapse during stressful or other craving-inducing situations. In some embodiments, an immediate release formulation of bupropion may be administered to a subject in the evening, for example, several hours (e.g., 4 or 5 hours) before sleep. In some embodiments, an immediate release formulation of bupropion may be combined with the simultaneous or substantially simultaneous administration of an anticonvulsant or GABAergic agent, preferably zonisamide. In some embodiments, an immediate release formulation of bupropion may be administered to a subject before or after the administration of an anticonvulsant or GABAergic agent, preferably zonisamide. Typically, the dose of the anticonvulsant or GABAergic agent, preferably zonisamide, provides a suitable pharmacokinetic profile so that side effects associated with the administration of a bupropion immediate release formulation, such as, for example, insomnia, can be reduced, minimized, or eliminated.

[0039] The daily dose of zonisamide for the methods described herein (e.g., any of those described herein, e.g., those set forth in the Summary of the Invention section [1] to

[0148] , as the case may be) is generally in the range of about 25 mg to about 400 mg, e.g., about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or any range between the recited values, e.g., about 25 mg to about 100 mg, about 50 mg to about 100 mg, etc. The daily dose of zonisamide is typically administered orally to the subject. Zonisamide formulations suitable for the methods described herein include any formulation known in the art, including any formulation approved by the US Food and Drug Administration (FDA) or equivalent agencies outside the US, or immediate release ZONEGRAN® (zonisamide) capsules containing 25 mg, 50 mg, or 100 mg of zonisamide, or generic bioequivalents approved by the FDA. In some embodiments, zonisamide can be present in a formulation (e.g., capsule) containing 25 mg, 50 mg, or 100 mg of zonisamide, with the following inactive ingredients: microcrystalline cellulose, hydrogenated vegetable oil, sodium lauryl sulfate, gelatin, and coloring agents. Although the zonisamide typically used herein is present in an immediate release formulation, in some embodiments, zonisamide may also be present in a sustained release formulation. Suitable sustained release formulations include those known in the art, for example, those described in US Patent Application Publication No. 2007 / 0148237 A1, the contents of which are incorporated herein by reference in their entirety.Typically, zonisamide is administered once a day.In some embodiments, zonisamide can be administered once a day in the morning.In some embodiments, zonisamide can also be administered once a day in the evening, for example, several hours (for example, 4 hours or 5 hours) before sleep.

[0040] For the methods described herein (e.g., any of those described herein, e.g., those set forth in [1] to

[0148] of the Summary of the Invention section, as the case may be), zonisamide can be administered to a subject simultaneously with bupropion, or sequentially in any order. For example, in some embodiments, a dosage form containing both zonisamide and bupropion as active ingredients can be administered to a subject. Dosage forms containing both zonisamide and bupropion as active ingredients are known, such as the layered tablets described in U.S. Pat. Nos. 8,318,788 B2 and 8,088,786 B2. In some embodiments, separate dosage forms each containing zonisamide and bupropion can be administered to a subject simultaneously. In some embodiments, zonisamide can be administered to a subject before or after bupropion.

[0041] Generally, for zonisamide and bupropion to be administered sequentially according to the methods described herein, zonisamide and bupropion can be administered to a subject several hours apart on the same day, such as about 1, 2, 4, 6, 8, 10, or 12 hours. However, it is also contemplated that in some embodiments, bupropion and zonisamide are not administered on the same day. For example, in some embodiments, a subject is treated with bupropion once a day for a first period without zonisamide, followed by a second period in which the subject is treated with zonisamide once a day with bupropion or without bupropion. For example, in some embodiments, a subject is treated with zonisamide once a day for a first period without bupropion, followed by a second period in which the subject is treated with bupropion once a day with zonisamide or without zonisamide. In some embodiments, there may be a gap period between the first period and the second period. In some embodiments, there is no gap period between the first period and the second period.

[0042] The mass ratio of the daily dose of zonisamide to bupropion in the methods described herein (e.g., any of those described herein, e.g., those set forth in the Summary of the Invention section [1] to

[0148] , as the case may be) can typically range from about 20:1 to about 1:20, preferably from about 1:1 to about 1:10, e.g., about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, or any range between the recited ratios (provided that the daily dose of bupropion is higher). For example, in some embodiments, the daily dose of zonisamide can be about 50 mg and the daily dose of bupropion can be about 300 mg, i.e., a ratio of about 1:6. In some embodiments, the daily dose of zonisamide may be about 100 mg and the daily dose of bupropion may be about 300 mg, ie, a ratio of about 1:3.

[0043] One advantage of the methods described herein is that the incidence of adverse events associated with either bupropion or zonisamide is reduced. This may be accomplished by adjusting the doses, timing, formulations, etc. of zonisamide and bupropion such that the side effects of the two drugs counterbalance each other. For example, in some embodiments according to the methods described herein (e.g., any of those described herein, e.g., those set forth in [1] to

[0148] of the Summary of the Invention section, as the case may be), zonisamide is administered in an amount effective to reduce one or more adverse effects associated with bupropion or hydroxybupropion, e.g., insomnia. In some embodiments, zonisamide is administered in an amount effective to reduce the incidence of insomnia and / or agitation without increasing the incidence of sleepiness or fatigue. In some embodiments, zonisamide is administered in an amount effective to reduce the incidence of seizures.

[0044] In some embodiments, zonisamide may be administered in an amount effective to enhance the smoking cessation effects of bupropion.

[0045] In typical embodiments according to the methods described herein, both zonisamide and bupropion are administered orally to the subject. However, in some embodiments, one or both of zonisamide and bupropion can also be administered to the subject via other routes of administration, for example, sublingually, rectally, parenterally (including subcutaneously, intramuscularly, and intravenously), or transdermally.

[0046] In some specific embodiments, the disclosure provides a method of treatment for promoting smoking cessation in a subject, the method comprising administering to the subject a) a daily dose of about 150 mg to about 450 mg (e.g., about 300 mg to about 450 mg) of bupropion in an extended release formulation (e.g., as described herein) once daily, b) a daily dose of about 25 mg to about 400 mg (e.g., about 25 mg to about 100 mg, or 50 mg to about 100 mg) of zonisamide in an immediate release formulation (e.g., as described herein) once daily, and c) optionally a nicotine substitute or replacement (e.g., as described herein). In some embodiments, the weight ratio of the daily dose of zonisamide to bupropion ranges from about 1:1 to about 1:10, e.g., about 1:3 to about 1:6. Zonisamide and bupropion are typically administered orally to the subject. In some embodiments, zonisamide and bupropion are administered to the subject simultaneously. In some embodiments, zonisamide is administered before or after bupropion. In some embodiments, bupropion is administered in the morning. In some embodiments, bupropion is administered in the evening. In some embodiments, zonisamide is administered in the morning. In some embodiments, zonisamide is administered in the evening. In some embodiments, the method includes administering to the subject a nicotine substitute or replacement, such as an e-cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, a nicotine inhaler (including a nicotine salt inhaler, such as Philip Morris International's Platform 3 product), and / or a reduced-risk tobacco product (e.g., a smokeless tobacco product, such as chewing tobacco, or a non-combustible tobacco product). In some embodiments, the method does not administer to the subject a nicotine substitute or replacement. Subject characteristics and therapeutic effects suitable for the present methods include any of those described herein.

[0047] In some specific embodiments, the disclosure provides a method of treatment for reducing a craving for combustible tobacco in a subject, the method comprising administering to the subject a) a daily dose of bupropion in an extended release formulation (e.g., as described herein) of about 150 mg to about 450 mg (e.g., about 300 mg to about 450 mg) once daily, b) a daily dose of zonisamide in an immediate release formulation (e.g., as described herein) of about 25 mg to about 400 mg (e.g., about 25 mg to about 100 mg, or 50 mg to about 100 mg) once daily, and c) optionally a nicotine substitute or replacement (e.g., as described herein). In some embodiments, the weight ratio of the daily dose of zonisamide to bupropion ranges from about 1:1 to about 1:10, e.g., about 1:3 to about 1:6. Zonisamide and bupropion are typically administered orally to the subject. In some embodiments, zonisamide and bupropion are administered to the subject simultaneously. In some embodiments, zonisamide is administered before or after bupropion. In some embodiments, bupropion is administered in the morning. In some embodiments, bupropion is administered in the evening. In some embodiments, zonisamide is administered in the morning. In some embodiments, zonisamide is administered in the evening. In some embodiments, the method includes administering to the subject a nicotine substitute or replacement, such as an e-cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, a nicotine inhaler (including a nicotine salt inhaler, such as Philip Morris International's Platform 3 product), and / or a reduced-risk tobacco product (e.g., a smokeless tobacco product, such as chewing tobacco, or a non-combustible tobacco product). In some embodiments, the method does not administer to the subject a nicotine substitute or replacement. Subject characteristics and therapeutic effects suitable for the present methods include any of those described herein.

[0048] In some specific embodiments, the disclosure provides a method for treating a dependence, addiction, or withdrawal associated with combustible tobacco in a subject, the method comprising administering to the subject a) a daily dose of bupropion in an extended release formulation (e.g., as described herein) of about 150 mg to about 450 mg (e.g., about 300 mg to about 450 mg) once daily, b) a daily dose of zonisamide in an immediate release formulation (e.g., as described herein) of about 25 mg to about 400 mg (e.g., about 25 mg to about 100 mg, or 50 mg to about 100 mg) once daily, and c) optionally a nicotine substitute or replacement (e.g., as described herein). In some embodiments, the weight ratio of the daily dose of zonisamide to bupropion ranges from about 1:1 to about 1:10, e.g., about 1:3 to about 1:6. Zonisamide and bupropion are typically administered orally to the subject. In some embodiments, zonisamide and bupropion are administered to the subject simultaneously. In some embodiments, zonisamide is administered before or after bupropion. In some embodiments, bupropion is administered in the morning. In some embodiments, bupropion is administered in the evening. In some embodiments, zonisamide is administered in the morning. In some embodiments, zonisamide is administered in the evening. In some embodiments, the method includes administering to the subject a nicotine substitute or replacement, such as an e-cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, a nicotine inhaler (including a nicotine salt inhaler, such as Philip Morris International's Platform 3 product), and / or a reduced-risk tobacco product (e.g., a smokeless tobacco product, such as chewing tobacco, or a non-combustible tobacco product). In some embodiments, the method does not administer to the subject a nicotine substitute or replacement. Subject characteristics and therapeutic effects suitable for the present methods include any of those described herein.

[0049] In some specific embodiments, the disclosure provides methods for reducing the rewarding effects (e.g., gratification, taste enjoyment, enhanced attention, reduced irritability) and / or increasing the aversion effects (e.g., nausea, dizziness) of combustible cigarette smoking in a subject, the methods comprising administering to the subject: a) a daily dose of about 150 mg to about 450 mg (e.g., about 300 mg to about 450 mg) of bupropion once daily in an extended release formulation (e.g., as described herein); b) a daily dose of about 25 mg to about 400 mg (e.g., about 25 mg to about 100 mg or about 50 mg to about 100 mg) of zonisamide once daily in an immediate release formulation (e.g., as described herein); and c) optionally a nicotine substitute or replacement (e.g., as described herein). In some embodiments, the weight ratio of the daily dose of zonisamide to bupropion ranges from about 1:1 to about 1:10, for example, from about 1:3 to about 1:6. Zonisamide and bupropion are typically administered orally to a subject. In some embodiments, zonisamide and bupropion are administered to a subject simultaneously. In some embodiments, zonisamide is administered before or after bupropion. In some embodiments, bupropion is administered in the morning. In some embodiments, bupropion is administered in the evening. In some embodiments, zonisamide is administered in the morning. In some embodiments, zonisamide is administered in the evening. In some embodiments, the method includes administering to the subject a nicotine substitute or replacement, such as an e-cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, a nicotine inhaler (including a nicotine salt inhaler, such as Philip Morris International's Platform 3 product), and / or a reduced-risk tobacco product (e.g., a smokeless tobacco product, such as chewing tobacco, or a non-combustible tobacco product). In some embodiments, the method does not administer a nicotine substitute or replacement to the subject. Subject characteristics and therapeutic effects suitable for the method include any described herein.

[0050] In some specific embodiments, the present disclosure provides a method of treatment for encouraging a smoker to switch from a combustible cigarette to an e-cigarette, the method comprising administering to the smoker a) a daily dose of about 150 mg to about 450 mg (e.g., about 300 mg to about 450 mg) of bupropion in an extended release formulation (e.g., as described herein) once daily, and b) a daily dose of about 25 mg to about 400 mg (e.g., about 25 mg to about 100 mg, or 50 mg to about 100 mg) of zonisamide (e.g., as described herein) in an immediate release formulation once daily. In some embodiments, the weight ratio of the daily dose of zonisamide to bupropion ranges from about 1:1 to about 1:10, e.g., about 1:3 to about 1:6. Zonisamide and bupropion are typically administered orally to the smoker. In some embodiments, zonisamide and bupropion are administered to the smoker simultaneously. In some embodiments, zonisamide is administered before or after bupropion. In some embodiments, bupropion is administered in the morning. In some embodiments, bupropion is administered in the evening. In some embodiments, zonisamide is administered in the morning. In some embodiments, zonisamide is administered in the evening. Smoker characteristics and therapeutic effects suitable for the present methods include any of those described herein.

[0051] In some specific embodiments, the disclosure provides a method for smokers to transition from combustible cigarettes to electronic cigarettes, nicotine patches, nicotine gum, nicotine lozenges, nicotine pouches, nasal spray nicotine, dissolvable nicotine products, sublingual nicotine tablets, nicotine inhalers (including nicotine salt inhalers, such as Philip Morris International's Platform 3 products), and reduced-risk tobacco products, e.g., smokeless tobacco, such as chewing tobacco, or heat-not-burn types (e.g., Philip Morris The present invention provides a method of treatment for promoting switching to one or more nicotine replacements or substitutes selected from International's IQOS non-combustible tobacco products, the method comprising administering to a smoker a) a daily dose of about 150 mg to about 450 mg (e.g., about 300 mg to about 450 mg) of bupropion in an extended release formulation (e.g., as described herein) once daily, and b) a daily dose of about 25 mg to about 400 mg (e.g., about 25 mg to about 100 mg, or about 50 mg to about 100 mg) of zonisamide in an immediate release formulation (e.g., as described herein) once daily. In some embodiments, the weight ratio of the daily dose of zonisamide to bupropion ranges from about 1:1 to about 1:10, e.g., about 1:3 to about 1:6. Zonisamide and bupropion are typically administered orally to the smoker. In some embodiments, zonisamide and bupropion are administered to the smoker simultaneously. In some embodiments, zonisamide is administered before or after bupropion. In some embodiments, bupropion is administered in the morning. In some embodiments, bupropion is administered in the evening. In some embodiments, zonisamide is administered in the morning. In some embodiments, zonisamide is administered in the evening. Smoker characteristics and therapeutic effects suitable for the present methods include any of those described herein.

[0052] Nicotine replacements or substitutes Nicotine substitutes or replacements suitable for the methods described herein (e.g., any of those described herein, e.g., those set forth in Summary of the Invention Sections [1] through

[0148] , as the case may be) are not particularly limited and broadly include any product capable of delivering nicotine to a target user through a non-combustion method. For example, the nicotine substitute or replacement may be an e-cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, and / or a nicotine inhaler (including a nicotine salt inhaler, such as Philip Morris International's Platform 3 product).

[0053] In some preferred embodiments, according to the methods described herein (e.g., any of those described herein, e.g., those set forth in the Summary of the Invention Sections [1] to

[0148] , as the case may be), the nicotine substitute or replacement is an electronic cigarette. Suitable electronic cigarettes are not particularly limited and include any known in the art, e.g., the Halo G6 electronic nicotine delivery system described herein, or any of the commercially available electronic cigarettes. Electronic cigarettes typically include an atomizer, a power source such as a battery, and a container for e-liquid, such as a cartridge or tank. E-liquid typically includes nicotine, propylene glycol, glycerin, and flavorings. See, e.g., U.S. Pat. Nos. 10,952,468, 10,463,069, etc.

[0054] In some embodiments, the nicotine replacement or substitution may also be a nicotine replacement therapy, including, for example, (1) nicotine transdermal patches, such as NicoDerm® CQ® (GlaxoSmithKline), Habitrol® (Novartis Consumer Health), and Nicotrol® (Pharmacia Consumer Healthcare); (2) nicotine gum, such as Nicorette® (GlaxoSmithKline); (3) nicotine nasal spray, such as Nicotrol NS® (Pharmacia Consumer Healthcare); and (4) nicotine inhalers, such as Nicotrol® Nicotine Inhalation System (Pharmacia Consumer Healthcare).

[0055] In some embodiments, the nicotine replacement or substitution may be a reduced-risk tobacco product. For example, in some embodiments, the reduced-risk tobacco product is a smokeless tobacco product, such as chewing tobacco, or a non-combustible tobacco product, such as Heat Not Burn (e.g., IQOS by Philip Morris International).

[0056] In some embodiments, the nicotine substitute or replacement may be a nicotine salt delivery system, such as Philip Morris International's Platform 3 product, which mechanically generates nicotine-containing aerosol without tobacco, combustion or heating. Such nicotine-based electronic free products, such as Platform 3, typically consist of two parts, i.e., a consumable containing a highly soluble encapsulated nicotine powder and a non-electronic device that activates it.

[0057] When nicotine substitute or replacement is used in the method described herein, the amount, frequency and type of such product are not particularly limited.For example, when nicotine substitute or replacement is electronic cigarette, the use of electronic cigarette is typically not limited.In some cases, two or more of such substitutes or replacements may be used.

[0058] kit In some embodiments, the disclosure also provides kits useful for the methods described herein. For example, in some embodiments, the disclosure provides kits including a) bupropion, b) zonisamide, and, optionally, c) a nicotine substitute or replacement. The bupropion included in the kit may be present in any of the bupropion dosage forms described herein, e.g., as a sustained or extended release bupropion formulation. Similarly, the zonisamide and the nicotine substitute or replacement may each be any of those described herein. In some embodiments, the kit may include a) one or more daily doses of bupropion, including an extended release formulation (e.g., as described herein), each comprising about 150 mg to about 450 mg of bupropion, and b) one or more daily doses of zonisamide, including a pharmaceutical composition, each comprising about 25 mg to about 400 mg of zonisamide, and, optionally, c) a nicotine substitute or replacement. In some embodiments, the kit may include: a) one or more daily doses of bupropion, including an extended release formulation (e.g., as described herein), each containing about 300 mg to about 450 mg of bupropion, suitable for once-daily administration; b) one or more daily doses of zonisamide, including a pharmaceutical composition each containing about 25 mg to about 400 mg of zonisamide, e.g., about 25 mg to about 100 gm, or about 50 mg to about 100 mg of zonisamide; and, optionally, c) a nicotine substitute or replacement. In some embodiments, the kit includes: a) one or more daily doses of bupropion, including extended release formulations suitable for once-daily administration, each containing about 300 mg to about 450 mg of bupropion; and b) one or more daily doses of zonisamide, including pharmaceutical compositions each containing about 25 mg to about 400 mg of zonisamide, e.g., about 25 mg to about 100 mg, or about 50 mg to about 100 mg of zonisamide, but does not include a nicotine substitute or replacement.In some embodiments, the kit may further include instructions on how to use the kit, e.g., instructions describing the kit as being for promoting smoking cessation, reducing a subject's craving for combustible tobacco products such as cigarettes, treating dependence, addictive properties, or withdrawal associated with combustible tobacco products such as cigarettes, reducing the rewarding effects of smoking (e.g., satisfaction, taste enjoyment, increased attention, reduced irritability), and / or increasing the aversion effects of smoking combustible tobacco products (e.g., nausea, dizziness), or encouraging a smoker to switch from combustible cigarettes to an e-cigarette or another nicotine substitute or replacement.

[0059] definition As used herein, the singular forms "a," "an," and "the" include plural references unless expressly stated or clearly clear from the context that this is not intended.

[0060] The term "and / or," when used herein in a phrase such as "A and / or B," is intended to include both A and B, A or B, A (alone), and B (alone). Similarly, the term "and / or," when used herein in a phrase such as "A, B, and / or C," is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0061] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject technology, and should not be referenced in connection with interpreting the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined with features described under other headings or subheadings in various embodiments. Moreover, all features under a single heading or a single subheading may not necessarily be used together in an embodiment.

[0062] As used herein, the term "about" modifies quantities related to the present invention, and refers to variations in quantity that may occur, for example, through routine testing and handling, through unintentional errors in such testing and handling, through differences in manufacture, source, or purity of the components used in the present invention, and the like. As used herein, "about" a particular value includes the particular value, for example, about 10% includes 10%. Whether or not modified by the term "about", the claims include the equivalent of the recited amount. In one embodiment, the term "about" means within 20% of the reported numerical value.

[0063] The terms "subject" or "smoker" are used interchangeably herein and should be understood to refer to a human. EXAMPLES

[0064] Example 1. Effect of zonisamide / bupropion on switching to e-cigarettes

[0065] This example presents an open-label study investigating the effect of a combination of zonisamide and bupropion on the switching process from combustible cigarettes (CC) to e-cigarettes using the following protocol.

[0066] Clinical Protocol Overall Study Design: This small, single-group, open-label study (N=24) evaluated the effect of the combination of zonisamide and bupropion on the switching process from combustible cigarettes (CC) to e-cigarettes. There was a data collection period of at least 5 days to obtain baseline data on combustible cigarette use. Participants enrolled in the study received and used G6 e-cigarettes at V2, without restriction. After the first week of e-cigarette use (at V3), participants were administered zonisamide (100 mg / day; Glenmark Pharmaceuticals, Inc., 750 Coporate Drive, Mahwah, NJ 07430, distributed by Cardinal Health, 7000 Cardinal Place, Dublin, OH 43017) and initiated extended-release bupropion (150 mg daily in the morning on days 1-3, then 300 mg / day; Lupin Pharmaceuticals, Inc., USA Headquarters: Harborplace Tower, 111 S. Calvert Street, 21st Floor, Baltimore, MD 21202, distributed by Cardinal Health, 7000 Cardinal Place, Dublin, OH 43017) in addition to continued use of G6. At each visit, participants received enough zonisamide, bupropion, and Halo G6 cartomizer to continue until the next study visit. Halo G6 and the combination of zonisamide and bupropion were continued until participants returned for the final study visit (V7). The overall study design is also shown in Figure 1.

[0067] At each session, exhaled CO was measured along with blood pressure, heart rate, respiratory rate, and weight. Participants also completed questionnaires assessing the subjective effects of smoking and e-cigarette use. Participants were given enough cartomizers and study medication to last until the next scheduled session, plus 4 extra days to allow for flexibility if a session needed to be rescheduled. Compliance with e-cigarette use and study medication was tracked by self-reported number of uses, as well as number of cartomizers (used or unused) and returned study medication.

[0068] Inclusion and Exclusion Criteria: Healthy adult smokers aged 21-65 years who smoked an average of at least 10 commercially available (combustible) cigarettes per day during the past 12 months were screened for enrollment in the study, with no restrictions on sex, race and ethnicity, or socioeconomic status.

[0069] [Table 1]

[0070] HALO-G6 Electronic Nicotine Delivery System: The Halo G6 is a breath-actuated, rechargeable e-cigarette equipped with a pre-filled e-liquid cartomizer. The e-cigarette's shape and size are similar to a cigarette, which is why it was chosen over other tank- or pod-style e-cigarette models. One of the goals is to provide a smoking habit replacement that zonisamide / bupropion cannot provide, and this "cigarette-like" design is considered advantageous. Each pre-filled G6 cartomizer contains a 50 / 50 blend of propylene glycol and vegetable glycerin with nicotine salts with a nicotine strength of 35mg / mL. A nicotine concentration of 3.5% was chosen over higher (e.g., 5%) concentrations to reduce the potential for nausea. The cartomizers are provided in a pack of 5. All Halo brand e-liquids are independently tested and manufactured by Nicopure labs. The study used "Tribeca" (tobacco) and "menthol" flavored cartomizers, and participants were given their preferred tobacco flavor. At Visit 2, participants were allowed unrestricted use of the device for up to 10 minutes. Study staff determined eligibility by asking participants if they were willing and able to use the Halo G6 during the study. The maximum period for which the G6 was used was 13 weeks, plus an additional 4 days (considering schedule timeframes). Participants were instructed on how to use the e-cigarette before distribution.

[0071] Zonisamide: Zonisamide is currently commercially available as an antiepileptic drug for the treatment of partial seizures. The dosing of zonisamide was unchanged during the 12-week dosing period unless modified according to the following guidance: Participants were expected to take 100 mg (two 50 mg capsules) orally once daily. Zonisamide was dispensed in the form of 50 mg capsules. The timing of dosing (morning or afternoon) or amount (one or two capsules) could be adjusted depending on the somnolence / activation experienced by each individual participant. Initially, both bupropion and zonisamide were taken in the morning. If the participant experienced significant drowsiness, the healthcare provider (MD / PA) could change the dosing to nighttime (2 hours before bedtime) or reduce the dose to one 50 mg capsule per day. All dosing adjustments would be approved by the Medical Director of the study.

[0072] Bupropion: Bupropion inhibits the reuptake of both noradrenaline and dopamine and also causes some blockade of nicotinic acetylcholine receptors. The drug has been approved as an antidepressant for over 20 years. The U.S. Food and Drug Administration approved the use of bupropion in smoking cessation in 1997. The usual dose of bupropion for smoking cessation is 150 mg once daily for 3 days, followed by 300 mg once daily for 7 to 12 weeks. The maximum prescribed dose of bupropion is 450 mg / day, which is the maximum dose for treating major depression and attention deficit hyperactivity disorder in adults. Dose for this study: 150 mg bupropion tablet orally once daily for 3 days, followed by two 150 mg tablets (300 mg) orally once daily for the remainder of study participation. Bupropion tablets were dispensed in the form of 150 mg extended release tablets, initially one tablet per day for three days, followed by two tablets per day until the end of the study. The extended release tablets have a pharmacokinetic profile that supports once-daily dosing. The drug, when combined with zonisamide, reduces the risk of side effects and allows for daily dosing, which is likely to improve compliance. Adjustments may be made depending on the side effects experienced by each individual participant. Initially, both bupropion and zonisamide were taken in the morning. If the participant experiences significant activation during the day, the healthcare provider (MD / PA) may adjust the dose up to 150 mg per day or split the dose (150 mg taken twice a day, which is the usual dose for smoking cessation). All dose adjustments will be approved by the Medical Director of the study.

[0073] evaluation A summary of all evaluations will be provided in the study schedule: [Table 2]

[0074] Exhaled CO Breath Test: Carbon monoxide (CO) in participants' exhaled breath (expressed in ppm) was measured using a Vitalograph CO monitor. Participants were required to have an exhaled CO reading of at least 10 ppm at V1 to be included in the study. This test was repeated in each session.

[0075] AE / SAE reporting: AEs / SAEs were assessed using questionnaires and interviews at designated time points and spontaneous reporting from the time of ICF signing until the participant's EOS.

[0076] The questionnaire was administered to participants using a paper questionnaire and / or an electronic data collection system.

[0077] Modified Smoking Effects Questionnaire-Extended (mCEQ-E) and Modified E-Cigarette Smoking Effects Questionnaire-Extended (mECEQ-E): Initially, the Smoking Effects Questionnaire was developed in the PI's laboratory and has been used in many studies to evaluate the effect of pharmacological treatments on the rewarding effects of cigarette smoking. The mCEQ-E was used to assess the extent to which participants experienced smoking-reinforced experiences and provided five subscale scores, calculated as the mean score per item: smoking satisfaction (satisfying, tasty, enjoyable to smoke), psychological reward (calming, more alert, less irritable, helps concentrate, reduces hunger), avoidance (dizziness, nausea), enjoyment of respiratory sensations (single item rating), and reduced craving (single item rating). Participants were asked to rate 12 items on the questionnaire on a 7-point scale ranging from "not at all" to "extremely so." These 12 items asked about "smoking the first cigarette," "smoking a cigarette shortly after a meal," and "all other cigarettes." An electronic cigarette version of this questionnaire (mECEQ-E) was also used. See Figures 4A and 4B.

[0078] Schiffman-Jarvik Withdrawal Scale: The Schiffman-Jarvik Withdrawal Scale was used to measure withdrawal symptoms and participants' smoking desire. This scale is composed of five subscales, and the average score per item is calculated for craving, psychological symptoms, physical symptoms, sedation, and appetite (Lee YY, Khoo S, Morris T, et al. A mixed-method study of the efficacy of physical activity consultation as an adjunct to standard smoking cessation treatment among male smokers in Malaysia. SpringerPlus. 2016;5(1):2012. doi:10.1186 / s40064-016-3675-2). The Schiffman-Jarvik Withdrawal Scale questionnaire is shown in Figure 3.

[0079] Fagerström Test for Nicotine Dependence: The Fagerström Test for Nicotine Dependence is a six-item questionnaire developed by Karl Olo Fagerström that is used to determine the degree of a person's nicotine dependence. Depending on the total score obtained in the test, nicotine dependence can be classified into three different levels: mild (0-3 points), moderate (4-6 points), and severe (7-10 points).

[0080] Participants who completed the study were contacted 6 months after the switch date using an automated SMS messaging system to confirm their current smoking status and e-cigarette use. If participants self-reported current abstinence, they were asked to return to the facility for a CO2 exhalation collection for confirmation.

[0081] All data measurements (e.g., withdrawal symptom questionnaires, smoking history, smoking diaries, etc.) were initially recorded using paper or electronic data capture systems. Validated data files were analyzed using Statview or SAS (Statview, SAS Institute, Cary NC). Data were inspected for outliers, and sufficiently extreme cases (Chauvenet criterion after verifying normality of distribution) were censored from data analysis.

[0082] Outcome Switching outcomes: Complete switching from combustible cigarette use at each time point was defined by self-report of no cigarette smoking since the previous session and confirmed by exhaled CO readings <5 ppm. The primary switching outcome was abstinence from smoking for weeks 8-11 after the switch date. In an intention-to-treat approach, participants who were lost to follow-up after the randomization time point or who smoked between weeks 8-11 were counted as not having switched completely to e-cigarette use.

[0083] The secondary outcome was 7-day abstinence 6 months after switching, assessed by self-report using an automated SMS messaging system.The primary goal of the 6-month follow-up was to assess persistence of switching to e-cigarettes.

[0084] Change in rewarding effects: Compared the change in reported rewarding effects of smoking when smoking in the morning, after meals, and at other times of the day. Time period: Week 1 compared to after starting study medication. Characterize changes in two main scales of the smoking effects questionnaire (mCEQ), assessing smoking satisfaction and psychological reward from cigarettes smoked after meals compared to cigarettes smoked at other times of the day, and explore how this difference changes after use of zonisamide / bupropion. The mCEQ uses a 7-point scale (0=not at all; 1=hardly; 2=a little; 3=somewhat; 4=very much; 5=very much; 6=extremely) to measure the following subscales: satisfaction, psychological reward, enjoyment of airway sensations, craving reduction, and avoidance.

[0085] result Exhaled CO levels: Successful smoking cessation was observed from this clinical trial. For example, see Figure 2, which is a graph of the mean (± standard error) exhaled carbon monoxide (CO) in ppm, a quantitative marker of tobacco smoke inhalation, for study participants during the 11-week period from the target "switch" date (which would typically correspond to the "quit date") for the study participants. In fact, study participants were asked to quit all combustible cigarettes when switching to non-combustible e-cigarette alternatives.

[0086] There was an approximately 50% drop in mean CO levels, indicating a significant reduction in smoking. Taking a conservative approach of attributing failure to participants who dropped out or were lost contact, 50% (12 / 24) and 37.5% (9 / 24) achieved CO values ​​below 5 ppm at weeks 8 and 11, respectively, indicating no or minimal smoking.

[0087] Abstinence: When more stringent criteria were imposed, requiring not only exhaled CO <5 ppm but also self-report of complete smoking abstinence (zero cigarettes smoked in the past 4 weeks), the abstinence rates were 45.8% at V6 (8 weeks after target switch date) and 33.3% at V7 (week 11). This is as high as the typical rate achieved with bupropion alone (~25%), but of note is the absence of bupropion-related side effects (see discussion below). This suggests that switching to e-cigarettes helped successful participants maintain abstinence. There is also evidence that the pharmacological treatment in this study added to the benefits of e-cigarettes from our previous study (NCT04188197) in the same geographic region and with the same sample of smokers. In this previous study, which offered e-cigarettes without pharmacological treatment, the rate of complete abstinence was only 20% (10 / 50).

[0088] Side effects of and adherence to treatment: The treatment was well tolerated, with no dropouts due to drug-related side effects, which were generally mild (i.e., easily tolerated and did not interfere with daily activities) and consistent with the expected effects of zonisamide, bupropion, and ENDS use. The most commonly reported side effects, each occurring in 17% (4 / 24), were pharyngeal irritation, constipation, nausea, and changes in alertness. One report of nausea was moderate in intensity (i.e., interfered with daily activities) and was managed with a temporary reduction in the bupropion dose. Another moderate rating of fatigue occurred, which was attributed to unintentionally taking twice the dose planned for that day. Only one case of (mild) insomnia occurred among the 25 study participants, whereas approximately 20%, or 5 cases, would have been expected according to the bupropion / Wellbutrin prescribing information. Adherence to medication use was very good; overall, participants reported taking study medication on 95.2% of days (SD = 16.96%). High adherence was confirmed by the number of pills returned in unopened blister packs, with 95.6% (SD = 7.1%) of pills being taken.

[0089] ENDS use (in this example, e-cigarette use): During the last 4 weeks of the treatment period, 83.3% (20 / 24) of participants reported using ENDS on 84.1% of days (SD=28.05). At 6 months, 32% (7 / 22) of all participants contacted and 62.5% (5 / 8) of those abstinent at the end of treatment reported using ENDS.

[0090] Smoking Withdrawal Symptoms: Withdrawal symptoms were minimal and, with the exception of cigarette cravings, showed a significant reduction across sessions, see FIG. 5.

[0091] Reward / avoidance effects: The ratings of the first combustible cigarette ("CC") or ENDS (in this example, e-cigarette) of the day showed very similar rating patterns for post-meal and other time points. Therefore, only the ratings of the first use of the day are shown in FIG. 6. The satisfaction, psychological reward, and airway sensation enjoyment of CC showed a significant decrease over time, while the ratings of ENDS on all positive reward scales increased. In fact, the reward ratings of ENDS exceeded the reward ratings of CC by the end of treatment. Moreover, in contrast to the ratings of ENDS, the avoidance ratings of CC increased over time.

[0092] conclusion The above results indicate that the combination of bupropion, zonisamide, and e-cigarettes was effective in helping subjects quit smoking and switch from combustible cigarettes to e-cigarettes.

[0093] It should be appreciated that it is intended that the Detailed Description section, rather than the Summary and Abstract sections, be used to interpret the claims. The Summary and Abstract sections may set forth one or more, but not all, exemplary embodiments of the invention as contemplated by the inventor(s) and are not intended to limit the scope of the invention and the appended claims in any manner.

[0094] The present invention has been described above using functional components that indicate the implementation of specific functions and their relationships. The boundaries of these functional components have been arbitrarily defined herein for the convenience of description. Alternative boundaries may be defined as long as the specific functions and their relationships are appropriately implemented.

[0095] For aspects of the invention described as genus, all individual species are separate aspects of the invention considered individually. When aspects of the invention are described as "comprising" an element, embodiments "consisting of" or "consisting essentially of" that element are also contemplated.

[0096] All ranges recited herein encompass any and all possible subranges and combinations of such subranges, as well as the individual values, particularly integer values, making up the ranges. The recited ranges include each specific value, integer, decimal, or unit within the range.

[0097] The above description of specific embodiments fully illustrates the general nature of the present invention, so that others, applying knowledge within the skill of the art, can easily modify and / or adapt such specific embodiments to various applications without undue experimentation and without departing from the general concept of the present invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teachings and guidance presented herein. The words or terms used herein are for the purpose of description and not for the purpose of limitation, and the words or terms used herein should be understood by those skilled in the art in light of the teachings and guidance presented herein.

[0098] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0099] Any of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0100] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition of the term in this document shall control.

Claims

1. A pharmaceutical composition comprising bupropion or hydroxybupropion for use in a method of treatment for (i) promoting smoking cessation in a subject, (ii) reducing craving for combustible tobacco in a subject, or (iii) treating dependence, addiction, or withdrawal associated with combustible tobacco in a subject, said method comprising administering to said subject a) said bupropion or hydroxybupropion, b) an anticonvulsant or GABAergic agent, and optionally c) a nicotine substitute or replacement. Pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein the method comprises administering to the subject a daily dose of bupropion in the range of about 150 mg to about 450 mg, e.g., about 300 mg to about 450 mg, optionally wherein the bupropion is administered in the form of a controlled release formulation, such as a sustained or extended release formulation formulated for once-daily or twice-daily administration, or wherein the bupropion is administered in the form of an immediate release formulation.

3. The pharmaceutical composition of claim 2, characterized by one or more of: (i) the bupropion is administered orally; (ii) the bupropion is administered to the subject once daily or twice daily; (iii) the bupropion is administered in the form of a pharma- ceutically acceptable salt; (iv) the method comprises administering the bupropion to the subject in the morning; or (v) the method comprises administering the bupropion to the subject in the evening.

4. 2. The pharmaceutical composition of claim 1, wherein the anticonvulsant or GABAergic agent is zonisamide.

5. The pharmaceutical composition of claim 4, wherein the method is characterized by one or more of the following: (i) administering to the subject zonisamide at a daily dose in the range of about 25 mg to about 400 mg, e.g., about 25 mg to about 100 mg, about 50 mg to about 100 mg, etc.; (ii) administering zonisamide simultaneously with bupropion, e.g., administering a dosage form containing both zonisamide and bupropion as active ingredients, or simultaneously administering separate dosage forms each containing zonisamide and bupropion; or (iii) administering zonisamide and bupropion sequentially in any order.

6. The pharmaceutical composition of claim 4, wherein the method comprises (i) administering the zonisamide in an amount effective to reduce one or more adverse effects associated with bupropion or hydroxybupropion, (ii) administering the zonisamide in an amount effective to reduce the incidence of insomnia and / or agitation without increasing the incidence of somnolence or fatigue, (iii) administering the zonisamide in an amount effective to reduce the incidence of seizures, and / or (iv) administering the zonisamide in an amount effective to enhance the smoking cessation effects of bupropion.

7. The pharmaceutical composition of claim 1, wherein the method does not involve administering a nicotine substitute or replacement to the subject.

8. The pharmaceutical composition of claim 1, wherein the method comprises administering to the subject a nicotine substitute or replacement, optionally wherein the nicotine substitute or replacement is an e-cigarette, a nicotine patch, a nicotine gum, a nicotine lozenge, a nicotine pouch, a nasal spray nicotine, a dissolvable nicotine product, a sublingual nicotine tablet, and / or a nicotine inhaler (including a nicotine salt inhaler, such as Philip Morris International's Platform 3 products), and optionally wherein the nicotine substitute or replacement is a reduced risk tobacco product, preferably wherein the reduced risk tobacco product is a smokeless tobacco product, such as chewing tobacco, or a non-combustible tobacco product, such as a heat not burn type (e.g., IQOS by Philip Morris International).

9. The pharmaceutical composition of claim 1, wherein the method is characterized in that (i) the subject is not in need of treatment for obesity, (ii) the subject is a smoker who uses both e-cigarettes and combustible cigarettes prior to the treatment, (iii) the subject smokes at least 10 commercial cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to the treatment, and / or (iv) the subject has a breath CO reading of at least 10 ppm prior to the treatment.

10. The method comprises the steps of: (i) reducing the subject's daily combustible cigarette consumption; (ii) reducing the subject's exhaled CO levels by 20% or more (e.g., about 50%) compared to baseline, and / or reducing urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) by 20% or more (e.g., about 50%) compared to baseline; and (iii) reducing the subject's craving for combustible cigarettes, e.g., reducing the subject's average per-item craving score to 4 or less on the 7-point Schiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale) and / or reducing the subject's average per-item craving score to 7 points or less on the Schiffman-Jarvik Withdrawal Scale (or less than 50 on a 100-point visual analog scale).

2. The pharmaceutical composition of claim 1, wherein the subject does not increase by more than 1 point on the Shiffman-Jarvik Withdrawal Scale (or more than 10 points on a 100-point visual analog scale), and / or (iv) the subject achieves abstinence from smoking combustible tobacco.

11. 1. A pharmaceutical composition comprising bupropion or hydroxybupropion for use in a method of treatment for encouraging a smoker to switch from combustible cigarettes to an e-cigarette or other nicotine substitute or replacement, the method comprising administering to the smoker a) said bupropion or hydroxybupropion, and b) an anticonvulsant or a GABAergic agent, preferably the method is for encouraging the smoker to switch from combustible cigarettes to an e-cigarette or for encouraging the smoker to switch from combustible cigarettes to an e-cigarette, nicotine patches, nicotine gum, nicotine lozenges, nicotine pouches, nasal spray nicotine, dissolvable nicotine products, sublingual nicotine tablets, nicotine inhalers (including nicotine salt inhalers such as Philip Morris International's Platform 3 products), and reduced risk tobacco products, e.g. smokeless tobacco such as chewing tobacco, or heat not burn types (e.g. Philip Morris International's 2. To promote switching from non-combustible tobacco products (such as IQOS from EPA and EPA-European Tobacco Products) to a nicotine replacement or substitute selected from non-combustible tobacco products, Pharmaceutical compositions.

12. The method comprises the steps of: (1) the method comprises administering to the smoker a daily dose of bupropion in the range of about 150 mg to about 450 mg, e.g., about 300 mg to about 450 mg; (2) the bupropion is administered in a controlled release form, such as a sustained or extended release form, formulated for once-daily or twice-daily administration; (3) the bupropion is administered in the form of an immediate release formulation; (4) The bupropion is administered orally; (5) The bupropion is administered to the smoker once a day or twice a day; (6) The bupropion is administered in the form of a pharma- ceutically acceptable salt; (7) The method comprises administering the bupropion to the smoker in the morning; and (8) The method includes administering the bupropion to the smoker in the evening. The pharmaceutical composition according to claim 11, characterized by one or more of the following:

13. The anticonvulsant or GABAergic agent is zonisamide, and optionally, the method comprises the steps of: (1) the method comprises administering zonisamide in a daily dose range of about 25 mg to about 400 mg, e.g., about 25 mg to about 100 mg, about 50 mg to about 100 mg, etc.; (2) The method includes administering zonisamide simultaneously with bupropion, e.g., administering a dosage form containing both zonisamide and bupropion as active ingredients, or administering separate dosage forms each containing zonisamide and bupropion simultaneously; (3) The method comprises administering zonisamide and bupropion sequentially in any order; (4) administering the zonisamide in an amount effective to reduce one or more adverse effects associated with bupropion or hydroxybupropion; (5) administering the zonisamide in an amount effective to reduce the incidence of insomnia and / or agitation without increasing the incidence of somnolence or fatigue; (6) administering the zonisamide in an amount effective to reduce the incidence of seizures; and (7) The zonisamide is administered in an amount effective to enhance the smoking cessation effect of bupropion. The pharmaceutical composition according to claim 11, characterized by one or more of the following:

14. The method is for use in treating a subject in which: (1) the smoker does not require treatment for obesity; (2) the smoker uses both e-cigarettes and combustible cigarettes prior to the treatment; (3) the smoker smokes at least 10 commercial cigarettes (combustible cigarettes) or equivalent per day for at least 12 months prior to the treatment; (4) the smoker has a breath CO reading of at least 10 ppm prior to the treatment; (5) the method reduces the smoker's daily combustible cigarette consumption; (6) the method reduces the smoker's breath CO level by 20% or more (e.g., about 50%) compared to baseline and / or reduces urinary NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) by 20% or more (e.g., about 50%) compared to baseline; and (7) the method reduces the smoker's craving for combustible cigarettes, e.g., by increasing the subject's average craving score per item by 7 points.

12. The pharmaceutical composition of claim 11, characterized by one or more of the following: (1) reducing the subject's average craving score per item to 7 points on the Shiffman-Jarvik Withdrawal Scale to 4 or less (or less than 50 on a 100-point visual analog scale); and / or (2) not increasing the subject's average craving score per item by 7 points on the Shiffman-Jarvik Withdrawal Scale by more than 1 point (or more than 10 points on a 100-point visual analog scale); and (3) the smoker achieves abstinence from smoking combustible tobacco.

15. A kit comprising: a) one or more daily doses of bupropion, each comprising an extended release formulation comprising from about 150 mg to about 450 mg of bupropion; b) one or more daily doses of zonisamide, each comprising a pharmaceutical composition comprising from about 25 mg to about 400 mg of zonisamide; and, optionally, c) a nicotine substitute or replacement, wherein optionally said extended release formulations are formulated for once-daily administration. kit.

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