Title of Invention

LIMPID PARENTERAL FORMULATION OF 2,6 DIISOPROPHYLPHENOL

Abstract

Process for manufacturing of the pharmaceutical composition which comprises 2,6-disopropylphenol of formula (1) and 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol of formula (2) and optionally water and /or one more antioxidants, comprising adding said 2,6-diisopropylphenol and optionally one or more antioxidants to said compound of general formula(2) as defined above and if desired adjusting the pH of the solution obtained.

Full Text

THE PATENTS ACT, 1970 COMPLETE SPECIFICATION SECTION 10 PRODUCT PATENT FOR A PREPARATION OF A LIMPID PARENTERAL SOLUTION OF 2,6-DHSOPROPHYLPHENOL AS AN ANAESTHETIC DRUG AND l5-DI-0-METHYL-L4;3.6-DIANHYDRO-D-GLUC1TOL AS A SOLVENT FOR MAKING CLEAR I.V. FORMULATION THEMIS CHEMICALS LIMITED Indian company incorporated under the Companies Act, 1956, having its Registered Office at 11/12 Udyog Nagar Industrial Estate, S.V.Road, Goregaon (West), Mumbai - 400 104. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed: ORIGINAL GRANTED 8-11-2005 REFERENCES CITED Patent no. 3,219,529 Nov.23, 1965 U.S.Patent Robert Arnold Nash et al Patent no. 3,699,230 Oct.17, 1972 U.S. Patent Beauchamp, Jr.et. al. Patent no. 4,082,881 Apr.4, 1978 U.S. Patent Chen et al. Patent no. 4,228,162 Oct. 14,1980 U.S. Patent Luzzi et al. Field of lnvention This invention relates to a novel therapeutic formulation for a parentral application. The formulation is an economical stable potent limpid solution of a strong lipophilic anaesthetic compound 2,6-diisoprophylphenol. (l)More particularly it relates to a stable limpid composition with 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol (2) used as a solvent. Description of prior art 2,6-diisoprophylphenol (Propofol) is a known parenteral, short-acting general anaesthetic which is characterized by rapid onset of action and rapid recovery from anaesthesia without confusion or nausea. It is widely used, in the form of injections, by anaesthetists for induction and maintenance of anaesthesia and for sedation. The present commonly available formulation of 2,6-diisoprophylphenol, is in the form of emulsion. The compound 2,6-diisoprophylphenol is hpophilic as well as insoluble and immiscible in water. To prepare and formulate for use, its present pharmaceutical formulation - in emulsion form - involves high technology as well as a costly plant and machinery. In the past, efforts were made to prepare a solubilized clear injection. An attempt was made to prepare an injection in the form of a clear solution using Cremophor EL (Polyethxylated castor oil). This vehicle is a derivative of castor oil derived from plant origin. The formulation on administration lead to severe anaphylactic shocks, histamine release and reactions when tested in animals and humans, hence limiting its use and application. The emulsion formulation of 2,6-diisoprophylphenol also gave anaphylactic shocks in a patient while it was used and tried. (Ref: Laxenaire MC, et al, Anaphylactic shock due to propofol Lancet 1988 ii. 739 - 40) The preparation of the present marketed emulsion formulation of 2,6-diisoprophylphenol, requires special technology, also involves strict controls for aseptic production and filling. Monitoring the particle size of the emulsion as well as keeping the product in a homogenous form are very critical and essential parts of the technology. The presently marketed emulsion formulation of 2,6-diisoprophylphenol has certain further limitations in the form of its ingredients viz., egg phospholipid, soya oil, etc. These are natural products either of plant or animal origin which require strict quality control and monitoring. They are also a good source, as nutrients, for growth of micro organisms. Hence there is the need for an anti-microbial agent for protection against growth of microbes. Further once opened or diluted, the solution in glucose has to be utilized within a few hours, as fat emulsion is also a very favourable media for micro organism growth. The use of fat emulsion however has its limitations especially in patients suffering from fat metabolism, as continuous monitoring of the lipid level is required. The drug 2,6-diisoprophylphenol is soluble in PEG 300, however its use is limited because of large volumes of solvent required to prepare parentrals for attaining a satisfactory dose level. In addition to its solubility and manufacturing difficulties that have been inherited, it is confronted with the further difficulty of being available in only one strength which is 1O mg/ml. This does not allow for flexibility of dose. Dose adjustment, with the presently marketed emulsion formulation of 2,6-diisoprophylphenol, is difficult for anaesthetists when they use the drug in anaesthesia. The dose is calculated on body weight. Hence more flexibility is needed for anaesthetists to administer the drug. Even the administration of an anaesthetic drug needs high technique. After literature survey and since the time of development of the formulation containing 2,6-diisopropylphenol, there are no reports of such a limpid economical and safe preparation being prepared anywhere, in any laboratory. Thus the preparation of a stable and clear liquid solution of 2,6-diisoprophylphenol has become a classic pharmaceutical problem because of its high lipophilicity and insolubility in water. 2,6-diisoprophylphenol is soluble in solvents like ether, chloroform, etc., however the use of these solvents for therapeutic purposes viz., for intravenous application as an anaesthetic, is limited due to their toxicity. There is still a need for relatively stable, dose flexible anaesthetic solution, which can be conveniently filtered, sterilized and free from all the limitations of emulsion formulations. Compatibility with water is a desirable characteristic, as 2.5-di-O-methyl-1.4,3.6-dianhydro-D-glucitol is water soluble. The referred proposed formulation containing 2,6-diisoprophylphenol as the anaesthetic agent and 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol as the carrier solvent, is an effective, economic, stable preparation meeting all the criteria of an ideal formulation for anaesthesia. Summary of Invention Accordingly, one object of the invention is to provide a stable solvent carrier based composition which is a clear, limpid easily injectable formulation and which can be conveniently given intravenously, with flexibility of dose as per the need of the patient. Another object of this invention is to provide a stable formulation in various concentrations, which does not require any specialized high technique and cost, avoids derivatives of egg albumin and soya fat material and in turn avoids growth of micro organisms. Briefly these and other objectives of this invention, as hereunder, will be more apparent and can be attained by a pharmaceutical preparation which comprises of 2,6-diisoprophylphenol and 2.5-di-0-methyl-l.4;3.6-dianhydro-D-glucitol to make an ideal anaesthetic formulation. Description of the Preferred Embodiments We have used 2.5-di-0-methyl-l.4;3.6-dianhydro-D-glucitol as the vehicle for the injectable preparation. Preliminary studies from literature, surveys and further verification of the same on animal models viz., mice, have shown that 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol is non-toxic and water miscible. Following patents were referred and studied :- 1. Patent no. 3,219,529 Nov. 23, 1965 U.S. Patent Robert Arnold Nash 2. Patent no. 3,699,230 Oct. 17, 1972 U.S.Patent Beauchamp, Jr.et al. 3. Patent no. 4,082,881 April 4, 1978 U.S. Patent Chen et al. 4. Patent no. 4,228,162 Oct. 14, 1980 U.S. Patent Luzzi et al. After, studying the various patents as cited above and going through the literature, it is learned that the use of 2.5-di-0-methyl-1.4; 3.6-dianhydro-D-glucitol for formulation of intravenous anaesthesia or for similar requirements has never been tried. This invention, profoundly claims to be a totally novel invention - with the use of such non-toxic material in a therapeutic dosage - which has produced the "first-ever limpid, stable, economical, beneficial and acceptable intravenous injection It is seen from prior art that 2.5-di-0-methyl-l.4;3.6-dianhydro-D-glucitol has been used in formulations of tetracyclines, liquid formulations of aspirin, in the formulations of muscle relaxant drugs and that none of the above cited patents has ever used the parenteral formulation of 2,6-diisoprophylphenol. The drug 2,6-diisoprophylphenol was made soluble in the organic solvent 2.5-di-0-methyl-l.4;3.6-dianhydro-D-glucitol. Solubility of 2,6- diisoprophylphenol had been found to be very satisfactory in 2.5-di-O-methyl-I.4;3.6-dianhydro-D-glucitol and in various desired proportions, to produce a product of desired concentrations. Thus present invention involves discovery of 2.5-di-O-methyl-l 4;3.6-dianhydro-D-glucitol as an excellent and elegant solvent for anaesthetic agent 2,6-diisoprophylphenol. Thus varied concentrations, with various strengths of injections have been prepared viz., in the strengths of 5 mg/ml, 10 mg/ml, 50 mg/ml and 100 mg/ml which can be used by medical practitioners as per the choice of operative surgery or need of the patient, with or without dilution. The formulations have been found to be stable. The active ingredient 2,6-diisoprophylphenol neither shows degradation nor precipitates or crystallizes out in room temperature or cold conditions. Other additives, like Tocopherol or other anti-oxidants, may be optionally added to prepare the solution. The pH of the solution can be either natural pH or pH 7 adjusted potentiometrically with 0.1 M sodium hydroxide or with other suitable alkali. The drug 2,6-diisoprophylphenol, in a composition containing 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol, is safe and as effective as emulsion formulations available in the market. The studies carried out in our laboratory on animals like - mice, dogs and pigs, have shown that the drug 2,6-diisoprophylphenol, when conjuncted with 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol, is a potent inducer of anaesthesia with least side effects for internal use and it is found that 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol is easily metabolised. (Ref. Patent 4,228,162 Oct. 14, 1980 U.S. Patent Luzzietal) The results of the experiments are as follows :- TABLE - I Product Concentration No.of Mice/Group Duration of Anaesthesia I) Market sample 16.6 mg/ml 6 2.53 mins. (emulsion) II) Limpid sample (A) 16.6 mg/ml 6 4.52 mins. (B) 16.6 mg/ml 6 5.42 mins. Parameters Checked Loss of righting effect. Results of Study The duration of general anaesthetic was found to be longer in the test compounds, as compared to the marketed emulsion formulation of 2,6-diisoprophylphenol. The mice were observed for 96 hours and there was no adverse effect seen on the animal after the experiments. Having seen the effect of the initial induction of anaesthetic effect, further studies for the efficacy, against the presently available emulsion formulation of 2,6-diisoprophylpheno, were carried out in bigger animals like dogs and Pigs. Experiments for Induction of Anaesthesia in Dogs TABLE - II A With Market Preparation (Emulsion Formulation of 2,6-diisoprophylphenol) NO.OF ANIMALS DOSE 2MG/KGWT. PARAMETERS CHECKED BODY REFLEXES B.P. TEMP. RESPIRATION PULSE Dog l Slight sedation calming at 5 minutes 120/90 102°F 40 54 Neck move¬ment & pain reflexes. Dog 2 Slight sedation sleeping after 10 minutes 110/90 102°F 45 60 Neck move¬ment & pain Dog 3 Sedation in .30 secs.upto 3 minutes. Recovery: Head lift to Ataxia 7 mins. 120/90 101.5°F 50 62 Relaxed, no pain reflexes TABLE -II B With Limpid Formulation of 2,6-diisoprophylphenol NO.OF DOSE P PARAMETERS CHECKED BODY ANIMALS 2MG/KG WT. B.P. TEMP. RESPtRATION PULSE REFLEXES Dog 4 Sedation in 30 seconds lasted for 4.5 mins. Recovery: Head lift to Ataxia 6lth min. 120/90 102°F 45 53 Relaxed Dog 5 Sedation in 30 seconds lasted for 3.5 mins. Recovery: Head lift to Ataxia 6th min. 110/90 102°F 45 60 Relaxed Dog 6 Slight sedation Sleeping after 4 to 5 mins. Recovery: Head lift to Ataxia 6th min. 120/90 102°F 44 58 Neck move¬ment. Following parameters were studied : 1. Time of Induction, Recovery after initial administration. 2. B.P., Respiration, Pulse, Temperature - before and after injections. 3. Hb.,CBC, - before and after injections. 4. Dilation of pupils, sedation, pinch reflexes, peddle reflexes at the time of anaesthesia. 5. Any adverse effects. Conclusion: The onset of action in the clear formulation of the invention, was comparable and effect of the drug is slightly better as compared to the marketed emulsion formulation of 2,6-diisoprophylphenol. The physiological parameters during anaesthesia remained unaltered, before and after injection. The blood profile has also shown no changes when compared with the initial studies. Dogs were observed over a period of 72 hours after the experiments, to observe any adverse effect of anaesthesia. The observation revealed no adverse / abnormal effect or behaviour. Maintenance of Anaesthesia experiments, carried out on a single dog for one & half hour, showed that there was no toxicity at higher dose and physiological side effects too were the least. The Righting and Co-ordination effects too were not affected. Thus the total maintenance therapy of anaesthesia was found to be satisfactory. Further the same dog was observed for one week and there was no abnormal behaviour or effect post anaesthesia. TABLE - III Comparative Anaesthetic Activity of the Clear Formulations on Pigs (n = 2) Single Dose Study Activity Animal 1 (Wt.21 kgs.) Emulsion Formulation Dose 8.6 mg/kg in 30 secs. Animal 2 (Wt.23 kgs.) Clear Invented preparation 7.8 mg/kg in 30 secs Induction of 6.5 mins. 7.0 mins Anaesthesia Head lift to 22 mins. 25 mins. Ataxia Before After Before After Injection Injection Injection Injection Temperature Pulse 1010C . 94/min 101° 95/min 101°F 101°F 80/min 82/min Respiration 22/min 20/min 19/min 18/min INTERMITTANT LNJECTION (After Loading Dose) 2nd Dose of 8.5 mg/kg PIG1 2nd Dose of 7.8 mg/kg PIG 2 Induction Time 7 mins. 8.0 mins. Sleeping Time Total Recovery 25 mins 31 mins. 30 mins. 33 mins. TABLE - IV Maintenance of Anaesthesia - Emulsion Formulation Dose : 10 mg/minute Clear Invented preparation Dose: 10 mg/minute a. b. Maintenance of Anaesthesia Recovery Time End of Infusion To Head Lift up to "45 minutes 5 mins. up to 50 minutes 5.5 mins Following parameters were studied : 1. Any anaphylactic reaction, excitation. 2. B.P./Respiration / Pulse / Temperature / Before & After injection. 3. Hb., CBC, before & after injection. Observations: A. Clear invented formulation shows comparable activity for induction, maintenance and recovery of anaesthesia. There was no unexpected adverse reactions as compared to the emulsion formulation of 2,6- diisoprophylphenol. B. Repeated injections of the clear invented formulation, when given intravenously to the pig, did not give rise to any hypersensitivity reactions. There was no Bronchospasm, Tachycardia, respiratory distress or cardiac arrest even at higher dose. C. Recovery from anaesthesia was smooth with no excitatory reactions. D. Blood profile before and after injection showed no changes in both the preparations. E. Pigs were observed for 72 hours post anaesthesia and showed no anaphylactic reactions nor abnormal signs. Examples Examples, of preferred formulations in accordance with present invention, include but are not limited to the following :- Example 1 A solution containing 2.8 m.mol. of 2,6-diisoprophylphenol in 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol was prepared by stirring with 100 ml. of 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol - the natural pH is 5.3 read potentiometncally. The solution is stirred for 15 minutes in a hermatic condition, filtered aseptically and then filled and sealed in a vial / ampoule. Example 2 2.8 m.mol of 2,6-diisoprophylphenol is dissolved in sufficient 2.5-di-O-methyl-1.4; 3.6-dianhydro-D-glucitol, stirred for 15 minutes and the pH of solution adjusted with 0.1 M Sodium hydroxide to pH 7. The solution is made to 100 ml. with 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol. The solution is filtered aseptically, filled and then sealed in containers. Example 3 The addition of Tocopherol in the concentration range of 0.05%, 0.1% added to each of Example 1 and Example 2 to see the effect of anti-oxidant on the formulation. Example 4 The solution of Example 1, containing 5.61 mmol, 28.04 mmol and 56.09 mmol. of 2,6-diisoprophylphenol per 100 ml. of 2.5-di-O-methyl-l.4;3.6-dianhydro-D-glucitol containing 0.1% Tocopherol and without Tocopherol, with and without adjustment of pH to 7.O., was stirred for 15 minutes and prepared. In each of the preparations, solution filtered aseptically in a hermatic condition, filled and then sealed in amber vials. The stability studies carried out, on a selected set of formulations, show a retention of potency at room temperature (25°C) and even at accelarated temperature of 40°C / 60% RH. Summary of Stability Tests A: The following six formulations, each containing 10 mg/ml of 2,6-diisoprophylphenol in 2.5-di-0-methyl-I. 4;3.6-dianhydro-D-glucitol. "Three with and "Three without" pH adjustment, were studied for stability of formulations. The pH adjustment carried out by 0.1 M sodium hydroxide, filling and sealing in amber vials, the stability study at room temperature as well as the Accelerated study, reveal that the injections are very stable. The test for Assay content was carried out by stability indicating HPLC method. TABLE - V-A Clear Invented Preparation FORMULATION Drug Concentration 10 mg/ml ; pH 7.0 Initial Room Temp. 40°C/60%RH 3 months 3 months With Without With Without With Without VitE VitE VitE VitE VitE VitE A 98.9% 99% 98.8% 99.1% 98.5% 97.5% B 99.3% 99.6% 99.6% 99.5% 97.5% 96.8% C 100.3% 101% 100.1% 100% 93.5% 94.5% TABLE - V-B Emulsion Formulation Initial 99% Room Temp. 3 months 98.6% 40°C/60%RH 3 months 98.2% Similarly products with 5 mg/ml, 50-mg/ml and 100 mg/ml were found to be stable. Stability was carried out using stability indicating HPLC method. B: Similarly stabihty of the injections in concentrations of 5 mg/ml, 50 mg/ml and 100 mg/ml of drug using 0.1 M Sodium hydroxide for adjustment of pH7 and Potency study were carried out at room temperature as well as 40°C for 3 months and these too showed good stabihty. The method used for Assay was stability indicating HPLC method. TABLE - VI Formulation Room Temp. 40°C/60% RH 3 months 3 months 5 mg/ml 99.8% 97.6% 50 mg/ml 103 % 101.2% 100 mg/ml 101.6% 101.3% Thus if summarized it is seen that the following are the limitations of the past formulations :- 1. The Cremophor EL preparation used for solubalising 2,6-diisoprophylphenol had a high occurrence of pain at the site of injection. Analphylactic reactions associated with Cremophor EL & emulsion formulation of 2,6-diisoprophylphenol limits their use. 2. The soyabean oil, glycerine and purified egg phospholipids, require strict quality control checks and specialized technique during manufacture and during their usage in anaesthesia, to avoid micro organism growth. 3. Presently available market formulation of 2,6-diisoprophylphenol is available only in one strength. 4. There were reported cases of excitatory side effects and hypotension in emulsion form. Having now fully described the limitations of Cremophor EL as well as the emulsion formulation and the comparative advantages of our invention, it will be apparent to one ordinary in the skill of art that many changes and modifications can be made, without departing from the spirit or scope of the invention as set forth in. In utilizing the novel process of this invention, we have been able to obtain a new composition of the matter 2,6-diisqprophylphenol. WE CLAIM 1. Process for manufacturing of the pharmaceutical composition which comprises 2,6-diisopropylphenol of formula (1) and 2.5-di-0-methyl-1.4;3.6-dianhydro-D-glucitol of formula (2) and optionally water and / or one or more antioxidants, comprising adding said 2,6-diisopropylphenol and optionally one or more antioxidants to said compound of general formula (2) as defined above and if desired adjusting the pH of the solution obtained. 2. Process for manufacture of the pharmaceutical composition of 2,6-diisopropylphenol for parenteral application substantially as herein described and illustrated with reference to the examples. Dated this 28th day of January 1999 S. MAJUMDAR of S. Majumdar & Co. Applicant"s Agent

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