[go: up one dir, main page]

WO2019150381A1 - Composition pharmaceutique stable et procédé de production d'une injection de chlorhydrate d'isoprotérénol - Google Patents

Composition pharmaceutique stable et procédé de production d'une injection de chlorhydrate d'isoprotérénol Download PDF

Info

Publication number
WO2019150381A1
WO2019150381A1 PCT/IN2018/000028 IN2018000028W WO2019150381A1 WO 2019150381 A1 WO2019150381 A1 WO 2019150381A1 IN 2018000028 W IN2018000028 W IN 2018000028W WO 2019150381 A1 WO2019150381 A1 WO 2019150381A1
Authority
WO
WIPO (PCT)
Prior art keywords
isoproterenol
stable
acid
aqueous formulation
pharmaceutical composition
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/IN2018/000028
Other languages
English (en)
Inventor
Mahendra R. Joshi
Kamalanathan S
Ravindhar Reddy MANDAPATI
Trinath Kumar IMMANNI
Ananya De BHOWMICK
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of WO2019150381A1 publication Critical patent/WO2019150381A1/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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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 refers to stable pharmaceutical compositions of Isoproterenol Hydrochloride for pharmaceutical use and to a method of preparation.
  • Isoproterenol Hydrochloride is 3,4-Dihydroxy-a-[(isopropylamino)methyl] benzyl alcohol hydrochloride, a synthetic sympathomimetic amine that is structurally related to epinephrine but acts almost exclusively on beta receptors.
  • Isoproterenol hydrochloride is a racemic compound.
  • Isoproterenol is a potent nonselective beta-adrenergic agonist with very low affinity for alphaadrenergic receptors. Intravenous infusion of Isoproterenol in man lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds. Innovator product is available in the brand name of ISUPREL TM (Isoproterenol Hydrochloride) sterile Injection, USP in US market.
  • ISUPREL TM Isoproterenol Hydrochloride
  • the sterile solution is nonpyrogenic and can be administered by the intravenous, intramuscular, subcutaneous, or intracardiac routes.
  • ISUPREL TM is supplied in 1 mL & 5ml ampoule 0.02% sterile, non-pyrogenic aqueous solution.
  • Catecholamines such as Isoproterenol and epinephrine are highly subject to degradative oxidation in solutions.
  • Isoproterenol HC injection in aqueous solutions is highly unstable when packed without control on dissolved oxygen and head space oxygen in glass vials and ampoules. Due to the fact that lsoproterenol in aqueous medium is unstable in the presence of oxygen and/or light, it is difficult to obtain a pharmaceutical ready-to-use solution for intravenous perfusion.
  • US patent 3039928 also address the problem of stability of Isoproteronol and solutions by adding ascorbic acid effectively prevents breakdown and deterioration of isoproteronol in aqueous compositions.
  • the inherent properties of ascorbic acid are unique because many other antioxidants fail to display the beneficial properties of stabilizing Isoproteronol.
  • antioxidants which have been found undesirable are butylatedhydroxy anisole, propyl gal late nor-dihydroguaretic acid sodium metabisulfite, ethyl hydrocatfeate, di-tertbutyl-paracresol and others.
  • the present inventors have carried out various researches in order to develop a Isoproterenol pharmaceutical formulation in the form of a solution for injection, having an improved stability.
  • the present inventors surprisingly found that, when headspace oxygen in the vials & ampoules filled with solution for injection was substantially removed (i.e.. approximately less than 2%) by e.g.. bubbling of nitrogen gas into the solution & purging nitrogen gas over head space of vials/ ampoules after solution filling, a stable liquid formulation containing isoproterenol or its salt is obtained.
  • the present invention provides a method for preparing a pharmaceutical formulation in the form of a stable solution for injection containing Isoproterenol or its salt as an active ingredient.
  • the present invention overcomes the limitations of lsoproterenol solutions by stabilizing solutions of Isoproterenol by controlling the level of dissolved oxygen content and head space oxygen in the container.
  • Stringent control of the oxygen levels in the headspace and the dissolved oxygen that is absorbed into the drug solution provide beneficial effects for decreasing the total impurities of the drug product. Purging a sufficient amount of nitrogen over headspace of the composite solution affords an overall more stable formulation of lsoproterenol.
  • the composition should have less than or equal to 5-Oppin oxygen in bulk solution, and less than or equal to 2% head space oxygen content in the unit dose container.
  • one object of the present invention relates to providing a composition of lsoproterenol having low oxygen levels of less than or equal to 5.0 ppm oxygen in bulk solution.
  • Another object of the invention relates to preparing a unit dose system in a sealed vessel comprising an aqueous solution of a therapeutic amount of Isoproterenol having oxygen levels less than or equal to 2.0% in the headspace.
  • the invention relates to a composition
  • a composition comprising a therapeutically effective amount of lsoproterenol in an aqueous solution having less than or equal to 2.0% oxygen in the headspace of a container when determined immediately after container sealing, said solution consisting essentially of a complexing agent and buffers.
  • the compositions provide a stable low oxygen formulation having less than or equal to 5 ppm of oxygen.
  • Yet another aspect of the invention relates to a process for preparing a low oxygen composition of aqueous lsoproterenol, comprising the steps of: Step-l : Add and dissolve batch quantity of complexing agent in 80% of water for injection at 60- 65°C.
  • Step-2 To the step-l solution add buffers and stabilizing agents at room temperature.
  • Step-3 Nitrogen purge the bulk solution continuously to get dissolved oxygen below 5ppm.
  • Step-4 Add and dissolve drug substance to step-3 solution and adjust the pH of bulk solution to 3.5 - 4.5 either by use of hydrochloric acid or sodium hydroxide.
  • Step-5 Make up the volume to 100% V/V with use of water for injection.
  • Step-6 Continuously nitrogen purge the bulk solutions to maintain dissolved oxygen below 5ppm.
  • Step-7 Filter the bulk solution using 0.2 micron PVDF sterile filter membrane.
  • Step-8 Fill the filtered solution in to 5 mL clear glass vial (USP type I glass) stoppered with coated rubber stopper and flip off seal. And ensure that the head space was blanketed with nitrogen gas.
  • clear glass vial USP type I glass
  • the composition can be prepared in a vial according to steps (1 ) through (8) as described above.
  • Appropriate means of closure was placed into the opening of the filled container in a manner which does not allow the exchange of gas from an interior side of the container to an exterior side of the container.
  • the container headspace was treated with vacuum and purging the container headspace with an inert gas (nitrogen); and repeating the vacuum treating and purging step to control oxygen content in the container headspace before suitably sealing the container.
  • Drug stability means the ability of the pharmaceutical dosage form to maintain the physical, chemical, therapeutic and microbial properties during the time of storage and usage by the patient. It is measured by the rate of changes that take place in the pharmaceutical dosage forms. Stability is defined by the criteria set by ICH Q1 A for injections.
  • the invention relates to the use of a stable Pharmaceutical composition of Isoproterenol.
  • composition characterized in that it is as a liquid stable Isoproterenol formulation.
  • the solution is an aqueous solution.
  • the formulations as developed by the Inventors of the present Application are suitable for parenteral administration.
  • Such stable liquid formulation of Isoproterenol can be developed with the use of tonicity agent, chelating agents and buffers and by controlling the oxygen content of drug solution and vial/ampoule headspace with the use of an inert gas viz nitrogen.
  • These formulations are presented as a single unit dose (vial/ ampoule) presentation having Isoproterenol concentrations 0.2 mg/ml.
  • These pharmaceutical compositions are then administered usually via intravenous infusion or bolus intravenous injection. In dire emergencies, the drug may be administered by intracardiac injection. If time is not of the utmost importance, initial therapy by intramuscular or subcutaneous injection is preferred.
  • the stable ready-to-use pharmaceutical composition of Isoproterenol is usually solvated in an aqueous solvent comprising water for injection.
  • the ready-to-use pharmaceutical composition of Isoproterenol has a pH between about 2.5 and about 4.5, preferably between about 3.5 and about 4.5 and more preferably in the range of about 3.5 and about 4.0.
  • the pl-l of such ready-to-use pharmaceutical compositions of Isoproterenol may be achieved by use of suitable buffers and adjusted with a pharmacologically acceptable pH adjusting agent such as an acid& base.
  • a pharmacologically acceptable pH adjusting agent such as an acid& base.
  • the pH adjusting agents are citrate buffers, acid and bases or their combination thereof.
  • the hydrochloric acid or sodium hydroxide may be in any suitable form, such as a 0.01N to 1N solution.
  • the composition can contain one or more chelating agents whose presence will further improve the stability of the Isoproterenol present therein.
  • Chelating agents which may be mentioned in particular are ethy!enediamine tetraacetic acid, diethy!enetriaminepentaacetic acid, 1 ,4,7, 10-tetraazacyclododecane-N,N',N",N M, -tetraacetic acid, trans- 1 ,2-cycIohexylenediamine- N,N,N',N'-tetraacetic acid, N 6 -carboxymethyl-N 3 ,N 9 - 2,3-dihydroxy-N- methylpropylcarbamoylmethyI-3,6,9-triazaundecanedioic acid, N 6 -carboxymethyl-N 3 ,N 9 -bis (methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid, N 3 ,N 6 -bis (carboxymethyl) -N 9 -3- oxapentamethyIene
  • the compositions are obtained by a deoxygenation process and inerting.
  • Deoxygenation and inerting is carried out by use of inert gas and preferably dense as nitrogen is circulated and / or sparging facilities and other tubing and solutions in order to eliminate most of any trace of oxygen and residual volumes in solution.
  • the pharmaceutical composition is characterized by its oxygen content which is less than 5ppm in bulk solution and less than 5% in head space.
  • the oxygen content may be less than 5ppm in bulk solution and less than 2% in head space.
  • the gas used for purging the sealable container may be any appropriate inert gas known to those in the art, the most commonly used gases being argon, helium or nitrogen, or mixtures thereof. However the most preferred inert gas is nitrogen.
  • the sealable container so as to minimize oxidation of the sensitive material it is also desirable to remove headspace oxygen from the sealable vessel as quickly as possible. This may be aided by, for example, purging the sealable container with a gas which is substantially oxygen-free, or substantially oxygen and moisture free before, during or after step, or any combination thereof. Purging can be expected to reduce the oxygen level in the sealable container to a level of from about 0%to about 5% typically about 2%or lower, depending on the efficiency of flushing and how quickly the container is sealed after flushing.
  • Table #1 Formula composition for evaluation of product stability in glass vials
  • Step- 1 Add and dissolve batch quantity of edetate disodium in 80% of water for injection at 60- 65 C.
  • Step-2 To the step- l solution add sodium chloride, trisodium citrate and citric acid at room temperature.
  • Step-3 Nitrogen purge the bulk solution continuously to get dissolved oxygen below 5ppm.
  • Step-4 Add and dissolve drug substance to step-3 solution and adjust the pH of bulk solution to 3.5 - 4.5 either by useof dilute Hydrochloric acid or sodium hydroxide solution.
  • Step-5 Make up the volume to 100% V/V with use of water for injection.
  • Step-6 Continuously nitrogen purge the bulk solutions to maintain dissolved oxygen below 5ppm.
  • Step-7 Fiiter the bulk solution using 0.2 micron PVDF sterile filter membrane.
  • Step-8 Fill the filtered solution in to 5 mL clear glass vial (USP type I glass) stoppered with coated rubber stopper and flip off seal. And ensure that the head space was blanketed with nitrogen gas.
  • clear glass vial USP type I glass
  • Table #3 Formula composition and parameters for different head space nitrogen purging trials
  • Table#4 Head space oxygen content measured by FMS- Oxygen Head space analyzer from Lighthouse

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dans un aspect, l'invention concerne une formulation liquide stable pour composition parentérale comprenant une quantité thérapeutiquement efficace d'isoproterénol et une solution aqueuse ayant un niveau d'oxygène contrôlé dans l'espace de tête d'un récipient et dans une solution en vrac.
PCT/IN2018/000028 2018-02-01 2018-05-14 Composition pharmaceutique stable et procédé de production d'une injection de chlorhydrate d'isoprotérénol Ceased WO2019150381A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201841003813 2018-02-01
IN201841003813 2018-02-01

Publications (1)

Publication Number Publication Date
WO2019150381A1 true WO2019150381A1 (fr) 2019-08-08

Family

ID=67479073

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2018/000028 Ceased WO2019150381A1 (fr) 2018-02-01 2018-05-14 Composition pharmaceutique stable et procédé de production d'une injection de chlorhydrate d'isoprotérénol

Country Status (1)

Country Link
WO (1) WO2019150381A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021168133A1 (fr) * 2020-02-19 2021-08-26 Nevakar Inc. Compositions d'isoprotérénol et méthodes associées
CN114668714A (zh) * 2020-12-24 2022-06-28 远大医药（中国）有限公司 盐酸肾上腺素注射液制备方法及注射液

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040054012A1 (en) * 2000-06-06 2004-03-18 Francois Dietlin Method for obtaining aqueous formulations of oxidation-sensitive active principles
US7199269B2 (en) * 2001-11-15 2007-04-03 Bernard Dinnequin Method for producing stable solutions of phenolic substances and resulting solutions
CN102525894A (zh) * 2012-01-04 2012-07-04 上海禾丰制药有限公司 盐酸异丙肾上腺素注射液及其制剂工艺

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040054012A1 (en) * 2000-06-06 2004-03-18 Francois Dietlin Method for obtaining aqueous formulations of oxidation-sensitive active principles
US7199269B2 (en) * 2001-11-15 2007-04-03 Bernard Dinnequin Method for producing stable solutions of phenolic substances and resulting solutions
CN102525894A (zh) * 2012-01-04 2012-07-04 上海禾丰制药有限公司 盐酸异丙肾上腺素注射液及其制剂工艺

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021168133A1 (fr) * 2020-02-19 2021-08-26 Nevakar Inc. Compositions d'isoprotérénol et méthodes associées
US11806320B2 (en) * 2020-02-19 2023-11-07 Endo Ventures Limited Isoproterenol compositions and methods
CN114668714A (zh) * 2020-12-24 2022-06-28 远大医药（中国）有限公司 盐酸肾上腺素注射液制备方法及注射液
CN114668714B (zh) * 2020-12-24 2024-01-19 远大医药（中国）有限公司 盐酸肾上腺素注射液制备方法及注射液

Similar Documents

Publication Publication Date Title
JP2977912B2 (ja) 向精神薬の安定化溶液
EP2307056B1 (fr) Compositions pharmaceutiques aqueuses stables contenant du paracetamol
TWI673065B (zh) 用於製造穩定低濃度之可注射的去甲腎上腺素溶液之方法
US6528540B2 (en) Esmolol formulation
WO2013144814A1 (fr) Composition pharmaceutique prête-à-l'emploi stable de pemetrexed
AU2016239772B2 (en) Stable formulation for parenteral administration of Tapentadol
AU2002309475B2 (en) Esmolol formulation
WO2019150381A1 (fr) Composition pharmaceutique stable et procédé de production d'une injection de chlorhydrate d'isoprotérénol
JP2916340B2 (ja) ナトリウムクロモグリケートの水性医薬組成物
WO2009047634A2 (fr) Préparations aqueuses d'acétaminophène pour injection
CN113453663B (zh) 稳定的可注射肾上腺素水溶液
WO2009081283A2 (fr) Formulations aqueuses d'acétaminophène pour injection
JP6598158B2 (ja) パロノセトロンを含有する安定な注射用液剤の製造方法
US20050176650A1 (en) Stable parenteral formulation of levomepromazine and a method for stabilizing said formulation
EP4099980B1 (fr) Compositions pharmaceutiques stables de ropinirole
WO2019176239A1 (fr) Composition médicinale liquide de pth (1-34) humaine conditionnée dans un récipient et procédé pour la fabriquer
AU2023304691A1 (en) Injectable phenylephrine compositions
EP3515412B1 (fr) Formulation stable pour l'administration parentérale de tapentadol
US20220233473A1 (en) Injectable solution of norepinephrine
HK40077253B (en) Stable pharmaceutical compositions of ropinirole
HK40077253A (en) Stable pharmaceutical compositions of ropinirole
WO2024008293A1 (fr) Compositions de phényléphrine injectables

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: 18903318

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: 18903318

Country of ref document: EP

Kind code of ref document: A1