Compositions of enantiomerically concentrated or pure bupropion

Abstract

The present disclosure relates to dosage forms including enantiomerically enriched or pure dosage forms, such as enantiomerically excess (S)-bupropion, enantiomerically enriched (S)-bupropion, or enantiomerically pure (S)-bupropion, and methods of using these dosage forms, which can be administered to humans in smaller amounts compared to the amount of racemic bupropion that would be administered under the same circumstances.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests of U.S. Provisional Application No. 62 / 971,174 filed on 6 February 2020, No. 62 / 978,626 filed on 19 February 2020, and No. 62,992,060 filed on 19 March 2020, and is also a continuation in part of No. 16 / 830,637 filed on 26 March 2020, and is also a continuation in part of International Patent Application PCT / US2019 / 052210 filed on 20 September 2019, and is also a continuation in part of No. 16 / 907,691 filed on 22 June 2020, all of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Bupropion is approved for human use as a racemic mixture. Many believed that bupropion and its metabolites rapidly racemized in the human body. [Overview of the project] [Means for solving the problem]

[0003] Described herein are dosage forms containing enantiomeric (S)-bupropion, enantiomerically concentrated (S)-bupropion, or enantiomerically pure (S)-bupropion, and methods of using these dosage forms. These dosage forms can be administered to humans in smaller amounts compared to the amount of racemipupion administered under the same circumstances.

[0004] Some embodiments include a method for supplying bupropion to human plasma, comprising: selecting a human patient who requires a pharmacokinetic profile obtained by orally administering a reference dosage form containing a first amount of racemibpropion at a first frequency of administration; and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at the first frequency of administration to obtain the same pharmacokinetic profile obtained by administering the reference dosage form at the first frequency of administration, wherein the first frequency of administration is once or twice daily, and the second amount is about 20-70%, about 40-60%, about 45-55%, or about 50% of the first amount. For example, if a specific pharmacokinetic profile can be obtained by orally administering a dosage form containing 150 mg of racemibpropion, and the second amount is 40-60% of the first amount, then the second amount is 60-90 mg. Therefore, in this situation, administer 60-90 mg of (S)-bupropion once daily to obtain the same pharmacokinetic profile as that obtained by administering 150 mg of racemibpropion once daily, or administer 60-90 mg of (S)-bupropion twice daily to obtain the same pharmacokinetic profile as that obtained by administering 150 mg of racemibpropion twice daily.

[0005] For the purposes of this disclosure, if a dosage form containing enantiomerically pure (S)-bupropion is recognized by the FDA as bioequivalent to a dosage form containing racemipupion, then the two dosage forms have the same pharmacokinetic profile.

[0006] Some embodiments include a method for treating a racemibpropion-treated condition, comprising: selecting a human patient whose condition is treatable by orally administering a reference dosage form containing a first amount of racemibpropion at a first frequency of administration; and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure, at the first frequency of administration, to obtain the same therapeutic effect as that obtained by administering the reference dosage form at the first frequency of administration, wherein the first frequency of administration is once or twice daily, and the second amount is about 20-70%, about 40-60%, about 45-55%, or about 50% of the first amount. For example, if the condition is treatable by orally administering a dosage form containing 150 mg of racemibpropion, and the second amount is 40-60% of the first amount, then the second amount is 60-90 mg. Therefore, in this situation, 60-90 mg of (S)-bupropion is administered once daily to treat the condition, to achieve the same therapeutic effect as that obtained by administering 150 mg of racemibpropion once daily, and 60-90 mg of (S)-bupropion is administered twice daily to treat the condition, to achieve the same therapeutic effect as that obtained by administering 150 mg of racemibpropion twice daily.

[0007] Some embodiments include a method of treating a human being, comprising orally administering to a human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion.

[0008] Some embodiments include a dosage form for treating a human condition comprising at least 95% enantiomerically pure (S)-bupropion, the dosage form being administered orally to the human once or twice daily.

[0009] Some embodiments involve the use of (S)-bupropion that is at least 95% enantiomerically pure in the manufacture of a drug for treating a human condition, the drug being administered orally to humans once or twice daily.

[0010] Some embodiments include a kit comprising a dosage form and a label, wherein the dosage form comprises at least 95% enantiomerically pure (S)-bupropion, and the label indicates that the dosage form is administered orally to a human once or twice daily to treat a human condition. [Brief explanation of the drawing]

[0011] [Figure 1] AUC0-12 values ​​of bupropion and hydroxybupropion in healthy volunteers after administration of S-bupropion and racemibpropion tablets. [Figure 2] Mean plasma levels of bupropion and hydroxybupropion after administration of (S)-bupropion or (R)-bupropion tablets. [Figure 3] Cmax of R,R-hydroxybupropion after administration of (S)-bupropion or (R)-bupropion tablets. [Modes for carrying out the invention]

[0012] (S)-bupropion administered to humans may be enantiomerically pure or enantiomerically concentrated. For example, (S)-bupropion may be at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure, and up to (or nearly) 100% enantiomerically pure. 99.99% enantiomerically pure (S)-bupropion contains 99.99% (S)-bupropion and 0.001% (R)-bupropion. For convenience, all of the above may be referred to as "(S)-bupropion". This type of dosage form may be useful in treating a condition if an increase in levels of (S)-bupropion and / or (R,R)-hydroxybupropion is therapeutically beneficial, or if it is for treating a person who requires treatment with (S)-bupropion and / or (R,R)-hydroxybupropion.

[0013] Oral administration of (S)-bupropion has been found to be bioequivalent or pharmacokinetically equivalent to approximately twice the dose of racemibpropion. For example, a 75 mg dose of (S)-bupropion is bioequivalent to approximately a 150 mg dose of racemibpropion.

[0014] (S)-bupropion may be administered alone or in combination with other drugs. However, in some treatments, the use of other drugs may be undesirable with (S)-bupropion or (R,R)-hydroxybupropion. For example, (S)-bupropion or (R,R)-hydroxybupropion may be the only compound necessary to treat the condition, and additional drugs may not provide a significant benefit, or adding additional drugs may increase the risk of adverse events to an unacceptable degree, outweighing any potential benefits they may offer. Therefore, some dosage forms contain substantially no other drugs, and some treatments involve the administration of (S)-bupropion without the co-administration of other drugs. For example, a dosage form may contain less than 10% by weight, less than 5% by weight, less than 2.5% by weight, less than 1% by weight, or less than 0.1% by weight of any other active pharmaceutical agent, or may not contain any other drugs.

[0015] The above dosage forms and methods can be incorporated into methods for treating mammals such as humans to provide therapeutically effective plasma levels of (S)-bupropion or its metabolites, such as (R,R)-hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion, or to provide desirable or enhanced plasma levels or pharmacokinetic properties of (S)-bupropion or its metabolites.

[0016] For example, the dosage form and method may be used to treat neurological disorders, central nervous system disorders, psychiatric disorders, neuropsychiatric disorders, or related conditions.

[0017] The phrase “to treat” or “treatment” includes any activity that diagnoses, cures, alleviates, treats or prevents disease in humans or other animals, or any activity that affects the structure or function of the body of a human or other animal.

[0018] (S)-bupropion may be administered orally or more once or twice a day, or once or twice a day for several consecutive days. For example, (S)-bupropion may be administered once or twice a day for 1, 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59, 60, 61-89, 90, or more consecutive days. Patients may be kept fasting before and / or after oral administration of a dosage form containing (S)-bupropion.

[0019] To reduce the risk of seizures or other adverse events, it may be useful to start with a lower initial daily dose of (S)-bupropion and then increase the dose to a higher target daily dose. "Daily dose" refers to the total amount of bupropion given in a day (for example, a dose of 75 mg given in the morning and another 75 mg given in the evening is a daily dose of 150 mg). For example, a lower initial daily dose is a lower total amount of bupropion given in a day, and a higher target daily dose is a higher total amount of bupropion given in a day. One way to achieve this is to administer a lower dose of (S)-bupropion in a formulation alone or in combination with other drugs once or twice daily for 1, 2, 3, 4, 5, 6, 7, or more days, followed by treatment with a higher dose of (S)-bupropion in a formulation at the same frequency of administration as the lower dose. For example, a dosage form containing a lower dose of (S)-bupropion may be administered once daily on days 1, 2, and 3, followed by a higher dose of (S)-bupropion once daily from day 4, and then once daily for a longer period, such as 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59, 60, 61-89, 90, or more consecutive days, or for the remainder of the treatment period. Alternatively, a lower dose of (S)-bupropion may be administered twice daily on days 1, 2, and 3, followed by a higher dose of (S)-bupropion twice daily starting on day 4, and this twice-daily administration may be continued for a longer period, such as 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59, 60, 61-89, 90, or more consecutive days, or for the remainder of the treatment period.

[0020] Another way to achieve this, for example, increasing from a lower starting daily dose to a higher target dose, is to administer a dosage form containing (S)-bupropion, alone or in combination with other drugs, once daily for 1, 2, 3, 4, 5, 6, 7, or more days, followed by treatment twice daily. For example, a dosage form containing (S)-bupropion may be administered once daily on days 1, 2, and 3, then twice daily from day 4, and then twice daily for a longer period, such as 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59, 60, 61-89, 90, or more consecutive days, or for the remainder of the treatment period. (S)-bupropion has the structure shown below. [ka]

[0021] Unless otherwise specified, any structural, name, or other reference to a compound herein, such as (S)-bupropion, includes alternative solids such as pharmaceutically acceptable salts, polymorphs, crystals, solvates, hydrates, tautomers, isotope-enriched compounds (e.g., deuterium-enriched bupropion), or any chemical species of a compound described herein that may rapidly change under the conditions in which the compound is used as described herein.

[0022] Any appropriate amount of (S)-bupropion can be used as a dosage form containing at least 95%, at least 97%, at least 99%, or at least 99.9% enantiomerically pure (S)-bupropion. In some embodiments, the dosage forms are at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, about 1-50 mg, about 50-150 mg, about 50-100 mg, about 100-150 mg, about 150 -200mg, about 100-200mg, about 1-10mg, about 10-20mg, about 20-30mg, about 30-40mg, about 40-50mg, about 50-60mg, about 60-70mg, about 7 0-80mg, about 80-90mg, about 90-100mg, about 100-110mg, about 100-120mg, about 120-150mg, about 1-30mg, about 20-50mg, about 50-80m g, about 80-120mg, about 100-150mg, about 150-180mg, about 180-200mg, about 70-95mg, about 50-70mg, about 60-80mg, about 60-90mg, about 70-80mg, about 70-74mg, about 72-76mg, about 74-76mg, about 74-78mg, about 70-90mg, about 30-60mg, about 40-75mg, about 50-90mg, about 60 Contains (S)-bupropion in amounts of -105 mg, approximately 60-120 mg, approximately 70-120 mg, approximately 80-135 mg, approximately 80-150 mg, approximately 100-180 mg, approximately 120-210 mg, approximately 140-240 mg, approximately 160-270 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 100 mg, or any amount within the ranges indicated by any of these values. A range of amounts of (S)-bupropion obtained by combining any of the above ranges or endpoints is also intended, and the obtained range is particularly intended to include, or be close to, one or more of the following values ​​as the amount of (S)-bupropion in the dosage form: approximately 60 mg, approximately 75 mg, or approximately 90 mg. These are values ​​that are considered to have potentially specific utility.Dosage forms containing the amounts of (S)-bupropion listed above may be administered once, twice, or three times daily as a daily dose (i.e., one, two, or three times any amount or range of any dose listed above, e.g., a daily dose of 100-200 mg twice at 50-100 mg doses, or a daily dose of 150-300 mg three times at 50-100 mg doses). Any daily dose obtained by combining any of the above dose ranges or endpoints and multiplying the result by 1, 2, or 3 is also intended, especially if the resulting range includes or is close to one or more of the following values: approximately 120 mg, approximately 150 mg, or approximately 180 mg. These are values ​​considered to be potentially somewhat more beneficial for an average-sized adult. Lower doses, such as approximately 1-50 mg or approximately 1-70 mg administered once or twice daily, may be somewhat more useful for treating children. Higher doses, such as amounts exceeding approximately 100 mg administered two or three times a day, may be somewhat more useful in treating larger adults.

[0023] The daily dose of (S)-bupropion is the amount of racemibpropion administered to produce certain pharmacokinetic parameters (bupropion, (S)-bupropion, hydroxybupropion, (R,R)-hydroxybupropion, (S,S)-hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or another metabolite of racemibpropion, or a combination thereof). max , AUC (for example, AUC 0-12 AUC 0-24 , or AUC 0-inf(S)-bupropion may be intended to target (S)-bupropion (Rasembupropion) and / or other pharmacokinetic parameters. For example, a daily dose of (S)-bupropion can be administered to target the pharmacokinetic parameters resulting from a daily dose of racembupropion of approximately 100-500 mg, 150-200 mg, 200-250 mg, 250-300 mg, 300-350 mg, 350-400 mg, 400-450 mg, or 450-500 mg. To achieve these pharmacokinetic parameters, for example, the daily dose of (S)-bupropion administered may be approximately 20-70%, 40-60%, 45-55%, or 50% of the daily dose of racembupropion.

[0024] Surprisingly, (S)-bupropion is the primary source of bupropion and its metabolites in the bloodstream, so the amount of (S)-bupropion administered to a human can be considerably less than the amount of racemic bupropion (or (R)-bupropion) administered to treat the same condition with the same effect. For example, if 150 mg of racemic bupropion is administered to treat a condition, a smaller amount of (S)-bupropion, such as 5-50% or 20-70% of that amount, i.e., 30-105 mg, can be administered to achieve a similar effect. In some embodiments, the amount of (S)-bupropion administered is selected to be about 5-70%, about 5-50%, about 20-70%, about 5-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 20-50%, about 40-70%, about 40-60%, about 40-45%, or about 45-55% of the amount of racemipupion that would be administered to treat the same person with the same condition.

[0025] Some solid compositions may contain at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, about 10-30%, about 30-50%, about 50-80%, about 80-95%, about 10-50%, about 30-70%, or about 50-90% by weight of (S)-bupropion.

[0026] In some embodiments, the dosage form may not contain or may substantially not contain any active pharmaceutical ingredient or drug other than (S)-bupropion. For example, the dosage form may contain less than 10% by weight, less than 5% by weight, 1% by weight, or less than 0.1% by weight of other pharmaceutical active ingredients compared to the weight of (S)-bupropion.

[0027] Administration of (S)-bupropion results in a plasma level of (S)-bupropion that is at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, about 5 - 20-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 10 - 15-fold, about 10 - 25-fold, about 5 - 20-fold, about 20 - 30-fold, about 30 - 40-fold, about 40 - 50-fold, about 50 - 60-fold, about 60 - 70-fold, about 70 - 80-fold, about 80 - 90-fold, about 90 - 100-fold, about 100 - 110-fold, about 110 - 120-fold, about 120 - 130-fold, about 130 - 140-fold, about 140 - 150-fold, about 150 - 160-fold, about 160 - 170-fold, about 170 - 180-fold, or about 190 - 200-fold higher compared to the plasma level of (R)-bupropion obtained by administering a dosage form containing the same amount of (R)-bupropion to a human.

[0028] In some embodiments, this method provides an AUC of (S)-bupropion 0-12 compared to the AUC of (R)-bupropion obtained by administering a dosage form containing the same amount of (R)-bupropion to a human, for representative value AUC 0-12 , mean value AUC 0-12 , median value AUC 0-12 , or individual AUC 0-12 such as AUC 0-12to at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, at least approximately 8 times, at least approximately 10 times, approximately 10 times, at least approximately 15 times, at least approximately 20 times, at least approximately 25 times, at least approximately 50 times, at least approximately 100 times, at least approximately It is effective in increasing by 150 times, at least about 200 times, or more, about 10-15 times, about 10-25 times, about 5-20 times, about 20-30 times, about 30-40 times, about 40-50 times, about 50-60 times, about 60-70 times, about 70-80 times, about 80-90 times, about 90-100 times, about 100-110 times, about 110-120 times, about 120-130 times, about 130-140 times, about 140-150 times, about 150-160 times, about 160-170 times, about 170-180 times, about 180-190 times, or about 190-200 times.

[0029] In some embodiments, this method provides at least about 300 ng·hr / mL, at least about 400 ng·hr / mL, at least about 500 ng·hr / mL, at least about 600 ng·hr / mL, at least about 700 ng·hr / mL, at least about 750 ng·hr / mL, at least about 800 ng·hr / mL, at least about 850 ng·hr / mL, at least about 900 ng·hr / mL, at least about 950 ng·hr / mL, and at least about 1,000 ng·hr / mL. g·hr / mL, at least about 1,100 ng·hr / mL, maximum about 1,200 ng·hr / mL, maximum about 1,300 ng·hr / mL, maximum about 1,400 ng·hr / mL, maximum about 1,500 ng·hr / mL, maximum about 1,600 ng·hr / mL, maximum about 1,700 ng·hr / mL, maximum about 1,800 ng·hr / mL, about 300-400 ng·hr / mL, about 400-500 ng·hr / mL, about 500-600 ng·hr / mL, about 600-700 ng·hr r / mL, approximately 700-800ng hr / mL, approximately 800-900ng hr / mL, approximately 900-1,000ng hr / mL, approximately 1,000-1,100ng hr / mL, approximately 1,100-1,200ng hr / mL, approximately 1,20 0-1,300ng·hr / mL, approximately 1,300-1,400ng·hr / mL, approximately 1,400-1,500ng·hr / mL, approximately 1,500-1,600ng·hr / mL, approximately 1,600-1,700ng·hr / mL, approximately 1,70 The typical AUC of (S)-bupropion is 0-1,800 ng·hr / mL, approximately 300-600 ng·hr / mL, approximately 600-900 ng·hr / mL, approximately 900-1,200 ng·hr / mL, approximately 1,200-1,500 ng·hr / mL, approximately 1,500-1,800 ng·hr / mL, approximately 300-800 ng·hr / mL, approximately 800-1,300 ng·hr / mL, approximately 1,300-1,800 ng·hr / mL, or approximately 300-1,800 ng·hr / mL. 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC such as 0-12 Achieves the AUC obtained by combining either the above range or endpoints. 0-12The range was also considered, and the obtained range was AUC 0-12 The following values ​​are particularly intended: including or near one or more of 350 ng·hr / mL, 400 ng·hr / mL, 750 ng·hr / mL, or 900 ng·hr / mL. These are values ​​that are considered to have potentially specific utility.

[0030] In some embodiments, this method provides a representative value of C for (S)-bupropion compared to administering a dosage form containing the same amount of (R)-bupropion to humans. max , average value C max , median C max , or individual C max C such as max to at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, at least approximately 8 times, approximately 5-20 times, at least approximately 10 times, approximately 10 times, at least approximately 20 times, at least approximately 25 times, at least approximately 50 times, at least approximately 100 times, and at least It is effective in increasing it by approximately 150 times, at least approximately 200 times, or more, approximately 10-15 times, approximately 10-25 times, approximately 5-20 times, approximately 20-30 times, approximately 30-40 times, approximately 40-50 times, approximately 50-60 times, approximately 70-80 times, approximately 80-90 times, approximately 90-100 times, approximately 100-110 times, approximately 110-120 times, approximately 120-130 times, approximately 130-140 times, approximately 140-150 times, approximately 150-160 times, approximately 160-170 times, approximately 170-180 times, approximately 180-190 times, or approximately 190-200 times.

[0031] In some embodiments, this method provides a dose of at least about 30 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, and less Even without it, it's about 125 ng / mL, with a maximum of about 130 ng / mL, with a maximum of about 140 ng / mL, with a maximum of about 150 ng / mL, with a maximum of about 160 ng / mL, with a maximum of about 170 ng / mL, with a maximum of about 180 ng / mL, with a maximum of about 190 ng / mL, with a maximum of about 200 ng / mL, with a maximum of about 210 ng / mL, with a maximum of about 220 ng / mL, with a maximum of about 30-40 ng / mL, about 40-50 ng / mL, about 50-60 ng / mL, about 60-70 ng / mL, and about 70-80 ng / mL. L, about 80-90ng / mL, about 90-100ng / mL, about 100-110ng / mL, about 110-120ng / mL, about 120-130ng / mL, about 130-140ng / mL, about 140-150ng / mL , about 150-160ng / mL, about 160-170ng / mL, about 170-180ng / mL, about 180-190ng / mL, about 190-200ng / mL, about 200-210ng / mL, about 210-220ng / Typical values ​​of (S)-bupropion are mL, approximately 50-70 ng / mL, approximately 70-90 ng / mL, approximately 30-60 ng / mL, approximately 60-90 ng / mL, approximately 90-120 ng / mL, approximately 120-160 ng / mL, approximately 160-220 ng / mL, approximately 30-90 ng / mL, approximately 90-150 ng / mL, approximately 150-220 ng / mL, approximately 30-110 ng / mL, approximately 110-220 ng / mL, or approximately 30-220 ng / mL. max , average value C max , median C max , or individual C max C such as max Achieves the C obtained by combining either the above range or endpoints. max The range was also considered, and the resulting range was C maxOne or more of the following values ​​are included, or are particularly intended if close to, 45 ng / mL, 90 ng / mL, 125 ng / mL, 150 ng / mL, or 180 ng / mL. These are values ​​that are considered to have potentially specific utility.

[0032] In some embodiments, this method provides a dose of (S)-bupropion, with a representative value of C, compared to administering a dosage form containing the same amount of (R)-bupropion to a human. min , average value C min , median C min , or individual C min C such as min to at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, at least approximately 8 times, at least approximately 10 times, at least approximately 20 times, at least approximately 50 times, at least approximately 100 times, at least approximately 150 times, and at least It is effective in increasing by approximately 200 times or more, approximately 10-15 times, approximately 10-25 times, approximately 5-20 times, approximately 20-30 times, approximately 30-40 times, approximately 40-50 times, approximately 50-60 times, approximately 70-80 times, approximately 80-90 times, approximately 90-100 times, approximately 100-110 times, approximately 110-120 times, approximately 120-130 times, approximately 130-140 times, approximately 140-150 times, approximately 150-160 times, approximately 160-170 times, approximately 170-180 times, approximately 180-190 times, or approximately 190-200 times.

[0033] In some embodiments, this method is C of (S)-bupropion, where the C is at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, about 20-60 ng / mL, about 20-25 ng / mL, about 25-30 ng / mL, about 30-35 ng / mL, about 35-40 ng / mL, about 30-40 ng / mL, about 40-45 ng / mL, about 45-50 ng / mL, about 30-50 ng / mL, about 40-50 ng / mL, or about 50-60 ng / mL.min , typical value C min , average value C min , median C min , or individual C min C such as min Achieves the C obtained by combining either the above range or endpoints. min The range is also intended, and the range obtained is C min One or more of the following values ​​are included, or are particularly intended if close to, 20 ng / mL, 30 ng / mL, 40 ng / mL, or 50 ng / mL. These are values ​​that are considered to have potentially specific utility.

[0034] Administering (S)-bupropion increases plasma levels of (R,R)-hydroxybupropion by at least approximately 1.1 times, at least approximately 1.5 times, at least approximately 2 times, at least approximately 3 times, at least approximately 5 times, at least approximately 10 times, at least approximately 15 times, at least approximately 20 times, at least approximately 40 times, at least approximately 50 times, at least approximately 100 times, at least approximately 150 times, and at least approximately 20 times compared to administering a dosage form containing the same amount of (R)-bupropion to humans. It may be useful to increase it by 0 times, or more, approximately 5-10 times, approximately 5-25 times, approximately 5-20 times, approximately 20-30 times, approximately 30-40 times, approximately 40-50 times, approximately 50-60 times, approximately 70-80 times, approximately 80-90 times, approximately 90-100 times, approximately 100-110 times, approximately 110-120 times, approximately 120-130 times, approximately 130-140 times, approximately 140-150 times, approximately 150-160 times, approximately 160-170 times, approximately 170-180 times, approximately 180-190 times, or approximately 190-200 times.

[0035] Administering (S)-bupropion results in a representative AUC of (R,R)-hydroxybupropion compared to administering a dosage form containing the same amount of (R)-bupropion to humans. 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC such as 0-12to at least approximately 1.1 times, at least approximately 1.5 times, at least approximately 2 times, at least approximately 3 times, at least approximately 5 times, approximately 6 times, at least approximately 10 times, at least approximately 15 times, at least approximately 20 times, at least approximately 40 times, at least approximately 50 times, at least approximately 100 times, at least approximately 150 times, at least approximately 200 times, or more, approximately 5-10 times, approximately 5-25 times, approximately 5-20 times, approximately 20 It may be useful to increase it by -30 times, approximately 30-40 times, approximately 40-50 times, approximately 50-60 times, approximately 70-80 times, approximately 80-90 times, approximately 90-100 times, approximately 100-110 times, approximately 110-120 times, approximately 120-130 times, approximately 130-140 times, approximately 140-150 times, approximately 150-160 times, approximately 160-170 times, approximately 170-180 times, approximately 180-190 times, or approximately 190-200 times.

[0036] In some embodiments, this method provides at least about 1,000 ng·hr / mL, at least about 3,000 ng·hr / mL, at least about 4,000 ng·hr / mL, at least about 6,000 ng·hr / mL, at least about 7,000 ng·hr / mL, at least about 7,500 ng·hr / mL, at least about 8,000 ng·hr / mL, at least about 8,500 ng·hr / mL, and at least about 9,000 0 ng·hr / mL, at least about 9,500 ng·hr / mL, at least about 10,000 ng·hr / mL, at least about 12,000 ng·hr / mL, at least about 13,000 ng·hr / mL, about 4,000-6,000 ng·hr / mL, about 6,000-8,000 ng·hr / mL, about 8,000-10,000 ng·hr / mL, about 10,000-12,000 ng·hr / mL, about 12,000- 14,000ng·hr / mL, approximately 14,000-16,000ng·hr / mL, approximately 16,000-18,000ng·hr / mL, approximately 18,000-20,000ng·hr / mL, approximately 20,000-22 ,000ng·hr / mL, approximately 22,000-24,000ng·hr / mL, approximately 4,000-10,000ng·hr / mL, approximately 10,000-16,000ng·hr / mL, approximately 16,000-24,00 Typical AUC values ​​for (R,R)-hydroxybupropion are 0 ng·hr / mL, approximately 4,000–24,000 ng·hr / mL, maximum approximately 14,000 ng·hr / mL, maximum approximately 16,000 ng·hr / mL, maximum approximately 18,000 ng·hr / mL, maximum approximately 20,000 ng·hr / mL, maximum approximately 22,000 ng·hr / mL, maximum approximately 24,000 ng·hr / mL, or maximum approximately 30,000 ng·hr / mL. 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC such as O-12 Achieves the AUC obtained by combining either the above range or endpoints. 0-12 The range was also considered, and the obtained range was AUC 0-12The following values ​​are particularly intended: 4,000 ng·hr / mL, 5,000 ng / mL, 10,000 ng·hr / mL, 16,000 ng·hr / mL, or 22,000 ng·hr / mL, or if close to these values. These are values ​​that are considered to have potentially specific utility.

[0037] Administering (S)-bupropion results in a representative value of C for (R,R)-hydroxybupropion compared to administering a dosage form containing the same amount of (R)-bupropion to humans. max , average value C max , median C max , or individual C max , etc. C max to at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, approximately 6 times, at least approximately 10 times, at least approximately 20 times, at least approximately 50 times, at least approximately 100 times, at least approximately 150 times, at least approximately 2 It may be useful to increase it by 00 times or more, approximately 5-10 times, approximately 10-20 times, approximately 5-20 times, approximately 20-30 times, approximately 30-40 times, approximately 40-50 times, approximately 50-60 times, approximately 70-80 times, approximately 80-90 times, approximately 90-100 times, approximately 100-110 times, approximately 110-120 times, approximately 120-130 times, approximately 130-140 times, approximately 140-150 times, approximately 150-160 times, approximately 160-170 times, approximately 170-180 times, approximately 180-190 times, or approximately 190-200 times.

[0038] In some embodiments, this method provides at least about 150 ng / mL, at least about 200, at least about 300 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 700 ng / mL, at least about 800 ng / mL, at least about 900 ng / mL, at least about 1,000 ng / mL, at least about 1,100 ng / mL, and at least about 1,200 ng / mL. mL, at least about 1,300 ng / mL, maximum about 1,400 ng / mL, maximum about 1,500 ng / mL, maximum about 1,600 ng / mL, maximum about 1,700 ng / mL, maximum about 1,800 ng / mL, maximum about 1,900 ng / mL, maximum about 2,000 ng / mL, maximum about 2,100 ng / mL, maximum about 2,200 ng / mL, maximum about 2,300 ng / mL, about 300-400 ng / mL, about 400-500 ng / mL, about 500-60 0ng / mL, about 600-700ng / mL, about 700-800ng / mL, about 800-900ng / mL, about 900-1,000ng / mL, about 1,000-1,100ng / mL, about 1,100-1,200ng / mL, about 1,200-1,300ng / mL, about 1,300-1,400ng / mL, about 1,400-1,500ng / mL, about 1,500-1,600ng / mL, about 1,600-1,700ng / mL, about 1,7 Typical values ​​of (R,R)-hydroxybupropion are 0-1,800 ng / mL, approximately 1,800-1,900 ng / mL, approximately 1,900-2,000 ng / mL, approximately 2,000-2,100 ng / mL, approximately 2,100-2,200 ng / mL, approximately 2,200-2,300 ng / mL, approximately 300-800 ng / mL, approximately 800-1,300 ng / mL, approximately 1,300-2,300 ng / mL, or approximately 300-2,300 ng / mL. max , average value C max , median C max , or individual C max C such as max Achieves the AUC obtained by combining either the above range or endpoints. 0-12 The range was also considered, and the obtained range is C maxThe following values ​​are particularly intended: including or near one or more of 400 ng / mL, 950 ng / mL, 1,500 ng / mL, or 2,100 ng / mL. These are values ​​that are considered to have potentially specific utility.

[0039] Administering (S)-bupropion results in a representative value of C for (R,R)-hydroxybupropion compared to administering a dosage form containing the same amount of (R)-bupropion to humans. min , average value C min , median C min , or individual C min C such as min to at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, at least approximately 10 times, at least approximately 20 times, at least approximately 50 times, at least approximately 60 times, at least approximately 100 times, at least approximately 150 times, at least approximately 2 It may be useful to increase it by 00 times or more, approximately 1-5 times, approximately 5-10 times, approximately 5-20 times, approximately 20-30 times, approximately 30-40 times, approximately 40-50 times, approximately 50-60 times, approximately 60-70 times, approximately 70-80 times, approximately 80-90 times, approximately 90-100 times, approximately 100-110 times, approximately 110-120 times, approximately 120-130 times, approximately 130-140 times, approximately 140-150 times, approximately 150-160 times, approximately 160-170 times, approximately 170-180 times, approximately 180-190 times, or approximately 190-200 times.

[0040] In some embodiments, this method provides a maximum of approximately 150 ng / mL, at least approximately 200 ng / mL, at least approximately 300 ng / mL, at least approximately 400 ng / mL, at least approximately 500 ng / mL, at least approximately 600 ng / mL, at least approximately 700 ng / mL, at least approximately 800 ng / mL, at least approximately 900 ng / mL, at least approximately 1,000 ng / mL, at least approximately 1,100 ng / mL, at least approximately 1,200 ng / mL, up to approximately 1,300 ng / mL, up to approximately 1,400 ng / mL, up to approximately 1,500 ng / mL, up to approximately 1,600 ng / mL, up to approximately 1,700 ng / mL, up to approximately 1,800 ng / mL, up to approximately 1,900 ng / mL, up to approximately 2,000 ng / mL, and up to approximately 2,100 ng / mL. L, maximum approximately 2,200ng / mL, maximum approximately 2,300ng / mL, approximately 200-300ng / mL, approximately 300-400ng / mL, approximately 400-500ng / mL, approximately 500-600ng / mL, about 600-700ng / mL, about 700-800ng / mL, about 800-900ng / mL, about 900-1,000ng / mL, about 1,000-1,100ng / mL, about 1 The typical value of (R,R)-hydroxybupropion is C, which is 100-1,200 ng / mL, approximately 1,200-1,300 ng / mL, approximately 1,300-1,400 ng / mL, approximately 1,400-1,500 ng / mL, approximately 1,500-1,600 ng / mL, approximately 300-700 ng / mL, approximately 700-1,100 ng / mL, or approximately 1,100-1,600 ng / mL. min , average value C min , median C min , or individual C min C such as min Achieves the C obtained by combining either the above range or endpoints. min The range was also considered, and the obtained range is C min The following values ​​are particularly intended: including or near one or more of 350 ng / mL, 600 ng / mL, 700 ng / mL, 1,000 ng / mL, or 1,400 ng / mL. These are values ​​that are considered to have potentially specific utility.

[0041] Administration of (S)-bupropion to humans may result in (R,R)-hydroxybupropion accounting for at least 90%, 95%, 97%, 97.2%, 97.4%, 97.6%, 97.8%, or 98% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in human plasma.

[0042] In some embodiments, this method provides a maximum of approximately 500 ng·hr / mL, at least approximately 600 ng·hr / mL, at least approximately 800 ng·hr / mL, at least approximately 1,000 ng·hr / mL, at least approximately 1,200 ng·hr / mL, up to approximately 1,400 ng·hr / mL, up to approximately 1,600 ng·hr / mL, up to approximately 1,800 ng·hr / mL, up to approximately 2,000 ng·hr / mL, and up to approximately 2, 200ng·hr / mL, maximum approximately 2,400ng·hr / mL, maximum approximately 2,600ng·hr / mL, maximum approximately 2,800ng·hr / mL, maximum approximately 3,000ng·hr / mL, approximately 500-600ng·h r / mL, approximately 600-800ng hr / mL, approximately 800-1,000ng hr / mL, approximately 1,000-1,200ng hr / mL, approximately 1,200-1,400ng hr / mL, approximately 1,400-1,6 00ng·hr / mL, approximately 1,600-1,800ng·hr / mL, approximately 1,800-2,000ng·hr / mL, approximately 2,000-2,200ng·hr / mL, approximately 2,200-2,400ng·hr / mL, approximately 2,400-2,600ng hr / mL, approximately 2,600-2,800ng hr / mL, approximately 2,800-3,000ng hr / mL, approximately 500-1,000ng hr / mL, approximately 1,000-1 Typical AUC values ​​for erythrohydroxybupropion are 500 ng·hr / mL, approximately 1,500-2,000 ng·hr / mL, approximately 2,000-2,500 ng·hr / mL, approximately 2,500-3,000 ng·hr / mL, approximately 500-1,500 ng·hr / mL, approximately 1,500-3,000 ng·hr / mL, approximately 2,000-3,000 ng·hr / mL, or approximately 500-3,000 ng·hr / mL. 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12AUC such as 0-12 is achieved. The AUC obtained by combining any of the above ranges or endpoints 0-12 is also contemplated, and the obtained range is the AUC 0-12 with the following values: 500 ng·hr / mL, 1,300 ng·hr / mL, 1,800 ng·hr / mL, or 2,600 ng·hr / mL, including one or more of these, or particularly contemplated when close. These are values that are potentially of certain usefulness.

[0043] In some embodiments, this method achieves a representative value C of erythrohydroxybupropion that is at least about 40 ng / mL, at least about 60 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 120 ng / mL, at least about 140 ng / mL, up to about 160 ng / mL, up to about 180 ng / mL, up to about 200 ng / mL, up to about 220 ng / mL, up to about 240 ng / mL, up to about 260 ng / mL, up to about 280 ng / mL, about 40 - 60 ng / mL, about 60 - 80 ng / mL, about 80 - 100 ng / mL, about 100 - 120 ng / mL, about 120 - 140 ng / mL, about 140 - 160 ng / mL, about 160 - 180 ng / mL, about 180 - 200 ng / mL, about 200 - 220 ng / mL, about 220 - 240 ng / mL, about 240 - 260 ng / mL, about 260 - 280 ng / mL, about 280 - 300 ng / mL, about 40 - 100 ng / mL, about 100 - 150 ng / mL, about 150 - 200 ng / mL, about 200 - 250 ng / mL, about 250 - 280 ng / mL, about 40 - 120 ng / mL, about 120 - 200 ng / mL, about 200 - 280 ng / mL, or about 40 - 280 ng / mL. max average value C max median value C max or an individual's C max such as C max is achieved. The range of C obtained by combining any of the above ranges or endpoints max is also contemplated, and the obtained range is the C maxOne or more of the following values: 60 ng / mL, 120 ng / mL, 200 ng / mL, or 240 ng / mL are included or are particularly contemplated if close. These are values that are potentially of specific usefulness.

[0044] In some embodiments, the method achieves a representative value AUC of threo-hydroxybutyric acid that is at least about 2,000 ng·hr / mL, at least about 3,000 ng·hr / mL, at least about 4,000 ng·hr / mL, at least about 5,000 ng·hr / mL, at least about 6,000 ng·hr / mL, at least about 7,000 ng·hr / mL, up to about 8,000 ng·hr / mL, up to about 9,000 ng·hr / mL, up to about 10,000 ng·hr / mL, up to about 11,000 ng·hr / mL, up to about 12,000 ng·hr / mL, up to about 13,000 ng·hr / mL, up to about 14,000 ng·hr / mL, up to about 15,000 ng·hr / mL, about 2,000 - 15,000 ng·hr / mL, about 2,000 - 3,000 ng·hr / mL, about 3,000 - 4,000 ng·hr / mL, about 4,000 - 5,000 ng·hr / mL, about 5,000 - 6,000 ng·hr / mL, about 6,000 - 7,000 ng·hr / mL, about 7,000 - 8,000 ng·hr / mL, about 8,000 - 9,000 ng·hr / mL, about 9,000 - 10,000 ng·hr / mL, about 10,000 - 11,000 ng·hr / mL, about 11,000 - 12,000 ng·hr / mL, about 12,000 - 13,000 ng·hr / mL, about 13,000 - 14,000 ng·hr / mL, about 14,000 - 15,000 ng·hr / mL, about 2,000 - 6,000 ng·hr / mL, about 6,000 - 10,000 ng·hr / mL, about 10,000 - 15,000 ng·hr / mL, about 2,000 - 9,000 ng·hr / mL, or about 9,000 - 15,000 ng·hr / mL. 0-12 , mean value AUC 0-12 , median value AUC 0-12 , or an individual's AUC 0-12 such as AUC 0-12 is achieved. The AUC obtained by combining any of the above ranges or endpoints.0-12 The range was also considered, and the obtained range was AUC 0-12 The following values ​​are particularly intended: 3,000 ng·hr / mL, 6,000 ng·hr / mL, 8,000 ng·hr / mL, or 12,000 ng·hr / mL, or if close to these values. These are values ​​that are considered to have potentially specific utility.

[0045] In some embodiments, this method provides a range of approximately 200 ng / mL, 300 ng / mL, 400 ng / mL, 450 ng / mL, 500 ng / mL, 600 ng / mL, 700 ng / mL, 800 ng / mL, 900 ng / mL, 1,000 ng / mL, 1,100 ng / mL, 1,200 ng / mL, 1,300 ng / mL, 1,400 ng / mL, 200-300 ng / mL, 300-400 ng / mL, 400-500 ng / mL, and 500-600 ng / mL. Typical values ​​of threohydroxybupropion are ng / mL, approximately 600-700 ng / mL, approximately 700-800 ng / mL, approximately 800-900 ng / mL, approximately 900-1000 ng / mL, approximately 1,000-1,100 ng / mL, approximately 1,100-1,200 ng / mL, approximately 1,200-1,300 ng / mL, approximately 1,300-1,400 ng / mL, approximately 200-500 ng / mL, approximately 500-800 ng / mL, approximately 800-1,100 ng / mL, approximately 1,100-1,400 ng / mL, approximately 200-800 ng / mL, approximately 800-1,400 ng / mL, or approximately 200-1,400 ng / mL. max , average value C max , median C max , or individual C max C such as max Achieves the C obtained by combining either the above range or endpoints. max The range was also considered, and the obtained range is C maxThe following values ​​are particularly intended: 300 ng / mL, 600 ng / mL, 900 ng / mL, or 1,200 ng / mL, or one or more of these values ​​if they are close to these values. These are values ​​that are considered to have potentially specific utility.

[0046] Unless otherwise specified, references to compounds herein, such as (S)-bupropion, by structure, name, or other means, include pharmaceutically acceptable alternative solids such as salts, polymorphs, crystals, solvates, hydrates, tautomers, deuterium-modified compounds, or any chemical species of the compounds described herein that may rapidly change under the conditions in which the compounds are used as described herein.

[0047] (S)-bupropion can be used alone or in combination with other drugs, as described, for example, in Remington's Pharmaceutical Sciences, 2005, and in combination with a pharmaceutical carrier selected based on a chosen route of administration and standard pharmaceutical practice. The relative ratio of the active ingredient to the carrier may be determined, for example, by the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0048] (S)-bupropion drugs can be administered to human patients in various forms to suit the selected route of administration, e.g., orally or parenterally. Parenteral administration in this sense includes the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrabursal, transepithelial including percutaneous, ophthalmic, sublingual, and oral administration, as well as topical administration including the eyes, skin, eyeballs, rectum, and nose.

[0049] (S)-bupropion can be formulated for oral administration, for example, with an inert diluent or food carrier, or encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or directly incorporated into food. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc.

[0050] Tablets, lozenges, pills, capsules, etc., containing (S)-bupropion may contain one or more of the following: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; or flavoring agents such as peppermint, wintergreen oil, or cherry flavor. If the dosage form is a capsule, it may contain a liquid carrier in addition to the above types of materials. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs may contain the active compound, sucrose as a sweetener, methyl and propylparaben as preservatives, dyes, and flavors such as cherry or orange flavor. It is desirable that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and substantially nontoxic in the amount used.

[0051] Some compositions or dosage forms may be liquids or may contain a solid phase dispersed in a liquid.

[0052] (S)-bupropion can be formulated for parenteral or intraperitoneal administration. Solutions of the active compound as a free base or a pharmacokinetically acceptable salt can be prepared in water appropriately mixed with a surfactant. Dispersions may also have oil dispersed inside or within glycerol, liquid polyethylene glycol, and mixtures thereof. Under normal storage and use conditions, these preparations may contain preservatives to prevent microbial growth.

[0053] Some embodiments involve the administration of tablets containing (S)-bupropion in a form that provides sustained release of (S)-bupropion. Sustained-release formulations containing (S)-bupropion provide sustained release of (S)-bupropion for about 2-4 hours, 4-6 hours, or 6-8 hours. maxIt may have the following properties. There are many methods to achieve sustained release of bupropion, but in some embodiments, (S)-bupropion or (R)-bupropion may be acrylic acid or methacrylic acid copolymers or esters thereof, for example methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polyacrylamide, poly(methacrylic anhydride), glycidyl methacrylate copolymer, quaternized aminoalkyl esters or aminoalkylamides of acrylic acid and / or methacrylic acid, for example β-methacryloxyethyltrimethylammonium methosulfate, β- It is combined with sustained-release polymers such as oxypropyltrimethylammonium chloride, trimethylaminomethylmethacrylamide methosulfate, quaternary vinyl-substituted nitrogen heterocycles such as methyl-vinylpyridinium salts, vinyl esters of quaternary aminocarboxylic acids, styryltrialkylammonium salts, benzyldimethylammonium ethyl methacrylate chloride, diethylmethylammonium ethyl acrylate, diethylmethylammonium ethyl methacrylate methosulfate, N-trimethylammonium propyl methacrylamide chloride, N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride, carboxyalkyl cellulose (e.g., carboxymethylcellulose), and cellulose derivatives such as hydroxypropyl methylcellulose. In some embodiments, the sustained-release polymer is hydroxypropyl methylcellulose. For example, (S)-bupropion particles are combined with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL). R ) can be blended with to form a mixture of blended powders.

[0054] Examples of neurological or central nervous system disorders that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, affective disorders, psychiatric disorders, brain dysfunction, motor disorders, dementia, motor neuron diseases, neurodegenerative diseases, paroxysmal disorders, and headaches.

[0055] Affective disorders that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, depression, major depressive disorder, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorders including cyclothymic disorder, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity disorder (ADDH), and attention deficit / hyperactivity disorder (AD / HD), bipolar disorders and manic states, obsessive-compulsive disorder, bulimia nervosa, obesity or weight gain, paroxysmal sleep disorders, chronic fatigue syndrome, premenstrual syndrome, drug dependence or abuse, nicotine dependence, psychogenic dysfunction, emotional dysregulation, and emotional instability.

[0056] Depression can manifest as depressive symptoms. These symptoms may include mood swings, intense sadness, despair, mental sluggishness, difficulty concentrating, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. Physical symptoms of depression may include insomnia, loss of appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, pain, distress, headaches, seizures, digestive problems, and / or circadian rhythm disturbances.

[0057] Some patients may remain unresponsive or unresponsive to treatment even after being treated with medications such as antidepressants. Treatment-resistant depression (TRD), or treatment-refractory depression, is generally a condition associated with patients who have failed treatment with at least two antidepressants. Part of the diagnosis of TRD is made by the patient's unresponsiveness to antidepressant treatment after appropriate doses and appropriate units. TRD can be more difficult to treat due to comorbidities of other medical or psychological illnesses, such as drug / alcohol abuse or eating disorders, or because the TRD has been misdiagnosed. Some TRD patients have shown an unresponsiveness to one, two, three, or more appropriate antidepressant treatment trials, or have failed or shown an unresponsiveness to one, two, three, or more conventional antidepressant treatments. In some embodiments, patients being treated for treatment-resistant depression have failed treatment with at least one, two, three, four, five, six, seven, eight, nine, ten, or more antidepressant therapies.

[0058] Measures of therapeutic effects that may be improved by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, the following: Montgomery-Asberg Depression Rating Scale (MADRS), Short-Answer Questionnaire on Quality of Life Enjoyment and Satisfaction, Range of Functional Impairment Tools, Sheehan's Disorder Scale, Patient Assessment of Adverse Events (PRISE), Columbia Suicide Severity Rating Scale (C-SSRS), Rapid Inventory of Depressive Symptoms, Self-Report (QID(S)-SR), Clinical Global Impression (CGI) Scale, Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), Hamilton Rating Scale for Depression (HAM-D17), and Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ), 16-item rapid self-report inventory of depressive symptoms (QID(S)-SR16), Sheehan's Disorder Scale (SDS), Clinical Global Impression of Illness Severity (CGI-S), Clinical Global Impression of Change (CGI-C), Euro Quality of Life 5-Dimensional 5-Level (EQ-5D-5L), General Impression of Patient Change (PGIC), 7-item General Anxiety Disorder (GAD-7), Clinical Global Impression - Improvement (CGI-I). Sheehan's Disorder Scale (SDS). The following are some of the tests used to assess depression: the 16-item Quick Inventory of Depressive Symptoms - Self-Report (QID(S)-SR16), the Hamilton Anxiety Scale (HAM-A), the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), the CPFQ-Cognitive Subscales (4 to 7 items), the Brief Psychiatric Symptom Rating Scale (BPRS), the Number-Symptom Substitution Test (DSST), the Ray Auditory Language Learning Task (RAVLT), the Trace Making Test (TMT), the Stroop Color Naming Test (STROOP), Simple Reaction Time (SRT), and Choice Reaction Time (CRT).

[0059] Patients who may benefit from the treatments described herein include pediatric patients such as those under approximately 18 years of age, approximately 0-5 years, approximately 5-10 years, approximately 10-12 years, or approximately 12-18 years; adult patients such as those approximately 18-65 years, approximately 18-30 years, approximately 30-50 years, and approximately 50-65 years; and elderly patients such as those over 65 years of age, approximately 65-75 years, approximately 75-90 years, or over 90 years of age.

[0060] Treatment of TRD by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) may result in a reduction of depressive symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or other reduction rates within the range limited by any of these values.

[0061] Mental disorders that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, anxiety disorders such as phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD), mania, manic-depressive illness, hypomania, unipolar depression, depression, stress disorders, motor disorders, personality disorder psychoses, schizophrenia, delusional disorder, schizoaffective disorder, schizotypal tendencies, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

[0062] Excitation associated with Alzheimer's disease occurs as the disease progresses. Excitation can manifest as inappropriate verbal, emotional, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, slurred speech, inappropriate emotional responses, attention-seeking, threatening, excitability, frustration, screaming, repetitive questioning, mood swings, swearing, verbal abuse, physical outbursts, emotional distress, restlessness, cutting, sleep disturbances, delusions, hallucinations, slow gait, wandering, searching, rummaging, repetitive body movements, hoarding, shadowing, hitting, scratching, biting, aggression, hyperactivity, and / or kicking.

[0063] In some embodiments, treatment of Alzheimer's disease-related agitation by administering (S)-bupropion (including administering (S)-bupropion to achieve one therapeutic plasma level of its metabolite, such as (R,R)-hydroxybupropion) may result in a reduction of agitation-related symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and / or up to about 100%.

[0064] Measures of the therapeutic effect of agitation that may be improved by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, the overall and all domains of the Neuropsychiatric Inventory-Clinical (NPI-C) Rating Scale, the Neuropsychiatric Inventory-Clinical (NPI-C) Rating Scale agitation domain, the Cohen-Mansfield Agitation Inventory (CMAI), the Cornell Scale for Depression in Dementia (CSDD), the Neuropsychiatric Inventory (NPI agitation / aggression domain), concomitant medications (frequency of concomitant medication use), the Alzheimer's Disease Collaborative Study-Activities of Daily Living Inventory (ADC(S)-ADL), and individual domains of the Neuropsychiatric Inventory (NPI), including the NPI-C apathy domain. This includes the total score of the domains and NPI (range 0-144), NPI agitation / aggression caregiver distress, modified Alzheimer's Disease Collaborative – Clinical Global Impression of Change Agitation (mADC(S)-CGIC agitation), Global Impression of Patient Change (PGIC) (assessed by caregivers), quality of life in dementia (DEMQOL), quality of life-measures for Alzheimer's disease (QoL-AD), Zarit burden scale, resource utilization in dementia (RUD), Alzheimer's Disease Rating Scales – Cognitive Subscales (ADA(S)-Cog), Mini-Mental State Examination (MMSE), Caregiver Stress Index (CSI), individual domains of the Neuropsychiatric Inventory (NPI), total Neuropsychiatric Inventory (NPI) score, Neuropsychiatric Inventory (NPI agitation / aggression domain), Neuropsychiatric Inventory (NPI domain caregiver distress), etc.

[0065] Drug addictions that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, drug addiction, cocaine addiction, psychostimulants (such as crack, cocaine, speed, and stimulants), nicotine, alcohol, opioids, anti-anxiety and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrite compounds. Nicotine addiction includes all known forms of nicotine addiction, such as smoking cigarettes, cigars and / or pipe tobacco, e-cigarettes, and chewing tobacco.

[0066] Brain dysfunctions that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, senile dementia, Alzheimer's disease, amnesia, amnesia / amnesic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention-seeking syndrome, and intellectual disability disorders such as schizophrenia. Brain dysfunctions also include, but are not limited to, disorders caused by cerebrovascular diseases, including stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, and head trauma, if symptoms include impaired consciousness, senile dementia, coma, decreased attention, and speech disorders.

[0067] Motor disorders that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, sitting incapacitation, akinesia, synkinesis, athetosis, ataxia, ballism, unilateral ballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless leg syndrome (RLS), tremor, essential tremor, Tourette's syndrome, and Wilson's disease.

[0068] Dementia that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0069] Motor neuron diseases that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0070] Neurodegenerative diseases that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar spinal muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, and amyotrophic lateral sclerosis. This includes (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, autosomal dominant arterial disease with subcortical infarction and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0071] Paroxysmal disorders that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile seizures, partial seizures (including, but not limited to, simple partial epilepsy, Jacksonian seizures, complex partial seizures, and persistent partial epilepsy), generalized seizures (including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms), and status epilepticus.

[0072] The types of headaches that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0073] Other neurological disorders that can be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to, Rett syndrome, autism, tinnitus, disturbance of consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy, dysphonia due to uncontrolled laryngeal muscle spasms (including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, myotonic dysphonia, and tremor of the voice), diabetic neuropathy, chemotherapy-induced neurotoxicities such as methotrexate neurotoxicity, incontinence (including, but not limited to, stress urinary incontinence, urge urinary incontinence, and fecal incontinence), and erectile dysfunction.

[0074] In some embodiments, administering (S)-bupropion (including administering (S)-bupropion to achieve one therapeutic plasma level of its metabolites, such as (R,R)-hydroxybupropion) may be useful in treating pain, arthralgia, pain associated with sickle cell disease, emotional dysregulation, depression (including treatment-resistant depression), memory and cognitive impairments, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), seizures, cough (including chronic cough), and the like.

[0075] In some embodiments, treatment-resistant depression may be treated by administering (S)-bupropion (including administering (S)-bupropion to achieve one therapeutic plasma level of its metabolites, such as (R,R)-hydroxybupropion).

[0076] (S)-bupropion may also be used to treat or alleviate any type of pain, including but not limited to musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritis pain, and complex regional pain syndrome, either by the direct action of (S)-bupropion or by administering (S)-bupropion to achieve one of its metabolites, such as (R,R)-hydroxybupropion, to a therapeutic plasma level.

[0077] In some embodiments, (S)-bupropion may be administered to relieve neuropathic pain (either for its direct effect or to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion).

[0078] Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradicular pain, phantom limb pain, and central pain. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and neuropathy associated with radiation therapy or chemotherapy.

[0079] In some embodiments, (S)-bupropion may be administered to alleviate fibromyalgia (either for its direct effect or to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion).

[0080] Adverse events related to bupropion that can be avoided or reduced by the methods described herein include central nervous system adverse events, gastrointestinal events, or other types of adverse events related to any of these compounds. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, insomnia, lightheadedness, tremors, hallucinations, convulsions, central nervous system depression, phobias, anxiety, headache, increased irritability or agitation, tinnitus, drowsiness, dizziness, sedation, drowsiness, confusion, disorientation, malaise, ataxia, fatigue, euphoria, tension, insomnia, sleep disturbances, seizures, agitation, tension, hysteria, hallucinations, delusions, paranoia, headache and / or migraine, and extrapyramidal symptoms such as gaze onset, torticollis, hyperexcitability, hypertonia, ataxia, and / or tongue thrust.

[0081] Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, indigestion, diarrhea, abdominal distension, flatulence, hemorrhagic peptic ulcers, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, bloating, indigestion, swelling, hyperacidity, dryness of the cavity, gastrointestinal disorders, and gastric pain.

[0082] Other adverse events that may be reduced or avoided by the methods described herein include: paresthesia of rotation and movement, excitement, weakness in the arms, bloating, blurred vision, burning sensation in the eyes, tinnitus, changes in vital signs (including but not limited to heart rate, respiratory rate, body temperature, blood pressure), coldness, constipation, difficulty concentrating, insomnia, difficulty falling asleep, difficulty urinating, difficulty defecating, ear discomfort, eye discomfort, stomach discomfort, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feverish feeling, heavy head feeling, feeling more excited than usual, feeling more tired than usual, fatigue, hand tremors. Side effects include decreased grip strength, headache, heartburn, hot flashes, increased blood pressure, increased skin sensitivity, increased skin sensitivity of the head and face, involuntary muscle contractions, generalized involuntary muscle contractions, knee pain, leg weakness, dizziness, loose stools, decreased appetite, lower back pain, menstrual irregularities, metallic taste, increased saliva, dry mucous membranes, nasal congestion, nausea, runny nose, mild eye pressure, tremors when stretching or yawning, skin irritation, skin irritation of the arms, face, and / or head, sleep disturbances, loose stools, stomach pain, stomach discomfort, sweating of the hands and / or feet, throat inflammation, sore throat, tinnitus, tremors, and / or weakness. Any of these side effects may be referenced or grouped according to the corresponding, equivalent, or other relevant terms listed in the Medical Regulatory Terminology (MedRA).

[0083] The following embodiments are intended: Embodiment 1. A method for supplying (R)-bupropion and (S)-bupropion to plasma, Selecting individuals who require the pharmacokinetic profile obtained by orally administering a reference dosage form containing a first dose of racemibpropion at a first dosing frequency, and To obtain the same pharmacokinetic profile as that obtained by administering the reference dosage form at the first dose frequency, the method includes orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at the first dose frequency, The first medication frequency is once or twice a day. The method wherein the second amount is approximately 40% to 60% of the first amount.

[0084] Embodiment 2. A method for treating conditions treatable with racemibpropion, Select human patients who have a condition that can be treated by orally administering a reference dosage form containing a first dose of racemibpropion at a first frequency, and The method includes orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion in a second amount at a first dose frequency to obtain the same therapeutic effect achieved by administering a reference dose form at a first dose frequency, The first dosage frequency is once or twice a day. The second amount is approximately 40% to 60% of the first amount, according to the method.

[0085] Embodiment 3. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being is in a condition treatable with (S)-bupropion, and the amount of (S)-bupropion administered is selected to be about 20% to about 70% by weight of the amount of racemipupion that would be administered to treat the same condition in the same human being.

[0086] Embodiment 4. A method for providing a therapeutically effective plasma level of (R,R)-hydroxybupropion, comprising orally administering to a person in need of treatment with (R,R)-hydroxybupropion a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily, wherein the (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the person, and the method provides at least about 500 ng / mL of (R,R)-hydroxybupropion in the person. max A method to achieve this.

[0087] Embodiment 5. A method for treating a human being, comprising orally administering to the human being a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being requires treatment with (S)-bupropion, and the (S)-bupropion is the only active agent used to treat the human being.

[0088] Embodiment 6. A method for treating a human being, comprising orally administering to the human being, once or twice daily, a dosage form containing at least 50 mg to 100 mg of (S)-bupropion that is at least 95% enantiomerically pure, wherein the human being is in need of treatment with (S)-bupropion.

[0089] Embodiment 7. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the method involves at least about 60 ng / mL of (S)-bupropion C max A method to achieve this.

[0090] Embodiment 8. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the human's plasma.

[0091] Embodiment 9. A method for providing therapeutically effective plasma levels of (R,R)-hydroxybupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion to a person in need of treatment with (R,R)-hydroxybupropion once or twice daily, wherein the (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the person.

[0092] Embodiment 10. A method for providing therapeutically effective plasma levels of (R,R)-hydroxybupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion to a person in need of treatment with (R,R)-hydroxybupropion once or twice daily, wherein the method provides at least about 500 ng / mL of (R,R)-hydroxybupropion to the person. max A method to achieve this.

[0093] Embodiment 11. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being requires treatment with (S)-bupropion, and the method comprises at least about 70 ng / mL of (S)-bupropion. max A method to achieve this.

[0094] Embodiment 12. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being requires treatment with (S)-bupropion, and the method provides at least about 600 ng·h / mL of (S)-bupropion AUC 0-12 A method to achieve this.

[0095] Embodiment 13. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being requires treatment with (S)-bupropion, and the method comprises at least about 800 ng / mL of (R,R)-hydroxybupropion. max A method to achieve this.

[0096] Embodiment 14. A method for treating a human being comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being requires treatment with (S)-bupropion, and the method comprises the AUC of at least about 8,000 ng·h / mL of (R,R)-hydroxybupropion. 0-12 A method to achieve this.

[0097] Embodiment 15. A method for treating a human being comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being requires treatment with (S)-bupropion, and the method comprises at least about 90 ng / mL of erythrohydroxybupropion C max A method to achieve this.

[0098] Embodiment 16. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being requires treatment with (S)-bupropion, and the method comprises the AUC of erythrohydroxybupropion being at least about 1,000 ng·h / mL. 0-12 A method to achieve this.

[0099] Embodiment 17. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the human being requires treatment with (S)-bupropion, and the method comprises at least about 450 ng / mL of threohydroxybupropion C max A method to achieve this.

[0100] Embodiment 18. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being in need of treatment with (S)-bupropion, wherein the method comprises the AUC of threohydroxybupropion being at least about 5,000 ng·h / mL 0-12 A method to achieve this.

[0101] Embodiment 19. The method of Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the human being is in need of treatment with (S)-bupropion.

[0102] Embodiment 20. The above method involves at least about 60 ng / mL of (S)-bupropion C max Methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 that achieve the above.

[0103] Embodiment 21. The above method involves C of (S)-bupropion max The C of (R)-bupropion produced as a result of administering the same amount of (R)-bupropion to the aforementioned human max The methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 are effective in increasing the amount by at least five times compared to the other method.

[0104] Embodiment 22. The method involves the C of (R,R)-hydroxybupropion in a human being at least about 500 ng / mL. max Methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 that achieve the above.

[0105] Embodiment 23. The above method involves C of (R,R)-hydroxybupropion min The C of (R,R)-hydroxybupropion produced as a result of administering the same amount of (R)-bupropion to the aforementioned human min The methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 are effective in increasing the amount by at least five times compared to the other method.

[0106] Embodiment 24. The dosage form is administered once daily, according to the method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.

[0107] Embodiment 25. The dosage form is administered twice daily, according to the method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24.

[0108] Embodiment 26. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein (R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the human plasma.

[0109] Embodiment 27. The methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, which are effective in providing therapeutically effective plasma levels of (R,R)-hydroxybupropion.

[0110] Embodiment 28. The methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, which are effective in providing therapeutically effective plasma levels of (S)-bupropion.

[0111] Embodiment 29. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein the human is in need of treatment with (R,R)-hydroxybupropion.

[0112] Embodiment 30. The method involves the C of (R,R)-hydroxybupropion in a human being at least about 500 ng / mL. max Methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 that achieve the objectives.

[0113] Embodiment 31. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, wherein the dosage form is administered for at least 8 consecutive days.

[0114] Embodiment 32. The method of Embodiment 31, wherein the dosage form is administered for at least 14 consecutive days.

[0115] Embodiment 33. The method of Embodiment 31, wherein the dosage form is administered continuously for at least 21 days.

[0116] Embodiment 34. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33, wherein the dosage form contains approximately 60 mg to approximately 90 mg of (S)-bupropion.

[0117] Embodiment 35. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the dosage form is administered once or twice daily for a total of at least 8 consecutive days, and then the dosage form is administered twice daily for at least the next 4 to 7 consecutive days.

[0118] Embodiment 36. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the dosage form is administered once or twice daily for a total of at least eight consecutive days, and then the dosage form is administered twice daily for at least the next seven consecutive days.

[0119] Embodiment 37. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein the dosage form contains approximately 70 mg to approximately 80 mg of (S)-bupropion.

[0120] Embodiment 38. The method involves the concentration of (S)-bupropion in humans at least about 70 ng / mL. max Methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37 that achieve the above.

[0121] Embodiment 39. The above method is the AUC of (S)-bupropion in humans, which is at least about 400 ng·hr / mL. 0-12 Methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38 that achieve the above.

[0122] Embodiment 40. The above method provides the AUC of (S)-bupropion in humans, which ranges from approximately 500 ng·hr / mL to approximately 900 ng·hr / mL.0-12 The method of embodiment 39 achieves the objective.

[0123] Embodiment 41. The dosage form is a method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, which provides sustained release of (S)-bupropion.

[0124] Embodiment 42. The dosage form contains about 70 mg to about 80 mg of (S)-bupropion, according to the method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41.

[0125] Embodiment 43. The above method provides a concentration of at least about 600 ng / mL of (R,R)-hydroxybupropion in humans. max Methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42 that achieve the above.

[0126] Embodiment 44. The above method provides an AUC of (R,R)-hydroxybupropion in humans that is at least about 7000 ng·hr / mL. 0-12 Methods of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44 that achieve the above.

[0127] Embodiment 45. The method of Embodiment 44 achieves an AUC0-12 of (R,R)-hydroxybupropion in humans of at least about 8000 ng·hr / mL.

[0128] Embodiment 46. A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion.

[0129] Embodiment 47. A dosage form for treating a human condition, comprising at least 95% enantiomerically pure (S)-bupropion, wherein the dosage form is administered orally to the human once or twice daily.

[0130] Embodiment 48. The use of (S)-bupropion in the manufacture of a drug for treating a human condition, wherein the drug is administered orally to the human once or twice daily.

[0131] Embodiment 49. A kit comprising a dosage form and a label, wherein the dosage form comprises at least 95% enantiomerically pure (S)-bupropion, and the label indicates that the dosage form is administered orally to a human once or twice daily to treat a human condition.

[0132] Embodiment 50. The aforementioned condition is a neurological disorder or a central nervous system disorder, according to the methods, dosage forms, uses, or kits of Embodiments 46, 47, 48, or 49.

[0133] Embodiment 51. The aforementioned human being is selected because of the aforementioned condition, the method, dosage form, use, or kit of Embodiment 50.

[0134] Embodiment 52. The condition is treated by achieving a first AUC of bupropion, the first AUC of bupropion being the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, the daily dose of racemic bupropion being about 150 mg to about 200 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of bupropion, the daily dose of (S)-bupropion being about 60 mg to about 120 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemic bupropion, according to Embodiment 51, method, dosage form, use, or kit.

[0135] Embodiment 53. The condition is treated by achieving a first AUC of bupropion, the first AUC of bupropion being the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, the daily dose of racemic bupropion being about 200 mg to about 250 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of bupropion, the daily dose of (S)-bupropion being about 80 mg to about 150 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemic bupropion, according to Embodiment 51, method, dosage form, use, or kit.

[0136] Embodiment 54. The method, dosage form, use, or kit of Embodiment 51, wherein the condition is treated by achieving a first AUC of bupropion, the first AUC of bupropion being the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, the daily dose of racemic bupropion being about 250 mg to about 300 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of bupropion, the daily dose of (S)-bupropion being about 100 mg to about 180 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemic bupropion.

[0137] Embodiment 55. The condition is treated by achieving a first AUC of bupropion, the first AUC of bupropion being the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, the daily dose of racemic bupropion being about 300 mg to about 350 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of bupropion, the daily dose of (S)-bupropion being about 120 mg to about 210 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemic bupropion, according to Embodiment 51, method, dosage form, use, or kit.

[0138] Embodiment 56. The condition is treated by achieving a first AUC of bupropion, the first AUC of bupropion being the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, the daily dose of racemic bupropion being about 350 mg to about 400 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of bupropion, the daily dose of (S)-bupropion being about 140 mg to about 240 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemic bupropion, according to Embodiment 51, method, dosage form, use, or kit.

[0139] Embodiment 57. The condition is treated by achieving a first AUC of bupropion, the first AUC of bupropion being the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, the daily dose of racemic bupropion being about 400 mg to about 450 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of bupropion, the daily dose of (S)-bupropion being 160 mg to about 270 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemic bupropion, according to the method, dosage form, use, or kit of Embodiment 51.

[0140] Embodiment 58. The condition is treated by achieving a first AUC of hydroxybupropion, the first AUC of hydroxybupropion being the same as the reference AUC of hydroxybupropion resulting from administration of a daily dose of racemibpropion, the daily dose of racemibpropion being about 150 mg to about 200 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of hydroxybupropion, the daily dose of (S)-bupropion being about 60 mg to about 120 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemibpropion, according to Embodiment 51, method, dosage form, use, or kit.

[0141] Embodiment 59. The condition is treated by achieving a first AUC of hydroxybupropion, the first AUC of hydroxybupropion being the same as the reference AUC of hydroxybupropion resulting from administration of a daily dose of racemibpropion, the daily dose of racemibpropion being about 200 mg to about 250 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of hydroxybupropion, the daily dose of (S)-bupropion being about 80 mg to about 150 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemibpropion, according to Embodiment 51, method, dosage form, use, or kit.

[0142] Embodiment 60. The condition is treated by achieving a first AUC of hydroxybupropion, the first AUC of hydroxybupropion being the same as the reference AUC of hydroxybupropion resulting from administration of a daily dose of racemibpropion, the daily dose of racemibpropion being about 250 mg to about 300 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of hydroxybupropion, the daily dose of (S)-bupropion being about 100 mg to about 180 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemibpropion, according to Embodiment 51, method, dosage form, use, or kit.

[0143] Embodiment 61. The condition is treated by achieving a first AUC of hydroxybupropion, the first AUC of hydroxybupropion being the same as the reference AUC of hydroxybupropion resulting from administration of a daily dose of racemibpropion, the daily dose of racemibpropion being about 300 mg to about 350 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of hydroxybupropion, the daily dose of (S)-bupropion being about 120 mg to about 210 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemibpropion, according to Embodiment 51, method, dosage form, use, or kit.

[0144] Embodiment 62. The condition is treated by achieving a first AUC of hydroxybupropion, the first AUC of hydroxybupropion being the same as the reference AUC of hydroxybupropion resulting from the administration of a daily dose of racemibpropion, the daily dose of racemibpropion being about 350 mg to about 400 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of hydroxybupropion, the daily dose of (S)-bupropion being about 140 mg to about 240 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemibpropion, according to Embodiment 51, method, dosage form, use, or kit.

[0145] Embodiment 63. The condition is treated by achieving a first AUC of hydroxybupropion, the first AUC of hydroxybupropion being the same as the reference AUC of hydroxybupropion resulting from administration of a daily dose of racemibpropion, the daily dose of racemibpropion being about 400 mg to about 450 mg, the daily dose of (S)-bupropion being administered to the human to achieve the first AUC of hydroxybupropion, the daily dose of (S)-bupropion being about 160 mg to about 270 mg, the (S)-bupropion being at least 95% enantiomerically pure, no other bupropion being administered with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion being about 40% to about 60% of the daily dose of racemibpropion, according to Embodiment 51, method, dosage form, use, or kit.

[0146] Embodiment 64. The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, the first AUC of (R,R)-hydroxybupropion being the same as the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion, the daily dose of racemibpropion being approximately 150 mg to approximately 200 mg, and the daily dose of (S)-bupropion being the same as the first AUC of (R,R)-hydroxybupropion A method, dosage form, use, or kit of Embodiment 51, administered to a human to achieve AUC, wherein the daily dose of (S)-bupropion is approximately 60 mg to approximately 120 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0147] Embodiment 65. The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, the first AUC of (R,R)-hydroxybupropion being the same as the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion, the daily dose of racemibpropion being approximately 200 mg to approximately 250 mg, and the daily dose of (S)-bupropion being the same as the first AUC of (R,R)-hydroxybupropion A method, dosage form, use, or kit of Embodiment 51, administered to a human to achieve AUC, wherein the daily dose of (S)-bupropion is approximately 80 mg to approximately 150 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemic bupropion.

[0148] Embodiment 66. The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, the first AUC of (R,R)-hydroxybupropion being the same as the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion, the daily dose of racemibpropion being approximately 250 mg to approximately 300 mg, and the daily dose of (S)-bupropion being the first AUC of (R,R)-hydroxybupropion A method, dosage form, use, or kit of Embodiment 51, administered to a human to achieve AUC, wherein the daily dose of (S)-bupropion is approximately 100 mg to approximately 180 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemic bupropion.

[0149] Embodiment 67. The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, the first AUC of (R,R)-hydroxybupropion being the same as the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion, the daily dose of racemibpropion being approximately 300 mg to approximately 350 mg, and the daily dose of (S)-bupropion being the first AUC of (R,R)-hydroxybupropion A method, dosage form, use, or kit of Embodiment 51, administered to a human to achieve AUC, wherein the daily dose of (S)-bupropion is approximately 120 mg to approximately 210 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0150] Embodiment 68. The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, the first AUC of (R,R)-hydroxybupropion being the same as the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion, the daily dose of racemibpropion being approximately 350 mg to approximately 400 mg, and the daily dose of (S)-bupropion being the first AUC of (R,R)-hydroxybupropion A method, dosage form, use, or kit of Embodiment 51, administered to a human to achieve AUC, wherein the daily dose of (S)-bupropion is approximately 140 mg to approximately 240 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemic bupropion.

[0151] Embodiment 69. The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, the first AUC of (R,R)-hydroxybupropion being the same as the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion, the daily dose of racemibpropion being approximately 400 mg to approximately 450 mg, and the daily dose of (S)-bupropion being the first AUC of (R,R)-hydroxybupropion A method, dosage form, use, or kit of Embodiment 51, administered to a human to achieve AUC, wherein the daily dose of (S)-bupropion is approximately 160 mg to approximately 270 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemic bupropion.

[0152] Embodiment 70. The aforementioned AUC is AUC 0-12The method, dosage form, use, or kit described in any one of embodiments 52-69.

[0153] Embodiment 71. The aforementioned AUC is AUC 0-24 The method, dosage form, use, or kit described in any one of embodiments 52-69.

[0154] Embodiment 72. The (S)-bupropion is administered once daily, according to any of the embodiments described above.

[0155] Embodiment 73. The method according to any one of embodiments 46-71, wherein the (S)-bupropion is administered twice daily, and the sum of the two daily doses is the daily dose.

[0156] Embodiment 74. The method according to any of the above embodiments, wherein the (S)-bupropion is administered for at least 8 consecutive days.

[0157] Embodiment 75. The method according to any of the above embodiments, wherein the (S)-bupropion is administered for at least 14 consecutive days.

[0158] Embodiment 76. The method according to any of the above embodiments, wherein the (S)-bupropion is administered for at least 21 consecutive days.

[0159] Embodiment 77. The method according to any of the above embodiments, wherein the (S)-bupropion is administered for at least 28 consecutive days.

[0160] Embodiment 78. The method according to any of the above embodiments, wherein the (S)-bupropion is administered in a dosage form that provides sustained release of (S)-bupropion.

[0161] Embodiment 79. The aforementioned dosage form is (S)-bupropion, with an effective duration of approximately 2 to 4 hours. max The method of Embodiment 78, which is formulated to have the following properties.

[0162] Embodiment 80. The above method provides an AUC of (S)-bupropion in humans that is at least about 300 ng·hr / mL. 0-12 A method of any of the above embodiments that achieves the above.

[0163] Embodiment 81. The above method provides an AUC of (S)-bupropion in humans that is at least about 400 ng·hr / mL. 0-12 A method of any of the above embodiments that achieves the above.

[0164] Embodiment 82. The above method is used to determine the AUC of (S)-bupropion in humans, ranging from approximately 500 ng·hr / mL to approximately 900 ng·hr / mL. 0-12 A method of any of the above embodiments that achieves the above.

[0165] Embodiment 83. The above method involves the concentration of (S)-bupropion in humans, ranging from approximately 60 ng / mL to approximately 140 ng / mL. max A method of any of the above embodiments that achieves the above.

[0166] Example 1 Part 1 Fifteen healthy adults were administered 150 mg of sustained-release racemipupine twice daily for 7 days under fasting conditions. The tablet dosage was increased from once daily from day 1 to day 3 to twice daily thereafter, with the final dose administered on the morning of day 7. Plasma concentrations of bupropion and its metabolites were measured 3-4 hours after administration on day 7. Chiral bioanalysis was used to determine the enantiomer concentrations of bupropion and its major metabolites. AUC or C12C2 was used. max The result was standardized to 210 mg by multiplying by 210 / 150.

[0167] Part 2 Healthy adults were administered either 105 mg of S-bupropion or 105 mg of R-bupropion sustained-release tablets (10 subjects per group) twice daily for 8 days under fasting conditions. The tablet dosage was increased from once daily from day 1 to day 3 to twice daily thereafter, with the final dose administered on the morning of day 8. Plasma concentrations of bupropion and its metabolites were measured on days 1 and 8 for a complete pharmacokinetic evaluation. Chiral bioanalysis was used to measure the enantiomer concentrations of bupropion and its major active metabolite, hydroxybupropion.

[0168] Table 1 shows the values ​​for tablets containing 105 mg of S-bupropion from Part 2. Values ​​for racemipupine tablets containing 75 mg of R- and 75 mg of S-bupropion were obtained from Part 1 and standardized to 105 mg of R- and 105 mg of S-bupropion by multiplying by 105 / 150 to allow comparison with the aforementioned 105 mg S-bupropion tablets. Both S-bupropion and racemipupine tablets were sustained-release formulations administered to healthy volunteers. AUC values ​​for bupropion and hydroxybupropion. 0-12 The values ​​are also shown in Figure 1.

[0169] [Table 1]

[0170] Part 3 To investigate the safety and tolerability of pure S- and R-enantiomers of bupropion, a randomized, double-blind, multi-dose, placebo-controlled, parallel-group study was conducted using pharmacokinetic sampling. In this study, healthy adult subjects received 105 mg of S-bupropion, 105 mg of R-bupropion sustained-release tablets, or placebo (15 subjects per group) twice daily for 7 days under fasting conditions. The tablet dosage was increased from once daily from days 1 to 3 to twice daily thereafter, with the final dose administered on the morning of day 7. Plasma concentrations of bupropion and its metabolites were measured 3–4 hours after the dose on day 7. Chiral bioanalysis was used to measure the concentrations of bupropion and its major active metabolite, hydroxybupropion, enantiomers. The mean plasma concentrations measured for bupropion and hydroxybupropion are shown in Table 2 and Figure 2. As shown in Figure 3, the C of R,R-hydroxybupropion after administration of 105 mg of S-bupropion max The C2 level of R,R-hydroxybupropion was 1,268.5 ng / mL, which was the result of administering 105 mg of R-bupropion. max The value was 135.1 ng / mL.

[0171] [Table 2]

[0172] The above-mentioned dosage forms containing (S)-bupropion max It was between two and four hours.

[0173] Unless otherwise specified, all figures used in the specification and claims, representing properties such as the quantity of a component, the amount of a component, the AUC value, etc., should be understood in all cases to represent both the exact value shown and the value modified by the term "approximately." Therefore, unless otherwise indicated, numerical parameters described in the specification and the attached claims are approximations that may vary depending on the desired properties to be obtained. Each numerical parameter should be interpreted, at least in light of the reported number of significant figures and by applying common rounding techniques, not as an attempt to limit the application of the doctrine of equivalents to the claims.

[0174] In the context describing the present invention (particularly in the context of the following claims), the terms “a,” “an,” “the,” and similar reference subjects should be interpreted as including both singular and plural forms unless otherwise indicated or clearly contradicted by the context. All methods described herein may be carried out in any suitable order unless otherwise indicated herein or clearly contradicted by the context. Any examples or illustrative language provided herein (e.g., “such as”) are intended solely to better illustrate the present invention and do not impose limitations on the claims. Nothing in this specification should be interpreted as indicating any non-claimed element essential to the carrying out of the invention.

[0175] The grouping of alternative elements or embodiments disclosed herein should not be construed as limitation. Elements of each group may be referenced and claimed individually or in any combination with other elements of the group or other elements found herein. For convenience and / or patentability reasons, it is anticipated that one or more elements of a group may be included in or removed from a group. If such inclusion or removal occurs, the specification shall be deemed to include the modified group and thus satisfy the specification of all Markush groups used in the appended claims.

[0176] Specific embodiments, including the best mode known to the inventors for carrying out the present invention, are described herein. Of course, variations of these described embodiments will be apparent to those skilled in the art by reading the preceding description. The inventors expect that those skilled in the art will use such modifications as needed, and the inventors intend to carry out the present invention in ways other than those specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter described herein, as permitted by applicable law. Furthermore, unless otherwise indicated herein or unless it is clearly inconsistent by context, any combination of the above elements in all possible variations thereof is contemplated.

[0177] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be used are within the scope of the claims. These are, but are not limiting examples, alternative embodiments that can be utilized in accordance with the teachings herein. Thus, the claims are not limited to the embodiments precisely shown and described.

[0178] (Note) (Note 1) A method for treating a human being, comprising orally administering to the human being once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion.

[0179] (Note 2) A dosage form for treating a human condition, comprising at least 95% enantiomerically pure (S)-bupropion, wherein the dosage form is administered orally to the human once or twice daily.

[0180] (Note 3) The use of (S)-bupropion in the manufacture of a drug for treating a human condition, wherein the drug is administered orally to the human once or twice daily.

[0181] (Supplementary Note 4) A kit comprising a dosage form and a label, wherein the dosage form comprises at least 95% enantiomerically pure (S)-bupropion, and the label indicates that the dosage form is to be orally administered to a human once or twice a day for treating a human condition.

[0182] (Supplementary Note 5) The method, dosage form, use, or kit according to Supplementary Note 1, 2, 3, or 4, wherein the condition is a neurological disorder or a central nervous system disorder.

[0183] (Supplementary Note 6) The method, dosage form, use, or kit according to Supplementary Note 5, wherein the human is selected because of having the condition.

[0184] (Supplementary Note 7) The condition is treated by achieving a first AUC of bupropion 0-24 and the first AUC of bupropion 0-24 is the same as the reference AUC of bupropion resulting from administering a daily dose of racemic bupropion 0-24 where the daily dose of racemic bupropion is from about 150 mg to about 200 mg, the daily dose of (S)-bupropion is administered to the human to achieve the first AUC of bupropion 0-24 and the daily dose of (S)-bupropion is from about 60 mg to about 120 mg, the (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is from about 40% to about 60% of the daily dose of racemic bupropion. The method, dosage form, use, or kit according to Supplementary Note 6.

[0185] (Supplementary Note 8) The condition is treated by achieving a first AUC of bupropion 0-24 and the first AUC of bupropion 0-24This is the reference AUC of bupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 200 mg to approximately 250 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of bupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 80 mg to approximately 150 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0186] (Note 9) The aforementioned state is the first AUC of bupropion. 0-24 The treatment is achieved by achieving the first AUC of bupropion. 0-24 This is the reference AUC of bupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 250 mg to approximately 300 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of bupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 100 mg to approximately 180 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0187] (Note 10) The aforementioned state is the first AUC of bupropion. 0-24 The treatment is achieved by achieving the first AUC of bupropion. 0-24 This is the reference AUC of bupropion resulting from the administration of a daily dose of racemibpropion.0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 300 mg to approximately 350 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of bupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 120 mg to approximately 210 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0188] (Note 11) The aforementioned state is the first AUC of bupropion. 0-24 The treatment is achieved by achieving the first AUC of bupropion. 0-24 This is the reference AUC of bupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 350 mg to approximately 400 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of bupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to the human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 140 mg to approximately 240 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0189] (Note 12) The aforementioned state is the first AUC of bupropion. 0-24 The treatment is achieved by achieving the first AUC of bupropion. 0-24 This is the reference AUC of bupropion resulting from the administration of a daily dose of racemibpropion. 0-24The same applies, and the aforementioned daily dose of racemibpropion is approximately 400 mg to approximately 450 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of bupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 160 mg to approximately 270 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0190] (Note 13) The aforementioned state is the first AUC of hydroxybupropion. 0-24 The treatment is achieved by achieving the first AUC of hydroxybupropion. 0-24 This is the reference AUC of hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 150 mg to approximately 200 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 60 mg to approximately 120 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0191] (Note 14) The aforementioned state is the first AUC of hydroxybupropion. 0-24 The treatment is achieved by achieving the first AUC of hydroxybupropion. 0-24 This is the reference AUC of hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24The same applies, and the aforementioned daily dose of racemibpropion is approximately 200 mg to approximately 250 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 80 mg to approximately 150 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0192] (Note 15) The aforementioned state is the first AUC of hydroxybupropion. 0-24 The treatment is achieved by achieving the first AUC of hydroxybupropion. 0-24 This is the reference AUC of hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies to the aforementioned daily dose of racemibpropion, which is approximately 250 mg to approximately 300 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 100 mg to approximately 180 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0193] (Note 16) The aforementioned state is the first AUC of hydroxybupropion. 0-24 The treatment is achieved by achieving the first AUC of hydroxybupropion. 0-24 This is the reference AUC of hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24The same applies, and the aforementioned daily dose of racemibpropion is approximately 300 mg to approximately 350 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 120 mg to approximately 210 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0194] (Note 17) The aforementioned state is the first AUC of hydroxybupropion. 0-24 The treatment is achieved by achieving the first AUC of hydroxybupropion. 0-24 This is the reference AUC of hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 350 mg to approximately 400 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to the human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 140 mg to approximately 240 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0195] (Note 18) The aforementioned state is the first AUC of hydroxybupropion. 0-24 The treatment is achieved by achieving the first AUC of hydroxybupropion. 0-24 This is the reference AUC of hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24The same applies to the aforementioned daily dose of racemibpropion, which is approximately 400 mg to approximately 450 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 160 mg to approximately 270 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0196] (Note 19) The aforementioned state is the first AUC of (R,R)-hydroxybupropion. 0-24 The treatment is achieved by achieving the aforementioned first AUC of (R,R)-hydroxybupropion. 0-24 This is the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 150 mg to approximately 200 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of (R,R)-hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 60 mg to approximately 120 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0197] (Note 20) The aforementioned state is the first AUC of (R,R)-hydroxybupropion. 0-24 The treatment is achieved by achieving the aforementioned first AUC of (R,R)-hydroxybupropion. 0-24This is the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 200 mg to approximately 250 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of (R,R)-hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 80 mg to approximately 150 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0198] (Note 21) The aforementioned state is the first AUC of (R,R)-hydroxybupropion. 0-24 The treatment is achieved by achieving the aforementioned first AUC of (R,R)-hydroxybupropion. 0-24 This is the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 250 mg to approximately 300 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of (R,R)-hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 100 mg to approximately 180 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0199] (Note 22) The aforementioned state is the first AUC of (R,R)-hydroxybupropion. 0-24is treated by achieving the first AUC of (R,R)-hydroxybupropion 0-24 which is the reference AUC of (R,R)-hydroxybupropion resulting from administering a daily dose of racemic bupropion 0-24 where the daily dose of racemic bupropion is from about 300 mg to about 350 mg, and the daily dose of (S)-bupropion is administered to the human to achieve the first AUC of (R,R)-hydroxybupropion 0-24 where the daily dose of (S)-bupropion is from about 120 mg to about 210 mg, the (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is from about 40% to about 60% of the daily dose of racemic bupropion, the method, dosage form, use or kit according to appendix 6

[0200] (Appendix 23) the condition is treated by achieving the first AUC of (R,R)-hydroxybupropion 0-24 which is the reference AUC of (R,R)-hydroxybupropion resulting from administering a daily dose of racemic bupropion 0-24 where the daily dose of racemic bupropion is from about 350 mg to about 400 mg, and the daily dose of (S)-bupropion is administered to the human to achieve the first AUC of (R,R)-hydroxybupropion 0-24 where the daily dose of (S)-bupropion is from about 140 mg to about 240 mg, the (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with the daily dose of (S)-bupropion, and the daily dose of (S)-bupropion is from about 40% to about 60% of the daily dose of racemic bupropion, the method, dosage form, use or kit according to appendix 6 0-24 the condition is treated by achieving the first AUC of (R,R)-hydroxybupropion

[0201] (Appendix 24) The aforementioned state is the first AUC of (R,R)-hydroxybupropion. 0-24 The treatment is achieved by achieving the aforementioned first AUC of (R,R)-hydroxybupropion. 0-24 This is the reference AUC of (R,R)-hydroxybupropion resulting from the administration of a daily dose of racemibpropion. 0-24 The same applies, and the aforementioned daily dose of racemibpropion is approximately 400 mg to approximately 450 mg, and the daily dose of (S)-bupropion is the same as the aforementioned first AUC of (R,R)-hydroxybupropion. 0-24 The method, dosage form, use, or kit as described in Appendix 6, administered to a human being to achieve the above, wherein the daily dose of the (S)-bupropion is approximately 160 mg to approximately 270 mg, the (S)-bupropion is at least 95% enantiomerically pure, no other bupropion is administered together with the daily dose of the (S)-bupropion, and the daily dose of the (S)-bupropion is approximately 40% to approximately 60% of the daily dose of racemipupion.

[0202] (Note 25) The (S)-bupropion is administered once daily according to any one of the methods described in Appendix 1 to 24.

[0203] (Note 26) The method according to any one of the appendices 1 to 24, wherein the (S)-bupropion is administered in two doses per day, and the total of the two daily doses is the daily dose.

[0204] (Note 27) The method according to any one of the appendices 1 to 26, wherein the (S)-bupropion is administered for at least 8 consecutive days.

[0205] (Note 28) The method according to any one of the appendices 1 to 27, wherein the (S)-bupropion is administered for at least 14 consecutive days.

[0206] (Note 29) The method according to any one of the appendices 1 to 28, wherein the (S)-bupropion is administered for at least 21 consecutive days.

[0207] (Note 30) The method according to any one of the appendices 1 to 29, wherein the (S)-bupropion is administered for at least 28 consecutive days.

[0208] (Note 31) The method according to any one of the appendices 1 to 30, wherein the (S)-bupropion is administered in a dosage form that provides sustained release of (S)-bupropion.

[0209] (Note 32) The aforementioned dosage form is (S)-bupropion, which has an effective duration of approximately 2 to 4 hours. max The method described in Appendix 31, which is formulated to have the following properties.

[0210] (Note 33) The above method provides an AUC of (S)-bupropion in humans that is at least about 300 ng·hr / mL. 0-12 A method to achieve any one of the methods described in Appendix 1 to 32.

[0211] (Note 34) The above method provides an AUC of (S)-bupropion in humans that is at least about 400 ng·hr / mL. 0-12 A method to achieve any one of the methods described in Appendix 1 to 33.

[0212] (Note 35) The above method is used to determine the AUC of (S)-bupropion in humans, ranging from approximately 500 ng·hr / mL to approximately 900 ng·hr / mL. 0-12 A method to achieve any one of the methods described in Appendix 1 to 34.

[0213] (Note 36) The above method involves the C20 max A method to achieve any one of the methods described in Appendix 1 to 35.

Claims

1. A composition for treating a human condition, A single dose contains approximately 80 mg to 120 mg of (S)-bupropion that is at least 95% enantiomerically pure. The dosage form is a sustained-release tablet with a T max of approximately 2 to 4 hours. The composition is administered orally to a human once or twice daily, and is effective in treating the same condition in the human compared to the administration of a composition containing the same amount of (R)-bupropion, in terms of increasing the AUC 0-12 (ng·h / mL) of bupropion and hydroxybupropion, increasing the mean plasma concentration (ng / mL) of bupropion, and increasing the C max (ng / mL) of R,R-hydroxybupropion.

2. The composition according to claim 1, wherein the condition is a neurological disorder or a central nervous system disorder.

3. The composition according to claim 1 or 2, wherein the human is selected because of the aforementioned condition.

4. The composition according to any one of claims 1 to 3, wherein the (S)-bupropion is administered once daily.

5. The composition according to any one of claims 1 to 3, wherein the (S)-bupropion is administered in a dose twice daily, and the total of the twice daily doses is the daily dose.

6. The composition according to any one of claims 1 to 5, wherein the (S)-bupropion is administered for at least eight consecutive days.

7. The composition according to any one of claims 1 to 6, wherein the (S)-bupropion is administered for at least 14 consecutive days.

8. The composition according to any one of claims 1 to 7, wherein the (S)-bupropion is administered continuously for at least 21 days.

9. The composition according to any one of claims 1 to 8, wherein the (S)-bupropion is administered continuously for at least 28 days.

10. The composition has an AUC of at least about 300 ng·hr / mL of (S)-bupropion in humans. ０－１２ A composition according to any one of claims 1 to 9, which provides the following:

11. The composition has an AUC of at least about 400 ng·hr / mL of (S)-bupropion in humans. ０－１２ A composition according to any one of claims 1 to 10, which provides the following:

12. The composition has an AUC of (S)-bupropion in humans, ranging from approximately 500 ng·hr / mL to approximately 900 ng·hr / mL. ０－１２ A composition according to any one of claims 1 to 11, which provides the following:

13. The composition is a C2 (S)-bupropion C2 concentration in humans ranging from approximately 60 ng / mL to approximately 140 ng / mL. ｍａｘ A composition according to any one of claims 1 to 12, which provides the following:

14. The composition according to any one of claims 1 to 13, wherein the composition substantially contains no active pharmaceutical ingredient other than (S)-bupropion.

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