# US 2008/0188403 A1 · Parenteral Combination Therapy For Infective Conditions With Drug Resistant Bacterium > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2008/0188403 A1 - Document ID: US20080188403A1 - Status: Published application - Kind: A1 - Application number: 11/816,179 - Filed: 2006-02-08 - Published: 2008-08-07 - Earliest claimed: 2005-02-14 - Assignees: Venus Remedies Limited - Inventors: Manu Chaudhary - Web page: https://patentgrep.com/patent/US20080188403A1 ## CPC - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61K 31/546: containing further heterocyclic rings, e.g. cephalothin - A61P 31/04: Antibacterial agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - 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 - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## Abstract The invention describes a pharmaceutical composition to combat multiple-drug-resistant bacteria in non-ocular infective conditions. Compositions comprising glycopeptides, in particular vancomycin, and cephalosporins, in particular ceftriaxone, are disclosed. Such compositions are found to be useful for parenteral administration for hospitalized patients with serious infections. Specifically, this invention also discloses a pharmaceutical composition further including an excipient such as CVMC agent and is available in dry powder form for reconstitution before injection with a suitable solvent. The pharmaceutical compositions of this invention have been found normally to enhance resistance to precipitation in solutions to be administered parenterally. The invention also gives details of the dosage forms stored in sealed containers to be reconstituted before use. The invention further provides a process to manufacture these compositions and also a method of treating a subject having non-ocular infective conditions due to multi drug resistant bacterium. ## Claims ### Claim 1 A parenteral combination therapy for non-ocular infective conditions with drug resistant bacterium, comprising a pharmaceutical composition, comprising: a. an antibacterially effective amount of a first antibacterial agent, preferably a glycopeptide, acting as a first active ingredient, and b. an antibacterially effective amount of a second antibacterial, preferably a cephalosporin, acting as a second active ingredient, wherein said first and said second antibacterial agents are present in predetermined weight ratios. ### Claim 2 (depends on 1) A pharmaceutical composition as claimed in claim 1, further comprising: a. a stable pharmaceutically acceptable excipient working as a chemical vector to mediate the compatibility of said first antibacterial agent and said second antibacterial agent for rendering stability to said composition, b. a suitable pharmaceutically acceptable sterile solvent vehicle with or without an additional excipient or a neutralising agent, said vehicle having solubilised and stabilised therein said first and second antibacterial agents in an antibacterially effective amount, said solvent vehicle being preferably aqueous based, and c. at least one excipient selected from the group comprising diluents, antioxidants, preservatives, stabilizers, thickening agents, suspending agents, dispersing agents, solubilization agents, isotonic agents, buffering agents, wetting agents, lubricants, emulsifiers, salts for influencing osmotic pressure, coloring agents, alcohols, other surfactants and conventional pharmaceutical additives. ### Claim 3 (depends on 1, 2) A pharmaceutical composition as claimed in any of claims 1 and 2, wherein said first antibacterial agent is selected from a group comprising glycopeptides such as vancomycin, avoparcin, ramoplanin, teicoplanin, and daptomycin and the like. ### Claim 4 (depends on 1, 2, 3) A pharmaceutical composition as claimed in any of claims 1 to 3, wherein said second antibacterial agent is selected form a group comprising beta-lactam antibacterials such as natural and synthetic penicillin type agents including penam penicillins (such as benzyl penicillin, phenoxymethyl penicillin, coxacillin, nafcillin, methicillin, oxacillin, amoxycillin, temocillin, ticarcillin and the like), penicillinase-stable penicillins, acylamino and carboxypenicillins (such as piperacillin, aziocillin, meziocillin, carbenicillin, temocillin, ticarcillin and the like), and broader spectrum penicillins (such as streptomycin, neomycin, framycetin, gentamicin, apramycin, amikacin, spectinomycin, amoxycillin, ampicillin and the like), cephalosporins (such as ceftriaxone, cefepime, ceftazidime, cefotaxime, cefuroxime and cefaclor). ### Claim 5 (depends on 1, 2, 3, 4) A pharmaceutical composition as claimed in any of claims 1 to 4 wherein said first antibacterial agent is a glycopeptide selected from the group consisting of avoparcin, ramoplanin, vancomycin, teicoplanin, daptomycin, and preferably vancomycin or a pharmaceutically acceptable salt thereof. ### Claim 6 (depends on 1, 2, 3, 4, 5) A pharmaceutical composition as claimed in any of claims 1 to 5 wherein said pharmaceutically acceptable salt of said vancomycin is vancomycin hydrochloride. ### Claim 7 (depends on 1, 2, 3, 5) A pharmaceutical composition as claimed in any of claims 1, 2, 3, 5, and 6, wherein said first antibacterial agent is present in said composition at a concentration in the range from about 1 mg/ml to about 100 mg/ml, preferably in the range from about 5 mg/ml to about 75 mg/ml, and more preferably in the range of about 10 mg/ml to about 50 mg/ml. ### Claim 8 (depends on 1, 2, 4) A pharmaceutical composition as claimed in any of claims 1, 2 and 4 wherein said second antibacterial agent is a cephalosporin and is elected from a group of cephazoline, cefuroxime, cefotaxime, cefpirome, cefepime, ceftriaxone, ceftazidime, and cefoperazone. ### Claim 9 (depends on 1, 2, 4) A pharmaceutical composition as claimed in any of claims 1, 2, 4, and 8, wherein said second second antibacterial agent is ceftriaxone or a pharmaceutically acceptable salt thereof. ### Claim 10 (depends on 9) A pharmaceutical composition as claimed in claim 9 wherein said pharmaceutically acceptable salt of said ceftriaxone is ceftriaxone sodium. ### Claim 11 (depends on 1, 2, 4, 8, 9) A pharmaceutical composition as claimed in any of claims 1, 2, 4, 8, 9, and 10 wherein said second antibacterial agent is present in said composition at a concentration in the range from about 1 mg/ml to about 200 mg/ml, preferably in the range from about 5 mg/ml to about 150 mg/ml, and more preferably in the range from about 10 mg/ml to about 100 mg/ml. ### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11) A pharmaceutical composition as claimed in any of claims 1 to 11 wherein said predetermined weight ratio of said first antibacterial agent to said second antibacterial agent is in the range from about 1:4 to about 4:1 respectively, probably in the range from about 1:3 to about 3:1 respectively, more preferably in the range from about 1:2 to about 2:1 respectively. ### Claim 13 (depends on 2) A pharmaceutical composition as claimed in claim 2, wherein when making said suitable solvent vehicle, a neutralising agent is optionally mixed with a desired quantity of water for injection and aminocarboxylic acid chelating agent such as ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetriaceti-c acid (HEDTA), nitrilotriacetic acid (NTA) and neutralized with sodium bicarbonate or L-arginine or other suitable agents, to bring the concentration of the solution within the preferred range of about 10 to about 100 mg/ml, more preferably within the range of about 20 to about 90 mg/ml, and most preferably within the range of about 40 to about 80 mg/ml or any combination or sub combination of ranges therein. ### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13) A pharmaceutical composition as claimed in any of claims 1 to 13 wherein said composition is in the form of a sterile powder reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration. ### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14) A pharmaceutical composition as claimed in any of claims 1 to 14 wherein said composition can be reconstituted by addition of a compatible reconstitution diluent vehicle prior to parenteral administration and is made chemically by use of the chemical vector mediated compatibility technology. ### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) A pharmaceutical composition as claimed in any of claims 1 to 15, wherein said first and second antibacterial agents are present in said composition in any form comprising particles, powders, granules, nanoparticles, microparticulates, microspheres, or lyphilised form and the like. ### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) A pharmaceutical composition as claimed in any of claims 1 to 16, wherein a pharmaceutically effective unit/multiple dose of said combination, in the form of the concentrate of said dose, wherein said dose is provided in a sealed airtight container which is selected from the group consisting of a vial, a mono vial, an ampoule, a syringe, a packet, a pouch and an auto-injector, wherein said container has a head space volume sufficient for introduction of appropriate volume of an aqueous solvent sufficient to form a unit dose in the form of an appropriate reconstituted solution of said combination. ### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17) A pharmaceutical combination, as claimed in any of claims 1 to 17, wherein said combination is provided in the form of a dry sterilized powder, in said sealed airtight container to form a pharmaceutically acceptable required fixed dose combination for reconstitution prior to intramuscular or intravenous administration for the treatment of the non-ocular infective conditions with drug resistant bacterium, wherein the combination dosage form after reconstitution is a sterile solution with the pH of the constituted solution being in the range from about 7 to about 9. ### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) A pharmaceutical composition, as claimed in any of claims 1 to 18, wherein said combination is provided in said sealed container wherein said vial is made of transparent glass and is capped with appropriate halogenated stopper and seal, and is used for reconstitution for intramuscular or intravenous administration for the treatment of the non-ocular infective conditions with drug resistant bacterium in mammals. ### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19) A pharmaceutical composition, as claimed in any of claims 1 to 19, wherein said combination is provided in a reconstituted form in said sealed airtight container which is selected from said group consisting of said vial, said mono vial, said ampoule, said syringe, said packet, said pouch, and said auto-injector, wherein interior space of said container comprises a fill volume occupied by said composition in reconstituted form and a head space volume occupied aseptically by an inert-gas-limited microatmosphere, which comprises essentially one or more inert gas which is selected from the group consisting of noble gases and nitrogen; preferably nitrogen, volume of said nitrogen gas being not more than 5% of said head space volume, and wherein ratio of said fill volume to said head space volume is not less than 1:1. ### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) A pharmaceutical composition, as claimed in any of claims 1 to 20 wherein said first antibacterial agent and said second antibacterial agent are present in pharmaceutically effective total amount corresponding to a single unit or multiple dose, in said sealed container, filled aseptically under inert gas blanket. ### Claim 22 A process for preparing a pharmaceutical composition suitable for parenteral combination therapy for non-ocular infective conditions with drug resistant bacterium, comprising the steps of: a. sterile filling/blending said first and said second antibacterial agents, wherein said first antibacterial agent, being a first antibacterial active ingredient, is vancomycin or a first pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride; wherein said second antibacterial agent, being a second active ingredient, is ceftriaxone or a second pharmaceutically acceptable salt thereof, such as ceftriaxone sodium; b. adding a particulate formation/precipitation inhibitor present in the form of a chemical vector; c. continuing said sterile filling/blending operation for a period of about 1 hour to about 8 hours; d. proportioning the sterile fill/blend of step (a) to get desired pharmaceutically effective dose in weight ratio of said first antibacterial agent to said second antibacterial agent in the range from about 1:4 to about 4:1 respectively; preferably in the range from about 1:3 to about 3:1 respectively; and more preferably in the range from about 1:2 to about 2:1 respectively; the range of said chemical vector being in the range from about 10% to about 40% of the total weight of the blended/filled composition; and e. e. capping aseptically with pre/post inert gassing. ### Claim 23 (depends on 1) A method of treatment and/or prevention of a non-ocular infective condition caused by drug resistant bacterium, said method comprising the step of parenterally administering the pharmaceutical composition of claim 1 in an antibacterially effective amount. ### Claim 24 A pharmaceutical composition suitable for parenteral combination therapy for non-ocular infective condition with drug resistant bacterium substantially as herein described and illustrated. ### Claim 25 A process for preparing a pharmaceutical composition suitable for parenteral combination therapy for non-ocular infective conditions with drug resistant bacterium substantially as herein described and illustrated. ### Claim 26 A method of treatment and/or prevention of a non-ocular infective condition caused by drug resistant bacterium, substantially as herein described and illustrated.