Pharmaceutical formulations comprising naltrexone and/or bupropion
Described are pharmaceutical formulations comprising naltrexone and/or bupropion. Such pharmaceutical formulations can comprise extended-release, multilayer beads. Also described are methods of administering such formulations, such as for the treatment of overweight or obesity.
1. A method of treating overweight or obesity in a subject in need thereof, the method comprising:
administering to the subject a first oral dosage form comprising about 8 mg of naltrexone or salt thereof and about 90 mg of bupropion or salt thereof, wherein the first oral dosage form is administered once a day for a first week;
administering to the subject a second oral dosage form comprising about 16 mg of naltrexone or salt thereof and about 180 mg of bupropion or salt thereof, wherein the second oral dosage form is administered once a day for a second week;
administering to the subject a third oral dosage form comprising about 24 mg of naltrexone or salt thereof and about 270 mg of bupropion or salt thereof, wherein the third oral dosage form is administered once a day for a third week; and
administering to the subject a fourth oral dosage form comprising about 32 mg of naltrexone or salt thereof and about 360 mg of bupropion or salt thereof, wherein the fourth oral dosage form is administered once a day for a fourth and subsequent weeks,
wherein each of the first oral dosage form, the second oral dosage form, the third oral dosage form and the fourth oral dosage form comprises a capsule; and
wherein each capsule comprises a bupropion extended-release formulation having an in vitro bupropion dissolution profile in a dissolution test of USP Apparatus 1 Basket Method at 100 rpm in a dissolution medium of water at 37° C. of:
i. 2% to 20% of the bupropion released in one hour;
ii. 10% to 50% of the bupropion released in two hours; and
iii. 50% to 90% of the bupropion released in four hours.
2. The method of claim 1 ,
wherein each capsule comprises a naltrexone extended-release formulation having an in vitro naltrexone dissolution profile in a dissolution test of USP Apparatus 1 Basket Method at 100 rpm in a dissolution medium of water at 37° C. of:
a) 2% to 20% of the naltrexone released in one hour;
b) 10% to 50% of the naltrexone released in two hours; and
c) 60% to 90% of the naltrexone released in four hours; and
wherein administration of the fourth oral dosage form to a group of subjects at steady state provides an average maximum naltrexone plasma concentration C max of 1.1 to 1.8 ng/ml, an average naltrexone plasma area under the curve AUC 0-24h of 13 to 22 ng*h/mL, an average maximum bupropion plasma concentration C max of 150 to 260 ng/ml and an average bupropion plasma area under the curve AUC 0-24h of 2,200 to 3,600 ng*h/mL.
3. The method of claim 1 , wherein the fourth oral dosage form comprises:
a naltrexone extended-release formulation having an in vitro naltrexone dissolution profile in a dissolution test of USP Apparatus 1 Basket Method at 100 rpm in a dissolution medium of water at 37° C. of:
a) less than 30% of the naltrexone released in one hour; or
b) less than 60% of the naltrexone released in two hours.
4. The method of claim 3 , wherein the in vitro naltrexone dissolution profile in the dissolution test is:
i. 2% to 20% of the naltrexone released in one hour; and
ii. 10% to 50% of the naltrexone released in two hours.
5. The method of claim 4 , wherein the in vitro naltrexone dissolution profile in the dissolution test is:
a) 2% to 20% of the naltrexone released in one hour;
b) 10% to 50% of the naltrexone released in two hours; and
c) 60% to 90% of the naltrexone released in four hours.
6. The method of claim 3 , wherein administration of the fourth oral dosage form to a group of subjects at steady state provides an average maximum naltrexone plasma concentration C max of 1.1 to 1.8 ng/ml.
7. The method of claim 3 , wherein administration of the fourth oral dosage form to a group of subjects at steady state provides an average naltrexone plasma area under the curve AUC 0-24h of 13 to 22 ng*h/mL.
8. The method of claim 1 , wherein administration of the fourth oral dosage form to a group of subjects at steady state provides an average maximum bupropion plasma concentration C max of 150 to 260 ng/mL.
9. The method of claim 1 , wherein administration of the fourth oral dosage form to a group of subjects at steady state provides an average bupropion plasma area under the curve AUC 0-24h of 2,200 to 3,600 ng*h/mL.
10. The method of claim 2 , wherein the fourth oral dosage form, when administered to a human subject once daily, is bioequivalent to a US FDA-approved trilayer tablet dosage form comprising naltrexone hydrochloride and bupropion hydrochloride administered to a human subject twice daily, under the bioequivalence parameters of: (a) a 90% Confidence Interval for AUC which is between 80% and 125%, and (b) a 90% Confidence Interval for C max , which is between 80% and 125%.
11. The method of claim 1 , wherein the naltrexone salt is naltrexone hydrochloride.
12. The method of claim 11 , wherein the naltrexone hydrochloride is substantially free of amorphous naltrexone hydrochloride.
13. The method of claim 5 , wherein the naltrexone extended-release formulation comprises a plurality of extended-release, multilayer beads comprising:
a core particle, wherein the core particle is drug-free;
an optional seal coating coated on the surface of the core particle;
a drug layer comprising naltrexone, or a salt thereof, coated on the surface of the core particle or, when present, the seal coating;
a non-aqueous barrier coating coated on the surface of the drug layer;
an extended-release coating coated on the surface of the barrier coating; and
an optional top coating coated on the surface of the extended-release coating; and
wherein the bupropion extended-release formulation comprises a plurality of extended-release, multilayer beads comprising:
a core particle comprising bupropion, or a salt thereof;
an optional seal coating coated on the surface of the core particle;
an extended-release coating coated on the surface of the core particle, or if present, on the surface of the seal coating; and
an optional top coating coated on the surface of the extended-release coating.
14. The method of claim 1 , wherein the fourth oral dosage form has a release profile such that, when administered to a human subject once daily, is bioequivalent to a US FDA-approved trilayer tablet dosage form comprising naltrexone hydrochloride and bupropion hydrochloride administered to a human subject twice daily, under the bioequivalence parameters of: (a) a 90% Confidence Interval for AUC which is between 80% and 125%, and (b) a 90% Confidence Interval for C max , which is between 80% and 125%.
15. The method of claim 13 , wherein the core particle of the naltrexone-containing beads is selected from a microcrystalline cellulose particle, a silica particle, and a sugar particle.
16. The method of claim 13 , wherein the drug layer of the naltrexone-containing beads comprises about 50% to about 95% by weight of naltrexone, or a salt thereof.
17. The method of claim 16 , wherein the drug layer of the naltrexone-containing beads comprises further comprises a low viscosity binder selected from Hypromellose 3 cps, Hypromellose 5 cps, and Hydroxypropyl cellulose.
18. The method of claim 16 , wherein the naltrexone comprises an anhydrous polymorph of the hydrochloride salt (Form L) and/or an ethanol solvate of the hydrochloride salt (Form F).
19. The method of claim 18 , wherein the non-aqueous barrier coating of the naltrexone-containing beads is prepared under anhydrous conditions.
20. The method of claim 19 , wherein the non-aqueous barrier coating of the naltrexone-containing beads is prepared using a solvent selected from the group consisting of class 3 solvents.
21. The method of claim 14 , wherein the naltrexone-containing beads comprise no more than 0.5% 2-chloro-10α-hydroxynaltrexone, based on the weight of naltrexone.
22. The method of claim 14 , wherein the bupropion, or a salt thereof, is present in the core particle of bupropion-containing beads ≥70% w/w.
23. The method of claim 13 , wherein the bupropion-containing beads comprise no more than 1% (2R,3R,5R)-2-(3-chlorophenyl)-2-hydroxy-3-methylthiomorpholine-5-carboxylic acid (RRR-CHMTCA) and no more than 0.5% (2S,3S,5R)-2-(3-chlorophenyl)-2-hydroxy-3-methylthiomorpholine-5-carboxylic acid (SSR-CHMTCA), based on the weight of bupropion.
24. The method of claim 13 , wherein the extended-release coating of the naltrexone-containing beads and/or the bupropion-containing beads comprises a release controlling polymer and a pore former.
25. The method of claim 24 , wherein the wherein the release controlling polymer is present in an amount of about 5% to about 25% by weight of the extended-release, multilayer bead.
26. The method of claim 25 , wherein the extended-release coating comprises a plasticizer present in an amount of about 5% to about 15% of dry polymer concentration.