Claims
- 1. A pharmaceutical composition comprising a codrug, or a pharmaceutically acceptable salt or prodrug thereof, in admixture with a hydrogel-forming compound, wherein the codrug comprises:
a) at least two constituent moieties, each moiety being a residue of a biologically active compound or a prodrug thereof, including a first constituent moiety and a second constituent moiety; and b) a linkage covalently linking the at least two constituent moieties to form the codrug, wherein the linkage is cleaved under physiological conditions to regenerate the constituent moieties.
- 2. The pharmaceutical composition according to claim 1, wherein the first constituent moiety is selected from analgesic compounds, anti-inflammatory steroidal compounds (corticosteroids), non-steroidal anti-inflammatory compounds (NSAIDs), antibiotic compounds, anti-fungal compounds, antiviral compounds, antiproliferative compounds, antiglaucoma compounds, immunomodulatory compounds, cell transport/mobility impeding agents, cytokines and peptides/proteins, alpha-blockers, anti-androgens, anti-cholinergic, adrenergic, puninergic, dopaminergic, local anesthetics, vanilloids, anti-angiogenic agents, nitrous oxide inhibitors, anti-apoptotic agents, macrophage activation inhibitors, and antimetabolite compounds.
- 3. The pharmaceutical composition according to claim 2, wherein the second constituent moiety is selected from analgesic compounds, anti-inflammatory steroidal compounds (corticosteroids), non-steroidal anti-inflammatory compounds. (NSAIDs), antibiotic compounds, anti-fungal compounds, antiviral compounds, antiproliferative compounds, antiglaucoma compounds, immunomodulatory compounds, cell transport/mobility impeding agents, cytokines and peptides/proteins, alpha-blockers, anti-androgens, anti-cholinergic, adrenergic, purinergic, dopaminergic, local anesthetics, vanilloids, anti-angiogenic agents, nitrous oxide inhibitors, anti-apoptotic agents, macrophage activation inhibitors, and antimetabolite compounds.
- 4. The pharmaceutical composition according to claim 1, wherein the codrug has the following structural formula:
- 5. The pharmaceutical composition according to claim 1, wherein the codrug has the following structural formula:
- 6. The pharmaceutical composition according to claim 1, wherein the codrug has the following structural formula:
- 7. The pharmaceutical composition according to claim 4, 5, or 6, wherein R1 is a residue of diclofenac, etodolac, ketorolac, indomethacin, salicylic acid, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, aspirin, choline magnesium trisalicylate, diflunisal, meclofenamic acid, mefenamic acid, phenylbutazone, or salts thereof.
- 8. The pharmaceutical composition according to claim 4, 5, or 6, wherein R2 is a residue of diclofenac, etodolac, ketorolac, indomethacin, salicylic acid, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, aspirin, choline magnesium trisalicylate, diflunisal, meclofenamic acid, mefenamic acid, phenylbutazone, or salts thereof.
- 9. The pharmaceutical composition according to claim 4, 5, or 6, wherein R1 is a residue of alitretinoin (9-cis-retinoic acid); amifostine; bexarotene (4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid); bleomycin; capecitabine (5′-deoxy-5-fluoro-cytidine); chlorambucil; bleomycin; BCNU; cladribine; cytarabine; daunorubicin; docetaxel; doxorubicin; epirubicin; estramustine; etoposide; exemestane (6-methylenandrosta-1,4-diene-3,17-dione); fludarabine; 5-fluorouracil; gemcitabine; hydroxyurea; idarubicin; irinotecan; melphalan; methotrexate; mitoxantrone; paclitaxel; pentostatin; streptozocin; temozolamide; teniposide; tomudex; topotecan; valrubicin (N-trifluoroacetyladriamycin-14-valerate); or vinorelbine.
- 10. The pharmaceutical composition according to claim 4, 5, or 6, wherein R2 is a residue of:
- 11. The pharmaceutical composition according to claim 4, 5, or 6, wherein R2 is a residue of 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts thereof.
- 12. The pharmaceutical composition according to claim 1, wherein the first constituent moiety is the same as the second constituent moiety.
- 13. The pharmaceutical composition according to claim 1, wherein the first constituent moiety is different from the second constituent moiety.
- 14. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises less than 15 wt. % water.
- 15. The pharmaceutical composition according to claim 1 or 14, wherein the pharmaceutical composition contains less than 10 wt. % water.
- 16. The pharmaceutical composition according to any of claims 1-6, wherein the pharmaceutical composition comprises from about 5 wt. % to about 90 wt. % codrug.
- 17. The pharmaceutical composition according to any of claims 1-6, wherein the hydrogel-forming compound forms a physical gel.
- 18. The pharmaceutical composition according to any of claims 1-6, wherein the pharmaceutical composition is hydrated prior to implantation, injection, insertion, or administration.
- 19. The pharmaceutical composition according to according to any of claims 1-6, wherein said hydrogel-forming compound is hyaluronic acid or a derivative thereof.
- 20. The pharmaceutical composition according to claim 1, said composition is in an implantable, injectable, insertable, or otherwise administrable single-dosage form.
- 21. The pharmaceutical composition according to claim 1, said composition is in an implantable, injectable, insertable, or otherwise administrable partial-dosage form.
- 22. The pharmaceutical composition according to any of claims 1-6, 20, and 21, wherein the composition is in the form of an implantable, injectable, insertable, or otherwise administrable pellet, tablet, caplet, or capsule.
- 23. The pharmaceutical composition according to claim 22, wherein the composition is in the form of an implantable, injectable, insertable, or otherwise administrable pellet.
- 24. The pharmaceutical composition according to claim 23, wherein the pellet has a diameter from about 0.1 mm to about 5.0 mm.
- 25. The pharmaceutical composition according to claim 23, wherein the pellet has a length of from about 0.3 mm to about 3.0 mm.
- 26. The pharmaceutical composition according to claim 23, wherein the pellet is sized for administration with an 18 gauge needle.
- 27. The pharmaceutical composition according to claim 23, wherein the pellet weighs from about 0.5 g to about 5 g.
- 28. The pharmaceutical composition according to any of claims 1-6 or 16, further comprising a pharmaceutically acceptable carrier, excipient, solvent, adjuvant, additive, diluent, dispersant, or surfactant.
- 29. The pharmaceutical composition according to claim 28, wherein the pharmaceutically acceptable carrier comprises a biocompatible polymer.
- 30. The pharmaceutical composition according to claim 29, wherein the polymer is selected from collagen, carbopol, hydroxypropylmethyl cellulose (“HPMC”), polyanhydride, polylactic acid, poly(ethylene glycol) (“PEG”), and poly(ethylene-co-vinyl acetate).
- 31. The pharmaceutical composition according to claim 28, wherein the pharmaceutically acceptable additive is selected from sodium alginate, magnesium stearate, and CaHPO4.
- 32. The pharmaceutical composition according to claim 1, which when placed in the body hydrates to release drug such that the rate of release of the drug is controlled by the dissolution of the codrug within the hydrogel.
- 33. The pharmaceutical composition according to claim 1, which hydrates when placed in the body and releases drug such that a diffusion coefficient of drug molecules or ions through the hydrogel is substantially the same as the diffusion coefficient of drug molecules or ions through a surrounding bodily fluid.
- 34. The pharmaceutical composition according to claim 1, wherein the first and second constituent moieties are directly linked through a covalent bond formed between a functional group of the first constituent moiety and a functional group of the second constituent moiety.
- 35. The pharmaceutical composition according to claim 1, wherein the first and second constituent moieties are linked to one another via a linking group that is covalently bonded to the first and second constituent moieties via functional groups thereon.
- 36. The pharmaceutical composition according to any of claims 1-6, wherein the first constituent moiety is an NSAID compound.
- 37. The pharmaceutical composition according to any of claims 1-6, wherein the second constituent moiety is an analgesic compound.
- 38. The pharmaceutical composition according to any of claims 1-6, wherein the first constituent moiety is diclofenac or ketorolac and the second constituent moiety is morphine.
- 39. The pharmaceutical composition according to any of claims 1-6, wherein the first constituent moiety is an antiproliferative agent and the second constituent moiety is an NSAID agent, with the proviso that the first constituent moiety is not floxuridine, and with the further proviso that when the first constituent moiety is 5-fluorouracil, the second constituent moiety is not flurbiprofen or indomethacin.
- 40. The pharmaceutical composition according to any of claims 1-6, wherein the first constituent moiety is an antiproliferative agent and the second constituent moiety is a corticosteroid agent, with the proviso that when the antiproliferative agent is 5-fluorouracil, the corticosteroid is not fluocinolone acetonide, triamcinolone, triamcinolone acetonide, desoximetasone, or hydrocortisone-17-butyrate, and with the further proviso that the antiproliferative agent is not a 1-β-arabinofuranosylcytosine derivative.
- 41. The pharmaceutical composition according to any of claims 1-6, wherein the codrug, or a pharmaceutically acceptable salt or prodrug thereof, is distributed as particles within a hydrogel-forming compound.
- 42. The pharmaceutical composition according to any of claims 1-6, wherein the codrug, or a pharmaceutically acceptable salt or prodrug thereof, is dissolved in a hydrogel-forming compound.
- 43. A method of treatment, comprising administering to a patient in need thereof a therapeutically effective amount of at least one constituent moiety in a composition comprising a codrug, or a pharmaceutically acceptable salt or prodrug thereof, in admixture with a hydrogel-forming compound, wherein the codrug comprises:
a) at least two constituent moieties, each moiety being a residue of a biologically active compound or a prodrug thereof, including a first constituent moiety and a second constituent moiety; and b) a linkage covalently linking the at least two constituent moieties to form the codrug, wherein the linkage is cleaved under physiological conditions to regenerate the constituent moieties.
- 44. The method according to claim 43, wherein the therapeutically effective amount is an amount effective to produce an analgesic, an anti-inflammatory, an antibiotic, an anti-fungal, an antiviral, and/or an antiproliferative effect in the patient.
- 45. A method of administering a pharmaceutical composition according to any of claims 1-6, comprising implanting the codrug composition into a synovial joint, a fibrous joint, or a cartilaginous joint, or the tissues surrounding said joint.
- 46. A method of administering a pharmaceutical composition according to any of claims 1-6, comprising injecting the codrug composition into a synovial joint, a fibrous joint, or a cartilaginous joint, or the tissues surrounding said joint.
- 47. The method according to claim 43, 45, or 46, wherein from about 5 to about 40 pellets, tablets, caplets, or capsules are administered into a synovial joint, a fibrous joint, or a cartilaginous joint, or the tissues surrounding said joint.
- 48. A method of administering a biologically active agent to a patient, comprising implanting, injecting, or inserting a pharmaceutical composition comprising a codrug, or a pharmaceutically acceptable salt or prodrug thereof, in admixture with a hydrogel-forming compound, for administration of at least one biologically active moiety, which codrug comprises:
a) at least two constituent moieties, each moiety being a residue of a biologically active compound or a prodrug thereof, including a first constituent moiety and a second constituent moiety; and b) a linkage covalently linking said at least two constituent moieties to form said codrug, wherein said linkage is cleaved under physiological conditions to regenerate said constituent moieties; wherein the composition is implanted, injected, inserted, or administered in a synovial joint, a fibrous joint, or a cartilaginous joint, or the tissues surrounding said joint.
- 49. A method of inhibiting cell proliferation in a patient in need of treatment, comprising implanting, injecting, or inserting a pharmaceutical composition comprising a codrug, or a pharmaceutically acceptable salt or prodrug thereof, in admixture with a hydrogel-forming compound, for administration of at least one biologically active moiety, which codrug comprises:
a) at least two constituent moieties, each moiety being a residue of a biologically active compound or a prodrug thereof, including a first constituent moiety and a second constituent moiety; and b) a linkage covalently linking said at least two constituent moieties to form said codrug, wherein said linkage is cleaved under physiological conditions to regenerate said constituent moieties; wherein the composition includes a therapeutically effective amount of at least one constituent moiety of a codrug, or a pharmaceutically acceptable salt thereof.
- 50. A method of inhibiting inflammation in a patient in need of treatment, comprising implanting, injecting, or inserting a pharmaceutical composition comprising a codrug, or a pharmaceutically acceptable salt or prodrug thereof, in admixture with a hydrogel-forming compound, for administration of at least one biologically active moiety, which codrug comprises:
a) at least two constituent moieties, each moiety being a residue of a biologically active compound or a prodrug thereof, including a first constituent moiety and a second constituent moiety; and b) a linkage covalently linking said at least two constituent moieties to form said codrug, wherein said linkage is cleaved under physiological conditions to regenerate said constituent moieties; wherein the composition includes a therapeutically effective amount of at least one constituent moiety of a codrug, or a pharmaceutically acceptable salt thereof.
- 51. The method according to claim 45 or 46, wherein the synovial joint is of a jaw, shoulder, knee, elbow, hip, ankle, wrist, finger, or toe.
- 52. The method according to claim 43, wherein the patient is being treated for an autoimmune disease, pain, or inflammation.
- 53. The method according to claim 52, wherein the autoimmune disease is rheumatoid arthritis.
- 54. A method of manufacturing a pharmaceutical composition, comprising providing a codrug, or a pharmaceutically acceptable salt or prodrug thereof, wherein the codrug comprises:
a) at least two constituent moieties, each moiety being a residue of a biologically active compound or a prodrug thereof, including a first constituent moiety and a second constituent moiety; and b) a linkage covalently linking said at least two constituent moieties to form said codrug, said linkage is cleaved under physiological conditions to regenerate said constituent moieties; and combining the codrug with a hydrogel-forming compound.
- 55. A method of preparing a pharmaceutical composition according to any of claims 1-6, comprising combining a powder, including a codrug, with a hydrogel-forming compound.
- 56. The pharmaceutical composition according to any of claims 1-6, wherein at least one constituent moiety of the codrug, taken alone, is effective for treating an autoimmune disease.
- 57. The pharmaceutical composition according to any of claims 1-6, wherein at least one constituent moiety of the codrug, taken alone, is effective for treating rheumatoid arthritis or osteoarthritis.
- 58. The pharmaceutical composition according to any of claims 1-6, wherein at least one constituent moiety of the codrug, taken alone, is effective for treating pain.
- 59. The pharmaceutical composition according to any of claims 1-6, wherein at least one constituent moiety of the codrug, taken alone, is effective for treating inflammation.
- 60. The pharmaceutical composition according to any of claims 1-6, wherein the constituent moieties are steroids.
- 61. The pharmaceutical composition according to any of claims 1-6 and 20, further comprising a biocompatible polymer.
- 62. The pharmaceutical composition according to claim 61, wherein the codrug comprises from about 5 wt. % to about 90 wt. % of the pharmaceutical composition, the hydrogel-forming compound comprises from about 10 wt. % to about 90 wt. % of the pharmaceutical composition, and the biocompatible polymer comprises from about 0 wt. % to about 50 wt. % of the pharmaceutical composition.
- 63. The pharmaceutical composition according to claim 62, wherein the composition substantially excludes water.
- 64. The pharmaceutical composition according to claim 62, wherein the biocompatible polymer is selected from collagen, carbopol, hydroxypropylmethyl cellulose (“HPMC”), polyanhydride, polylactic acid, poly(ethylene glycol), and poly(ethylene-co-vinyl acetate).
- 65. A pharmaceutical composition comprising poly(ethylene glycol), hyaluronic acid, and a codrug of diclofenac covalently linked to morphine.
- 66. The pharmaceutical composition according to claim 65, wherein a diclofenac-morphine codrug comprises from about 5 wt. % to about 90 wt. % of the pharmaceutical composition, hyaluronic acid or a derivative thereof comprises from about 10 wt. % to about 90 wt. % of the pharmaceutical composition, and the poly(ethylene glycol) comprises from about 0 wt. % to about 50 wt. % of the pharmaceutical composition.
- 67. The pharmaceutical composition according to claim 1, wherein the composition comprises more than one hydrogel-forming compound.
- 68. The pharmaceutical composition according to claim 1, wherein the composition comprises more than one polymer.
- 69. An injectable pellet comprising a pharmaceutical composition according to any of claims 1-6 or 65-66, wherein the pellet forms a hydrogel in vivo.
- 70. The method according to any of claims 43, 45, 46, 48, 49, and 50, wherein the pharmaceutical composition is hydrated prior to implantation, injection, insertion, or administration.
- 71. A kit comprising a pharmaceutical composition according to any of claims 1-6, 18, or 64-65, in association with instructions (written and/or pictorial) describing the use of the composition for treatment or prevention of autoimmune disease, pain, or inflammation, and optionally, warnings of possible side effects and drug-drug interactions.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority from U.S. Provisional Application No. 60/349,241, filed Jan. 18, 2002, the specification of which is incorporated by reference herein in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60349241 |
Jan 2002 |
US |