# US 2014/0194380 A1 · Method of manufacturing composition comprising local anesthetic, heparinoid, and buffer > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0194380 A1 - Document ID: US20140194380A1 - Status: Published application - Kind: A1 - Application number: 13/978,441 - Filed: 2012-01-05 - Published: 2014-07-10 - Earliest claimed: 2011-01-06 - Inventors: Lowell C. Parsons - Web page: https://patentgrep.com/patent/US20140194380A1 ## CPC - A61K 31/727: Heparin; Heparan - A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 13/00: Drugs for disorders of the urinary system - A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers - A61P 13/08: of the prostate - A61P 13/10: of the bladder - A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives - A61P 15/02: for disorders of the vagina - A61P 23/02: Local anaesthetics - A61P 25/04: Centrally acting analgesics, e.g. opioids - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract An improved method for preparing a composition including a heparinoid, a local anesthetic, and a buffer for treatment of a lower urinary tract disease or condition can comprise either: (A) (i) providing a heparinoid in solid form or liquid form; (ii) providing a local anesthetic in solid form or liquid form; (iii) adding a liquid buffer to the heparinoid in solid form or liquid form; (iv) adding the local anesthetic to the mixture of the liquid buffer and the heparinoid; and (v) if necessary, adjusting the pH of the mixture of the liquid buffer, the local anesthetic, and the heparinoid so that a pH is achieved of from about 6.8 to about 8.3 is achieved without precipitation of the local anesthetic; or (B) (i)providing a heparinoid in solid form or liquid form; (ii) providing a local anesthetic in solid form or liquid form; (iii) mixing the heparinoid in solid form or liquid form and the local anesthetic in solid form or liquid form; (iv) adding a liquid buffer to the mixture of the heparinoid and the local anesthetic to form a mixture of liquid buffer, the heparinoid, and the local anesthetic; and (v) if necessary, adjusting the pH of the mixture of the liquid buffer, the local anesthetic, and the heparinoid so that a pH is achieved of from about 7.0 to about 7.8 is achieved without precipitation of the local anesthetic. The invention also encompasses a stable premixed liquid composition that avoids precipitation of the local anesthetic. ## Claims ### Claim 1 A method for preparing a composition useful for treatment of a lower urinary tract condition by instilling the composition into the urinary bladder, the composition comprising a mixture comprising a heparinoid, a local anesthetic, and a buffer, the method comprising the steps of: (a) providing a heparinoid in solid form or liquid form; (b) providing a local anesthetic in solid form or liquid form; (c) adding a liquid buffer to the heparinoid in solid form or liquid form; (d) adding the local anesthetic to the mixture of the liquid buffer and the heparinoid; and (e) if necessary, adjusting the pH of the mixture of the liquid buffer, the local anesthetic, and the heparinoid so that a pH is achieved of from about 6.7 to about 8.3 without precipitation of the local anesthetic. ### Claim 2 (depends on 1) The method of claim 1 wherein the heparinoid is selected from the group consisting of heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, and sodium pentosanpolysulfate. ### Claim 3 (depends on 2) The method of claim 2 wherein the heparinoid is selected from the group consisting of heparin and sodium pentosanpolysulfate. ### Claim 4 (depends on 3) The method of claim 3 wherein the heparinoid is heparin. ### Claim 5 (depends on 4) The method of claim 4 wherein the heparin is heparin sodium. ### Claim 6 (canceled) ### Claim 7 (canceled) ### Claim 8 (canceled) ### Claim 9 (depends on 1) The method of claim 1 wherein the local anesthetic is selected from the group consisting of benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, flecainide, mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, and pharmaceutically acceptable derivatives and bioisosteres thereof, and a combination thereof. ### Claim 10 (canceled) ### Claim 11 (depends on 9) The method of claim 9 wherein the local anesthetic is lidocaine. ### Claim 12 (canceled) ### Claim 13 (depends on 1) The method of claim 1 wherein the buffer is selected from the group consisting of bicarbonate buffer, Tris (Tris(hydroxymethyl)aminomethane) buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA (N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine (N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphate buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)) buffer, TAPS (N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer; TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, 2-amino-2-methyl-1-propanol buffer, and a combination thereof. ### Claim 14 (canceled) ### Claim 15 (depends on 13) The method of claim 13 wherein the buffer is bicarbonate buffer. ### Claim 16 (depends on 15) The method of claim 15 wherein the buffer is sodium bicarbonate. ### Claim 17 (depends on 13) The method of claim 13 wherein the buffer is Tris buffer. ### Claim 18 (depends on 1) The method of claim 1 wherein the method further comprises the step of adding one or more of: (i) an osmolar component; (ii) a compound that enables persistence of the composition to the surface of the bladder epithelium; (iii) an antibacterial agent; (iv) an antifungal agent; (v) a vasoconstrictor; or (vi) a preservative, subsequent to preparation of a buffered composition including the heparinoid, the local anesthetic, and the buffer. ### Claim 19 (depends on 1) The method of claim 1 wherein the heparinoid and the local anesthetic are provided in forms selected from the group consisting of: both the heparinoid and the local anesthetic are provided in solid form; (ii) both the heparinoid and the local anesthetic are provided in powdered form; (iii) both the heparinoid and the local anesthetic are provided in liquid form; and (iv) the heparinoid is provided in solid form and the local anesthetic is provided in liquid form. ### Claim at position 20 20-25. (canceled) ### Claim 26 (depends on 1) The method of claim 1 wherein the heparinoid is heparin, the local anesthetic is lidocaine, and the buffer is bicarbonate buffer. ### Claim 27 (depends on 26) The method of claim 26 wherein the heparin is heparin sodium, the local anesthetic is lidocaine hydrochloride, and the bicarbonate buffer is sodium bicarbonate. ### Claim 28 (depends on 1) The method of claim 1 wherein the pH achieved is from about 7.0 to about 7.8. ### Claim 29 (depends on 1) The method of claim 1 wherein the pH achieved is about 7.4. ### Claim 30 (depends on 1) The method of claim 1 wherein the heparinoid, the local anesthetic, and the buffer are originally provided in solid form and hydrated simultaneously. ### Claim 31 A method for preparing a composition useful for treatment of a lower urinary tract condition by instilling the composition into the urinary bladder, the composition comprising a mixture comprising a heparinoid, a local anesthetic, and a buffer, the method comprising the steps of: (a) providing a heparinoid in solid form or liquid form; (b) providing a local anesthetic in solid form or liquid form; (c) mixing the heparinoid in solid form or liquid form and the local anesthetic in solid form or liquid form; (d) adding a liquid buffer to the mixture of the heparinoid and the local anesthetic to form a mixture of liquid buffer, the heparinoid, and the local anesthetic; and (e) if necessary, adjusting the pH of the mixture of the liquid buffer, the local anesthetic, and the heparinoid so that a pH of from about 6.7 to about 8.3 is achieved without precipitation of the local anesthetic. ### Claim 32 (depends on 31) The method of claim 31 wherein the heparinoid is selected from the group consisting of heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, and sodium pentosanpolysulfate. ### Claim 33 (depends on 32) The method of claim 32 wherein the heparinoid is selected from the group consisting of heparin and sodium pentosanpolysulfate. ### Claim 34 (depends on 33) The method of claim 33 wherein the heparinoid is heparin. ### Claim 35 (canceled) ### Claim at position 31 36-37. (canceled) ### Claim 38 (depends on 32) The method of claim 32 wherein the heparinoid is sodium pentosanpolysulfate. ### Claim 39 (depends on 31) The method of claim 31 wherein the local anesthetic is selected from the group consisting of benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, flecainide, mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, and pharmaceutically acceptable derivatives and bioisosteres thereof, and a combination thereof. ### Claim 40 (canceled) ### Claim 41 (depends on 39) The method of claim 39 wherein the local anesthetic is lidocaine. ### Claim 42 (depends on 41) The method of claim 41 wherein the lidocaine is lidocaine hydrochloride. ### Claim 43 (depends on 31) The method of claim 31 wherein the buffer is selected from the group consisting of bicarbonate buffer, Tris (Tris(hydroxymethyl)aminomethane) buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA (N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine (N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphate buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)) buffer, TAPS (N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer; TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, 2-amino-2-methyl-1-propanol buffer, and a combination thereof. ### Claim 44 (canceled) ### Claim 45 (depends on 43) The method of claim 43 wherein the buffer is bicarbonate buffer. ### Claim 46 (depends on 43) The method of claim 43 wherein the buffer is sodium bicarbonate. ### Claim 47 (depends on 43) The method of claim 43 wherein the buffer is Tris buffer. ### Claim 48 (depends on 31) The method of claim 31 wherein the method further comprises the step of adding one or more of: (i) an osmolar component; (ii) a compound that enables persistence of the composition to the surface of the bladder epithelium; (iii) an antibacterial agent; (iv) an antifungal agent; (v) a vasoconstrictor; or (vi) a preservative, subsequent to preparation of a buffered composition including the heparinoid, the local anesthetic, and the buffer. ### Claim 49 (depends on 31) The method of claim 31 wherein the heparinoid and the local anesthetic are provided in forms selected from the group consisting of: (i) both the heparinoid and the local anesthetic are provided in solid form; (ii) both the heparinoid and the local anesthetic are provided in powdered form; (iii) both the heparinoid and the local anesthetic are provided in liquid form; (iv) the heparinoid is provided in solid form and the local anesthetic is provided in liquid form; (v) the heparinoid is provided in powdered form and the local anesthetic is provided in liquid form; (vi) the heparinoid is provided in liquid form and the local anesthetic is provided in solid form; and (vii) the heparinoid is provided in liquid form and the local anesthetic is provided in powdered form. ### Claim at position 44 50-55. (canceled) ### Claim 56 (depends on 31) The method of claim 31 wherein the heparinoid is heparin, the local anesthetic is lidocaine, and the buffer is bicarbonate buffer. ### Claim 57 (depends on 56) The method of claim 56 wherein the heparin is heparin sodium, the local anesthetic is lidocaine hydrochloride, and the bicarbonate buffer is sodium bicarbonate. ### Claim 58 (depends on 29) The method of claim 29 wherein the pH achieved is about 7.4. ### Claim 59 A method for preparing a composition useful for treatment of a lower urinary tract condition by instilling the composition into the urinary bladder, the composition comprising a mixture comprising a heparinoid, a local anesthetic, and a buffer, the method comprising the steps of: (a) providing a heparinoid in liquid form; (b) providing a local anesthetic in liquid form; (c) providing a buffer in liquid form; (d) simultaneously mixing the heparinoid, the local anesthetic, and the buffer, avoiding precipitation of the local anesthetic; and (e) if necessary, adjusting the pH of the mixture of the liquid buffer, the liquid local anesthetic, and the liquid heparinoid so that a pH of from about 6.7 to about 8.3 is achieved without precipitation of the local anesthetic. ### Claim 60 (depends on 59) The method of claim 59 wherein the heparinoid is heparin, the local anesthetic is lidocaine, and the buffer is sodium bicarbonate. ### Claim 61 (depends on 59) The method of claim 59 wherein the pH achieved is about 6.8 to about 7.2 and the quantity of the buffer required is reduced. ### Claim 62 A premixed liquid composition comprising a heparinoid, a local anesthetic, and a buffer that is stable for at least three months without precipitation of the local anesthetic. ### Claim 63 (depends on 62) The composition of claim 62 wherein the composition is prepared by a method comprising the steps of: (a) providing a heparinoid in solid form or liquid form; (b) providing a local anesthetic in solid form or liquid form; (c) adding a liquid buffer to the heparinoid in solid form or liquid form; (d) adding the local anesthetic to the mixture of the liquid buffer and the heparinoid; and (e) if necessary, adjusting the pH of the mixture of the liquid buffer, the local anesthetic, and the heparinoid so that a pH is achieved of from about 6.8 to about 8.3 is achieved without precipitation of the local anesthetic. ### Claim 64 (depends on 62) The composition of claim 62 wherein the composition is prepared by a method comprising the steps of: (a) providing a heparinoid in solid form or liquid form; (b) providing a local anesthetic in solid form or liquid form; (c) mixing the heparinoid in solid form or liquid form and the local anesthetic in solid form or liquid form; (d) adding a liquid buffer to the mixture of the heparinoid and the local anesthetic to form a mixture of liquid buffer, the heparinoid, and the local anesthetic; and (e) if necessary, adjusting the pH of the mixture of the liquid buffer, the local anesthetic, and the heparinoid so that a pH is achieved of from about 6.8 to about 8.3 is achieved without precipitation of the local anesthetic. ### Claim 65 (depends on 62) The composition of claim 62 wherein the composition is prepared by a method comprising the steps of: (a) providing a heparinoid in liquid form; (b) providing a local anesthetic in liquid form; (c) providing a buffer in liquid form; (d) simultaneously mixing the heparinoid, the local anesthetic, and the buffer, avoiding precipitation of the local anesthetic; and (e) if necessary, adjusting the pH of the mixture of the liquid buffer, the liquid local anesthetic, and the liquid heparinoid so that a pH of from about 6.7 to about 8.3 is achieved without precipitation of the local anesthetic. ### Claim 66 (depends on 62) The composition of claim 62 wherein the heparinoid is selected from the group consisting of heparin, chondroitin sulfate, heparan sulfate, hyaluronic acid, keratan sulfate, dermatan sulfate, hyaluronan, and sodium pentosanpolysulfate. ### Claim 67 (depends on 66) The composition of claim 66 wherein the heparinoid is selected from the group consisting of heparin and sodium pentosanpolysulfate. ### Claim 68 (depends on 67) The composition of claim 67 wherein the heparinoid is heparin. ### Claim at position 58 69-71. (canceled) ### Claim 72 (depends on 67) The composition of claim 67 wherein the heparinoid is sodium pentosanpolysulfate. ### Claim 73 (depends on 62) The composition of claim 62 wherein the local anesthetic is selected from the group consisting of benzocaine, lidocaine, tetracaine, bupivacaine, cocaine, etidocaine, flecainide, mepivacaine, pramoxine, prilocaine, procaine, chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine, chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, and pharmaceutically acceptable derivatives and bioisosteres thereof, and a combination thereof. ### Claim 74 (canceled) ### Claim 75 (depends on 73) The composition of claim 73 wherein the local anesthetic is lidocaine. ### Claim 76 (depends on 75) The composition of claim 75 wherein the lidocaine is lidocaine hydrochloride. ### Claim 77 (depends on 63) The composition of claim 63 wherein the buffer is selected from the group consisting of bicarbonate buffer, Tris (Tris(hydroxymethyl)aminomethane) buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES (N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, ACES (2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA (N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine (N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole buffer, glycine buffer, ethanolamine buffer, phosphate buffer, MOPSO (3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)) buffer, TAPS (N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer; TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, 2-amino-2-methyl-1-propanol buffer, and a combination thereof. ### Claim 78 (canceled) ### Claim 79 (depends on 77) The composition of claim 77 wherein the buffer is bicarbonate buffer. ### Claim 80 (depends on 79) The composition of claim 79 wherein the buffer is sodium bicarbonate. ### Claim 81 (depends on 77) The composition of claim 77 wherein the buffer is Tris buffer. ### Claim 82 (depends on 63) The composition of claim 63 wherein the composition further comprises one or more of: (i) an osmolar component; (ii) a compound that enables persistence of the composition to the surface of the bladder epithelium; (iii) an antibacterial agent; (iv) an antifungal agent; (v) a vasoconstrictor; or (vi) a preservative. ### Claim 83 (depends on 63) The composition of claim 63 wherein the heparinoid is heparin, the local anesthetic is lidocaine, and the buffer is bicarbonate buffer. ### Claim 84 (depends on 83) The composition of claim 83 wherein the heparin is heparin sodium, the local anesthetic is lidocaine hydrochloride, and the bicarbonate buffer is sodium bicarbonate. ### Claim at position 72 85-86. (canceled) ### Claim 87 (depends on 63) The composition of claim 63 wherein the pH of the composition is from about 7.0 to about 7.8. ### Claim 88 (depends on 87) The composition of claim 87 wherein the pH of the composition is about 7.4.