WO2000072848A1

WO2000072848A1 - Composition comprising (±)-5-ethyldihydro-5-(1-methylbutyl)-2-thioxo 4,6(1h,5h)-pyrimidinedione dissolved in 2,5-di-o-methyl-1,4:3,6-dianhydro-d-glucitol

Info

Publication number: WO2000072848A1
Application number: PCT/IN1999/000048
Authority: WO
Inventors: Dinesh Shantilal Patel; Shashikant Prabhudas Kurani
Original assignee: Dinesh Shantilal Patel; Shashikant Prabhudas Kurani
Priority date: 1999-05-31
Filing date: 1999-09-14
Publication date: 2000-12-07
Also published as: AU1889000A

Abstract

This invention relates to an injectable ready-to-use formulation of THIOPENTAL the chemical name of which is (±)-5-Ethyldihydro-5-(1-methylbutyl)-2-thioxo 4,6(1H,5H)-Pyrimidinedione and which is used in inducing anaesthesia. The invention utilizes crysalline THIOPENTAL which is dissolved in 2,5-di-O-methyl-1,4:3,6-dianhydro-D-glucitol, which is a biologically acceptable non-toxic solvent, for administration parenterally to mammals including humans.

Description

COMPOSITION COMPRISING (±)-5-ETHYLDI -T)RO-5-(l-METΗYLBUTYL)-2-TI-IOXO 4,6(1H,5H)-PYR-M- IDINEDIONE DISSOLVED IN 2,5-DI-0-METHYL-l,4:3,6-DIANHYDRO-D-GLUCITOL

Technical Field

This invention relates to an improved pharmaceutical composition, which may be administered parenterally to a mammal for the production of general anaesthesia, more specifically to a limpid, stable, injectable pharmaceutical formulation comprising Thiopental dissolved in 2,5-di- 0-methyl-l,4:3,6-dianhydro-D-glucitol. Backeround Art

Thiopental has the chemical name (±)-5-Ethyldihydro-5-(l-methylbutyl)-2-thioxo 4,6(lH,5H)-Pyrimidinedione. Thiopental Sodium is a synthetic compound also known in the literature as Thiomembunal Sodium, Penthiobarbital Sodium, Intraval Sodium, Pentothal Sodium and Trapanal. The drug is administered intravenously as 'Sodium Salt' only since its introduction. [U.S.Patent nos. 2,153,729 (1939); 2,876,225 (1959); 3,109,001 (1963).]

Thiopental Sodium is used for induction of general anaesthesia or production of complete anaesthesia of short duration. (Extrapharmacopia 30^th addition, page 920, Edited by James E.F. Reynolds, Published by - Royal Pharmaceutical Society of Great Britian). The ultra short acting effect is attributed to CNS depression to produce anaesthesia without analgesia. Other uses may include - the supplementation of regional anaesthesia or low potency agents such as nitrous oxide or for control of convulsive state or for use in hypnosis.

It is also used as an aid for diagnosis and treatment of a variety of disorders in psychiatry, (i) Drug Facts and Comparisons, 50^th Ed., 1996, page 1641 ; (ii) Prescription Products Guide Vol.II 1990, pp 867-868, 1245 - Australian Pharmaceutical Publishing Co.Ltd., Melbourne, Australia through "Florey". Analytical Profile of Drug Substances and Excipients, Vol.21).

Thiopental Sodium, is soluble in water yielding an alkaline solution having a pH of 10. The solution is to be prepared at site before administration to patients by mixing lyophilized Pentothal sodium and water. [Handbook of Injectable Drugs - (Published by American Society of Hospital Pharmacist) - 8^th Edition, Page 993].

Thiopental Sodium is a lyophilized or precipitated powder filled in vials aseptically. The presently available formulation of Pentothal sodium requires a special aseptic expensive process and technique for the preparation. The process described in prior art and in vogue requires special quality control measures since the preparation involves dissolution of the sodium salt of Thiopental, and evaporation or precipitation of the drug substance from the solvent for aseptic preparation. The presently available Thiopental Sodium is available along with anhydrous sodium carbonate as buffer in vials or bottles. Before administration of Thiopental Sodium along with anhydrous sodium carbonate as buffer filled in vials or bottles, it is dissolved with sterile water and the contents are shaken vigorously to ensure that all the Thiopental Sodium goes into the solution and then the required amount is taken from the vial for administering intravenously to patients. As a result of the various transfers that could take place, there is a likelihood of microbial contamination of the drug substance thereby causing considerable problem both to the administrator and patient. Moreover, an aqueous solution once prepared has to be preserved at a temperature of about 25°C otherwise the material starts deteriorating. Thiopental being a weak acid, the pH of Thiopental Sodium in aqueous solution is highly alkaline viz., 10.2 or thereabouts.

As mentioned hereinbefore, Thiopental is insoluble in water and it has to be converted to the Sodium Salt to render it soluble. The manufacture of Thiopental Sodium, as practised in prior art involves synthesis of Thiopental Sodium from Thiopental. This is a lengthy and tedious process, involving costly instruments for conversion. It also adds one more step to the synthesis of the drug i.e., the conversion of acid to Sodium salt. It might be mentioned that the synthesis of Thiopental Sodium involves a reaction between Thiopental and an alkali metal alkoxide such as sodium ethoxide in Ethanol. Thiopental Sodium being hygroscopic, the material has to be preserved in an environment whose relative humidity is strictly controlled.

The Sodium Salt thus prepared has to be lyophilized in sterile conditions or Sodium Salt has to be precipitated out under sterile conditions. Sterile Sodium Salt is also hygroscopic hence careful humidity control is an absolute necessity during the process of drying and packing. The process is cumbersome because all the unit operations / processes have production to be carried out in an aseptic area. The process is expensive too because of high requirement of environmental and other parameter controls which consumes substantial power / electricity and thus increasing the cost of production.

Further, Thiopental Sodium has several limitations including a- pH dependence of the precipitation of Thiopental from aqueous Thiopental Sodium solution. b. Divalent and Trivalent metal ions can form through double decomposition insoluble carbonates like Magnesium carbonate, Calcium carbonate, etc., rendering the drug substance useless for obvious reasons, c. Any contamination of an amine salt which liberates free base in alkaline solution also renders the preparation useless. (Ref: Florey, Analytical Profile of Drug Substances & Excipients - Vol.

21).

Furthermore, it is very difficult very often to find veins in emaciated patients, a common occurrence in countries like India, where a large number of people suffer from malnutrition and under-nourishment. If Thiopental Sodium is injected accidentally in the arteries of such patients, it may lead to severe arterial spasm with intense burning pain, the occurrence of anaesthesia, paresis, paralysis and gangrene. (Ref: Martindale 30^th Ed., The Extra Pharmacopia).

There are references in literature where Thiopental mixed with glycine and sodium hydroxide has been used. However the pH of such mixtures is also on the alkaline side like 9.0 hence there is a limitation of use of such type of formulations. Thiopental Sodium is insoluble in other therapeutically acceptable solvents. Disclosure of the Invention

The applicants have found that crystalline Thiopental may be provided in the form of ready- to-use storage-stable and sterile injectable solution when it is dissolved in 2,5-di-O-methyl-l,4:3,6- dianhydro-D-glucitol. Thus the present invention relates to a solution of Thiopental in 2,5-di-O-methyl-l,4:3,6- dianhydro-D-glucitol having a pH in the range of 3.5 to 6.5. The solution optionally contains water at a concentration up to 5%.

According to a preferred aspect an injection form of the solution contains 5 mg/ml to 100 mg ml of 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol in combination with water in proportions of between 0-5%.

The present invention also relates to a process for preparing the solution according to the invention which comprises mixing Thiopental with 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol under heating and recovering a clear solution from the mixture. Preferably, 2,5-di-O-methyl-l,4:3,6-dianhydro-D-g-ucitol is added to Thiopental under heating at temperature of between 25-50°C, the mixture is allowed to cool and a clear, transparent solution is recovered by filtration.

The solution is then submitted for conventional aseptic filtration for injectable preparations and kept in hermetic conditions - sealed in ampoules / vials ready for medical use.

Importantly the pH of the solution of Thiopental and 2,5-di-O-methyl-l,4:3,6-dianhydro-D- glucitol is 6.0 thus avoiding all the problems associated with higher pH mentioned hereinbefore. There is no need for external addition of alkali to solubilize this preparation and direct acid form of drug has been used - thus making it a 'ready-to-use' formula, which can remain quite stable for a long period.

The solution according to the invention is stable at temperature between 2 and 35°C. The solution may be provided in single dose / multi dose injectable forms.

The solubility of Thiopental in the solvent 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol is 125 gms. per litre at 30°C.

This invention also provides a formulation which is stable within the temperature range between 2-35°C, which is a vast improvement over the existing formulation of Thiopental Sodium in water as described in prior art.

The process for preparing the solution of the invention will now be illustrated with the help of the following non-limiting example:

EXAMPLE

Preparation of Thiopental dissolved in 2-5-di-O-πιethyl-l,4;3-6-dian-rydro-D-glucitol

12.5 g of Thiopental was taken in a round bottom flask having stirring attachment and facility to heat and Nitrogen flushing. 80 ml of 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol was slowly added and heated at 40°C for 30 minutes. The mixture was cooled to room temperature. The Oxygen level was measured and when it reached 1 ppm it was taken out of the flask and mixture was made up to 100 ml with 2,5-di-O-methyl-l ,4:3.6-dianhydro-D-glucitol. Nitrogen was flushed and filtered through 0.2 μ filter previously approved for its integrity. Ampoules and vials were filled under Nitrogen atmosphere by controlling the amount of residual oxygen in the head space below 1%.

Animal experiments as to anaesthetic effect were carried out using the Thiopental sodium of prior art Vs the Thiopental according to the invention and the experimental data is furnished in TABLE- 1 below. Further details as to the evaluation of anaesthetic activity are also furnished below under the wording "Evaluation of General Anaesthetic Activity of Test Injection".

TABLE - 1

The data, with reference to 'B', clearly indicates the superiority of the invented formulation over that of the currently available market preparation viz., which is mentioned under 'A', as far as duration of anaesthesia is concerned. The test was carried out at the BOMBAY COLLEGE OF PHARMACY, Kalina, Santacruz, Mumbai.

The TABLE- 1 also indicates, that the cost of conversion of acid to sodium form of Thiopental is reduced without the efficacy of the drug being effected. Evaluation of General Anaesthetic Activity of Test Injection

Summary; The test agent (125 mg/ml, acid form) at the dose of 400 μg i.v. produced general anaesthetic activity. It produced a significant increase in the duration of anaesthesia as compared to Thiopental sodium injection (400μg i.v.). The placebo did not show anaesthetic activity. Materials and Methods: Test System Source Animal house of Biology College of Pharmacy,

Mumbai - 98. Number of Groups Number of animals 6 per group

Body weight 20 - 25 gms.

By unique cage number and individual markings

Acclimatization 5 days under test conditions

Accomodation Animals were housed in groups of 6 of either sex in polypropylene cages with wire mesh top and rice husk.

Diet Pelleted mice feed supplied by Lipton India Ltd., ad libitum. Water Tap water supplied by BrihanMumbai Municipal Corporation, ad libitum.

Test Material

Common name - Test Injection: (Thiopental 125 mg/ml) Manufactured by Themis Chemicals Ltd., Mumbai.

- Reference Standard : Thiopental sodium injection, manufactured by Abbot Laboratories Mumbai.

- Placebo: 20% PEG 400

Treatment

Route of Adminsitration Intravenous (through tail vein of mice)

Dose Levels -

Method:

Loss of righting reflex :

The mice were given intravenous injections of the test as well as standard agents through the tail vein. The mice were then laid on their back. If the mouse failed to right itself within a short while, it was deemed to be unconscious. The time required for the animal to recover from the loss of righting reflex and regain its normal posture was recorded as the duration of anaesthesia.

Standardization of dose of anaesthesia : Serial dilutions of the reference standard injection of Thiopental sodium were made in distilled water and tested for anaesthetic activity. The lowest dose of standard which produced anaesthesia was determined and selected for testing. Dilutions of the test injection were made using PEG 400 and distilled water.

Results :

Animals treated with the test agent and the reference standard produced general anaesthetic activity in mice. The test agent exhibited a significant increase in the duration of anaesthesia. The placebo had no significant anaesthetic activity.

Conclusion :

The test agent at the dose of 400 μg i.v., produced general anaesthetic activity in mice. The duration of general anaesthetic was found to be longer in the test compound as compared to the reference standard.

Stability Assay

The stability of Thiopental according to the invention is demonstrated in TABLE-II below. The Assay of Thiopental, for its potency, was carried out by Stability Indicating Method which is also tabulated under TABLE-II.

TABLE - II

STABILITY STUPI S OF mtømNTAt INJECTION*

Plain Solution

REMARKS : 1) The product is found stable at 25°C ± 2°C / 60% RH ± 5% upto six months 2) The product is found stable at 40°C ± 2°C / 75% RH ± 5% upto three months

if) Advantages of the product according to the invention

• The product is stable. On prolonged storage - sterile Thiopental sodium in 2,5-di-O-methyl- l,4:3,6-dianhydro-D-glucitol - does not crystallize and precipitate out nor does it decompose.

• The solution of Thiopental and 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol can withstand a wide range of temperature fluctuations. A condition which is very important in countries like India where most of the primary health centres, district authorities, etc., do not have the facilities for keeping substances at controlled temperature and humidity.

• Thiopental with 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol does not have any adverse biological activity and is non-toxic at appropriate doses.

• Cost effective, application is safe and smooth and strength of injection may be varied.

• Obviates the limitations associated with Thiopental sodium as hereinbefore stated.

Advantages of the process for preparing the product according to the invention

• is simple, economic and does not use a tedious process of lypholization ;

• minimizes, if not eliminates chance of microbial contamination ;

• does not require any specialized technique and equipment for preparation and for administering the solution.

Claims

1. A pharmaceutical composition which comprises: (±)-5-Ethyldihydro-5-(l-methylbutyl)-2-thioxo 4,6(lH,5H)-Pyrimidinedione dissolved in 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol

2. A pharmaceutical composition as claimed in Claim 1, further comprising water.

3. A pharmaceutical composition as claimed in anyone of Claims 1 or 2 wherein the concentration of (+)-5-Ethyldihydro-5-(l-methylbutyl)-2-thioxo 4,6(lH,5H)-Pyrimidinedione is between 5 mg and 100 mg/ml of the composition.

4. A pharmaceutical composition as claimed in anyone of Claims 2 or 3, wherein concentration of water is up to 5%.

5. A pharmaceutical composition as claimed in any one of Claims 1 to 4 which has pH between 3.5 to 6.5.

6. A pharmaceutical composition as claimed in any one of the preceding claims which is in the form of injectables in single dose or multiple dose container.

7. A process for preparing the pharmaceutical composition as claimed in Claim 1 which comprises mixing thiopental and 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol under heating and recovering a clear solution from the mixture.

8. A process for preparing the pharmaceutical composition as claimed in claim 7 wherein said mixing of thiopental and 2,5-di-O-methyl-l,4.3,6-dianhydro-D-glucitol under heating is carried out and a clear solution having pH in the range of 3.5 to 6.5 is recovered.

9. A process for preparing the pharmaceutical composition as claimed in anyone of Claims 7 or 8 wherein the amount of (±)-5-Ethyldihydro-5-(l-methylbutyl)-2-thioxo 4,6(1H,5H)- Pyrimidinedione and 2,5-di-O-methyl-l,4:3,6-dianhydro-D-glucitol is so selected that (±)-5- Ethyldihydro-5-(l-methylbutyl)-2-thioxo 4,6(lH,5H)-Pyrimidinedione present in the composition is between 5 mg/ml and 100 mg ml of the composition.

10. A process for preparing the pharmaceutical composition as claimed in anyone of Claims 7 to

9 wherein water is added to the mixture in amounts such that the concentration of water in the composition is up to 5%.

11. A process for preparing the pharmaceutical composition as claimed in anyone of Claims 7 to

10 wherein the step of mixing is effected at temperature of between 25-50°C and thereafter the mixture is allowed to cool and the solution is recovered by filtration.

12. A process for preparing the pharmaceutical composition as claimed in Claim 11 wherein the solution is subjected to conventional aseptic filtration of injectable preparations and kept in hermetic conditions in ampoules / vials ready for medical use.

13. Use of the injectable pharmaceutical composition comprising Thiopental dissolved in 2,5-di- O-methyl-l,4:3,6-dianhydro-D-glucitol for parentral administration to a mammal for producing general anaesthesia.

14. A pharmaceutical composition and a process for preparing the same substantially as hereindescribed and illustrated with reference to the example.