Blends of temperature sensitive and anionic polymers for drug delivery

• US 20060280797A1
• Filed: 04/25/2006
• Published: 12/14/2006
• Est. Priority Date: 04/25/2005
• Status: Active Grant

• Current Assignee: Charles H. Tator, Dimpy Gupta, Molly S. Shoichet
• Original Assignee: Charles H. Tator, Dimpy Gupta, Molly S. Shoichet
• Inventors: Tator, Charles H., Gupta, Dimpy, Shoichet, Molly S.
• Granted Patent: US 7,767,656 B2
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• 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

Abstract

A physical blend of inverse thermal gelling and shear-thinning, thixotropic polymers that has a lower gelation temperature than the thermal gelling polymer alone is provided. The blend results in an injectable hydrogel that does not flow freely at room temperature, but is injectable due to its shear-thinning properties. The thermal-gelling properties of the polymer promote a more mechanically stable gel at body temperature than at room temperature. The polymer matrix gel has inherent therapeutic benefit and can also be used as a drug delivery vehicle for localized release of therapeutic agents.

Claims

1. A polymer matrix comprising:

(a) a solution of at least one inverse thermal gelling polymer, and,

(b) at least one anionic gelling polymer in powdered form;

wherein the polymer matrix is a solid gel that is injectable due to shear thinning properties of the anionic gelling polymer and returns to its original viscosity after shearing.

2. The polymer matrix of claim 1 wherein the inverse thermal gelling polymer is selected from:

methylcellulose, a chitosan and β

-glycerophosphate solution, collagen, tri-block copolymer of poly(ethylene glycol)-poly(lactic-co-glycolic acid)-poly(ethylene glycol), tri-block copolymer of poly(propylene glycol)-poly(ethylene glycol)-poly (propylene glycol), poly(N-isopropyl acrylamide), agarose, copolymers of poly-N-isopropylacrylamide, polysaccharides and mixtures thereof.

3. The polymer matrix of claim 1 wherein the anionic gelling polymer is selected from:

hyaluronic acid, derivatives of hyaluronic acid, alginate, derivatives of alginate, carboxymethylcellulose, and mixtures thereof.

4. The polymer matrix of claim 1 wherein the inverse thermal gelling polymer has a molecular weight between 2,000 Da and 1,000,000 Da.

5. The polymer matrix of claim 1 wherein the anionic gelling polymer has a molecular weight between 100,000 Da and 7,000,000 Da.

6. The polymer matrix of claim 1 having a gelling temperature range of from at least 10°

C. to at least 70°

C.

7. The polymer matrix of claim 1 having a gelling temperature range from at least 10°

C. to at least 37°

C.

8. The polymer matrix of claim 1 wherein the ratio of the inverse thermal gelling polymer to the anionic polymer is at least 1:

1 to 20;

1 w/w.

9. The polymer matrix of claim 8 wherein the matrix is comprised of 7% w/w methylcellulose and 2% w/w hyaluronic acid.

10. The polymer matrix of claim 1 wherein the inverse thermal gelling polymer is methylcellulose (MC) and the anionic gelling polymer is hyaluronic acid (HA).

11. The polymer matrix of claim 1 wherein the ratio of the inverse thermal gelling polymer to the anionic polymer is 3.5:

1 w/w.

12. The polymer matrix of claim 1 wherein the inverse gelling polymer is the chitosan and β

-glycerophosphate solution and the anionic gelling polymer is hyaluronic acid.

13. The polymer matrix of claim 1 wherein the inverse thermal gelling polymer and the anionic gelling polymer are dissolved in an aqueous solvent selected from the group comprising:

water, saline, artificial cerebrospinal fluid, and buffered solutions.

14. The polymer matrix of claim 1 having an altered rate of degradation by increasing the hydrophobicity of the anionic gelling polymer.

15. The polymer matrix of claim 1 having an altered rate of degradation rate by the addition of at least one of a thiol group and an acrylate group to the anionic gelling polymer.

16. The polymer matrix of claim 1 for transdermal, oral, sub-cutaneous, intranasal, vaginal, buccal, intrathecal, epidural, ocular space, dental, intratumoral, intramuscular, intraarticular, or intravenous injectable delivery.

17. The polymer matrix of claim 1 for use in the treatment of central nervous system disorders.

18. The polymer matrix of claim 1 for dura matter repair following wounding.

34. A pharmaceutical composition comprising as active ingredient a polymer matrix according to claim 1 for use in the treatment of dura mater wound healing.

35. A use of the polymer matrix of claim 1 in repair of dura mater following a traumatic event comprising at least one of a puncture wound, a tear and a break.

36. A use of the polymer matrix of claim 1 to decrease inflammatory reaction following traumatic injury to dura mater.

37. The use according to claim 35 wherein the polymer matrix is 7% w/w methylcellulose and 2% w/w hyaluronic acid.

38. The use according to claim 36 wherein the polymer matrix is 7% w/w methylcellulose and 2% w/w hyaluronic acid.

19. A polymer matrix pharmaceutical delivery vehicle comprising:

(c) at least one solution of inverse thermal gelling polymer, and,

(b) at least one anionic gelling polymer in powdered form;

for use as a carrier for a pharmaceutical agent, wherein the polymer matrix is a solid gel that is injectable due to shear thinning properties of the anionic gelling polymer and returns to its original viscosity after shearing.

20. The polymer matrix pharmaceutical delivery vehicle of claim 19 wherein the pharmaceutical agent is selected from the group comprising:

anesthetics for use in caudal, epidural, inhalation, injectable, retrobulbar, and spinal applications;

analgesics, selected from the group comprising acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren, phenacetin and salicylamide;

anti-inflammatories selected from the group comprising naproxen and indomethacin;

antihistamines, selected from the group comprising chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, henyltoloxamine citrate, diphenhydramine hydrochloride, promethazine, brompheniramine maleate, dexbrompheniramine maleate, clemastine fumarate and triprolidine;

antitussives selected from the group comprising dextromethorphan hydrobromide and guaifenesin;

expectorants;

decongestants, selected from the group comprising phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine;

antibiotics selected from the group comprising amebicides, broad and medium spectrum, fungal medications, monobactams and viral agents;

bronchodilators selected from the group comprising theophylline, albuterol and terbutaline;

cardiovascular preparations selected from the group comprising diltiazem, propranolol, nifedepine, clonidine, alpha adrenoceptor agonists, alpha receptor blocking agents, alpha and beta receptor blocking agents, antiotensin converting enzyme inhibitors, beta blocking agents, calcium channel blockers, and cardiac glycosides;

central nervous system drugs selected from the group comprising thioridazine, diazepam, meclizine, ergoloid mesylates, chlorpromazine, carbidopa and levodopa;

metal salts selected from the group comprising potassium chloride and lithium carbonate;

minerals selected from the group consisting of iron, chromium, molybdenum and potassium;

immunomodulators;

immunosuppressives selected from the group comprising minocycline, cyclosporine A;

thyroid preparations selected from the group comprising synthetic thyroid hormone, and thyroxine sodium;

peptide and glycoprotein hormones and analogues selected from the group comprising human chorionic gonadotrophin (HCG), corticotrophin, human growth hormone (HGH—

Somatotrophin) and erythropoietin (EPO);

steroids and hormones selected from the group comprising ACTH, anabolics, androgen and estrogen combinations, androgens, corticoids and analgesics, estrogens, glucocorticoid, gonadotropin, gonadotropin releasing, hypocalcemic, menotropins, parathyroid, progesterone, progestogen, progestogen and estrogen combinations, somatostatin-like compounds, urofollitropin, vasopressin, methyl prednisolone, GM1 ganglioside, cAMP, and others;

vitamins selected from the group comprising water-soluble vitamins and veterinary formulations;

growth factors selected from the group comprising EGF, FGF2 and neurotrophin;

peptides, peptide mimetics and other protein preparations;

DNA; and

,

small interfering RNAs;

with or without a pharmaceutically acceptable carrier or preservative.

21. The polymer matrix pharmaceutical delivery vehicle of claim 20 having an altered rate of degradation by cross-linking the anionic gelling polymer.

22. The polymer matrix pharmaceutical delivery vehicle of claim 21 wherein the polymer matrix is reduced through the addition of at least one of a thiol group and an acrylate group to the anionic gelling polymer.

23. The polymer matrix pharmaceutical delivery vehicle of claim 19 having an altered rate of degradation by increasing the hydrophobicity of the anionic gelling polymer.

24. The polymer matrix pharmaceutical delivery vehicle of claim 23 wherein hydrophobicity is modified by acetic hydrazide coupling at a carboxyl group of the anionic gelling polymer using standard coupling agents.

25. The polymer matrix pharmaceutical delivery vehicle of claim 19 wherein the pharmaceutical is encapsulated in a microsphere, nanoparticle or liposome.

26. The polymer matrix pharmaceutical delivery vehicle of claim 25 wherein at least one of a cationic and a cationic/anionic combination is added to prevent dispersion of the microsphere, nanoparticle or liposome from the matrix.

27. The polymer matrix pharmaceutical delivery vehicle of claim 19 wherein a charge stabilizer is added to promote an interaction between the polymer matrix and the pharmaceutical.

28. The polymer matrix pharmaceutical delivery vehicle of claim 19 wherein the pharmaceutical is covalently bonded to the anionic gelling polymer.

29. The polymer matrix pharmaceutical delivery vehicle of claim 19 wherein the pharmaceutical is EPO.

30. A polymer matrix pharmaceutical delivery vehicle of claim 19 for delivery of neuroprotective, angiogenic or neuroregenerative pharmaceuticals.

31. The polymer matrix pharmaceutical delivery vehicle of claim 30 for use as a carrier for at least one growth factor capable of stimulating endogenous stem cells.

32. The polymer matrix pharmaceutical delivery vehicle of claim 31 wherein the growth factor is at least one of EGF, FGF2 and a neurotrophin.

33. A biodegradable polymer matrix pharmaceutical delivery vehicle as claimed in claim 19 wherein the polymer matrix is biodegradable and the delivery is by sustained release.