AU2024200081B2 - Dosage forms and methods for enantiomerically enriched or pure bupropion - Google Patents

Abstract

This disclosure relates to dosage forms containing an enantiomerically enriched or pure bupropion such as enantiomeric excess of (S)-bupropion, enantiomerically enriched (S)-bupropion, or enantiomerically pure (S)-bupropion and methods of using these dosage forms. These dosage forms may be administered to human beings in a reduced amount as compared to the amount of racemic bupropion that would be administered in the same situation.

Description

DOSAGE FORMS AND METHODS FOR ENANTIOMERICALLY ENRICHED OR PURE BUPROPION CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patent application numbers 2024200081

5 62/971,174, filed February 6, 2020; 62/978,626, filed February 19, 2020; and 62,992,060, filed

March 19, 2020; this application is also a continuation-in-part of 16/830,637, filed March 26,

this is also 2020; application a continuation-in-part of

PCT/US2019/052210, filed September 20, 2019; this application is also a continuation-in-part of

16/907,691, filed June 22, 2020; all of which are incorporated by reference herein in their

10 entirety.

BACKGROUND Bupropion is approved for human use as a racemic mixture. It was believed by many that

bupropion and its metabolites rapidly racemize in the human body.

SUMMARY

15 Described herein are dosage forms containing an enantiomeric excess of (S)-bupropion,

enantiomerically enriched (S)-bupropion, or enantiomerically pure (S)-bupropion and methods

of using those dosage forms. These dosage forms may be administered to human beings in a

reduced amount as compared to the amount of racemic bupropion that would be administered

in the same situation.

20 Some embodiments include a method of providing bupropion to the plasma of a human

being, comprising: selecting a human patient in need of a pharmacokinetic profile provided by

orally administering a reference dosage form containing a first amount of racemic bupropion at

a first dosing frequency; and orally administering a dosage form containing a second amount of

(S)-bupropion that is at least 95% enantiomerically pure at the first dosing frequency to achieve

25 the same pharmacokinetic profile that would be achieved by administering the reference dosage

form at the first dosing frequency; wherein the first dosing frequency is once daily or twice daily;

and wherein the second amount is about 20-70%, about 40-60%, about 45-55%, or about 50% of

the first amount. For example, if a particular pharmacokinetic profile is achievable by orally

administering a dosage form containing 150 mg of racemic bupropion and the second amount is

40-60% of the first amount, the second amount is 60-90 mg. Thus, in this situation, 60-90 mg of

5 (S)-bupropion would be administered once daily to achieve the same pharmacokinetic profile as 2024200081

would be achieved by administering 150 mg of racemic bupropion once daily; or 60-90 mg of (S)-

bupropion would be administered twice daily to achieve the same pharmacokinetic profile as

would be achieved by administering 150 mg of racemic bupropion twice daily.

For the purposes of this disclosure, if the dosage form containing enantiomerically pure

10 (S)-bupropion is recognized by the FDA as bioequivalent to a dosage form containing racemic

bupropion, then the two dosage forms have the same pharmacokinetic profile.

Some embodiments include a method of treating a condition that is treatable with

racemic bupropion, comprising: selecting a human patient having the condition that is treatable

by orally administering a reference dosage form containing a first amount of racemic bupropion

15 at a first dosing frequency; and orally administering a dosage form containing a second amount

of (S)-bupropion that is at least 95% enantiomerically pure at the first dosing frequency to achieve

the same therapeutic effect that would be achieved by administering the reference dosage form

at the first dosing frequency; wherein the first dosing frequency is once daily or twice daily; and

wherein the second amount is about 20-70%, about 40-60%, about 45-55%, or about 50% of the

20 first amount. For example, if a condition is treatable by orally administering a dosage form

containing 150 mg of racemic bupropion and the second amount is 40-60% of the first amount,

the second amount is 60-90 mg. Thus, in this situation, 60-90 mg of (S)-bupropion would be

administered once daily to treat a condition so that the same therapeutic effect is achieved as

would be achieved by administering 150 mg of racemic bupropion once daily; or 60-90 mg of (S)-

25 bupropion would be administered twice daily to treat a condition so that the same therapeutic

effect is achieved as would be achieved by administering 150 mg of racemic bupropion twice

daily.

Some embodiments include a method of treating a human being, comprising orally

administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

one or two times per day, to the human being.

Some embodiments include a dosage form for treating a condition in a human being,

5 comprising (S)-bupropion that is at least 95% enantiomerically pure, wherein the dosage form is 2024200081

orally administered one or two times per day to the human being.

Some embodiments include use of (S)-bupropion that is at least 95% enantiomerically

pure in the manufacture of a medicament for treating a condition in a human being, wherein the

medicament is orally administered one or two times per day to the human being.

10 Some embodiments include a kit comprising a dosage form and a label, wherein the

dosage form comprises (S)-bupropion that is at least 95% enantiomerically pure, and the label

states that the dosage form is orally administered one or two times per day to the human being

for treating a condition in the human being.

BRIEF DESCRIPTION OF THE DRAWINGS

15 FIG. 1 depicts the AUC0-12 values for bupropion and hydroxybupropion in healthy

volunteers after dosing S-bupropion and racemic bupropion tablets.

FIG. 2 shows the mean plasma levels of bupropion and hydroxybupropion after dosing

(S)-bupropion or (R)-bupropion tablets.

FIG. 3 shows the Cmax of R,R-hydroxybupropion after dosing (S)-bupropion or (R)-

20 bupropion tablets.

DETAILED DESCRIPTION

The (S)-bupropion administered to the human being may be enantiomerically pure or

enantiomerically enriched. For example, the (S)-bupropion may be at least 70%, at least 80%, at

least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at

25 least 99.9%, or at least 99.99% enantiomerically pure, up to (or nearly) 100% enantiomerically

pure. (S)-bupropion that is 99.99% enantiomerically pure contains 99.99% (S)-bupropion and

0.001% (R)-bupropion. For convenience, any of the above may be referred to as "(S)-bupropion."

This type of dosage form may be useful in treating conditions where increased levels of (S)-

bupropion and/or (R,R)-hydroxybupropion are therapeutically beneficial, or for treating human

beings in need of treatment with (S)-bupropion and/or (R,R)-hydroxybupropion.

It has been discovered that orally administering (S)-bupropion is bioequivalent or

pharmacokinetically equivalent to administering about twice as much racemic bupropion. For

5 example, a 75 mg dose of (S)-bupropion is bioequivalent to a dose of about 150 mg of racemic 2024200081

bupropion.

(S)-bupropion may be administered alone or in combination with another drug. However,

for some treatments, use of another drug may not be desirable with (S)-bupropion or (R,R)-

hydroxybupropion. For example, (S)-bupropion or (R,R)-hydroxybupropion may be the only

10 compounds needed to treat the condition, additional drugs may not provide any significant

benefit, or adding additional drugs may unacceptably increase the risk of adverse events which

outweigh any potential benefit that they may provide. Thus, some dosage forms are substantially

free of any other drug, and some treatments involve administration of (S)-bupropion without co-

administration of any other drug. For example, the dosage form may contain less than 10% by

15 weight, less than 5% by weight, less than 2.5% by weight, less than 1% by weight, or less than

0.1% by weight of any other active pharmaceutical agent, as compared to the weight of the (S)-

bupropion, or may contain no other drug.

The dosage forms and methods described above may be incorporated into methods for

treating a mammal, such as a human being, for providing therapeutically effective plasma levels

20 of (S)-bupropion or one of its metabolites, such as (R,R)-hydroxybupropion,

erythrohydroxybupropion, or threohydroxybupropion, or for otherwise providing desirable or

enhanced plasma levels or pharmacokinetic properties of (S)-bupropion or one of its metabolites.

For example, the dosage forms and methods may be used to treat neurological disorders,

central nervous system disorders, psychiatric disorders, neuropsychiatric disorders, or related

25 conditions.

The term "treating" or "treatment" includes the diagnosis, cure, mitigation, treatment, or

prevention of disease in man or other animals, or any activity that otherwise affects the structure

or any function of the body of man or other animals.

Administration of (S)-bupropion, e.g. by oral administration, may occur one or more times

in a single day, or one or more times a day for multiple days, such as multiple consecutive days.

For example, (S)-bupropion may be administered once or twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9-

13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59,

5 60, 61-89, 90, or more consecutive days. The patient may be fasted prior to and/or after oral 2024200081

administration of a dosage form containing (S)-bupropion.

To reduce the risk of seizure or another adverse event, it may be helpful to start with a

lower starting daily dose of (S)-bupropion, and then later increasing the dose to a higher target

daily dose. A "daily dose" refers to the total amount of bupropion received in a day (e.g., a 75

10 mg administered in the morning and a 75 mg dose administered in the evening would be a daily

dose of 150 mg). For example, a lower starting daily dose is a lower total amount of bupropion

received in a day, and a higher target daily dose is a higher total amount of bupropion received

in a day. One way to accomplish this is by administering a dosage form containing a lower dose

of (S)-bupropion, alone or in combination with other drug, once or twice a day for 1, 2, 3, 4, 5, 6,

15 7, or more days, followed by treatment with a dosage form containing a higher dose of (S)-

bupropion at the same dosing frequency that was used with the lower dose. For example, the

dosage form containing a lower dose of (S)-bupropion could be administered once daily on day

1, 2, and 3, and then a higher dose of (S)-bupropion could be administered once daily starting on

day 4, and continued once daily for an extended period of time, such as 2, 3, 4, 5, 6, 7, 8, 9-13,

20 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59, 60,

61-89, 90, or more consecutive days, or for the remainder of the treatment period. Alternatively,

the dosage form containing lower dose of (S)-bupropion could be administered twice daily on

day 1, 2, and 3, and then a higher dose of (S)-bupropion could be administered twice daily starting

on day 4, and continued twice a daily for an extended period of time, such as 2, 3, 4, 5, 6, 7, 8, 9-

25 13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-34, 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59,

60, 61-89, 90, or more consecutive days, or for the remainder of the treatment period.

Another way to accomplish this, e.g. increasing from a lower starting daily dose to a target

higher dose, is by administering the dosage form containing (S)-bupropion, alone or in

combination with other drug, once a day for 1, 2, 3, 4, 5, 6, 7, or more days, followed by twice a

day treatment. For example, the dosage form containing (S)-bupropion could be administered

once a day on day 1, 2, and 3, and then twice a day starting on day 4, and continued twice a day

for an extended period of time, such as 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30,

31, 32-34, 35, 36-41, 42, 43-48, 49, 50-55, 56, 57-59, 32-59, 60, 61-89, 90, or more consecutive

5 days, or for the remainder of the treatment period. (S)-Bupropion has the structure shown 2024200081

below.

O H CI N

Unless otherwise indicated, any reference to a compound herein, such as (S)-bupropion,

by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate

10 solid forms, such as polymorphs, crystals, solvates, hydrates, etc.; tautomers; isotopically-

enriched compounds (e.g. deuterium enriched bupropion); or any chemical species that may

rapidly convert to a compound described herein under conditions in which the compounds are

used as described herein.

For dosage forms comprising (S)-bupropion, such as at least 95%, at least 97%, at least

15 99%, or at least 99.9% enantiomerically pure bupropion, any suitable amount of (S)-bupropion

may be used. In some embodiments, a dosage form contains 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,

20 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,

25 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 of (S)-bupropion, or any amount in a range bounded by any of these values.

Ranges of amounts of (S)-Bu obtained by combining any of the ranges or endpoints above are

5 also contemplated, especially if the range obtained encompasses, or is near, one or more the 2024200081

following values for the amount of (S)-bupropion in the dosage form: about 60 mg, about 75 mg,

or about 90 mg. These are values that are believed to potentially be of particular utility. A dosage

form containing an amount of (S)-bupropion listed above may be administered once, twice, or

three times a day for a daily dose that is 1, 2, or 3 times that of any dose amount or any dose

10 range listed above, e.g. 2 times 50-100 mg for a daily dose of 100-200 mg, or 3 times 50-100 mg

for a daily dose of 150-300 mg. Any daily dose obtained by combining any of the dose ranges or

endpoints above and multiplying that result by 1, 2, or 3 are also contemplated, especially if the

range obtained encompasses, or is near, one or more the following values: about 120 mg, about

150 mg, or about 180 mg. These are values that are believed to potentially be of somewhat more

15 interest for average sized adults. Lower doses, such as about 1-50 mg or about 1-70 mg, given

once or twice a day, may be somewhat more useful for the treatment of children. Higher doses,

e.g. over about 100 mg, given twice or three times a day, may be somewhat more useful for the

treatment of larger adults.

The daily dose of (S)-bupropion may be intended to target specific pharmacokinetic

20 parameters (such as a Cmax, an AUC (e.g. an AUC0-12, AUCo-24, or AUCo-inf), and/or another

pharmacokinetic parameter of: bupropion, (S)-bupropion, hydroxybupropion, (R,R)-

hydroxybupropion, (S,S)-hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion,

or another metabolite of racemic bupropion, or a combination thereof) that result from

administering a certain amount of racemic bupropion. For example, a daily dose of (S)-bupropion

25 may be administered to target a pharmacokinetic parameter that would result from a daily dose

of 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 450-500 mg of racemic bupropion. In order

to achieve that pharmacokinetic parameter, for example, the amount of daily dose of (S)-

bupropion administered may be about 20-70%, about 40-60%, about 45-55%, or about 50% of

the amount of the daily dose of racemic bupropion.

Because (S)-bupropion is unexpectedly the primary source of the bupropion and

bupropion metabolites present in the blood, the amount of (S)-bupropion administered to a

5 person can be considerably lower than the amount of racemic bupropion (or (R)-bupropion) that 2024200081

would be administered to treat the same condition with the same effect. For example, if the

amount of racemic bupropion administered to treat a condition is 150 mg, a lower amount of (S)-

bupropion such as 5-50% or 20-70% of that amount, i.e. 30-105 mg, can be administered to

achieve a similar effect. In some embodiments, the amount of (S)-bupropion administered is

10 selected to be about 5-70%, about 5-50%, about 20-70%, about 5-10%, about 10-20%, about 20-

30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 20-50%, about 40-70%,

about 40-60%, about 40-45%, or about 45-55%, of the amount of racemic bupropion that would

be administered to treat the same human being for the same condition

Some solid compositions may comprise at least about 5%, at least about 10%, at least

15 about 20%, at least about 50%, at least about 70%, at least about 80%, about 10-30%, about 30-

50%, about 50-80%, about 80-95%, about 10-50%, about 30-70%, or about 50-90% of (S)-

bupropion by weight.

In some embodiments, the dosage form may be free, or substantially free, of any active

pharmaceutical ingredients, or drugs, other than the (S)-bupropion. For example, the dosage

20 form may contain less than 10% by weight, less than 5% by weight, less than 1% by weight, or

less than 0.1% by weight of any other active pharmaceutical ingredient, as compared to the

weight of the (S)-bupropion.

Administering (S)-bupropion may be useful in increasing plasma levels of (S)-bupropion

by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold,

25 at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at

least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least

about 4-fold, at least about 5-fold, about 5-20 fold, at least about 10-fold, at least about 20-fold,

at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or

more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold,

about 40-50 fold, about 50-60 fold, about 60-70 fold, about 70-80 fold, about 80-90 fold, about

90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold,

about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190

fold, or about 190-200 fold, as compared to the plasma level of (R)-bupropion obtained by

5 administering a dosage form containing the same amount of (R)-bupropion to the human being. 2024200081

In some embodiments, the method is effective in increasing the AUC0-12, such as the

average AUCo-12, the mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, of (S)-

bupropion by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about

1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-

fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at 10

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 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold,

15 about 50-60 fold, about 60-70 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about

100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold,

about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-

200 fold, as compared to the AUC0-12 of (R)-bupropion obtained administering a dosage form

containing the same amount of (R)-bupropion to the human being.

20 In some embodiments, the method achieves an AUC0-12, such as the average AUC0-12, the

mean AUC0-12, the median AUCo-12, or the AUC0-12 of an individual, of (S)-bupropion that is 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

25 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, up to about 1,600

ng.hr/mL, up to about 1,700 ng.hr/mL, up to 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-

5 1,300 ng.hr/mL, about 1,300-1,800 ng.hr/mL, or about 300-1,800 ng.hr/mL. Ranges of AUC0-12 2024200081

obtained by combining any of the ranges or endpoints above are also contemplated, especially if

the range obtained encompasses, or is near, one or more the following values for AUC0-12 350

ng.hr/mL, 400 ng.hr/mL, 750 ng.hr/mL, or 900 ng.hr/mL, . These are values that are believed to

potentially be of particular utility.

10 In some embodiments, the method is effective in increasing the Cmax, such as the average

Cmax, the mean Cmax, the median Cmax, or the Cmax of an individual, of (S)-bupropion by at least

about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least

about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least

about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about

15 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 fold, about

70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about

20 120-130 fold, 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, as compared to administering a

dosage form containing the same amount of (R)-bupropion to the human being.

In some embodiments, the method achieves a Cmax, such as the average Cmax, the mean

Cmax, the median Cmax, or the Cmax of an individual, of (S)-bupropion that is at least about 30

25 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about

80 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least

about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL,

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, bout 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

5 170-180 ng/mL, about 180-190 ng/mL, about 190-200 ng/mL, about 200-210 ng/mL, about 210- 2024200081

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, about 30-110 ng/mL, about 110-220 ng/mL, or about 30-220

ng/mL. Ranges of Cmax obtained by combining any of the ranges or endpoints above are also

10 contemplated, especially if the range obtained encompasses, or is near, one or more the

following values for Cmax: 45 ng/mL, 90 ng/mL, 125 ng/mL, 150 ng/mL, or 180 ng/mL. These are

values that are believed to potentially be of particular utility.

In some embodiments, the method is effective in increasing the Cmin, such as the average

Cmin, the mean Cmin, the median Cmin, or the Cmin of an individual, of (S)-bupropion by at least

15 about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least

about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least

about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about

4-fold, at least about 5-fold, 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

20 more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold,

about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about

100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold,

about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-

200 fold, as compared to administering a dosage form containing the same amount of (R)-

25 bupropion to the human being.

In some embodiments, the method achieves a Cmin, such as the average Cmin, the mean

Cmin, the median Cmin, or the Cmin of an individual, of (S)-bupropion that is at least about 20 ng/mL,

at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40

ng/mL, about 20-60 ng/mL, about 20-25 ng/mL, about 25-30 ng/mL, about 30-35 ng/mL, about

35-40 ng/mL, about 30-40 ng/mL, about 40-45 ng/mL, about 45-50 ng/mL, about 30-50 ng/mL,

about 40-50 ng/mL, or about 50-60 ng/mL. Ranges of Cmin obtained by combining any of the

ranges or endpoints above are also contemplated, especially if the range obtained encompasses,

or is near, one or more the following values for Cmin: 20 ng/mL, ng/mL, 40 ng/mL, or 50 ng/mL.

5 These are values that are believed to potentially be of particular utility. 2024200081

Administering (S)-bupropion may be useful in increasing plasma levels of (R,R)-

hydroxybupropion, by 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, 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

10 150-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 fold, about 50-60 fold, about 70-80 fold, about

80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about

130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold,

about 180-190 fold, or about 190-200 fold, as compared to administering a dosage form

15 containing the same amount of (R)-bupropion to the human being.

Administering (S)-bupropion may be useful in increasing the AUC0-12, such as the average

AUC0-12, the mean AUCo-12, the median AUCo-12, or the AUC0-12 of an individual, of (R,R)-

hydroxybupropion, by 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-

20 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 fold, about 50-60 fold, about 70-80

fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-

130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about

25 170-180 fold, about 180-190 fold, or about 190-200 fold, as compared to administering a dosage

form containing the same amount of (R)-bupropion to the human being.

In some embodiments, the method achieves an AUCo-12, such as the average AUC0-12, the

mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, of (R,R)-hydroxybupropion that

is 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, about 6,000-8,000 ng.hr/mL, about 8,000-

5 10,000 ng.hr/mL, about 10,000-12,000 ng.hr/mL, about 12,000-14,000 ng.hr/mL, about 14,000- 2024200081

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

10 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. Ranges of AUC0-12 obtained by combining any of the ranges or endpoints above

are also contemplated, especially if the range obtained encompasses, or is near, one or more the

following values for AUC0-12: 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 believed to potentially be of particular utility.

15 Administering (S)-bupropion may be useful in increasing the Cmax, such as the average

Cmax, the mean Cmax, the median Cmax, or the Cmax of an individual, of (R,R)-hydroxybupropion, by

at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at

least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least

about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about

4-fold, at least about 5-fold, about 6-fold, at least about 10-fold, at least about 20-fold, at least 20

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 10-20 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-

50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110

fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-

25 160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, as

compared to administering a dosage form containing the same amount of (R)-bupropion to the

human being.

In some embodiments, the method achieves a Cmax, such as the average Cmax, the mean

Cmax, the median Cmax, or the Cmax of an individual, of (R,R)-hydroxybupropion that is 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, up to about 1,500 ng/mL, up to

5 about 1,600 ng/mL, up to about 1,700 ng/mL, up to about 1,800 ng/mL, up to about 1,900 g/mL, 2024200081

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, 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

10 1,400-1,500 ng/mL, about 1,500-1,600 ng/mL, about 1,600-1,700 ng/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. Ranges of Cmax obtained by combining any

of the ranges or endpoints above are also contemplated, especially if the range obtained

15 encompasses, or is near, one or more of the following values for Cmax: 400 ng/mL, 950 ng/mL,

1,500 ng/mL, or 2,100 ng/mL. These are values that are believed to potentially be of particular

utility.

Administering (S)-bupropion may be useful in increasing the Cmin, such as the average Cmin,

the mean Cmin, the median Cmin, or the Cmin of an individual, of (R,R)-hydroxybupropion, by at least

20 about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least

about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least

about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about

4-fold, at least about 5-fold, 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

25 more, about 1-5 fold, about 5-10 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about

40-50 fold, about 50-60 fold, about 60-70 fold, about 70-80 fold, about 80-90 fold, about 90-100

fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-

150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or

about 190-200 fold, as compared to administering a dosage form containing the same amount of

(R)-bupropion to the human being.

In some embodiments, the method achieves a Cmin, such as the average Cmin, the mean

Cmin, the median Cmin, or the Cmin of an individual, of (R,R)-hydroxybupropion that is at least about

5 150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, at least about 400 ng/mL, at least 2024200081

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

10 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,

15 about 700-1,100 ng/mL, or about 1,100-1,600 ng/mL. Ranges of Cmin obtained by combining any

of the ranges or endpoints above are also contemplated, especially if the range obtained

encompasses, or is near, one or more of the following values for Cmin: 350 ng/mL, 600 ng/mL, 700

ng/mL, 1,000 ng/mL, or 1,400 ng/mL. These are values that are believed to potentially be of

particular utility.

20 Administering (S)-bupropion to a human being may result in (R,R)-hydroxybupropion

being at least 90%, 95%, 97%, 97.2%, 97.4%, 97.6%, 97.8%, or 98% of the total of amount of (R,R)-

hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human being.

In some embodiments, the method achieves an AUC0-12, such as the average AUCo-12, the

mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, of erythrohydroxybupropion

25 that is 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, up to about 1,400 ng.hr/mL, up to

about 1,600 ng.hr/mL, up to about 1,800 ng.hr/mL, up to about 2,000 ng.hr/mL, up to about

2,200 ng.hr/mL, up to about 2,400 ng.hr/mL, up to about 2,600 ng.hr/mL, up to about 2,800

ng.hr/mL, up to 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, 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, about 500-1,000 ng.hr/mL, about 1,000-1,500 ng.hr/mL,

5 about 1,500-2,000 ng.hr/mL, about 2,000-2,500 ng.hr/mL, about 2,500-3,000 ng.hr/mL, about 2024200081

500-1,500 ng.hr/mL, about 1,500-3,000 ng.hr/mL, about 2,000-3,000 ng.hr/mL, or about 500-

3,000 ng.hr/mL. Ranges of AUC0-12 obtained by combining any of the ranges or endpoints above

are also contemplated, especially if the range obtained encompasses, or is near, one or more the

following values for AUC0-12: 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 believed to potentially be of particular utility. 10

In some embodiments, the method achieves a Cmax, such as the average Cmax, the mean

Cmax, the median Cmax, or the Cmax of an individual, of erythrohydroxybupropion that is at least

about 40 ng/mL, at least about 60 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, at

least about 100 ng/mL, at least about 120 ng/mL, at least about 140 ng/mL, up to about 160

15 ng/mL, up to about 180 ng/mL, up to about 200 ng/mL, up to about 220 ng/mL, up to about 240

ng/mL, up to about 260 ng/mL, up to about 280 ng/mL, about 40-60 ng/mL, about 60-80 ng/mL,

about 80-100 ng/mL, about 100-120 ng/mL, about 120-140 ng/mL, about 140-160 ng/mL, about

160-180 ng/mL, about 180-200 ng/mL, about 200-220 ng/mL, about 220-240 ng/mL, about 240-

260 ng/mL, about 260-280 ng/mL, about 280-300 ng/mL, about 40-100 ng/mL, about 100-150

20 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. Ranges of Cmax obtained

by combining any of the ranges or endpoints above are also contemplated, especially if the range

obtained encompasses, or is near, one or more the following values for Cmax: 60 ng/mL, 120

ng/mL, 200 ng/mL, or 240 ng/mL. These are the values that are believed to potentially be of

particular utility. 25

In some embodiments, the method achieves an AUC0-12, such as the average AUC0-12, the

mean AUCo-12, the median AUC0-12, or the AUC0-12 of an individual, of threohydroxybupropion that

is at least about 2,000 ng.hr/mL, at least about 3,000 ng.hr/mL, at least about 4,000 ng.hr/mL, at

least about 5,000 ng.hr/mL, at least about 6,000 ng.hr/mL, at least about 7,000 ng.hr/mL, up to

about 8,000 ng.hr/mL, up to about 9,000 ng.hr/mL, up to about 10,000 ng.hr/mL, up to about

11,000 ng.hr/mL, up to about 12,000 ng.hr/mL, up to about 13,000 ng.hr/mL, up to about 14,000

ng.hr/mL, up to about 15,000 ng.hr/mL, about 2,000-15,000 ng.hr/mL, about 2,000-3,000

ng.hr/mL, about 3,000-4,000 ng.hr/mL, about 4,000-5,000 ng.hr/mL, about 5,000-6,000

5 ng.hr/mL, about 6,000-7,000 ng.hr/mL, about 7,000-8,000 ng.hr/mL, about 8,000-9,000 2024200081

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. Ranges of AUC0-12

10 obtained by combining any of the ranges or endpoints above are also contemplated, especially if

the range obtained encompasses, or is near, one or more the following values for AUC0-12: 3,000

ng.hr/mL, 6,000 ng.hr/mL, 8,000 ng.hr/mL, or 12,000 ng.hr/mL. These are the values that are

believed to potentially be of particular utility.

In some embodiments, the method achieves a Cmax, such as the average Cmax, the mean

15 Cmax, the median Cmax, or the Cmax of an individual, of threohydroxybupropion that is 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

20 300-400 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/mL, or about 200-1,400 ng/mL. Ranges of Cmax obtained by combining any of

25 the ranges or endpoints above are also contemplated, especially if the range obtained

encompasses, or is near, one or more the following values for Cmax: 300 ng/mL, 600 ng/mL, 900

ng/mL, or 1,200 ng/mL. These are values that are believed to potentially be of particular utility.

Unless otherwise indicated, any reference to a compound herein, such as (S)-bupropion,

by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate

solid forms, such as polymorphs, crystals, solvates, hydrates, etc.; tautomers; deuterium-

modified compounds; or any chemical species that may rapidly convert to a compound described

herein under conditions in which the compounds are used as described herein.

(S)-Bupropion, alone or in a combination with another drug may be combined with a

5 pharmaceutical carrier selected on the basis of the chosen route of administration and standard 2024200081

pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences,

2005. The relative proportions of active ingredient and carrier may be determined, for example,

by the solubility and chemical nature of the compounds, chosen route of administration, and

standard pharmaceutical practice.

10 (S)-bupropion drug may be administered to a human patient in a variety of forms adapted

to the chosen route of administration, e.g., orally or parenterally. Parenteral administration in

this respect includes administration by the following routes: intravenous, intramuscular,

subcutaneous, intraocular, intrasynovial, transepithelial including transdermal; ophthalmic;

sublingual; and buccal, and topically including ophthalmic; dermal; ocular; rectal; nasal; etc.

15 (S)-bupropion may be formulated for oral administration, for example, with an inert

diluent or with an edible carrier, or it may be enclosed in hard or soft shell gelatin capsules,

compressed into tablets, or incorporated directly with the food of the diet. For oral therapeutic

administration, the active compound may be incorporated with an excipient and used in the form

of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and

20 the like.

Tablets, troches, pills, capsules and the like containing (S)-bupropion may also contain

one or more of the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; an

excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch,

alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as

25 sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or

cherry flavoring. When the dosage form is a capsule, it may contain, in addition to materials of

the above type, a liquid carrier. Various other materials may be present as coating, for instance,

tablets, pills, or capsules may 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. It may be desirable for material

in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially

non-toxic in the amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise a solid phase

5 dispersed in a liquid. 2024200081

(S)-bupropion may be formulated for parental or intraperitoneal administration.

Solutions of the active compounds as free bases or pharmacologically acceptable salts can be

prepared in water suitably mixed with a surfactant. A dispersion can also have an oil dispersed

within, or dispersed in, glycerol, liquid polyethylene glycols, and mixtures thereof. Under ordinary

10 conditions of storage and use, these preparations may contain a preservative to prevent the

growth of microorganisms.

Some embodiments include administration of a tablet that contains (S)-Bupropion in a

form that provides sustained release of (S)-Bupropion. A sustained release dosage form

containing (S)-Bupropion may have a Tmax of about 2-4 hours, 4-6 hours, or 6-8 hours. While

15 there are many ways that sustained release of bupropion may be achieved, in some

embodiments, (S)-Bupropion or (R)-bupropion is combined with a sustained release polymer,

such as an acrylic acid or a methacrylic acid copolymer or an ester thereof, e.g. a methyl

methacrylate copolymer, an ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl

methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine

20 copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polyacrylamide,

poly(methacrylic acid anhydride), a glycidyl methacrylate copolymers; a quaternized aminoalkyl

ester or an aminoalkyl amide of acrylic acid and/or methacrylic acid, for example, B-

methacryloxyethyltrimethylammonium methosulfate, B-acryloxypropyltrimethylammonium

chloride, and trimethylaminomethylmethacrylamide methosulfate, quaternized vinyl-

25 substituted nitrogen heterocycles such as methyl-vinyl pyridinium salts, vinyl esters of

quaternized amino carboxylic acids, styryltrialkyl ammonium salts, benzyldimethylammoniumethylmethacrylate chloride, diethylmethylammoniumethyl-acrylate,

diethylmethylammoniumethylmethacrylate methosulfate, N-

trimethylammoniumpropylmethacrylamide chloride, N-trimethylammonium-2,2-

dimethylpropyl-1-methacrylate chloride; a cellulose derivative such as a carboxyalkylcellulose

(e.g. carboxymethylcellulose), hydroxypropyl methylcellulose, etc. In some embodiments, the

sustained release polymer is hydroxypropyl methylcellulose. For example, particles of (S)-

Bupropion could be blended with microcrystalline cellulose and hydroxypropyl methylcellulose

5 (e.g., METHOCEL®) to form a mixture of blended powders. 2024200081

Examples of neurological disorders or central nervous system disorders that may be

treated by administering (S)-bupropion (including administering (S)-bupropion to achieve

therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) include, but

are not limited to: affective disorders, psychiatric disorders, cerebral function disorders,

10 movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure

disorders, and headaches.

Affective disorders that may be treated by administering (S)-bupropion (including

administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such

as (R,R)-hydroxybupropion) include, but are not limited to, depression, major depression,

15 treatment resistant depression and treatment resistant bipolar depression, bipolar disorders

including cyclothymia, seasonal affective disorder, mood disorders, chronic depression

(dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder

(PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit

disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention

20 deficit/hyperactivity disorder (AD/HD), bipolar and manic conditions, obsessive-compulsive

disorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual

syndrome, substance addiction or abuse, nicotine addiction, psycho-sexual dysfunction,

pseudobulbar affect, and emotional lability.

Depression may be manifested by depressive symptoms. These symptoms may include

25 psychological changes such as changes in mood, feelings of intense sadness, despair, mental

slowing, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger,

feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and/or self-

deprecation. Physical symptoms of depression may include insomnia, anorexia, appetite loss,

weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains,

headaches, cramps, digestive issues, and/or abnormal hormonal circadian rhythms.

Some patients, even after treatment with medications such as antidepressants, may have

an inadequate or no response to the treatment. Treatment resistant depression (TRD), or

5 treatment-refractory depression, is a condition generally associated with patients who have 2024200081

failed treatment with at least two antidepressants. Part of the diagnosis for TRD is for the patient

to have had an inadequate response to treatment with the antidepressants after an adequate

dose and adequate course. TRD may be more difficult to treat due to the comorbidity of other

medical or psychological illnesses, such as drug/alcohol abuse or eating disorders, or TRD being

10 misdiagnosed. Some TRD patients have had an inadequate response to 1, 2, 3, or more adequate

antidepressant treatment trials or have failed or had an inadequate response to 1, 2, 3, or more

prior antidepressant treatments. In some embodiments, a patient being treated for treatment

resistant depression has failed treatment with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more

antidepressant therapies.

15 Measures of treatment effect that may be improved by administering (S)-bupropion

(including administering (S)-bupropion to achieve therapeutic plasma levels of one of its

metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to: Montgomery-

Äsberg Depression Rating Scale (MADRS), Quality of Life Enjoyment and Satisfaction

Questionnaire Short Form, Range of Impaired Functioning Tool, Sheehan Disability Scale, Patient

20 Rated Inventory of Side Effects (PRISE), Columbia-Suicide Severity Rating Scale (C-SSRS), Quick

Inventory of Depressive Symptomatology, Self-Report (QID(S)-SR), Clinical Global Impression

(CGI) scale, 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-item Quick

25 Inventory of Depressive Symptomatology - Self Report (QID(S)-SR16), Sheehan Disability Scale

(SDS), Clinical Global Impression of Severity of Illness (CGI-S), Clinical Global Impression of Change

(CGI-C), EuroQOL 5 Dimension 5 Level (EQ-5D-5L), Patient Global Impression of Change (PGIC), 7-

item Generalized Anxiety Disorder (GAD-7), Clinical Global Impressions- Improvement (CGI-I).

Sheehan Disability Scale (SDS). 16-item Quick Inventory of Depressive Symptomatology - Self

Report (QID(S)-SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital

Cognitive and Physical Functioning Questionnaire (CPFQ), CPFQ - Cognitive subscales (Items 4 to

7), Brief Psychiatric Rating Scale (BPRS), etc.; Digit Symbol Substitution Test (DSST), Rey Auditory

Verbal Learning Task (RAVLT), Trail Making Test (TMT), Stroop Colour Naming Test

5 (STROOP), Simple Reaction Time (SRT), Choice Reaction Time (CRT), etc. 2024200081

Patients who may benefit from the treatments described herein include pediatric

patients, such as patients under about 18 years of age, about 0-5 years of age, about 5-10 years

of age, about 10-12 years of age, or about 12-18 years of age, adult patients, such as patients

having an age of about 18-65 years; about 18-30 years; about 30-50 years; about 50-65 years,

10 and elderly patients, such as patients over 65 years of age; about 65-75 years of age; about 75-

90 years of age; or over 90 years of age.

Treatment of TRD by administering (S)-bupropion (including administering (S)-bupropion

to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion)

may result in a reduction of depressive symptoms of at least about 5%, at least about 10%, at

15 least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%,

at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any other

reduction percentage in a range bounded by any of these values.

Psychiatric disorders that may be treated by administering (S)-bupropion (including

administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such

20 as (R,R)-hydroxybupropion) include, but are not limited to, anxiety disorders, such as phobias,

generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-

compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depressive illness,

hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality

disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy,

25 aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

Agitation associated with Alzheimer's disease occurs as the disease progresses. Agitation

may present itself as inappropriate verbal, emotional, and/or physical behaviors. Inappropriate

behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional

response, demands for attention, threats, irritability, frustration, screaming, repetitive questions,

mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness,

shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching,

rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting,

combativeness, hyperactivity, and/or kicking.

5 In some embodiments, treatment of agitation associated with Alzheimer's disease by 2024200081

administering (S)-bupropion (including administering (S)-bupropion to achieve therapeutic

plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion) may result in a

reduction of agitation-related symptoms of at least about 5%, at least about 10%, at least about

20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about

10 70%, at least about 80%, at least about 90%, and/or up to about 100%.

Measures of treatment effect of agitation that may be improved by administering (S)-

bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of

its metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to,

Neuropsychiatric Inventory-Clinician (NPI-C) rating scale, overall and all domains;

15 Neuropsychiatric Inventory-Clinician (NPI-C) rating scale Agitation domain; Cohen-Mansfield

Agitation Inventory (CMAI); Cornell Scale for Depression in Dementia (CSDD); Neuropsychiatric

Inventory (NPI Agitation/Aggression Domain); Cocomitant Medications (Frequency of using

concomitant medications); Alzheimer's Disease Cooperative Study - Activities of Daily Living

Inventory (ADC(S)-ADL); Neuropsychiatric Inventory (NPI) Individual Domains and NPI Total

20 Scores (range 0-144), including NPI-C Apathy domain, NPI Agitation/Aggression Caregiver

Distress, Modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change

Agitation (mADC(S)-CGIC Agitation), Patient Global Impression of Change (PGIC) (rated by

caregiver), 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 Assessment

25 Scale-Cognitive Subscale (ADA(S)-Cog), Mini-mental State Examination (MMSE), Caregiver Strain

Index (CSI), Individual Domain of the Neuropsychiatric Inventory (NPI), Total Neuropsychiatric

Inventory (NPI) Score, Neuropsychiatric Inventory (Agitation/Aggression Domain of NPI),

Neuropsychiatric Inventory (Caregiver Distress for NPI Domains), etc.

Substance addiction abuse that may be treated by administering (S)-bupropion (including

administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such

as (R,R)-hydroxybupropion) includes, but is not limited to, drug dependence, addiction to

cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids,

5 anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, 2024200081

phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine

addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, electronic

cigarettes, and addiction to chewing tobacco.

Cerebral function disorders that may be treated by administering (S)-bupropion (including

10 administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such

as (R,R)-hydroxybupropion) include, but are not limited to, disorders involving intellectual deficits

such as senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome,

epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice

spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and

15 schizophrenia. Cerebral function disorders also include disorders caused by cerebrovascular

diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral

arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include

disturbance of consciousness, senile dementia, coma, lowering of attention, and speech

disorders.

20 Movement disorders that may be treated by administering (S)-bupropion (including

administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such

as (R,R)-hydroxybupropion) include, but are not limited to, akathisia, akinesia, associated

movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea,

Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia,

25 dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's

disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and

Wilson's disease.

Dementias that may be treated by administering (S)-bupropion (including administering

(S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-

hydroxybupropion) include, but are not limited to, Alzheimer's disease, Parkinson's disease,

vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia,

Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-

Korsakoff Syndrome, and Pick's disease.

5 Motor neuron diseases that may be treated by administering (S)-bupropion (including 2024200081

administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such

as (R,R)-hydroxybupropion) include, but are not limited to, amyotrophic lateral sclerosis (ALS),

progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio

syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sach's disease,

10 Sandoff disease, and hereditary spastic paraplegia.

Neurodegenerative diseases that may be treated by administering (S)-bupropion

(including administering (S)-bupropion to achieve therapeutic plasma levels of one of its

metabolites, such as (R,R)-hydroxybupropion) include, but are not limited to Alzheimer's disease,

prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy

15 (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease,

Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis

(MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive

supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral

autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL),

20 muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis,

neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration,

Guillain-Barré syndrome, and spastic paraplesia.

Seizure disorders that may be treated by administering (S)-bupropion (including

administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such

25 as (R,R)-hydroxybupropion) include, but are not limited to, epileptic seizures, nonepileptic

seizures, epilepsy, febrile seizures; partial seizures including, but not limited to, simple partial

seizures, Jacksonian seizures, complex partial seizures, and epilepsia partialis continua;

generalized seizures including, but not limited to, generalized tonic-clonic seizures, absence

seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms;

and status epilepticus.

Types of headaches that may be treated administering (S)-bupropion (including

administering (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites, such

5 as (R,R)-hydroxybupropion) include, but are not limited to, migraine, tension, and cluster 2024200081

headaches.

Other neurological disorders that may be treated by administering (S)-bupropion

(including administering (S)-bupropion to achieve therapeutic plasma levels of one of its

metabolites, such as (R,R)-hydroxybupropion) include, Rett Syndrome, autism, tinnitus,

10 disturbances of consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy,

cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not

limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension

dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as

methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence,

15 urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

In some embodiments, administering (S)-bupropion (including administering (S)-

bupropion to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-

hydroxybupropion) may be useful to treat pain, joint pain, pain associated with sickle cell disease,

pseudobulbar affect, depression (including treatment resistant depression), disorders related to

20 memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS),

seizures, cough (including chronic cough), etc.

In some embodiments, refractory depression may be treated by administering (S)-

bupropion (including administering (S)-bupropion to achieve therapeutic plasma levels of one of

its metabolites, such as (R,R)-hydroxybupropion).

25 (S)-bupropion may also be used (either by direct action of (S)-bupropion, or by

administration of (S)-bupropion to achieve therapeutic plasma levels of one of its metabolites,

such as (R,R)-hydroxybupropion) to treat, or provide relief to, any type of pain including, but not

limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive

pain, inflammatory pain, arthritis pain, complex regional pain syndrome, etc.

In some embodiments, (S)-bupropion may be administered (either for its direct action, or

to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion)

to relieve neuropathic pain.

Examples of neuropathic pain include diabetic peripheral neuropathy, post-herpetic

5 neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, etc. 2024200081

Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression,

spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-associated neuropathy,

and radio- or chemo-therapy associated neuropathy, etc.

In some embodiments, (S)-bupropion may be administered (either for its direct action, or

10 to achieve therapeutic plasma levels of one of its metabolites, such as (R,R)-hydroxybupropion)

to relieve fibromyalgia.

Adverse events associated with bupropion that may be avoided or reduced by a method

described herein include a central nervous system adverse event, a gastrointestinal event, or

another type of adverse event associated with any of these compounds. Central nervous system

15 (CNS) adverse events include, but are not limited to, nervousness, dizziness, sleeplessness, light-

headedness, tremor, hallucinations, convulsions, CNS depression, fear, anxiety, headache,

increased irritability or excitement, tinnitus, drowsiness, dizziness, sedation, somnolence,

confusion, disorientation, lassitude, incoordination, fatigue, euphoria, nervousness, insomnia,

sleeping disturbances, convulsive seizures, excitation, catatonic-like states, hysteria,

20 hallucinations, delusions, paranoia, headaches and/or migraine, and extrapyramidal symptoms

such as oculogyric crisis, torticollis, hyperexcitability, increased muscle tone, ataxia, and/or

tongue protrusion.

Gastrointestinal adverse events include, but are not limited to, nausea, vomiting,

abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic ulcers

25 with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, feeling

of fullness in stomach, indigestion, bloating, hyperacidity, dry mouth, gastrointestinal

disturbances, and gastric pain.

Other adverse events that may be reduced or avoided by a method described herein

include abnormal sensation of rotation and movement, agitation, arm weakness, bloating,

blurred vision, burning sensation in the eyes, buzzing sound in ear, changes in vital signs

(including, but not limited to, heart rate, respiratory rate, body temperature, blood pressure),

cold sensation, constipation, difficulty concentrating, difficulty sleeping, difficulty in falling

asleep, difficulty urinating, difficulty with bowel movement, discomfort in the ear, discomfort in

5 the eye, discomfort in the stomach, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, 2024200081

fatigue, feeling feverish, feeling heavy headed, feeling more agitated than usual, feeling more

tired than usual, feeling tired, hand tremors, hand weakness, headache, heartburn, hot flashes,

increased blood pressure, increased skin sensitivity, increased skin sensitivity at head and face,

involuntary muscle contraction, involuntary muscle contractions at all over the body, knee pain,

10 leg weakness, lightheadedness, loose stool, loss of appetite, low back pain, menstrual disorder,

metallic taste, more saliva than usual, mucosal dryness, nasal congestion, nausea, runny nose,

sensation of light pressure sensation in the eyes, shivers when stretching or yawning, skin

sensitivity, skin sensitivity in arm, face, and/or head, sleep difficulties, soft stools, stomach ache,

stomach discomfort, sweaty hands and/or feet, throat irritation, throat pain, tinnitus, tremors,

15 and/or weakness. Any of these side effects may also be referred to, or grouped, according to a

corresponding, equivalent, or otherwise relevant term found in the Medical Dictionary for

Regulatory Activities (MedRA).

The following embodiments are contemplated:

Embodiment 1. A method of providing (R)-bupropion and (S)-bupropion to the

20 plasma, comprising:

selecting a human being in need of the pharmacokinetic profile provided by orally

administering a reference dosage form containing a first amount of racemic bupropion at a first

dosing frequency; and

orally administering a dosage form containing a second amount of (S)-bupropion that is

25 at least 95% enantiomerically pure at the first dosing frequency to achieve the same

pharmacokinetic profile that would be achieved by administering the reference dosage form at

the first dosing frequency;

wherein the first dosing frequency is once daily or twice daily; and

wherein the second amount is about 40% to about 60% of the first amount.

Embodiment 2. A method of treating a condition that is treatable with racemic

bupropion, comprising:

selecting a human patient having the condition that is treatable by orally administering a

reference dosage form containing a first amount of racemic bupropion at a first dosing frequency;

5 and 2024200081

orally administering a dosage form containing a second amount of (S)-bupropion that is

at least 95% enantiomerically pure at the first dosing frequency to achieve the same therapeutic

effect that would be achieved by administering the reference dosage form at the first dosing

frequency;

10 wherein the first dosing frequency is once daily or twice daily; and

wherein the second amount is about 40% to about 60% of the first amount.

Embodiment 3. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

one or two times per day, to the human being, wherein the human being has a condition that is

15 treatable with (S)-bupropion, wherein the amount of (S)-bupropion administered is selected to

be about 20% to about 70% by weight of the amount of racemic bupropion that would be

administered to treat the same human being for the same condition.

Embodiment 4. A method of providing therapeutically effective plasma levels of

(R,R)-hydroxybupropion comprising orally administering, one or two times per day, a dosage

20 form containing (S)-bupropion that is at least 95% enantiomerically pure, to a human being in

need of treatment with (R,R)-hydroxybupropion, wherein (R,R)-hydroxybupropion is at least 97%

of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the

plasma of the human being, and wherein the method achieves a Cmax of (R,R)-hydroxybupropion

that is at least about 500 ng/ml in the human being.

25 Embodiment 5. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure

to the human being, wherein the human being is in need of treatment with (S)-bupropion,

wherein the (S)-bupropion is the sole active agent used to treat the human being.

Embodiment 6. A method of treating a human being comprising orally administering a dosage form containing about 50 mg to about 100 mg of (S)-bupropion that is at

least 95% enantiomerically pure, one or two times per day, to the human being, wherein the

human being is in need of treatment with (S)-bupropion.

5 Embodiment 7. A method of treating a human being comprising orally 2024200081

administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

one or two times per day, to the human being, wherein the human being is in need of treatment

with (S)-bupropion, wherein the method achieves a Cmax of (S)-bupropion that is at least about

60 ng/mL.

10 Embodiment 8. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

one or two times per day, to the human being, wherein the human being is in need of treatment

with (S)-bupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total of amount of

(R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human being.

15 Embodiment 9. A method of providing therapeutically effective plasma levels of

(R,R)-hydroxybupropion comprising orally administering, one or two times per day, a dosage

form containing (S)-bupropion that is at least 95% enantiomerically pure, to a human being in

need of treatment with (R,R)-hydroxybupropion, wherein (R,R)-hydroxybupropion is at least 97%

of the total of amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the

20 plasma of the human being.

Embodiment 10. A method of providing therapeutically effective plasma levels of

(R,R)-hydroxybupropion comprising orally administering, one or two times per day, a dosage

form containing (S)-bupropion that is at least 95% enantiomerically pure, to a human being in

need of treatment with (R,R)-hydroxybupropion, wherein the method achieves a Cmax of (R,R)-

25 hydroxybupropion that is at least about 500 ng/ml in the human being.

Embodiment 11. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

one or two times per day, to the human being, wherein the human being is in need of treatment

with (S)-bupropion, wherein the method achieves a Cmax of (S)-bupropion that is at least about

70 ng/mL.

Embodiment 12. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

5 one or two times per day, to the human being, wherein the human being is in need of treatment 2024200081

with (S)-bupropion, wherein the method achieves an AUCo-12 of (S)-bupropion that is at least

about 600 ng.h/mL.

Embodiment 13. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

10 one or two times per day, to the human being, wherein the human being is in need of treatment

with (S)-bupropion, wherein the method achieves a Cmax of (R,R)-hydroxybupropion that is at

least about 800 ng/mL.

Embodiment 14. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

15 one or two times per day, to the human being, wherein the human being is in need of treatment

with (S)-bupropion, wherein the method achieves an AUCo-12 of (R,R)-hydroxybupropion that is

at least about 8,000 ng.h/mL.

Embodiment 15. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

20 one or two times per day, to the human being, wherein the human being is in need of treatment

with (S)-bupropion, wherein the method achieves a Cmax of erythrohydroxybupropion that is at

least about 90 ng/mL.

Embodiment 16. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

25 one or two times per day, to the human being, wherein the human being is in need of treatment

with (S)-bupropion, wherein the method achieves an AUCo-12 of erythrohydroxybupropion that is

at least about 1,000 ng.h/mL.

Embodiment 17. A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

one or two times per day, to the human being, wherein the human being is in need of treatment

with (S)-bupropion, wherein the method achieves a Cmax of threohydroxybupropion that is at

least about 450 ng/mL.

Embodiment 18. A method of treating a human being comprising orally

5 administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, 2024200081

one or two times per day, to the human being in need of treatment with (S)-bupropion, wherein

the method achieves an AUC0-12 of threohydroxybupropion that is at least about 5,000 ng.h/mL.

Embodiment 19. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, or 18, wherein the human being is in need of treatment with (S)-bupropion.

10 Embodiment 20. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, or 19, wherein the method achieves a Cmax of (S)-bupropion that is at least

about 60 ng/mL.

Embodiment 21. 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 effective in increasing the Cmax of (S)-

15 bupropion at least 5-fold as compared to the Cmax of (R)-bupropion that results from

administering the same amount of (R)-bupropion to the human being.

Embodiment 22. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, or 21, wherein the method achieves a Cmax of (RR)-hydroxybupropion

that is at least about 500 ng/ml in the human being.

20 Embodiment 23. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the method is effective in increasing the Cmin of (R,R)-

hydroxybupropion at least 3-fold as compared to the Cmin of (R,R)-hydroxybupropion that results

from administering the same amount of (R)-bupropion to the human being.

Embodiment 24. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

25 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, wherein the dosage form is administered once daily.

Embodiment 25. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein the dosage form is administered twice daily.

Embodiment 26. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein (R,R)-hydroxybupropion is at least 97%

of the total of amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the

plasma of the human being.

Embodiment 27. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, which is effective in providing therapeutically

5 effective plasma levels of (R,R)-hydroxybupropion. 2024200081

Embodiment 28. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, which is effective in providing

therapeutically effective plasma levels of (S)-bupropion.

Embodiment 29. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

10 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein the human being is in need of

treatment with (R,R)-hydroxybupropion.

Embodiment 30. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29, wherein the method achieves a Cmax

of (R,R)-hydroxybupropion that is at least about 500 ng/mL in the human being.

15 Embodiment 31. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, wherein the dosage form is

administered for at least 8 consecutive days.

Embodiment 32. The method of embodiment 31, wherein the dosage form is

administered for at least 14 consecutive days.

20 Embodiment 33. The method of embodiment 31, wherein the dosage form is

administered for at least 21 consecutive days.

Embodiment 34. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26,27,28,29,30,31,32,or33,wherein the dosage

form contains about 60 mg to about 90 mg of (S)-bupropion.

25 Embodiment 35. The method of embodiment 1, 2,3,4,5,6,7,8,9,10,11,12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the

dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is

administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage

form is administered once daily or twice daily for a total of at least 8 consecutive days.

Embodiment 36. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the

dosage form is administered once daily for 1 to 7 consecutive days, then the dosage form is

administered twice a day for at least the following 7 consecutive days, so that the dosage form is

5 administered once daily or twice daily for a total of at least 8 consecutive days. 2024200081

Embodiment 37. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein

the dosage form contains about 70 mg to about 80 mg of the (S)-bupropion.

Embodiment 38. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

10 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, wherein

the method achieves a Cmax of (S)-bupropion in the human being that is at least about 70 ng/mL.

Embodiment 39. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38,

wherein the method achieves an AUC0-12 of (S)-bupropion in the human being that is at least

15 about 400 ng.hr/mL.

Embodiment 40. The method of embodiment 39, wherein the method achieves an

AUC0-12 of (S)-bupropion in the human being that is about 500 ng.hr/mL to about 900 ng.hr/mL.

Embodiment 41. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,

20 or 40, wherein the dosage form provides sustained release of the (S)-bupropion.

Embodiment 42. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,

40, or 41, wherein the dosage form contains about 70 mg to about 80 mg of the (S)-bupropion.

Embodiment 43. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

25 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, wherein the method achieves a Cmax of (R,R)-hydroxybupropion in the human being

that is at least about 600 ng/mL.

Embodiment 44. The method of embodiment 1, 2,3,4,5,6,7,8,9,10,11,12, 13,

14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29,30,31,32,33,34,35,36,37,38 39,

40, 41, 42, 43, or 44, wherein the method achieves an AUC0-12 of (R,R)-hydroxybupropion in the

human being that is at least about 7000 ng.hr/mL.

Embodiment 45. The method of embodiment 44, wherein the method achieves an

AUC0-12 of (R,R)-hydroxybupropion in the human being that is at least about 8000 ng.hr/mL.

5 Embodiment 46. A method of treating a human being, comprising orally 2024200081

administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure,

one or two times per day, to the human being.

Embodiment 47. A dosage form for treating a condition in a human being,

comprising (S)-bupropion that is at least 95% enantiomerically pure, wherein the dosage form is

10 orally administered one or two times per day to the human being.

Embodiment 48. Use of (S)-bupropion that is at least 95% enantiomerically pure in

the manufacture of a medicament for treating a condition in a human being, wherein the

medicament is orally administered one or two times per day to the human being.

Embodiment 49. A kit comprising a dosage form and a label, wherein the dosage

15 form comprises (S)-bupropion that is at least 95% enantiomerically pure, and the label states that

the dosage form is orally administered one or two times per day to the human being for treating

a condition in the human being.

Embodiment 50. The method, the dosage form, the use, or the kit of embodiment

46, 47, 48, or 49, wherein the condition is a neurological disorder or a central nervous system

20 disorder.

Embodiment 51. The method, the dosage form, the use, or the kit of embodiment

50, wherein the human being is selected for having the condition.

Embodiment 52. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of bupropion, wherein the first AUC

25 of bupropion is the same as a reference AUC of bupropion that results from administering a daily

dose of racemic bupropion, wherein the daily dose of racemic bupropion is about 150 mg to

about 200 mg; wherein a daily dose of an (S)-bupropion is administered to the human being to

achieve the first AUC of bupropion, wherein the daily dose of the (S)-bupropion is about 60 mg

to about 120 mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other

bupropion is administered with the daily dose of the (S)-bupropion; and wherein the daily dose

of the (S)-bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 53. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of bupropion, wherein the first AUC

5 of bupropion is the same as a reference AUC of bupropion that results from administering a daily 2024200081

dose of racemic bupropion, wherein the daily dose of racemic bupropion is about 200 mg to

about 250 mg; wherein a daily dose of an (S)-bupropion is administered to the human being to

achieve the first AUC of bupropion, wherein the daily dose of the (S)-bupropion is about 80 mg

to about 150 mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other

10 bupropion is administered with the daily dose of the (S)-bupropion; and wherein the daily dose

of the (S)-bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 54. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of bupropion, wherein the first AUC

of bupropion is the same as a reference AUC of bupropion that results from administering a daily

15 dose of racemic bupropion, wherein the daily dose of racemic bupropion is about 250 mg to

about 300 mg; wherein a daily dose of an (S)-bupropion is administered to the human being to

achieve the first AUC of bupropion, wherein the daily dose of the (S)-bupropion is about 100 mg

to about 180 mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other

bupropion is administered with the daily dose of the (S)-bupropion; and wherein the daily dose

20 of the (S)-bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 55. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of bupropion, wherein the first AUC

of bupropion is the same as a reference AUC of bupropion that results from administering a daily

dose of racemic bupropion, wherein the daily dose of racemic bupropion is about 300 mg to

25 about 350 mg; wherein a daily dose of an (S)-bupropion is administered to the human being to

achieve the first AUC4 of bupropion, wherein the daily dose of the (S)-bupropion is about 120 mg

to about 210 mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other

bupropion is administered with the daily dose of the (S)-bupropion; and wherein the daily dose

of the (S)-bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 56. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of bupropion, wherein the first AUC

of bupropion is the same as a reference AUC of bupropion that results from administering a daily

dose of racemic bupropion, wherein the daily dose of racemic bupropion is about 350 mg to

5 about 400 mg; wherein a daily dose of an (S)-bupropion is administered to the human being to 2024200081

achieve the first AUC of bupropion, wherein the daily dose of the (S)-bupropion is about 140 mg

to about 240 mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other

bupropion is administered with the daily dose of the (S)-bupropion; and wherein the daily dose

of the (S)-bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

10 Embodiment 57 The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of bupropion, wherein the first AUC

of bupropion is the same as a reference AUC of bupropion that results from administering a daily

dose of racemic bupropion, wherein the daily dose of racemic bupropion is about 400 mg to

about 450 mg; wherein a daily dose of an (S)-bupropion is administered to the human being to

15 achieve the first AUC of bupropion, wherein the daily dose of the (S)-bupropion is about 160 mg

to about 270 mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other

bupropion is administered with the daily dose of the (S)-bupropion; and wherein the daily dose

of the (S)-bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 58. The method, the dosage form, the use, or the kit of embodiment

20 51, wherein the condition is treated by achieving a first AUC of hydroxybupropion, wherein the

first AUC of hydroxybupropion is the same as a reference AUC of hydroxybupropion that results

from administering a daily dose of racemic bupropion, wherein the daily dose of racemic

bupropion is about 150 mg to about 200 mg; wherein a daily dose of an (S)-bupropion is

administered to the human being to achieve the first AUC of hydroxybupropion, wherein the daily

25 dose of the (S)-bupropion is about 60 mg to about 120 mg; wherein the (S)-bupropion is at least

95% enantiomerically pure, and no other bupropion is administered with the daily dose of the

(S)-bupropion; and wherein the daily dose of the (S)-bupropion is about 40% to about 60% of the

daily dose of racemic bupropion.

Embodiment 59. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of hydroxybupropion, wherein the

first AUC of hydroxybupropion is the same as a reference AUC of hydroxybupropion that results

from administering a daily dose of racemic bupropion, wherein the daily dose of racemic

5 bupropion is about 200 mg to about 250 mg; wherein a daily dose of an (S)-bupropion is 2024200081

administered to the human being to achieve the first AUC of hydroxybupropion, wherein the daily

dose of the (S)-bupropion is about 80 mg to about 150 mg; wherein the (S)-bupropion is at least

95% enantiomerically pure, and no other bupropion is administered with the daily dose of the

(S)-bupropion; and wherein the daily dose of the (S)-bupropion is about 40% to about 60% of the

10 daily dose of racemic bupropion.

Embodiment 60. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of hydroxybupropion, wherein the

first AUC of hydroxybupropion is the same as a reference AUC of hydroxybupropion that results

from administering a daily dose of racemic bupropion, wherein the daily dose of racemic

15 bupropion is about 250 mg to about 300 mg; wherein a daily dose of an (S)-bupropion is

administered to the human being to achieve the first AUC of hydroxybupropion, wherein the daily

dose of the (S)-bupropion is about 100 mg to about 180 mg; wherein the (S)-bupropion is at least

95% enantiomerically pure, and no other bupropion is administered with the daily dose of the

(S)-bupropion; and wherein the daily dose of the (S)-bupropion is about 40% to about 60% of the

20 daily dose of racemic bupropion.

Embodiment 61. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of hydroxybupropion, wherein the

first AUC of hydroxybupropion is the same as a reference AUC of hydroxybupropion that results

from administering a daily dose of racemic bupropion, wherein the daily dose of racemic

25 bupropion is about 300 mg to about 350 mg; wherein a daily dose of an (S)-bupropion is

administered to the human being to achieve the first AUC of hydroxybupropion, wherein the daily

dose of the (S)-bupropion is about 120 mg to about 210 mg; wherein the (S)-bupropion is at least

95% enantiomerically pure, and no other bupropion is administered with the daily dose of the

(S)-bupropion; and wherein the daily dose of the (S)-bupropion is about 40% to about 60% of the

daily dose of racemic bupropion.

Embodiment 62. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of hydroxybupropion, wherein the

5 first AUC of hydroxybupropion is the same as a reference AUC of hydroxybupropion that results 2024200081

from administering a daily dose of racemic bupropion, wherein the daily dose of racemic

is bupropion is about 350 mg to about 400 mg; wherein a daily dose of an (S)-bupropion

administered to the human being to achieve the first AUC of hydroxybupropion, wherein the daily

dose of the (S)-bupropion is about 140 mg to about 240 mg; wherein the (S)-bupropion is at least

10 95% enantiomerically pure, and no other bupropion is administered with the daily dose of the

(S)-bupropion; and wherein the daily dose of the (S)-bupropion is about 40% to about 60% of the

daily dose of racemic bupropion.

Embodiment 63. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of hydroxybupropion, wherein the

15 first AUC of hydroxybupropion is the same as a reference AUC of hydroxybupropion that results

from administering a daily dose of racemic bupropion, wherein the daily dose of racemic

bupropion is about 400 mg to about 450 mg; wherein a daily dose of an (S)-bupropion is

administered to the human being to achieve the first AUC of hydroxybupropion, wherein the daily

dose of the (S)-bupropion is about 160 mg to about 270 mg; wherein the (S)-bupropion is at least

20 95% enantiomerically pure, and no other bupropion is administered with the daily dose of the

(S)-bupropion; and wherein the daily dose of the (S)-bupropion is about 40% to about 60% of the

daily dose of racemic bupropion.

Embodiment 64. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, wherein

25 the first AUC of (R,R)-hydroxybupropion is the same as a reference AUC of (R,R)-

hydroxybupropion that results from administering a daily dose of racemic bupropion, wherein

the daily dose of racemic bupropion is about 150 mg to about 200 mg; wherein a daily dose of

an (S)-bupropion is administered to the human being to achieve the first AUC of (R,R)-

hydroxybupropion, wherein the daily dose of the (S)-bupropion is about 60 mg to about 120 mg;

wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other bupropion is

administered with the daily dose of the (S)-bupropion; and wherein the daily dose of the (S)-

bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 65. The method, the dosage form, the use, or the kit of embodiment

5 51, wherein the condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, wherein 2024200081

the first AUC of (R,R)-hydroxybupropion is the same as a reference AUC of (R,R)-

hydroxybupropion that results from administering a daily dose of racemic bupropion, wherein

the daily dose of racemic bupropion is about 200 mg to about 250 mg; wherein a daily dose of

an (S)-bupropion is administered to the human being to achieve the first AUC of (R,R)-

10 hydroxybupropion, wherein the daily dose of the (S)-bupropion is about 80 mg to about 150 mg;

wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other bupropion is

administered with the daily dose of the (S)-bupropion; and wherein the daily dose of the (S)-

bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 66. The method, the dosage form, the use, or the kit of embodiment

15 51, wherein the condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, wherein

the first AUC of (R,R)-hydroxybupropion is the same as a reference AUC of (R,R)-

hydroxybupropion that results from administering a daily dose of racemic bupropion, wherein

the daily dose of racemic bupropion is about 250 mg to about 300 mg; wherein a daily dose of

an (S)-bupropion is administered to the human being to achieve the first AUC of (R,R)-

20 hydroxybupropion, wherein the daily dose of the (S)-bupropion is about 100 mg to about 180

mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other bupropion is

administered with the daily dose of the (S)-bupropion; and wherein the daily dose of the (S)-

bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

Embodiment 67. The method, the dosage form, the use, or the kit of embodiment

25 51, wherein the condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, wherein

the first AUC of (R,R)-hydroxybupropion is the same as a reference AUC of (R,R)-

hydroxybupropion that results from administering a daily dose of racemic bupropion, wherein

the daily dose of racemic bupropion is about 300 mg to about 350 mg; wherein a daily dose of

an (S)-bupropion is administered to the human being to achieve the first AUC of (R,R)-

hydroxybupropion, wherein the daily dose of the (S)-bupropion is about 120 mg to about 210

mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other bupropion is

administered with the daily dose of the (S)-bupropion; and wherein the daily dose of the (S)-

bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

5 Embodiment 68. The method, the dosage form, the use, or the kit of embodiment 2024200081

51, wherein the condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, wherein

the first AUC of (R,R)-hydroxybupropion is the same as a reference AUC of (R,R)-

hydroxybupropion that results from administering a daily dose of racemic bupropion, wherein

the daily dose of racemic bupropion is about 350 mg to about 400 mg; wherein a daily dose of

10 an (S)-bupropion is administered to the human being to achieve the first AUC of (R,R)-

hydroxybupropion, wherein the daily dose of the (S)-bupropion is about 140 mg to about 240

mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other bupropion is

administered with the daily dose of the (S)-bupropion; and wherein the daily dose of the (S)-

bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

15 Embodiment 69. The method, the dosage form, the use, or the kit of embodiment

51, wherein the condition is treated by achieving a first AUC of (R,R)-hydroxybupropion, wherein

the first AUC of (R,R)-hydroxybupropion is the same as a reference AUC of (R,R)-

hydroxybupropion that results from administering a daily dose of racemic bupropion, wherein

the daily dose of racemic bupropion is about 400 mg to about 450 mg; wherein a daily dose of

20 an (S)-bupropion is administered to the human being to achieve the first AUC of (R,R)-

hydroxybupropion, wherein the daily dose of the (S)-bupropion is about 160 mg to about 270

mg; wherein the (S)-bupropion is at least 95% enantiomerically pure, and no other bupropion is

administered with the daily dose of the (S)-bupropion; and wherein the daily dose of the (S)-

bupropion is about 40% to about 60% of the daily dose of racemic bupropion.

25 Embodiment 70. The method, the dosage form, the use, or the kit of any one of

embodiments 52-69, wherein the AUC is an AUCo-12

Embodiment 71. The method, the dosage form, the use, or the kit of any one of

embodiments 52-69, wherein the AUC is an AUC0-24-

Embodiment 72. The method of any preceding embodiment, wherein the (S)-

bupropion is administered once daily.

Embodiment 73. The method of any one of embodiments 46-71, wherein the (S)-

bupropion is administered in two doses per day, wherein the sum of the two doses per day is the

5 daily dose. 2024200081

Embodiment 74. The method of any preceding embodiment, wherein the (S)-

bupropion is administered for at least 8 consecutive days.

Embodiment 75. The method of any preceding embodiment, wherein the (S)-

bupropion is administered for at least 14 consecutive days.

10 Embodiment 76. The method of any preceding embodiment, wherein the (S)-

bupropion is administered for at least 21 consecutive days.

Embodiment 77. The method of any preceding embodiment, wherein the (S)-

bupropion is administered for at least 28 consecutive days.

Embodiment 78. The method of any preceding embodiment, wherein the (S)-

15 bupropion is administered in a dosage form that provides sustained release of (S)-bupropion.

Embodiment 79. The method of embodiment 78, wherein the dosage form is

formulated to have a Tmax of (S)-bupropion that is about 2 hours to about 4 hours.

Embodiment 80. The method of any preceding embodiment, wherein the method

achieves an AUC0-12 of (S)-bupropion in the human being that is at least about 300 ng.hr/mL.

20 Embodiment 81. The method of any preceding embodiment, wherein the method

achieves an AUC0-12 of (S)-bupropion in the human being that is at least about 400 ng.hr/mL.

Embodiment 82. The method of any preceding embodiment, wherein the method

achieves an AUCo-12 of (S)-bupropion in the human being that is about 500 ng.hr/ml to about 900

ng.hr/mL.

25 Embodiment 83. The method of any preceding embodiment, wherein the method

achieves a Cmax of (S)-bupropion in the human being that is about 60 ng/mL to about 140 ng/mL.

Example 1

Part 1

Fifteen healthy adult subjects were administered 150 mg of racemic bupropion sustained

release twice daily for 7 days under fasting conditions. Tablet dosing was escalated from once

daily for Days 1 to 3, to twice daily thereafter with a final morning dose on Day 7. Plasma

concentrations of bupropion and its metabolites were measured on Day 7 at 3-4 hours after

5 dosing. Chiral bioanalytical methods were used to measure concentrations of the enantiomers 2024200081

of bupropion and its major metabolites. The results were normalized to 210 mg by multiplying

the AUC or Cmax by 210/150.

Part 2

Healthy adult subjects were administered either 105 mg S-bupropion or 105 mg R-

10 bupropion sustained release tablets (10 subjects per group), twice daily for 8 days under fasting

conditions. Tablet dosing was escalated from once daily for Days 1 to 3, to twice daily thereafter

with a final morning dose on Day 8. Plasma concentrations of bupropion and its metabolites were

measured for full pharmacokinetic assessments on Days 1 and 8. Chiral bioanalytical methods

were used to measure concentrations of the enantiomers of bupropion and its major active

15 metabolite hydroxybupropion.

In Table 1, values are shown for tablets containing 105 mg S-bupropion from Part 2.

Values for racemic bupropion tablets, containing 75 mg R- and 75 mg S-bupropion, were taken

from Part 1 and normalized to 105 mg R- and 105 mg S-bupropion by multiplying by 105/150 to

allow comparison to the 105 mg S-bupropion tablets. Both S-bupropion and racemic bupropion

20 tablets were sustained release formulations dosed to healthy volunteers. AUCO-12 values for

bupropion and hydroxybupropion are also depicted in FIG. 1.

Table 1

AUC0-12 (ng-h/mL)

Racemic Bupropion S-Bupropion (105 mg R- and (105 mg S-bupropion) Analyte 105 mg S-bupropion) BID BID (n = 10)

(n = 15)

Bupropion 644.6 793.1

Hydroxybupropion 3,561.1 3,464.4 AUC0-12

Part 3

A randomized, double-blind, multiple-dose, placebo-controlled, parallel group trial was 2024200081

conducted to examine the safety and tolerability of the pure S- and R- enantiomers of bupropion,

5 with pharmacokinetic sampling. In this trial healthy adult subjects were administered 105 mg S-

bupropion, 105 mg R-bupropion sustained release tablets, or placebo (15 subjects per group),

twice daily for 7 days under fasting conditions. Tablet dosing was escalated from once daily for

Days 1 to 3, to twice daily thereafter with a final morning dose on Day 7. Plasma concentrations

of bupropion and its metabolites were measured on Day 7 at 3-4 hours after dosing. Chiral

10 bioanalytical methods were used to measure concentrations of the enantiomers of bupropion

and its major active metabolite hydroxybupropion. The mean plasma concentrations measured

for bupropion and hydroxybupropion are shown in Table 2 and in Fig. 2. As shown in Fig. 3, the

Cmax of R,R-hydroxybupropion that resulted from administering 105 mg of S-bupropion was

1,268.5 ng/mL, and the Cmax of R,R-hydroxybupropion that resulted from administering 105 mg

15 of -bupropion was 135.1 ng/mL.

Table 2

Mean concentration (ng/mL)

S-bupropion R-bupropion Analyte 105 mg BID 105 mg BID (n = 15) (n = 15)

Bupropion 170.9 15.1

Hydroxybupropion 1,393 195.5

The Tmax for the dosage form comprising (S)-bupropion described above was between two

hours and four hours.

20 Unless otherwise indicated, all numbers expressing quantities of ingredients, properties

such as amounts, AUC values, and so forth used in the specification and claims are to be

understood in all instances as indicating both the exact values as shown and as being modified

by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters

set forth in the specification and attached claims are approximations that may vary depending

upon the desired properties sought to be obtained. At the very least, and not as an attempt to

limit the application of the doctrine of equivalents to the scope of the claims, each numerical

parameter should at least be construed in light of the number of reported significant digits and

5 by applying ordinary rounding techniques. 2024200081

The terms "a," "an," "the" and similar referents used in the context of describing the

invention (especially in the context of the following claims) are to be construed to cover both the

singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All

methods described herein can be performed in any suitable order unless otherwise indicated

10 herein or otherwise clearly contradicted by context. The use of any and all examples, or

exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the

invention and does not pose a limitation on the scope of any claim. No language in the

specification should be construed as indicating any non-claimed element essential to the practice

of the invention.

15 Groupings of alternative elements or embodiments disclosed herein are not to be

construed as limitations. Each group member may be referred to and claimed individually or in

any combination with other members of the group or other elements found herein. It is

anticipated that one or more members of a group may be included in, or deleted from, a group

for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the

20 specification is deemed to contain the group as modified thus fulfilling the written description 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.

25 The inventor expects skilled artisans to employ such variations as appropriate, and the inventors

intend for the invention to be practiced otherwise than specifically described herein.

Accordingly, the claims include all modifications and equivalents of the subject matter recited in

the claims as permitted by applicable law. Moreover, any combination of the above-described

elements in all possible variations thereof is contemplated unless otherwise indicated herein or

otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed herein are illustrative of

the principles of the claims. Other modifications that may be employed are within the scope of

5 the claims. Thus, by way of example, but not of limitation, alternative embodiments may be 2024200081

utilized in accordance with the teachings herein. Accordingly, the claims are not limited to

embodiments precisely as shown and described.

Claims (30)

2024200081 11 Apr 2025 What is Claimed What is Claimedis: is:

1. 1. A method of treating attention deficit/hyperactivity disorder, agitation or Huntington’s disease chorea in a human being, comprising orally administering a dosage form containing about 80 mg to about 120 mg of (S)-bupropion that is at least 95% by weight enantiomerically pure, one 2024200081

or two times per day, to the human being, wherein the dosage form is substantially free of any active pharmaceutical agent other than (S)-bupropion.

2. 2. A dosage form when used in treating attention deficit/hyperactivity disorder, agitation or Huntington’s disease chorea in a human being, the dosage form comprising about 80 mg to about 120 mg of (S)-bupropion that is at least 95% by weight enantiomerically pure, wherein the dosage form is orally administered one or two times per day to a human being, and wherein the dosage form is substantially free of any active pharmaceutical agent other than (S)-bupropion.

3. Use of about 80 mg to about 120 mg of (S)-bupropion that is at least 95% by weight enantiomerically pure in the manufacture of a medicament for treating attention deficit/hyperactivity disorder, agitation or Huntington’s disease chorea in a human being, wherein the medicament is orally administered in a dosage form one or two times per day to the human being, and wherein the medicament is substantially free of any active pharmaceutical agent other than (S)-bupropion.

4. 4. Use of a kit comprising the dosage form of claim 2, wherein the dosage form comprises (S)-bupropion that is at least 95% enantiomerically pure, and the dosage form is orally administered one or two times per day to the human being when the dosage form is used in treating attention deficit/hyperactivity disorder, agitation or Huntington’s disease chorea in the human being.

5. 5. The method, the dosage form, the use of (S)-bupropion, or the use of kit of claim 1, 2, 3, or 4, wherein the human being is selected for having attention deficit/hyperactivity disorder, agitation or Huntington’s disease chorea.

6. 6. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is administered once daily.

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2024200081 11 Apr 2025

7. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any one of claims 1-6, wherein the (S)-bupropion is administered in two doses per day, and wherein the sum of the two doses per day is the daily dose.

8. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding 2024200081

claim, wherein the (S)-bupropion is administered for at least 8 consecutive days.

9. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is administered for at least 14 consecutive days.

10. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is administered for at least 21 consecutive days.

11. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is administered for at least 28 consecutive days.

12. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is administered in a dosage form that provides sustained release of (S)-bupropion.

13. 13. The method, the dosage form, the use of (S)-bupropion, or the use of kit of claim 12, wherein the dosage form is formulated to have a Tmax of (S)-bupropion that is about 2 hours to about 4 hours.

14. 14. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form provides an AUC0-12 of (S)-bupropion in the human being that is at least about 300 ng·hr/mL.

15. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form provides an AUC0-12 of (S)-bupropion in the human being that is at least about 400 ng·hr/mL.

16. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form provides an AUC0-12 of (S)-bupropion in the human being that is about 500 ng·hr/mL to about 900 ng·hr/mL.

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2024200081 11 Apr 2025

17. 17. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form provides a Cmax of (S)-bupropion in the human being that is about 60 ng/mL to about 140 ng/mL.

18. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding 2024200081

claim, wherein the dosage form includes about 80 mg to about 120 mg of (S)-bupropion.

19. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form includes about 160 mg to about 240 mg of (S)-bupropion.

20. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form includes about 120 mg to about 210 mg of (S)-bupropion.

21. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form includes about 60 mg to about 110 mg of (S)-bupropion.

22. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is not deuterium-enriched.

23. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is at least 97% enantiomerically pure.

24. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is at least 99% enantiomerically pure.

25. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is in a salt form.

26. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the (S)-bupropion is in the free base form.

27. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein orally administering the (S)-bupropion to the human being results in a reduction of adverse events associated with racemic bupropion.

28. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form contains less than 0.1% of dextromethorphan.

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29. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein the dosage form contains no dextromethorphan.

30. The method, the dosage form, the use of (S)-bupropion, or the use of kit of any preceding claim, wherein no other bupropion is orally administered with the (S)-bupropion. 2024200081

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