JP2022549192A - Dosage Forms of Enantiomerically Enriched or Pure Bupropion - Google Patents

Abstract

The present disclosure provides enantiomerically enriched (S)-bupropion, enantiomerically enriched (S)-bupropion, or enantiomerically pure (S)-bupropion. Dosage forms including concentrated or pure dosage forms and methods of using these dosage forms. These dosage forms may be administered to humans in smaller amounts compared to the amount of racembupropion that would be administered in the same circumstances. [Selection figure] None

Description

Cross-reference to related applications No. 62,992,060, filed March 19, 2020, and this application is also a continuation-in-part of Serial No. 16/830,637, filed March 26, 2020. , this application is also a continuation-in-part of International Patent Application No. PCT/US2019/052210 filed on September 20, 2019, and this application is also a continuation-in-part of International Patent Application No. 16/US2019/052210 filed on June 22, 2020. 907,691, all of which are hereby incorporated by reference in their entireties.

Bupropion is approved for human use as a racemic mixture. Bupropion and its metabolites were believed by many to undergo rapid racemization in the human body.

Described herein contain enantiomeric excess (S)-bupropion, enantiomerically enriched (S)-bupropion, or enantiomerically pure (S)-bupropion Dosage forms, and methods of using those dosage forms. These dosage forms can be administered to humans in lower amounts compared to the amount of racemic bupropion administered in the same circumstances.

Some embodiments select a human patient in need of a pharmacokinetic profile provided by oral administration of a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and A second amount of (S)-bupropion that is at least 95% enantiomerically pure to obtain the same pharmacokinetic profile as obtained by administering said reference dosage form at said first dosing frequency orally administering a dosage form containing said first dosing frequency, wherein said first dosing frequency is once a day or twice a day, and said second amount is equal to said first of about 20-70%, about 40-60%, about 45-55%, or about 50% of the amount of bupropion in human plasma. For example, oral administration of a dosage form containing 150 mg of racemic bupropion can produce a particular pharmacokinetic profile, and said second amount is 40-60% of said first amount. If so, said second amount is 60-90 mg. Thus, in this situation, 60-90 mg of (S)-bupropion once daily, or , 60-90 mg of (S)-bupropion twice daily to produce the same pharmacokinetic profile as that obtained with 150 mg racemic bupropion twice daily.

For the purposes of this disclosure, if a dosage form containing enantiomerically pure (S)-bupropion is accepted by the FDA as bioequivalent to a dosage form containing racemic bupropion, then that The two dosage forms have the same pharmacokinetic profile.

Some embodiments select a human patient having a condition treatable by oral administration of a first dose frequency of a reference dosage form containing a first amount of racemic bupropion, and said reference agent A dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure to obtain the same therapeutic effect as obtained by administering the form at said first dosing frequency. at said first dosing frequency, wherein said first dosing frequency is once daily or twice daily, and said second amount is about said first amount Methods of treating racembupropion-treatable conditions that are 20-70%, about 40-60%, about 45-55%, or about 50% are included. For example, if a condition is treatable by oral administration of a dosage form containing 150 mg of racemic bupropion, and said second amount is 40-60% of said first amount, said second amount is 60-90 mg. Therefore, in this situation, 60-90 mg of (S)-bupropion daily to treat the condition would provide the same therapeutic effect as would be obtained with 150 mg of racemic bupropion administered once daily. 60-90 mg of (S)-bupropion twice daily to treat the condition to provide the same therapeutic effect as a single dose and 150 mg of racemic bupropion twice daily. dose.

Some embodiments are methods of treating a human comprising orally administering to the human a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily. including.

Some embodiments comprise a dosage form for treating a condition in a human comprising at least 95% enantiomerically pure (S)-bupropion, said dosage form administered to said human once daily or twice orally.

Some embodiments comprise the use of at least 95% enantiomerically pure (S)-bupropion in the manufacture of a medicament for treating a human condition, wherein the medicament is administered to the human once daily or twice orally.

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 human is administered orally to said human once or twice daily to treat the condition of

AUC _0-12 values of bupropion and hydroxybupropion in healthy volunteers after administration of S-bupropion and racemic bupropion tablets. Mean plasma levels of bupropion and hydroxybupropion after administration of (S)-bupropion or (R)-bupropion tablets. C _max of R,R-hydroxybupropion after administration of (S)-bupropion or (R)-bupropion tablets.

(S)-Bupropion administered to humans can be enantiomerically pure or enantiomerically enriched. For example, (S)-bupropion is 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, 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, any of the above may be referred to as "(S)-bupropion." increasing levels of (S)-bupropion and/or (R,R)-hydroxybupropion is therapeutically beneficial or in humans in need of treatment with (S)-bupropion and/or (R,R)-hydroxybupropion If it is for treatment, this type of dosage form can help treat the condition.

Oral administration of (S)-bupropion was found to be bioequivalent or pharmacokinetically equivalent to approximately twice the administration of racemic bupropion. For example, a 75 mg dose of (S)-bupropion is bioequivalent to an approximately 150 mg dose of racemic bupropion.

(S)-Bupropion can be administered alone or in combination with other agents. However, in some therapies, (S)-bupropion or (R,R)-hydroxybupropion may not be desirable to use other agents. For example, (S)-bupropion or (R,R)-hydroxybupropion may be the only compounds needed to treat the condition, and additional agents may not provide significant benefit. Also, adding additional agents may unacceptably increase the risk of adverse events outweighing any potential benefits they may provide. Thus, some dosage forms are substantially free of other agents and some treatments include administration of (S)-bupropion without co-administration of other drugs. For example, the 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 or no other drug.

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

For example, the dosage forms and methods can be used to treat neurological disorders, central nervous system disorders, psychiatric disorders, neuropsychiatric disorders, or related conditions.

The terms "treating" or "treatment" include the diagnosis, cure, mitigation, treatment or prevention of disease in humans or other animals, or any activity that affects the structure or function of the human or other animal body. .

Administration of (S)-bupropion, such as by oral administration, can occur once or more than once a day, or once or more than once a day for several days, such as several consecutive days. For example, (S)-bupropion is 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 in one day One or two doses may be administered. The patient can be fasted before and/or after oral administration of a dosage form containing (S)-bupropion.

To reduce the risk of seizures or other adverse events, it may be useful to start with a lower starting daily dose of (S)-bupropion, then increase the dose to a higher target daily dose. "Daily dose" refers to the total amount of bupropion given in a day (eg, a dose of 75 mg in the morning and 75 mg in the evening is a daily dose of 150 mg). For example, a lower starting daily dose is a lower total amount of bupropion given daily and a higher target daily dose is a higher total amount of bupropion given daily. One way to achieve this is to use dosage forms containing lower doses of (S)-bupropion alone or in combination with other agents once or twice daily, 1, 2, 3 , 4, 5, 6, 7, or more days followed by a higher dose of (S)-bupropion at the same dosing frequency used for the lower dose. is to treat with For example, a dosage form containing a lower dose of (S)-bupropion is administered once daily on days 1, 2, and 3, followed by a higher dose of (S)-bupropion once daily starting on day 4 and 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. Once daily can continue for the duration, or the remainder of the treatment period. Alternatively, a dosage form containing a lower dose of (S)-bupropion was administered twice daily on days 1, 2, and 3, followed by a higher dose of (S)-bupropion on day 4. and twice daily from , 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59, 60, 61-89, 90 or more consecutive days, or therapeutic Twice daily may continue for the remainder of the period.

Another way to accomplish this, for example increasing from a lower starting daily dose to a higher target dose, is to use a dosage form containing (S)-bupropion, alone or in combination with other agents, By administration once daily for 1, 2, 3, 4, 5, 6, 7, or more days, followed by twice daily treatment. For example, a dosage form containing (S)-bupropion is administered once daily on days 1, 2, and 3, then twice daily from day 4, and then on days 2, 3, and 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, Continue twice daily for long periods such as 49, 50-55, 56, 57-59, 32-59, 60, 61-89, 90 or more consecutive days or for the remainder of the treatment period can be done. (S)-Bupropion has the structure shown below.

Unless otherwise specified, references herein by structure, name, or otherwise to compounds such as (S)-bupropion are pharmaceutically acceptable salts, polymorphs, crystals, solvates, hydrates, etc. Alternative solid forms such as compounds, tautomers, isotopically enriched compounds (e.g. deuterium-enriched bupropion), or compounds described herein where the compound was used as described herein Any chemical species that can change rapidly under conditions.

Any suitable amount of (S)-bupropion as a dosage form containing (S)-bupropion, such as at least 95%, at least 97%, at least 99%, or at least 99.9% enantiomerically pure bupropion can be used. In some embodiments, the dosage form is 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 150-200 mg, about 100-200 mg, about 1-10 mg, about 10-20 mg, about 20-30 mg, about 30-40 mg, about 40 -50 mg, about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-110 mg, about 100-120 mg, about 120-150 mg, about 1-30 mg, about 20 -50 mg, about 50-80 mg, about 80-120 mg, about 100-150 mg, about 150-180 mg, about 180-200 mg, about 70-95 mg, about 50-70 mg, about 60-80 mg, about 60-90 mg, about 70 -80 mg, about 70-74 mg, about 72-76 mg, about 74-76 mg, about 74-78 mg, about 70-90 mg, about 30-60 mg, about 40-75 mg, about 50-90 mg, about 60-105 mg, about 60 -120 mg, about 70-120 mg, about 80-135 mg, about 80-150 mg, about 100-180 mg, about 120-210 mg, about 140-240 mg, about 160-270 mg, about 70 mg, about 75 mg, about 80 mg, about 100 mg (S)-Bupropion, or any amount within the range bounded by any of these values. Ranges of amounts of (S)-bupropion obtained by combining any of the above ranges or endpoints are also contemplated, wherein the resulting range is one or more of the amounts of (S)-bupropion in the dosage form. It is specifically contemplated to include or be close to the following values of: about 60 mg, about 75 mg, or about 90 mg. These are possible values of potential particular utility. Dosage forms containing (S)-bupropion in the amounts listed above may be administered once, twice or three times daily in a daily dose (i.e., any dose amount listed above or any A daily dose range of 1, 2 or 3 doses may be administered, for example a daily dose of 100-200 mg twice at 50-100 mg or a daily dose of 150-300 mg at 50-100 mg three times). 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 contemplated, wherein the resulting range is one or more It is specifically contemplated to include or be close to the following values of: about 120 mg, about 150 mg, or about 180 mg. These are values considered potentially somewhat more beneficial for average-sized adults. Lower doses, such as about 1-50 mg or about 1-70 mg administered once or twice daily, may be somewhat more useful in treating children. Higher doses, such as amounts greater than about 100 mg administered two or three times daily, may be somewhat more useful in treating larger adults.

The daily dose of (S)-bupropion is determined by specific pharmacokinetic parameters (bupropion, (S)-bupropion, hydroxybupropion, (R,R)-hydroxybupropion, (S ,S)-Hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or another metabolite of racemic bupropion, or a combination thereof, C _max , AUC (eg, AUC _0-12 , AUC _0-24 , or AUC _{0- inf} ) and/or another pharmacokinetic parameter). For example, the daily dose of (S)-bupropion is about 100-500 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, or about Pharmacokinetic parameters resulting from daily doses of 450-500 mg racemic bupropion can be targeted and administered. To achieve its pharmacokinetic parameters, for example, the daily dose of (S)-bupropion administered is about 20-70%, about 40-60%, about 45-55% of the daily dose of racemic bupropion. , or about 50%.

Since (S)-bupropion is surprisingly the major source of bupropion and bupropion metabolites present in the blood, the amount of (S)-bupropion administered to humans may be similar to treating the same condition with the same effect. can be considerably less than the amount of racemic bupropion (or (R)-bupropion) administered to For example, if the amount of racemic bupropion administered to treat a condition is 150 mg, then to achieve similar effects, 5-50% or 20-70% of that amount, such as 30-105 mg, Lower doses of (S)-bupropion are administered. In some embodiments, the amount of (S)-bupropion administered is about 5-70%, about 5-50% of the amount of racemic bupropion that would be administered to treat the same human with the same condition. %, about 20-70%, about 5-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, It is selected to be about 20-50%, about 40-70%, about 40-60%, about 40-45%, or about 45-55%.

Some solid compositions 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% by weight. %, about 50-80%, about 80-95%, about 10-50%, about 30-70%, or about 50-90% (S)-bupropion.

In some embodiments, the dosage form may be free or substantially free of any active pharmaceutical ingredient or drug other than (S)-bupropion. For example, the dosage form may contain less than 10%, less than 5%, 1%, or less than 0.1% by weight of the other active pharmaceutical ingredient compared to the weight of (S)-bupropion.

Administration of (S)-bupropion reduces the amount of (S)-bupropion compared to plasma levels of (R)-bupropion obtained by administering a dosage form containing the same amount of (R)-bupropion to humans. plasma levels 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 1.5-fold 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-fold 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 It may be useful to increase 180-190 fold, or about 190-200 fold.

In some embodiments, the method compares the AUC _0-12 of (R)-bupropion obtained by administering a dosage form containing the same amount of (R)-bupropion to a human as compared to (S ₎ -Bupropion _{at least} about 1.1 _- fold _, at least about 1 .2 times, at least about 1.3 times, at least about 1.4 times, at least about 1.5 times, at least about 1.6 times, at least about 1.7 times, at least about 1.8 times, at least about 1.0 times. 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, at least about 8-fold, at least about 10-fold, about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-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-fold 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 It is effective in increasing 180-190 fold, or about 190-200 fold.

In some embodiments, the method comprises 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, at least about 1,000 ng-hr/mL , at least about 1,100 ng-hr/mL, up to about 1,200 ng-hr/mL, up to about 1,300 ng-hr/mL, up to about 1,400 ng-hr/mL, up to 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/mL, about 700-800 ng-hr/mL, about 800-900 ng-hr/mL, about 900-1,000 ng-hr/mL, about 1,000 -1,100 ng-hr/mL, about 1,100-1,200 ng-hr/mL, about 1,200-1,300 ng-hr/mL, about 1,300-1,400 ng-hr/mL, about 1 , 400-1,500 ng-hr/mL, about 1,500-1,600 ng-hr/mL, about 1,600-1,700 ng-hr/mL, about 1,700-1,800 ng-hr/mL, about 300-600 ng-hr/mL, about 600-900 ng-hr/mL, about 900-1,200 ng-hr/mL, about 1,200-1,500 ng-hr/mL, about 1,500-1,800 ng hr/mL, about 300-800 ng-hr/mL, about 800-1,300 ng-hr/mL, about 1,300-1,800 ng-hr/mL, or about 300-1,800 ng-hr/mL AUC 0-12, such as representative AUC _0-12 , mean AUC _{0-12 ,} median AUC _0-12 , or individual AUC _0-12 for a given (S)-bupropion is achieved. A range of AUC _0-12 obtained by combining any of the above ranges or endpoints is also contemplated, wherein the resulting range is AUC _0-12 with the following values: 350 ng-hr/mL, 400 ng-hr/mL. , 750 ng-hr/mL, or 900 ng-hr/mL. These are values that are potentially of particular utility.

In some embodiments, the method provides a representative C _max , mean C C _max , such as median C _max , or individual C _max , at least about 1.1 times, at least about 1.2 times, at least about 1.3 times, at least _about 1.4 times, at least about 1.5 times. 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, at least about 8-fold, about 5-20-fold, at least about 10-fold, about 10-fold, at least about 20-fold, at least about 25-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 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 times effective to increase by 150-fold, about 150-160-fold, about 160-170-fold, about 170-180-fold, about 180-190-fold, or about 190-200-fold.

In some embodiments, the method reduces the /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, at least about 125 ng/mL, up to about 130 ng/mL, up to about 140 ng/mL up to about 150 ng/mL, up to about 160 ng/mL, up to about 170 ng/mL, up to about 180 ng/mL, up to about 190 ng/mL, up to about 200 ng/mL, up to about 210 ng/mL, up to about 220 ng/mL, about 30-40 ng/mL, about 40-50 ng/mL, about 50-60 ng/mL, about 60-70 ng/mL, about 70-80 ng/mL, about 80-90 ng/mL, about 90-100 ng/mL, about 100 -110 ng/mL, about 110-120 ng/mL, about 120-130 ng/mL, about 130-140 ng/mL, about 140-150 ng/mL, about 150-160 ng/mL, about 160-170 ng/mL, about 170- 180 ng/mL, about 180-190 ng/mL, about 190-200 ng/mL, about 200-210 ng/mL, about 210-220 ng/mL, about 50-70 ng/mL, about 70-90 ng/mL, about 30-60 ng /mL, about 60-90 ng/mL, about 90-120 ng/mL, about 120-160 ng/mL, about 160-220 ng/mL, about 30-90 ng/mL, about 90-150 ng/mL, about 150-220 ng/mL mL, _about 30-110 ng/mL, about 110-220 ng/mL, or about 30-220 _ng / _mL of (S)-bupropion; Achieving C _max , such as C _max . Ranges of C _max obtained by combining any of the above ranges or endpoints are also contemplated, wherein the resulting range comprises one or more of the following values for C _max : 45 ng/mL, 90 ng/mL, 125 ng/mL Including or approximating mL, 150 ng/mL, or 180 ng/mL is specifically contemplated. These are values that are potentially of particular utility.

In some embodiments, the method provides a representative C _min , mean C C _min , such as median C _min , or individual C _min , at least about 1.1 times, at least about 1.2 times, at least about 1.3 times, at least _about 1.4 times, at least about 1.5 times. 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, at least about 8-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-fold -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 70-80 times, about 80-90 times 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, Effective for about 170-180 fold, about 180-190 fold, or about 190-200 fold increase.

In some embodiments, the method comprises 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- C min of (S)-bupropion that is 50 ng/mL, about 40-50 ng/mL, or about 50-60 ng/mL, _{such as the representative C min , mean C min , median C min , or individual} C _min achieve a C _min of Ranges of C _min obtained by combining any of the above ranges or endpoints are also contemplated, wherein the resulting range comprises one or more of the following values for C _min : 20 ng/mL, 30 ng/mL, 40 ng/mL. , or 50 ng/mL, including or near is specifically contemplated. These are values that are potentially of particular utility.

Administering (S)-bupropion reduces the plasma levels of (R,R)-hydroxybupropion by at least about 1% compared to administering a dosage form containing the same amount of (R)-bupropion to a human. .1-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 40-fold, at least about 50-fold , at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 5-10-fold, about 5-25-fold, about 5-20-fold, about 20-30-fold, about 30-40-fold , about 40-50 times, about 50-60 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 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold increase .

Administering (S)-bupropion increased the typical AUC _{0- 12} , mean AUC _0-12 , median AUC _0-12 , or individual AUC _0-12 at least about 1.1-fold, at least about 1.5-fold, at least _about 2-fold; at least about 3-fold, at least about 5-fold, about 6-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200 times or more, about 5-10 times, about 5-25 times, about 5-20 times, about 20-30 times, about 30-40 times, about 40-50 times, about 50-60 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 It may be useful to increase by 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold.

In some embodiments, the method comprises 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, at least about 9,000 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 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, 000 ng-hr/mL, about 14,000-16,000 ng-hr/mL, about 16,000-18,000 ng-hr/mL, about 18,000-20,000 ng-hr/mL, about 20,000- 22,000 ng-hr/mL, about 22,000-24,000 ng-hr/mL, about 4,000-10,000 ng-hr/mL, about 10,000-16,000 ng-hr/mL, about 16, 000-24,000 ng-hr/mL, about 4,000-24,000 ng-hr/mL, up to about 14,000 ng-hr/mL, up to about 16,000 ng-hr/mL, up to about 18,000 ng-hr /mL, up to about 20,000 ng-hr/mL, up to about 22,000 ng-hr/mL, up to about 24,000 ng-hr/mL, or up to about 30,000 ng-hr/mL (R, R) - achieve AUC 0-12, such as representative AUC _0-12 , mean AUC _0-12 , median AUC _0-12 , or individual _{AUC 0-12 for} hydroxybupropion. A range of AUC _0-12 obtained by combining any of the above ranges or endpoints is also contemplated, wherein the resulting range is AUC _0-12 with the following values: 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. These are values that are potentially of particular utility.

Administering (S)-bupropion reduces the typical C _max of (R,R)-hydroxybupropion to _{Cmax, such} as mean Cmax, median _Cmax , or individual _Cmax , at least about 1.1 times, at least about 1.2 times, at least about 1.3 times, at least about 1.4 times; 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 times, at least about 4 times, at least about 5 times, about 6 times, at least about 10 times, at least about 20 times, at least about 50 times, at least about 100 times, at least about 150 times, at least about 200 times, or more , about 5-10 times, about 10-20 times, about 5-20 times, about 20-30 times, about 30-40 times, about 40-50 times, about 50-60 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- It may be useful to increase by 170-fold, about 170-180-fold, about 180-190-fold, or about 190-200-fold.

In some embodiments, the method comprises 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, at least about 1,200 ng/mL, at least about 1,300 ng/mL, up to about 1,400 ng/mL mL, up to about 1,500 ng/mL, up to about 1,600 ng/mL, up to about 1,700 ng/mL, up to about 1,800 ng/mL, up to about 1,900 ng/mL, up to about 2,000 ng/mL, up to about 2,100 ng/mL, up to about 2,200 ng/mL, up to about 2,300 ng/mL, about 300-400 ng/mL, about 400-500 ng/mL, about 500-600 ng/mL, about 600-700 ng/mL mL, about 700-800 ng/mL, about 800-900 ng/mL, about 900-1,000 ng/mL, about 1,000-1,100 ng/mL, about 1,100-1,200 ng/mL, about 1, 200-1,300 ng/mL, about 1,300-1,400 ng/mL, about 1,400-1,500 ng/mL, about 1,500-1,600 ng/mL, about 1,600-1,700 ng/mL mL, about 1,700-1,800 ng/mL, about 1,800-1,900 ng/mL, about 1,900-2,000 ng/mL, about 2,000-2,100 ng/mL, about 2,100 -2,200 ng/mL, about 2,200-2,300 ng/mL, about 300-800 ng/mL, about 800-1,300 ng/mL, about 1,300-2,300 ng/mL, or about 300-2 , 300 ng/mL of (R,R)-hydroxybupropion to achieve a C _max , such as a representative C _max , mean C _max , median C _max , or individual C _max . Also contemplated is a range of AUC _0-12 obtained by combining any of the above ranges or endpoints, wherein the resulting range is C _max with the following values: 400 ng/mL, 950 ng/mL, 1,500 ng/mL. , or 2,100 ng/mL, is specifically contemplated. These are values that are potentially of particular utility.

Administering (S)-bupropion reduces the typical C _min , C min such as mean C _{min ,} median C _min , or individual C _min at least about 1.1 times, at least about 1.2 times, at least about 1.3 times, at least about 1.4 times, 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, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 60-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more , about 1-5 times, about 5-10 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 times It may be useful to increase by 160-fold, about 160-170-fold, about 170-180-fold, about 180-190-fold, or about 190-200-fold.

In some embodiments, the method provides at least about 150 ng/mL, at least about 200 ng/mL, 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, at least about 1,200 ng/mL, up to about 1,300 ng/mL, up to about 1 , 400 ng/mL, up to about 1,500 ng/mL, up to about 1,600 ng/mL, up to about 1,700 ng/mL, up to about 1,800 ng/mL, up to about 1,900 ng/mL, up to about 2,000 ng /mL, up to about 2,100 ng/mL, up to about 2,200 ng/mL, up to about 2,300 ng/mL, about 200-300 ng/mL, about 300-400 ng/mL, about 400-500 ng/mL, about 500 -600 ng/mL, about 600-700 ng/mL, about 700-800 ng/mL, about 800-900 ng/mL, about 900-1,000 ng/mL, about 1,000-1,100 ng/mL, about 1,100 -1,200 ng/mL, about 1,200-1,300 ng/mL, about 1,300-1,400 ng/mL, about 1,400-1,500 ng/mL, about 1,500-1,600 ng/mL , about 300-700 ng/mL, about 700-1,100 ng/mL, or about 1,100-1,600 ng/mL (R,R)-hydroxybupropion, a typical C _min , a mean C _min , A C _min is achieved, such as the median C _min , or the individual C _min . Also contemplated is a range of C _min obtained by combining any of the above ranges or endpoints, the resulting range having the following values for C _min : 350 ng/mL, 600 ng/mL, 700 ng/mL, 1,000 ng. /mL, or including or near one or more of 1,400 ng/mL. These are values that are potentially of particular utility.

Administering (S)-bupropion to humans reduces the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in human plasma by at least 90%, 95%, 97%, It can be 97.2%, 97.4%, 97.6%, 97.8%, or 98% (R,R)-hydroxybupropion.

In some embodiments, the method comprises at least about 500 ng-hr/mL, at least about 600 ng-hr/mL, at least about 800 ng-hr/mL, at least about 1,000 ng-hr/mL, at least about 1,200 ng-hr/mL. hr/mL, maximum about 1,400 ng-hr/mL, maximum about 1,600 ng-hr/mL, maximum about 1,800 ng-hr/mL, maximum about 2,000 ng-hr/mL, maximum about 2,200 ng・hr/mL, maximum about 2,400 ng・hr/mL, maximum about 2,600 ng・hr/mL, maximum about 2,800 ng・hr/mL, maximum about 3,000 ng・hr/mL, about 500-600 ng・hr/mL, about 600-800 ng-hr/mL, about 800-1,000 ng-hr/mL, about 1,000-1,200 ng-hr/mL, about 1,200-1,400 ng-hr/mL, About 1,400-1,600 ng-hr/mL, about 1,600-1,800 ng-hr/mL, about 1,800-2,000 ng-hr/mL, about 2,000-2,200 ng-hr/mL mL, about 2,200-2,400 ng-hr/mL, about 2,400-2,600 ng-hr/mL, about 2,600-2,800 ng-hr/mL, about 2,800-3,000 ng-hr/mL hr/mL, about 500-1,000 ng-hr/mL, about 1,000-1,500 ng-hr/mL, about 1,500-2,000 ng-hr/mL, about 2,000-2,500 ng-hr/mL hr/mL, about 2,500-3,000 ng-hr/mL, about 500-1,500 ng-hr/mL, about 1,500-3,000 ng-hr/mL, about 2,000-3,000 ng-hr/mL hr/mL, or about 500-3,000 ng·hr/mL, of erythrohydroxybupropion, representative AUC _0-12 , mean AUC _0-12 , median AUC _0-12 , or individual AUC _0-12 Achieve an AUC _0-12, such as ₁₂ . A range of AUC _0-12 obtained by combining any of the above ranges or endpoints is also contemplated, wherein the resulting range is 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. These are values that are potentially of particular utility.

In some embodiments, the method provides 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 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; to achieve a C _max such as a representative C _max , mean C _max , median C _max , or individual C _max of erythrohydroxybupropion that is Also contemplated is a range of _Cmax obtained by combining any of the above ranges or endpoints, wherein the resulting range has the following values for _Cmax : 60 ng/mL, 120 ng/mL, 200 ng/mL, or 240 ng/mL. Including or near one or more of mL is specifically contemplated. These are values that are potentially of particular utility.

In some embodiments, the method comprises 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, AUC 0-12 is achieved for a given threohydroxybupropion, such as representative AUC _0-12 , mean AUC _0-12 , _median AUC _0-12 , or individual AUC _0-12 . A range of AUC _0-12 obtained by combining any of the above ranges or endpoints is also contemplated, wherein the resulting range is AUC _0-12 with the following values: 3,000 ng·hr/mL, 6,000 ng Including or near one or more of • hr/mL, 8,000 ng • hr/mL, or 12,000 ng • hr/mL is specifically contemplated. These are values that are potentially of particular utility.

In some embodiments, the method provides at least about 200 ng/mL, at least about 300 ng/mL, at least about 400 ng/mL, at least about 450 ng/mL, at least about 500 ng/mL, at least about 600 ng/mL, at least about 700 ng /mL, up to about 800 ng/mL, up to about 900 ng/mL, up to about 1,000 ng/mL, up to about 1,100 ng/mL, up to about 1,200 ng/mL, up to about 1,300 ng/mL, up to about 1 , 400 ng/mL, about 200-300 ng/mL, about 300-400 ng/mL, about 400-500 ng/mL, about 500-600 ng/mL, about 600-700 ng/mL, about 700-800 ng/mL, about 800- 900 ng/mL, about 900-1000 ng/mL, about 1,000-1,100 ng/mL, about 1,100-1,200 ng/mL, about 1,200-1,300 ng/mL, about 1,300-1 , 400 ng/mL, about 200-500 ng/mL, about 500-800 ng/mL, about 800-1,100 ng/mL, about 1,100-1,400 ng/mL, about 200-800 ng/mL, about 800-1400 ng A C max is achieved, such as a _{representative} C _max , mean C max _, median C _max , or individual C _max , of threohydroxybupropion that is approximately 200-1,400 ng/mL, or approximately 200-1,400 ng/mL. Also contemplated is a range of _Cmax obtained by combining any of the above ranges or endpoints, wherein the resulting range has the following values for _Cmax : 300 ng/mL, 600 ng/mL, 900 ng/mL, or 1, Including or near one or more of 200 ng/mL is specifically contemplated. These are values that are potentially of particular utility.

Unless otherwise specified, reference to compounds herein, such as (S)-bupropion, by structure, name, or otherwise, may include pharmaceutically acceptable salts, polymorphs, crystals, solvates, water Alternate solids such as hydrates, tautomers, deuterium-modified compounds, or compounds described herein can be rapidly converted to Any chemical species that can vary.

(S)-Bupropion, alone or in combination with another drug, may be administered by a selected route of administration and standard It can be combined with a pharmaceutical carrier selected on the basis of good pharmaceutical practice. The relative proportions of active ingredient and carrier can be determined by, for example, the solubility and chemical properties of the compound, chosen route of administration, and standard pharmaceutical practice.

The (S)-bupropion drug can be administered to human patients in a variety of forms adapted to the chosen route of administration, eg, oral or parenteral. Parenteral administration in this respect includes the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial, including transdermal, eye drops, sublingual, and buccal, and ocular, dermal, ocular. , rectal, topical, including nasal, and the like.

(S)-Bupropion can be formulated for oral administration, for example, using an inert diluent or an edible carrier, or enclosed in a hard or soft shell gelatin capsule, or compressed into tablets. , or can be incorporated directly into the food of the diet. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

Tablets, troches, pills, capsules, etc., containing (S)-bupropion may contain: binders such as gum tragacanth, acacia, corn starch, gelatin; excipients such as dicalcium phosphate; lubricating agents such as magnesium stearate, sweeteners such as sucrose, lactose, or saccharin, or flavoring agents such as peppermint, oil of wintergreen, cherry flavor. When the dosage form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier. Various other materials can be present as coatings, for example tablets, pills, or capsules can be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Materials in dosage forms or pharmaceutical compositions can be desired to be pharmaceutically pure and substantially non-toxic in the amounts used.

Some compositions or dosage forms may be liquid or may contain a solid phase dispersed in a liquid.

(S)-Bupropion may be formulated for parenteral or intraperitoneal administration. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant. Dispersions can also have oils dispersed within or dispersed in glycerol, liquid polyethylene glycols, and mixtures thereof. Under normal conditions of storage and use, these preparations may contain a preservative to prevent microbial growth.

Some embodiments include administration of tablets containing (S)-bupropion in a form that provides sustained release of (S)-bupropion. Sustained release dosage forms containing (S)-bupropion can have a T _max of about 2-4 hours, 4-6 hours, or 6-8 hours. Although there are many ways to achieve sustained release of bupropion, in some embodiments, (S)-bupropion or (R)-bupropion is combined with acrylic acid or methacrylic acid copolymers or their esters, such as methyl methacrylate copolymers. Coalescing, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride) ), polyacrylamides, poly(methacrylic anhydride), glycidyl methacrylate copolymers, quaternized aminoalkyl esters or aminoalkylamides of acrylic and/or methacrylic acid, such as β-methacryloxyethyltrimethylammonium methosulfate, β-acryloxypropyltrimethylammonium chloride and trimethylaminomethyl methacrylamide methosulfate, quaternized vinyl-substituted nitrogen heterocycles such as methyl-vinylpyridinium salts, vinyl esters of quaternized aminocarboxylic acids, styryltrialkylammonium salts, benzyldimethylammonium ethyl methacrylate chloride, diethylmethylammonium ethyl-acrylate, diethylmethylammonium ethyl methacrylate methacrylate chloride, N-trimethylammonium propyl methacrylamide chloride, N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride, carboxyalkyl It is combined with slow-release polymers such as cellulose (eg, carboxymethylcellulose), cellulose derivatives such as hydroxypropylmethylcellulose. In some embodiments, the sustained release polymer is hydroxypropylmethylcellulose. For example, particles of (S)-bupropion can be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (eg, ^METHOCEL® ) to form a blended powder mixture.

Treat by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Examples of neurological or central nervous system disorders that can include, but are not limited to, affective disorders, psychiatric disorders, brain dysfunction, movement disorders, dementia, motor neuron disorders, neurodegenerative disorders, seizure disorders, and Includes headache.

by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Affective disorders that can be treated include, but are not limited to, depression, major depression, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorders including cyclothymic disorder, seasonal affective disorder, mood disorders. disorder, chronic depression (dysthymia), psychological depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), multiple Attention Deficit Disorder with Mobility Disorder (ADDH), and Attention Deficit/Hyperactivity Disorder (AD/HD), Bipolar Disorder and Manic States, Obsessive Compulsive Disorder, Bulimia, Obesity or Weight Gain, Paroxysmal Sleep, Chronic Includes fatigue syndrome, premenstrual syndrome, substance dependence or abuse, nicotine dependence, psychosexual dysfunction, dysregulation, and emotional lability.

Depression may be manifested by depressive symptoms. These symptoms include mood changes, intense sadness, despair, mental slowness, inability to concentrate, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, and suicidal thoughts. and/or suicide attempts, and/or psychological changes such as demeaning. Physical symptoms of depression include insomnia, loss of appetite, anorexia, weight loss, weight gain, decreased energy and libido, malaise, restlessness, pain, distress, headaches, cramps, and digestive problems. , and/or hormonal circadian rhythm abnormalities.

Some patients may be inadequate or unresponsive to treatment, even after treatment with medications such as antidepressants. Treatment-resistant depression (TRD), or treatment-refractory depression, is a condition commonly associated with patients who have failed treatment with at least two antidepressants. Part of the diagnosis of TRD is made by the patient's inadequate response to treatment with antidepressants after an appropriate dose and an appropriate course of treatment. TRD can be more difficult to treat due to comorbidities of other medical or psychological ailments, such as drug/alcohol abuse or eating disorders, or because TRD has been misdiagnosed. Some TRD patients have had an inadequate response to 1, 2, 3, or more appropriate antidepressant treatment trials, or 1, 2, 3, or more conventional Have failed or had an inadequate response to antidepressant treatment. In some embodiments, the patient being treated for treatment-resistant depression is on at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more antidepressants Failure to treat with therapy.

ameliorated by administering (S)-bupropion, including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion Measures of treatment efficacy obtained include, but are not limited to: Montgomery Asberg Depression Rating Scale (MADRS), short-form questionnaire on quality of life enjoyment and satisfaction, range of functional impairment tools, Sheehan Disability Scale, Patient Rating Inventory of Side Effects (PRISE), Columbia-Suicide Severity Rating Scale (C-SSRS), Rapid Inventory of Depressive Symptoms, Self-report (QID(S)-SR), Clinical Global Impressions ( Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), 17-item Hamilton Rating Scale for Depression (HAM-D17), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ), 16 Rapid Inventory of Item Depressive Symptoms - Self-report (QID(S)-SR16), Sheehan Disability Scale (SDS), Clinical Global Impression of Illness Severity (CGI-S), Impression of Clinical Global Change ( (CGI-C), Euro QOL 5 Dimensions 5 Levels (EQ-5D-5L), Patient Global Impression of Change (PGIC), 7-Item Global Anxiety Disorder (GAD-7), Clinical Global Impression-Improvement (CGI-I). Sheehan Disability Scale (SDS). 16-Item Quick Inventory of Depressive Symptoms-Self-Report (QID(S)-SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), CPFQ-Cognitive Subordinate scales (4 to 7 items), such as the Brief Psychiatric Rating Scale (BPRS), Number Symbol Substitution Test (DSST), Ray Auditory Verbal Learning Task (RAVLT), Tracing Test (TMT), Stroop Color Naming Test (STROOP) , simple reaction time (SRT), choice reaction time (CRT), etc.

Patients who may benefit from the treatments described herein include children, such as patients less than about 18 years old, about 0-5 years old, about 5-10 years old, about 10-12 years old, or about 12-18 years old. Patients, adult patients, such as patients about 18-65 years old, about 18-30 years old, about 30-50 years old, and about 50-65 years old, and over 65 years old, about 65-75 years old, about 75-90 years old, Or geriatric patients, such as those over the age of 90.

TRD by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Treatment is 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 It may result in relief of depressive symptoms of 90%, up to about 100%, or any other rate of relief within the range bounded by either of these values.

Treat by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Psychiatric disorders that can include, but are not limited to, anxiety such as phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD). Neurosis, mania, manic depression, hypomania, unipolar depression, depression, stress disorder, movement disorder, personality disorder psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophrenic tendency, aggression sexuality, aggression in Alzheimer's disease, agitation, agitation in Alzheimer's disease.

Agitation associated with Alzheimer's disease occurs as the disease progresses. Agitation can manifest as inappropriate verbal, emotional, and/or physical behavior. Inappropriate behavior includes, but is not limited to, incoherent babbling, inappropriate emotional reactions, attention demands, intimidation, irritability, frustration, screaming, repetitive questioning, mood swings, swearing, Verbal abuse, physical outbursts, emotional distress, restlessness, chopping, sleep disturbance, delusions, hallucinations, slow walking, wandering, searching, hunting, repetitive body movements, hoarding, shadowing, beating, scratching , biting, combativeness, hyperactivity, and/or kicking.

In some embodiments, administering (S)-bupropion ((S)-bupropion to achieve therapeutic plasma levels of one of its metabolites such as (R,R)-hydroxybupropion treatment of agitation associated with Alzheimer's disease by 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%, A reduction in agitation-related symptoms of at least about 70%, at least about 80%, at least about 90%, and/or up to about 100% may result.

ameliorated by administering (S)-bupropion, including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion Measures of possible arousal therapeutic efficacy include, but are not limited to, Neuropsychiatric Inventory-Clinician (NPI-C) Rating Scale Global and All Domains, Neuropsychiatric Inventory-Clinician (NPI-C) C) Rating Scale Excitability Domain, Cohen-Mansfield Agitation Inventory (CMAI), Cornell Scale for Depression in Dementia (CSDD), Neuropsychiatric Inventory (NPI Excitability/Aggression Domain), Concomitant Medications frequency of use), Alzheimer's Disease Collaborative-Activities Inventory (ADC(S)-ADL), NPI-C individual domains of the Neuropsychiatric Inventory (NPI), including the asthenia domain and NPI total scores ( Range 0-144), NPI Agitation/Aggression Caregiver Distress, Modified Alzheimer's Disease Collaborative Study-Clinical Global Impression of Change Agitation (mADC(S)-CGIC Agitation), Patient Global Impression of Change ( PGIC) (assessed by caregivers), Dementia Quality of Life (DEMQOL), Quality of Life - Alzheimer's Disease Measure (QoL-AD), Zarit Burden Scale, Resource Utilization in Dementia (RUD), Alzheimer's Disease Rating Scale - Cognitive Subscales (ADA(S)-Cog), Mini-Mental Status Examination (MMSE), Caregiver Stress Index (CSI), Neuropsychiatric Inventory Individual Domains (NPI), Total Neuropsychiatric Inventory (NPI) score, Neuropsychiatric Inventory (NPI Agitation/Aggression Domain), Neuropsychiatric Inventory (NPI Domain Caregiver Distress), and the like.

(S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Possible drug addiction abuses include, but are not limited to, drug addiction, cocaine addiction, psychostimulants (crack, cocaine, speedo, stimulants, etc.), nicotine, alcohol, opioids, anxiety and hypnotics, cannabis (marijuana), Included are amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrous compounds. Nicotine dependence includes all known forms of nicotine dependence, such as cigarette, cigar and/or pipe tobacco, electronic cigarette smoking, and chewing tobacco dependence.

(S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Possible brain dysfunctions include, but are not limited to, senile dementia, dementia of the Alzheimer's type, memory loss, amnesia/amnestic syndrome, epilepsy, disturbance of consciousness, coma, attention deficit, speech impairment, voice spasms, Parkinson's. disorders with intellectual deficits such as disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome, and schizophrenia. Cerebral dysfunction includes, but is not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis when symptoms include, but are not limited to, impaired consciousness, senile dementia, coma, decreased attention, and speech impairment. Also included are disorders caused by cerebrovascular disease, including stroke, head trauma, and the like.

by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Movement disorders that can be treated include, but are not limited to, akathisia, akinesia, coordination, athetosis, ataxia, ballismus, hemiballismus, 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, and Tourette's syndrome, and Wilson's disease. included.

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

by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Motor neuron diseases that can be treated 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.

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

by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Seizure disorders that can be treated include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile seizures, partial-onset seizures (simple partial-onset seizures, Jackson seizures, complex partial-onset seizures, and persistent partial-onset seizures). ), generalized seizures (including but not limited to generalized tonic-clonic seizures, absence seizures, cataplexy, myoclonic seizures, juvenile myoclonic seizures, and spasmodic epilepsy), and status epilepticus .

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

by administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) Other neurological disorders that can be treated include, but are not limited to, Rett syndrome, autism, tinnitus, disturbed consciousness, sexual dysfunction, refractory cough, narcolepsy, cataplexy, and uncontrolled laryngeal muscle spasm. Dysphonia (including but not limited to abductor spasmodic dysphonia, adductor spasmodic dysphonia, myotonic hoarseness, and tremor), diabetic neuropathy, chemotherapy such as methotrexate neurotoxicity Induced neurotoxicity, incontinence (including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence), and erectile dysfunction are included.

In some embodiments, administering (S)-bupropion (administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites such as (R,R)-hydroxybupropion pain, arthralgia, pain associated with sickle cell disease, affect regulation disorders, depression (including treatment-resistant depression), memory and cognition-related disorders, schizophrenia, Parkinson's disease, It may be useful in treating amyotrophic lateral sclerosis (ALS), stroke, cough (including chronic cough), and the like.

In some embodiments, refractory depression is treated by administering (S)-bupropion ((R,R)-hydroxybupropion to achieve therapeutic plasma levels of one of its metabolites (S )—including administering bupropion).

(S)-Bupropion also includes but is not limited to musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritic pain, complex regional pain syndrome, etc. Administration of (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion, or any type of pain that is not caused by the direct effects of ((S)-bupropion) by) can be used to treat or palliate.

In some embodiments, (S)-bupropion is used for alleviating neuropathic pain (either for its direct effects or for therapeutic use with one of its metabolites such as (R,R)-hydroxybupropion). to achieve plasma levels).

Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathy, phantom limb pain, central pain, and the like. 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 radiation or chemotherapy-related pain. including neurological disorders that

In some embodiments, (S)-bupropion is used to ameliorate fibromyalgia (either for its direct effects or for therapeutic plasma treatment with one of its metabolites such as (R,R)-hydroxybupropion). to achieve levels).

Bupropion-related adverse events that may be avoided or reduced by the methods described herein include central nervous system adverse events, gastrointestinal events, or other types of adverse events associated with 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, fear, anxiety, headache, irritability or agitation. Increased tinnitus, drowsiness, dizziness, sedation, drowsiness, confusion, disorientation, malaise, incoordination, fatigue, euphoria, nervousness, insomnia, sleep disturbance, seizures, agitation, nervousness, hysteria, hallucinations , delusions, paranoia, headaches and/or migraines, and extrapyramidal symptoms such as gaze episodes, torticollis, hyperexcitability, hypertonia, ataxia, and/or tongue protrusion.

Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, bloating, flatulence, bleeding peptic ulcer, loose stools, constipation, stomach pain, heartburn, Includes gas, loss of appetite, stomach bloating, indigestion, swelling, hyperacidity, xerostomia, gastrointestinal disturbances, and gastric pain.

Other adverse events that may be reduced or avoided by the methods described herein include rotational and motor paresthesias, agitation, arm weakness, bloating, blurred vision, burning eyes, tinnitus, decreased vital signs, Changes (including but not limited to heart rate, breathing rate, body temperature, blood pressure), coldness, constipation, poor concentration, insomnia, difficulty falling asleep, difficulty urinating, difficulty defecation, ear discomfort, eye discomfort, Stomach discomfort, dizziness, dry lips, dry mouth, dry throat, dysmenorrhoea, fatigue, feverish feeling, heavy head feeling, feeling more agitated than usual, feeling more tired than usual, tired feeling, Hand tremors, decreased grip strength, headaches, heartburn, hot flashes, increased blood pressure, increased skin sensitivity, increased skin sensitivity on the head and face, involuntary muscle contractions, involuntary muscle contractions throughout the body, knee pain, weakness in the legs, Lightheadedness on standing up, loose stools, loss of appetite, back pain, menstrual irregularities, metallic taste, more saliva than usual, dry mucous membranes, nasal congestion, nausea, runny nose, light eye pressure, shaking when stretching or yawning, skin irritation irritability, skin sensitivities on the arms, face, and/or head, sleep disturbance, loose stools, stomach pain, stomach discomfort, sweating in the hands and/or feet, sore throat, ringing in the ears, tremors, and / Or weakness is included. Any of these side effects may be referred to or grouped according to corresponding, equivalent, or other related terms found in the Medical Regulatory Dictionary (MedRA).

The following embodiments are contemplated:
Embodiment 1.
A method of delivering (R)-bupropion and (S)-bupropion to plasma comprising:
selecting a human in need of a pharmacokinetic profile resulting from oral administration of a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and a reference agent at said first dosing frequency. A dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure is administered in said first administration in order to obtain the same pharmacokinetic profile as obtained by administering the form. administering orally at a frequency;
said first dosing frequency is once daily or twice daily;
The method, wherein the second amount is about 40% to about 60% of the first amount.

Embodiment 2.
A method of treating a racembupropion-treatable condition comprising:
selecting a human patient having a condition treatable by oral administration of a reference dosage form containing a first amount of racemic bupropion at a first dosage frequency; and administering the reference dosage form at the first dosage frequency. orally administering at a first dosing frequency a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure to obtain the same therapeutic effect as achieved by including
the first dosing frequency is once daily or twice daily;
The method, wherein the second amount is about 40% to about 60% of the first amount.

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

Embodiment 4.
A method of providing therapeutically effective plasma levels of (R,R)-hydroxybupropion comprising at least 95% enantiomerically pure orally administering once or twice daily a dosage form containing (S)-bupropion, wherein (R,R)-hydroxybupropion is present in said plasma of said human (R,R)- is at least 97% of the total amount of hydroxybupropion and (S,S)-hydroxybupropion, said method achieving a C _max of (R,R)-hydroxybupropion of at least about 500 ng/mL in said human. .

Embodiment 5.
A method of treating a human comprising orally administering to said human a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said human being treated with (S)-bupropion and said (S)-bupropion is the only active agent used to treat said human.

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

Embodiment 7.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said The method achieves a C _max for (S)-bupropion of at least about 60 ng/mL.

Embodiment 8.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, The method, wherein R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in plasma of said human.

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

Embodiment 10.
A method of providing therapeutically effective plasma levels of (R,R)-hydroxybupropion comprising a dosage form containing at least 95% enantiomerically pure (S)-bupropion, comprising (R,R) - orally administering once or twice daily to a human in need of treatment with hydroxybupropion, said method having _{a Cmax} of (R,R)-hydroxybupropion of at least about 500 ng/mL in said human how to achieve

Embodiment 11.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said A method, wherein the human is in need of treatment with (S)-bupropion, said method achieving a C _max of (S)-bupropion of at least about 70 ng/mL.

Embodiment 12.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said A method, wherein the human is in need of treatment with (S)-bupropion, and wherein the method achieves an AUC _0-12 of (S)-bupropion of at least about 600 ng·h/mL.

Embodiment 13.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said A method, wherein the human is in need of treatment with (S)-bupropion, and wherein the method achieves a C _max of (R,R)-hydroxybupropion of at least about 800 ng/mL.

Embodiment 14.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said wherein the human is in need of treatment with (S)-bupropion, said method achieving an AUC _0-12 of (R,R)-hydroxybupropion of at least about 8,000 ng·h/mL.

Embodiment 15.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said A method, wherein the human is in need of treatment with (S)-bupropion, said method achieving a C _max of erythrohydroxybupropion of at least about 90 ng/mL.

Embodiment 16.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said A method, wherein the human is in need of treatment with (S)-bupropion, said method achieving an AUC _0-12 of erythrohydroxybupropion of at least about 1,000 ng·h/mL.

Embodiment 17.
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion, said A method, wherein the human is in need of treatment with (S)-bupropion, said method achieving a C _max of threohydroxybupropion of at least about 450 ng/mL.

Embodiment 18.
A method of treating a human requiring treatment with (S)-bupropion once or twice daily in a dosage form containing at least 95% enantiomerically pure (S)-bupropion orally administering to said human, said method achieving an AUC _0-12 of threohydroxybupropion of at least about 5,000 ng·h/mL.

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

Embodiment 20.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, wherein said method achieves a C _max of (S)-bupropion of at least about 60 ng/mL; 14, 15, 16, 17, 18, or 19.

Embodiment 21.
The method is effective in increasing the C _max of (S)-bupropion by at least 5-fold compared to the C _max of (R)-bupropion resulting from administration of the same amount of (R)-bupropion to the human. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the method is

Embodiment 22.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, wherein said method achieves a C _max of (R,R)-hydroxybupropion of at least about 500 ng/mL in said human , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21.

Embodiment 23.
The method comprises measuring the C _min of (R,R)-hydroxybupropion by at least 5 compared to the C _min of (R,R)-hydroxybupropion resulting from administration of the same amount of (R)-bupropion to the human. Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, which are effective in increasing fold 20, 21, or 22 methods.

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

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

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

Embodiment 27.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 effective to provide therapeutically effective plasma levels of (R,R)-hydroxybupropion , 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

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

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

Embodiment 30.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, wherein said method achieves a C _max of (R,R)-hydroxybupropion of at least about 500 ng/mL in said human , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29.

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

Embodiment 32.
32. The method of embodiment 31, wherein said dosage form is administered for at least 14 consecutive days.

Embodiment 33.
32. The method of embodiment 31, wherein said dosage form is administered for at least 21 consecutive days.

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

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

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

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

Embodiment 38.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, wherein said method achieves a C _max of (S)-bupropion in said human of at least about 70 ng/mL, 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 ways.

Embodiment 39.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, wherein said method achieves an AUC _0-12 of (S)-bupropion in said human of at least about 400 ng·hr/mL. 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, The method of 35, 36, 37, or 38.

Embodiment 40.
40. The method of embodiment 39, wherein said method achieves an AUC _0-12 of (S)-bupropion in said human that is from about 500 ng-hr/mL to about 900 ng-hr/mL.

Embodiment 41.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, wherein said dosage form provides sustained release of (S)-bupropion , 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 Method.

Embodiment 42.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, wherein the dosage form contains from about 70 mg to about 80 mg of (S)-bupropion. 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 methods.

Embodiment 43.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, wherein said method achieves a C _max for (R,R)-hydroxybupropion in humans of at least about 600 ng/mL , 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.

Embodiment 44.
Embodiments 1, 2, 3, 4, 5, 6, 7, 8, wherein said method achieves an AUC _0-12 of (R,R)-hydroxybupropion in humans of at least about 7000 ng·hr/mL , 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.

Embodiment 45.
The method of embodiment 44, wherein said method achieves an AUC 0-12 of (R,R)-hydroxybupropion in humans of at least about 8000 ng·hr/mL.

Embodiment 46.
A method of treating a human, wherein a dosage form containing at least 95% enantiomerically pure (S)-bupropion is orally administered to said human once or twice daily.

Embodiment 47.
A dosage form for treating a condition in a human comprising at least 95% enantiomerically pure (S)-bupropion, said dosage form being orally administered to said human once or twice daily. , dosage form.

Embodiment 48.
Use of at least 95% enantiomerically pure (S)-bupropion in the manufacture of a medicament for treating a condition in a human, said medicament being orally administered to said human once or twice daily be used.

Embodiment 49.
A dosage form and a label, said dosage form comprising at least 95% enantiomerically pure (S)-bupropion, said label indicating that said dosage form is administered once daily for treating a human condition. A kit provided to be orally administered to said human once or twice.

Embodiment 50.
The method, dosage form, use, or kit of embodiment 46, 47, 48, or 49, wherein said condition is a neurological disorder or a central nervous system disorder.

Embodiment 51.
51. The method, dosage form, use, or kit of embodiment 50, wherein said human is selected for having said condition.

Embodiment 52.
The condition is treated by achieving a first AUC of bupropion, wherein said first AUC of bupropion is the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, and said daily dose of is from about 150 mg to about 200 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of bupropion, said (S)-bupropion wherein said daily dose of is about 60 mg to about 120 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of said (S)-bupropion is administered together with other bupropion 52. The method, dosage form, use, or kit of embodiment 51, wherein the daily dose of (S)-bupropion is from about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 53.
The condition is treated by achieving a first AUC of bupropion, wherein said first AUC of bupropion is the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, and said daily dose of is from about 200 mg to about 250 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of bupropion, said (S)-bupropion wherein said daily dose of is from about 80 mg to about 150 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of said (S)-bupropion is administered with no other bupropion 52. The method, dosage form, use, or kit of embodiment 51, wherein the daily dose of (S)-bupropion is from about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 54.
The condition is treated by achieving a first AUC of bupropion, wherein said first AUC of bupropion is the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, and said daily dose of is from about 250 mg to about 300 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of bupropion, said (S)-bupropion wherein said daily dose of is from about 100 mg to about 180 mg, said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion 52. The method, dosage form, use, or kit of embodiment 51, wherein the daily dose of (S)-bupropion is from about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 55.
The condition is treated by achieving a first AUC of bupropion, wherein said first AUC of bupropion is the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, and said daily dose of is from about 300 mg to about 350 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of bupropion, said (S)-bupropion wherein said daily dose of is about 120 mg to about 210 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of said (S)-bupropion is administered with no other bupropion 52. The method, dosage form, use, or kit of embodiment 51, wherein the daily dose of (S)-bupropion is from about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 56.
The condition is treated by achieving a first AUC of bupropion, wherein said first AUC of bupropion is the same as the reference AUC of bupropion resulting from administration of a daily dose of racemic bupropion, and said daily dose of is from about 350 mg to about 400 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of bupropion, said (S)-bupropion wherein said daily dose of is about 140 mg to about 240 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of said (S)-bupropion is administered with no other bupropion 52. The method, dosage form, use, or kit of embodiment 51, wherein the daily dose of (S)-bupropion is from about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 57.
The condition is treated by achieving a first AUC of bupropion, wherein said first AUC of bupropion is the same as the reference AUC of bupropion resulting from administering a daily dose of racemic bupropion, and said daily dose of is from about 400 mg to about 450 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of bupropion, said (S)-bupropion wherein said daily dose of is 160 mg to about 270 mg, said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion and said daily dose of said (S)-bupropion is from about 40% to about 60% of said daily dose of racemic bupropion.

Embodiment 58.
The condition is treated by achieving a first AUC of hydroxybupropion, wherein said first AUC of hydroxybupropion is the same as the reference AUC of hydroxybupropion resulting from administering a daily dose of racemic bupropion. , said daily dose of racemic bupropion is from about 150 mg to about 200 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of hydroxybupropion, said ( Said daily dose of S)-bupropion is from about 60 mg to about 120 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of said (S)-bupropion is is not administered, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion; Or kit.

Embodiment 59.
The condition is treated by achieving a first AUC of hydroxybupropion, wherein said first AUC of hydroxybupropion is the same as the reference AUC of hydroxybupropion resulting from administering a daily dose of racemic bupropion. , said daily dose of racemic bupropion is from about 200 mg to about 250 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of hydroxybupropion, said ( Said daily dose of S)-bupropion is from about 80 mg to about 150 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of (S)-bupropion is is not administered, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion; Or kit.

Embodiment 60.
The condition is treated by achieving a first AUC of hydroxybupropion, wherein said first AUC of hydroxybupropion is the same as the reference AUC of hydroxybupropion resulting from administering a daily dose of racemic bupropion. , said daily dose of racemic bupropion is from about 250 mg to about 300 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of hydroxybupropion, said ( Said daily dose of S)-bupropion is from about 100 mg to about 180 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of said (S)-bupropion is not administered, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion; Or kit.

Embodiment 61.
The condition is treated by achieving a first AUC of hydroxybupropion, wherein said first AUC of hydroxybupropion is the same as the reference AUC of hydroxybupropion resulting from administering a daily dose of racemic bupropion. , said daily dose of racemic bupropion is from about 300 mg to about 350 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of hydroxybupropion, said ( Said daily dose of S)-bupropion is from about 120 mg to about 210 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of (S)-bupropion is combined with said daily dose of (S)-bupropion is not administered, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion; Or kit.

Embodiment 62.
The condition is treated by achieving a first AUC of hydroxybupropion, wherein said first AUC of hydroxybupropion is the same as the reference AUC of hydroxybupropion resulting from administering a daily dose of racemic bupropion. , said daily dose of racemic bupropion is from about 350 mg to about 400 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of hydroxybupropion, said ( Said daily dose of S)-bupropion is from about 140 mg to about 240 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of (S)-bupropion is combined with said daily dose of (S)-bupropion is not administered, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion; Or kit.

Embodiment 63.
The condition is treated by achieving a first AUC of hydroxybupropion, wherein said first AUC of hydroxybupropion is the same as the reference AUC of hydroxybupropion resulting from administering a daily dose of racemic bupropion. , said daily dose of racemic bupropion is from about 400 mg to about 450 mg, said daily dose of (S)-bupropion is administered to said human to achieve said first AUC of hydroxybupropion, said ( Said daily dose of S)-bupropion is from about 160 mg to about 270 mg, said (S)-bupropion is at least 95% enantiomerically pure and said daily dose of (S)-bupropion is is not administered, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion; Or kit.

Embodiment 64.
The condition was treated by achieving a first AUC of (R,R)-hydroxybupropion, wherein said first AUC of (R,R)-hydroxybupropion was administered with a daily dose of racemic bupropion The resulting reference AUC for (R,R)-hydroxybupropion is the same, said daily dose of racemic bupropion being about 150 mg to about 200 mg, and the daily dose of (S)-bupropion being about (R, wherein said daily dose of said (S)-bupropion administered to said human to achieve said first AUC of R)-hydroxybupropion is from about 60 mg to about 120 mg, and said (S)-bupropion is at least is 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said daily dose of said (S)-bupropion is less than said 1 52. The method, dosage form, use, or kit of embodiment 51 from about 40% to about 60% of the daily dose.

Embodiment 65.
The condition was treated by achieving a first AUC of (R,R)-hydroxybupropion, wherein said first AUC of (R,R)-hydroxybupropion was administered with a daily dose of racemic bupropion The resulting reference AUC for (R,R)-hydroxybupropion is the same, said daily dose of racemic bupropion is about 200 mg to about 250 mg, and the daily dose of (S)-bupropion is (R, wherein said daily dose of said (S)-bupropion administered to said human is about 80 mg to about 150 mg, said (S)-bupropion being administered to said human to achieve said first AUC of R)-hydroxybupropion; is 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said daily dose of said (S)-bupropion is less than said 1 52. The method, dosage form, use, or kit of embodiment 51 from about 40% to about 60% of the daily dose.

Embodiment 66.
The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, said first AUC of (R,R)-hydroxybupropion administered a daily dose of racemic bupropion The resulting reference AUC for (R,R)-hydroxybupropion is the same, said daily dose for racemic bupropion is about 250 mg to about 300 mg, and the daily dose for (S)-bupropion is (R, wherein said daily dose of said (S)-bupropion is from about 100 mg to about 180 mg, said (S)-bupropion administered to said human to achieve said first AUC of R)-hydroxybupropion, wherein said (S)-bupropion is at least is 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said daily dose of said (S)-bupropion is less than said 1 52. The method, dosage form, use, or kit of embodiment 51 from about 40% to about 60% of the daily dose.

Embodiment 67.
The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, said first AUC of (R,R)-hydroxybupropion administered a daily dose of racemic bupropion The resulting reference AUC for (R,R)-hydroxybupropion is the same, said daily dose of racemic bupropion is about 300 mg to about 350 mg, and the daily dose of (S)-bupropion is (R, wherein said daily dose of said (S)-bupropion is from about 120 mg to about 210 mg, said (S)-bupropion administered to said human to achieve said first AUC of R)-hydroxybupropion, wherein said (S)-bupropion is at least is 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said daily dose of said (S)-bupropion is less than said 1 52. The method, dosage form, use, or kit of embodiment 51 from about 40% to about 60% of the daily dose.

Embodiment 68.
The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, said first AUC of (R,R)-hydroxybupropion administered a daily dose of racemic bupropion The resulting reference AUC for (R,R)-hydroxybupropion is the same, said daily dose of racemic bupropion is about 350 mg to about 400 mg, and the daily dose of (S)-bupropion is (R, wherein said daily dose of said (S)-bupropion administered to said human to achieve said first AUC of R)-hydroxybupropion is from about 140 mg to about 240 mg, said (S)-bupropion being at least is 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said daily dose of said (S)-bupropion is less than said 1 52. The method, dosage form, use, or kit of embodiment 51 from about 40% to about 60% of the daily dose.

Embodiment 69.
The condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, said first AUC of (R,R)-hydroxybupropion administered a daily dose of racemic bupropion The resulting reference AUC for (R,R)-hydroxybupropion is the same, said daily dose for racemic bupropion is about 400 mg to about 450 mg, and the daily dose for (S)-bupropion is (R, wherein said daily dose of said (S)-bupropion administered to said human to achieve said first AUC of R)-hydroxybupropion is from about 160 mg to about 270 mg, said (S)-bupropion being at least is 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said daily dose of said (S)-bupropion is less than said 1 52. The method, dosage form, use, or kit of embodiment 51 from about 40% to about 60% of the daily dose.

Embodiment 70.
The method, dosage form, use, or kit of any one of embodiments 52-69, wherein said AUC is AUC _0-12 .

Embodiment 71.
The method, dosage form, use, or kit of any one of embodiments 52-69, wherein said AUC is AUC _0-24 .

Embodiment 72.
The method of any of the preceding embodiments, wherein said (S)-bupropion is administered once daily.

Embodiment 73.
The method of any one of embodiments 46-71, wherein said (S)-bupropion is administered twice daily and the sum of the twice daily doses is the daily dose.

Embodiment 74.
The method of any of the preceding embodiments, wherein said (S)-bupropion is administered continuously for at least 8 days.

Embodiment 75.
The method of any of the preceding embodiments, wherein said (S)-bupropion is administered continuously for at least 14 days.

Embodiment 76.
The method of any of the preceding embodiments, wherein said (S)-bupropion is administered continuously for at least 21 days.

Embodiment 77.
The method of any of the preceding embodiments, wherein said (S)-bupropion is administered continuously for at least 28 days.

Embodiment 78.
The method of any of the preceding embodiments, wherein the (S)-bupropion is administered in a dosage form that provides sustained release of (S)-bupropion.

Embodiment 79.
79. The method of embodiment 78, wherein said dosage form is formulated to have a T _max for (S)-bupropion that is from about 2 hours to about 4 hours.

Embodiment 80.
The method of any preceding embodiment, wherein the method achieves an AUC _0-12 for (S)-bupropion in humans of at least about 300 ng·hr/mL.

Embodiment 81.
The method of any preceding embodiment, wherein the method achieves an AUC _0-12 for (S)-bupropion in humans of at least about 400 ng·hr/mL.

Embodiment 82.
The method of any of the preceding embodiments, wherein the method achieves an AUC _0-12 for (S)-bupropion in humans of from about 500 ng·hr/mL to about 900 ng·hr/mL.

Embodiment 83.
The method of any preceding embodiment, wherein the method achieves a C _max for (S)-bupropion in the human of from about 60 ng/mL to about 140 ng/mL.

Example 1
Part 1 Fifteen healthy adult subjects were administered 150 mg sustained release racembupropion twice daily under fasting conditions for 7 days. Tablet administration was increased from once daily on days 1 through 3 to twice daily thereafter, with the last dose given on the morning of day 7. Plasma concentrations of bupropion and its metabolites were measured on day 7, 3-4 hours after dosing. A chiral bioanalytical method was used to measure the enantiomeric concentrations of bupropion and its major metabolites. Results were normalized to 210 mg by multiplying the AUC or C _max by 210/150.

Part 2 Healthy adult subjects were administered either 105 mg S-bupropion or 105 mg R-bupropion extended release tablets (10 subjects per group) twice daily for 8 days under fasting conditions. Tablet administration was increased from once daily on days 1 through 3 to twice daily thereafter, with the final administration on the morning of day 8. Plasma concentrations of bupropion and its metabolites were measured on days 1 and 8 for complete pharmacokinetic evaluation. A chiral bioanalytical method was used to measure the enantiomeric concentrations of bupropion and its major active metabolite hydroxybupropion.

Table 1 shows the values for tablets containing 105 mg of S-bupropion in Part 2. Values for racemic bupropion tablets containing 75 mg R- and 75 mg S-bupropion were taken from Part 1 and multiplied by 105/150 to allow comparison with the 105 mg S-bupropion tablets described above. Standardized to 105 mg R- and 105 mg S-bupropion. Both S-bupropion and racemic bupropion tablets were sustained release formulations administered to healthy volunteers. The AUC _0-12 values for bupropion and hydroxybupropion are also shown in FIG.

Part 3 Randomized, Double-Blind, Multiple-Dose, Placebo Using Pharmacokinetic Sampling to Determine the Safety and Tolerability of the Pure S- and R-Enantiomers of Bupropion A controlled, parallel group study was performed. In this study, healthy adult subjects were administered 105 mg S-bupropion, 105 mg R-bupropion extended release tablets, or placebo (15 subjects per group) twice daily for 7 days under fasting conditions. did. Tablet administration was increased from once daily on days 1 through 3 to twice daily thereafter, with the last dose given on the morning of day 7. Plasma concentrations of bupropion and its metabolites were measured 3-4 hours after the 7th dose. A chiral bioanalytical method was used to measure the concentrations of enantiomers of bupropion and its major active metabolite hydroxybupropion. Mean plasma concentrations measured for bupropion and hydroxybupropion are shown in Table 2 and FIG. As shown in FIG. 3, the C _max for R,R-hydroxybupropion after administration of 105 mg S-bupropion was 1,268.5 ng/mL, and the R,R -Hydroxybupropion had a C _max of 135.1 ng/mL.

The T _max for the above (S)-bupropion containing dosage forms was between 2 and 4 hours.

Unless otherwise stated, all numbers expressing amounts of ingredients, properties such as amounts, AUC values, etc. used in the specification and claims are in all cases the exact values and terms indicated. "About" should be understood to indicate both modified values. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending on the desired properties sought to be obtained. At least, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be interpreted at least in the light of reported significant digits and by applying conventional rounding techniques. is.

The terms “a,” “an,” “the,” and similar referents used in the context of describing the present invention (especially in the context of the claims below) may be used unless otherwise indicated or in the context. should be construed to include both singular and plural forms unless clearly contradicted by. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. Any and all examples, or use of exemplary language (e.g., "such as") provided herein, are merely intended to better clarify the invention, and the claims impose no restrictions on No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

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

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors do not practice the invention otherwise than as specifically described herein. intended to be Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other refinements that may be used are within the scope of the claims. These are by way of example, but not limitation, alternative embodiments may be utilized in accordance with the teachings herein. Therefore, the claims are not limited to the precise embodiments shown and described.

(Appendix)
(Appendix 1)
A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion.

(Appendix 2)
A dosage form for treating a condition in a human comprising at least 95% enantiomerically pure (S)-bupropion, said dosage form being orally administered to said human once or twice daily. , dosage form.

(Appendix 3)
Use of at least 95% enantiomerically pure (S)-bupropion in the manufacture of a medicament for treating a condition in a human, said medicament being orally administered to said human once or twice daily be used.

(Appendix 4)
A dosage form and a label, said dosage form comprising at least 95% enantiomerically pure (S)-bupropion, said label indicating that said dosage form is administered once daily for treating a human condition. A kit provided to be orally administered to said human once or twice.

(Appendix 5)
5. The method, dosage form, use or kit of Clause 1, 2, 3 or 4, wherein said condition is a neurological disorder or a central nervous system disorder.

(Appendix 6)
6. The method, dosage form, use or kit of Clause 5, wherein said human is selected for having said condition.

(Appendix 7)
The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is equal to the reference AUC ₀ of bupropion resulting from administering a daily dose of racemic bupropion. _-24 , the daily dose of racemic bupropion is from about 150 mg to about 200 _mg , and the daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 60 mg to about 120 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- No other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described.

(Appendix 8)
The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is equal to the reference AUC ₀ of bupropion resulting from administering a daily dose of racemic bupropion. _-24 , wherein said daily dose of racemic bupropion is from about 200 mg to about 250 _mg , and said daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 80 mg to about 150 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- No other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described.

(Appendix 9)
The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is equal to the reference AUC ₀ of bupropion resulting from administering a daily dose of racemic bupropion. _-24 , wherein said daily dose of racemic bupropion is from about 250 mg to about ₃₀₀ mg, and said daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 100 mg to about 180 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- No other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described.

(Appendix 10)
The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is equal to the reference AUC ₀ of bupropion resulting from administering a daily dose of racemic bupropion. _-24 , the daily dose of racemic bupropion is from about 300 mg to about 350 _mg , and the daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 120 mg to about 210 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- No other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described.

(Appendix 11)
The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is equal to the reference AUC ₀ of bupropion resulting from administering a daily dose of racemic bupropion. _-24 , wherein said daily dose of racemic bupropion is from about 350 mg to about 400 _mg , and said daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 140 mg to about 240 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- No other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described.

(Appendix 12)
The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is equal to the reference AUC ₀ of bupropion resulting from administering a daily dose of racemic bupropion. _-24 , wherein said daily dose of racemic bupropion is from about 400 mg to about 450 _mg , and said daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 160 mg to about 270 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- No other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described.

(Appendix 13)
The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 150 mg to about 200 mg, and said daily dose of (S)-bupropion is greater than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 60 mg to about 120 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. , Appendix 6.

(Appendix 14)
The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 200 mg to about 250 mg, and said daily dose of (S)-bupropion is greater than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 80 mg to about 150 mg, said (S)-bupropion being at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. , Appendix 6.

(Appendix 15)
The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 250 mg to about 300 mg, and said daily dose of (S)-bupropion is greater than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 100 mg to about 180 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. , Appendix 6.

(Appendix 16)
The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 300 mg to about 350 mg, and said daily dose of (S)-bupropion is greater than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 120 mg to about 210 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. , Appendix 6.

(Appendix 17)
The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 350 mg to about 400 mg, and said daily dose of (S)-bupropion is less than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 140 mg to about 240 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. , Appendix 6.

(Appendix 18)
The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 400 mg to about 450 mg, and said daily dose of (S)-bupropion is less than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 160 mg to about 270 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. , Appendix 6.

(Appendix 19)
The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 150 mg to about 200 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 60 mg to about 120 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of Claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racemic bupropion.

(Appendix 20)
The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 200 mg to about 250 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 80 mg to about 150 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of Claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racemic bupropion.

(Appendix 21)
The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 250 mg to about 300 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 100 mg to about 180 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of Claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racemic bupropion.

(Appendix 22)
The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 300 mg to about 350 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 120 mg to about 210 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of Claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racemic bupropion.

(Appendix 23)
The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 350 mg to about 400 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 140 mg to about 240 mg, said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of Claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racemic bupropion.

(Appendix 24)
The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 400 mg to about 450 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 160 mg to about 270 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of Claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racemic bupropion.

(Appendix 25)
25. The method of any one of Clauses 1-24, wherein said (S)-bupropion is administered once daily.

(Appendix 26)
25. The method of any one of clauses 1-24, wherein said (S)-bupropion is administered in twice daily doses, the sum of said twice daily doses being said daily dose.

(Appendix 27)
27. The method of any one of Clauses 1-26, wherein said (S)-bupropion is administered continuously for at least 8 days.

(Appendix 28)
28. The method of any one of Clauses 1-27, wherein said (S)-bupropion is administered continuously for at least 14 days.

(Appendix 29)
29. The method of any one of Clauses 1-28, wherein said (S)-bupropion is administered continuously for at least 21 days.

(Appendix 30)
30. The method of any one of Clauses 1-29, wherein said (S)-bupropion is administered continuously for at least 28 days.

(Appendix 31)
31. The method of any one of Clauses 1-30, wherein said (S)-bupropion is administered in a dosage form that provides sustained release of (S)-bupropion.

(Appendix 32)
32. The method of paragraph 31, wherein said dosage form is formulated to have a T _max for (S)-bupropion that is from about 2 hours to about 4 hours.

(Appendix 33)
33. The method of any one of Supplements 1-32, wherein the method achieves an AUC _0-12 for (S)-bupropion in humans of at least about 300 ng·hr/mL.

(Appendix 34)
34. The method of any one of Supplements 1-33, wherein the method achieves an AUC _0-12 for (S)-bupropion in humans of at least about 400 ng·hr/mL.

(Appendix 35)
35. The method of any one of Supplements 1-34, wherein the method achieves an AUC _0-12 for (S)-bupropion in humans of about 500 ng-hr/mL to about 900 ng-hr/mL.

(Appendix 36)
36. The method of any one of Supplements 1-35, wherein the method achieves a C _max for (S)-bupropion in humans of about 60 ng/mL to about 140 ng/mL.

Claims (36)

A method of treating a human comprising orally administering to said human once or twice daily a dosage form containing at least 95% enantiomerically pure (S)-bupropion. A dosage form for treating a condition in a human comprising at least 95% enantiomerically pure (S)-bupropion, said dosage form being orally administered to said human once or twice daily. , dosage form. Use of at least 95% enantiomerically pure (S)-bupropion in the manufacture of a medicament for treating a condition in a human, said medicament being orally administered to said human once or twice daily be used. A dosage form and a label, said dosage form comprising at least 95% enantiomerically pure (S)-bupropion, said label indicating that said dosage form is administered once daily for treating a human condition. A kit provided to be orally administered to said human once or twice. 5. The method, dosage form, use or kit of claim 1, 2, 3 or 4, wherein said condition is a neurological or central nervous system disorder. 6. The method, dosage form, use or kit of claim 5, wherein said human is selected for having said condition. The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is the reference AUC ₀ of bupropion resulting from administration of a daily dose of racemic bupropion. _-24 , the daily dose of racemic bupropion is from about 150 mg to about 200 _mg , and the daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 60 mg to about 120 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- Claim 6, wherein no other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described in . The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is the reference AUC ₀ of bupropion resulting from administration of a daily dose of racemic bupropion. _-24 , the daily dose of racemic bupropion is from about 200 mg to about 250 _mg , and the daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 80 mg to about 150 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- Claim 6, wherein no other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described in . The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is the reference AUC ₀ of bupropion resulting from administration of a daily dose of racemic bupropion. _-24 , wherein said daily dose of racemic bupropion is from about 250 mg to about 300 _mg , and said daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 100 mg to about 180 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- Claim 6, wherein no other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described in . The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is the reference AUC ₀ of bupropion resulting from administration of a daily dose of racemic bupropion. _-24 , wherein said daily dose of racemic bupropion is from about 300 mg to about 350 _mg , and said daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 120 mg to about 210 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- Claim 6, wherein no other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described in . The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is the reference AUC ₀ of bupropion resulting from administration of a daily dose of racemic bupropion. _-24 , wherein said daily dose of racemic bupropion is from about 350 mg to about 400 _mg , and said daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 140 mg to about 240 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- Claim 6, wherein no other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described in . The condition is treated by achieving a first AUC _0-24 of bupropion, wherein said first AUC _0-24 of bupropion is the reference AUC ₀ of bupropion resulting from administration of a daily dose of racemic bupropion. _-24 , wherein said daily dose of racemic bupropion is from about 400 mg to about 450 _mg , and said daily dose of (S)-bupropion is wherein said daily dose of said (S)-bupropion administered to said human is from about 160 mg to about 270 mg, said (S)-bupropion is at least 95% enantiomerically pure and said (S)- Claim 6, wherein no other bupropion is administered with said daily dose of bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. A method, dosage form, use or kit as described in . The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 150 mg to about 200 mg, and said daily dose of (S)-bupropion is less than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 60 mg to about 120 mg, said (S)-bupropion being at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. 7. A method, dosage form, use or kit according to claim 6. The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 200 mg to about 250 mg, and said daily dose of (S)-bupropion is greater than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 80 mg to about 150 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. 7. A method, dosage form, use or kit according to claim 6. The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 250 mg to about 300 mg, and said daily dose of (S)-bupropion is greater than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 100 mg to about 180 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. 7. A method, dosage form, use or kit according to claim 6. The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 300 mg to about 350 mg, and said daily dose of (S)-bupropion is greater than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 120 mg to about 210 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. 7. A method, dosage form, use or kit according to claim 6. The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 350 mg to about 400 mg, and said daily dose of (S)-bupropion is less than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 140 mg to about 240 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. 7. A method, dosage form, use or kit according to claim 6. The condition is treated by achieving a first AUC _0-24 of hydroxybupropion, wherein said first AUC _0-24 of hydroxybupropion is less than that of hydroxybupropion resulting from administering a daily dose of racemic bupropion. Same as Reference AUC _0-24 , said daily dose of racemic bupropion is from about 400 mg to about 450 mg, and said daily dose of (S)-bupropion is less than said first AUC _0-24 of hydroxybupropion. wherein said daily dose of said (S)-bupropion is from about 160 mg to about 270 mg, said (S)-bupropion is at least 95% enantiomerically pure and said No other bupropion is administered with said daily dose of (S)-bupropion, and said daily dose of said (S)-bupropion is about 40% to about 60% of said daily dose of racemic bupropion. 7. A method, dosage form, use or kit according to claim 6. The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 150 mg to about 200 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 60 mg to about 120 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racembupropion. The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 200 mg to about 250 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 80 mg to about 150 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racembupropion. The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 250 mg to about 300 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 100 mg to about 180 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racembupropion. The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 300 mg to about 350 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 120 mg to about 210 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racembupropion. The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 350 mg to about 400 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 140 mg to about 240 mg, said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racembupropion. The condition is treated by achieving a first AUC _0-24 of (R,R)-hydroxybupropion, wherein said first AUC _0-24 of (R,R)-hydroxybupropion is same as the reference AUC _0-24 of (R,R)-hydroxybupropion resulting from administering a daily dose, said daily dose of racemic bupropion being from about 400 mg to about 450 mg, and (S)-bupropion is administered to said human to achieve said first AUC _0-24 of (R,R)-hydroxybupropion, and said daily dose of said (S)-bupropion is from about 160 mg to about 270 mg, wherein said (S)-bupropion is at least 95% enantiomerically pure and no other bupropion is administered with said daily dose of said (S)-bupropion, and said (S)-bupropion 7. The method, dosage form, use or kit of claim 6, wherein said daily dose of is from about 40% to about 60% of said daily dose of racembupropion. 25. The method of any one of claims 1-24, wherein the (S)-bupropion is administered once daily. 25. The method of any one of claims 1-24, wherein said (S)-bupropion is administered in twice daily doses, the sum of said twice daily doses being said daily dose. 27. The method of any one of claims 1-26, wherein the (S)-bupropion is administered for at least 8 consecutive days. 28. The method of any one of claims 1-27, wherein the (S)-bupropion is administered continuously for at least 14 days. 29. The method of any one of claims 1-28, wherein the (S)-bupropion is administered for at least 21 consecutive days. 30. The method of any one of claims 1-29, wherein the (S)-bupropion is administered continuously for at least 28 days. 31. The method of any one of claims 1-30, wherein the (S)-bupropion is administered in a dosage form that provides sustained release of (S)-bupropion. 32. The method of claim 31, wherein the dosage form is formulated to have a T _max for (S)-bupropion that is from about 2 hours to about 4 hours. 33. The method of any one of claims 1-32, wherein the method achieves an AUC _0-12 for (S)-bupropion in humans of at least about 300 ng·hr/mL. 34. The method of any one of claims 1-33, wherein the method achieves an AUC _0-12 for (S)-bupropion in humans of at least about 400 ng·hr/mL. 35. The method of any one of claims 1-34, wherein the method achieves an AUC _0-12 of (S)-bupropion in humans of about 500 ng-hr/mL to about 900 ng-hr/mL. . 36. The method of any one of claims 1-35, wherein the method achieves a _Cmax for (S)-bupropion in humans of about 60 ng/mL to about 140 ng/mL.

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