# US 5,346,703 A · Body cavity drug delivery with thermo-irreversible polyoxyalkylene and ionic polysaccharide gels > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,346,703 A - Document ID: US5346703A - Status: Granted - Kind: A - Application number: 07/939,475 - Filed: 1992-08-31 - Granted: 1994-09-13 - Earliest claimed: 1990-08-07 - Assignees: Mediventures, Inc. - Inventors: Tacey X. Viegas; Lorraine E. Reeve; Raymond L. Henry - Web page: https://patentgrep.com/patent/US5346703A ## CPC - A61K 9/0048: {Eye, e.g. artificial tears} - A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)} - A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers - A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids - A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin - 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) ## Abstract Balanced pH, thermo-irreversible gels are ideal vehicles for drug delivery to a body cavity of a mammal. The gels contain a mixture of a polyoxyalkylene block copolymer or polyether together with an ionic polysaccharide which is thermo-irreversibly gelled in the presence of a counter-ion. ## Claims ### Claim 1 A pharamaceutical aqueous gel composition, said composition comprising (1) about 0.2% to about 2.5% by weight of an ionic polysaccharide; (2) about 10% to about 50% by weight of a polyoxyalkylene block copolymer of general formula Y[(A).sub.n - - - E - - - H].sub.x where A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of less than 0.5, x is at least 2, Y is derived from water or an organic compound containing x reactive hydrogen atoms, E is a polyoxyethylene moiety constituting at least 60 percent by weight of the polyoxyalkylene block copolymer, n has a value such that the minimum molecular weight of A is between about 500 and about 900, as determined by the hydroxyl number of an intermediate of general formula Y [(A).sub.n - - - H].sub.x and the average molecular weight of the polyoxyalkylene block copolymer is between about 5000 and about 50,000; (3) about 0.01% to about 60% by weight of a pharmacologically effective amount of a drug selected from the group consisting of antibacterials, antihistamines, decongestants, antiinflammatories, antiparasitics, antivirals, local anesthetics, antifungals, analgesics, antiarthritics, antiastrunatics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antieoplastics, antipsychotics, antihypertensives, spermicidals, and muscle relaxants; (4) a pharmaceutically acceptable buffer sufficient to maintain the p.sub.H of the aqueous gel composition at a desired level; and (5) optionally, a latent form of a counter-ion capable of cross-linking the ionic polysaccharide, wherein the aqueous gel composition is a liquid at room temperature or below and a gel at mammalian body temperature. ### Claim 2 (depends on 1) The composition of claim 1, wherein the polyoxyalkylene block copolymer is prepared using a water soluble organic initiator Y having 1 to about 6 carbon atoms and wherein the pH of the aqueous gel composition is maintained at about 7.4 and the osmolality of the aqueous gel composition at mammalian body temperature is about 290 mOsm/kg. ### Claim 3 (depends on 2) The composition of claim 2, wherein the polyoxyalkylene moiety is derived from an alkylene oxide selected from the group consisting of butylene oxide, propylene oxide, and mixtures thereof and Y is derived from an organic compound selected from the group consisting of propylene glycol, glycerin, pentaerythritol, trimethylpropane, ethylenediamine, and mixtures thereof. ### Claim 4 (depends on 3) The composition of claim 3, wherein the polyoxyalkylene block copolymer is a polyoxyethylene-polyoxypropylene block copolymer wherein the polyoxyethylene moiety constitutes at least about 70 percent by weight of the polyoxyalkylene block copolymer, wherein the average molecular weight of A is at least 1200, and wherein the molecular weight of the polyoxyalkylene block copolymer is at least about 5,000. ### Claim 5 (depends on 4) The composition of claim 4, wherein the intermediate is prepared by initiation with propylene glycol and has a molecular weight of at least 1500. ### Claim 6 (depends on 5) The composition of claim 5, wherein the polyoxyalkylene block copolymer has: (1) general formula HO(C.sub.2 H.sub.4 O).sub.b (C.sub.4 H.sub.8 O).sub.8 (C.sub.2 H.sub.4 O).sub.b H wherein a and b are integers such that the hydrophobe base represented by (C.sub.4 H.sub.8 O).sub.a has a molecular weight of at least about 500 as determined by hydroxyl number, the polyoxyethylene chain constitutes at least about 70 percent by weight of the polyoxyalkylene block copolymer, and the polyoxyalkylene block copolymer has an average molecular weight of at least 5,000; or (2) general formula HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.8 (C.sub.2 H.sub.4 O).sub.b H wherein a and b are integers such that the hydrophobe base represented by (C.sub.3 H.sub.6).sub.a has a molecular weight of at least about 900 as determined by hydroxyl number, the polyoxyethylene chain constitutes at least about 70 percent by weight of the polyoxyalkylene block copolymer, and the polyoxyalkylene block copolymer has an average molecular weight of at least 5,000; or (3) general formula ##STR3## wherein a and b are integers such that the polyoxyalkylene block copolymer has a hydrophobe molecular weight of at least about 1500, a hydrophobe content of at least about 70 percent by weight, and an average molecular weight of at least 5,000. ### Claim 7 (depends on 6) The composition of claim 6, wherein the polyoxyalkylene block copolymer is of average formula ##STR4## and wherein the polyoxyalkylene block copolymer constitutes about 10 to about 40 percent by weight of the composition. ### Claim 8 (depends on 6) The composition of claim 6, wherein the polyoxyalkylene block copolymer constitutes about 15 to about 30 percent by weight of the composition, the optional latent form of the counter-ion is present as a microencapsulated component or as an ion-exchange resin, the counter-ion is selected from the group consisting of calcium, strontium, and aluminum, and the ionic polysachharide is an ammonium alginate, a metal alginate, or mixtures thereof wherein said counter-ion and said alginate being present at a molar ratio between about 1:1 to about 10:1. ### Claim 9 (depends on 6) The composition of claim 6, wherein the polyoxyalkylene block copolymer constitutes abut 15 to about 30 percent by weight of the composition, the optional latent form of the counter-ion is present es a microencapsulated components or as an ion-exchange resin, the counter-ion is selected from the group consisting of metal phosphates, metaphosphates, pyrophosphates, and tripolyphosphates, and the ionic polysaccharide is chitosan wherein said counter-ion and said chitosan being present at a molar ratio between about 1:1 about 10:1. ### Claim 10 A hyperosomotic, iso-osmotic, or hypoosmotic aqueous gel composition comprising (1) about 0.2% to about 2.5% by weight of an ionic polysaccharide; (2) about 10% to about 50% by weight of a polyoxyalkylene block copolymer of general formula Y[(A).sub.n - - - E - - - H].sub.x where A is a polyoxyalkylene moiety having an oxygen/carbon atom ratio of less than 0.5, x is at least 2, Y is derived from water or an organic compound containing x reactive hydrogen atoms, E is a polyoxyethylene moiety constituting at least 60 percent by weight of the polyoxyalkylene block copolymer, n has a value such that the minimum molecular weight of A is between about 500 and about 900, as determined by the hydroxyl number of an intermediate of general formula Y[(A).sub.n - - - H].sub.x and the average molecular weight of the polyoxyalkylene block copolymer is between about 5000 and about 50,000; and (3) optionally, a latent form of a counter-ion capable of cross-linking the ionic polysaccharide, wherein the aqueous gel composition is a liquid at room temperature or below and a gel at mammalian body temperature. ### Claim 11 (depends on 10) The composition of claim 10, wherein the polyoxyalkylene block copolymer is prepared using a water soluble organic initiator Y having 1 to about 6 carbon atoms and wherein the pH of the composition is maintained at about 7.4 and the osmolality of the composition at mammalian body temperature is about 290 mOsm/kg. ### Claim 12 (depends on 11) The composition of claim 11, wherein the polyoxyalkylene moiety is derived from an alkylene oxide selected from the group consisting of butylene oxide, propylene oxide, and mixtures thereof and Y is derived from an organic compound selected from the group consisting of propylene glycol, glycerin, pentaerythritol, trimethylpropane, ethylenediamine, and mixtures thereof. ### Claim 13 (depends on 12) The composition of claim 12, wherein the polyoxyalkylene block copolymer is a polyoxyethylene-polyoxypropylene block copolymer wherein the polyoxyethylene moiety constitutes at least about 70 percent by weight, wherein the average molecular weight of A is at least 1200, and wherein the molecular weight of the polyoxyalkylene block copolymer is at least about 5,000. ### Claim 14 (depends on 13) The composition of claim 13, wherein the intermediate is prepared by initiation with propylene glycol and has a molecular weight of at least 1500. ### Claim 15 (depends on 14) The composition of claim 14, wherein the polyoxyalkylene block copolymer has: (1) general formula HO(C.sub.2 H.sub.4 O).sub.b (C.sub.4 H.sub.8 O).sub.8 (C.sub.2 H.sub.4 O).sub.b H wherein a and b are integers such that the hydrophobe base represented by (C.sub.4 H.sub.8 O).sub.8 has a molecular weight of at least about 500 as determined by hydroxyl number, the polyoxyethylene chain constitutes at least about 70 percent by weight of the polyoxyalkylene block copolymer, and the polyoxyalkylene block copolymer has an average molecular weight of at least 5,000; or (2) general formula HO(C.sub.2 H.sub.4 O).sub.b (C.sub.3 H.sub.6 O).sub.8 (C.sub.2 H.sub.4 O).sub.b H wherein a and b are integers such that the hydrophobe base represented by (C.sub.3 H.sub.6 O).sub.8 has a molecular weight of at least about 900 as determined by hydroxyl number, the polyoxyethylene chain constitutes at least about 70 percent by weight of the polyoxyalkylene block copolymer, and the polyoxyalkylene block copolymer has an average molecular weight of at least 5,000; or (3) general formula ##STR5## wherein a and b are integers such that the polyoxyalkylene block copolymer has a hydrophobe molecular weight of at least about 1500, a hydrophobe content of at least about 70 percent by weight, and an average molecular weight of at least 5,000. ### Claim 16 (depends on 15) The composition of claim 15, wherein the polyoxyalkylene block copolymer is of average formula ##STR6## and wherein the polyoxyalkylene block copolymer constitutes about 10 to about 40 percent by weight of the composition. ### Claim 17 (depends on 15) The composition of claim 15, wherein the polyoxyalkylene block copolymer constitutes about 15 to about 30 percent by weight of the composition, the optional latent form of tile counter-ion is present as a microencapsulated component or as an ion-exchange resin, the counter-ion is selected from the group consisting of calcium, strontium, and aluminum, and the ionic polysaccharide is an ammonium alginate, a metal alginate, or mixtures thereof wherein said counter-ion and said alginate being present at a molar ratio between about 1:1 to about 10:1. ### Claim 18 (depends on 15) The composition of claim 15, wherein the polyoxyalkylene block copolymer constitutes about 15 to about 30 percent by weight of the composition, the optional latent form of the counter-ion is present as a microencapsulated component or as an ion-exchange resin, the counter-ion is selected from the group consisting of metal phosphates, pyrophosphates, and tripolyphosphates, and the ionic polysaccharide is chitosan wherein said counter-ion and said chitosan being present at a molar ratio between about 1:1 to about 10:1. ### Claim 19 A hyperosmottc, iso-osmotic, or hypoosmotic aqueous gel composition having a desired osmolality and pH, said composition comprising (1) about 0,2% to about 2.5% by weight of an ionic polysaccharide; (2) about 0.1% to about ! 0% by weight of a combination of a surfactant and a polyoxyalkylene polyether, wherein sais polyether having a molecular weight of about 10,000 to about 100,000 which is selected from the group consisting of (A) a polyoxalkylene polyether prepared by reacting ethylene oxide and at least one lower alkylene oxide having 3 to 4 carbon atoms with at least one active hydrogen-containing compound having from 3 to 10 carbon atoms and from 3 to 6 active hydrogens to prepare a heretic or block copolymer intermediate and further reacting the copolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to about 45 aliphatic carbon atoms, wherein the alpha-olefin oxide is present in the amount of about 0.3 to about 10 percent by weight based on the total weight of the polyether; and (B) a polyoxalkylene polyether prepared by reacting ethylene oxide with at least one active hydrogen-containing compound having from 2 to 10 carbon atoms and from 2 to 6 active hydrogens to prepare a homopolymer intermediate and further reacting the homopolymer intermediate with at least one alpha-olefin oxide having an average carbon chain length of about 20 to 45 aliphatic carbon atoms, wherein the alpha-olefin oxide is present in the amount of about 0.3 to 10 percent by weight based on the total weight of the polyether; and (3) optionally, a latent form of a counter-ion capable of cross-linking the ionic polysaccharide. ### Claim 20 (depends on 19) A composition as defined in claim 19, wherein the polyether is polyether (A) and the pH of the composition is maintained at about 7.4 and the osmolality of the composition at mammalian body temperature is about 290 mOsm/kg. ### Claim 21 (depends on 19) A composition as defined in claim 19, wherein the polyether is polyether (B) and the pH of the composition is maintained at about 7.4 and the osmolality of the composition at mammalian body temperature is about 290 mOsm/kg. ### Claim 22 (depends on 19) The composition as defined in claim 19, wherein the optional latent form of the counter-ion is present as a microencapsulated component or as an ion-exchange resin, the counter-ion is selected from the group consisting of calcium, strontium, and aluminum, and the ionic polysaccharide is an ammonium alginate, a metal alginate, or mixtures thereof wherein said counter-ion and said alginate being present at a molar ratio between about 1:1 to about 10:1. ### Claim 23 (depends on 19) The composition as defined in claim 19, wherein the optional latent form of the counter-ion is present as a microencapsulated components or as an ion-exchange resin, the counter-ion is selected from the group consisting of metal phosphates, metaphosphates, pyrophosphates, and tripolyphosphates, and the ionic polysaccharide is chitosan wherein said counter-ion and said chitosan being present at a molar ratio between about 1:1 to about 10:1. ### Claim 24 (depends on 19) A composition as defined in claim 19, wherein said composition further contains: (1) a pharmacologically effective amount of a drug selected from the group consisting of antibacterials, antihistamines, decongestants, anti-inflammatories, antiparasitics, antivirals, local anesthetics, antifungals, trichomonocidal, analgesics, antiarthritics, antiasthmatics, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antineoplastics, antipsychotics, antihypertensives, spermicidals, and muscle relaxants; and (2) a pharmaceutically acceptable buffer sufficient to maintain the pH of the aqueous gel composition at the desired level. ### Claim 25 (depends on 24) A composition as defined in claim 24, wherein the polyether is polyether (A) and the pH of the composition is maintained at about 7.4 and the osmolality of the composition at mammalian body temperature is about 290 mOsm/kg. ### Claim 26 (depends on 24) A composition as defined in claim 24, wherein the polyether is polyether (B) and the pH of the composition is maintained at about 7.4 and the osmolality of the composition at mammalian body temperature is about 290 mOsm/kg. ### Claim 27 (depends on 24) The composition as defined in claim 24, wherein the optional latent form of the counter-ion is present as a microencapsulated component or as an ion-exchange resin, the counter-ion is selected from the group consisting of calcium, strontium, and aluminum, and the ionic polysaccharide is an ammnonium alginate, a metal alginate, or mixtures thereof wherein said counter-ion and said alginate being present at a molar ratio between about 1:1 to about 10:1. ### Claim 28 (depends on 24) The composition as defined in claim 24, wherein the optional latent form of the counter-ion is present as a microencapsulated components or as an ion-exchange resin, the counter-ion is selected from the group consisting of metal phosphates, metaphosphates, pyrophosphates, and tripolyphosphates, and the ionic polysaccharide is chitosan wherein said counter-ion and said chitosan being present at a molar ratio between about 1:1 to about 10:1.