# US 6,719,990 B2 · Non-aqueous injectable formulations for extended release of somatotropin > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 6,719,990 B2 - Document ID: US6719990B2 - Status: Granted - Kind: B2 - Application number: 09/789,392 - Filed: 2001-02-21 - Published: 2001-11-29 - Granted: 2004-04-13 - Earliest claimed: 2000-02-24 - Assignees: Monsanto Technology LLC - Inventors: Kanaiyalal R. Patel; Yunhua N. Jeng - Web page: https://patentgrep.com/patent/US6719990B2 ## CPC - A61K 38/27: Growth hormone [GH], i.e. somatotropin - A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)} - A61K 47/02: Inorganic compounds - A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids - A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame} - A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin - A61K 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14) - 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 The present invention provides compositions which allow for the extended release and enhanced bioavailability of biologically-active polypeptides following parenteral delivery to an animal. More particularly, it concerns compositions comprising biologically-active somatotropin formulated for extended release, methods of preparing these compositions, and methods of using the same. These compositions comprise somatotropin, a bioavailability-enhancing constituent (BEC), and a substantially non-aqueous, hydrophobic excipient. The BEC may comprise (i) amino acids or amino acid derivatives, such as histidine-HCl; (ii) hydroxamate derivatives, such as histidine hydroxamate or suberohydroxamic acid; (iii) non-reducing carbohydrates, such as trehalose or trehalose octaacetate; (iv) oxo-acid salts, such as a mixture of monobasic and dibasic sodium phosphate; or (v) a mixture of two or more compounds from within the foregoing classes (i)-(iv). ## Claims ### Claim 1 A composition of matter, comprising: somatotropin and a constituent that enhances bioavailability of the somatotropin in an animal to which the composition of matter has been administered parenterally; wherein the bioavailability enhancing constituent is selected from the group consisting of one or a mixture of both of the following: a) one or more non-reducing carbohydrate(s) and b) one or more oxo-acid salt(s); wherein the somatotropin and the bioavailability enhancing constituent are suspended in a substantially non-aqueous hydrophobic carrier, wherein the somatotropin is present at from about 10 to about 50% by weight of the composition, wherein the bioavailability enhancing constituent is present at from about 1% to about 20% by weight of the composition, and wherein the composition is fluidly injectable at 25° C. ### Claim 2 (depends on 1) The composition of matter of claim 1 wherein the somatotropin is human, equine, bovine, or porcine. ### Claim 3 (depends on 1) The composition of matter of claim 1, wherein the bioavailability enhancing constituent is non-reducing carbohydrate selected from the group consisting of: at least one polyol, at least one carbohydrate ester, and mixtures thereof. ### Claim 4 (depends on 1) The composition of matter of claim 1, wherein the bioavailability enhancing constituent comprises non-reducing carbohydrate; wherein the non-reducing carbohydrate is polyol present at from about 5% to about 20% by weight of the composition. ### Claim 5 (depends on 1) The composition of claim 1, wherein the bioavailability enhancing constituent comprises at least one oxo-acid salt. ### Claim 6 (depends on 5) The composition of claim 5, wherein the oxo-acid salt is selected from one or a mixture of two or more of the following: monobasic sodium phosphate, dibasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, monobasic calcium phosphate, dibasic calcium phosphate, sodium nitrate, dibasic sodium sulfate, and mixtures thereof. ### Claim 7 (depends on 1) The composition of matter of claim 1, wherein the hydrophobic carrier comprises an oil or a fat. ### Claim 8 (depends on 1) The composition of matter of claim 1, wherein the somatotropin is a zinc salt of bovine somatotropin present at from about 32% to about 42% by weight; wherein, the bioavailability enhancing constituent is a mixture of monobasic sodium phosphate and dibasic sodium phosphate salts, wherein the molar ratio of monobasic sodium phosphate to dibasic sodium phosphate is about 6 to 4, present at from about 2% to about 10% by weight. ### Claim 9 A method of making a composition of matter, comprising: somatotropin and a bioavailability enhancing constituent; wherein the bioavailability enhancing constituent is selected from the group consisting of one or a mixture of both of the following: a) one or more non-reducing carbohydrate(s) and b) one or more oxo-acid salt(s); wherein the somatotropin and the bioavailability enhancing constituent are suspended in a substantially non-aqueous hydrophobic carrier, wherein the somatotropin is present at from about 10 to about 50% by weight of the composition, wherein the bioavailability enhancing constituent is present at from about 1% to about 20% by weight of the composition, and wherein the composition is fluidly injectable at 25° C.; the method comprising: providing the somatotropin as a lyophilized dry solid, the bioavailability enhancing constituent, as a dry solid, and the hydrophobic carrier; mixing the bioavailability enhancing constituent with the hydrophobic carrier, to produce a first suspension; and, mixing the somatotropin with the first suspension to produce a second suspension. ### Claim 10 A composition of matter, comprising: somatotropin and a bioavailability enhancing constituent; wherein the bioavailability enhancing constituent comprises one or more non-reducing carbohydrates; wherein the somatotropin and the bioavailability enhancing constituent are suspended in a substantially non-aqueous hydrophobic carrier, wherein the somatotropin is present at from about 10 to about 50% by weight of the composition, wherein the bioavailability enhancing constituent is present at from about 1% to about 20% by weight of the composition, and wherein the composition is fluidly injectable at 25° C. ### Claim 11 A composition of matter, comprising: somatotropin and a bioavailability enhancing constituent; wherein the bioavailability enhancing constituent comprises one or more oxo-acid salts; wherein the somatotropin and the bioavailability enhancing constituent are suspended in a substantially non-aqueous hydrophobic carrier, wherein the somatotropin is present at from about 10 to about 50% by weight of the composition, wherein the bioavailability enhancing constituent is present at from about 1% to about 20% by weight of the composition, and wherein the composition is fluidly injectable at 25° C.