Delivery of drugs

• US 8,956,602 B2
• Filed: 12/04/2007
• Issued: 02/17/2015
• Est. Priority Date: 12/05/2006
• Status: Expired due to Fees

• Current Assignee: Landec Corporation
• Original Assignee: Landec Incorporated
• Inventors: Taft, David, Bitler, Steven, Zheng, Qiang, Bell, Adam, Tzannis, Stelios
• Primary Examiner(s): DICKINSON, PAUL W
• Application Number:
  US11/999,415
• Publication Number:
  US 20080269105A1
• Time in Patent Office: 2,632 Days
• Field of Search: None
• US Class Current: 424/78.17
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Formulations of drugs and crystalline side chain polymers to provide controlled and/or sustained release drug formulations.

Claims

1. A pharmaceutical formulation which (a) comprises (i) a side-chain crystalline (CYSC) polymer which has a polymer backbone and (ii) a single drug, the drug being associated with the CYSC polymer, (b) is free from oil, and (c) is in a dosage form which can be administered by ingestion, injection, subcutaneous implantation, intramuscular administration, intrathecal administration or inhalation, wherein the CYSC polymer,

(A) comprises a plurality of moieties which

(a) have the formula

-b-Cy

and

(b) are present (i) as a part of a repeating unit which provides at least part of the polymeric backbone of the polymer, or (ii) as part of a terminal unit of the polymer backbone, or (iii) as both (i) and (ii), the repeating units having formula (1) below,

2. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties are present in repeating units having the formula

3. A pharmaceutical formulation according to claim 2 wherein b is a moiety having the formula

4. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties comprise 12 to 50 substantially linear carbon atoms.

5. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties comprise 18 linear carbon atoms.

6. A pharmaceutical formulation according to claim 1 wherein the repeating units of the formula

7. A pharmaceutical formulation according to claim 1 wherein the drug is a neurotransmitter agonist or antagonist.

8. A pharmaceutical formulation according to claim 1 wherein the drug is an antipsychotic.

9. A pharmaceutical formulation according to claim 1 wherein the drug is RISPERIDONE or a pharmacologically active metabolite thereof.

10. A pharmaceutical formulation according to claim 1 wherein the CYSC polymer is a copolymer comprising units derived from octadecyl acrylate (C18A) and acrylic acid (AA), and the drug is a neurotransmitter agonist or antagonist.

11. A pharmaceutical formulation according to claim 10 wherein the drug is RISPERIDONE.

12. A pharmaceutical formulation according to claim 1 wherein the CYSC polymer is a polyacrylate or polymethacrylate.

13. A pharmaceutical formulation according to claim 1 wherein the CYSC polymer is a polyester or a polycarbonate.

14. A pharmaceutical formulation according to claim 1 wherein the CYSC polymer has a number average molecular weight less than 10,000 Daltons.

15. A pharmaceutical formulation according to claim 1 wherein the CYSC polymer is a block copolymer.

16. A pharmaceutical formulation according to claim 1 which contains a first CYSC polymer having a first melting point Tp1 and a second CYSC polymer having a second melting point Tp2 which is at least 2°

C. different from Tp1.

17. A pharmaceutical formulation according to claim 1

(A) which contains a compound which (i) contains Cy moieties, and (ii) is not a CYSC polymer, and

(B) in which the Cy moieties in the CYSC polymer and the Cy moieties in the compound which is not a CYSC polymer together form crystalline aggregates.

18. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties are present in the terminal units and comprise 12-50 substantially linear carbon atoms.

19. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties are present in the terminal units and comprise 18-22 substantially linear carbon atoms.

20. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties are present in the terminal units and comprise 18 substantially linear carbon atoms.

21. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties contain a polyoxyalkylene moiety.

22. A pharmaceutical formulation according to claim 1 wherein at least some of the Rz moieties contain a carboxyl group, or a hydroxyl group.

23. A pharmaceutical formulation according to claim 1 wherein the CYSC polymer is a graft copolymer which comprises a backbone which comprises one or more —

Z(Rz)- moieties, and grafted side chains each of which comprises one or more —

Y(Rc)- moieties.

24. A pharmaceutical formulation according to claim 1 wherein the drug is associated with the CYSC polymer through chemical bonds.

25. A pharmaceutical formulation according to claim 1 wherein the drug is an antipsychotic drug.

26. A pharmaceutical formulation according to claim 1 wherein the drug is RISPERIDONE or a pharmacologically active metabolite thereof.

27. A pharmaceutical formulation according to claim 1 which contains at least 5% by weight of the drug and which, when tested in vitro (elution into 1 L PBS, pH 7.2 at 37°

C., stirred at 100 rpm), releases the drug in a way which has one or more of the following characteristics;

(a) an average rate of release no greater than 50 milligrams per day averaged over any 24 hour period during the first 168 hours of elution;

(b) an average rate no greater than 25 milligrams per day averaged over any 24 hour period during a period from 12 hours to 168 hours following inception of elution;

(c) continuously releases between 1 milligram and 60 milligram of the drug per day over a period of at least 30 days;

(d) continuously releases between 1 milligram and 60 milligrams of the drug per day averaged over any 24 hour period during a period from 12 hours to 168 hours following inception of elution;

(e) releases no more than 10% by weight of the drug present in the formulation over a period of 24 hours; and

,

(f) continuously releases a therapeutic dose of drug over a period of at least 30 days wherein the average 24 hour drug release rate is within one standard deviation of the 30 day mean.

34. A pharmaceutical formulation according to claim 1 wherein the CYSC polymer is a block copolymer.

35. A pharmaceutical formulation according to claim 1 which contains a first CYSC polymer having a first melting point Tp1 and a second CYSC polymer having a second melting point Tp2 which is at least 2°

C. different from Tp1.

36. A pharmaceutical formulation according to claim 26

(A) which contains a compound which (i) contains Cy moieties, and (ii) is not a CYSC polymer, and

(B) in which the Cy moieties in the CYSC polymer and the Cy moieties in the compound which is not a CYSC polymer together form crystalline aggregates.

37. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties comprise 12-50 substantially linear carbon atoms.

38. A pharmaceutical formulation according to claim 1 wherein at least some of the Cy moieties comprise 18-22 substantially linear carbon atoms.

39. A pharmaceutical formulation according to claim 1 for use in therapy or diagnosis.

40. A method of making a pharmaceutical formulation as claimed in claim 1 which comprises melting the CYSC polymer, mixing the drug with the molten polymer in the absence of solvents, and cooling the mixture to below its melting point to cause crystallization and solidification of the formulation.

41. A pharmaceutical formulation according to claim 1 which is in a dosage form selected from liquids, tablets, pills and capsules.

43. A pharmaceutical formulation according to claim 1 wherein the percentage by weight of the repeating units of the formula

44. A pharmaceutical formulation according to claim 1 wherein the percentage by weight of the repeating units of the formula

45. A pharmaceutical formulation according to claim 1 wherein, in each of the repeating units of formula (1), b is not an amide linkage, and the percentage by weight of the repeating units of the formula

46. A pharmaceutical formulation according to claim 1 wherein, in each of the repeating units of formula (1), the b moiety is selected from the group consisting of ester, carbonyl, amine oxide, hydrocarbon, amino, ether, polyoxyalkylene and ionic salt linkages, and the percentage by weight of the repeating units of the formula

47. A pharmaceutical formulation according to claim 1 wherein, in each of the repeating units of formula (1), the b moiety is an ester linkage, and the percentage by weight of the repeating units of the formula

48. A pharmaceutical formulation according to claim 1 wherein, in each of the repeating units of formula (1), the b moiety is a moiety selected from one or more of carbonyl, amine oxide, amino, polyoxyalkylene and ionic salt linkages.

49. A pharmaceutical formulation according to claim 1 wherein in each of the repeating units of the formula

28. A pharmaceutical formulation which (a) is in a dosage form which can be administered by ingestion, injection, subcutaneous implantation, intramuscular administration, intrathecal administration or inhalation, and (b) comprises (i) a side-chain crystalline (CYSC) polymer which has a polymer backbone and (ii) a single drug which is associated with the CYSC polymer, wherein the CYSC polymer,

(A) comprises a plurality of moieties which

(a) have the formula

-b-Cy

and

(b) are present (i) as a part of a repeating unit which provides at least part of the polymeric backbone of the polymer, or (ii) as part of a terminal unit of the polymer backbone, or (iii) as both (i) and (ii), the repeating units having formula (1) below,

29. A pharmaceutical formulation according to claim 28 wherein the CYSC polymer has a number average molecular weight, Mn, of 1,000 to 20,000 Daltons.

30. A pharmaceutical formulation according to claim 28 wherein the CYSC polymer has a number average molecular weight, Mn, of less than 10,000 Daltons.

31. A pharmaceutical formulation according to claim 28 wherein the CYSC polymer is a polyacrylate or polymethacrylate.

32. A pharmaceutical formulation according to claim 28 wherein the CYSC polymer is a polyester.

33. A pharmaceutical formulation according to claim 28 wherein the CYSC polymer is a polycarbonate.

42. A pharmaceutical formulation according to claim 28 which is in a dosage form selected from liquids, tablets, pills and capsules.

58. A pharmaceutical formulation according to claim 28 which contains, in addition to the single drug, hyaluronic acid.

50. A pharmaceutical formulation which

(a) comprises (i) a side-chain crystalline (CYSC) polymer which has a polymer backbone, (ii) hyaluronic acid, and (ii), in addition to the hyaluronic acid, a single other drug which is associated with the CYSC polymer,

(b) is free from oil, and

(c) is in a dosage form which can be administered by ingestion, injection, subcutaneous implantation, intramuscular administration, intrathecal administration or inhalation,

wherein the CYSC polymer,

(A) comprises a plurality of moieties which

(a) have the formula

-b-Cy

and

(b) are present (i) as a part of a repeating unit which provides at least part of the polymeric backbone of the polymer, or (ii) as part of a terminal unit of the polymer backbone, or (iii) as both (i) and (ii), the repeating units having formula (1) below,

51. A pharmaceutical formulation according to claim 50 wherein the percentage by weight of the repeating units of the formula

52. A pharmaceutical formulation according to claim 50 wherein the percentage by weight of the repeating units of the formula

53. A pharmaceutical formulation according to claim 50 wherein, in each of the repeating units of formula (1), b is not an amide linkage, and the percentage by weight of the repeating units of the formula

54. A pharmaceutical formulation according to claim 50 wherein, in each of the repeating units of formula (1), the b moiety is selected from the group consisting of ester, carbonyl, amine oxide, hydrocarbon, amino, ether, polyoxyalkylene and ionic salt linkages, and the percentage by weight of the repeating units of the formula

55. A pharmaceutical formulation according to claim 50 wherein, in each of the repeating units of formula (1), the b moiety is an ester linkage, and the percentage by weight of the repeating units of the formula

56. A pharmaceutical formulation according to claim 50 wherein, in each of the repeating units of formula (1), the b moiety is a moiety selected from one or more of carbonyl, amine oxide, amino, polyoxyalkylene and ionic salt linkages.

57. A pharmaceutical formulation according to claim 50 wherein, in each of the repeating units of the formula