WO2008023384A1 - Compositions de propofol sous forme d'emulsion administrées par voie intraveineuse - Google Patents

Compositions de propofol sous forme d'emulsion administrées par voie intraveineuse Download PDF

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Publication number
WO2008023384A1
WO2008023384A1 PCT/IN2006/000466 IN2006000466W WO2008023384A1 WO 2008023384 A1 WO2008023384 A1 WO 2008023384A1 IN 2006000466 W IN2006000466 W IN 2006000466W WO 2008023384 A1 WO2008023384 A1 WO 2008023384A1
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oil
propofol
composition
water
capric acid
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PCT/IN2006/000466
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English (en)
Inventor
Gautam Vinod Daftary
Srikanth Annappa Pai
Sangeeta Hanurmesh Rivankar
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Bharat Serums & Vaccines Ltd.
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Publication of WO2008023384A1 publication Critical patent/WO2008023384A1/fr

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    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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 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.
  • 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 inj ections.
  • 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.
  • 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.
  • noscomial infections 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.
  • 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.
  • 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.
  • sulphite has two problems; viz. (a) stability of the emulsion is affected and (b) it is potentially toxic material at little higher dose level.
  • Pentetate refers to diethylene triamine pentaacetate or "DTPA", and derivatives thereof.
  • 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, 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.
  • an antimicrobial agent selected from (a) benzyl alcohol alone or, preferably, together with either sodium edetate or sodium benzoate and (b) benzethonium chloride.
  • 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.
  • compositions can be medicaments containing lipophilic drugs, especially
  • 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.
  • Propofol compositions with edetate, metabisulphite and benzyl alcohol are commercially available. These materials act as preservatives in a particular 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.
  • the principal object of the present invention is to provide an oil-in- water emulsion composition
  • 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 of 20 - 25 0 C and are tested for viable counts of said organisms after 24 hours.
  • 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.
  • 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.
  • the oil is emulsified in water using natural phosphatides as 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.
  • 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),
  • 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 C 10 carbon atom naturally found in oils and fats.
  • Capric acid is also known as Decanoic acid - CAS No.
  • Capric acid has better anti-fungal properties than monolaurin.
  • Oral LD 50 in rats is more than 10,000mg/kg.
  • Purified capric acid is preferred. However, presence of small amounts of C 8 or Ci 2 or C 14 or such fatty acids are acceptable.
  • capric acid sodium salt When used in Propofol compositions, when pH is adjusted with sodium hydroxide, some capric acid sodium salt may be formed. Alternately sodium eaprate i.e. sodium salt of capric acid can also be used to provide required amount of capric acid which will also control the pH.
  • 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 CH 3 (CH 2 ) S COONa 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 compositions of the present invention typically comprise 0.01% - 5% w/v of Propofol.
  • the compositions 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.
  • Triglyceride oil suitable for the compositions of present invention include natural oils such as vegetable oils and/or synthetic oils such as MCT oil.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition of the present invention preferably is isotonic with blood by incorporating suitable tonicity modifying agents such as Glycerin, Dextrose, or Mannitol.
  • 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.
  • 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.
  • 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 0 C 5 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) 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 homo
  • 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.
  • Capric acid and/or its water soluble alkali salts when used alone, it can be added in aqueous phase or in to oily phase or partly into aqueous phase and partly into oily phase.
  • the following combinations are possible.
  • 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; 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
  • the preservative Capric acid and/or its water soluble alkali salts is added to the preformed Propofol emulsion prepared without any preservative in it.
  • the Propofol and capric acid and /or its soluble salt are added to a preformed lipid emulsion like Intralipid and homogenized.
  • Propofol complies with the European Pharmacopoeia (Ph.Eur.) specifications. Glycerin, Sodium hydroxide, Water for Injection complies with Indian
  • 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
  • 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 30OmL quantities.
  • Propofol oil-in-water emulsion composition was prepared using Capric acid as given in Table 1 below: Table 1: Composition of Example I
  • 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.
  • 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.
  • 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.
  • Propofol oil-in-water emulsion composition comprising Sodium decanoate is given in Table 4 and a process for its preparation is described below:
  • Preparation of Aqueous Phase To Water for Injection at 65 - 70°C, added Glycerin and Sodium decanoate. Mixed well to get a clear solution. Emulsif ⁇ cation: 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.
  • 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:
  • 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.
  • 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
  • a process for the preparation of the emulsion composition of Example IV is as follows:
  • 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.
  • Example IVB 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 Example IVB:
  • the Purified egg lecithin was added in the oily phase, instead of adding it into the aqueous phase.
  • the Capric acid was added to aqueous phase.
  • Globule size is determined using N4-Plus instrument from Coulter Counter. Average globule size is reported.
  • Propofol content and degradation products content Propofol content and degradation products content was determined by HPLC. The details are as follows:
  • Capric acid / Sodium decanoate content was determined by HPLC. The details are as follows:
  • composition of Examples was tested for determining preservative activity using the following procedure:
  • test samples do not support proliferation of microorganisms.
  • 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.

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  • Health & Medical Sciences (AREA)
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Abstract

L'invention concerne une composition sous forme d'émulsion huile dans eau de propofol comprenant de l'acide caprique et/ou ses sels alcalins solubles dans l'eau, utilisés de manière à empêcher la prolifération de micro-organismes, cette dernière étant engendrée par une contamination accidentelle de la composition lors d'une administration par voie intraveineuse prolongée.
PCT/IN2006/000466 2006-08-24 2006-11-22 Compositions de propofol sous forme d'emulsion administrées par voie intraveineuse WO2008023384A1 (fr)

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IN1328/MUM/2006 2006-08-24
IN1328MU2006 2006-08-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015506378A (ja) * 2012-02-06 2015-03-02 西安力邦制▲薬▼有限公司Ｘｉ‘Ａｎ Ｌｉｂａｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ ２，２’，６，６’−テトライソプロピル−４，４’−２−ビフェノールリピッドマイクロスフェア製剤及びその調製方法
CN112168780A (zh) * 2020-10-13 2021-01-05 西安力邦制药有限公司 一种加快药物吸收和脂质代谢的丙泊酚脂肪乳制剂

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023050A1 (fr) * 1998-10-22 2000-04-27 American Home Products Corporation Composition a base de propofol contenant du pentetate
EP1576953A1 (fr) * 2002-12-06 2005-09-21 Otsuka Pharmaceutical Factory, Inc. Emulsions grasses contenant du propofol
WO2007052288A2 (fr) * 2005-08-05 2007-05-10 Bharat Serums & Vaccines Ltd. Compositions d'emulsion de propofol pour administration intraveineuse presentant une efficacite de conservation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000023050A1 (fr) * 1998-10-22 2000-04-27 American Home Products Corporation Composition a base de propofol contenant du pentetate
EP1576953A1 (fr) * 2002-12-06 2005-09-21 Otsuka Pharmaceutical Factory, Inc. Emulsions grasses contenant du propofol
WO2007052288A2 (fr) * 2005-08-05 2007-05-10 Bharat Serums & Vaccines Ltd. Compositions d'emulsion de propofol pour administration intraveineuse presentant une efficacite de conservation

Non-Patent Citations (1)

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Title
BERGSSON ET AL: "In Vitro Killing of Candida Albicans by Fatty Acids and Monoglycerides", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, WASHINGTON, DC, US, vol. 45, no. 11, November 2001 (2001-11-01), pages 3209 - 3212, XP003000265, ISSN: 0066-4804 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015506378A (ja) * 2012-02-06 2015-03-02 西安力邦制▲薬▼有限公司Ｘｉ‘Ａｎ Ｌｉｂａｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ ２，２’，６，６’−テトライソプロピル−４，４’−２−ビフェノールリピッドマイクロスフェア製剤及びその調製方法
CN112168780A (zh) * 2020-10-13 2021-01-05 西安力邦制药有限公司 一种加快药物吸收和脂质代谢的丙泊酚脂肪乳制剂

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