WO2000067753A1

WO2000067753A1 - Parenteral formulation of 5-(2-chloroethyl)-4-methylthiazole edisylate(clomethiazole edisylate)

Info

Publication number: WO2000067753A1
Application number: PCT/SE2000/000876
Authority: WO
Inventors: Ola Camber; Karin Ellström; Ingrid JÄPPINEN; Tomas PETERSSON-NORDÉN
Original assignee: Astrazeneca Ab
Priority date: 1999-05-06
Filing date: 2000-05-04
Publication date: 2000-11-16
Also published as: JP2002544164A; SE9901658D0; AR023873A1; EP1178798A1; TNSN00094A1; AU4792200A

Abstract

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.

Description

PARENTERAL FORMULAΗON OF 5-(2-CHLOROETHYL>-4-METHYLTHIAZOLE EDISYLATE(CLOMETHIAZOLE EDISYLATE)

Field of the Invention

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.

Background of the Invention

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. However, this composition can not be used for treatment of neurode generation since dextrose is considered contra-indicated for this therapeutic indication.

Pharmaceutical products that are aseptically filled (i.e. terminally sterilized by filtration through a 0.22 μm filter) are extra sensitive to microbiological contamination during the manufacturing process. It is therefore considered a great advantage if the drug substance itself exhibits antimicrobial properties, both from a manufacturing point of view as well as for safety reasons (i.e. possible contamination due to damage caused during handling and storage of the product at the clinic). For multidose products it is a regulatory demand that they contain a preservative. If the pharmaceutical substance itself fulfils the regulatory requirements put on preservatives, this is considered a great advantage since the need for adding a preservative is abolished.

Since clomethiazole edisylate is sensitive to heat it should accordingly not be terminally heat sterilized by for example autoclavation, the most common method for terminal sterilization. Therefore, 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.

Brief Disclosure of the Invention

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.

It has surprisingly been found that when comparing the formulation according to the invention with the current market formulation of clomethiazole edisylate, Heminevrin®, the formulation according to the invention shows a significantly better antimicrobial efficacy. There is no verified antimicrobial efficacy in sodium chloride 8 mg/mL or dextrose monohydrate 40 mg/mL and the concentration of clomethiazole edisylate is exactly the same in Heminevrin® and the formulation according to the invention. Due to this, no difference in efficacy between Heminevrin® and the present invention was expected but surprisingly, sodium chloride seems to improve the antimicrobial efficacy of clomethiazole edisylate compared to dextrose monohydrate.

Accordingly, 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. For the sake of simplicity 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.

Detailed Disclosure of the Invention According to the present 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

- clomethiazole edisylate

- water and - sodium chloride

Hereinafter, the amounts of each of the ingredients in the compositions are expressed as percentages by weight based on the total volume of the formulation, unless otherwise indicated.

In one particular aspect of the invention, 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 %.

Further, the formulation in this aspect of the invention comprises from 0.1 to 1.8 % 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. Preferably, 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. Preferably, the pH of the formulations is adjusted by addition of appropriate amounts of sodium hydroxide.

Optionally an acid substance, such as hydrochloric acid, may be used to adjust the pH of the final formulation.

Preferably, this aspect of the invention relates to formulations comprising: (a) 0.1 to 2.0 % clomethiazole edisylate;

(b) 0.1 to 1.8 % sodium chloride;

(c) optionally sodium hydroxide to adjust the pH in the range from 2.0 to 8.5; and

(d) water q.s. ad 100%.

More preferred are formulations comprising

(a) 0.4 to 1.0 % clomethiazole edisylate;

(b) 0.7 to 0.9 % sodium chloride;

(c) optionally sodium hydroxide to adjust the pH in the range from 4.5 to 8.0; and

(d) water q.s. ad 100%.

Most preferred are formulations comprising

(a) 0.7 to 0.9 % clomethiazole edisylate;

(b) 0.7 to 0.9 % sodium chloride;

(c) optionally sodium hydroxide to adjust the pH in the range from 6.0 to 8.0; and (d) water q.s. ad 100%.

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%-.

Further, 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.

Preferably, the preparation involves the following steps:

(a) charging the main part of the water

(b) cooling to room temperature (c) charging sodium chloride and dissolving by stirring

(d) charging clomethiazole edisylate and dissolving by stirring

(e) optionally charging base substance

(f) optionally adjusting pH by slowly adding further base and/or acid substance

(g) adjusting to final volume by adding water (h) terminally sterilizing the solution using sterile filtration

Step h) may be conducted by filtering the solution through a sterile membrane filter of pore size at most 0.22 μm.

The above procedure may be conducted under an inert atmosphere, e.g. nitrogen or oxygen-free argon.

The preparation of clomethiazole edisylate is described in e.g. GB 847 520.

The term "antimicrobial properties" and "antimicrobial efficacy" as used herein refers to the ability to reduce the amount of microorganisms.

The term "physical stability" as used herein 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.

The term "chemical stability" as used herein 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.

The term "microbiological stability" as used herein refers to a formulation which fulfils the pharmacopoeia requirements regarding sterility and endotoxins after 3 years of storage at +2-+8°C.

The term "biological compatibility" as used herein refers to a formulation not containing any ingredients considered as contra-indicative in stroke treatment.

Method of Preparation

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.

Medicinal Indication

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. In general it is contemplated that 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

Route of Administration The new formulation of clomethiazole edisylate is to be parenterally administered as for instance an injection or preferably as an intravenous infusion In acute stroke treatment 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

Stability and Compatibility

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 Moreover, the new formulation does not contain any ingredient which is considered as contra-indicative in stroke treatment

The following examples are intended to illustrate but not limit the scope of the present invention

Examples

Example 1

Clomethiazole edisylate 8 mg/mL (containing 8 mg/mL sodium chloride and pH ad_justed 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 Λureus, 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.

RESULTS AND CONCLUSION FROM Example 1

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®.

For S. Aureits the difference between to two formulations was more than 10 times after 60 minutes and there was also a difference in efficacy after 2 and 4 hours.

For C. Albicans the difference between to two formulations was more than 10 times after 2, 4 and 6 hours.

For A. Niger the difference between to two formulations was more than 10 times after 6 days and after 11 days there were no detectable micro organisms in the formulation

3 according to the invention while 2. Ox 10 CFU/mL were found in Heminevrin®.

For Pen. Chrysogemtm the difference between the two formulations was more than 10 times after 30 and 48 hours as well as after 3 days.

In conclusion it is obvious that the formulation according to the invention exhibits much better antimicrobial efficacy than the commercial product Heminevrin®.

Example 2

90 mL water is charged and cooled to room temperature. 800 mg sodium chloride and 800 mg CMZ-edisylate are added and dissolved by stirring. 0.5 mL sodium hydroxide 5 M is added and pH is adjusted by slow addition of sodium hydroxide 2 M so as to obtain the pH of 7.4. 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 μm sterile membrane. Example 3

90 mL water is charged and cooled to room temperature 800 mg sodium chloride and 500 mg CMZ-edisylate are added and dissolved by stirring 0 3 mL sodium hydroxide 5 M is added and pH is adjusted by slow addition of sodium hydroxide 2 M so as to obtain the pH of 7 4 About 10 mL water at room temperature is added in order to ad_just to the final volume The solution is filtered through a 0 22 μm sterile membrane

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_justed 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 μm sterile membrane

Example 5

90 mL water is charged and cooled to room temperature 600 mg sodium chloride and 2000 mg CMZ-edisylate are added and dissolved by stirring The resulting pH in the solution is about 2 About 10 mL water at room temperature is added in order to ad_just to the final volume The solution is filtered through a 0 22 μm sterile membrane

Comparative examples

In Comparative Examples 1-2 below sodium bicarbonate and Tribonate^® were used as both an isotonizing agent and a buffer instead of sodium chloride and sodium hydroxide as in Examples 1-2 above

Comparative Example 1

90 mL aqueous sodium bicarbonate solution (50 mg/mL) is charged at room temperature

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.

Comparative Example 2 90 mL Tribonate^® (solution containing: Trometamol. sodium bicarbonate, disodiumphosphate, acetic acid) is charged at room temperature. 800 mg CMZ-edisylate is added and dissolved by stirring. About 10 mL Tribonate^® at room temperature is added to adjust to final volume. Precipitation is observed instantly.

RESULTS AND CONCLUSIONS FROM Examples 2-5 and Comparative Examples 1-2

Dissolving 800 mg CMZ-edisylate in either 100 mL sodium bicarbonate (50 mg/mL) or 100 mL Tribonate^® results in precipitation.

Claims

1. A formulation for parenteral administration comprising water, clomethiazole edisylate and sodium chloride.

2. A formulation according to claim 1 comprising from about 0.1 %(w/v) to about 2.0 %(w/v) of clomethiazole edisylate of the total formulation.

3. A formulation according to claim 2 comprising from about 0.4 %(w/v) to about 1.0 %(w/v) of clomethiazole edisylate.

4. A formulation according to claim 3 comprising from about 0.7 %(w/v) to about 0.9 %(w/v) of clomethiazole edisylate.

5. A formulation according to claim 1 comprising from about 0.1 %(w/v) to about 1.8 %(w/v) of sodium chloride.

6. A formulation according to claim 5 comprising from about 0.7 %(w/v) to about 0.9 %(w/v) of sodium chloride.

7. A formulation according to claim 1 optionally comprising a base substance and optionally an acid substance to adjust the pH of the formulation in the range from 2.0 to 8.5.

8. A formulation according to claim 7 comprising a base substance and optionally an acid substance to adjust the pH of the formulation in the range from 4.5 to 8.0.

9. A formulation according to claim 8 comprising a base substance and optionally an acid substance to adjust the pH of the formulation in the range from 6.0 to 8.0.

10. A formulation according to claim 7 wherein the base substance is sodium hydroxide.

1 1. A formulation according to claim 1 comprising:

(a) 0.1 to 2.0 % clomethiazole edisylate;

(b) 0.1 to 1.8 % sodium chloride; (c) optionally sodium hydroxide to adjust the pH in the range from 2.0 to 8.5; and

(d) water q.s. ad 100%.

12. A formulation according to claim 1 1 comprising:

(a) 0.4 to 1.2 % clomethiazole edisylate; (b) 0.7 to 0.9 % sodium chloride;

(c) optionally sodium hydroxide to adjust the pH in the range from 4.5 to 8.0 ; and

(d) water q.s. ad 100%.

13. A formulation according to claim 12 comprising: (a) 0.7 to 0.9 % clomethiazole edisylate;

(b) 0.7 to 0.9 % sodium chloride;

(c) optionally sodium hydroxide to adjust the pH in the range from 6.0 to 8.0 ; and

(d) water q.s. ad 100%.

14. A formulation according to claim 13 comprising approximately:

(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%.

15. A process for preparing a formulation according to any one of claims 1 to 14 characterized by

(a) charging the main part of the water

(b) cooling to room temperature (c) charging sodium chloride and dissolving by stirring (d) charging clomethiazole edisylate and dissolving by stirring

(e) optionally charging base substance

(f) optionally adjusting pH by slowly adding further base and/or acid substance

16. The use of a formulation according to any one of claims 1 to 14 for the prevention or treatment of neurodegeneration.

17. The use according to claim 16 for the prevention or treatment of stroke, such as acute stroke, cerebral ischaemia, hypoxia or spinal cord injury.

18. The use according to claim 17 for the prevention or treatment of acute stroke.

19. A pharmaceutical formulation comprising water, clomethiazole edisylate and sodium chloride for use in the prevention or treatment of neurodegeneration.

20. A pharmaceutical formulation according to claim 19 for use in the prevention or treatment of neurodegeneration in connection with stroke, such as acute stroke.

21. A pharmaceutical formulation according to claim 19 for use in the prevention or treatment of neurodegeneration in connection with cerebral ischaemia.

22. A pharmaceutical formulation according to claim 19 for use in the prevention or treatment of neurodegeneration in connection with hypoxia.

23. A pharmaceutical formulation according to claim 19 for use in the prevention or treatment of neurodegeneration in connection with spinal cord injury.

24. A method for the treatment or prevention of neurodegeneration by administering to a mammal including man in need of such a treatment a pharmaceutical formulation defined in any of claims 1-14.

25. A method for the treatment or prevention of neurodegeneration according to claim 24 in connection with stroke, such as acute stroke, by administering to a mammal including man in need of such a treatment a pharmaceutical formulation defined in any of claims 1-14.

26. A method for the treatment or prevention of neurodegeneration according to claim 24 in connection with cerebral ischaemia by administering to a mammal including man in need of such a treatment a pharmaceutical formulation defined in any of claims 1-14.

27. A method for the treatment or prevention of neurodegeneration according to claim 24 in connection with hypoxia by administering to a mammal including man in need of such a treatment a pharmaceutical formulation defined in any of claims 1-14.

28. A method for the treatment or prevention of neurodegeneration according to claim 24 in connection with spinal cord injury by administering to a mammal including man in need of such a treatment a pharmaceutical formulation defined in any of claims 1-14.