Indian Patents. 219419:PROPOFOL EMULSION COMPOSITIONS FOR INTRAVENOUS ADMINISTRATION

Title of Invention	PROPOFOL EMULSION COMPOSITIONS FOR INTRAVENOUS ADMINISTRATION
Abstract	The present invention discloses Propofol oil-in-water emulsion composition comprising capric and / or its water soluble alkali salts as preservative to prevent proliferation of microorganisms due to any accidental contamination of the composition during prolonged intravenous administration.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) AND THE PATENT RULES, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) Title of the Invention: “Propofol Emulsion Compositions for Intravenous Administration " Applicant(s): (a) Name (b) Nationality (c) Address BHARAT SERUMS & VACCINES LTD. An Indian company incorporated under the Companies Act 1956. 16th Floor, Hoechst House Nariman Point Mumbai 400 021. Maharashtra, India The following specification particularly describes the invention and the manner in which it is to be performed This invention relates to Propofol oil-in-water emulsion composition for intravenous administration. This invention particularly relates to Propofol in oil-in-water emulsion composition having compounds capable of preventing proliferation of any accidental extrinsic contamination of the composition during prolonged administration. Background and Prior arts Propofol (2,6-Diisopropylphenol) is a well-known and widely used intravenous anesthetic agent. Propofol administration is painful; therefore Propofol is diluted with oils and provided as oil-in-water type emulsion for intravenous injections. The Propofol / soybean oil emulsion has gained widespread use for induction and/or maintenance of anesthesia, for maintenance of monitored anesthesia care and for sedation in the Intensive Care Unit (ICU). It is advantageous in that it possesses both a rapid onset anesthesia and a short recovery time. Intravenous Propofol emulsion compositions are continuously infused for sedation of seriously ill patients. However, the presence of vegetable oils and phospholipids makes the emulsion highly prone to the risk of microbial growth due to adventitious extrinsic contamination especially during long term use in patients undergoing ICU sedation. There are noscomial (i.e. hospital acquired) infections observed very often in ICU patients. Microbial contamination of total intravenous nutritional emulsion formulation supplements, administered through infusion sets, is recognized as one of the main reasons of noscomial infection among ICU patients. Hence it is recommended that the intravenous administration sets be changed frequently, at least every 6 or 12 hours. Continuous infusion makes the product susceptible to microbial growth. 2 In order to reduce the risk of uncontrolled microbial growth, additions of various potential preservatives into intravenous Propofol emulsion compositions have been tried. Some of the potential agents found to cause instability of the emulsion. Other potential agents failed to provide the level of antimicrobial activity being sought. It is necessary to preserve the compositions with preservatives that would provide the required levels of antimicrobial activity at as low a concentration as possible in order to minimise the potential for physical instability and to minimise toxicity concerns. US 5714520, (1998) discloses an oil-in-water emulsion of Propofol containing an edetate as an antimicrobial agent. Edetate has been shown to delay but not to prevent the onset of microbial growth in Propofol emulsions (see WO-A-00/24376, infra). Propofol emulsion compositions are required to be diluted up to 5 times (1:4) for long-term infusion. On dilution the edetate concentration gets reduced to 0.0011%. Edetate alone is found to be ineffective in preventing a no more than 10 fold increase in broad-spectrum microbial growth at concentrations of 0.0025% and below (see US-A-6028108; infra). Edetate acting as a preservative in this formulation is a metal ion chelator that removes essential trace elements like zinc. This can be potentially dangerous to patients who are administered Propofol for a prolonged duration as it will cause deficiency of zinc in certain individuals. Even the manufacturer of this product recommends supplemental zinc therapy to overcome the untoward effects. US 6469069 (2002): An oil-in-water emulsion of Propofol containing a sulphite as an antimicrobial agent has been described in this patent. The amount of sulphite preferably is in the range 0.0075% to 0.66% by weight. 3 The use of sulphite has two problems; viz. (a) stability of the emulsion is affected and (b) it is potentially toxic material at little higher dose level. US 6028108 (2000): An oil-in-water emulsion of Propofol containing a pentetate as an antimicrobial agent has been described in this patent. Pentetate, as used herein, refers to diethylene triamine pentaacetate or "DTPA", and derivatives thereof. In general suitable derivatives of DTPA are those salts having lower affinity for DTPA than calcium. Particular derivatives include but are not limited to calcium trisodium pentetate. The invention is a sterile pharmaceutical composition for parenteral administration comprising an oil-in-water emulsion of Propofol and an amount of pentetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination. Pentetate acting as a preservative in this formulation is a metal ion chelator that removes cations like calcium, magnesium and zinc. This can be potentially dangerous to patients who are administered Propofol for a prolonged duration. US 6140373 & US 6140374, (both 2000) discloses an oil-in-water emulsion of Propofol containing an antimicrobial agent selected from (a) benzyl alcohol alone or, preferably, together with either sodium edetate or sodium benzoate and (b) benzethonium chloride. For long-term use, the antimicrobial agents such as benzyl alcohol and benzethonium chloride are not recommended as they are toxic US 6177477, (2001) discloses sterile pharmaceutical compositions for parenteral administration containing Propofol in an oil-in-water emulsion containing tromethamine (i.e. 2-amino-2-hydroxymethyl-1,3-propanediol) as an antimicrobial agent. However, tromethamine is known to cause extravasation at the site of 4 injection and may cause tissue damage and also is reported to cause respiratory depression. Further, the pH of the composition is highly alkaline and will degrade phospholipids and Propofol on long- term usage. WO 2006/030450, (2006) discloses Monoglycerides, especially Monolaurin, are used to protect intravenously administrable oil-in-water emulsion compositions against growth of E.coli, P.aeruginosa, S.aureus and C.albicans. The compositions can be medicaments containing lipophilic drugs, especially Propofol, and/or total intravenous nutritional compositions. This patent discloses use of Monolaurin in Propofol oil-in-water emulsion compositions as a preservative. We are continuing our studies to explore other alternative safe preservatives for Propofol oil-in-water emulsion compositions for intravenous administration. The possible type and load of the contaminant is variable from time to time and place-to-place and totally unpredictable. A small amount of a preservative may be effective when the contamination is nil or negligibly small. But for adequate precaution larger amount of preservative is used. Hence tests using some selected bacteria and fungi have been considered as adequate to give an indication of minimum quantity of preservative to prevent proliferation of such contaminants. The tendency, however, is towards providing abundant excess of the preservative because, exact minimum amount that will work is not easy to find. It is only an estimate based on these tests. Therefore, it is necessary to fix the maximum amount of the preservative in a composition, in order to avoid any side effects on the patient due to its toxicity. This is also a fairly based estimate because there is no method to find out such a value for safe limits when toxicity of a compound on patients under different pathological state is uncertain. Propofol compositions with edetate, metabisulphite and benzyl alcohol are commercially available. These materials act as preservatives in a particular 5 minimum concentration below which they are not preservatives. At higher levels of usage they are toxic and at lower levels they are ineffective. There is, thus, a need to develop an intravenous Propofol emulsion composition with new safer compounds, in amounts sufficient to prevent proliferation of microorganisms for at least 24 hours. Object of the Invention: The principal object of the present invention is to provide an oil-in-water emulsion composition comprising Propofol and safe microbial growth controlling compounds in amounts that will prevent no more than 10 fold increase in the growth of each of staphylococcus aureus (ATCC 6538) Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 hours as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition in such quantities to obtain approximately 50 - 250 colony-forming units per ml of the composition and incubated at a temperature in the range of20-25°Cand are tested for viable counts of said organisms after 24 hours. Summary of the Invention The present invention discloses a Propofol oil-in-water emulsion composition for intravenous administration comprising Propofol, one or more triglyceride oils, purified natural phosphatides, tonicity modifying agents, water and capric acid and / or its water soluble alkali salts as preservative. Detailed Description of the Invention The present invention is an oil-in-water emulsion in which Propofol is an active anesthetic agent and capric acid and / or its water soluble alkali salts are preservatives. Triglyceride oils are used for diluting Propofol to reduce pain while administering the Propofol intravenously. And for injecting into blood, for aqueous miscibility, the oil is emulsified in water using natural phosphatides as 6 emulsifier, for making it isotonic with blood, tonicity modifying agents are added and for adjustment of pH and for stabilizing the emulsion alkali is used. In the present invention the amount of capric acid and / or its water soluble alkali salts is provided in sufficient quantity to preserve any accidental contamination of the composition during prolonged administration. The Propofol oil-in-water emulsion composition for intravenous administration have capric acid and / or its water soluble alkali salts are in amounts sufficient to prevent a no more than 10 fold increase in the growth of each of staphylococcus aureus (ATCC 6538) Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC9027), and Candida albicans (ATCC 10231) for at least 24 hours as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition in such quantities to obtain approximately 50 - 250 colony-forming units per ml of the composition and incubated at a temperature in the range 20 - 25 °C and are tested for viable counts of said organisms after 24 hours. The compounds used in the composition are described below. Capric Acid: Capric acid has not been reported previously as preservative in any oil-in-water emulsion, and particularly in oil-in-water emulsions containing Propofol. Capric acid is a saturated fatty acid containing C10 carbon atom naturally found in oils and fats. Capric acid is also known as Decanoic acid - CAS No. 334-48-5 having Molecular formula C10H20O2 and Molecular weight 172.27. Capric acid has better anti-fungal properties than monolaurin. Oral LD50 in rats is more than 10,000mg/kg. 7 Purified capric acid is preferred. However, presence of small amounts of C8 or C12 or C14 or such fatty acids are acceptable. When used in Propofol compositions, when pH is adjusted with sodium hydroxide, some capric acid sodium salt may be formed. Alternately sodium caprate i.e. sodium salt of capric acid can also be used to provide required amount of capric acid which will also control the pH. Salts of Capric acid: Any pharmaceutically acceptable soluble alkaline salts are useful. These include sodium, potassium and ammonium salts. Of these sodium salt is more useful. Sodium salt is preferred. Sodium salt of Capric acid commonly known as Sodium decanoate is soluble in water and has a molecular formula of CH3(CH2)8COONa and has molecular weight of 194.25. Capric acid sodium salt is a white powder. In the present invention it is also found to be a good preservative for the Propofol emulsions. None of the capric acid salts have been previously reported to be useful as preservative in any oil-in-water emulsion, and particularly in oil-in-water emulsions containing Propofol. Propofol 2,6-bis(l-methylethyl)-phenol or 2,6-diisopropylphenol CAS Number 2078-54-8 ; C12H18O; Mol. Wt. 178.273 The Propofol compositions of the present invention typically comprise 0.01% - 5% w/v of Propofol. Preferably the compositions comprise 0.1% - 2% w/v of Propofol. More preferably the compositions comprise about 1% and about 2% w/v of Propofol. 8 Triglyceride Oils Triglyceride oil suitable for the compositions of present invention include natural oils such as vegetable oils and/or synthetic oils such as MCT oil. Typically, the natural oil will be a vegetable oil and preferably is selected from the group consisting of Soybean oil, Sunflower oil, Sesame oil, Safflower oil, Arachis oil, Cottonseed oil, Olive oil. The synthetic oil typically is manufactured from a vegetable oil which is chemically and/or physically modified and/or purified. MCT oil is a typical example of synthetic oil and is obtained from the fixed oil extracted from the hard, dried fraction of the endosperm of Cocos nucifera L. Hydrolysis of the fixed oil followed by distillation yields the required fatty acids, which are then re-esterified to produce MCT oil (Medium-chain Triglycerides). The present invention may also comprise any combination of one or more vegetable oils and / or synthetic oils. Soybean oil is the preferred natural vegetable oil used in the compositions of the present invention. Soybean oil used in these compositions is preferably refined, bleached, deodorised and preferably free of heavy metal contaminants. The triglyceride oil(s) content in compositions of the invention is up to 30% w/v of the composition, preferably in the range of 5% - 30% w/v of the composition, more preferably 10% - 20% w/v of the composition. Purified natural phosphatides In the oil-in water emulsion compositions of the present invention natural phosphatides are used as an emulsifier for stabilization of the oil-in-water emulsion. The preferred natural phosphatides used are purified egg lecithin and/or purified soya lecithin. More preferably the natural phosphatide used is purified egg lecithin. In the present invention, it is preferred that no emulsifiers other than phosphatides are used. 9 Phosphatides are well known for forming liposomes when hydrated with aqueous media and are used in the present invention as emulsifier and for stabilizing the emulsion. They are not used in the present forming liposomal compositions. In the compositions of present invention natural phosphatides are present in the range of 0.1% - 3% w/v, preferably in the range of 0.5% - 3% w/v and more preferably about 1.2% w/v of the composition. Tonicity Modifying Agents The composition of the present invention preferably is isotonic with blood by incorporating suitable tonicity modifying agents such as Glycerin, Dextrose, or Mannitol. Glycerin is the preferred tonicity modifying agent. Glycerin is used in an amount 2.25% w/v of the composition. Capric acid and / or its water soluble alkali salts In the Propofol oil-in-water emulsion composition of the present invention, the amount of capric acid and / or its water soluble alkali salts expressed as capric acid is 0.005 - 0.5 % w/v of the composition, preferably 0.02 - 0.1 % and more preferably 0.025 - 0.075 % w/v of the composition. In a typical Propofol oil-in-water emulsion composition comprises Propofol about 1 % w/v; soybean oil about 10 % w/v; purified egg lecithin about 1.2 % w/v; Glycerin about 2.25 % w/v; Capric acid about 0.05% w/v; Water for Injection q.s. to 100% by volume of the composition; sodium hydroxide solution q.s. to obtain composition of pH 6 - 8.5. A process of preparing a Propofol oil-in-water composition comprises the steps of: i) preparing oil phase in triglyceride oil maintained at about 75 °C, by dissolving in it propofol; 10 ii) preparing an aqueous phase in water at about 70°C; by adding tonicity modifying agent and alkali solution sufficient to make the pH of the final composition 6-8.5; iii) dispersing the purified natural phosphatide either into oil phase or into aqueous phase; or partly into oil phase and remaining part into aqueous phase; iv) adding capric acid and / or its water soluble alkali salts either into oil phase or into aqueous phase or partly in oil phase and remaining part in aqueous phase v) mixing said oil phase obtained at step iv), and said aqueous phase obtained at step iv under stirring to produce a coarse emulsion; vi) homogenizing said coarse emulsion obtained at the end of step v), to form homogenised bulk emulsion having an average globule size of less than 500 nanometers; vi) filtering the said emulsion composition obtained at the end of step vi); viii) filling the filtrate obtained at the end of step vii) in containers such as vials, ampoules, blanketing under inert gas such as nitrogen and sealing the filled containers; ix) autoclaving said filtrate in said sealed containers to give end sterilised Propofol oil-in-water emulsion composition. It will be seen that the process is flexible in addition of preservatives - Capric acid and/or its water soluble alkali salts at step iv) in oily phase or in aqueous phase. For example when Capric acid and/or its water soluble alkali salts is used alone, it can be added in aqueous phase or in to oily phase or partly into aqueous phase and partly into oily phase. When they are used, the following combinations are possible. Oily phase Aqueous phase (a) Capric acid Capric acid (b) Water soluble alkali salts of Capric acid Water soluble alkali salts of Capric acid 11 (c) Capric acid Water soluble alkali salts of Capric acid (d) Water soluble alkali salts of Capric acid Capric acid (e) Capric acid + Water soluble alkali salts of Capric acid Capric acid + Water soluble alkali salts of Capric acid (f) Capric acid Capric acid + Water soluble alkali salts of Capric acid (g) Capric acid + Water soluble alkali salts of Capric acid Capric acid (h) Water soluble alkali salts of Capric acid Capric acid + Water soluble alkali salts of Capric acid (i) Capric acid + Water soluble alkali salts of Capric acid Water soluble alkali salts of Capric acid The number of combinations multiply with variations in addition of phosphatides in oil phase, aqueous phase or in both phases in step iii). Not bound by theory, it is believed that the distribution of the preservative both in the oil phase and in the aqueous phase contributes to substantial enhancement of the preservative activity. Another process of preparing a Propofol oil-in-water composition comprises the steps of: i) preparing oil phase in triglyceride oil maintained at about 75°C, by dissolving in it propofol; ii) preparing an aqueous phase in water at about 70°C; by adding tonicity modifying agent and alkali solution sufficient to make the pH of the final composition 6-8.5; iii) dispersing the purified natural phosphatide either into oil phase or into aqueous phase; or partly into oil phase and remaining part into aqueous phase; iv) mixing said oil phase obtained at step iii), and said aqueous phase obtained at step iii under stirring to produce a coarse emulsion; 12 v) homogenizing said coarse emulsion obtained at the end of step iv), to form homogenised bulk emulsion having an average globule size of less than 500 nanometers; vi) mixing capric acid and / or its water soluble alkali salts dispersed or dissolved in a small quantity of water in to homogenised bulk emulsion obtained at the end of step v) to give bulk emulsion composition; vii) filtering the said bulk emulsion composition obtained at the end of step vi); viii) filling the filtrate obtained at the end of step vii) in containers such as vials, ampoules, blanketing under inert gas such as nitrogen and sealing the filled containers; ix) autoclaving said filtrate in said sealed containers to give end sterilised Propofol oil-in-water emulsion composition. In this process the preservative Capric acid and/or its water soluble alkali salts is added to the preformed Propofol emulsion prepared without any preservative in it. In another embodiment of the invention, the Propofol and capric acid and /or its soluble salt are added to a preformed lipid emulsion like Intralipid and homogenized. Some variations in compositions and processes are described in the Examples provided below. Examples: The invention will now be illustrated by way of Examples. The Examples are by way of illustration only and in no way restrict the scope of the invention. Materials and equipment used in the Examples Materials and equipments used in the Examples are as follows: Propofol complies with the European Pharmacopoeia (Ph.Eur.) specifications. 13 Glycerin, Sodium hydroxide, Water for Injection complies with Indian Pharmacopoeia (LP.) / Ph.Eur. specifications. Soya oil (Soybean oil) complies with Ph.Eur. / U.S.P. specifications. Purified egg lecithin (referred to as Egg lecithin in examples) is manufactured by M/s.Lipoid. Capric acid is obtained from Sigma. Sodium decanoate (sodium salt of capric acid) is obtained from Sigma High speed mixing was done using a laboratory Remi stirrer. Emulsions were homogenised using high pressure APV homogenizer. The batch size of the Propofol oil-in-water emulsion compositions illustrated in Examples are in 300mL quantities. Method of analysis and determining the preservative efficacy are given at the end of Examples. Example I: Propofol oil-in-water emulsion composition was prepared using Capric acid as given in Table 1 below: Table 1: Composition of Example I Ingredients % w/v Propofol 1 Capric acid 0.05 Soya Oil 10 Purified Egg lecithin 1.2 Glycerin 2.25 Sodium hydroxide(O.lN) q.s.* Water for Injection q.s. to 100% by volume * To adjust pH to obtain pH of the final composition at about 6.4 14 Procedure The procedure used for making the composition is described below: Preparation of Oil Phase: Propofol was added to Soya oil maintained at 70-75 °C. Purified egg lecithin was added to it and mixed. Preparation of Aqueous Phase: To Water for Injection at 65 - 70°C, added Glycerin. The pH was then adjusted to 10.5 with sodium hydroxide solution. Emulsification: The Oil Phase was added to the Aqueous Phase under mixing to get a coarse emulsion. The coarse emulsion was then homogenized to get desired average globule size of less than 500 nanometers. Addition of preservatives: Capric acid was melted at 30°C - 35°C in a water bath and required quantity dispersed in minimum quantity of water (10 part by volume of water for 1 part of Capric acid by weight) and added to the bulk homogenised emulsion. Mixed well. The emulsion was filtered, filled in U.S.P. Type I vials and sealed after blanketing with Nitrogen gas. The vials were then sterilized by autoclaving. The product was then examined for its quality, stability and preservative efficacy. The analytical data on the composition of Example I and its Preservative efficacy is presented in Table 2: 15 Table 2: Analytical data and Preservative Efficacy of composition of Example I Appearance White opaque liquid pH 6.40 Propofol content (mg/mL) 9.88 Degradation products (% of Propofol content) Benzo-quinone 0.075 Bis-propofol 0.114 Average Globule Size (μm) 0.24 Capric acid content (mg/mL) 0.55 Preservative efficacy C. albicans 2.0xl02 1.9xl03 Does not support proliferation E. coli 9.3xl01 *1.2xl01 Does not support proliferation P. aeruginosa 1.7xl02 *5.0xl01 Does not support proliferation S. aureus 1.2xl02 *7.0xl0' Does not support proliferation Initial count* * Count at the end of 24 hours The study carried out indicated that composition of the Example I showed no more than 10-fold growth at the end of 24 hours, thereby indicating that it does not support proliferation. The chemical stability observations at the end of 3 months at 40°C and 25°C and the preservative efficacy at the end of 10 weeks is presented in Table 3: 16 Table 3: Chemical Stability Data and Preservative Efficacy of composition of Example I Tests 40°C-3 Months 25°C-3 Months Appearance White opaque liquid White opaque liquid PH 6.00 6.18 Propofol content (mg/mL) 9.60 9.89 Degradation products (% of Propofol content) Benzo-quinone 0.077 0.073 Bis-propofol 0.124 0.116 Average Globule Size (um) 0.24 0.24 Capric acid content (mg/mL) 0.53 0.54 25°C-10 Weeks Test 40°C-10 Weeks Preservativeefficacy at the endof 10 weeks C. albicans 68 510 68 *50 DNSP DNSP E. coli 75 *55 75 *50 DNSP DNSP P. aeruginosa 69 *15 69 *35 DNSP DNSP S. aureus 120 *120 120 *170 DNSP DNSP Initial count ** Count at the end of 24 hoursDNSP - Does not support proliferationend of 24 hours jport proliferation This study shows that (i) the degradation products of Propofol of samples of Example I are within the acceptable limits on preparation and on storage for 3 months, (ii) The composition of Example I stored at 25°C or at 40°C for 10 weeks do not support the growth of C.albicans, E.coli, P.aeruginosa and S. aureus beyond 10-fold count of the initial counts indicating that it does not support proliferation of these organisms for 24 hours. 17 Example II: Propofol oil-in-water emulsion composition comprising Sodium decanoate is given in Table 4 and a process for its preparation is described below: Table 4: Composition of Example II Ingredients % w/v Propofol 1 Soya Oil 10 Purified Egg lecithin 1.2 Glycerin 2.25 Sodium Decanoate 56.5mg* Water for Injection q.s. to 100% by volume * equivalent to 0 .05gof Capric acid Procedure The procedure used for making the composition is described below: Preparation of Oil Phase: Propofol was added to Soya oil maintained at 70-75 °C. Purified egg lecithin was added and mixed. Preparation of Aqueous Phase: To Water for Injection at 65 - 70°C, added Glycerin and Sodium decanoate. Mixed well to get a clear solution. Emulsification: The Oil Phase was added to the Aqueous Phase under mixing to get a coarse emulsion. The coarse emulsion was then homogenized to get desired average globule size of less than 500 nanometers. The emulsion was filtered, filled in U.S.P. Type I vials and sealed after blanketing with Nitrogen gas. The vials were then sterilized by autoclaving. Results of analysis of the composition of Example II are given in Table 5. 18 Table 5: Results of Analysis of composition of Example II Appearance White opaque liquid pH 7.17 Propofol content (mg/mL) 10.40 Degradation products (% of Propofol content) Benzo-quinone 0.03 Bis-propofol 0.059 Sodium Decanoate content (mg/mL) 0.558 Example III: Propofol oil-in-water emulsion composition was prepared comprising Sodium decanoate and Sodium hydroxide is given in Table 6 and a process for its preparation is described below: Table 6: Composition of Example III Ingredients % w/v Propofol 1 Sodium Decanoate 56.5 mg* Soya Oil 10 Purified Egg lecithin 1.2 Glycerin 2.25 Sodium hydroxide(0.lN) q.s.** Water for Injection q.s. to 100% by volume * equivalent to 0.05g of Capric acid ** To adjust the pH to obtain pH of the final composition at about 7.6■ Capric acid3tain pH of the final compo Procedure The procedure used for making the composition is described below: Preparation of Oil Phase: Propofol was added to Soya oil maintained at 70-75°C. Purified egg lecithin was added and mixed. Preparation of Aqueous Phase: To Water for Injection at 65 - 70°C, added Glycerin. The pH was then adjusted to 9.5 with sodium hydroxide solution. 19 Emulsification: The Oil Phase was added to the Aqueous Phase under mixing to get a coarse emulsion. The coarse emulsion was then homogenized to get desired average globule size of less than 500 nanometers. Addition of preservatives: Sodium decanoate was dissolved in Water for Injection and added to the bulk homogenised emulsion. Mixed well. The emulsion was filtered, filled in U.S.P. Type I vials and sealed after blanketing with Nitrogen gas. The vials were then sterilized by autoclaving. Results of analysis of the composition of Example III are given in Table 7. Table 7: Results of Analysis of Composition of Example III Appearance White opaque liquid pH 7.58 Propofol content (mg/mL) 10.50 Degradation products (% of Propofol content) Benzo-quinone 0.04 Bis-propofol 0.007 Sodium Decanoate content (mg/mL) 0.575 Example IV: The composition of Example IV comprising Capric acid as shown in Table 8 was prepared by 4 different processes as Examples IVA, IVB, IVC, and IVD. Table 8: Propofol oil-in-water Emulsion Composition of Example IV Ingredients % w/v Propofol 1 Soybean oil 10 Purified egg lecithin 1.2 Glycerin 2.25 Capric acid 0.025 Sodium hydroxide q.s.* Water for Injection q.s. to 100% by volume * for adjusting pH Example IVA; A process for the preparation of the emulsion composition of Example IV is as follows: Preparation of Oil Phase: Soya oil was heated to 70-75°C, Capric acid and Propofol were added and mixed. Preparation of Aqueous Phase: To Water for Injection, added Glycerin and mixed well. Purified egg lecithin was added and dispersed in the aqueous phase. The pH was then adjusted to 10.5 with sodium hydroxide solution. Emulsification: The Oil Phase was added to the Aqueous Phase with mixing and stirred at high-speed for about 10 minutes to get a coarse emulsion. The coarse emulsion was then homogenized and the average globule size obtained was less than 500 nanometers. The emulsion was filtered, filled in U.S.P. Type I vials and sealed after blanketing with Nitrogen gas. The vials were then sterilized by autoclaving. Example IVB: The process followed in this Example is similar to that of Example IVA, but with following change: The Purified egg lecithin was added in the oily phase, instead of adding it into the aqueous phase. Example IVC: The process followed in this Example is similar to that of Example IVA, but with following change: Half the quantity of Purified egg lecithin was added in the oily phase and half of the quantity was added in the aqueous phase. 21 Example IVD: The process followed in this Example is similar to that of Example IVA, but with following change: The Capric acid was added to aqueous phase. Results of analysis of the products obtained by processes IVA, IVB, IVC and IVD are given in Table 9. Table 9: Results of Analysis of Composition of Example IV Description Example IVA Example IVB Example IVC Example IVD Appearance Whiteopaqueliquid Whiteopaqueliquid Whiteopaqueliquid White opaque liquid pH 7.62 7.76 7.24 8.02 Propofol content (mg/mL) 10.01 9.87 9.85 10.03 Degradationproducts (% ofPropofol content) Benzo-quinone 0.01 0.02 0.01 0.02 Bis-propofol 0.08 0.06 0.05 0.07 Capric acid content (mg/mL) 0.248 0.23 0.251 0.24 The above data showed that there was no significant difference in the products made by any of these 4 processes. Method of Analysis: The method of analysis followed in these Examples are given below: Samples were examined for globule size, Propofol content, degradation products content, Capric acid content / Sodium decanoate content and preservative efficacy by the methods given below: 1. Globule size: Globule size is determined using N4-Plus instrument from Coulter Counter. Average globule size is reported. 22 2. Propofol content and degradation products content: Propofol content and degradation products content was determined by HPLC. The details are as follows: Column - Hypersil ODS Detector - Ultraviolet detector Detection wavelength - 270nm Mobile phase - 60 : 15 : 25 Acetonitrile : methanol: l0mM potassium phosphate Buffer Sample concentration - 0.2mg/ml Flow rate - 1ml / min. 3. Determination of Capric acid content / Sodium decanoate content: Capric acid / Sodium decanoate content was determined by HPLC. The details are as follows: ■ Chromatographic system: The Liquid Chromatograph equipped with RI detector and 150 mm x 4.6 mm x 5μ, ODS Cosmosil, column. Maintain Column temperature at 35°C ± 0.5°C ■ Mobile Phase: Methanol: Phosphate Buffer 80:20 " ■ Flow Rate: lmL/min. 4. Determination of Preservative Efficacy Composition of Examples was tested for determining preservative activity using the following procedure: Washed suspension of standardised cultures of each of Candida albicans ATCC 10231, Pseudomonas aeruginosa ATCC 9027, Escherichia coli ATCC 8739 and 23 Staphylococcus aureus ATCC 6538, the four standard U.S.P. organism cultures specified under "Antimicrobial Effectiveness Testing" were added to a separate aliquot of the composition in such quantities to obtain approximately 50 - 250 colony-forming units (cfu) per ml of the composition and incubated at 22 ± 2°C. The viable counts of the test organisms were determined after 24 hours. No more than ten-fold increase in the cell counts in the test samples indicate preservative efficacy of the test samples i.e. the test samples do not support proliferation of microorganisms. Advantages of the present invention Capric acid and / or its water soluble alkali salts can be used safely in amounts that help in controlling the proliferation of contaminating microorganisms during the administration of the composition. 24 We Claim 1. Propofol oil-in-water emulsion composition for intravenous administration comprising propofol, one or more triglyceride oils, purified natural phosphatides, tonicity modifying agents, water and capric acid and / or its water soluble alkali salts as preservative. 2. Propofol oil-in-water emulsion composition for intravenous administration comprising propofol, as claimed in claim 1 wherein composition with capric acid and / or its water soluble alkali salts are in amounts sufficient to prevent a no more than 10 fold increase in the growth of each of staphylococcus aureus (ATCC 6538) Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 hours as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition in such quantities to obtain approximately 50 - 250 colony-forming units per ml of the composition and incubated at a temperature in the range 20 - 25°C and are tested for viable counts of said organisms after 24 hours. 3. Propofol oil-in-water emulsion composition as claimed in claim lor 2 wherein, the amount of capric acid and / or its water soluble alkali salts expressed as capric acid is 0.005 - 0.5 % w/v of the composition 4. Propofol oil-in-water emulsion composition as claimed in claim 3 wherein, the amount of capric acid and / or its water soluble alkali salts expressed as capric acid is 0.02 - 0.1 % w/v of the composition. 5. Propofol oil-in-water emulsion composition as claimed in claim 4 wherein, the amount of capric acid and / or its water soluble alkali salts expressed as capric acid is 0.025 - 0.075 % w/v of the composition. 25 6. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein; the amount of Propofol is 0.1 - 2.0 % w/v of the composition. 7. Propofol oil-in-water emulsion composition as claimed in claim 6 wherein, the amount of Propofol is about 1.0 % w/v of the composition. 8. Propofol oil-in-water emulsion composition as claimed in claim 6 wherein, the amount of Propofol is about 2.0 % w/v of the composition. 9. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein, said triglyceride oils are selected from vegetable oils such as soybean oil, sesame oil, safflower oil, olive oil, sunflower oil, arachis oil, cottonseed oil and/or synthetic triglyceride oils such as Medium chain triglyceride (MCT) oil. 10. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein, the amount of triglyceride oils is 5.0 - 30 % w/v of the composition. 11. Propofol oil-in-water emulsion composition as claimed in claim 10 wherein, the amount of triglyceride oils is 10 - 20 % w/v of the composition. 12. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein, said purified natural phosphatides are egg lecithin and/or soya lecithin. 13. Propofol oil-in-water emulsion composition as claimed in claim 12 wherein, the amount of said purified natural phosphatide is 0.5% - 3% w/v. 26 14. Propofol oil-in-water emulsion composition as claimed in claim 13 wherein, the amount of said purified natural phosphatide is about 1.2% w/v. 15. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein, the tonicity-modifying agent is glycerin. 16. Propofol oil-in-water emulsion composition as claimed in any preceding claim comprises, Propofol about 1 % w/v; soybean oil about 10 % w/v; purified egg lecithin about 1.2 % w/v; Glycerin about 2.25 % w/v; Capric acid about 0.05% w/v; Water for Injection q.s. to 100% by volume of the composition; sodium hydroxide solution q.s. to obtain composition of pH 6 -8.5. 17. Propofol oil-in-water emulsion composition as claimed in any claim in claims 1-15 comprises, Propofol about 1 % w/v; soybean oil about 10 % w/v; purified egg lecithin about 1.2 % w/v; Glycerin about 2.25 % w/v; Sodium decanoate equivalent to capric acid about 0.05% w/v; Water for Injection q.s. to 100% by volume of the composition; sodium hydroxide solution q.s. to obtain composition of pH 6 - 8.5. 18. Propofol oil-in-water emulsion composition as claimed in any claim in claims 1-15 comprises, Propofol about 1 % w/v; soybean oil about 10 % w/v; purified egg lecithin about 1.2 % w/v; Glycerin about 2.25 % w/v; Sodium decanoate equivalent to capric acid about 0.05% w/v; Water for Injection q.s. to 100% by volume of the composition. 19. A process of preparing a Propofol oil-in-water composition as claimed in any preceding claim, comprising the steps of: i) preparing oil phase in triglyceride oil maintained at about 75°C, by dissolving in it propofol; 27 ii) preparing an aqueous phase in water at about 70°C; by adding tonicity modifying agent and alkali solution sufficient to make the pH of the final composition 6-8.5; iii) dispersing the purified natural phosphatide either into oil phase or into aqueous phase; or partly into oil phase and remaining part into aqueous phase; iv) adding capric acid and / or its water soluble alkali salts either into oil phase or into aqueous phase or partly in oil phase and remaining part in aqueous phase; v) mixing said oil phase obtained at step iv), and said aqueous phase obtained at step iv) under stirring to produce a coarse emulsion; vi) homogenizing said coarse emulsion obtained at the end of step v), to form homogenised bulk emulsion having an average globule size of less than 500 nanometers; vii) filtering the said emulsion composition obtained at the end of step vi); viii) filling the filtrate obtained at the end of step vii) in containers such as vials, ampoules, blanketing under inert gas such as nitrogen and sealing the filled containers; ix) autoclaving said filtrate in said sealed containers to give end sterilised Propofol oil-in-water emulsion composition. 20. A process of preparing a Propofol oil-in-water composition as claimed in any claim in claims 1-18, comprising the steps of: i) preparing oil phase in triglyceride oil maintained at about 75 °C, by dissolving in it propofol; ii) preparing an aqueous phase in water at about 70°C; by adding tonicity modifying agent and alkali solution sufficient to make the pH of the final composition 6-8.5; 28 iii) dispersing the purified natural phosphatide either into oil phase or into aqueous phase; or partly into oil phase and remaining part into aqueous phase; iv) mixing said oil phase obtained at step iii), and said aqueous phase obtained at step iii) under stirring to produce a coarse emulsion; v) homogenizing said coarse emulsion obtained at the end of step iv), to form homogenised bulk emulsion having an average globule size of less than 500 nanometers; vi) mixing capric acid and / or its water soluble alkali salts dispersed or dissolved in a small quantity of water in to homogenised bulk emulsion obtained at the end of step v) to give bulk emulsion composition; vii) filtering the said bulk emulsion composition obtained at the end of step vi); viii) filling the filtrate obtained at the end of step vii) in containers such as vials, ampoules, blanketing under inert gas such as nitrogen and sealing the filled containers; ix) autoclaving said filtrate in said sealed containers to give end sterilised Propofol oil-in-water emulsion composition. 21. Propofol oil-in-water emulsion composition for intravenous administration comprising propofol, one or more triglyceride oils, purified natural phosphatides, tonicity modifying agents, water and capric acid and/or its water soluble alkali salts substantially as herein described in the text and in examples. Dated this 24th day of August.'06. KASBEKAR MADHAV GAJANAN Agent for the Applicants To The Controller of Patents, The Patent Office, At Mumbai. Abstract The present invention discloses Propofol oil-in-water emulsion composition comprising capric acid and / or its water soluble alkali salts as preservative to prevent proliferation of microorganisms due to any accidental contamination of the composition during prolonged intravenous administration. To The Controller of Patents, The Patent Office, At Mumbai. 30

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
AND
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
Title of the Invention:

“Propofol Emulsion Compositions for Intravenous Administration "

Applicant(s):
(a) Name
(b) Nationality
(c) Address

BHARAT SERUMS & VACCINES LTD.
An Indian company incorporated under the Companies Act 1956.
16th Floor, Hoechst House Nariman Point Mumbai 400 021. Maharashtra, India

The following specification particularly describes the invention and the manner in which it is to be performed

This invention relates to Propofol oil-in-water emulsion composition for intravenous administration. This invention particularly relates to Propofol in oil-in-water emulsion composition having compounds capable of preventing proliferation of any accidental extrinsic contamination of the composition during prolonged administration.
Background and Prior arts
Propofol (2,6-Diisopropylphenol) is a well-known and widely used intravenous anesthetic agent. Propofol administration is painful; therefore Propofol is diluted with oils and provided as oil-in-water type emulsion for intravenous injections.
The Propofol / soybean oil emulsion has gained widespread use for induction and/or maintenance of anesthesia, for maintenance of monitored anesthesia care and for sedation in the Intensive Care Unit (ICU). It is advantageous in that it possesses both a rapid onset anesthesia and a short recovery time.
Intravenous Propofol emulsion compositions are continuously infused for sedation of seriously ill patients. However, the presence of vegetable oils and phospholipids makes the emulsion highly prone to the risk of microbial growth due to adventitious extrinsic contamination especially during long term use in patients undergoing ICU sedation.
There are noscomial (i.e. hospital acquired) infections observed very often in ICU patients. Microbial contamination of total intravenous nutritional emulsion formulation supplements, administered through infusion sets, is recognized as one of the main reasons of noscomial infection among ICU patients. Hence it is recommended that the intravenous administration sets be changed frequently, at least every 6 or 12 hours. Continuous infusion makes the product susceptible to microbial growth.
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In order to reduce the risk of uncontrolled microbial growth, additions of various potential preservatives into intravenous Propofol emulsion compositions have been tried. Some of the potential agents found to cause instability of the emulsion. Other potential agents failed to provide the level of antimicrobial activity being sought. It is necessary to preserve the compositions with preservatives that would provide the required levels of antimicrobial activity at as low a concentration as possible in order to minimise the potential for physical instability and to minimise toxicity concerns.
US 5714520, (1998) discloses an oil-in-water emulsion of Propofol containing an edetate as an antimicrobial agent.
Edetate has been shown to delay but not to prevent the onset of microbial growth in Propofol emulsions (see WO-A-00/24376, infra). Propofol emulsion compositions are required to be diluted up to 5 times (1:4) for long-term infusion. On dilution the edetate concentration gets reduced to 0.0011%. Edetate alone is found to be ineffective in preventing a no more than 10 fold increase in broad-spectrum microbial growth at concentrations of 0.0025% and below (see US-A-6028108; infra).
Edetate acting as a preservative in this formulation is a metal ion chelator that removes essential trace elements like zinc. This can be potentially dangerous to patients who are administered Propofol for a prolonged duration as it will cause deficiency of zinc in certain individuals. Even the manufacturer of this product recommends supplemental zinc therapy to overcome the untoward effects.
US 6469069 (2002): An oil-in-water emulsion of Propofol containing a sulphite as an antimicrobial agent has been described in this patent. The amount of sulphite preferably is in the range 0.0075% to 0.66% by weight.
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The use of sulphite has two problems; viz. (a) stability of the emulsion is affected and (b) it is potentially toxic material at little higher dose level.
US 6028108 (2000): An oil-in-water emulsion of Propofol containing a pentetate as an antimicrobial agent has been described in this patent. Pentetate, as used herein, refers to diethylene triamine pentaacetate or "DTPA", and derivatives thereof. In general suitable derivatives of DTPA are those salts having lower affinity for DTPA than calcium. Particular derivatives include but are not limited to calcium trisodium pentetate.
The invention is a sterile pharmaceutical composition for parenteral administration comprising an oil-in-water emulsion of Propofol and an amount of pentetate sufficient to prevent significant growth of microorganisms for at least 24 hours after adventitious extrinsic contamination.
Pentetate acting as a preservative in this formulation is a metal ion chelator that removes cations like calcium, magnesium and zinc. This can be potentially dangerous to patients who are administered Propofol for a prolonged duration.
US 6140373 & US 6140374, (both 2000) discloses an oil-in-water emulsion of Propofol containing an antimicrobial agent selected from (a) benzyl alcohol alone or, preferably, together with either sodium edetate or sodium benzoate and (b) benzethonium chloride.
For long-term use, the antimicrobial agents such as benzyl alcohol and benzethonium chloride are not recommended as they are toxic
US 6177477, (2001) discloses sterile pharmaceutical compositions for parenteral administration containing Propofol in an oil-in-water emulsion containing tromethamine (i.e. 2-amino-2-hydroxymethyl-1,3-propanediol) as an antimicrobial agent. However, tromethamine is known to cause extravasation at the site of
4

injection and may cause tissue damage and also is reported to cause respiratory depression. Further, the pH of the composition is highly alkaline and will degrade phospholipids and Propofol on long- term usage.
WO 2006/030450, (2006) discloses Monoglycerides, especially Monolaurin, are used to protect intravenously administrable oil-in-water emulsion compositions against growth of E.coli, P.aeruginosa, S.aureus and C.albicans. The compositions can be medicaments containing lipophilic drugs, especially Propofol, and/or total intravenous nutritional compositions.
This patent discloses use of Monolaurin in Propofol oil-in-water emulsion compositions as a preservative. We are continuing our studies to explore other alternative safe preservatives for Propofol oil-in-water emulsion compositions for intravenous administration.
The possible type and load of the contaminant is variable from time to time and place-to-place and totally unpredictable. A small amount of a preservative may be effective when the contamination is nil or negligibly small. But for adequate precaution larger amount of preservative is used. Hence tests using some selected bacteria and fungi have been considered as adequate to give an indication of minimum quantity of preservative to prevent proliferation of such contaminants. The tendency, however, is towards providing abundant excess of the preservative because, exact minimum amount that will work is not easy to find. It is only an estimate based on these tests. Therefore, it is necessary to fix the maximum amount of the preservative in a composition, in order to avoid any side effects on the patient due to its toxicity. This is also a fairly based estimate because there is no method to find out such a value for safe limits when toxicity of a compound on patients under different pathological state is uncertain.
Propofol compositions with edetate, metabisulphite and benzyl alcohol are commercially available. These materials act as preservatives in a particular
5

minimum concentration below which they are not preservatives. At higher levels of usage they are toxic and at lower levels they are ineffective. There is, thus, a need to develop an intravenous Propofol emulsion composition with new safer compounds, in amounts sufficient to prevent proliferation of microorganisms for at least 24 hours.
Object of the Invention:
The principal object of the present invention is to provide an oil-in-water emulsion composition comprising Propofol and safe microbial growth controlling compounds in amounts that will prevent no more than 10 fold increase in the growth of each of staphylococcus aureus (ATCC 6538) Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 hours as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition in such quantities to obtain approximately 50 - 250 colony-forming units per ml of the composition and incubated at a temperature in the range of20-25°Cand are tested for viable counts of said organisms after 24 hours.
Summary of the Invention
The present invention discloses a Propofol oil-in-water emulsion composition for intravenous administration comprising Propofol, one or more triglyceride oils, purified natural phosphatides, tonicity modifying agents, water and capric acid and / or its water soluble alkali salts as preservative.
Detailed Description of the Invention
The present invention is an oil-in-water emulsion in which Propofol is an active anesthetic agent and capric acid and / or its water soluble alkali salts are preservatives. Triglyceride oils are used for diluting Propofol to reduce pain while administering the Propofol intravenously. And for injecting into blood, for aqueous miscibility, the oil is emulsified in water using natural phosphatides as
6

emulsifier, for making it isotonic with blood, tonicity modifying agents are added and for adjustment of pH and for stabilizing the emulsion alkali is used.
In the present invention the amount of capric acid and / or its water soluble alkali salts is provided in sufficient quantity to preserve any accidental contamination of the composition during prolonged administration.
The Propofol oil-in-water emulsion composition for intravenous administration have capric acid and / or its water soluble alkali salts are in amounts sufficient to prevent a no more than 10 fold increase in the growth of each of staphylococcus aureus (ATCC 6538) Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC9027), and Candida albicans (ATCC 10231) for at least 24 hours as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition in such quantities to obtain approximately 50 - 250 colony-forming units per ml of the composition and incubated at a temperature in the range 20 - 25 °C and are tested for viable counts of said organisms after 24 hours.
The compounds used in the composition are described below.
Capric Acid:
Capric acid has not been reported previously as preservative in any oil-in-water emulsion, and particularly in oil-in-water emulsions containing Propofol.
Capric acid is a saturated fatty acid containing C10 carbon atom naturally found in oils and fats. Capric acid is also known as Decanoic acid - CAS No. 334-48-5 having Molecular formula C10H20O2 and Molecular weight 172.27. Capric acid has better anti-fungal properties than monolaurin. Oral LD50 in rats is more than 10,000mg/kg.
7

Purified capric acid is preferred. However, presence of small amounts of C8 or C12 or C14 or such fatty acids are acceptable.
When used in Propofol compositions, when pH is adjusted with sodium hydroxide, some capric acid sodium salt may be formed. Alternately sodium caprate i.e. sodium salt of capric acid can also be used to provide required amount of capric acid which will also control the pH.
Salts of Capric acid:
Any pharmaceutically acceptable soluble alkaline salts are useful. These include sodium, potassium and ammonium salts. Of these sodium salt is more useful. Sodium salt is preferred.
Sodium salt of Capric acid commonly known as Sodium decanoate is soluble in water and has a molecular formula of CH3(CH2)8COONa and has molecular weight of 194.25.
Capric acid sodium salt is a white powder. In the present invention it is also found to be a good preservative for the Propofol emulsions. None of the capric acid salts have been previously reported to be useful as preservative in any oil-in-water emulsion, and particularly in oil-in-water emulsions containing Propofol.
Propofol
2,6-bis(l-methylethyl)-phenol or 2,6-diisopropylphenol
CAS Number 2078-54-8 ; C12H18O; Mol. Wt. 178.273
The Propofol compositions of the present invention typically comprise 0.01% -
5% w/v of Propofol. Preferably the compositions comprise 0.1% - 2% w/v of
Propofol. More preferably the compositions comprise about 1% and about 2%
w/v of Propofol.
8

Triglyceride Oils
Triglyceride oil suitable for the compositions of present invention include natural oils such as vegetable oils and/or synthetic oils such as MCT oil. Typically, the natural oil will be a vegetable oil and preferably is selected from the group consisting of Soybean oil, Sunflower oil, Sesame oil, Safflower oil, Arachis oil, Cottonseed oil, Olive oil. The synthetic oil typically is manufactured from a vegetable oil which is chemically and/or physically modified and/or purified. MCT oil is a typical example of synthetic oil and is obtained from the fixed oil extracted from the hard, dried fraction of the endosperm of Cocos nucifera L. Hydrolysis of the fixed oil followed by distillation yields the required fatty acids, which are then re-esterified to produce MCT oil (Medium-chain Triglycerides). The present invention may also comprise any combination of one or more vegetable oils and / or synthetic oils. Soybean oil is the preferred natural vegetable oil used in the compositions of the present invention. Soybean oil used in these compositions is preferably refined, bleached, deodorised and preferably free of heavy metal contaminants.
The triglyceride oil(s) content in compositions of the invention is up to 30% w/v of the composition, preferably in the range of 5% - 30% w/v of the composition, more preferably 10% - 20% w/v of the composition.
Purified natural phosphatides
In the oil-in water emulsion compositions of the present invention natural phosphatides are used as an emulsifier for stabilization of the oil-in-water emulsion. The preferred natural phosphatides used are purified egg lecithin and/or purified soya lecithin. More preferably the natural phosphatide used is purified egg lecithin.
In the present invention, it is preferred that no emulsifiers other than phosphatides are used.
9

Phosphatides are well known for forming liposomes when hydrated with aqueous media and are used in the present invention as emulsifier and for stabilizing the emulsion. They are not used in the present forming liposomal compositions.
In the compositions of present invention natural phosphatides are present in the range of 0.1% - 3% w/v, preferably in the range of 0.5% - 3% w/v and more preferably about 1.2% w/v of the composition.
Tonicity Modifying Agents
The composition of the present invention preferably is isotonic with blood by incorporating suitable tonicity modifying agents such as Glycerin, Dextrose, or Mannitol. Glycerin is the preferred tonicity modifying agent. Glycerin is used in an amount 2.25% w/v of the composition.
Capric acid and / or its water soluble alkali salts
In the Propofol oil-in-water emulsion composition of the present invention, the amount of capric acid and / or its water soluble alkali salts expressed as capric acid is 0.005 - 0.5 % w/v of the composition, preferably 0.02 - 0.1 % and more preferably 0.025 - 0.075 % w/v of the composition.
In a typical Propofol oil-in-water emulsion composition comprises Propofol about 1 % w/v; soybean oil about 10 % w/v; purified egg lecithin about 1.2 % w/v; Glycerin about 2.25 % w/v; Capric acid about 0.05% w/v; Water for Injection q.s. to 100% by volume of the composition; sodium hydroxide solution q.s. to obtain composition of pH 6 - 8.5.
A process of preparing a Propofol oil-in-water composition comprises the steps of: i) preparing oil phase in triglyceride oil maintained at about 75 °C, by dissolving in it propofol;
10

ii) preparing an aqueous phase in water at about 70°C; by adding tonicity
modifying agent and alkali solution sufficient to make the pH of the final
composition 6-8.5;
iii) dispersing the purified natural phosphatide either into oil phase or into
aqueous phase; or partly into oil phase and remaining part into aqueous
phase;
iv) adding capric acid and / or its water soluble alkali salts either into oil phase or into aqueous phase or partly in oil phase and remaining part in aqueous phase
v) mixing said oil phase obtained at step iv), and said aqueous phase obtained at step iv under stirring to produce a coarse emulsion;
vi) homogenizing said coarse emulsion obtained at the end of step v), to form
homogenised bulk emulsion having an average globule size of less than
500 nanometers;
vi) filtering the said emulsion composition obtained at the end of step vi);
viii) filling the filtrate obtained at the end of step vii) in containers such as vials,
ampoules, blanketing under inert gas such as nitrogen and sealing the filled
containers;
ix) autoclaving said filtrate in said sealed containers to give end sterilised
Propofol oil-in-water emulsion composition.
It will be seen that the process is flexible in addition of preservatives - Capric acid and/or its water soluble alkali salts at step iv) in oily phase or in aqueous phase. For example when Capric acid and/or its water soluble alkali salts is used alone, it can be added in aqueous phase or in to oily phase or partly into aqueous phase and partly into oily phase. When they are used, the following combinations are possible.

Oily phase Aqueous phase
(a) Capric acid Capric acid
(b) Water soluble alkali salts of Capric acid Water soluble alkali salts of Capric acid
11

(c) Capric acid Water soluble alkali salts of Capric acid
(d) Water soluble alkali salts of Capric acid Capric acid
(e) Capric acid + Water soluble alkali salts of Capric acid Capric acid + Water soluble alkali salts of Capric acid
(f) Capric acid Capric acid + Water soluble alkali salts of Capric acid
(g) Capric acid + Water soluble alkali salts of Capric acid Capric acid
(h) Water soluble alkali salts of Capric acid Capric acid + Water soluble alkali salts of Capric acid
(i) Capric acid + Water soluble alkali salts of Capric acid Water soluble alkali salts of Capric acid
The number of combinations multiply with variations in addition of phosphatides in oil phase, aqueous phase or in both phases in step iii).
Not bound by theory, it is believed that the distribution of the preservative both in the oil phase and in the aqueous phase contributes to substantial enhancement of the preservative activity.
Another process of preparing a Propofol oil-in-water composition comprises the
steps of:
i) preparing oil phase in triglyceride oil maintained at about 75°C, by
dissolving in it propofol;
ii) preparing an aqueous phase in water at about 70°C; by adding tonicity
modifying agent and alkali solution sufficient to make the pH of the final
composition 6-8.5;
iii) dispersing the purified natural phosphatide either into oil phase or into
aqueous phase; or partly into oil phase and remaining part into aqueous
phase;
iv) mixing said oil phase obtained at step iii), and said aqueous phase obtained
at step iii under stirring to produce a coarse emulsion;
12

v) homogenizing said coarse emulsion obtained at the end of step iv), to form
homogenised bulk emulsion having an average globule size of less than
500 nanometers;
vi) mixing capric acid and / or its water soluble alkali salts dispersed or
dissolved in a small quantity of water in to homogenised bulk emulsion
obtained at the end of step v) to give bulk emulsion composition;
vii) filtering the said bulk emulsion composition obtained at the end of step vi); viii) filling the filtrate obtained at the end of step vii) in containers such as vials,
ampoules, blanketing under inert gas such as nitrogen and sealing the filled
containers;
ix) autoclaving said filtrate in said sealed containers to give end sterilised
Propofol oil-in-water emulsion composition.
In this process the preservative Capric acid and/or its water soluble alkali salts is added to the preformed Propofol emulsion prepared without any preservative in it.
In another embodiment of the invention, the Propofol and capric acid and /or its soluble salt are added to a preformed lipid emulsion like Intralipid and homogenized.
Some variations in compositions and processes are described in the Examples provided below.
Examples:
The invention will now be illustrated by way of Examples. The Examples are by way of illustration only and in no way restrict the scope of the invention.
Materials and equipment used in the Examples
Materials and equipments used in the Examples are as follows:
Propofol complies with the European Pharmacopoeia (Ph.Eur.) specifications.
13

Glycerin, Sodium hydroxide, Water for Injection complies with Indian
Pharmacopoeia (LP.) / Ph.Eur. specifications.
Soya oil (Soybean oil) complies with Ph.Eur. / U.S.P. specifications.
Purified egg lecithin (referred to as Egg lecithin in examples) is manufactured by
M/s.Lipoid.
Capric acid is obtained from Sigma.
Sodium decanoate (sodium salt of capric acid) is obtained from Sigma
High speed mixing was done using a laboratory Remi stirrer. Emulsions were
homogenised using high pressure APV homogenizer. The batch size of the
Propofol oil-in-water emulsion compositions illustrated in Examples are in 300mL
quantities.
Method of analysis and determining the preservative efficacy are given at the end of Examples.
Example I:
Propofol oil-in-water emulsion composition was prepared using Capric acid as given in Table 1 below:
Table 1: Composition of Example I

Ingredients % w/v
Propofol 1
Capric acid 0.05
Soya Oil 10
Purified Egg lecithin 1.2
Glycerin 2.25
Sodium hydroxide(O.lN) q.s.*
Water for Injection q.s. to 100% by volume
* To adjust pH to obtain pH of the final composition at about 6.4
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Procedure
The procedure used for making the composition is described below:
Preparation of Oil Phase: Propofol was added to Soya oil maintained at 70-75 °C. Purified egg lecithin was added to it and mixed.
Preparation of Aqueous Phase: To Water for Injection at 65 - 70°C, added Glycerin. The pH was then adjusted to 10.5 with sodium hydroxide solution.
Emulsification: The Oil Phase was added to the Aqueous Phase under mixing to get a coarse emulsion. The coarse emulsion was then homogenized to get desired average globule size of less than 500 nanometers.
Addition of preservatives: Capric acid was melted at 30°C - 35°C in a water bath and required quantity dispersed in minimum quantity of water (10 part by volume of water for 1 part of Capric acid by weight) and added to the bulk homogenised emulsion. Mixed well.
The emulsion was filtered, filled in U.S.P. Type I vials and sealed after blanketing with Nitrogen gas. The vials were then sterilized by autoclaving.
The product was then examined for its quality, stability and preservative efficacy. The analytical data on the composition of Example I and its Preservative efficacy is presented in Table 2:
15

Table 2: Analytical data and Preservative Efficacy of composition of Example I

Appearance White opaque liquid
pH 6.40
Propofol content (mg/mL) 9.88
Degradation products (% of Propofol content) Benzo-quinone 0.075
Bis-propofol 0.114
Average Globule Size (μm) 0.24
Capric acid content (mg/mL) 0.55
Preservative efficacy C. albicans *2.0xl02 **1.9xl03
Does not support proliferation
E. coli *9.3xl01 **1.2xl01
Does not support proliferation
P. aeruginosa *1.7xl02 **5.0xl01
Does not support proliferation
S. aureus *1.2xl02 **7.0xl0'
Does not support proliferation
* Initial count* * Count at the end of 24 hours
The study carried out indicated that composition of the Example I showed no more than 10-fold growth at the end of 24 hours, thereby indicating that it does not support proliferation.
The chemical stability observations at the end of 3 months at 40°C and 25°C and the preservative efficacy at the end of 10 weeks is presented in Table 3:
16

Table 3: Chemical Stability Data and Preservative Efficacy of composition of
Example I

Tests 40°C-3 Months 25°C-3 Months
Appearance White opaque liquid White opaque liquid
PH 6.00 6.18
Propofol content (mg/mL) 9.60 9.89
Degradation products (% of Propofol content) Benzo-quinone 0.077 0.073
Bis-propofol 0.124 0.116
Average Globule Size (um) 0.24 0.24
Capric acid content (mg/mL) 0.53 0.54 25°C-10 Weeks
Test 40°C-10 Weeks
Preservativeefficacy at the endof 10 weeks C. albicans *68 **510 *68 **50
DNSP DNSP
E. coli *75 **55 *75 **50
DNSP DNSP
P. aeruginosa *69 **15 *69 **35
DNSP DNSP
S. aureus *120 **120 *120 **170
DNSP DNSP
* Initial count ** Count at the end of 24 hoursDNSP - Does not support proliferationend of 24 hours jport proliferation
This study shows that
(i) the degradation products of Propofol of samples of Example I are within
the acceptable limits on preparation and on storage for 3 months,
(ii) The composition of Example I stored at 25°C or at 40°C for 10 weeks do
not support the growth of C.albicans, E.coli, P.aeruginosa and S. aureus
beyond 10-fold count of the initial counts indicating that it does not
support proliferation of these organisms for 24 hours.
17

Example II:
Propofol oil-in-water emulsion composition comprising Sodium decanoate is given in Table 4 and a process for its preparation is described below:
Table 4: Composition of Example II

Ingredients % w/v
Propofol 1
Soya Oil 10
Purified Egg lecithin 1.2
Glycerin 2.25
Sodium Decanoate 56.5mg*
Water for Injection q.s. to 100% by volume
* equivalent to 0 .05gof Capric acid
Procedure
The procedure used for making the composition is described below:
Preparation of Oil Phase: Propofol was added to Soya oil maintained at 70-75 °C. Purified egg lecithin was added and mixed.
Preparation of Aqueous Phase: To Water for Injection at 65 - 70°C, added Glycerin and Sodium decanoate. Mixed well to get a clear solution.
Emulsification: The Oil Phase was added to the Aqueous Phase under mixing to get a coarse emulsion. The coarse emulsion was then homogenized to get desired average globule size of less than 500 nanometers.
The emulsion was filtered, filled in U.S.P. Type I vials and sealed after blanketing with Nitrogen gas. The vials were then sterilized by autoclaving. Results of analysis of the composition of Example II are given in Table 5.
18

Table 5: Results of Analysis of composition of Example II

Appearance White opaque liquid
pH 7.17
Propofol content (mg/mL) 10.40
Degradation products (% of Propofol content) Benzo-quinone 0.03
Bis-propofol 0.059
Sodium Decanoate content (mg/mL) 0.558
Example III:
Propofol oil-in-water emulsion composition was prepared comprising Sodium decanoate and Sodium hydroxide is given in Table 6 and a process for its preparation is described below:
Table 6: Composition of Example III

Ingredients % w/v
Propofol 1
Sodium Decanoate 56.5 mg*
Soya Oil 10
Purified Egg lecithin 1.2
Glycerin 2.25
Sodium hydroxide(0.lN) q.s.**
Water for Injection q.s. to 100% by volume
* equivalent to 0.05g of Capric acid ** To adjust the pH to obtain pH of the final composition at about 7.6■ Capric acid3tain pH of the final compo
Procedure
The procedure used for making the composition is described below:
Preparation of Oil Phase: Propofol was added to Soya oil maintained at 70-75°C. Purified egg lecithin was added and mixed.
Preparation of Aqueous Phase: To Water for Injection at 65 - 70°C, added Glycerin. The pH was then adjusted to 9.5 with sodium hydroxide solution.
19

Emulsification: The Oil Phase was added to the Aqueous Phase under mixing to get a coarse emulsion. The coarse emulsion was then homogenized to get desired average globule size of less than 500 nanometers.
Addition of preservatives: Sodium decanoate was dissolved in Water for Injection and added to the bulk homogenised emulsion. Mixed well.
The emulsion was filtered, filled in U.S.P. Type I vials and sealed after blanketing with Nitrogen gas. The vials were then sterilized by autoclaving. Results of analysis of the composition of Example III are given in Table 7.
Table 7: Results of Analysis of Composition of Example III

Appearance White opaque liquid
pH 7.58
Propofol content (mg/mL) 10.50
Degradation products (% of Propofol content) Benzo-quinone 0.04
Bis-propofol 0.007
Sodium Decanoate content (mg/mL) 0.575
Example IV:
The composition of Example IV comprising Capric acid as shown in Table 8 was prepared by 4 different processes as Examples IVA, IVB, IVC, and IVD.
Table 8: Propofol oil-in-water Emulsion Composition of Example IV

Ingredients % w/v
Propofol 1
Soybean oil 10
Purified egg lecithin 1.2
Glycerin 2.25
Capric acid 0.025
Sodium hydroxide q.s.*
Water for Injection q.s. to 100% by volume
* for adjusting pH

Example IVA;
A process for the preparation of the emulsion composition of Example IV is as follows:
Preparation of Oil Phase: Soya oil was heated to 70-75°C, Capric acid and Propofol were added and mixed.
Preparation of Aqueous Phase: To Water for Injection, added Glycerin and mixed well. Purified egg lecithin was added and dispersed in the aqueous phase. The pH was then adjusted to 10.5 with sodium hydroxide solution.
Emulsification: The Oil Phase was added to the Aqueous Phase with mixing and stirred at high-speed for about 10 minutes to get a coarse emulsion. The coarse emulsion was then homogenized and the average globule size obtained was less than 500 nanometers.
The emulsion was filtered, filled in U.S.P. Type I vials and sealed after blanketing with Nitrogen gas. The vials were then sterilized by autoclaving.
Example IVB:
The process followed in this Example is similar to that of Example IVA, but with following change:
The Purified egg lecithin was added in the oily phase, instead of adding it into the aqueous phase.
Example IVC:
The process followed in this Example is similar to that of Example IVA, but with following change:
Half the quantity of Purified egg lecithin was added in the oily phase and half of the quantity was added in the aqueous phase.
21

Example IVD:
The process followed in this Example is similar to that of Example IVA, but with following change:
The Capric acid was added to aqueous phase.
Results of analysis of the products obtained by processes IVA, IVB, IVC and IVD are given in Table 9.
Table 9: Results of Analysis of Composition of Example IV

Description Example IVA Example IVB Example IVC Example IVD
Appearance Whiteopaqueliquid Whiteopaqueliquid Whiteopaqueliquid White opaque liquid
pH 7.62 7.76 7.24 8.02
Propofol content (mg/mL) 10.01 9.87 9.85 10.03
Degradationproducts (% ofPropofol content) Benzo-quinone 0.01 0.02 0.01 0.02
Bis-propofol 0.08 0.06 0.05 0.07
Capric acid content (mg/mL) 0.248 0.23 0.251 0.24
The above data showed that there was no significant difference in the products made by any of these 4 processes.
Method of Analysis:
The method of analysis followed in these Examples are given below:
Samples were examined for globule size, Propofol content, degradation products content, Capric acid content / Sodium decanoate content and preservative efficacy by the methods given below:
1. Globule size: Globule size is determined using N4-Plus instrument from Coulter Counter. Average globule size is reported.
22

2. Propofol content and degradation products content: Propofol content
and degradation products content was determined by HPLC. The details
are as follows:
Column - Hypersil ODS
Detector - Ultraviolet detector
Detection wavelength - 270nm
Mobile phase - 60 : 15 : 25 Acetonitrile : methanol: l0mM
potassium phosphate Buffer
Sample concentration - 0.2mg/ml
Flow rate - 1ml / min.
3. Determination of Capric acid content / Sodium decanoate content:
Capric acid / Sodium decanoate content was determined by HPLC. The details are as follows:
■ Chromatographic system:
The Liquid Chromatograph equipped with RI detector and 150 mm x 4.6 mm x 5μ, ODS Cosmosil, column. Maintain Column temperature at 35°C ± 0.5°C
■ Mobile Phase:
Methanol: Phosphate Buffer 80:20 " ■ Flow Rate:
lmL/min.
4. Determination of Preservative Efficacy
Composition of Examples was tested for determining preservative activity using the following procedure:
Washed suspension of standardised cultures of each of Candida albicans ATCC 10231, Pseudomonas aeruginosa ATCC 9027, Escherichia coli ATCC 8739 and
23

Staphylococcus aureus ATCC 6538, the four standard U.S.P. organism cultures specified under "Antimicrobial Effectiveness Testing" were added to a separate aliquot of the composition in such quantities to obtain approximately 50 - 250 colony-forming units (cfu) per ml of the composition and incubated at 22 ± 2°C. The viable counts of the test organisms were determined after 24 hours.
No more than ten-fold increase in the cell counts in the test samples indicate preservative efficacy of the test samples i.e. the test samples do not support proliferation of microorganisms.
Advantages of the present invention
Capric acid and / or its water soluble alkali salts can be used safely in amounts that help in controlling the proliferation of contaminating microorganisms during the administration of the composition.
24

We Claim
1. Propofol oil-in-water emulsion composition for intravenous administration comprising propofol, one or more triglyceride oils, purified natural phosphatides, tonicity modifying agents, water and capric acid and / or its water soluble alkali salts as preservative.
2. Propofol oil-in-water emulsion composition for intravenous administration comprising propofol, as claimed in claim 1 wherein composition with capric acid and / or its water soluble alkali salts are in amounts sufficient to prevent a no more than 10 fold increase in the growth of each of staphylococcus aureus (ATCC 6538) Escherichia coli (ATCC 8739), Pseudomonas aeruginosa (ATCC 9027), and Candida albicans (ATCC 10231) for at least 24 hours as measured by a test wherein a washed suspension of each organism is added to a separate aliquot of said composition in such quantities to obtain approximately 50 - 250 colony-forming units per ml of the composition and incubated at a temperature in the range 20 - 25°C and are tested for viable counts of said organisms after 24 hours.
3. Propofol oil-in-water emulsion composition as claimed in claim lor 2 wherein, the amount of capric acid and / or its water soluble alkali salts expressed as capric acid is 0.005 - 0.5 % w/v of the composition
4. Propofol oil-in-water emulsion composition as claimed in claim 3 wherein, the amount of capric acid and / or its water soluble alkali salts expressed as capric acid is 0.02 - 0.1 % w/v of the composition.
5. Propofol oil-in-water emulsion composition as claimed in claim 4 wherein, the amount of capric acid and / or its water soluble alkali salts expressed as capric acid is 0.025 - 0.075 % w/v of the composition.
25

6. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein; the amount of Propofol is 0.1 - 2.0 % w/v of the composition.
7. Propofol oil-in-water emulsion composition as claimed in claim 6 wherein, the amount of Propofol is about 1.0 % w/v of the composition.
8. Propofol oil-in-water emulsion composition as claimed in claim 6 wherein, the amount of Propofol is about 2.0 % w/v of the composition.
9. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein, said triglyceride oils are selected from vegetable oils such as soybean oil, sesame oil, safflower oil, olive oil, sunflower oil, arachis oil, cottonseed oil and/or synthetic triglyceride oils such as Medium chain triglyceride (MCT) oil.
10. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein, the amount of triglyceride oils is 5.0 - 30 % w/v of the composition.
11. Propofol oil-in-water emulsion composition as claimed in claim 10 wherein, the amount of triglyceride oils is 10 - 20 % w/v of the composition.
12. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein, said purified natural phosphatides are egg lecithin and/or soya lecithin.
13. Propofol oil-in-water emulsion composition as claimed in claim 12 wherein, the amount of said purified natural phosphatide is 0.5% - 3% w/v.
26

14. Propofol oil-in-water emulsion composition as claimed in claim 13
wherein, the amount of said purified natural phosphatide is about 1.2%
w/v.
15. Propofol oil-in-water emulsion composition as claimed in any preceding claim wherein, the tonicity-modifying agent is glycerin.
16. Propofol oil-in-water emulsion composition as claimed in any preceding claim comprises, Propofol about 1 % w/v; soybean oil about 10 % w/v; purified egg lecithin about 1.2 % w/v; Glycerin about 2.25 % w/v; Capric acid about 0.05% w/v; Water for Injection q.s. to 100% by volume of the composition; sodium hydroxide solution q.s. to obtain composition of pH 6 -8.5.
17. Propofol oil-in-water emulsion composition as claimed in any claim in claims 1-15 comprises, Propofol about 1 % w/v; soybean oil about 10 % w/v; purified egg lecithin about 1.2 % w/v; Glycerin about 2.25 % w/v; Sodium decanoate equivalent to capric acid about 0.05% w/v; Water for Injection q.s. to 100% by volume of the composition; sodium hydroxide solution q.s. to obtain composition of pH 6 - 8.5.
18. Propofol oil-in-water emulsion composition as claimed in any claim in claims 1-15 comprises, Propofol about 1 % w/v; soybean oil about 10 % w/v; purified egg lecithin about 1.2 % w/v; Glycerin about 2.25 % w/v; Sodium decanoate equivalent to capric acid about 0.05% w/v; Water for Injection q.s. to 100% by volume of the composition.
19. A process of preparing a Propofol oil-in-water composition as claimed in any preceding claim, comprising the steps of:
i) preparing oil phase in triglyceride oil maintained at about 75°C, by
dissolving in it propofol;
27

ii) preparing an aqueous phase in water at about 70°C; by adding
tonicity modifying agent and alkali solution sufficient to make the
pH of the final composition 6-8.5;
iii) dispersing the purified natural phosphatide either into oil phase or
into aqueous phase; or partly into oil phase and remaining part into
aqueous phase;
iv) adding capric acid and / or its water soluble alkali salts either into
oil phase or into aqueous phase or partly in oil phase and
remaining part in aqueous phase;
v) mixing said oil phase obtained at step iv), and said aqueous phase
obtained at step iv) under stirring to produce a coarse emulsion;
vi) homogenizing said coarse emulsion obtained at the end of step v),
to form homogenised bulk emulsion having an average globule size
of less than 500 nanometers;
vii) filtering the said emulsion composition obtained at the end of step
vi);
viii) filling the filtrate obtained at the end of step vii) in containers such
as vials, ampoules, blanketing under inert gas such as nitrogen and
sealing the filled containers;
ix) autoclaving said filtrate in said sealed containers to give end
sterilised Propofol oil-in-water emulsion composition.
20. A process of preparing a Propofol oil-in-water composition as claimed in
any claim in claims 1-18, comprising the steps of:
i) preparing oil phase in triglyceride oil maintained at about 75 °C, by
dissolving in it propofol;
ii) preparing an aqueous phase in water at about 70°C; by adding
tonicity modifying agent and alkali solution sufficient to make the
pH of the final composition 6-8.5;
28

iii) dispersing the purified natural phosphatide either into oil phase or
into aqueous phase; or partly into oil phase and remaining part into
aqueous phase;
iv) mixing said oil phase obtained at step iii), and said aqueous phase
obtained at step iii) under stirring to produce a coarse emulsion;
v) homogenizing said coarse emulsion obtained at the end of step iv),
to form homogenised bulk emulsion having an average globule size
of less than 500 nanometers;
vi) mixing capric acid and / or its water soluble alkali salts dispersed or
dissolved in a small quantity of water in to homogenised bulk
emulsion obtained at the end of step v) to give bulk emulsion
composition;
vii) filtering the said bulk emulsion composition obtained at the end of
step vi);
viii) filling the filtrate obtained at the end of step vii) in containers such
as vials, ampoules, blanketing under inert gas such as nitrogen and
sealing the filled containers;
ix) autoclaving said filtrate in said sealed containers to give end
sterilised Propofol oil-in-water emulsion composition.
21. Propofol oil-in-water emulsion composition for intravenous administration comprising propofol, one or more triglyceride oils, purified natural phosphatides, tonicity modifying agents, water and capric acid and/or its water soluble alkali salts substantially as herein described in the text and in examples.
Dated this 24th day of August.'06.

KASBEKAR MADHAV GAJANAN
Agent for the Applicants
To
The Controller of Patents, The Patent Office,
At Mumbai.
Abstract
The present invention discloses Propofol oil-in-water emulsion composition comprising capric acid and / or its water soluble alkali salts as preservative to prevent proliferation of microorganisms due to any accidental contamination of the composition during prolonged intravenous administration.
To
The Controller of Patents,
The Patent Office,
At Mumbai.
30

Documents:

1328-mum-2006-abstract(granted)-(6-5-2008).pdf

1328-mum-2006-abstract.doc

1328-mum-2006-abstract.pdf

1328-mum-2006-cancelled pages(18-1-2008).pdf

1328-mum-2006-claims(granted)-(6-5-2008).pdf

1328-mum-2006-claims.doc

1328-mum-2006-claims.pdf

1328-mum-2006-correspondence received.pdf

1328-mum-2006-correspondence(18-1-2008).pdf

1328-mum-2006-correspondence(ipo)-(21-5-2008).pdf

1328-mum-2006-description (complete).pdf

1328-mum-2006-description(granted)-(6-5-2008).pdf

1328-mum-2006-form 18(1-12-2006).pdf

1328-mum-2006-form 2(granted)-(6-5-2008).pdf

1328-mum-2006-form 2(title page)-(complete)-(24-8-2006).pdf

1328-mum-2006-form 2(title page)-(granted)-(6-5-2008).pdf

1328-mum-2006-form-1.pdf

1328-mum-2006-form-2.doc

1328-mum-2006-form-2.pdf

1328-mum-2006-form-26.pdf

1328-mum-2006-form-3.pdf

1328-mum-2006-form-5.pdf

1328-mum-2006-marked copy(18-1-2008).pdf

1328-mum-2006-specification(amended)-(18-1-2008).pdf

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Patent Number

219419

Indian Patent Application Number

1328/MUM/2006

PG Journal Number

33/2008

Publication Date

15-Aug-2008

Grant Date

06-May-2008

Date of Filing

24-Aug-2006

Name of Patentee

BHARAT SERUMS & VACCINES LTD.

Applicant Address

Inventors:

#	Inventor's Name	Inventor's Address
1	Pai Srikanth Annappa
2	DR DAFTARY GAUTAM VINOD
3	Rivankar Sangeeta Hanurmesh

PCT International Classification Number

A61K9/107

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA