WO1997010814A1 - Nanodispersions de propofol - Google Patents

Nanodispersions de propofol Download PDF

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Publication number
WO1997010814A1
WO1997010814A1 PCT/IB1996/000868 IB9600868W WO9710814A1 WO 1997010814 A1 WO1997010814 A1 WO 1997010814A1 IB 9600868 W IB9600868 W IB 9600868W WO 9710814 A1 WO9710814 A1 WO 9710814A1
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WO
WIPO (PCT)
Prior art keywords
component
ofthe
nanodispersion
intravenous administration
propofolum
Prior art date
Application number
PCT/IB1996/000868
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English (en)
Inventor
Hans Georg Weder
Original Assignee
Vesifact Ag
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 Vesifact Ag filed Critical Vesifact Ag
Priority to AU67080/96A priority Critical patent/AU6708096A/en
Publication of WO1997010814A1 publication Critical patent/WO1997010814A1/fr

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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
    • A61K9/10—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
    • 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
    • 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
    • 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

Definitions

  • the following invention relates to nanodispersions for the intravenous administration of an anaesthetic agent having lipophilic properties, a process for the preparation of these nano ⁇ dispersions and its use in therapeutic methods
  • Propofol (propofolum), cf Merck Index Tenth Edition (1989), entry No. 7847, page 1245, chemical name 2,6-diisopropylphenol, is an intravenous sedative hypnotic agent for use in the induction and maintenance of anaesthesia or sedation
  • Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly and smoothly with minimal excitation, usually within 40 seconds from the start of an injection, cf Physicians ' Desk Reference, 49th Edition 1995, Medical Economics (USA), page 2436.
  • the active agent propofol is commercially available only in a single pharmaceutical dosage form, e g which is an injectable emulsion marketed under the trade mark Disoprivan ® (Stuart, Zeneca)
  • Disoprivan ® This formulation is an emulsion consisting of soy bean oil, egg lecithin, and glycerol
  • Emulsions of this type used as injectables have serious drawbacks M Tressler et al report in Can. J. Anaesth. 1992, 39 (5 Pt 1), 509-511 of undesirable growth of bacteria in emulsions containing propofol C Pirttikangas et al report in Intensive Care Med. 1993, 19(5), 209-302 of undesirable immunesuppressive effects resulting from bolus administrations or rapid infusion treatment M Lindholm reports in Minerva Anaesthesiol 1992, 58 (10), pages 875-879 that the maximal lipid clearance is exceeded Physician 's Desk Reference, loc. cit., mention serious adverse reactions, such as bradycardia, apnea, hypotension, and others A detailed section is dedicated to Warnings, Precautions, and Drug Interactions
  • a suitable intravenous dosage form has not yet been available for the important anaesthetic agent propofol
  • the object ofthe present invention is to make available a suitable intravenous dosage form for the lipophilic active agent propofol
  • the object ofthe present invention is the preparation of a new, improved intravenous dosage form for the lipophilic agent propofol which contains physiologically acceptable amounts of carrier materials
  • the sparingly soluble therapeutic agent is encapsulated in lipid particles ofa particle size of less than 1 ⁇ m
  • the "loaded" lipid particles then form with the aqueous carrier liquid an aqueous phase of colloidally dispersed or, preferably, finely dispersed character, which differs from the true homogeneous distribution of solutes at molecularly dispersed level but is, nevertheless, sufficiently homogeneous for the preparation of intravenous and oral dosage forms
  • Numerous publications suggest the incorporation of therapeutic agents of low solubility in micelles, mixed micelles, reverse
  • the present invention therefore, relates to a nanodispersion for the intravenous administration of an anaesthetic agent having lipophilic properties, which comprises a) 1 0 - 2 0 weight % ofthe therapeutic agent 2,6-diisopropylphenol (propofolum), b) 1 0 - 3 0 weight % ofa partial fatty acid ester of polyoxyethylene sorbitan, c) the carrier liquid water, in the degree of purity necessary for intravenous administration, wherein the weight ratios of component a) to component b) are in the range of 0 33 - 1 2
  • the nanodispersion defined above is distinguished by useful phase properties ofthe solubilized therapeutic agent For example, where opalescence and transparency occur in incident light, only an extremely slight milky turbidity reveals that the dispersion formed still has physical differences vis-a-vis the ideal state ofa true molecular solution Electron microscope images show that a population of more than 95 % ofthe sparingly soluble propofol is present in the form ofa dispersion of nanoparticles having a particle size of less then 30 nm (“nano ⁇ dispersion”) However, these differences vis-a-vis a true solution are acceptable in view of some remarkable homogeneity properties ofthe nanodispersion These properties can be made apparent in a high storage stability, for example there is no separation after storage for several months at 2-8°C (by extrapolation the expected stability is more than two years) A comparison with the conventional injectable emulsion formulation Disoprivan ® reveals the following: A sample of Disoprivan ® of 1 0 ml contains a mean of about
  • a preferred embodiment ofthe present invention relates to a nanodispersion comprising a) 1 0 - 2 0 weight % ofthe therapeutic agent 2,6-diisopropylphenol (propofolum), b) 1 0 - 3 0 weight % of polyoxyethylene(20)sorbitan monooleate, c) the carrier liquid water, in the degree of purity necessary for intravenous administration, wherein the weight ratios of component a) to component b) are in the range of 0 33 - 1 0
  • the therapeutic agent propofol - component a) - is present in the nanodispersions defined above in the dose which is approved for injection formulations According to Physicia 's Desk Reference, loc. cit., an injectable formulation of 1 ml contains a dose of 10 mg
  • the partial fatty acid ester of polyoxyethylene sorbitan - component b) consists preferably of a substantially pure ester of sorbitan or a mixture of different esters of sorbitan in which the structure ofthe fatty acid groups and the length ofthe polyoxyethylene chains may vary
  • the hydrophilic sorbitan is preferably etherified by three hydrophilic polyoxyethylene chains and esterified by a hydrophobic fatty acid group
  • the sorbitan may, however, alternatively be etherified by only one or two polyoxyethylene chains and correspondingly esterified by two or three fatty acid groups
  • the basic sorbitan structure is altogether substituted by a minimum of two and a maximum of three hydrophilic groups, the term "hydrophilic group" embracing the polyoxyethylene chains, whereas the fatty acid groups are hydrophobic
  • the polyoxyethylene chain is linear and has preferably from 4 to 10, especially from 4 to 8, ethylene oxide units
  • the ester groups on the basic sorbitan structure are derived from a
  • Suitable partial fatty acid esters of polyoxyethylene sorbitan are commercially obtainable under the trademark Tween ® of ICI Co ⁇ and known by the chemical names polyoxyethylene (20 or 4)sorbitan monolaurate (TWEEN 20 and 21), polyoxyethylene(20)sorbitan mono- palmitate or monostearate (TWEEN 40 and 60), polyoxyethylene(4 or 20)sorbitan mono ⁇ stearate or tristearate (TWEEN 61 and 65), polyoxyethylene(20 or 5)sorb ⁇ tan monooleate (TWEEN 80 or 81) and polyoxyethylene(20)sorbitan trioleate (TWEEN 85)
  • polyoxyethylene(20)sorbitan monooleate (TWEEN 80) is used as component b)
  • the carrier liquid water having the degree of purity necessary for intravenous administration is, in accordance with the regulations of national pharmacopoeias, germ- and pyrogen-free
  • Excipients suitable for injection pu ⁇ oses are present in the nanodispersion if desired Suitable excipients are approved by Regulatory Authorities for injection purposes, e g glycerol, benzyl alcohol in the degree of purity prescribed for injection purposes, and also excipients suitable for the production of isotonic conditions, for example ionic excipients, e.g. sodium chloride, or other water-soluble excipients, e.g. sorbitan, mannitol, glucose, lactose or fructose
  • the present invention also relates to a process for the preparation ofthe nanodispersions defined above, which is known per-se and which process comprises.
  • the nanodispersion is prepared by adding the oily phase of pure propofol - component a) - to the aqueous phase containing the component b) This mixture is stirred during 2 to 3 houres using a magnetic stirrer or static mixer. Mixing preferably is effected at room temperature or under moderate heating up to 45°C.
  • the dispersion obtainable can be defined as a dispersion of colloidal nanoparticles ofthe sparingly soluble lipophilic active agent propofol, or, more simply, as a nanodispersion
  • the colloidal nanoparticles present in the nanodispersion can be distinguished from other particles such as liquid crystals, micelles, inverse micelles or liposomes.
  • an average particle size of less than 25 nm is typical.
  • the identification ofthe nanodispersions obtainable, methods known per se are suitable, for example optical examination: Transparence with slight to intense opalescence ofthe preparation is easily identifiable (indicates average particle size of less than 50 nm); laser light scattering (determination ofthe particle size and homogeneity); or electron microscopy (freeze fracture and negative contrast technique).
  • the necessary amount of water, which must be ofthe purity prescribed for injectables, can be added to the nanodispersion.
  • This nanodispersion can be directly administered after selecting the filtration method suitable for such types of dispersions, preferably sterile filtration (0.2 ⁇ m), for example with a PAL filter (Gelman), and optionally after adding further water-soluble excipients that can be used for intravenous dosage forms.
  • sterile filtration is applicable to separate off all relatively large particles in the nanodispersion having a diameter greater than about 200 nm, as well as floating and solid substances. This yields a nano ⁇ dispersion having a high proportion of hydrophilic particles of extremely uniform size.
  • the nano ⁇ dispersion may be converted into a dry preparation, especially into a lyophilisate, which is reconstituted prior to administration by the addition of water.
  • An administrable nanodispersion is obtained again after reconstitution ofthe lyophilisate.
  • so-called builders such as lactose or mannitol, is customary. These excipients are added in such amounts that after reconstitution ofthe lyophilisate the nanodispersion to be administered has isotonic properties.
  • Measured amounts of nanodispersion are introduced, optionally in the form of a concentrate, into containers suitable for a unit dose, for example glass ampoules (vials).
  • the filled containers can be cooled, if desired, to about -40° to -50°C, especially to about -45°C, and then lyophilised at a pressure of about 0 2 to 0 6 mbar by slowly heating to a final temperature of about 25° to 35°C
  • the nanodispersion according to the present invention is particularly useful as injection formulation for intravenous administration for the induction and maintenance of anaesthesia or sedation
  • the relevant physico-chemical parameters such as size and distribution ofthe nanoparticles (laser light scattering methods in the nm range), number of particles per ml (particle counter according to USP in the ⁇ m range), viscosity, and concentrations ofthe active agent in the formulation are shown in the TABLE attached to the Examples
  • Example 1 Formulation for an injectable formulation 10 mg/ml Percentages are given in weight percent
  • Example 3 Formulation for an injectable formulation 10 mg/ml Percentages are given in weight percent
  • the formulation is prepared in a manner analogous to Example 2 at room temperature
  • Example 4 Formulation for an injectable formulation 20 mg/ml Percentages are given in weight percent

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des nanodispersions pour l'administration intraveineuse de propofolum, un agent anesthésique doté de propriétés lipophiles. La nanodispersion se prépare par adjonction de propofolum dans une solution aqueuse d'ester partiel d'acide gras de sorbitane de polyoxyéthylène à basse concentration puis agitation modérée à température ambiante ou sous l'effet d'un chauffage modéré.
PCT/IB1996/000868 1995-09-18 1996-08-29 Nanodispersions de propofol WO1997010814A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67080/96A AU6708096A (en) 1995-09-18 1996-08-29 Propofol nanodispersions

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH262095 1995-09-18
CH2620/95-5 1995-09-18
CH3257/95 1995-11-17
CH325795 1995-11-17

Publications (1)

Publication Number Publication Date
WO1997010814A1 true WO1997010814A1 (fr) 1997-03-27

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AU (1) AU6708096A (fr)
WO (1) WO1997010814A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998053805A1 (fr) * 1997-05-26 1998-12-03 Westy Ag Formulation injectable et transparente constituee d'un compose anesthesique
WO1999039696A1 (fr) * 1998-02-10 1999-08-12 Sicor Inc. Composition a base de propofol contenant du sulfite
WO2000024376A1 (fr) * 1998-10-23 2000-05-04 Abbott Laboratories Composition de propofol
WO2002009671A2 (fr) * 2000-08-01 2002-02-07 University Of Florida Nouveaux systemes de micro-emulsions et de tensioactifs destines a la solubilisation de medicaments
WO2002085328A2 (fr) * 2001-02-11 2002-10-31 Aquanova German Solubilisate Technologies (Agt) Gmbh Procede de production d'un concentre de principe actif et concentre de principe actif
WO2004050059A1 (fr) * 2002-12-03 2004-06-17 Elan Pharma International Ltd. Formes posologiques liquides a faible viscosite
WO2006056064A1 (fr) * 2004-11-29 2006-06-01 Labopharm Inc. Formulations solides d'agents liquides biologiquement actifs
EP1935407A1 (fr) * 2002-12-03 2008-06-25 Elan Pharma International Limited Formules de dosage de liquide à faible viscosité
US7510731B2 (en) 2001-06-08 2009-03-31 Labopharm Inc. Water-soluble stabilized self-assembled polyelectrolytes
US7550155B2 (en) 2002-07-29 2009-06-23 Transform Pharmaceuticals Inc. Aqueous pharmaceutical compositions of 2,6-diisopropylphenol (propofol) and their uses
US7915317B2 (en) 2002-07-29 2011-03-29 Transform Pharmaceuticals, Inc. Aqueous 2,6-diisopropylphenol pharmaceutical compositions
US9040088B2 (en) 2002-04-12 2015-05-26 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
EP3129002A4 (fr) * 2014-04-09 2017-11-08 Nanoceutica Laboratories Pvt. Ltd Composition et procédé de production d'une nanoformulation de composés bioactifs insolubles dans l'eau dans un support aqueux

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452817A (en) * 1974-03-28 1984-06-05 Imperial Chemical Industries Plc Anaesthetic compositions containing 2,6-diisopropylphenol
EP0535567A1 (fr) * 1991-10-01 1993-04-07 B. Braun Melsungen AG Liposomes contenant des anéstésiques d'inhalation volatiles, leurs préparations et leurs utilisations
WO1995020943A1 (fr) * 1994-02-04 1995-08-10 Scotia Lipidteknik Ab Emulsions huile dans l'eau
US5496537A (en) * 1995-03-23 1996-03-05 Henry; Richard A. Propofol hydrofluorocarbon propellant formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452817A (en) * 1974-03-28 1984-06-05 Imperial Chemical Industries Plc Anaesthetic compositions containing 2,6-diisopropylphenol
EP0535567A1 (fr) * 1991-10-01 1993-04-07 B. Braun Melsungen AG Liposomes contenant des anéstésiques d'inhalation volatiles, leurs préparations et leurs utilisations
WO1995020943A1 (fr) * 1994-02-04 1995-08-10 Scotia Lipidteknik Ab Emulsions huile dans l'eau
US5496537A (en) * 1995-03-23 1996-03-05 Henry; Richard A. Propofol hydrofluorocarbon propellant formulations

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326406B1 (en) 1997-05-26 2001-12-04 Westy Ag Clear, injectable formulation of an anesthetic compound
WO1998053805A1 (fr) * 1997-05-26 1998-12-03 Westy Ag Formulation injectable et transparente constituee d'un compose anesthesique
US6469069B1 (en) 1998-02-10 2002-10-22 Gensia Sicor Pharmaceuticals, Inc. Propofol composition containing sulfite
WO1999039696A1 (fr) * 1998-02-10 1999-08-12 Sicor Inc. Composition a base de propofol contenant du sulfite
US6147122A (en) * 1998-02-10 2000-11-14 Gensia Sincor Inc. Propofol composition containing sulfite
WO2000024376A1 (fr) * 1998-10-23 2000-05-04 Abbott Laboratories Composition de propofol
US6140374A (en) * 1998-10-23 2000-10-31 Abbott Laboratories Propofol composition
US6623765B1 (en) 2000-08-01 2003-09-23 University Of Florida, Research Foundation, Incorporated Microemulsion and micelle systems for solubilizing drugs
WO2002009671A3 (fr) * 2000-08-01 2002-05-16 Univ Florida Nouveaux systemes de micro-emulsions et de tensioactifs destines a la solubilisation de medicaments
WO2002009671A2 (fr) * 2000-08-01 2002-02-07 University Of Florida Nouveaux systemes de micro-emulsions et de tensioactifs destines a la solubilisation de medicaments
US6638537B2 (en) 2000-08-01 2003-10-28 University Of Florida Microemulsion and micelle systems for solubilizing drugs
WO2002085328A2 (fr) * 2001-02-11 2002-10-31 Aquanova German Solubilisate Technologies (Agt) Gmbh Procede de production d'un concentre de principe actif et concentre de principe actif
WO2002085328A3 (fr) * 2001-02-11 2003-11-06 Aquanova Ger Solubilisate Tech Procede de production d'un concentre de principe actif et concentre de principe actif
US7510731B2 (en) 2001-06-08 2009-03-31 Labopharm Inc. Water-soluble stabilized self-assembled polyelectrolytes
US9101540B2 (en) 2002-04-12 2015-08-11 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US7101576B2 (en) 2002-04-12 2006-09-05 Elan Pharma International Limited Nanoparticulate megestrol formulations
US9101549B2 (en) 2002-04-12 2015-08-11 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US9040088B2 (en) 2002-04-12 2015-05-26 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US9107827B2 (en) 2002-04-12 2015-08-18 Alkermes Pharma Ireland Limited Nanoparticulate megestrol formulations
US7550155B2 (en) 2002-07-29 2009-06-23 Transform Pharmaceuticals Inc. Aqueous pharmaceutical compositions of 2,6-diisopropylphenol (propofol) and their uses
US7915317B2 (en) 2002-07-29 2011-03-29 Transform Pharmaceuticals, Inc. Aqueous 2,6-diisopropylphenol pharmaceutical compositions
US8133918B2 (en) 2002-07-29 2012-03-13 Janssen Biotech, Inc. Aqueous pharmaceutical compositions of 2,6-diisopropylphenol (propofol) and their uses
JP4838514B2 (ja) * 2002-12-03 2011-12-14 エラン ファーマ インターナショナル，リミティド 低粘度液体剤形
EP1935407A1 (fr) * 2002-12-03 2008-06-25 Elan Pharma International Limited Formules de dosage de liquide à faible viscosité
WO2004050059A1 (fr) * 2002-12-03 2004-06-17 Elan Pharma International Ltd. Formes posologiques liquides a faible viscosite
JP2008521755A (ja) * 2004-11-29 2008-06-26 ラボファーム インコーポレイテッド 液体生物活性物質の固体配合物
WO2006056064A1 (fr) * 2004-11-29 2006-06-01 Labopharm Inc. Formulations solides d'agents liquides biologiquement actifs
US10561735B2 (en) 2004-11-29 2020-02-18 Paladin Labs Inc. Solid formulations of liquid biologically active agents
EP3129002A4 (fr) * 2014-04-09 2017-11-08 Nanoceutica Laboratories Pvt. Ltd Composition et procédé de production d'une nanoformulation de composés bioactifs insolubles dans l'eau dans un support aqueux
AU2015246030B2 (en) * 2014-04-09 2020-03-12 Pulse Pharmaceuticals Pvt Ltd Composition and method of producing nanoformulation of water insoluble bioactives in aqueous base
US11458096B2 (en) 2014-04-09 2022-10-04 Pulse Pharmaceuticals Pvt. Ltd. Composition and method of producing nanoformulation of water insoluble bioactives in aqueous base

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