Injectable multimodal polymer depot compositions and uses thereof

• US 8,501,215 B2
• Filed: 07/28/2003
• Issued: 08/06/2013
• Est. Priority Date: 07/31/2002
• Status: Expired due to Fees

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Chen, Guohua, Houston, Paul, Kleiner, Lothar, Wright, Jeremy
• Primary Examiner(s): ARNOLD, ERNST V
• Application Number:
  US10/628,984
• Publication Number:
  US 20040022859A1
• Time in Patent Office: 3,662 Days
• Field of Search: None
• US Class Current: 424/426
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61P 23/02 Local anaesthetics

Abstract

Injectable depot compositions are provided that include a polymer matrix having a plurality of bioerodible, biocompatible polymers wherein each polymer of the plurality of polymers has a specified average molecular weight, and the polymer matrix has a broad molecular weight distribution of the plurality of polymers; a solvent having a miscibility in water of less than or equal to 7 wt % at 25° C., in an amount effective to plasticize the polymer and form a gel therewith; and a beneficial agent. The compositions have substantially improved shear thinning behavior and reduced injection force, rendering the compositions readily implanted beneath a patient'"'"'s body surface by injection.

Claims

1. An injectable depot composition comprising:

(a) a polymer matrix comprising a plurality of bioerodible, biocompatible lactic acid-based polymers, wherein a first of said plurality of polymers is a low molecular weight (LMW) polymer having a weight average molecular weight ranging from about 3000 to about 10,000 and a second is a high molecular weight (HMW) polymer having a weight average molecular weight of greater than about 30,000, the polymer matrix having a bimodal molecular weight distribution of the plurality of polymers;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the plurality of polymers and form a gel therewith, wherein the solvent is a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof; and

(c) a beneficial agent dissolved or dispersed in the gel.

3. The injectable depot composition of claim 1, wherein the polymer matrix comprises about 20 wt % to about 90 wt % of the low molecular weight (LMW) polymer.

4. The composition of claim 1, wherein each polymer is a copolymer of lactic acid and glycolic acid.

5. The composition of claim 1, comprising about 5 wt % to about 90 wt % of the biodegradable, biocompatible lactic acid-based polymers.

6. The composition of claim 5, comprising about 25 wt % to about 80 wt % of the biodegradable, biocompatible lactic acid-based polymers.

7. The composition of claim 1, wherein the solvent has a miscibility in water of less than or equal to 5 wt % at 25°

C.

8. The composition of claim 7, wherein the solvent has a miscibility in water of less than or equal to 3 wt % at 25°

C.

9. The composition of claim 8, wherein the solvent has a miscibility in water of less than or equal to 1 wt % at 25°

C.

10. The composition of claim 9, wherein the solvent has a miscibility in water of less than or equal to 0.5 wt % at 25°

C.

11. The injectable depot composition of claim 1, wherein the solvent is an aromatic alcohol that has the structural formula (I)

Ar-(L)_n-OH 

 

(I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety.

12. The composition of claim 11, wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom.

13. The composition of claim 12, wherein Ar is monocyclic aryl and L is lower alkylene.

14. The composition of claim 13, wherein Ar is phenyl and L is methylene.

15. The composition of claim 1, wherein the ester of an aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid.

16. The composition of claim 15, wherein the ester of an aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate.

17. The composition of claim 1, wherein the solvent is a mixture of an aromatic alcohol and an ester of an aromatic acid.

18. The composition of claim 17, wherein the ratio of the aromatic alcohol to the ester of the aromatic acid is in the range of about 1% to about 99% by weight.

19. The composition of claim 18, wherein the ratio of the aromatic alcohol to the ester of the aromatic acid is in the range of about 10% to about 90% by weight.

20. The composition of claim 19, wherein the ratio of the aromatic alcohol to the ester of the aromatic acid is in the range of about 20% to about 80% by weight.

2. An injectable depot composition comprising:

(a) a polymer matrix comprising a plurality of bioerodible, biocompatible lactic acid-based polymers, wherein a first of said plurality of polymers is a low molecular weight (LMW) polymer having a weight average molecular weight ranging from about 3000 to about 9000, a second is a high molecular weight (HMW) polymer having a weight average molecular weight greater than 30,000, and a third is a medium molecular weight (MMW) polymer having a weight average molecular weight ranging from 10,000 to 30,000, the polymer matrix having a multimodal molecular weight distribution of the plurality of polymers;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the plurality of polymers and form a gel therewith, wherein the solvent is a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof; and

(c) a beneficial agent dissolved or dispersed in the gel.

21. An injectable depot composition for systemic delivery of a beneficial agent to a subject in a controlled manner comprising:

(a) a polymer matrix comprising a plurality of bioerodible, biocompatible lactic acid-based polymers, wherein a first of said plurality of polymers is a low molecular weight (LMW) polymer having a weight average molecular weight ranging from about 3000 to about 9000, a second is a high molecular weight (HMW) polymer having a weight average molecular weight greater than 30,000, and a third is a medium molecular weight (MMW) polymer having a weight average molecular weight ranging from 10,000 to 30,000, the polymer matrix having a multimodal molecular weight distribution of the plurality of polymers;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the plurality of polymers and form a gel therewith, wherein the solvent is a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof; and

(c) a beneficial agent dissolved or dispersed in the gel.

25. The injectable depot composition of any one of claims 21, 22, 23 or 24, wherein the solvent is an aromatic alcohol.

26. The injectable depot composition of claim 25, wherein the polymer matrix comprises about 20 wt % to about 90 wt % of the low molecular weight (LMW) polymer.

30. The composition of claim 25, wherein the solvent has a miscibility in water of less than or equal to 5 wt % at 25°

C.

31. The composition of claim 30, wherein the solvent has a miscibility in water of less than or equal to 3 wt % at 25°

C.

32. The composition of claim 31, wherein the solvent has a miscibility in water of less than or equal to 1 wt % at 25°

C.

33. The composition of claim 32, wherein the solvent has a miscibility in water of less than or equal to 0.5 wt % at 25°

C.

34. The injectable depot composition of claim 25, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH 

 

(I)

in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety.

35. The composition of claim 34, wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom.

36. The composition of claim 35, wherein Ar is monocyclic aryl and L is lower alkylene.

37. The composition of claim 36, wherein Ar is phenyl and L is methylene.

38. The composition of claim 25, wherein the ester of the aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid.

39. The composition of claim 38, wherein the ester of the aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate.

40. The composition of claim 25, wherein the solvent is a mixture of the aromatic alcohol and the ester of the aromatic acid.

41. The composition of claim 40, wherein a ratio of the aromatic alcohol to the ester of the aromatic acid is in the range of about 1% to about 99% by weight.

42. The composition of claim 41, wherein the ratio of the aromatic alcohol to the ester of the aromatic acid is in the range of about 10% to about 90% by weight.

43. The composition of claim 42, wherein the ratio of the aromatic alcohol to the ester of the aromatic acid is in the range of about 20% to about 80% by weight.

22. An injectable depot composition for sustained delivery of a beneficial agent to a subject comprising:

(a) a polymer matrix comprising a plurality of bioerodible, biocompatible lactic acid-based polymers, wherein a first of said plurality of polymers is a low molecular weight (LMW) polymer having a weight average molecular weight ranging from about 3000 to about 9000, a second is a high molecular weight (HMW) polymer having a weight average molecular weight greater than 30,000, and a third is a medium molecular weight (MMW) polymer having a weight average molecular weight ranging from 10,000 to 30,000, the polymer matrix having a multimodal molecular weight distribution of the plurality of polymers;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the plurality of polymers and form a gel therewith, wherein the solvent is a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof; and

(c) a beneficial agent dissolved or dispersed in the gel, wherein the beneficial agent is delivered systemically in a controlled manner over a duration of one year.

23. An injectable depot composition for local delivery of a beneficial agent to a subject in a controlled manner comprising:

(a) a polymer matrix comprising a plurality of bioerodible, biocompatible lactic acid-based polymers, wherein a first of said plurality of polymers is a low molecular weight (LMW) polymer having a weight average molecular weight ranging from about 3000 to about 9000, a second is a high molecular weight (HMW) polymer having a weight average molecular weight greater than 30,000, and a third is a medium molecular weight (MMW) polymer having a weight average molecular weight ranging from 10,000 to 30,000, the polymer matrix having a multimodal molecular weight distribution of the plurality of polymers;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the plurality of polymers and form a gel therewith, wherein the solvent is a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof; and

(c) a beneficial agent dissolved or dispersed in the gel.

24. An injectable depot composition for sustained delivery of a beneficial agent to a subject comprising:

(a) a polymer matrix comprising a plurality of bioerodible, biocompatible lactic acid-based polymers, wherein a first of said plurality of polymers is a low molecular weight (LMW) polymer having a weight average molecular weight ranging from about 3000 to about 9000, a second is a high molecular weight (HMW) polymer having a weight average molecular weight greater than 30,000, and a third is a medium molecular weight (MMW) polymer having a weight average molecular weight ranging from 10,000 to 30,000, the polymer matrix having a multimodal molecular weight distribution of the plurality of polymers;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the plurality of polymers and form a gel therewith, wherein the solvent is a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof; and

(c) a beneficial agent dissolved or dispersed in the gel, wherein the beneficial agent is delivered locally in a controlled manner over a duration of up to one year.

27. The composition of claim 24, wherein each polymer is a copolymer of lactic acid and glycolic acid.

28. The composition of claim 24, comprising about 5 wt % to about 90 wt % of the biodegradable, biocompatible lactic acid-based polymers.

29. The composition of claim 28, comprising about 25 wt % to about 80 wt % of the biodegradable, biocompatible lactic acid-based polymers.

44. A kit for administration of a beneficial agent to a subject comprising:

(a) a polymer matrix comprising a plurality of bioerodible, biocompatible lactic acid-based polymers, wherein a first of said plurality of polymers is a low molecular weight (LMW) polymer having a weight average molecular weight ranging from about 3000 to about 9000, a second is a high molecular weight (HMW) polymer having a weight average molecular weight greater than 30,000, and a third is a medium molecular weight (MMW) polymer having a weight average molecular weight ranging from 10,000 to 30,000, the polymer matrix having a multimodal molecular weight distribution of the plurality of polymers;

(b) a solvent having a miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the plurality of polymers and form a gel therewith, wherein the solvent is a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof;

(c) a beneficial agent dissolved or dispersed in the gel; and

optionally, one or more of the following;

(d) an emulsifying agent;

(e) a pore former;

(f) a solubility modulator for the beneficial agent, optionally associated with the beneficial agent; and

(g) an osmotic agent, wherein at least the beneficial agent, optionally associated with the solubility modulator, is maintained separated from the solvent until a time of administration of the beneficial agent to a subject.