EP1178798A1 - Formulation parenterale de 5-(2-chloroethyle)-4-methylthiazole edisylate(clomethiazole edisylate) - Google Patents

Formulation parenterale de 5-(2-chloroethyle)-4-methylthiazole edisylate(clomethiazole edisylate)

Info

Publication number
EP1178798A1
EP1178798A1 EP00930026A EP00930026A EP1178798A1 EP 1178798 A1 EP1178798 A1 EP 1178798A1 EP 00930026 A EP00930026 A EP 00930026A EP 00930026 A EP00930026 A EP 00930026A EP 1178798 A1 EP1178798 A1 EP 1178798A1
Authority
EP
European Patent Office
Prior art keywords
treatment
formulation
edisylate
formulation according
prevention
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.)
Withdrawn
Application number
EP00930026A
Other languages
German (de)
English (en)
Inventor
Ola Camber
Karin Ellström
Ingrid JÄPPINEN
Tomas Petersson-Norden
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.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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 AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1178798A1 publication Critical patent/EP1178798A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a parenteral formulation of 5-(2-chloroethyl)-4- methylthiazole edisylate (generically known as clomethiazole edisylate) having improved antimicrobial properties in addition to physical, chemical and microbiological stability as well as biological compatibility.
  • Clomethiazole has been widely used for more than 25 years for sedation as well as an anticonvulsant, tranquilliser and hypnotic.
  • the active forms of the drug for clinical use are either the base or its edisylate salt.
  • the current market presentation for parenteral administration is Heminevrin ® 8 mg/mL comprising clomethiazole edisylate 8 mg/mL and dextrose monohydrate 40 mg/mL in an isotonic aqueous solution.
  • this composition can not be used for treatment of neurode generation since dextrose is considered contra-indicated for this therapeutic indication.
  • the formulation according to the invention has to be terminally sterilized by filtration and aseptically filled.
  • a parenteral formulation should be physically, chemically and microbiologically stable as well as biologically compatible.
  • the object of the present invention is to provide a parenteral formulation which has improved antimicrobial properties in addition to physical, chemical and microbiological stability as well as biological compatibility.
  • the present invention provides a stable, parenteral formulation comprising 5-(2-chloroethyl)-4-methylthiazole edisylate, water and sodium chloride.
  • 5-(2- chloroethyl)-4-methylthiazole edisylate is generically known as clomethiazole edisylate.
  • clomethiazole edisylate or CMZ-edisylate will be referred to throughout the specification.
  • Another object of the present invention is the use of said formulation for the treatment of neurode generation.
  • Another object of the present invention is a process for preparing the formulation according to the invention.
  • a formulation which is suitable for parenteral administration of clomethiazole edisylate is disclosed. It has surprisingly been found that by using sodium chloride as an isotonicity agent a stable formulation having improved antimicrobial properties in addition to physical, chemical and microbiological stability as well as biological compatibility for the treatment of patients suffering from neurodegeneration is obtained.
  • the formulation according to the invention comprises
  • the concentration of clomethiazole edisylate in the formulation according to the inventions may range from 0.1 % to 2.0 %, preferably from 0.4 % to 1.0 %, more preferably from 0.7 % to 0.9 % and in particular is about 0.8 %.
  • the formulation in this aspect of the invention comprises from 0.1 to 1.8 % sodium chloride used as isotonizing agent.
  • sodium chloride used as isotonizing agent.
  • the use of sodium chloride as isotonizing agent has the advantage that a clear solution with acceptable level of particulate matter and with significantly better antimicrobial efficacy is obtained.
  • sodium chloride is used in a concentration from 0.7 to 0.9 %.
  • the subject formulation may further comprise a base substance to maintain the pH of the formulation in the range from 2.0 to 8.5. preferably in the range from 4.5 to 8.0. more preferably in the range from 6.0 to 8.0 and most preferably at about 7.4.
  • the pH of the formulations is adjusted by addition of appropriate amounts of sodium hydroxide.
  • an acid substance such as hydrochloric acid, may be used to adjust the pH of the final formulation.
  • this aspect of the invention relates to formulations comprising: (a) 0.1 to 2.0 % clomethiazole edisylate;
  • formulations comprising
  • formulations comprising
  • An example of a formulation according to the invention is (a) 0.8 % clomethiazole edisylate; (b) 0.8 % sodium chloride; (c) sodium hydroxide to adjust the pH to about 7.4; and (d) water q.s. ad 100%-.
  • the present invention relates to the preparation of the described formulations.
  • the preparation involves dissolving clomethiazole edisylate and sodium chloride in WFI (water for injection) and thereafter optionally adjusting pH with a base substance.
  • the preparation involves the following steps:
  • Step h) may be conducted by filtering the solution through a sterile membrane filter of pore size at most 0.22 ⁇ m.
  • the above procedure may be conducted under an inert atmosphere, e.g. nitrogen or oxygen-free argon.
  • antimicrobial properties and “antimicrobial efficacy” as used herein refers to the ability to reduce the amount of microorganisms.
  • physical stability refers to a formulation for which precipitation of the drug substance or any other ingredient is prevented and which fulfils the pharmacopoeia requirements regarding particulate matter as determined by particle counting methods after 3 years of storage at +2-+8°C.
  • chemical stability refers to a formulation which fulfils the pharmacopoeia requirements regarding assay of drug substance, level of related substances and pH after 3 years of storage at +2-+8°C.
  • microbiological stability refers to a formulation which fulfils the pharmacopoeia requirements regarding sterility and endotoxins after 3 years of storage at +2-+8°C.
  • biological compatibility refers to a formulation not containing any ingredients considered as contra-indicative in stroke treatment.
  • the formulation according to the invention may be prepared by dissolving the sodium chloride in room temperature water, adding the clomethiazole edisylate and optionally adding the base substance. pH of the final formulation may be adjusted by the addition of base and/or acid substance.
  • the formulation according to the invention is conveniently used in the prevention or treatment of neurodegeneration, especially for treatment of patients suffering from stroke, such as acute stroke, cerebral ischaemia. hypoxia or spinal cord injury.
  • an effective amount per 24 hours would be from 25 to 150 mg/kg body weight, preferably from 50 to 100 mg/kg of active ingredient. It is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
  • the effective daily amount ranges mentioned hereinabove are theretore guidelines onlv and are not intended to limit the scope or use of the invention to any extent
  • the new formulation of clomethiazole edisylate is to be parenterally administered as for instance an injection or preferably as an intravenous infusion
  • a dose of about 70 mg per kg body weight is administered during 24 hours
  • the dosing is preferably started within 12 hours after stroke has occurred
  • the new formulation fulfils the requirements regarding large volume parenterals according to the pharmacopoeias when stored at +2-+8°C for 36 months
  • the shelf life at room temperature is at least 1 month
  • the new formulation does not contain any ingredient which is considered as contra-indicative in stroke treatment
  • Clomethiazole edisylate 8 mg/mL (containing 8 mg/mL sodium chloride and pH ad j usted to 7.4 with sodium hydroxide) and Heminevrin® 8 mg/mL (clomethiazole edisylate 8 mg/mL with dextrose monohydrate 40 mg/mL and pH adjusted to 7 4 with sodium hydroxide) were both tested for antimicrobial efficacy
  • the test was performed according to Ph Eur 1999
  • Six to eight portions of 20 mL were separately inoculated with 0 1 mL of each of the following test organisms S ⁇ ureus, C Albicans A Niger and Pen Chrysogenum The portions were then stored at controlled room temperature protected from light. At different intervals samples were withdrawn to determine the number of CFU/mL (colony forming unit/mL). The number of CFU was determined by plate count procedure with appropriate dilutions. See tables 1-3.
  • Tables 1-3 show that for all test organisms the decrease in CFU was much faster in the formulation according to the invention than in Heminevrin®.
  • Example 4 90 mL water is charged and cooled to room temperature 800 mg sodium chloride and 1000 mg CMZ-edisylate are added and dissolved by stirring and pH is ad j usted by slow addition of sodium hydroxide 2 M so as to obtain the pH of 4 5 About 10 mL water at room temperature is added in order to adjust to the final volume The solution is filtered through a 0 22 ⁇ m sterile membrane
  • CMZ-edisylate 800 mg CMZ-edisylate is added and dissolved by stirring Further 10 mL aqueous sodium bicarbonate solution (50 mg/mL) at room temperature is added to adjust to the final volume. Precipitation is observed instantly.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Inorganic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Dermatology (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation parentérale de 5-(2-chloroéthyle)-4-méthylthiazole edisylate (plus connue sous l'appellation de clomethiazole édisylate) dont les propriétés antimicrobiennes améliorées viennent s'ajouter à la stabilité physique, chimique et microbiologique ainsi qu'à la compatibilité biologique.
EP00930026A 1999-05-06 2000-05-04 Formulation parenterale de 5-(2-chloroethyle)-4-methylthiazole edisylate(clomethiazole edisylate) Withdrawn EP1178798A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9901658A SE9901658D0 (sv) 1999-05-06 1999-05-06 New formulation
SE9901658 1999-05-06
PCT/SE2000/000876 WO2000067753A1 (fr) 1999-05-06 2000-05-04 Formulation parenterale de 5-(2-chloroethyle)-4-methylthiazole edisylate(clomethiazole edisylate)

Publications (1)

Publication Number Publication Date
EP1178798A1 true EP1178798A1 (fr) 2002-02-13

Family

ID=20415507

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00930026A Withdrawn EP1178798A1 (fr) 1999-05-06 2000-05-04 Formulation parenterale de 5-(2-chloroethyle)-4-methylthiazole edisylate(clomethiazole edisylate)

Country Status (7)

Country Link
EP (1) EP1178798A1 (fr)
JP (1) JP2002544164A (fr)
AR (1) AR023873A1 (fr)
AU (1) AU4792200A (fr)
SE (1) SE9901658D0 (fr)
TN (1) TNSN00094A1 (fr)
WO (1) WO2000067753A1 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK733888A (da) * 1988-01-12 1989-07-13 Fujisawa Pharmaceutical Co Stabiliseringsmiddel
IL91856A0 (en) * 1988-10-11 1990-06-10 Schiapparelli Salute Spa Pharmaceutical compositions comprising calcitonin for intranasal administration and a spray unit for the administration of the same
SE8900564D0 (sv) * 1989-02-17 1989-02-17 Astra Ab Novel medicinal use
SE9002659D0 (sv) * 1990-08-15 1990-08-15 Astra Ab New pharmaceutical formulations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0067753A1 *

Also Published As

Publication number Publication date
AU4792200A (en) 2000-11-21
AR023873A1 (es) 2002-09-04
WO2000067753A1 (fr) 2000-11-16
JP2002544164A (ja) 2002-12-24
TNSN00094A1 (fr) 2002-05-30
SE9901658D0 (sv) 1999-05-06

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