Composition comprising biodegradable hydrating ceramics for controlled drug delivery

• US 8,124,118 B2
• Filed: 10/21/2004
• Issued: 02/28/2012
• Est. Priority Date: 10/22/2003
• Status: Active Grant

• Current Assignee: LIDDS AB
• Original Assignee: LIDDS AB
• Inventors: Lennernäs, Hans, Hugosson, Jonas, Axén, Niklas, Lennernäs, Bo
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): AL-AWADI, DANAH J
• Application Number:
  US10/576,857
• Publication Number:
  US 20090036392A1
• Time in Patent Office: 2,686 Days
• Field of Search: None
• US Class Current: 424/423
• 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The present invention relates to a drug carrier composition comprising i) one or more biodegradable hydrating ceramics ii) one or more expandable agents, and iii) sorbed aqueous medium which in solid form has a ruptured structure. The function of the expandable agent is to create a ruptured structure in the solidified composition, either a foam-like structure or a disintegrated structure where it is split into a large number of parts, particles, units, granules or pieces, so as to obtain an enlarged apparent surface area that is exposed to degradation or erosion upon administration. Suitable substances to obtain this surface enlarging effect are gas-forming agents or swelling agents, gelling agents or disintegrants, here referred to as expandable agents. The expandable agents may be bioresorbable or non-bioresorbable.

Claims

1. An injectable pharmaceutical composition comprising:

i) one or more biodegradable hydrating ceramics;

ii) one or more expandable agents, wherein the expandable agent is present in the composition at a concentration of at least about 0.1% w/w to about 2.5% w/w;

iii) a sorbed aqueous medium wherein the sorbed aqueous medium is present in the composition at a concentration of at the most about 30% w/w to about 60% w/w of the total composition; and

iv) one or more therapeutically and/or diagnostically active substances, which is an androgen, an anti-androgen, an oestrogen, an anti-oestrogen, a gestagen, an anti-gestagen, an oligonucleotide, a progestagen, a gonadotropin-releasing hormone, a gonadotropin inhibitor, an adrenal and/or prostate enzyme inhibitor, a membrane efflux and/or membrane transport protein, an immune system modulator, an angiogenesis inhibitor, or combinations thereof, which in solid form has a ruptured structure, and wherein the composition solidifies within 20 minutes or less when stored at 37°

C.

2. A pharmaceutical composition according to claim 1, wherein the active substance is flutamide, hydroxy-flutamide, cyproteron, nilutamide or bicalutamide or a mixture thereof.

3. A pharmaceutical composition according to claim 1, wherein the active substance is a combination of an anti-androgen and a gonadotropin-releasing hormone.

4. A pharmaceutical composition according to claim 1, which in solid form has a foam-like structure with openings, wherein at least 50% or more of the openings have a maximum width of at least about 0.1 mm.

5. A pharmaceutical composition according to claim 4, wherein, at least 60%, to 90% of the openings have a maximum width of at least about 0.1 mm.

6. A pharmaceutical composition according to claim 5, wherein the openings have a maximum width of at least about 0.2 mm to at least about 0.5 mm.

7. A pharmaceutical composition according to claim 5, wherein the openings have a largest width of at least about 0.6 mm to about 2 mm.

8. A pharmaceutical composition according to claim 1, wherein the surface area of an opening in cross sectional view having a maximum width of at least about 0.1 mm is at least about 3×

10<sup>−

8</sup> m² to about 5×

10<sup>−

6</sup> m².

9. A pharmaceutical composition according to claim 1, which in solid form has a ruptured structure obtained by disintegration into two or more parts.

10. A pharmaceutical composition according to claim 9, wherein the two or more parts have an external surface area that is at least about twice to about a thousand times as large as that of the composition before disintegration.

11. A pharmaceutical composition according to claim 1, wherein the biodegradable hydrating ceramic is selected from the group consisting of non-hydrated or hydrated calcium sulphate, calcium phosphate, calcium carbonate, calcium fluoride, calcium silicate, magnesium sulphate, magnesium phosphate, magnesium carbonate, magnesium fluoride, magnesium silicate, barium sulphate, barium phosphate, barium carbonate, barium fluoride, barium silicate, or mixtures thereof.

12. A pharmaceutical composition according to claim 1, wherein the biodegradable hydrating ceramic is non-hydrated or hydrated calcium sulphate.

13. A pharmaceutical composition according to claim 1, wherein the biodegradable hydrating ceramic employed in the preparation of the composition is in the form of a powder.

14. A pharmaceutical composition according to claim 13, wherein the powder has a mean particle size of at the most about 10 μ

m to about 75 μ

m.

15. A pharmaceutical composition according to claim 1, wherein the expandable agent is a gas-forming agent, a swelling agent, a gelling agent or a disintegrant.

16. A pharmaceutical composition according to claim 15, wherein the expandable agent is a gas-forming agent selected from the group consisting of alkali metal carbonates, alkali metal hydrogen carbonates, hydrogen peroxide and mixtures thereof.

17. A pharmaceutical composition according to claim 15, wherein the expandable agent is a swelling agent, a gelling agent, a disintegrant, or mixtures thereof.

18. A pharmaceutical composition according to claim 1;

in liquid or semi-solid form.

19. A pharmaceutical composition according to claim 1, wherein the ruptured structure has a shape selected from the group consisting of beads, tubes, polygons, spheres, stars, cubes, or mixtures thereof.

20. A pharmaceutical composition according to claim 1, wherein the active substance is homogeneously dispersed in the biodegradable hydrating ceramic.

21. A pharmaceutical composition according to claim 1, configured for parenteral use.

22. A pharmaceutical composition according to claim 1, wherein the one or more biodegradable hydrating ceramics, the expandable agent and the one or more active substance are homogeneously dispersed in water so that the hydrating ceramic, the expandable agent and/or the active substance sorbs water.

23. A pharmaceutical composition according to claim 1, wherein the one or more biodegradable hydrating ceramics have a microporous structure.

24. A pharmaceutical composition according to claim 23, wherein at least part of the microporous structures is sealed with a pore-sealing agent.

25. A pharmaceutical composition according to claim 23, wherein at least 50% or more of the microporous structures is sealed with a pore-sealing agent.

26. A pharmaceutical composition according to claim 24, wherein the pore-sealing agent is a hydrophobic agent, a hydrophilic agent, a water-absorbing agent, or mixtures thereof.

27. A pharmaceutical composition according to claim 24, wherein the pore-sealing agent is a hydrophobic agent that is selected from the group consisting of silicone oil, silicon rubber, waxes, paraffinic hydrocarbons, polyvinylalcohols, ethyl cellulose, and mixtures thereof.

28. A pharmaceutical composition according to claim 24, wherein the pore-sealing agent is a hydrophilic agent that is selected from the group consisting of methylcellulose, hyaluronic acid, dextran, poly-ethylene glycol (PEG), and mixtures thereof.

29. A pharmaceutical composition according to claim 24, wherein the pore-sealing agent is a water-absorbing agent that is selected from the group consisting of water glasses, silica gel, sodium phosphate, and mixtures thereof.

30. A pharmaceutical composition according to claim 24, wherein the concentration of the pore-sealing agent in the composition is about 30% w/w or less of the final composition.

31. A pharmaceutical composition according to claim 1, wherein the active substance is controllably released from the composition.

32. A pharmaceutical composition according to claim 31, wherein at most about 10% w/w of the active substance contained in the composition is released 5 days or more after implantation to a human.

33. A pharmaceutical composition according to claim 31, wherein at the most about 50% w/w of the active substance contained in the composition is released 1 month or more after implantation to a human.

34. A pharmaceutical composition according to claim 31, wherein at the most about 75% w/w of the active substance contained in the composition is released 1.5 month or more after implantation to a human.

35. A pharmaceutical composition according to claim 31, wherein at the most about 100% w/w of the active substance contained in the composition is released 2 month or more after implantation to a human.

36. A pharmaceutical composition according to claim 31, wherein at the most about 10% w/w of the active substance contained in the composition is released after 2 days or more when tested in an in vitro dissolution test according to Ph. Eur protocol.

37. A pharmaceutical composition according to claim 31, wherein at the most about 50% w/w of the active substance contained in the composition is released after 1 month or more when tested in an in vitro dissolution test according to Ph. Eur protocol.

38. A pharmaceutical composition according to claim 31, wherein at the most about 75% w/w of the active substance contained in the composition is released after 1.5 month or more when tested in an in vitro dissolution test according to Ph. Eur protocol.

39. A pharmaceutical composition according to claim 31, wherein at the most about 100% w/w of the active substance contained in the composition is released after 2 month or more when tested in an in vitro dissolution test according to Ph. Eur protocol.

40. A composition in particulate form for use in the preparation of an injectable pharmaceutical composition as recited in claim 1, the composition comprising:

i) one or more biodegradable hydrating ceramics in powder form;

ii) one or more expandable agents, in an amount sufficient to be present in the injectable composition at a concentration of at least about 0.1% w/w/ to about 2.5% w/w; and

iii) one or more therapeutically and/or diagnostically active substances, which is an androgen, an anti-androgen, an oestrogen, an anti-oestrogen, a gestagen, an anti-gestagen, an oligonucleotide, a progestagen, a gonadotropin-releasing hormone, a gonadotropin inhibitor, an adrenal and/or prostate enzyme inhibitor, a membrane efflux and/or membrane transport protein, an immune system modulator, an angiogenesis inhibitor, or combinations thereof.

41. A method for the preparation of an injectable pharmaceutical composition as recited in claim 1, comprising;

a) dispersing a mixture of;

i) one or more biodegradable ceramics in powder form, and ii) one or more expandable agents in an amount sufficient to be present in the injectable composition at a concentration of at least about 0.1% w/w to about 2.5% w/w;

in an amount of a sorbed aqueous medium sufficient to be present in the injectable composition at a concentration of at the most about 30% w/w to about 60% w/w of the total composition; and

b) adding one or more therapeutically or diagnostically active substances, which is an androgen, an anti-androgen, an oestrogen, an anti-oestrogen, a gestagen, an anti-gestagen, an oligonucleotide, a progestagen, a gonadotropin-releasing hormone, a gonadotropin inhibitor, an adrenal and/or prostate enzyme inhibitor, a membrane efflux and/or membrane transport protein, an immune system modulator, an angiogenesis inhibitor, or combinations thereof, such that in solid for said injectable composition has a ruptured structure, and wherein the injectable composition solidifies within 20 minutes or less when stored at 37°

C.

42. A method for treatment of a subject suffering from a prostate disease, comprising administering to the subject an injectable composition as recited in claim 1.

43. A method according to claim 42, wherein the prostate disease is prostate cancer or prostate hyperplasia.

44. A method according to claim 42, wherein the active substance is flutamide, hydroxy-flutamide, cyproteron, nilutamide or bicalutamide or a mixture thereof.

45. A method according to claim 42, wherein the active substance is a combination of anti-androgen and a gonadotropin-releasing hormone.

46. A method according to claim 42, wherein the active substance is hydroxyflutamide.

47. A method according to claim 42, wherein the active substance is hydroxyflutamide and a plasma concentration of from 0.001 to 1000 μ

M hydroxyflutamide is obtained in the subject after administration thereof.

48. A method according to claim 42, wherein the active substance is hydroxyflutamide and the treatment time for one dose is at least 3-6 months.

49. A method according to claim 42, wherein the composition solidifies in vivo after administration.