Catheter injectable depot compositions and uses thereof

• US 7,829,109 B2
• Filed: 11/14/2002
• Issued: 11/09/2010
• Est. Priority Date: 11/14/2001
• Status: Expired due to Fees

• Current Assignee: DURECT Corporation
• Original Assignee: DURECT Corporation
• Inventors: Spaltro, John, Chen, Guohua, Houston, Paul R., Kleiner, Lothar
• Primary Examiner(s): Azpuru; Carlos A
• Application Number:
  US10/295,603
• Publication Number:
  US 20030180364A1
• Time in Patent Office: 2,917 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

Catheter injectable depot compositions are provided that include a bioerodible, biocompatible polymer, a solvent having 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, a thixotropic agent, and a beneficial agent. The solvent comprises an aromatic alcohol, an ester of an aromatic acid, an aromatic ketone, or mixtures thereof. 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. A catheter injectable depot composition in the form of a thixotropic gel, said gel comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a bioerodible, biocompatible polymer, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof;

(b) approximately 5 wt % to approximately 95 wt % of an aromatic alcohol having miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, 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;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being greater than or equal to 0.01 wt % and less than or equal to 15 wt % of the combined weight of the aromatic alcohol and the thixotropic agent; and

(d) approximately 0.1 wt % to approximately 50 wt % of a beneficial agent.

3. The catheter injectable depot composition of claim 1, wherein the polymer represents approximately 10 wt. % to approximately 85 wt. % of the composition.

4. The catheter injectable depot composition of claim 3, wherein the polymer represents approximately 20 wt. % to approximately 75 wt. % of the composition.

5. The catheter injectable depot composition of claim 1, wherein the polymer is a copolymer of lactic acid and glycolic acid.

6. The catheter injectable depot composition of claim 5, wherein the polymer is a copolymer of at least two of the following monomers:

lactic acid, glycolic acid and caprolactone.

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

8. The catheter injectable depot composition of claim 7, wherein Ar is monocyclic aryl and L is lower alkylene.

9. The catheter injectable depot composition of claim 8, wherein Ar is phenyl and L is methylene.

10. The catheter injectable depot composition of claim 1, wherein the aromatic alcohol is benzyl alcohol.

11. The catheter injectable depot composition of claim 1, further including at least one of the following:

a pore former;

a solubility modulator for the beneficial agent; and

an osmotic agent.

12. The catheter injectable depot composition of claim 1, wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof.

13. The catheter injectable depot composition of claim 12, wherein the beneficial agent is a growth hormone.

14. The catheter injectable depot composition of claim 12, wherein the beneficial agent is a growth factor.

15. The catheter injectable depot composition of claim 14, wherein the growth factor is selected from epidermal growth factors (EGFs), platelet-derived growth factors (PDGFs), insulin-like growth factors (IGFs), fibroblast-growth factors (FGFs), transforming-growth factors (TGFs), interleukins (ILs), colony-stimulating factors (CSFs, MCFs, GCSFs, GMCSFs), Interferons (IFNs), endothelial growth factors (VEGF, EGFs), erythropoietins (EPOs), angiopoietins (ANGs), placenta-derived growth factors (PIGFs), and hypoxia induced transcriptional regulators (HIFs).

16. The catheter injectable depot composition of claim 12, wherein the beneficial agent is in the form of particles dispersed or dissolved in the gel.

17. The catheter injectable depot composition of claim 16, wherein the beneficial agent is in the form of the particles having an average particle size of from 0.1 to 250 microns.

27. The catheter injectable depot composition of claim 1, wherein the beneficial agent is in the form of the particles wherein the particles further comprise a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and buffering agent.

28. The catheter injectable depot composition of claim 16, wherein the beneficial agent is in the form of the particles wherein the particles further comprise a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and buffering agent.

2. A catheter injectable depot composition in the form of a thixotropic gel, said gel comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having an average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) approximately 5 wt % to approximately 95 wt % of an aromatic alcohol having miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, 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;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being greater than or equal to 0.01 wt % and less than or equal to 15 wt % of the combined weight of the aromatic alcohol and the thixotropic agent; and

(d) approximately 0.1 wt % to approximately 50 wt % of a beneficial agent.

18. A catheter injectable depot composition in the form of a thixotropic gel, said gel comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a poly(lactide-co-glycolide) (PLGA) copolymer having an average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) approximately 5 wt. % to approximately 90 wt. % an aromatic alcohol solvent having miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith;

(c) a thixotropic amount of a thixotropic agent mixed with the polymer effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and an amount of the ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and

(d) approximately 0.1 wt. % to approximately 50 wt. % of a beneficial agent.

19. The catheter injectable depot composition of claim 18, wherein the aromatic alcohol is benzyl alcohol.

20. A catheter injectable depot composition in the form of a thixotropic gel, said gel comprising:

up to about 90 wt. % of a bioerodible, biocompatible polymer, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof;

up to about 95 wt. % of an aromatic alcohol having 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

up to about 50 wt. % of a beneficial agent, wherein the composition is free of monohydric lower alkanols.

21. A catheter injectable depot composition in the form of a thixotropic gel, said gel comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having an average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) approximately 5 wt. % to approximately 95 wt. % of an aromatic alcohol having miscibility in water of less than or equal to 5% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH

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

(c) approximately 0.1 wt. % to approximately 50 wt. % of a beneficial agent, wherein the composition is free of monohydric lower alkanols.

22. The catheter injectable depot composition of claim 21, wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom.

23. The catheter injectable depot composition of claim 22, wherein Ar is monocyclic aryl and L is lower alkylene.

24. The catheter injectable depot composition of claim 23, wherein Ar is phenyl and L is methylene.

25. A catheter injectable depot composition in the form of a thixotropic gel, said gel comprising:

(a) approximately 5 wt. % to approximately 90 wt. % of a poly(lactide-co-glycolide) (PLGA) copolymer having an average molecular weight in the range of approximately 1,000 to approximately 120,000;

(b) approximately 5 wt. % to approximately 90 wt. % of an aromatic alcohol solvent having miscibility in water of less than or equal to 7% at 25°

C., in an amount effective to plasticize the polymer and form a gel therewith; and

(c) approximately 0.1 wt. % to approximately 50 wt. % of a beneficial agent, wherein the composition is free of monohydric lower alkanols.

26. The catheter injectable depot composition of claim 25, wherein the aromatic alcohol is benzyl alcohol.