# US 2014/0194393 A1 · Tetracycline compositions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0194393 A1 - Document ID: US20140194393A1 - Status: Published application - Kind: A1 - Application number: 14/204,881 - Filed: 2014-03-11 - Published: 2014-07-10 - Earliest claimed: 2010-05-12 - Assignees: Rempex Pharmaceuticals, Inc. - Applicants: Rempex Pharmaceuticals, Inc. - Inventors: David C. Griffith; Serge Boyer; Scott Hecker; Michael N. Dudley - Web page: https://patentgrep.com/patent/US20140194393A1 ## CPC - A61K 31/65: Tetracyclines - 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 - A61P 31/04: Antibacterial agents - 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 The present invention relates to compositions, pharmaceutical compositions, and methods for preparing the same, comprising a tetracycline with improved stability and solubility. Some embodiments include a tetracycline with an excess of a divalent or trivalent cation. ## Claims ### Claim 1 A method of treating or preventing a bacterial infection in a subject, comprising administering a pharmaceutical composition to the subject via an intravenous route, wherein the pharmaceutical composition comprises an aqueous solution of a 7-dimethylamino-tetracycline antibiotic and a divalent or trivalent cation, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than 2:1 and wherein the solution does not comprise a pharmaceutically acceptable oil, has a pH greater than 4 and less than 7. ### Claim 2 (depends on 1) The method of claim 1, wherein the concentration of the 7-dimethylamino-tetracycline antibiotic is at least 1 mg/ml. ### Claim 3 (depends on 1) The method of claim 1, wherein the solution does not comprise polyoxyethylene hydrogenated castor oil. ### Claim 4 (depends on 1) The method of claim 1, wherein the solution does not comprise an antioxidant. ### Claim 5 (depends on 1) The method of claim 1, wherein solution does not comprise a pyridine-containing compound. ### Claim 6 (depends on 1) The method of claim 1, wherein solution does not comprise nicotinamide. ### Claim 7 (depends on 1) The method of claim 1, wherein the solution does not comprise an alcohol. ### Claim 8 (depends on 1) The method of claim 1, wherein the solution does not comprise glycerol. ### Claim 9 (depends on 1) The method of claim 1, wherein the solution does not comprise polyethylene glycol. ### Claim 10 (depends on 1) The method of claim 1, wherein the solution does not comprise gluconate. ### Claim 11 (depends on 1) The method of claim 1, wherein the solution does not comprise a pyrrolidone compound. ### Claim 12 (depends on 1) The method of claim 1, wherein the solution does not comprise a water-miscible local anaesthetic. ### Claim 13 (depends on 1) The method of claim 1, wherein the solution does not comprise procaine. ### Claim 14 (depends on 1) The method of claim 1, wherein the solution does not comprise urea. ### Claim 15 (depends on 1) The method of claim 1, wherein the solution does not comprise lactose. ### Claim 16 (depends on 1) The method of claim 1, wherein the solution does not comprise a dehydrating agent. ### Claim 17 (depends on 1) The method of claim 1, wherein the solution does not comprise a dehydrating agent selected from the group consisting of ethyl acetate, acetic anhydride, absolute ethanol, and mixtures thereof. ### Claim 18 (depends on 1) The method of claim 1, wherein the solution has a pH of less than 6. ### Claim 19 (depends on 1) The method of claim 1, wherein the solution has a pH of less than 5. ### Claim 20 (depends on 1) The method of claim 1, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than 3:1. ### Claim 21 (depends on 1) The method of claim 1, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than or equal to 5:1. ### Claim 22 (depends on 1) The method of claim 1, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is from 5:1 to 10:1. ### Claim 23 (depends on 22) The method of claim 22, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is 5:1. ### Claim 24 (depends on 1) The method of claim 1, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than 8:1. ### Claim 25 (depends on 1) The method of claim 1, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than or equal to 10:1. ### Claim 26 (depends on 1) The method of claim 1, wherein the osmolality of the solution is less than 500 mOsm/kg. ### Claim 27 (depends on 1) The method of claim 1, wherein the osmolality of the solution is less than 400 mOsm/kg. ### Claim 28 (depends on 1) The method of claim 1, wherein the osmolality of the solution is less than 350 mOsm/kg. ### Claim 29 (depends on 1) The method of claim 1, wherein the solution comprises magnesium sulfate. ### Claim 30 (depends on 1) The method of claim 1, wherein the solution comprises magnesium oxide. ### Claim 31 (depends on 1) The method of claim 1, wherein the solution comprises magnesium acetate. ### Claim 32 (depends on 1) The method of claim 1, wherein the solution comprises magnesium chloride. ### Claim 33 (depends on 1) The method of claim 1, wherein the solution comprises a buffer. ### Claim 34 (depends on 33) The method of claim 33, wherein the solution comprises acetate. ### Claim 35 (depends on 1) The method of claim 1, wherein the solution comprises a base. ### Claim 36 (depends on 35) The method of claim 35, wherein the base is NaOH. ### Claim 37 (depends on 1) The method of claim 1, wherein the cation is selected from iron, copper, zinc, manganese, nickel, cobalt, aluminum, calcium, magnesium and gallium. ### Claim 38 (depends on 37) The method of claim 37, wherein the cation is selected from magnesium, calcium, and zinc. ### Claim 39 (depends on 38) The method of claim 38, wherein the cation is magnesium. ### Claim 40 (depends on 1) The method of claim 1, wherein the 7-dimethylamino-tetracycline is selected from minocycline, PTK796, and a glycylcycline. ### Claim 41 (depends on 40) The method of claim 40, wherein the glycylcycline is tigecycline. ### Claim 42 (depends on 41) The method of claim 41, wherein the pharmaceutical composition comprises 5 mg/ml tigecycline, MgSO4, and NaOH, wherein the Mg to tigecycline molar ratio is 5:1, and the pH is greater than 5.5 and less than 6.5. ### Claim 43 (depends on 41) The method of claim 41, wherein the pharmaceutical composition comprises 5 mg/ml tigecycline, MgSO4, and NaOH, wherein the Mg to tigecycline molar ratio is 12:1, and the pH is greater than 5.5 and less than 6.5. ### Claim 44 (depends on 41) The method of claim 41, wherein the pharmaceutical composition comprises 5 mg/ml tigecycline, MgCl2, and NaOH, wherein the Mg to tigecycline molar ratio is 5:1, and the pH is greater than 5.5 and less than 6.5. ### Claim 45 (depends on 41) The method of claim 41, wherein the pharmaceutical composition comprises 5 mg/ml tigecycline, MgCl2, and NaOH, wherein the Mg to tigecycline molar ratio is 12:1, and the pH is greater than 5.5 and less than 6.5. ### Claim 46 (depends on 41) The method of claim 41, wherein the pharmaceutical composition comprises 5 mg/ml tigecycline, CaSO4, and NaOH, wherein the Ca to tigecycline molar ratio is 5:1, and the pH is greater than 5.5 and less than 6.5. ### Claim 47 (depends on 41) The method of claim 41, wherein the pharmaceutical composition comprises 5 mg/ml tigecycline, CaSO4, and NaOH, wherein the Ca to tigecycline molar ratio is 12:1, and the pH is greater than 5.5 and less than 6.5. ### Claim 48 (depends on 41) The method of claim 41, wherein the pharmaceutical composition comprises 5 mg/ml tigecycline, CaCl2, and NaOH, wherein the Ca to tigecycline molar ratio is 5:1, and the pH is greater than 5.5 and less than 6.5. ### Claim 49 (depends on 41) The method of claim 41, wherein the pharmaceutical composition comprises 5 mg/ml tigecycline, CaCl2, and NaOH, wherein the Ca to tigecycline molar ratio is 12:1, and the pH is greater than 5.5 and less than 6.5. ### Claim 50 (depends on 1) The method of claim 1, wherein the 7-dimethylamino-tetracycline is PTK796. ### Claim 51 (depends on 1) The method of claim 1, wherein the 7-dimethylamino-tetracycline is minocycline. ### Claim 52 (depends on 51) The method of claim 51, wherein the concentration of minocycline is at least 5 mg/ml. ### Claim 53 (depends on 51) The method of claim 51, wherein the concentration of minocycline is at least 10 mg/ml. ### Claim 54 (depends on 51) The method of claim 51, wherein the pharmaceutical composition comprises 10 mg/ml minocycline, MgCl2, and NaOH, wherein the Mg to minocycline molar ratio is 5:1, and the pH is greater than 4.5 and less than 5.5. ### Claim 55 (depends on 51) The method of claim 51, wherein the pharmaceutical composition comprises 10 mg/ml minocycline, MgSO4, and sodium acetate, wherein the Mg to minocycline molar ratio is 5:1, the pH is greater than 4.5 and less than 5.5, and the osmolality is greater than 275 mOsm/kg and less than 375 mOsm/kg. ### Claim 56 (depends on 51) The method of claim 51, wherein the pharmaceutical composition comprises 10 mg/ml minocycline and Mg(C2H3O2)2, wherein the Mg to minocycline molar ratio is 5:1, and the pH is greater than 4.5 and less than 5.5. ### Claim 57 (depends on 51) The method of claim 51, wherein the pharmaceutical composition comprises 10 mg/ml minocycline, MgSO4, and NaOH, wherein the Mg to minocycline molar ratio is 5:1, the pH is greater than 4.5 and less than 5.5, and the osmolality is greater than 150 mOsm/kg and less than 250 mOsm/kg. ### Claim 58 A method of treating or preventing a bacterial infection in a subject, comprising administering a pharmaceutical composition to the subject via an intravenous route, wherein the pharmaceutical composition is prepared by a method comprising dissolving a water-soluble solid composition in water to form a solution, wherein the water-soluble composition comprises a 7-dimethylamino-tetracycline antibiotic or a salt thereof and a salt comprising a divalent or trivalent cation, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline is greater than 1:1 and wherein upon dissolution of the solid composition in water to make a solution having a pH greater than 4 and less than 7 is formed. ### Claim 59 (depends on 58) The method of claim 58, wherein the solution has a concentration of 7-dimethylamino-tetracycline antibiotic of at least 1 mg/ml. ### Claim 60 (depends on 58) The method of claim 58, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than 2:1. ### Claim 61 (depends on 58) The method of claim 58, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than 3:1. ### Claim 62 (depends on 61) The method of claim 61, wherein the divalent or trivalent cation is a divalent cation. ### Claim 63 (depends on 62) The method of claim 62, wherein the divalent cation is selected from magnesium, calcium, and zinc. ### Claim 64 (depends on 63) The method of claim 63, wherein the 7-dimethylamino-tetracycline is minocycline. ### Claim 65 (depends on 58) The method of claim 58, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than or equal to 5:1. ### Claim 66 (depends on 58) The method of claim 58, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is at greater than 8:1. ### Claim 67 (depends on 58) The method of claim 58, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline antibiotic is greater than or equal to 10:1. ### Claim 68 (depends on 58) The method of claim 58, wherein the water-soluble solid composition is in the form of a lyophile. ### Claim 69 (depends on 58) The method of claim 58, wherein the salt is magnesium sulfate. ### Claim 70 (depends on 58) The method of claim 58, wherein the salt is calcium chloride. ### Claim 71 (depends on 58) The method of claim 58, wherein the composition comprises sodium acetate. ### Claim 72 (depends on 58) The method of claim 58, wherein the composition comprises NaOH. ### Claim 73 (depends on 58) The method of claim 58, wherein the salt is selected from magnesium chloride, magnesium bromide, magnesium sulfate, calcium chloride, calcium bromide, calcium sulfate, zinc chloride, gallium chloride, magnesium malate, magnesium citrate, magnesium acetate, calcium citrate, zinc acetate, and zinc citrate. ### Claim 74 (depends on 58) The method of claim 58, wherein the composition does not comprise an antioxidant. ### Claim 75 (depends on 58) The method of claim 58, wherein composition does not comprise a pyridine-containing compound. ### Claim 76 (depends on 58) The method of claim 58, wherein composition does not comprise nicotinamide. ### Claim 77 (depends on 58) The method of claim 58, wherein the composition does not comprise gluconate. ### Claim 78 (depends on 58) The method of claim 58, wherein the 7-dimethylamino-tetracycline is selected from minocycline, PTK796, and a glycylcycline. ### Claim 79 (depends on 78) The method of claim 78, wherein the glycylcycline is tigecycline. ### Claim 80 (depends on 58) The method of claim 58, wherein the 7-dimethylamino-tetracycline is minocycline. ### Claim 81 (depends on 58) The method of claim 58, wherein the 7-dimethylamino-tetracycline is PTK796. ### Claim 82 (depends on 58) The method of claim 58, wherein the intravenous administration includes administering less than 200 ml of the composition. ### Claim 83 (depends on 58) The method of claim 58, wherein the intravenous administration includes administering the composition in less than 60 minutes. ### Claim 84 A method of treating or preventing a bacterial infection in a subject, comprising administering a pharmaceutical composition to the subject via an intravenous route, wherein the pharmaceutical composition is prepared by a method comprising dissolving a 7-dimethylamino-tetracycline in a solution comprising a divalent or trivalent cation, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline in the solution is greater than 1:1 and wherein after dissolving the 7-dimethylamino-tetracycline, the solution has a pH greater than 4 and less than 7. ### Claim 85 (depends on 84) The method of claim 84, wherein the solution has a concentration of 7-dimethylamino-tetracycline antibiotic of at least 1 mg/ml. ### Claim 86 (depends on 84) The method of claim 84, wherein the intravenous administration includes administering less than 200 ml of the composition. ### Claim 87 (depends on 84) The method of claim 84, wherein the intravenous administration includes administering the composition in less than 60 minutes. ### Claim 88 A method of treating or preventing a bacterial infection in a subject, comprising administering a pharmaceutical composition to the subject via an intravenous route, wherein the pharmaceutical composition is prepared by a method comprising: dissolving a 7-dimethylamino-tetracycline in a solution comprising a divalent or trivalent cation, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracycline in the solution is greater than 1:1; adjusting the pH of the solution to be greater than 4 and less than 7; and lyophilizing the composition. ### Claim 89 (depends on 88) The method of claim 88, wherein the intravenous administration includes administering less than 200 ml of the composition. ### Claim 90 (depends on 88) The method of claim 88, wherein the intravenous administration includes administering the composition in less than 60 minutes. ### Claim 91 (depends on 58) The method of claim 58, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is from 5:1 to 10:1. ### Claim 92 (depends on 91) The method of claim 91, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is 5:1. ### Claim 93 (depends on 84) The method of claim 84, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is from 5:1 to 10:1. ### Claim 94 (depends on 93) The method of claim 93, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is 5:1. ### Claim 95 (depends on 88) The method of claim 88, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is from 5:1 to 10:1. ### Claim 96 (depends on 95) The method of claim 95, wherein the molar ratio of divalent or trivalent cation to 7-dimethylamino-tetracylcine antibiotic is 5:1.