[go: up one dir, main page]

WO2018055581A1 - Composition injectable stable d'oxazolidinone - Google Patents

Composition injectable stable d'oxazolidinone Download PDF

Info

Publication number
WO2018055581A1
WO2018055581A1 PCT/IB2017/055786 IB2017055786W WO2018055581A1 WO 2018055581 A1 WO2018055581 A1 WO 2018055581A1 IB 2017055786 W IB2017055786 W IB 2017055786W WO 2018055581 A1 WO2018055581 A1 WO 2018055581A1
Authority
WO
WIPO (PCT)
Prior art keywords
solution
injection
linezolid
sodium
cyclodextrin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2017/055786
Other languages
English (en)
Inventor
Shashi Shanker Parsad SINGH
Venkataramana Rao PATHIPATI
Satyendra Kumar SINGH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jodas Expoim Private Ltd
Original Assignee
Jodas Expoim Private Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jodas Expoim Private Ltd filed Critical Jodas Expoim Private Ltd
Publication of WO2018055581A1 publication Critical patent/WO2018055581A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to a parenteral preparation of antimicrobial agent.
  • the present invention specifically relates to a parenteral preparation of oxazolidinone antimicrobial agent.
  • the present invention more specifically relates to a stable concentrated linezolid parenteral composition
  • a stable concentrated linezolid parenteral composition comprising Hydroxypropyl ⁇ Cyclodextrin and optionally one or more of Sugars, chelating agents, Buffers, pH modifiers and Aqueous Vehicles.
  • the present invention also relates to a process for the preparation linezolid parenteral composition comprising Hydroxypropyl ⁇ Cyclodextrin and optionally other excipients.
  • Linezolid is an antibiotic used for the treatment of serious infections caused by
  • Gram-positive bacteria that are resistant to other antibiotics.
  • the microbiological and clinical significance of linezolid is its spectrum of activity against gram-positive organisms, specifically methicillin- susceptible and resistant (MRSA) Staphylococcus aureus, Staphylococcus epidermidis and other coagulase-negative staphylococci vancomycin- susceptible and resistant (VRE) enterococci, and penicillin susceptible and resistant (PSRP) Streptococcus pneumoniae.
  • MRSA methicillin- susceptible and resistant
  • VRE coagulase-negative staphylococci vancomycin- susceptible and resistant
  • PSRP penicillin susceptible and resistant Streptococcus pneumoniae.
  • bactericidal activity has been demonstrated against S. pneumoniae, Clostridium perfringens, and Bacteroides fragilis, an anaerobic gram negative organism.
  • Linezolid (CAS No. 60-00-4) is a synthetic antibacterial agent of the oxazolidinone class.
  • the chemical name for linezolid is "(S)-N-[[3-[3-Fluoro-4- (4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide” has the empirical formula of C 16 H 2 oFN 3 O 4 with the molecular weight of 337.35. Its chemical structure is represented as below:
  • US 5,688,792 disclose that the subject antibiotic oxazolidinone compounds, including linezolid, can be formulated as liquid form compositions including solutions.
  • a solution can be provided of a subject oxazolidinone compound in water or in a water-propylene glycol or water- polyethylene glycol system, optionally containing conventional coloring agents, flavoring agents, stabilizers and thickening agents.
  • a suitable composition will generally contain a pharmaceutically acceptable amount of a subject oxazolidinone compound as a soluble salt dissolved in a liquid carrier such as water for injection to form a suitably buffered isotonic solution.
  • CN 104666241 discloses a method for preparing linezolid injection containing disodium hydrogen phosphate as pH adjusting agent, osmolality adjusting agent and stabilizers. This invention also discloses the process for preparing linezolid injection.
  • IN 2409/DELNP/2004 discloses a method of treating a diabetic foot infection in a mammal comprising parenterally administering to the mammal a pharmaceutically effective amount of an oxazolidinone antibiotic.
  • This invention also discloses linezolid as oxazolidinone antibiotic.
  • IN 307/CHE/2011 discloses aqueous concentrated antibacterial formulation of linezolid comprising at least one solubilizer. This invention also discloses composition of linezolid injection concentrate.
  • IN 822/KOLNP/2012 discloses a pharmaceutical composition
  • a pharmaceutical composition comprising an oxazolidinone antimicrobial agent or a pharmaceutically acceptable salt, ester, or prodrug thereof, buffer, pH modifier, and a solvent.
  • GR 1008260 discloses aqueous pharmaceutical composition for parenteral administration which contains linezolid or a pharmaceutically acceptable salt thereof as active ingredient, tonicity agent, buffering agent and a pH-adjusting agent.
  • Linezolid has a potent range of activity against gram-positive microorganisms, including multi-resistant strains. Its unique mode of action to inhibit protein synthesis exhibits no cross-resistance with other agents that act on gram-positive bacteria.
  • Compositions for preparing linezolid Injection contain linezolid as oxazolidinone antimicrobial agent, tonicity agent, buffering agent, a pH-adjusting agent and solvent.
  • none of the references specifically discloses the use of stable concentrated linezolid parenteral composition comprising Hydroxypropyl ⁇ Cyclodextrin for intravenous administration.
  • the objective of the present invention is to provide a parenteral composition comprising oxazolidinone antimicrobial agent.
  • Another objective of the present invention is to provide a stable concentrated Linezolid parenteral composition comprising Hydroxypropyl ⁇ Cyclodextrin for intravenous administration which optionally contain one or more of sugars, buffering agents, chelating agents, pH modifiers and water for injection.
  • Another objective of the present invention is a process for the preparation of linezolid parenteral composition comprising Hydroxypropyl ⁇ Cyclodextrin for intravenous administration which optionally contain one or more of sugars, buffering agents, chelating agents, pH modifiers and water for injection.
  • Another objective of the present invention is the use of Hydroxypropyl ⁇ Cyclodextrin in enhancing the stability of linezolid injection and preventing crystallization of linezolid during storage.
  • the present invention provides a parenteral composition of oxazolidinones antimicrobial agent comprising Hydroxypropyl ⁇ Cyclodextrin as a stabilizer and/or as a crystallization inhibitor.
  • Another embodiment of the present invention provides a parenteral composition comprising linezolid and Hydroxypropyl ⁇ Cyclodextrin for intravenous administration.
  • Yet another embodiment of the present invention provides a concentrated parenteral composition of Linezolid comprising Hydroxypropyl ⁇ Cyclodextrin for intravenous administration.
  • Yet another embodiment of the present invention provides a concentrated composition of linezolid injection which optionally comprises one or more of Sugars, Buffering agents, pH modifiers, Chelating agents and stabilizers or crystallization inhibitors.
  • Yet another embodiment of the present invention provides a concentrated composition of linezolid injection which comprises citric acid anhydrous, sodium citrate, EDTA, Sodium hydroxide/hydrochloric acid, Hydroxypropyl ⁇ Cyclodextrin and water for injection.
  • Yet another embodiment of the present invention provides a concentrated composition of linezolid injection which comprises dextrose, citric acid anhydrous, sodium citrate, EDTA, Sodium hydroxide/hydrochloric acid, Hydroxypropyl ⁇ Cyclodextrin and water for injection.
  • Yet another embodiment of the present invention provides a process for preparing linezolid injection for treating microbial infections which comprises: i. adding and dissolving citric acid, sodium citrate in water for injection and stir the solution till to get a clear solution,
  • step (i) adding and dissolving Hydroxypropyl ⁇ Cyclodextrin to step (i) solution and stir the solution till to get a clear solution
  • step 3 solution iv. adjusting the pH of step 3 solution to 4.4 - 5.2 and make the volume to 100%, stirring the solution for 20 mins,
  • Yet another embodiment of the present invention provides a process for preparing linezolid injection for treating microbial infections which comprises: i. adding and dissolving dextrose, citric acid, sodium citrate in water for injection and stir the solution till to get a clear solution,
  • step (i) adding and dissolving Hydroxypropyl ⁇ Cyclodextrin in step (i) solution, and stir the solution till a clear solution is obtained
  • step (iii) adding and dissolving Linezolid to step (ii) solution, and stirring the solution till a clear solution is obtained
  • step (iii) solution iv. adjusting the pH of step (iii) solution to 4.4 - 5.2 and make the volume to 100%, stirring the solution for 20 mins,
  • Yet another embodiment of the present invention provides a process for preparing linezolid injection for treating microbial infections which comprises: i. adding and dissolving dextrose, citric acid, sodium citrate in water for injection and stir the solution till to get a clear solution,
  • step (i) adding and dissolving Hydroxypropyl ⁇ Cyclodextrin in step (i) solution, and stir the solution till a clear solution is obtained
  • step (iii) adding and dissolving EDTA in step (ii) solution, and stir the solution till a clear solution is obtained
  • step (iii) solution iv. adding and dissolving Linezolid to step (iii) solution, and stirring the solution till a clear solution is obtained,
  • step (iv) solution adjusting the pH of step (iv) solution to 4.4 - 5.2 and make the volume to 100%, stirring the solution for 20 mins, vi. filtering the above solution through 0.22 micron PVDF membrane filter and fill into glass vials as per below target fill volumes,
  • oxazolidinones a new chemical class of synthetic antimicrobial agent, have a unique mechanism of inhibiting bacterial protein synthesis.
  • Antimicrobials of the present invention also include Penicillins, Cephalosporins, Monobactams, Carbapenems, Macrolide Antibiotics, Lincosamides, Streptogramins, Aminoglycoside Antibiotics, Quinolone Antibiotics, Sulfonamides, Tetracycline Antibiotics and Other Antibiotics or combinations thereof.
  • Oxazolidinones are a class of compounds containing 2-oxazolidine in the structure. Oxazolidinones represent a new class of synthetic antibacterial agents active against multiple-resistant gram-positive pathogens, including methicillin- resistant Staphylococcus aureus (MRSA), penicillin-resistant streptococci, and vancomycin-resistant enterococci.
  • MRSA methicillin- resistant Staphylococcus aureus
  • penicillin-resistant streptococci penicillin-resistant streptococci
  • vancomycin-resistant enterococci vancomycin-resistant enterococci.
  • Oxazolidinones are a class of azoles, oxazolidines with the carbon between the nitrogen and oxygen oxidized to a ketone, hence oxazolidinone.
  • the antibacterial oxazolidinone template has a common nomenclature specially for 'aryl-5-(substituted) methyl-2-oxazolidinone' and has a structural formula as follows
  • Oxazolidinones used in the present invention is selected from the group consisting of Linezolid, Posizolid, Tedizolid and Radezolid.
  • the sugar used in the present invention selected from the group consisting of galactose, dextrose, xylose, fructose, glucose, arabinose, ribose, lyxose, meso- erythritol, xylitol, dulcitol, myo-inositol, mannitol, sorbitol, adonitol, arabitol, cellobiose, maltose, raffinose, rhamnose, melibiose, fucose, maltodextrins, glucosamine, mannosamine, galactosamine, lactose and sucrose, more specifically dextrose.
  • the pH adjusting agents and/or buffering agents used in the present invention selected from the group consisting of acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, citrate/phosphate, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in a physiologically acceptable range, particularly where the composition is intended for parenteral delivery.
  • the chelating agents used in the present invention are selected from the group consisting of EDTA (Ethylene diamine tetra acetic acid), DOTA (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid), DTPA (diethylenetriamine pentaacetic acid), EGTA (ethylene glycol-bis(P-aminoethylether)-N,N,N',N'- tetraacetic acid), HEDTA (N (hydroxyethyl)ethylenediaminetriacetic acid) and salts thereof.
  • the pH adjusting agent can be a Sodium Hydroxide and/or Hydrochloric acid solution ranging from 0.1N solution to 5N solution.
  • Aqueous vehicle also includes Water for Injection (WFI), USP, Bacteriostatic Water for Injection (BWFI) and sterile water for injection (SWFI), USP.
  • WFI Water for Injection
  • BWFI Bacteriostatic Water for Injection
  • SWFI sterile water for injection
  • the formulation prepared in the invention can be easily diluted with any of the commonly available infusion solutions like Dextrose Injection, Sodium Chloride Injection, Lactated Ringer's Injection, 5% dextrose in Lactated Ringers Injection, 5% dextrose in 0.9% sodium chloride Injection, 5% dextrose in 0.225% sodium chloride Injection or others to the desired concentration prior to administration. Even Water for Injection can also be used to prepare the dilutions.
  • concentrated parenteral compositions refers to an aqueous solution of Linezolid having a concentration of about 3 mg/ml to about 30 mg/ml.
  • concentrated liquid Linezolid formulations can be made by dissolving Linezolid in a buffered aqueous solution comprising at least one stabilizing agent and one solubilizer.
  • Containers suitable for injection in connection with the invention refers to containers which do not interact physically or chemically with the preparation for injection in any manner to alter the strength, quality, or purity beyond the official requirements under the ordinary or customary conditions of handling, shipment, storage, sale and use.
  • Suitable containers in accordance with the invention are for example made of glass.
  • Particularly suitable are type 1 glass containers, which fulfills the criteria of type I glass containers according to European Pharmacopoeia, United States Pharmacopoeia and Japanese Pharmacopoeia.
  • vials with excellent barrier properties can be washed, autoclaved, sterilized, depyrogenated, filled, closed and inspected just like standard containers.
  • the container for injection according to the invention is closed or sealed with a suitable stopper in such a manner as to prevent contamination or loss of content.
  • the stoppers which can be used in the present invention include coated/laminated or uncoated Bromobutyl or Chlorobutyl or Fluoro butyl stoppers.
  • Sterilization methods that may be used in the present invention, include, but are not limited to, filtration sterilization, autoclaving, aseptically preparing and dispensing in the sterile containers or combination of one or more said methods.
  • the product of the present invention can be sterilized by aseptic filtration followed by moist heat sterilization up to 45 minutes, preferably up to 15 minutes or 30 minutes.
  • a daily dose for a human subject will typically be about 100 mg to about 1200 mg of Linezolid, administered in a composition of the invention.
  • the aqueous concentrated formulation according to examples 1-4 of present invention was prepared by the process wherein sodium citrate, citric acid, dextrose are added to water for injection and stirred until dissolved. Linezolid was added to this buffered solution with agitation along with hydroxy propyl ⁇ cyclodextrin was added into the solution. The solution was further heated up to 70-80° C until Linezolid fully dissolved. The pH of the solution was measured and adjusted in between 4.4 and 5.2, if necessary. Final volume is made up with the water for injection. The mixture is filtered, filled into sterile vials. The above filled and sealed vials were optionally sterilised by moist heat sterilization process for up to 15 mins at 121°C. The above sterilized vials were unloaded from sterilizer, label it and pack the labeled vials in individual cartons.
  • the aqueous concentrated formulation according to example 5 of present invention was prepared by the process wherein sodium citrate and citric acid are added to water for injection and stirred until dissolved. Linezolid was added to this buffered solution with agitation along with hydroxy propyl ⁇ cyclodextrin was added into the solution. The solution was further heated up to 70-80° C until Linezolid fully dissolved. The pH of the solution was measured and adjusted in between 4.4 and 5.2, if necessary. Final volume is made up with the water for injection. The mixture is filtered, filled into sterile vials. The above filled and sealed vials were optionally sterilised by moist heat sterilization process for up to 15 mins at 121°C. The above sterilized vials were unloaded from sterilizer, label it and pack the labeled vials in individual cartons.
  • Example 6 Example 6:
  • aqueous concentrated formulation according to examples 6 and 7 of present invention was prepared by the process wherein dextrose, sodium citrate, citric acid, are added to water for injection and stirred until dissolved, hydroxy propyl ⁇ cyclodextrin was added and dissolved. To this EDTA was added and dissolved. Linezolid was added to this buffered solution with agitation. The solution was further heated up to 70-80° C until Linezolid fully dissolved. The pH of the solution was measured and adjusted in between 4.4 and 5.2, if necessary. Final volume is made up with the water for injection. The mixture is filtered, filled into sterile vials.
  • the above filled and sealed vials were optionally sterilised by moist heat sterilization process for up to 15 mins at 121 °C.
  • the above sterilized vials were unloaded from sterilizer, label it and pack the labeled vials in individual cartons.
  • Test Limits Initial Test conditions parameters 40° C/ 75 RH 25° C/ 60 RH

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation parentérale d'agent antimicrobien. L'invention concerne en particulier une préparation parentérale d'agent antimicrobien à base d'oxazolidinone. L'invention concerne spécifiquement une composition d'injection de linézolide concentrée stable contenant de la bêta-cyclodextrine hydroxypropylique pour une administration intraveineuse, et contenant également du sucre, un tampon, un modificateur de pH et un excipient aqueux, ainsi qu'un procédé de préparation associé.
PCT/IB2017/055786 2016-09-24 2017-09-23 Composition injectable stable d'oxazolidinone Ceased WO2018055581A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201641032660 2016-09-24
IN201641032660 2016-09-24

Publications (1)

Publication Number Publication Date
WO2018055581A1 true WO2018055581A1 (fr) 2018-03-29

Family

ID=61690232

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/055786 Ceased WO2018055581A1 (fr) 2016-09-24 2017-09-23 Composition injectable stable d'oxazolidinone

Country Status (1)

Country Link
WO (1) WO2018055581A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112022802A (zh) * 2020-08-11 2020-12-04 太阳升(亳州)生物医药科技有限公司 用于制备利奈唑胺注射液的方法
CN119367287A (zh) * 2024-12-27 2025-01-28 成都硕德药业有限公司 一种重酒石酸去甲肾上腺素注射液及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020068720A1 (en) * 2000-08-22 2002-06-06 Sims Sandra M. Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
US20040019012A1 (en) * 2002-02-22 2004-01-29 Singh Satish K. Ophthalmic antibiotic drug formulations containing a cyclodextrin compound and cetyl pyridinium chloride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020068720A1 (en) * 2000-08-22 2002-06-06 Sims Sandra M. Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
US20040019012A1 (en) * 2002-02-22 2004-01-29 Singh Satish K. Ophthalmic antibiotic drug formulations containing a cyclodextrin compound and cetyl pyridinium chloride

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112022802A (zh) * 2020-08-11 2020-12-04 太阳升(亳州)生物医药科技有限公司 用于制备利奈唑胺注射液的方法
CN119367287A (zh) * 2024-12-27 2025-01-28 成都硕德药业有限公司 一种重酒石酸去甲肾上腺素注射液及其制备方法

Similar Documents

Publication Publication Date Title
AU2014227660B2 (en) Ceftolozane antibiotic compositions
US11433115B2 (en) Glycopeptide antibiotics liquid formulations and methods and uses thereof
US12220441B2 (en) Formulations of vancomycin
KR100900208B1 (ko) 감염의 치료에 대해 토탈 솔루션을 제공하는 항생제 배합물
US6544991B2 (en) Compositions and methods for treating bacterial infections
AU2001285087B2 (en) Solution of an oxazolidinone antibiotic drug
MX2007004490A (es) Composiciones que contienen piperacilina, tazobactam y un acido aminocarboxilico en un diluyente de lactato de sodio.
WO2018055581A1 (fr) Composition injectable stable d'oxazolidinone
AU2001285087A1 (en) Solution of an oxazolidinone antibiotic drug
US20040176321A1 (en) Compositions of benzoquinolizine carboxylic acid antibiotic drugs
WO2010146478A1 (fr) Composition parentérale comprenant un composé fluoroquinolone et un composé nitroimidazole
WO2012104874A2 (fr) Formulation concentrée aqueuse de linézolide
ZA200301281B (en) Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading.
AU2015200599A1 (en) Ceftolozane Antibiotic Compositions
NZ711823B2 (en) Ceftolozane antibiotic compositions
HK1069775B (en) Compositions containing piperacillin and tazobactam useful for injection

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17852525

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17852525

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205 DATED 03-06-2019)