Pharmaceutical compositions comprising 5HT receptor agonist and antiemetic particulates

• US 10,179,109 B2
• Filed: 03/03/2017
• Issued: 01/15/2019
• Est. Priority Date: 03/04/2016
• Status: Active Grant

• Current Assignee: Charleston Laboratories, Inc.
• Original Assignee: Charleston Laboratories, Inc.
• Inventors: Bosse, Paul, Ameling, John, Kozarek, William, Schachtel, Bernard, Higgins, John
• Primary Examiner(s): Azpuru, Carlos A
• Application Number:
  US15/449,798
• Publication Number:
  US 20170252302A1
• Time in Patent Office: 683 Days
• CPC Class Codes: A01N 43/42 condensed with carbocyclic rings
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Pharmaceutical compositions and methods are provided to treat headache, headache-associated symptoms, photophobia, or adverse effects associated with the headache. Also provided herein are small smooth particulates comprising a 5HT_1B/1D receptor agonist. Compositions for oral administration are described herein wherein the compositions comprise a combination of active agents, such as a 5HT_1B/1D receptor agonist and one or more antiemetics.

Claims

1. A pharmaceutical composition comprising:

a plurality of first particulates, wherein each first particulate comprises;

a 5HT_1B/1D receptor agonist wherein;

(a) each first particulate has an average diameter of less than about 500 μ

m;

or (b) each first particulate comprises from about 55% to about 65% of the 5HT_1B/1D receptor agonist (w/w); and

a plurality of second particulates, wherein each second particulate comprises;

(i) a core; and

(ii) a layer enclosing the core, wherein said layer comprises an antiemetic, and

wherein the pharmaceutical composition is in a solid oral dosage form.

2. The pharmaceutical composition of claim 1, wherein each first particulate further comprises a pharmaceutically acceptable excipient that is a non-pharmaceutically active ingredient that comprises at least one of microcrystalline cellulose, dicalcium phosphate, calcium sulfate, talc, an alkali metal stearate, silicon dioxide, or calcium carbonate.

3. The pharmaceutical composition of claim 2, wherein each first particulate comprises about 60% of the 5HT_1B/1D receptor agonist (w/w) and about 40% of the non-pharmaceutically active ingredient.

4. The pharmaceutical composition of claim 1, wherein each first particulate has an average diameter of between about 100 μ

m and about 500 μ

m.

5. The pharmaceutical composition of claim 1, wherein the core in each second particulate comprises a sugar sphere.

6. The pharmaceutical composition of claim 1, wherein the layer enclosing the core in each second particulate comprises one or more pharmaceutically acceptable excipients;

and wherein the one or more pharmaceutically acceptable excipients is hydroxypropyl methylcellulose (HPMC), low-substituted hydroxypropyl cellulose (L-HPC), or talc.

7. The pharmaceutical composition of claim 1, wherein each second particulate comprises from about 10% to about 40% of the antiemetic (w/w) and from about 50% to about 70% of a core (w/w).

8. The pharmaceutical composition of claim 1, wherein each first particulate further comprises a first coating or wherein each second particulate further comprises a second coating;

and wherein the first coating or the second coating comprises;

polyvinyl alcohol, cellulose acetate phthalate, polyvinyl acetate phthalate, methacrylic acid copolymer, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate succinate, shellac, sodium alginate, zein, or any combination thereof.

9. The pharmaceutical composition of claim 1, wherein the 5HT_1B/1D receptor agonist comprises a triptan or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 9, wherein the triptan or its pharmaceutically acceptable salt comprises sumatriptan or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutically acceptable salt of sumatriptan is sumatriptan succinate.

12. The pharmaceutical composition of claim 1, wherein the antiemetic comprises promethazine or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition of claim 12, wherein the pharmaceutically acceptable salt of promethazine is promethazine hydrochloride.

14. The pharmaceutical composition of claim 1, wherein a ratio by weight of the 5HT_1B/1D receptor agonist to the antiemetic is from about 1:

2 to about 15;

1, from about 3;

2 to about 11;

1, from about 3;

1 to about 7;

1, from about 1;

1 to about 5;

1, from about 9;

2 to about 11;

2, from about 4;

2 to about 6;

2, or about 5;

1 or about 2.5;

1.

28. The pharmaceutical composition of claim 11, wherein the sumatriptan succinate is present in an amount of from about 100 mg to about 140 mg.

29. The pharmaceutical composition of claim 13, wherein the promethazine hydrochloride is present in an amount from about 10 mg to about 60 mg.

15. A capsule comprising a pharmaceutical composition comprising:

a plurality of first particulates, wherein each first particulate comprises;

a 5HT_1B/1D receptor agonist wherein;

(a) each first particulate has an average diameter of less than about 500 μ

m;

or (b) each first particulate comprises from about 55% to about 65% of the 5HT_1B/1D receptor agonist (w/w); and

a plurality of second particulates, wherein each second particulate comprises;

(i) a core; and

(ii) a layer enclosing the core, wherein said layer comprises an antiemetic, and

wherein the pharmaceutical composition is in a solid oral dosage form.

16. The capsule of claim 15, wherein the 5HT_1B/1D receptor agonist comprises a triptan or a pharmaceutically acceptable salt thereof;

and wherein the triptan or its pharmaceutically acceptable salt comprises sumatriptan, almotriptan, frovatriptan, eletriptan, rizatriptan, naratriptan, or a pharmaceutically acceptable salt thereof.

17. The capsule of claim 15, wherein the antiemetic comprises promethazine, ondansetron, aprepitant, dronabinol, perphenazine, palonosetron, domperidone, prochlorperazine, chlorpromazine, trimethobenzamide, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, droperidol, haloperidol, metoclopramide, diphenhydramine, cannabinoid, midazolam, lorazepam, hyoscine, dexamethasone, emetrol, propofol, or a pharmaceutically acceptable salt thereof.

18. The capsule of claim 15, wherein at least about 32% of the antiemetic and at least about 56% of the 5HT_1B/1D receptor agonist are released within about 5 minutes following contact of the capsule with 500 mL of a dissolution fluid (0.1N HCl, pH 1.1) at 37+/−

0.5°

C. as measured by an Apparatus 2 (Paddle Apparatus) rotating at 50 rpm.

19. The capsule of claim 15, wherein at least about 63% of the antiemetic and at least about 81% of the 5HT_1B/1D receptor agonist are released within about 15 minutes following contact of the capsule with 500 mL of a dissolution fluid (0.1N HCl, pH 1.1) at 37+/−

0.5°

C. as measured by an Apparatus 2 (Paddle Apparatus) rotating at 50 rpm.

20. The capsule of claim 15, wherein at least about 79% of the antiemetic and at least about 87% of the 5HT_1B/1D receptor agonist are released within about 30 minutes following contact of the capsule with 500 mL of a dissolution fluid (0.1N HCl, pH 1.1) at 37+/−

0.5°

C. as measured by an Apparatus 2 (Paddle Apparatus) rotating at 50 rpm.

21. The capsule of claim 15, wherein at least about 88% of the antiemetic and at least about 92% of the 5HT_1B/1D receptor agonist are released within about 60 minutes following contact of the capsule with 500 mL of a dissolution fluid (0.1N HCl, pH 1.1) at 37+/−

0.5°

C. as measured by an Apparatus 2 (Paddle Apparatus) rotating at 50 rpm.

22. The capsule of claim 15, wherein a dissolution profile of the capsule when stored at 40°

C. for one month is;

at least about 47% of the 5HT_1B/1D receptor agonist is released within about 5 minutes, or at least about 69% of the 5HT_1B/1D receptor agonist is released within about 15 minutes, or at least about 80% of the 5HT_1B/1D receptor agonist is released within about 30 minutes, or at least about 86% of the 5HT_1B/1D receptor agonist is released within about 60 minutes following contact of the capsule with 500 mL of a dissolution fluid (0.1N HCl, pH 1.1) at 37+/−

0.5°

C. as measured by an Apparatus 2 (Paddle Apparatus) rotating at 50 rpm; and

at least about 35% of the antiemetic is released within about 5 minutes, or at least about 63% of the antiemetic is released within about 15 minutes, or at least about 74% of the antiemetic agonist is released within about 30 minutes, or at least about 84% of the antiemetic is released within about 60 minutes following contact of the capsule with 500 mL of a dissolution fluid (0.1N HC1, pH 1.1) at 37+/−

0.5°

C. as measured by an Apparatus 2 (Paddle Apparatus) rotating at 50 rpm.

23. A capsule comprising a pharmaceutical composition comprising:

a plurality of first particulates, wherein each first particulate comprises;

(i) about 100 mg to about 140 mg of sumatriptan succinate; and

(ii) about 50 mg to about 150 mg of microcrystalline cellulose; and

a plurality of second particulates, wherein each second particulate comprises;

(i) about 10 mg to about 60 mg of promethazine hydrochloride;

(ii) about 30 mg to about 150 mg of a sugar sphere;

(iii) about 2.5 mg to about 15 mg of hydroxypropyl methylcellulose (HPMC);

(iv) about 0.5 mg to about 10 mg of talc;

(v) about 0.5 mg to about 10 mg of low-substituted hydroxypropyl cellulose (L-HPC); and

(vi) about 5 mg to about 30 mg of a coating, wherein the promethazine hydrochloride, the HPMC, the talc, and the L-HPC are present in a layer enclosing the sugar sphere, and

wherein the pharmaceutical composition is in a solid oral dosage form.

24. The capsule of claim 23,

wherein the plurality of first particulates comprises:

(i) about 126 mg of the sumatriptan succinate; and

(ii) about 84 mg of the microcrystalline cellulose, wherein each first particulate has an average diameter of less than about 500 μ

m; and

wherein the plurality of second particulates comprises;

(i) about 25 mg of the promethazine hydrochloride;

(ii) about 66.6 mg of the sugar sphere;

(iii) about 6.6 mg of the hydroxypropyl methylcellulose (HPMC);

(iv) about 1.2 mg of the talc;

(v) about 2.5 mg of the low-substituted hydroxypropyl cellulose (L-HPC); and

(vi) about 10.2 mg of the coating.

25. The capsule of claim 23,

wherein the plurality of first particulates comprises:

(i) about 126 mg of the sumatriptan succinate; and

(ii) about 84 mg of the microcrystalline cellulose, wherein each first particulate has an average diameter of less than about 500 μ

m; and

wherein the plurality of second particulates comprises;

(i) about 50 mg of the promethazine hydrochloride;

(ii) about 133.2 mg of the sugar sphere;

(iii) about 13.2 mg of the hydroxypropyl methylcellulose (HPMC);

(iv) about 2.4 mg of the talc;

(v) about 5 mg of the low-substituted hydroxypropyl cellulose (L-HPC); and

(vi) about 20.4 mg of the coating.

26. A method of treating a headache in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising:

a plurality of first particulates, wherein each first particulate comprises;

a 5HT_1B/1D receptor agonist wherein;

(a) each first particulate has an average diameter of less than about 500 μ

m;

or (b) each first particulate comprises from about 55% to about 65% of the 5HT_1B/1D receptor agonist (w/w); and

a plurality of second particulates, wherein each second particulate comprises;

(i) a core; and

(ii) a layer enclosing the core, wherein said layer comprises an antiemetic.

27. The method of claim 26, wherein the pharmaceutical composition is in the form of a capsule.

30. The method of claim 26, wherein the antiemetic comprises promethazine or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the pharmaceutically acceptable salt of promethazine is promethazine hydrochloride.

32. The method of claim 26, wherein the 5HT _1B/1D receptor agonist comprises a triptan or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein the triptan or its pharmaceutically acceptable salt comprises sumatriptan or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the pharmaceutically acceptable salt of sumatriptan is sumatriptan succinate.