WO2004039355A1 - Therapeutic compositions - Google Patents
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- WO2004039355A1 WO2004039355A1 PCT/US2003/034183 US0334183W WO2004039355A1 WO 2004039355 A1 WO2004039355 A1 WO 2004039355A1 US 0334183 W US0334183 W US 0334183W WO 2004039355 A1 WO2004039355 A1 WO 2004039355A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
Definitions
- Rheumatoid arthritis is a debilitating disease affecting about 2.1 million Americans between the ages of 20 and 50. By far the most troubling symptoms are severe pain and swelling of the joints of the wrists, hands, ankles and feet, which occur when the body's immune system mistakenly attacks the synovial cells lining the joints, causing intense inflammation (Goronzy, J.J., and Weyand, CM. Rheumatoid Arthritis: Epidemiology, Pathology, and Pathogenesis, Primer on the Rheumatic Diseases, 12 Ed., Klippel,. J.H., Crofford, L.J., Stone, J.H., Weyand, CM., Eds. Atlanta: Arthritis Foundation, 2001).
- NSAIDs oral nonsteroidal anti-inflammatory drugs
- NSAIDs oral nonsteroidal anti-inflammatory drugs
- COX-1 and COX-2 cyclo-oxygenase enzymes involved in the production of prostaglandins
- RA RA remains a chronic disease, the severity of which fluctuates over time.
- a standard treatment is to inject corticosteroids directly into the affected joint, sometimes in combination with a local anesthetic.
- Such intra-articular (i.a.) injections provide rapid and long-lasting relief of pain and swelling, but only a few steroid injections can be administered safely at any one time, and repeated injections into the same joint can destroy cartilage (Stefanich, RJ. Intra-articular corticosteroids in treatment of osteoarthritis. Orthoped. Rev. 1986 32:65-71); Kongtawelert, P., Brooks, P., Ghosh, P.
- Pentosan polysulfate (Cartrophen) prevents the hydrocortisone-induced loss of hyaluronic acid and proteoglycans from cartilage of rabbit joints as well as normalizes the keratan sulfate levels in their serum. J. Rheumatol. 1989 16:1454- 1459).
- narcotic analgesics Long considered to produce analgesia by the activation of opioid receptors located exclusively within the central nervous system, newer evidence demonstrates that narcotic analgesics such as morphine also produce potent local analgesic effects when injected into chronically-inflamed tissues (Stein, C, Yassouridis, A. Peripheral morphine analgesia. Pain 1997 71: 119-121); Dionne, RA., Lepinski, A.M., Gordon, S.M., et al. Analgesic effects of peripherally administered opioids in clinical models of acute and chronic inflammation. Clin. Pharmacol. Ther.
- the present invention provides new formulations of injectable particles (e.g. microspheres) useful for intra-articular (i.a.) injection.
- the formulations are made of biocompatible polymers that biodegrade to generate NSAIDs, and are useful for treating inflamed joints, thus providing safe, long-lasting relief of joint pain and swelling.
- the present invention provides an injectable particle, comprising a biodegradable polymer comprising an agent selected from the group consisting of an NS ALU, a COX-2 inhibitor, an anesthetic and a narcotic analgesic.
- the present invention also provides formulations of such particles made of the above polymers into which have been added pharmacologically useful amounts of local anesthetic and/or narcotic analgesic drugs, thus providing additional therapeutic benefit.
- the present invention also provides an injectable particle comprising: 1) a biodegradable polymer comprising an NSAID in the polymer backbone; and in combination, 2) one or more NSAIDs, COX-2 inhibitors, local anesthetics or narcotic analgesics.
- the invention also provides an injectable particle of the invention which is a microsphere comprising: 1) polymer having a backbone, wherein the backbone comprises one or more groups that will yield an NSAID upon hydrolysis of the polymer; and optionally 2) a local anesthetic or a narcotic analgesic.
- the invention also provides a pharmaceutical composition of the invention that is a pharmaceutical composition comprising a plurality of microspheres of the invention and a pharmaceutically acceptable carrier.
- the invention also provides a method for treating RA in a mammal comprising administering to the mammal, an effective amount of a microsphere of the invention.
- the invention also provides a method for treating RA in a mammal comprising administering to the mammal, an effective amount of a pharmaceutical composition of the invention.
- the invention also provides a microsphere of the invention for use in medical therapy.
- the invention also provides a composition of the invention for use in medical therapy.
- the invention also provides the use of a microsphere of the invention for the manufacture of a medicament useful for the treatment of a RA in a mammal.
- the invention also provides synthetic processes disclosed herein that are useful for preparing an injectable particle of the invention.
- the present invention incorporates the discovery that additional therapeutic benefit is provided by the addition to the polymer of a local anesthetic drug and/or a narcotic analgesic drug.
- the present invention also incorporates the discovery that i.a. injection of a suitable formulation of microspheres made of a biocompatible, biodegradable polymer, alone or containing a local anesthetic drug and/or a narcotic analgesic drug, causes less destruction of joint cartilage, and fewer other adverse effects, compared to i.a. injection of a corticosteroid.
- the present invention also incorporates the discovery that, unlike many other injectable, inhalable, or oral formulations of narcotic analgesic drugs, the formulation of an injectable particle made of a biocompatible, biodegradable polymer containing a narcotic analgesic drug will have minimal potential for abuse.
- halo is fluoro, chloro, bromo, or iodo.
- Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to.
- Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
- Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (C ⁇ -C 6 )alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
- R is a suitable organic radical, such as, for example, hydrogen, (C ⁇ -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6
- amino acid comprises the residues of the natural amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Nal) in D or L form, as well as unnatural amino acids (e.g.
- the term also comprises natural and unnatural amino acids bearing a conventional amino protecting group (e.g.
- acetyl or benzyloxycarbonyl as well as natural and unnatural amino acids protected at the carboxy terminus (e.g. as a (C ⁇ -C 6 )alkyl, phenyl or benzyl ester or amide; or as an ⁇ - methylbenzyl amide).
- suitable amino and carboxy protecting groups are known to those skilled in the art (See for example, Greene, T.W.; Wutz, P.G.M. "Protecting Groups In Organic Synthesis” second edition, 1991, New York, John Wiley & sons, Inc., and references cited therein).
- peptide describes a sequence of 2 to 35 amino acids (e.g. as defined hereinabove) or peptidyl residues.
- the sequence may be linear or cyclic.
- a cyclic peptide can be prepared or may result from the formation of disulfide bridges between two cysteine residues in a sequence.
- a peptide comprises 3 to 20, or 5 to 15 amino acids.
- Peptide derivatives can be prepared as disclosed in U.S. Patent Numbers 4,612,302; 4,853,371; and 4,684,620, or as described in the Examples herein below. Peptide sequences specifically recited herein are written with the amino terminus on the left and the carboxy terminus on the right.
- a “narcotic analgesic” is any analgesic that produces a narcotic effect.
- the term “narcotic analgesic” also includes any habit-forming drug, such as, e.g., opiates such as, for example, morphine and heroin; opioids, such as, e.g., synthetic drugs such as meperidine (Demerol).
- Biocompatible, biodegradable polymers suitable for use in the present invention include all biodegradable polymers that are suitable for administration to a mammal and that are capable of acting as a carrier for a pharmaceutically active substance such as an NSATD, a narcotic analgesic, or a local anesthetic.
- a pharmaceutically active substance such as an NSATD, a narcotic analgesic, or a local anesthetic.
- Suitable polymers are also described in, e.g., U.S. Patent Nos. 6,328,988; 6,365,146; 6,468,519; 6,486,214; 6,497,895; 6,602,915; 6,613,807; U.S. Published Patent Applns.
- Biocompatible, biodegradable, anti-inflammatory polymers suitable for use in the present invention include, but are not limited to, polymers described by Erdmann, L., Uhrich, K.E., Biomaterials, 2000, 21:1941-1946.
- Biocompatible, biodegradable, anti-inflammatory polymers suitable for use in the present invention also include, but are not limited to, polymers described in International Patent Application Publication Number WO 02/09768A2.
- a suitable polymer is a polymer that comprises one or more units of formula (I):
- Ri is group that will provide an NSALD upon hydrolysis of the polymer; each A is independently an amide linkage, a thioester linkage, or an ester linkage; and L is a linking group.
- Another suitable polymer is a polymer that comprises one or more units of formula (II) in the backbone:
- R 2 and R 3 are each independently a group that will yield an NSAID upon hydrolysis of the polymer; each A is independently an amide, thioester, or ester linkage; and each L is independently a linking group.
- Biocompatible, biodegradable, anti-inflammatory polymers suitable for use in the present invention also include, but are not limited to, polymers described in International Patent Application Publication Number WO 02/09767 A2.
- a suitable polymer is a polymer that comprises a backbone, wherein the backbone comprises one or more anhydride linkages, and wherein the backbone comprises one or more groups that will yield an NSAID upon hydrolysis of the polymer.
- Another suitable polymer is a polymer that comprises one or more units of formula (III) in the backbone:
- Biocompatible, biodegradable, anti-inflammatory polymers suitable for use in the present invention also include, but are not limited to, polymers described in International Patent Application Publication Number WO 99/12990.
- a suitable polymer is a polymer described therein that will yield an NSAID upon hydrolysis of the polymer.
- Linking Group "L" is a polymer described therein that will yield an NSAID upon hydrolysis of the polymer.
- linking group "L” in a polymer is not critical provided the polymer possesses acceptable mechanical properties and release kinetics for the selected therapeutic application.
- the linking group L is typically a divalent organic radical having a molecular weight of from about 25 daltons to about 400 daltons. More preferably, L has a molecular weight of from about 40 daltons to about 200 daltons.
- the linking group L typically has a length of from about 5 angstroms to about 100 angstroms using standard bond lengths and angles. More preferably, the linking group L has a length of from about 10 angstroms to about 50 angstroms.
- the linking group may be biologically inactive, or may itself possess biological activity.
- the linking group can also comprise other functional groups (including hydroxy groups, mercapto groups, amine groups, carboxylic acids, as well as others) that can be used to modify the properties of the polymer (e.g. for branching, for cross linking, for appending other molecules (e.g. another biologically active compound) to the polymer, for changing the solubility of the polymer, or for effecting the biodistribution of the polymer).
- Specific And Preferred Values [0032] Specific and preferred values listed herein for radicals, substituents, groups, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
- (C ⁇ -C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
- (C -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
- (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylniethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl;
- (Ci- C 6 )alkoxy can be methoxy, ethoxy, propoxy, isoprop
- -C 6 )alkylthio can be methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, or hexylthio;
- (C 2 -C 6 )alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy;
- aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide),
- a specific value for L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-), and wherein the chain is optionally substituted on carbon with one or more (e.g.
- L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbon atoms, wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 - C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C ⁇ -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, (Q- C 6 )alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
- substituents selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 - C 6 )cycloalkyl, (C 1 -C 6 )alkan
- Another specific value for L is an amino acid.
- L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
- L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-), and wherein the chain is optionally substituted on carbon with one or more (e.g.
- substituents selected from the group consisting of (C- C 6 )alkoxy, (C -C 6 )cycloalkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (Ci- C 6 )alkoxycarbonyl, azido, cyano, nitro, halo, hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
- L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-) or (-NR-).
- L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms.
- L is a divalent, branched or unbranched, hydrocarbon chain, having from 3 to 15 carbon atoms.
- L is a divalent, branched or unbranched, hydrocarbon chain, having from 6, 1, or 8 carbon atoms.
- L is a divalent hydrocarbon chain having 8, 9, or 10 carbon atoms.
- L is a divalent hydrocarbon chain having 8 carbon atoms.
- NSAID possessing the requisite functionality to be incorporated into the backbone of a polymer as described herein is suitable for incorporation into the microspheres of the invention.
- Specific NSAIDS include 3-amino-4- hydroxybutyric acid, aceclofenac, alminoprofen, amfenac, bromfenac, bromosaligenin, bumadizon, carprofen, diclofenac, diflunisal, ditazol, enfenamic acid, etodolac, etofenamate, fendosal, fepradinol, flufenamic acid, gentisic acid, glucamethacin, glycol salicylate, meclofenamic acid, mefenamic acid, mesalamine, niflumic acid, olsalazine, oxaceprol, S-adenosylmethionine, salicylic acid, salsalate, sulfa
- Preferred NSAIDS include salicylic acid and diflunisal.
- the NSAID can also be a cyclooxygenase-2 (COX-2) inhibitor, such as, e.g., celecoxib, etoricoxib, lumiracoxib, meloxicam, onconoxib, parecoxib, rofecoxib, tilmacoxib, valdecoxib, any other COX-2 inhibitor, or any combinations thereof.
- COX-2 cyclooxygenase-2
- Local anesthetics suitable for mixing with the polymers include, but are not limited to, benzocaine, bupivacaine, butacaine, butanilicane, carticaine, chloroprocaine, cocaine, cyclomethycaine, dibucaine, diperocaine, etidocaine, fomocaine, isobucaine, ketamine, leucinocaine, lidocaine, lignocaine, mepivacaine, meprylcaine, myrtecaine, octacaine, oxybuprocaine, parethoxycaine, phenacaine, piperocaine, pramoxine, prilocaine, procaine, propanocaine, propoxycaine, proxymetacaine, pyrrocaine, ropivacaine, tetracaine, tolycaine, and the like (Catterall, W., Mackie, K.
- Narcotic analgesics suitable for mixing with the polymers include, but are not limited to, alfentanil, bremazocine, buprenorphine, butorphanol, codeine, CTOP, [d-Ala 2 ] deltorphin I, [d-Ala 2 , Glu 4 ] deltorphin (deltorphin II), DADL, DALCE, DAMGO, dihydrocodeine, dihydrocodeinone, diphenoxylate, DPDPE,
- FK-33824 [Leu 5 ] enkephalin, [Met 5 ] enkephalin, ethylketocyclazocine, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, levallorphan, levorphanol, meperidine, methadone, , morphiceptin, morphine, morphine-6-glucuronide,
- particles of the invention will have a maximum dimension of less than about 1 mm and a minimum dimension of greater than about 1 run. Preferably, particles of the invention will have a maximum dimension of less than
- injectable particle is a microsphere.
- the polymers are dissolved in a suitable organic solvent, including but not limited to chloroform, methylene chloride, and other water-immiscible vehicles.
- a suitable organic solvent including but not limited to chloroform, methylene chloride, and other water-immiscible vehicles.
- the local anesthetic and/or narcotic analgesic drugs, either as free bases or salts are dissolved directly in the polymer solutions.
- the polymers are dissolved in a suitable organic solvent, while the local anesthetic and/or narcotic analgesic drugs are dissolved in a different immiscible vehicle, such as water.
- a measured amount (e.g., 100 mg) of injectable particles are added to a measured volume (e.g., 1 ml) of a suitable pharmaceutical vehicle, the contents of which may include, but are not limited to, water for injection, sodium chloride injection, Ringer's injection, lactated Ringer's injection, dextrose injection, dextrose and sodium chloride injection, benzyl alcohol, ethyl alcohol, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, benzyl benzoate, phenylmercuric nitrate, thiomersal, benzethonium chloride, benzalkonium chloride, phenol, cresol, chlorobutanol benzoic acid, p-hydroxybenzoic acid, methyl- p-hydroxybenzoate, propyl-p-
- a formulation can be administered by injection to human subjects, by drawing the sterile formulation into a sterile syringe fitted with a needle of appropriate size. The area of skin through which the needle will pass is swabbed with alcohol, and a measured volume (e.g., 1 ml) of the formulation is injected into the intra-articular region of an inflamed joint or as appropriate based on the condition being treated.
- a measured volume e.g. 1 ml
- compositions required for use in treatment will vary with the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
- Example 1 Preparation, Formulation, and In Vivo Effects of NSAID Polymer Microspheres
- a biocompatible, biodegradable polymer incorporating an NSALD in the polymer backbone e.g. salicylic acid, a salicylate derivative, or diflunisal
- an NSALD in the polymer backbone e.g. salicylic acid, a salicylate derivative, or diflunisal
- a biocompatible, biodegradable polymer incorporating an NSALD in the polymer backbone is prepared (for example as described by Erdmann, L., et al., Biomaterials 2000 21:1941-1946; or for example, as described in International Patent Application Publication Numbers WO 02/09767A2, WO 09768A2, and WO 99/12990).
- the polymer is dissolved in anhydrous methylene chloride, and the
- microspheres having a mean diameter of 50 ⁇ m.
- the microspheres can be prepared using any suitable technique, for example, they can be prepared as described by O'Donnell, P.B., et al., Advanced Drug Delivery Reviews, 1997, 28:25-42.
- An aliquot e.g., 100 mg
- a volume e.g., 1 ml
- saline for injection also containing mannitol, hydroxymethylcellulose, and TWEEN-80 is drawn into another
- a disposable 3-ml syringe to which a disposable filter (0.22 ⁇ m pore size) is affixed.
- the liquid-filled syringe is attached to the sterilized syringe/stopcock assembly, and the liquid is transferred through the filter to the microsphere-filled syringe.
- the disposable filter is removed, the syringes are reconnected via the stopcock, and the contents are vigorously transferred back and forth to create a formulation for injection.
- a standard experimental model of arthritis is created by injecting an aqueous solution of ovalbumin into the knees of rabbits (for example, see Horisawa, E., et al., Pharm. Res., 2002 19:403-410.
- groups of four rabbits receive single 0.1 ml i.a. injections of 1) the salicylate polymer microsphere formulation, 2) injection vehicle without polymer microspheres; or 3) injection vehicle containing betamethasone sodium phosphate (2% free base).
- injection vehicle containing betamethasone sodium phosphate 2% free base
- synovial fluid samples (25 ⁇ l) are collected for analysis of salicylate and
- betamethasone concentrations and venous blood samples (0.5 ml) are collected for analysis of salicylate and betamethasone serum concentrations and ovalbumin antibody titers. At the end of 3 weeks the animals are sacrificed for histo logical assessment of joint damage.
- the animals receiving salicylate polymer microsphere injections will typically have high, sustained salicylate synovial fluid levels, and low salicylate serum levels, over the 3 -week post- injection period.
- the animals receiving betamethasone injections will typically have low betamethasone levels in both synovial fluid and serum at early time points, after which betamethasone levels will be undetectable.
- Both the salicylate polymer microsphere- and betamethasone- treated animals will typically have significantly reduced joint swelling and serum ovalbumin antibody titers compared to vehicle controls during the 3 -week period.
- the salicylate polymer microsphere-treated animals will typically have significantly less damage to the injected knee joints than the animals receiving betamethasone.
- Example 2 Preparation, Formulation, and In Vivo Effects of NSAID Polymer Microspheres Containing Local Anesthetic
- a biocompatible, biodegradable polymer incorporating an NSATD in the polymer backbone can be prepared as described in Example 1.
- the polymer is dissolved in anhydrous methylene chloride, and the solution is used together with an aqueous solution of lidocaine hydrochloride to prepare microspheres containing 1% lidocaine (free base) by weight, and having a
- microspheres can be prepared, for example, as
- An aliquot (e.g., 100 mg) of dry microspheres is transferred to a disposable 3-ml syringe fitted with a disposable 3-way stopcock, and the assembly is sterilized with gamma radiation.
- a volume (e.g., 1 ml) of saline for injection also containing mannitol, hydroxymethylcellulose, and TWEEN-80 is drawn into another disposable 3-ml syringe, to which a disposable filter (0.22 ⁇ m pore size) is affixed.
- the liquid-filled syringe is attached to the sterilized syringe/stopcock assembly, and the liquid is transferred through the filter to the microsphere-filled syringe.
- the disposable filter is removed, the syringes are reconnected via the stopcock, and the contents are vigorously transferred back and forth to create a formulation for injection.
- a standard experimental model of arthritis is created by injecting an aqueous solution of ovalbumin into the knees of rabbits (for example, see Horisawa, E., et al, Pharm. Res., 2002 19:403-410.
- groups of four rabbits receive single 0.1 ml i.a. injections of 1) the salicylate polymer/lidocaine microsphere formulation; 2) injection vehicle without salicylate polymer/lidocaine microspheres; or 3) injection vehicle containing lidocaine hydrochloride (1% free base).
- Example 3 Preparation, Formulation, and In Vivo Effects of NSAID Polymer Microspheres Containing Narcotic Analgesic
- a biocompatible, biodegradable polymer incorporating an NSATD in the polymer backbone can be prepared as described in Example 1.
- the polymer is dissolved in anhydrous methylene chloride, and the solution is used together with an aqueous solution of morphine sulfate to prepare microspheres containing 2% morphine (free base) by weight, and having a mean
- microspheres can be prepared, for example, as described in Example 1.
- An aliquot (e.g., 100 mg) of the dry microspheres is transferred to a disposable 3-ml syringe fitted with a disposable 3-way stopcock, and the assembly is sterilized with gamma radiation.
- a volume (e.g., 1 ml) of saline for injection also containing mannitol, hydroxymethylcellulose, and TWEEN-80 is drawn into another
- a disposable 3-ml syringe to which a disposable filter (0.22 ⁇ m pore size) was affixed.
- the liquid-filled syringe is attached to the sterilized syringe/stopcock assembly, and the liquid is transferred through the filter to the microsphere-filled syringe.
- the disposable filter is removed, the syringes are reconnected via the stopcock, and the contents are vigorously transferred back and forth to create a formulation for injection.
- a standard experimental model of arthritis is created by injecting an aqueous solution of ovalbumin into the knees of rabbits (for example, see Horisawa, E., et al., Pharm. Res., 2002 19:403-410.
- groups of four rabbits receive single 0.1 ml i.a. injections of 1) the salicylate polymer/morphine microsphere formulation; 2) injection vehicle without salicylate polymer/morphine microspheres; or 3) injection vehicle containing morphine sulfate (2% free base).
- injection vehicle containing morphine sulfate 2% free base
- the animals receiving salicylate polymer/morphine microsphere injections will typically have high, sustained salicylate and morphine synovial fluid levels, and low salicylate and morphine serum levels, over the 3-week post-injection period.
- the animals receiving morphine injections will typically have undetectable levels of morphine in synovial fluid and serum at every time point.
- the salicylate polymer/morphine microsphere- treated animals will typically have significantly reduced joint swelling and serum ovalbumin antibody titers compared to vehicle and morphine controls during the 3- week period.
- Example 4 Preparation, Formulation, and In Vivo Effects of NSAID Polymer Microspheres containing Local Anesthetic and Narcotic Analgesic
- a biocompatible, biodegradable polymer incorporating an NSALD in the polymer backbone can be prepared as described in Example 1.
- the polymer is dissolved in anhydrous methylene chloride, and the solution is used together with an aqueous solution of lidocaine hydrochloride and morphine sulfate to prepare microspheres containing 1% lidocaine and 2% morphine
- microspheres (free bases) by weight, and having a mean diameter of 50 ⁇ m; the microspheres can be prepared, for example, as described in Example 1.
- An aliquot (e.g., 100 mg) of the dry microspheres is transferred to a disposable 3-ml syringe fitted with a disposable 3-way stopcock, and the assembly is sterilized by using, e.g., gamma radiation.
- a volume (e.g., 1 ml) of saline for injection also containing mannitol, hydroxymethylcellulose, and TWEEN-80 is drawn into another disposable 3-ml syringe, to which a disposable filter (0.22 ⁇ m pore size) is affixed.
- the liquid-filled syringe is attached to the sterilized syringe/stopcock assembly, and the liquid is transferred through the filter to the microsphere-filled syringe.
- the disposable filter is removed, the syringes were reconnected via the stopcock, and the contents are vigorously transferred back and forth to create a formulation for injection.
- a standard experimental model of arthritis is created by injecting an aqueous solution of ovalbumin into the knees of rabbits (for example, see Horisawa, E., et al., Pharm. Res., 2002 19:403-410.
- groups of four rabbits received single 0.1 ml i.a. injections of 1) the salicylate polymer/lidocaine/morphine microsphere formulation; 2) injection vehicle without salicylate polymer/lidocaine/morphine microspheres; 3) injection vehicle containing lidocaine hydrochloride (1% free base); or 4) injection vehicle containing morphine sulfate (2% free base).
- the salicylate polymer/lidocaine/mo ⁇ hine microsphere-treated animals will typically show significantly reduced joint swelling and serum ovalbumin antibody titers compared to vehicle, lidocaine, and mo ⁇ hine controls during the 3 -week treatment period.
- Example 5 Representative injectable dosage forms, comprising injectable particles of the invention (' injectable particles '), for therapeutic use in humans.
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Abstract
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/532,703 US20070098800A1 (en) | 2002-10-28 | 2003-10-28 | Therapeutic compositions |
CA002503841A CA2503841A1 (en) | 2002-10-28 | 2003-10-28 | Therapeutic compositions |
MXPA05004500A MXPA05004500A (en) | 2002-10-29 | 2003-10-28 | Therapeutic compositions. |
JP2004548530A JP2006508941A (en) | 2002-10-28 | 2003-10-28 | Therapeutic composition |
EP03781417A EP1556011A1 (en) | 2002-10-28 | 2003-10-28 | Therapeutic compositions |
AU2003287235A AU2003287235A1 (en) | 2002-10-28 | 2003-10-28 | Therapeutic compositions |
Applications Claiming Priority (2)
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US42188802P | 2002-10-28 | 2002-10-28 | |
US60/421,888 | 2002-10-28 |
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WO2004039355A1 true WO2004039355A1 (en) | 2004-05-13 |
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PCT/US2003/034183 WO2004039355A1 (en) | 2002-10-28 | 2003-10-28 | Therapeutic compositions |
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US (1) | US20070098800A1 (en) |
EP (1) | EP1556011A1 (en) |
JP (1) | JP2006508941A (en) |
KR (1) | KR20050083853A (en) |
CN (1) | CN1717224A (en) |
AU (1) | AU2003287235A1 (en) |
CA (1) | CA2503841A1 (en) |
WO (1) | WO2004039355A1 (en) |
Cited By (22)
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WO2008014066A1 (en) * | 2006-07-26 | 2008-01-31 | Medtronic, Inc. | Nfkappab inhibitors to treat pain locally |
JP2008511673A (en) * | 2004-09-02 | 2008-04-17 | ウォーソー・オーソペディック・インコーポレーテッド | Controlled and specific local delivery of anti-inflammatory compositions |
US7748628B2 (en) | 2006-05-10 | 2010-07-06 | Mckesson Automation Inc. | Systems and methods for scanning an identification code of an unknown orientation |
US7985415B2 (en) | 1997-09-10 | 2011-07-26 | Rutgers, The State University Of New Jersey | Medical devices employing novel polymers |
US8009913B2 (en) | 2007-05-29 | 2011-08-30 | Mckesson Automation, Inc. | System, method, apparatus and computer program product for capturing human-readable text displayed on a unit dose package |
US8221790B2 (en) | 2000-07-27 | 2012-07-17 | Rutgers, The State University Of New Jersey | Therapeutic polyesters and polyamides |
US8263060B2 (en) | 2005-05-23 | 2012-09-11 | Rutgers, The State University Of New Jersey | Fast degrading polymers |
US8361453B2 (en) | 2006-06-06 | 2013-01-29 | Rutgers, The State University Of New Jersey | Iodinated polymers |
US8747832B2 (en) | 2007-04-12 | 2014-06-10 | Rutgers, The State University Of New Jersey | Biodegradable polyanhydrides with natural bioactive molecules |
US8929641B2 (en) | 2009-03-17 | 2015-01-06 | Aesynt Incorporated | System and method for determining the orientation of a unit dose package |
EP2694079A4 (en) * | 2011-04-06 | 2015-02-18 | Univ Rutgers | Polymers and methods for the treatment of pain |
US9108070B2 (en) | 2006-09-13 | 2015-08-18 | Polymerix Corporation | Active agents and their oligomers and polymers |
US9144579B2 (en) | 2012-08-17 | 2015-09-29 | Rutgers, The State University Of New Jersey | Polyesters and methods of use thereof |
US9387250B2 (en) | 2013-03-15 | 2016-07-12 | Rutgers, The State University Of New Jersey | Therapeutic compositions for bone repair |
US9782432B2 (en) | 2012-10-25 | 2017-10-10 | Rutgers, The State University Of New Jersey | Polymers and methods thereof for wound healing |
US9862672B2 (en) | 2013-05-29 | 2018-01-09 | Rutgers, The State University Of New Jersey | Antioxidant-based poly(anhydride-esters) |
US10023521B2 (en) | 2014-06-13 | 2018-07-17 | Rutgers, The State University Of New Jersey | Process and intermediates for preparing poly(anhydride-esters) |
EP3247462A4 (en) * | 2015-01-20 | 2018-08-08 | Visgo Therapeutics, Inc. | Injectable aggregates for joint and soft tissue distress |
US10543162B2 (en) | 2015-04-10 | 2020-01-28 | Rutgers, The State University Of New Jersey | Kojic acid polymers |
US10653619B2 (en) | 2009-03-23 | 2020-05-19 | Medtronic, Inc. | Drug depots for treatment of pain and inflammation |
USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
RU2805144C1 (en) * | 2022-10-20 | 2023-10-11 | Общество с ограниченной ответственностью "ЛАБОРАТОРИЯ АНГИОФАРМ" | Recombinant angiogenin in cosmetic and pharmaceutical compositions |
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US7122615B1 (en) * | 1998-09-10 | 2006-10-17 | Rutgers, The State University Of New Jersey | Polyanhydrides with therapeutically useful degradation products |
US6486214B1 (en) * | 1997-09-10 | 2002-11-26 | Rutgers, The State University Of New Jersey | Polyanhydride linkers for production of drug polymers and drug polymer compositions produced thereby |
US20040038948A1 (en) * | 1999-12-07 | 2004-02-26 | Uhrich Kathryn E. | Therapeutic compositions and methods |
US8741317B2 (en) | 2010-08-19 | 2014-06-03 | Rutgers, The State University Of New Jersey | Slow-degrading polymers comprising salicylic acid for undelayed and sustained drug delivery |
CN111514108B (en) * | 2014-04-08 | 2022-11-29 | 帝斯曼知识产权资产管理有限公司 | Biodegradable polyesteramides for the treatment of arthritic disorders |
EP4374861A2 (en) * | 2015-11-16 | 2024-05-29 | MedinCell S.A. | A method for morselizing and/or targeting pharmaceutically active principles to synovial tissue |
US20210369628A1 (en) * | 2018-11-01 | 2021-12-02 | New Jersey Institute Of Technology | Injectable formulations of anesthetics for any pathological pain |
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-
2003
- 2003-10-28 CA CA002503841A patent/CA2503841A1/en not_active Abandoned
- 2003-10-28 JP JP2004548530A patent/JP2006508941A/en active Pending
- 2003-10-28 KR KR1020057007433A patent/KR20050083853A/en not_active Application Discontinuation
- 2003-10-28 AU AU2003287235A patent/AU2003287235A1/en not_active Abandoned
- 2003-10-28 CN CNA2003801041526A patent/CN1717224A/en active Pending
- 2003-10-28 EP EP03781417A patent/EP1556011A1/en not_active Withdrawn
- 2003-10-28 WO PCT/US2003/034183 patent/WO2004039355A1/en active Application Filing
- 2003-10-28 US US10/532,703 patent/US20070098800A1/en not_active Abandoned
Patent Citations (2)
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US5916596A (en) * | 1993-02-22 | 1999-06-29 | Vivorx Pharmaceuticals, Inc. | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof |
WO1999012990A1 (en) * | 1997-09-10 | 1999-03-18 | Rutgers, The State University | Polyanhydrides with therapeutically useful degradation products |
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US7985415B2 (en) | 1997-09-10 | 2011-07-26 | Rutgers, The State University Of New Jersey | Medical devices employing novel polymers |
US8221790B2 (en) | 2000-07-27 | 2012-07-17 | Rutgers, The State University Of New Jersey | Therapeutic polyesters and polyamides |
US8241668B2 (en) | 2000-07-27 | 2012-08-14 | Rutgers, The State University Of New Jersey | Therapeutic polyesters and polyamides |
JP2008511673A (en) * | 2004-09-02 | 2008-04-17 | ウォーソー・オーソペディック・インコーポレーテッド | Controlled and specific local delivery of anti-inflammatory compositions |
US8969397B2 (en) | 2004-10-22 | 2015-03-03 | Warsaw Orthopedic, Inc. | Systems and methods to treat pain locally |
US8263060B2 (en) | 2005-05-23 | 2012-09-11 | Rutgers, The State University Of New Jersey | Fast degrading polymers |
US8036773B2 (en) | 2006-05-10 | 2011-10-11 | Mckesson Automation Inc. | System, method and corresponding apparatus for storing, retrieving and delivering unit dose blisters |
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US8361453B2 (en) | 2006-06-06 | 2013-01-29 | Rutgers, The State University Of New Jersey | Iodinated polymers |
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US8009913B2 (en) | 2007-05-29 | 2011-08-30 | Mckesson Automation, Inc. | System, method, apparatus and computer program product for capturing human-readable text displayed on a unit dose package |
USRE48948E1 (en) | 2008-04-18 | 2022-03-01 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
US9779507B2 (en) | 2009-03-17 | 2017-10-03 | Aesynt Incorporated | System and method for determining the orientation of a unit dose package |
US8929641B2 (en) | 2009-03-17 | 2015-01-06 | Aesynt Incorporated | System and method for determining the orientation of a unit dose package |
US10653619B2 (en) | 2009-03-23 | 2020-05-19 | Medtronic, Inc. | Drug depots for treatment of pain and inflammation |
EP2694079A4 (en) * | 2011-04-06 | 2015-02-18 | Univ Rutgers | Polymers and methods for the treatment of pain |
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US9782432B2 (en) | 2012-10-25 | 2017-10-10 | Rutgers, The State University Of New Jersey | Polymers and methods thereof for wound healing |
US9387250B2 (en) | 2013-03-15 | 2016-07-12 | Rutgers, The State University Of New Jersey | Therapeutic compositions for bone repair |
US9862672B2 (en) | 2013-05-29 | 2018-01-09 | Rutgers, The State University Of New Jersey | Antioxidant-based poly(anhydride-esters) |
US10023521B2 (en) | 2014-06-13 | 2018-07-17 | Rutgers, The State University Of New Jersey | Process and intermediates for preparing poly(anhydride-esters) |
EP3247462A4 (en) * | 2015-01-20 | 2018-08-08 | Visgo Therapeutics, Inc. | Injectable aggregates for joint and soft tissue distress |
US10543162B2 (en) | 2015-04-10 | 2020-01-28 | Rutgers, The State University Of New Jersey | Kojic acid polymers |
RU2805144C1 (en) * | 2022-10-20 | 2023-10-11 | Общество с ограниченной ответственностью "ЛАБОРАТОРИЯ АНГИОФАРМ" | Recombinant angiogenin in cosmetic and pharmaceutical compositions |
Also Published As
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US20070098800A1 (en) | 2007-05-03 |
CA2503841A1 (en) | 2004-05-13 |
AU2003287235A1 (en) | 2004-05-25 |
KR20050083853A (en) | 2005-08-26 |
CN1717224A (en) | 2006-01-04 |
EP1556011A1 (en) | 2005-07-27 |
JP2006508941A (en) | 2006-03-16 |
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