News Column

Patent Issued for Intravenous Propofol Emulsion Compositions Having Preservative Efficacy

July 7, 2014



By a News Reporter-Staff News Editor at Clinical Trials Week -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Daftary, Gautam Vinod (Mumbai, IN); Pai, Srikanth Annappa (Mumbai, IN); Shanbhag, Girish Narasimha (Mumbai, IN); Rivankar, Sangeeta Hanurmesh (Mumbai, IN), filed on March 2, 2007, was published online on June 24, 2014 (see also Bharat Serums & Vaccines Ltd.).

The assignee for this patent, patent number 8759404, is Bharat Serums & Vaccines Ltd. (Mumbai, IN).

Reporters obtained the following quote from the background information supplied by the inventors: "Propofol is a short-acting intravenous anesthetic agent used for the induction of general anesthesia in adult patients and pediatric patients older than 3 years of age; maintenance of general anesthesia in adult patients and pediatric patients older than 2 months of age; and intensive care unit (ICU) sedation for intubated, mechanically ventilated adults. 20 ml ampoule of 1% propofol emulsion.

"Initial clinical trials were in 1977, in a form solubilized in cremophor EL, but due to anaphylactic reactions it was withdrawn from the market. It was subsequently reformulated as an aqueous emulsion in intralipid and re-launched in 1986 by AstraZeneca with the brand name 'Diprivan'. The current preparation is 1% propofol solubilized in 10% soybean oil and contains 1.2% purified egg phospholipid, 2.25% glycerol and has a pH between 6.0 and 8.5 and a pKa of 11. Diprivan contains EDTA as an antimicrobial agent. Newer generic formulations contain sodium metabisulfite or benzyl alcohol.

"Propofol is approved for the induction and maintenance of anesthesia in more than 50 countries.

"Aside from the hypotension and transient apnea following induction doses, one of its most frequent side-effects is pain on injection, especially in smaller veins. This pain can be mitigated by pretreatment or mixing with intravenous lidocaine. Alternative formulations with a larger proportion of medium-chain triglycerides (as opposed to Intralipid) appear to have less pain on injection, possibly due to lower concentrations of free aqueous propofol. (Source: Wikipedia)

"Propofol injections usually are made by diluting Propofol in oils and then formulated into oil-in-water type of emulsions. The compositions of the Propofol incorporated into the oily phase and made into oil-in-water emulsions for intravenous administration.

"A Propofol/soybean oil emulsion has gained widespread use for induction and/or maintenance of anaesthesia, for maintenance of monitored anaesthesia care and for sedation in the Intensive Care Unit (ICU). It is advantageous in that it possesses both a rapid onset anaesthesia and a short recovery time. However, the presence of vegetable oils and phospholipids makes the emulsion highly prone to the risk of microbial growth.

"Intravenous Propofol emulsion compositions are being increasingly used for sedation of seriously ill patients particularly in ICUs wherein it is continuously infused. There are noscomial (i.e. hospital acquired) infections observed very often in ICU patients. Hence it is recommended that the intravenous administration sets are changed frequently, at least every 6 or 12 hours. Continuous infusion makes the product susceptible to microbial growth.

"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 minimize the potential for physical instability and to minimize toxicity concerns.

"EP-A-0814787 (published 7 Jan. 1998; corresponding to U.S. Pat. No. 5,714,520, issued 3 Feb. 1998) discloses an oil-in-water emulsion of Propofol containing an edetate as an antimicrobial agent. The amount of edetate is preferably no more than 0.1% by weight but is sufficient to prevent a no more than 10 fold increase in the growth of each of staphylococcus aureus (ATCC 6538) Eschericha 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 at approximately 50 to 250 colony-forming units per ml at a temperature in the range 20-25.degree. C., incubated in that temperature range and tested for viable counts of said organism after 24 hours. The currently marketed formulation comprises 1% w/v Propofol, 10% w/v Soybean Oil, 1.2% w/v Egg Phosphatides as an emulsifier, 2.25% w/v Glycerol and 0.0055% w/v disodium edetate, Sodium hydroxide and Water for Injection.

"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 U.S. Pat. No. 6,028,108; infra).

"WO-A-99/39696 (published 12 Aug. 1999; corresponding to U.S. Pat. No. 6,469,069 issued 22 Oct. 2002) discloses an oil-in-water emulsion of Propofol containing a sulphite as an antimicrobial agent. The amount of sulphite preferably is in the range 0.0075% to 0.66% by weight and is sufficient to prevent a no more than 10 fold increase in the growth of each of staphylococcus aureus (ATCC 6538) Eschericha 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 at approximately 50 to 250 colony-forming units per ml and incubated at a temperature in the range 30-35.degree. C. and tested for viable counts of said organism after 24 hours. 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.

"Reference is made to the water-immiscible solvent of the oil-in-water emulsion being a mono-, di-, or triglyceride. The preferred amount of solvent is 5 to 25% by weight.

"Infusion of preferred compositions is accordance with WO-A-99/39696/U.S. Pat. No. 6,469,069 at a rate of 50 .mu.g/kg/min for 24 hours will result in sulphite concentrations approaching the toxic levels. Further, the compositions may cause allergic reactions because of the sulphite molecule and the compositions have been reported to be physically and chemically unstable on exposure (see Han J et al International Journal of Pharmaceutics 2001, 215(1-2):207-220 & Baker M T et al Anesthesiology 2002, 97(5): 1162-1167).

"WO-A-00/24376 (published 4 May 2000; corresponding to U.S. Pat. No. 6,140,373 & U.S. Pat. No. 6,140,374, both issued 31 Oct. 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. Preferably, the composition comprises Propofol 0.1-5.0% by wt.; vegetable oil, preferably soybean oil, 1-30% by wt; surfactant, preferably egg phosphatide, 0.2 to 2% by wt.; glycerol 2-3% by wt.; and antimicrobial agent selected from (i) benzyl alcohol 0.0175-0.9% by wt., (ii) benzyl alcohol 0.07-0.9% by wt and sodium edetate 0.005% by wt., (iii) benzethonium chloride 0.01% to 0.1% by wt. and, most preferably, (iv) benzyl alcohol 0.0175-0.9% by wt. and sodium benzoate 0.07% by wt.

"Reference is made to the water-immiscible solvent of the oil-in-water emulsion being an ester of a medium or long chain fatty acid, exemplified as a mono-, di-, or triglyceride. The preferred amount of solvent is 10 to 20% by weight.

"For long-term use, the antimicrobial agents such as benzyl alcohol and benzethonium chloride are not recommended, as they are toxic.

"WO-A-00/59471 (published 12 Oct. 2000; corresponding to U.S. Pat. No. 6,100,302, issued 8 Aug. 2000) discloses intravenous anaesthetic Propofol emulsions having decreased levels of soybean oil, fats or triglycerides. The formulation preferably consists of phospholipid-coated microdroplets ranging from 160 to 200 nanometers in diameter. These microdroplets contain a sphere of Propofol dissolved in a solvent, such as vegetable oil, surrounded by a stabilizing layer of a phospholipid. It is reported that this formulation can safely provide sedation over extended periods of time and that the low oil concentration emulsion containing Propofol provides a stable oil-in-water emulsion and unexpectedly exhibits antimicrobial properties comparable to higher water immiscible solvent concentration emulsions containing preservatives.

"Typically the composition in the above patent specification comprises from 0.1 to 5%, by weight, preferably 1% to 2% by weight, of Propofol. The water-immiscible solvent, preferably soybean oil, is suitably present in an amount that is from 0.1 to 3% and more suitably from 1 to 3% by weight of the composition. However, the reduction in the oil content makes the injection more painful because of free Propofol in the aqueous phase."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "The present invention provides a sterile, stable pharmaceutical oil-in-water emulsion composition of Propofol for intravenous administration having a preservative system which overcomes the drawbacks of prior art compositions.

"More particularly the present invention is to provide oil-in-water emulsion compositions of Propofol having preservative efficacy to the extent that there will be no more than 10 fold increase for at least 24 hours in growth of each of Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus and Candida albicans, after adventitious extrinsic contamination.

"In accordance with the present inventions a stable, intravenously administrable, propofol oil-in-water emulsion composition, comprising triglyceride oils; emulsifiers selected from purified and/or modified natural phosphatides; water; tonicity modifying agents; and preservative system comprising of monoglyceryl ester of lauric acid (Monolaurin) and a member selected from (a) capric acid and/or its soluble alkaline salts or its monoglyceryl ester (Monocaprin); (b) edetate; and capric acid and/or its soluble alkaline salts or its monoglyceryl ester (Monocaprin) and edetate.

"In the Propofol oil-in-water emulsion composition, the preservative system is present in a sufficient concentration to prevent a no more than 10-fold increase in growth of each of Pseudomonas aeruginosa (ATCC 9027), Escherichia coli (ATCC 8739), Staphylococcus aureus (ATCC 6538) and Candida albicans (ATCC 10231) for at least 24 hours after adventitious extrinsic contamination."

For more information, see this patent: Daftary, Gautam Vinod; Pai, Srikanth Annappa; Shanbhag, Girish Narasimha; Rivankar, Sangeeta Hanurmesh. Intravenous Propofol Emulsion Compositions Having Preservative Efficacy. U.S. Patent Number 8759404, filed March 2, 2007, and published online on June 24, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8759404.PN.&OS=PN/8759404RS=PN/8759404

Keywords for this news article include: Antimicrobials, Drugs, Therapy, Anesthesia, Bacillales, Pediatrics, Hydrocarbons, Pain Medicine, Topical Agents, Benzyl Alcohols, Benzyl Compounds, Pseudomonadaceae, Staphylococcaceae, Benzene Derivatives, Biological Products, Gram-Positive Cocci, Dermatological Agents, Staphylococcus aureus, Gram-Negative Bacteria.

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Source: Clinical Trials Week


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