EP1165046A1 - Compositions de propofol contenant des additifs de preservation - Google Patents

Compositions de propofol contenant des additifs de preservation

Info

Publication number
EP1165046A1
EP1165046A1 EP00921506A EP00921506A EP1165046A1 EP 1165046 A1 EP1165046 A1 EP 1165046A1 EP 00921506 A EP00921506 A EP 00921506A EP 00921506 A EP00921506 A EP 00921506A EP 1165046 A1 EP1165046 A1 EP 1165046A1
Authority
EP
European Patent Office
Prior art keywords
emulsion
water
propofol
oil
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00921506A
Other languages
German (de)
English (en)
Inventor
Satish K. Pejaver
Rajeshwar Motheram
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Baxter International Inc
Original Assignee
Baxter International Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Baxter International Inc filed Critical Baxter International Inc
Publication of EP1165046A1 publication Critical patent/EP1165046A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention generally relates to improved pharmaceutical formulations of the intravenous anesthetic propofol with enhanced microbial characteristics. More particularly, this invention relates to an improved propofol emulsion formulation which is bacteriostatic and in certain forms bactericidal with the use of trace amounts of an antimicrobial additive.
  • Propofol (2,6 diisopropylphenol) is a hydrophobic, water-insoluble oil which is widely used as an anesthetic agent via IV administration. Propofol is generally incorporated in a vegetable oil emulsion to enable intravenous administration.
  • compositions of propofol and their use in inducing anesthesia are generally described in U.S. Patents Nos. 4,056,635; 4,452,817 and 4,798,846, all to Glen and James.
  • 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.
  • One problem associated with the compositions described in the before mentioned patents is the risk of bacterial contamination primarily due to the high soybean oil content, and lack of anti-microbial preservatives.
  • a second formulation is an oil-free formulation in which, in one described form, the propofol is in a 6.8% wt/wt concentration and dispersed in water as micro-droplets with a diameter generally less than 1 micron, having a phospholipid or monoglyceride outer covering.
  • this formulation may increase site irritation to an unacceptable level.
  • emulsion is a biphasic system
  • addition of known preservatives at their usual levels may lower the amount of preservative in the aqueous phase due to partitioning between the phases, to a degree dependent on lipophilic properties of preservative and hence, may not provide the anti microbial effect being sought.
  • inclusion of known preservatives can cause physical instability of emulsion system.
  • the preferred embodiment of the present invention provides a propofol formulation, preferably an emulsion having anti-microbial properties with the use of amounts of an additive at very low concentrations.
  • An important feature of the propofol formulation of the present invention is a reduced risk of bacterial growth after site contamination, which may occur, in a medical care giving setting
  • the present invention provides a sterile pharmaceutical composition for parenteral administration which, in the preferred embodiment, comprises an emulsion in which propofol is dissolved in a water-immiscible solvent, preferably soybean oil and which further comprises a trace amount of an antimicrobial additive such that there is a deterrence of significant growth of microorganisms for at least 24 hours, following adventitious, extrinsic contamination.
  • a sterile pharmaceutical composition for parenteral administration which, in the preferred embodiment, comprises an emulsion in which propofol is dissolved in a water-immiscible solvent, preferably soybean oil and which further comprises a trace amount of an antimicrobial additive such that there is a deterrence of significant growth of microorganisms for at least 24 hours, following adventitious, extrinsic contamination.
  • An emulsion meaning a distinct, two-phase system that is in equilibrium.
  • the composition of the present invention preferably contains a microdroplet, approximately 200 nanometers in mean diameter, comprised of propofol, dissolved in an oil or other solvent, surrounded by a surfactant, and suspended in a pharmaceutical acceptable injectable carrier and including a trace amount of an anti-microbial additive.
  • the water-immiscible solvent is a vegetable oil, for example soybean, safflower, cottonseed, corn, sunflower, arachis, castor or olive oil.
  • the vegetable oil is soybean oil.
  • the water-immiscible solvent is an ester of a medium or long-chain fatty acid, for example, a mono-, di-, or triglyceride; or is a chemically modified or manufactured material such as ethyl oleate, isopropyl myristate, isopropyl palmirate, a glycerol ester, polyoxyl hydrogenated castor oil.
  • the water-immiscible solvent may be a marine oil, for example cod liver or another fish-derived oil. Suitable solvents also include fractionated oils, for example, fractionated coconut oil or modified soy bean oil. Furthermore, the compositions of the present invention may comprise a mixture of two or more of the above water-immiscible solvents.
  • Suitable surfactants include synthetic non-ionic surfactants, for example ethoxylated ethers and esters polypropylene-polyethylene block co-polymers, and phospholipids for example, naturally-occurring phospholipids such as egg and soya phospolipids and modified or artificially manipulated phospholipids (for example prepared by physical fractionation and/or chromatography), or mixtures thereof.
  • Preferred surfactants are egg phospholipids, such as lecithin.
  • composition of the present invention may be made isotonic with blood by the incorporation of a suitable tonicity modifier, for example glycerin.
  • a suitable tonicity modifier for example glycerin.
  • composition of the pharmaceutically acceptable injectable carrier is preferably a pyrogen free water, or Water for Injection U. S. P.
  • a concentrated aqueous solution of an anti-microbial additive is added to yield a trace amount of such an additive in the final concentration.
  • pentetic acid or its derivatives thereof are added to the propofol emulsion to provide a concentration ranging from 0.0025% - 0.01%.
  • Pentetic acid includes, diethylene triamine penta acetic acid ("DPTA") and derivatives of pentetetic acid include calcium trisodium pentetate and pentetate penta sodium.
  • DPTA is an ion sequestering agent and has found wide use as an imaging agent in radio pharmaceuticals.
  • pentetic acid is included in pharmaceutical compositions as an anti oxidant for stabilization purposes, but it is not believed that DPTA has been used as an anti-microbial additive in an emulsion similar to a propofol emulsion.
  • propofol 1-2%) is dissolved in
  • Soybean oil (5-10%) constituting the oil phase.
  • Glycerin (2.25%) and Lecithin (1.2%) are added to Water for Injection at 60 ⁇ 10 °C and mixed until a uniform dispersion is formed, constituting the aqueous phase.
  • the oil phase is added to aqueous phase while stirring to form the primary emulsion.
  • the primary emulsion is then recirculated through a homogenizer under high pressure, until the globule size of the emulsion is approximately 200 nm.
  • DTPA free acid, DTPA calcium tri sodium salt or DTPA penta sodium salt are then added to arrive at a concentration of 0.0025%
  • the pH of the final emulsion is adjusted with sodium hydroxide, filtered and filled under nitrogen and steam sterilized.
  • the appearance of the formulation is a white opaque liquid.
  • the mean globule size is approximately 200 nm.
  • the pH of finished product is between 7 - 8.5.
  • the emulsions were stable after single and double autoclaving.
  • compositions of the present invention are useful as anesthetics, which includes sedation and induction and maintenance of general anesthesia. Accordingly, the present invention provides a method of producing anesthesia in a warm-blooded animal, including humans, comprising administering parenterally a sterile aqueous pharmaceutical composition which comprises an oil-in-water emulsion in which propofol, in a water-immiscible solvent, is emulsified with water and stabilized by means of a surfactant.
  • Dosage levels of propofol for producing general anesthesia may be derived from the substantial body of literature on propofol. Furthermore, the anesthetist and/or physician would modify the dose to achieve the desired effect in any particular patient, in accordance with normal skill in the art.
  • test formulations included the listed concentrations (expressed in percent wt/v) of DTPA free acid, DTPA calcium tri sodium salt or DTPA penta sodium salt and a similar propofol emulsion without any DPTA or other anti-microbial additive.
  • concentrations expressed in percent wt/v
  • the test formulations containing bacteria were then incubated at 30°C - 35°C and those containing Candida were incubated at 20°C - 25°C and counted for viable colonies after 24 and 48 hours in duplicate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Anesthesiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des formulations d'émulsions anesthésiques intraveineuses à base de propofol, destinées à produire une émulsion stable et à inhiber simultanément toute croissance microbienne, ce qui assure une protection contre une contamination microbienne accidentelle pouvant survenir lors de perfusions intraveineuses à long terme, en raison de l'utilisation d'acide pentétique ou de dérivés de celui-ci.
EP00921506A 1999-04-05 2000-03-29 Compositions de propofol contenant des additifs de preservation Withdrawn EP1165046A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US12842899P 1999-04-05 1999-04-05
US128428P 1999-04-05
US47424099A 1999-12-29 1999-12-29
US474240 1999-12-29
PCT/US2000/008379 WO2000059472A1 (fr) 1999-04-05 2000-03-29 Compositions de propofol contenant des additifs de preservation

Publications (1)

Publication Number Publication Date
EP1165046A1 true EP1165046A1 (fr) 2002-01-02

Family

ID=26826568

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00921506A Withdrawn EP1165046A1 (fr) 1999-04-05 2000-03-29 Compositions de propofol contenant des additifs de preservation

Country Status (5)

Country Link
EP (1) EP1165046A1 (fr)
JP (1) JP2002541087A (fr)
CA (1) CA2366799A1 (fr)
MX (1) MXPA01010065A (fr)
WO (1) WO2000059472A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6726919B2 (en) * 2000-06-16 2004-04-27 Rtp Pharma, Inc. Injectable dispersion of propofol
AU2003299590B8 (en) * 2002-12-09 2010-04-08 Abraxis Bioscience, Llc Compositions and methods of delivery of pharmacological agents
BRPI0615265A8 (pt) 2005-08-31 2018-03-06 Abraxis Bioscience Llc composições compreendendo agentes farmacêuticos pouco hidrossoluíveis e agentes antimicrobianos

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6028108A (en) * 1998-10-22 2000-02-22 America Home Products Corporation Propofol composition comprising pentetate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0059472A1 *

Also Published As

Publication number Publication date
MXPA01010065A (es) 2002-06-21
WO2000059472A1 (fr) 2000-10-12
CA2366799A1 (fr) 2000-10-12
JP2002541087A (ja) 2002-12-03

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