WO2004108113A1 - Preparation amelioree, claire et indolore de propofol - Google Patents

Preparation amelioree, claire et indolore de propofol Download PDF

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Publication number
WO2004108113A1
WO2004108113A1 PCT/IN2003/000217 IN0300217W WO2004108113A1 WO 2004108113 A1 WO2004108113 A1 WO 2004108113A1 IN 0300217 W IN0300217 W IN 0300217W WO 2004108113 A1 WO2004108113 A1 WO 2004108113A1
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propofol
range
concentration
ketamine
composition according
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Dinesh Shantilal Patel
Sachin Dinesh Patel
Shashikant Prabhudas Kurani
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Priority to PCT/IN2003/000217 priority Critical patent/WO2004108113A1/fr
Priority to AU2003260943A priority patent/AU2003260943A1/en
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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K9/08—Solutions

Definitions

  • This invention relates to a clear, stable, ready to use anaesthetic compositions containing 2,6 Diisopropylphenol (Propofol) and one or more Analgesic in a solvent system and a process for preparing the same.
  • Propofol 2,6 Diisopropylphenol
  • Analgesic anaesthetic compositions containing 2,6 Diisopropylphenol (Propofol) and one or more Analgesic in a solvent system and a process for preparing the same.
  • Propofol is used as an anaesthetic agent for various surgical procedures for the patients requiring general anaesthesia and for induction, maintenance, sedation for ICU patients and also in various other clinical situations.
  • "Propofol-An update on clinical use” Anaesthesiology, 81, 1005-1043.
  • Anaesthesiology 81, 1005-1043.
  • the causative factor of pain experienced during administration can be because of high viscosity of the injection flowing through vein as in case of Propofol prepared in Propylene glycol. (Ref. Anaesthesia and Analgesics, Vol. 79, 939-939.8 & Vol. 75431-435). This has also resulted to irritation, thrombo phlebitis and thrombosis.
  • Patent 6,071,974 and EP 1,143,962 deal with a composition which contains 2,5 di-omethyl- l,4;3,6-dianhydro-D-glucitol, which is slightly oily in nature might as well cause slight pain. Further Pain reduction in part was resolved and overcome by use of Analgesic agents administered before the induction of Anaesthesia. The use of pre-mixing 1 ml of Lignocaine 2% solution, with 9 ml of 1% Propofol during the induction of anaesthesia has shown a drastic reduction in pain (Ref. Anesth. Analg., April 1, 2000; 90(4): 989 - 992).
  • premixing has a limitations and Physician has to premix the mixture by cumbersome procedure of breaking the ampoule or withdrawal from separate Vials of Lignocaine and then mixing in appropriate dosage along with Propofol emulsion.
  • Patent, JP 2002179562 as an abstract hints for stable premix formulation of fat emulsion process showing stability in the range of 3.0 to 6.5 in the presence of stabilizer but total disclosure is not available due to lack of English version and does not hint at clear premixed solution of Propofol with Analgesics.
  • compositions are available as emulsions and as cocktail to oil, egg phospholipid and glycerin in water.
  • This media is very rich source of Carbon, Hydrogen and Nitrogen. It allows the growth of microorganism and hence, almost all the cited prior arts have mentioned how to prevent the growth of microorganisms in such formulations.
  • this emulsion being a opaque, becomes difficult for the anesthetist for dosing.
  • Such preparation of emulsion involves high technology for the preparation of formulation and once the vial or ampoule is opened it has to be consumed immediately and the product monograph also suggest not to use the vials or ampoules after certain hours .It may be further noted that it cannot be administered to the patient suffering from hyperlipidemia because of the incorporation of the fat in the formulation. Such injection also requires aseptic technology during the administration of injections because it is prone to Bio-burden.
  • Propofol based formulations in the form of a clear solution comprising an analgesic component may be formulated in solvent system.
  • the said formulation can be administered in patients relatively with no pain.
  • the main object of the present invention is to provide a formulation of Propofol, an analgesic component and antioxidants in a solvent system which is in the form of a clear solution and which is stable over a period of about six months or higher, cost effective, easy to administer and relatively pain free.
  • Another object of the invention is to provide a method of preparation of the said formulation.
  • Another object of the invention is to provide a formulation which is stable in the pH range of 5.0 to 7.0.
  • a further object of the invention is to provide a formulation that is available in the multidose vials which can be preserved at the room temperature even after multiple puncturing and still maintaining potency, biological effecacy and all other attributes of the formulation up to the end of shelf life.
  • Another object of the invention is that such injections can be conveniently prepared by conventional injection manufacturing procedure.
  • a ready to use stable anesthetic composition in the form of a clear solution comprising (i) Propofol, (ii) at least one analgesic and like drug (iii) antioxidants, all being in a solvent system selected from (a) water and 2,5 di-omethyl-l,4;3,6-dianhydro-D-glucitol and/or its derivatives (b) cyclodextrin and its derivative and water wherein cyclodextrin forms a complex with Propofol
  • a process for preparation of ready to use stable anaesthetic composition in the form of a clear solution comprising (i) Propofol, (ii) at least one analgesic and like drug (iii) antioxidants, all being in a solvent system selected from (a) water and 2,5 di-omethyl-l,4;3,6-dianhydro-D-glucitol and/or its derivatives (b) cyclodextrin and its derivative and water wherein cyclodextrin forms a complex with Propofol comprising the steps of:
  • the clear solution according to the invention is a sedative hypnotic agent used for induction and maintenance of anesthesia to mammals including humans.
  • the composition according to the invention is an effective anaesthetic which is useful for alleviation of the pain and is still, user-friendly for the physician and doctor and is economically beneficial.
  • the solvent system comprising water and 2,5 di-omethyl- l,4;3,6-dianhydro-D-glucitol and other alkyl derivative dissolves the lipophilic drug Propofol and antioxidant into a clear solution form and which is well tolerated, having elicited safety through toxicity studies.
  • Various alkyl derivatives of 2,5 di-omethyl-l,4;3,6-dianhydro-D- glucitol may be used in the solvent system.
  • the Propofol concentration may vary from 1% to 3% w/v and the ratio of 2,5 di-omethyl- l,4;3,6-dianhydro-D-glucitol: water may be from 70 to 30 : 30 to 70.
  • Preferred ratio of 2,5 di-omethyl-l,4;3,6-dianhydro-D-glucitol : water is about 65 : 35.
  • the solvent system selected is matrix of cyclodextrin and its derivatives and water, wherein Propofol being complexed with cyclodextrin and cyclodextrin and Propofol is in ratio of 1 :3 , preferably 1 : 1.
  • the antioxidants are selected from the group of Tocopherols especially Alpha Tocopherol.
  • the analgesics and like drugs that are selected from Lignocaine, (base & hydrochloride), Tramadol, Ketorolac, Ketamine, Alfentanil, Pethidine, Bupivacaine, Ropivacaine and other analgesics that can be administered paranterally.
  • the preferred analgesics that are used are Lignocaine, Tramadol, Ketorolac, Ketamine, Alfentanil.
  • the ratio of Propofol : Lignocaine in the composition is in the range of 10: 1 to 300: 1 , preferably 100: 1 while that for Propofol: Ketamine is in the range of !0: 5 to 300:5, preferably 100:5 as the case may be.
  • the concentration of Lignocaine in the composition is between 0.001% to 0.1% and preferably about 0.01%.
  • concentration of Ketamine is in the range of 0.001 to 0.10%) preferably 0.05%.
  • the concentration of Tramadol is in the range of 0.01% to 0.05%.
  • the concentration of Fentanyl is in the range of 0.001%) to 0.0015%.
  • the concentration of Alfentanil is in the range of 0.001% to 0.005%.
  • the concentration of Pethidine is in the range of 0.010% to 0.05% preferably 0.042%.
  • the antioxidant is selected from Vitamin E group and is present in the composition in amounts of between 0.01% to 0.2%.
  • Alpha tocopherol is the preferred Vitamin E compound being present in the range of 0.05 to 0.1%.
  • the composition is made by mixing Propofol to the solvent system comprising water and 2,5 di-omethyl-l,4;3,6-dianhydro-D-glucitol and/or derivatives thereof so as to dissolve Propofol.
  • the other components like Antioxidants and Analgesic agents are added in the desired levels.
  • the pH of the solution is adjusted to between 5.0 to 7.0.
  • the solution thus prepared is filtered and packaged appropriately.
  • the pH is preferably maintained at about 6.4.
  • the filtration is carried out aseptically through Nylon 66, 0.2 ⁇ membrane filter and filled in ampoules or multidose vials under hermetic conditions and sealed with non toxic, non reactive rubber stopper and followed by sealing with aluminium cap and dispensed after quality check.
  • Other conventional forms of packagings may also be used.
  • cyclodextrin solvent system Propofol is mixed with cyclodextrin in a ratio of 1 : 1 to form a complex.
  • the said complex is dissolved in water and analgesics and antoxidants are then added and mixed.
  • the solution is stirred thoroughly under hermatic condition to dissolve the material and pH adjusted to 6.0 - 6.5 with acid or alkali made to volume with 65 : 35 mixture of 2,5 di-omethyl-l,4;3,6-dianhydro-D-glucitol: Water mixture filtered through 0.22 ⁇ , Nylon 66 filter through aseptic filtration, flushing under Nitrogen and then filled in ampoules or multidose vials with butylated rubber cork on it and sealed with aluminium cap and sterilized.
  • the solution is stirred thoroughly under hermatic condition to dissolve the material and pH adjusted to 6.0 - 6.5 with acid or alkali made to volume with 65 : 35 mixture of 2,5 di-omethyl-l,4;3,6-dianhydro-D-glucitol: Water mixture filtered through 0.22 ⁇ , Nylon 66 filter through aseptic filtration, flushing under Nitrogen and then filled in ampoules or multidose vials with butylated rubber cork on it and sealed with aluminium cap and sterilized.
  • Control was Propofol injection containing solution without Lignocaine or Ketamine.
  • Anaesthetic activity is carried out.
  • the measurement of anaesthetic activity is seen by loss of righting reflex/consciousness and the recovery time in terms of head lift.
  • the injections were compared for observing the Pain by any noticeable irritation effect This is observed macroscopically for pain or phlebitis like oedema and erythema.
  • Test Solution solution prepared by Example 1 - Propofol injection (10 mg/ml) containing 0.01% Lignocaine :
  • Test Solution solution prepared by Example 4 Propofol injection (10 mg/ml) containing 0.05% Ketamine
  • the dose required for the injection with Ketamine and Lignocaine by the inventive process does not lead to any Irritancy or Pain at the site of injection and the equivalent dose causes more sedation than the drug containing Propofol alone. As the time require for the recovery is longer than the additional drugs, the dose of such injection will be less to achieve same recovery time.
  • the Anaesthetic activity is not exhibited by the Lignocaine in isolation at the prescribed dose level.
  • Analgesic activity is not exhibited by Propofol alone and there is a phenomena of pain. However, this is reduced to NIL level when combined with Lignocaine or Ketamine.
  • Lignocaine and Ketamine helps in the reduction of pain immediately and there is no phase separation in our clear solution.
  • the Anaesthetic activity at the prescribed dose level is almost absent in the Lignocaine Injection.
  • the Analgesic activity is seen in the Ketamine injection.
  • Example 7 A solution containing mixture of Lignocaine in emulsion formulation in the ratio of 100 : 1 of Propofol : Lignocaine and is prepared by conventional method of premixing comprising of 100ml of 1% solution of emulsion preparation is taken and 10 mg of Lignocaine is added shaken well to ensure the solubility . The solution is mixed and shaken well.
  • composition of the present invention containing Propofol Lignocaine prepared by mixing lOOOmg of Propofol in the mixture of 2,5 di-omethyl-l,4;3,6-dianhydro- D-glucitol and water (65:35) containing vitamin E and 10 mg of Lignocaine is added shaken well and diluted with mixture as given in the examples above in the same ratio of 100: 1.
  • the formulation was evaluated for the stability of Propofol and for the comparison of element of pain .
  • the Anaesthetic and Analgesic activity was carried out in the Sprague Dawley Rat by administering the injection intravenously. The element of pain was observed by noticeable irritation, oedema or erythema at the site of injection and is graded.
  • a solution containing mixture of Ketamine in emulsion formulation in the ratio of 100 : 5 of Propofol : Ketamine is prepared by conventional method of premixing 10 ml of emulsion is mixed with 5 mg of Ketamine shaken well to ensure proper mixing This is compared with the composition of the present invention containing Propofol : Ketamine in the ratio of 100 : 5 prepared by mixing lOOmg of Propofol inlO ml mixture of 2,5 di-omethyl-l,4;3,6- dianhydro-D-glucitol and water (65:35) containing vitamin E and adding 5 mg of Ketamine to the same. Mixing it well to ensure homogenicity The stability studies were carried out for the Assay of Ketamine content.
  • the Anaesthetic and Analgesic activity was carried out in the Sprague Dawley Rat by administering the injection intravenously.
  • the element of Pain was observed by noticeable irritation, oedema or erythema at the site of injection and is graded.
  • a solution containing mixture of Ketamine in emulsion formulation in the ratio according to Ho-yeung Kil etal. is prepared by conventional method of premixing.
  • the readily available two 10 ml portion of emulsion containing 10 mg/ml of Propofol of is taken in two clean and sterilized separate Vials and mixed with 16.66 mg and 33.22 mg of Ketamine respectively and thoroughly mixed to ensure solubility
  • the solution in emulsion contains Propofol : Ketamine in the ratio of 100 : 16.66 and 100 : 33.32 This is compared with the composition of the present invention containing Propofol : Ketamine in the ratio of 100 : 5 prepared as previously cited .
  • the stability studies were carried out for the Assay of Propofol content of the premixed solution as well as composition of the present invention at the interval of 1 hr, 3 hrs & 24 hrs as mentioned in the prior art.
  • composition of the present invention with Propofol : Ketamine in the ratio of 100:5 gives a homogenous clear solution with no phase separation . Moreover the concentration of Propofol is maintained.
  • solution in emulsion containing Propofol : Ketamine in the ratio of 100 : 16.66 and 100 : 33.32 according to the prior art there occurs phase separation with oily globules floating. The concentration of the Propofol however is maintained in these concentration too.

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Abstract

L'invention concerne une composition anesthésique claire, stable et prête à l'utilisation comprenant du 2,6 diisopropylphénol (propofol), au moins un analgésique et médicament similaire ainsi que des anti-oxydants dans un système solvant, et l'invention concerne également un procédé d'élaboration correspondant. Le système solvant peut être: eau et 2,5 di-ométhyle-1,4;3,6-dianhydro-D-glucitol et/ou ses dérivés en proportion 65:35 et cyclodextrine et son dérivé et eau, sachant que la cyclodextrine forme un complexe avec le propofol selon un rapport de 1:1. L'analgésique peut être lignocaine, kétamine, tramodol, alfentanil, péthidine, ropivacaine, bupivacaine, kétamine, etc., avec possibilité d'administration parentérale, sachant que le rapport propofol: lignocaine est de 100:1 et que le rapport propofol: kétamine est de 100:5. Le procédé d'élaboration comprend les étapes suivantes : mélange du propofol dans le système solvant pour une dissolution efficace du propofol, et adjonction des agents analgésiques puis adjonction des anti-oxydants selon la quantité et le mélange voulus, ajustement de pH, filtrage du mélange et remplissage de flacon multidose.
PCT/IN2003/000217 2003-06-10 2003-06-10 Preparation amelioree, claire et indolore de propofol Ceased WO2004108113A1 (fr)

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PCT/IN2003/000217 WO2004108113A1 (fr) 2003-06-10 2003-06-10 Preparation amelioree, claire et indolore de propofol
AU2003260943A AU2003260943A1 (en) 2003-06-10 2003-06-10 Improved novel, clear, painless preparation of propofol

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007052295A3 (fr) * 2005-08-12 2007-07-26 Bharat Serums & Vaccines Ltd Compositions aqueuses anesthesiques comprenant du propofol
CN103877252A (zh) * 2014-03-25 2014-06-25 王寿世 一种用于局部麻醉的复合药剂及其制备方法
WO2017017693A1 (fr) * 2015-07-24 2017-02-02 Neon Laboratories Limited Émulsion injectable stabilisée de propofol et de kétamine
WO2018195292A1 (fr) 2017-04-19 2018-10-25 Mayo Foundation For Medical Education And Research Mélange de kétamine et de propofol
WO2020028629A1 (fr) * 2018-08-01 2020-02-06 The Regents Of The University Of California Compositions comprenant du propofol, de la kétamine et un analgésique, et procédés d'utilisation
WO2021211575A1 (fr) * 2020-04-13 2021-10-21 The Regents Of The Univefisity Of California Compositions comprenant du propofol, de la kétamine et un analgésique non opioide et méthodes d'utilisation

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US5962536A (en) * 1998-07-31 1999-10-05 Komer; Gene Injectable propofol formulations
US6071974A (en) * 1999-01-28 2000-06-06 Themis Chemicals Limited Limpid parenteral solution of 2,6-diisoprophylphenol as an anaesthetic drug and 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol as a solvent for making clear I. V. formulation
US6071933A (en) * 1999-12-03 2000-06-06 Diversified Medical Innovations, Inc. Homogeneous remifentanil-propofol blend for patient controlled anesthesia and process for its use
WO2002074200A1 (fr) * 2001-03-20 2002-09-26 Cydex, Inc. Preparation contenant du propofol et de la cyclodextrine d'ether sulfoalkylique

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US4056637A (en) * 1976-06-08 1977-11-01 Japan Natural Food Co. Ltd. Process for preparing food products containing a lactic acid bacteria-fermented product of a cereal germ
US5962536A (en) * 1998-07-31 1999-10-05 Komer; Gene Injectable propofol formulations
US6071974A (en) * 1999-01-28 2000-06-06 Themis Chemicals Limited Limpid parenteral solution of 2,6-diisoprophylphenol as an anaesthetic drug and 2.5-di-O-methyl-1.4;3.6-dianhydro-D-glucitol as a solvent for making clear I. V. formulation
US6071933A (en) * 1999-12-03 2000-06-06 Diversified Medical Innovations, Inc. Homogeneous remifentanil-propofol blend for patient controlled anesthesia and process for its use
WO2002074200A1 (fr) * 2001-03-20 2002-09-26 Cydex, Inc. Preparation contenant du propofol et de la cyclodextrine d'ether sulfoalkylique

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ANESTH. ANALG., vol. 74, no. 2, 1992, pages 246 - 249 *
DATABASE MEDLINE [online] KING ET AL.: "Lidocaine for the prevention of pain due to injection of propofol", Database accession no. (NLM1731545) *
DATABASE MEDLINE [online] VALTONEN ET AL.: "Propofol as an induction agent in children: pain on injection and pharmacokinetics", Database accession no. (NLM2646847) *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007052295A3 (fr) * 2005-08-12 2007-07-26 Bharat Serums & Vaccines Ltd Compositions aqueuses anesthesiques comprenant du propofol
JP2009504634A (ja) * 2005-08-12 2009-02-05 ブハラット セルムズ アンド ヴァクシンズ リミテッド プロポフォールを含む水性麻酔剤組成物
EA014673B1 (ru) * 2005-08-12 2010-12-30 Бхарат Сирумс Энд Вэксинс Лтд. Водные анестезирующие композиции, содержащие пропофол
CN103877252A (zh) * 2014-03-25 2014-06-25 王寿世 一种用于局部麻醉的复合药剂及其制备方法
WO2017017693A1 (fr) * 2015-07-24 2017-02-02 Neon Laboratories Limited Émulsion injectable stabilisée de propofol et de kétamine
US20190133970A1 (en) * 2015-07-24 2019-05-09 Neon Laboratories Limited Stabilized injectable emulsion of propofol and ketamine
US10821087B2 (en) 2015-07-24 2020-11-03 Neon Laboratories Limited Stabilized injectable emulsion of Propofol and Ketamine
WO2018195292A1 (fr) 2017-04-19 2018-10-25 Mayo Foundation For Medical Education And Research Mélange de kétamine et de propofol
US11357743B2 (en) 2017-04-19 2022-06-14 Mayo Foundation For Medical Education And Research Ketamine and propofol admixture
WO2020028629A1 (fr) * 2018-08-01 2020-02-06 The Regents Of The University Of California Compositions comprenant du propofol, de la kétamine et un analgésique, et procédés d'utilisation
WO2021211575A1 (fr) * 2020-04-13 2021-10-21 The Regents Of The Univefisity Of California Compositions comprenant du propofol, de la kétamine et un analgésique non opioide et méthodes d'utilisation

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