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WO2000061113A1 - Compositions formant des agregats lipidiques, et leurs utilisations - Google Patents

Compositions formant des agregats lipidiques, et leurs utilisations Download PDF

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Publication number
WO2000061113A1
WO2000061113A1 PCT/GB2000/001361 GB0001361W WO0061113A1 WO 2000061113 A1 WO2000061113 A1 WO 2000061113A1 GB 0001361 W GB0001361 W GB 0001361W WO 0061113 A1 WO0061113 A1 WO 0061113A1
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WO
WIPO (PCT)
Prior art keywords
composition
lipid
biologically active
agents
active compound
Prior art date
Application number
PCT/GB2000/001361
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English (en)
Inventor
Steven Leigh
Mathew Louis Steven Leigh
Original Assignee
Phares Pharmaceuticals Research N.V.
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 Phares Pharmaceuticals Research N.V. filed Critical Phares Pharmaceuticals Research N.V.
Priority to EP00919049A priority Critical patent/EP1169020A1/fr
Priority to AU39804/00A priority patent/AU3980400A/en
Publication of WO2000061113A1 publication Critical patent/WO2000061113A1/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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to compositions useful as carriers to transport biologically active materials in general. More specifically, it relates to novel phospholipid formulations of biologically active compounds having improved bio-availability, less variability, low toxicity and ease of use in enhancing penetration, either as liquids or gels for topical and oral applications in various forms .
  • hydrophilic compounds e.g. peptides may also have low membrane permeability due to their polar nature and their large molecular size.
  • hydrophilic compounds e.g. peptides may also have low membrane permeability due to their polar nature and their large molecular size.
  • phospholipid mixtures in a hydrophilic medium described as pro-liposome compositions to carry active compounds as first disclosed in EP 0158441.
  • These latter compositions comprise blends of bilayer forming diacyl phospholipids , which on dilution with aqueous fluids formed closed vesicular structures with high entrapment of a biologically active compound.
  • WO 88/06438 discloses similar compositions to the above, and claims desalted charged diacyl lipids in a non aqueous water miscible medium.
  • EP 030577 discloses a method of preparing liposomes using mixtures of diacyl phospholipids dissolved or dispersed in a non-volatile hydrophilic maxim .
  • WO 98/58629 discloses substantially homogenous compositions for human administration comprising a biologically active lipophilic compound dissolved in or associated with at least one micelle-forming lipid ⁇ - - monoacyl phosphatidylcholine, or blends of monoacyl phosphatidylcholine with diacyl phosphatidylcholine .
  • the compositions were shown to be surprisingly effective in solubilising and improving the bioavailability of compounds that have poor or variable absorption.
  • EP 0256090 discloses the use of a specific monoacyl phospholipid species, namely monoacyl phosphatidyl- ethanolamine and a hydrophobic compound, in the form of a micellar suspension at a pH between 8.2 to 14, for intravenous and other injectable purposes.
  • An object of this invention is to improve the ability of compositions based on a monoacyl membrane lipids , preferably in combination with a diacyl membrane lipid, to deliver lipophilic and hydrophilic compounds.
  • Another object of this invention is to reduce variable absorption of lipophilic and hydrophilic compounds .
  • a further object of the invention is to enhance the penetration of active compounds in liquid or gel-like formulations .
  • a further object of the invention is to provide a way of making dispersions of lipid aggregates in aqueous media that are stable, of small average particle size, can disperse hydrophilic or lipoplilic materials, and do not require large quantities of energy for their production .
  • the present formulations contain at least one micelle forming monoacyl membrane lipid either alone or in combination with one or more bilayer-forming diacyl membrane lipids , preferably as a minor component . They are characterised by the inclusion in smaller amounts than the lipid components of a lipophilic or water-immiscible component (phase) which may be an oil and which may be in co-solution in a hydrophilic medium.
  • phase a lipophilic or water-immiscible component
  • the invention provides a composition for delivering a biologically active compound to a living organism.
  • the composition is further characterised in that it also contains at least one hydrophilic component, preferably a combination of at least two, in an amount effective to render the composition into a clear liquid.
  • the composition has the property of yielding discrete lipid aggregates with mean Z average diameter determined by photon correlation spectroscopy (PCS) below lOOOnm preferably below 500nm, upon contact or further dilution with an aqueous medium.
  • PCS photon correlation spectroscopy
  • the present compositions will improve the penetration and bioavailability of biologically active compounds for the following reasons .
  • the compound, and particularly a lipophilic biologically active compound is molecularly dispersed owing to the dispersing properties of the monoacyl component and hence is readily available for partition into biological membranes .
  • the monoacyl component, and in particular monoacyl phospholipid influences the fluidity of biological membranes and facilitates the transport of biologically active compounds across the membranes. The combined effects are predicted to result in improved bioavailability.
  • the invention further provides a liquid pharmaceutical composition comprising:
  • compositions described are ideally suited for a wide range of applications , externally and internally as a penetration enhancing carrier .
  • the above compositions may be formulated so as to be flowable at room temperature .
  • the composition may also optionally contain polymers which influence the dispersibility characteristics of the composition on exposure to water or aqueous solutions .
  • Other excipients and stabilisers such as organic thickeners, antioxidants , flavourings, anti-microbial agents, buffering agents, colouring agents and sweetening agents may also be included.
  • membrane stabilisers such as cholesterol, dicetyl phosphate, stearyl amine and other charged amphipathic compounds may be added to the compositions to improve stability.
  • the formulations exhibit remarkably good storage stability. They are normally liquid presentations at room temperature and may be used as such for topical or oral applications or filled into unit dosage forms e.g. soft gelatin capsules .
  • Lipophilic drugs and other compounds can be solubilised in solutions of at least one monoacyl lipid (e.g. MAPC), preferably with diacyl lipids (e.g. PC) in a hydrophilic medium wherein a lipophilic component is also present.
  • monoacyl lipid e.g. MAPC
  • diacyl lipids e.g. PC
  • a hydrophilic medium wherein a lipophilic component is also present.
  • the reason for the use of such mixtures is three-fold. Firstly, such mixtures can solubilise much higher amounts of lipophilic bioactive compounds .
  • the presence of the monoacyl lipid influences the structure and size of the lipid aggregates formed on dilution with aqueous medium, and improves the stability of the aggregates.
  • the bioavailability of biologically active compounds may be greatly improved because of better retention and penetration at the absorption surfaces due to the MAPC .
  • compositions On contact with water or other aqueous medium, or upon dilution in such media, the compositions have the potential to form discrete lipid aggregates with a Z average diameter below about lOOOnm, in most cases below 500nm and preferably below 200 nm.
  • the lipid aggregates formed with the lipophilic phase are extremely efficient vectors for transporting biologically active compounds across a membrane.
  • the invention further provides a process for dispersing a biologically active compound, which comprises : dispersing in a hydrophilic medium at least one micelle-forming membrane lipid and a biologically active compound to form an optically clear liquid, gel or semi- solid; and mixing the liquid, gel or semi-solid with aqueous medium to form lipid aggregates below 1000 nm dispersed in the aqueous medium, with the biologically active compound solution or stable dispersion.
  • compositions are a mixture of membrane lipid(s) , lipophilic component, hydrophilic medium and optionally a biologically active compound(s) .
  • the membrane lipid component consists of one or more monoacyl membrane lipids preferably, but not necessarily, in association with one or more diacyl membrane lipids .
  • the monoacyl lipid (s) is preferably the monoacyl derivative of a diacyl phospholipid, eg. monoacyl phosphatidylcholine (MAPC) , but it can also be the monoacyl derivative (s) of glycolipids , sphingolipids , or another micelle forming phospholipid.
  • the lipids may be derived from natural plant, or animal or microbiological sources, synthesised or partially synthesised including polyethyleneglycol (PEG) derived monoacyl phospholipids, eg . pegalated monoacyl phosphatidylethanolamine .
  • PEG polyethyleneglycol
  • the diacyl lipid(s) is preferably a phospholipid because such compounds are readily available and tend to be easy to incorporate in the mix.
  • phospholipids are phosphatidylcholine (PC) , phosphatidyl ethanolamine (PE) , phosphatidylglycerol (PG) , phosphatidylinositol (PI), phosphatidyl serine(PS), phosphatidic acid (PA) and spingomyelin.
  • the acyl chain can either be unsaturated or saturated and can have 12 to 22, preferably 14 to 18 carbon atoms.
  • Other membrane lipids such as glycolipids , ceramides , gangliosides and cerebrosides can be used in place of, or partial place of, phospholipids.
  • EML enzyme modified lecithin
  • the term lecithin generally refers to mixtures of bilayer forming diacyl phospholipids substantially free from micelle forming monoacyl phospholipids .
  • the upper limit for monoacyl phospholipids is usually about 1% to 2% .
  • the relative proportions of monoacyl to diacyl lipid can, however, be greatly enhanced by partial hydrolysis of one or more phospholipids e.g. lecithin. Hydrolysis can be chemical or by an enzyme (e.g.
  • phospholipase A2 or by a micro- organism.
  • the phospholipid mixtures which are classed as enzyme modified lecithins (EML) are freely used in foods without restrictions and provide no problems for oral use .
  • EML enzyme modified lecithins
  • Particularly preferred grades of EML used in this invention are refined by solvent extraction or are chromatographically fractionated, or both, free from residual phospholipase A2 activity.
  • the degree of purification or refinement needed will be appropriate for a pharmaceutical grade material and for the degree of stability required for each particular end use.
  • the methods of purification will be familiar to those skilled in the art. Commercial grades of such material may be obtained from Lucas Meyer GmbH .
  • the membrane lipid/lipids employed in the present invention may be:
  • the total weight of membrane lipid in the composition is usually between 20% to 80%, most preferably 40% to 60% , although lesser or greater amounts may be used without departing from the scope of the invention .
  • the proportion of the micelle-forming monoacyl membrane lipid to diacyl membrane lipid by weight in this invention is preferably from 1:20 to 20:1, more preferably 1:10 to 10:1, most preferably 1:5 to 5:1 and still more preferably amounts of the monoacyl component greater than 1:1, or in some cases MAPC on its own may be employed.
  • the amount of membrane lipid should be greater than the lipophilic content. Contrary to expectations , the lipophilic medium need not exist as stabilised, discrete oil droplets.
  • lipid aggregate structures which may be vesicular or non vesicular are formed, depending on the mixture of monoacyl and diacyl lipids , even in the presence of substantial amounts ( ⁇ 10%) of lipophilic medium (oil) .
  • the lipid aggregates formed with less than about 10% of the monoacyl component in the mixture tend to be mostly vesicular structures whilst those with larger amounts of monoacyl tend to be non vesicular until typical micelles are obtained when the monoacyl content approaches 100%.
  • the micelle forming lipid and the bilayer forming lipid may be in a mixture resulting from deacylation of a phospholipid by means of phospholipase A2.
  • Particularly preferred blends are enzyme modified phospholipids and lecithin of the type used in the food industry containing 60 to 80 mole percent of total monoacyl lipid which includes other phospholipids in addition to PC.
  • the hydrophilic medium is hydrophilic medium
  • the hydrophilic medium normally comprises 10% to 60% by weight, preferably 20% to 40%, of the overall composition, although in many cases amounts greater than 60% may be employed. It may be a C 1 - 5 alcohol eg. ethanol, isopropyl alcohol, propylene glycol, on its own or preferably, in combination with a second hydrophilic component e.g. glycerol, butylene glycol and less preferably polyethylene glycols with molecular weights up to about 1000.
  • the term "hydrophilic medium” is taken to include water-miscible media such as ethoxydiglycol and tetraglycol .
  • C ⁇ -C 5 alkyl or tetrahydrofurfuryl di- or partial ethers of low molecular weight mono- or poly-oxy alkanediols eg diethylene glycol monoethyl ether and tetrahydrofurf ryl alcohol polyethylene glycol ether . It also includes partially water-miscible polar media such as propylene carbonate , propylene glycol diacetate , triacetin and dimethyl iso-sorbide. Compounds of this latter type are classified as water-soluble (Martindale, The Extra Pharmacoepia Edition 31) .
  • hydrophilic media may be used, providing they are pharmaceutically acceptable and can substantially dissolve/disperse the lipid. They could also be present in any combination . In some cases , water may also orm the second hydrophilic component.
  • the preferred hydrophilic medium is chosen from an alkanol and at least one polyol .
  • the preferred alkanol is ethanol , iso-propyl alcohol or n-propyl alcohol and the preferred polyol is glycerol, propylene glycol, butylene glycol .
  • the nature of the active compound will to a large extent determine the amount and the type of hydrophilic medium used, as long as it is water miscible or water soluble within the definition .
  • ethanol or isopropyl alcohol, n-propyl alcohol or propylene glycol may be used on its own with water or a sugar solution as the second hydrophilic component, whilst in other cases a mixture comprising ethanol , butylene glycol , glycerol and propylene glycol may be preferred.
  • one or a combination of polyol , water miscible hydrophilic solvent eg . ethoxy diglycol , propylene glycol carbonate may be used in place of ethanol as the hydrophilic medium.
  • the lipophilic component is the lipophilic component
  • the lipophilic component in the composition normally comprises between 5% to 50%, preferably 10% to 30% by weight overall .
  • the lipophilic component may be an organic material that is liquid at ambient temperatures, is immiscible with water, and has no surface-active or amphiphilic properties . It will not normally contain ionised groups.
  • the lipophilic component is an oil and the amount present should be less than the lipid component .
  • It may be a hydrocarbon, fatty acid ester or ether, or a mixture. Alternatively, it may be a volatile oil or a volatile silicone .
  • Typical examples of preferred lipophilic components are ethyl oleate, isopropyl myristate, isopropyl palmitate, medium and long chain triglycerides , propylene glycol esters, volatile/essential oils, and mixtures thereof.
  • the composition may further comprise at lease one biologically active compound which has lipophilic and/or hydrophilic properties .
  • it is in solution in the composition but it may also be in dispersion.
  • the compounds may have pharmaceutical , dietetic or cosmetic uses .
  • Biologically active compounds which may be used with advantage are antioxidants , e.g. ubiquinone, tocopherols , carotenoids , and bioflavonoids .
  • compositions may be prepared by dissolving or dispersing the lipid, lipophilic component and the active compound (when present) in the hydrophilic medium to obtain a homogeneous solution.
  • the active compound may be dissolved or suspended in the composition after preparation.
  • the compositions On contact with water or other aqueous medium or upon dilution, the compositions have the potential to hydrate to form a gel phase prior to forming discrete lipid aggregates. This may take place either in situ before use or in the GI tract after oral administration. Whilst in many cases , it is important for the biologically active compound to be in molecular dispersion in the lipid aggregates after dilution, in other instances, it may not be necessary for it to be substantially associated with the lipid aggregates . In such cases, the active compound may either be in solution or micro suspension in the aqueous medium.
  • lipid aggregates is used here to describe vesicular and non-vesicular structures including liposomes , various species of mixed micelles , micelles , swollen micelles and oil droplets , either as single species or equilibrium mixtures.
  • a bi- continuous structure that consists of contiguous interpenetrating domains of both oil and water with neither one surrounding the other may be present, particularly when more than about 10% of lipophilic component is present and the monoacyl component in the phospholipid mixture is high .
  • the diluted forms of the compositions are clear to slightly opalescent solutions or dispersions of lipid aggregates .
  • the aggregates are below 500nm Z average diameter .
  • Dispersibility and the different types of aggregate structures formed also depend on a number of factors e.g. the relative amount and the type of diacyl to monoacyl lipid and hydrophilic medium, pH, temperature, viscosity and the presence of other components e.g. polymers and surfactants .
  • the invention is also concerned with the property of monoacyl membrane lipids, particularly monoacyl phospholipids in combination with diacyl phospholipids , or enzyme modi ied lecithin (EML) , to enhance the delivery of poorly absorbed compounds .
  • monoacyl membrane lipids particularly monoacyl phospholipids in combination with diacyl phospholipids , or enzyme modi ied lecithin (EML)
  • EML enzyme modi ied lecithin
  • spontaneous dispersion into lipid aggregates is not an essential feature of the invention.
  • the composition or its diluted/final dispersed form may also be suspended in an external milieu surrounding or in intimate contact with a tissue/organ, mucosal membrane , or skin, from which the active compound may diffuse out.
  • the dispersed form of the composition may be obtained in situ by the addition of water or other aqueous medium prior to use, or the compositions may be administered in unit dosage form e.g. in gelatin capsules or the like.
  • the capsules may be enteric coated or protected so that dispersion mainly takes place in the contents of the small intestines or lower in the gastro-intestinal tract eg. colon. Enteric coating or resistance may be obtained by means of e.g. acrylic and methacrylic polymers , whilst site specific colonic delivery may be achieved by the additional use of amylose in the coating or in the formulation .
  • the contents of the capsule On contact with the gastric or intestinal fluids , the contents of the capsule may also hydrate initially to form a gel .
  • the active compound may not have sufficient storage stability in aqueous or hydrophilic medium, it may be added extemporaneously as a powder or suspension to the compositions in situ, to form a structured gel or a suspension of lipid aggregates for administration.
  • Polymers may influence the dispersion characteristics of the compositions , which surprisingly affect lipid-drug association in this invention. This fact is of particular importance in liquid oral dosage forms .
  • Examples of polymers that affect hydration properties include cellulose derivatives , acrylic and methacrylic polymers , polyglycolic acid, polyethylenes , polypropylenes , polyhydroxybutyrates , etc.
  • the polymer is soluble in the hydrophilic me ium or in the composition.
  • Particularly preferred examples are acrylic and methacrylic polymers sold under the brand name Eudragit. Different grades with swelling properties that may be time or pH dependent are available, allowing for control of these parameters in the compositions .
  • water soluble polymers may also be used in those compositions that contain water .
  • examples of such polymers are the natural gums , hydroxy propyl methyl cellulose , modified starches , alginates , carboxy vinyl copolymer etc .
  • the amount of polymer, where used, usually need not exceed 10% by weight of the composition, preferably up to 5% , most preferably between 0.5% to 3% .
  • Suitable surfactants include nonionic, anionic, cationic and combinations thereof. Nonionic surfactants are preferred.
  • other excipients and stabilisers such as inorganic thickeners, antioxidants, flavourings, anti-microbial agents, buffering agents , colouring agents and sweetening agents may be included.
  • antioxidants include: ascorbic acid, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxy toulene , ⁇ tocopherol or its derivatives .
  • Stabilising agents or buffering agents should be incorporated at a level sufficient to maintain the pH of the composition within the range 4-8, preferably between 5 and 7.
  • compositions may also be administered by oral administration.
  • Topical formulations including creams, ointments, foams, gels, lotions, mousses, for skin and mucosal surfaces and transdermal patches are all within the claims of this invention, and may be easily formulated by those skilled in the art.
  • the compositions may be given by parenteral administration or for tissue wash-out and irrigation purposes following surgical procedures . They may be used in pulmonary delivery, by inhalation in pressurised metered inhalers or by nebulisation after in situ reconstitution.
  • the presence of aggregates of 1000 nm or smaller may be detected directly by an electron-micrograph (EM) or may be inferred from the absence of a tendency for the material to flocculate, settle out or sediment.
  • EM electron-micrograph
  • a clear solution with opalescence indicates that the lipid aggregates present have average sizes about 200 nm or below.
  • a clear solution without noticeable opalescence indicates that the lipid aggregates present have average sizes 100 nm or below.
  • Fig. 1 is a typical freeze-fracture electron micrograph showing discrete lipid aggregates. It is apparent from the figure that the aggregates are in the form of vesicles , and the size of the two largest vesicles is about 180 nm. The multi-layered structure is clearly shown in one of the vesicles , each of the layers shown being a lipid bilayer .
  • composition is suitable for topical application.
  • diclofenac may be added to the composition after preparation.
  • the resultant dispersion was a translucent opalescent yellow dispersion similar to those in the previous Examples .
  • This Example shows the dispersion of a hydrohlilic biologically active compound, the properties of the dispersion produced being similar to those of the earlier examples .
  • Example 10 25 parts of membrane lipid (containing 7.5%w/w of MAPC, 50%w/w PC, 15%w/w PE and 27.5%w/w of other membrane lipids including charged phospholipids and glycolipids) and 25 parts of IPM were dissolved in 50 parts of ethoxydiglycol .
  • This concentrate was diluted with 900 parts of water containing 10 parts of carbomer (a carboxyvinyl copolymer gelling agent) and 5 parts of vancomycin.
  • the resultant formulation was an opaque yellow gel whose properties were similar to that of Example 9 and which was suitable for topical delivery.
  • This example demonstrates the incorporation of hydrophilic drug into an aqueous medium with a stable dispersed lipid aggregates .
  • compositions of the invention may provide an efficient, effective and non-toxic carrier for compounds that have poor bioavailability for a variety of routes of administration .

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Abstract

L'invention concerne des formulations contenant au moins un lipide membranaire monoacyle formateur de micelles, seul ou de préférence associé à un ou plusieurs lipides membranaires diacyles formateurs de bicouche. Les compositions se caractérisent en ce qu'elles contiennent une quantité efficace de ce composant monoacyle ainsi qu'un composant dissous ou dispersé dans un milieu hydrophile en quantité efficace pour convertir la composition en un liquide, un gel ou une substance semi-solide capable de produire des agrégats lipidiques dispersés lors du contact avec un milieu aqueux ou lors d'une autre dilution dans ce milieu. Certaines compositions pharmaceutiques liquides contiennent (a) un mélange de lipides membranaires contenant un lipide formateur de micelles et de préférence un lipide formateur de bicouche, (b) un composant lipophile, (c) au moins un milieu hydrophile servant à mobiliser les lipides, et éventuellement (d) un composé biologiquement actif. D'autres compositions contiennent de l'eau en quantité efficace pour hydrater le mélange lipidique, et un composé biologiquement actif.
PCT/GB2000/001361 1999-04-12 2000-04-11 Compositions formant des agregats lipidiques, et leurs utilisations WO2000061113A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP00919049A EP1169020A1 (fr) 1999-04-12 2000-04-11 Compositions formant des agregats lipidiques, et leurs utilisations
AU39804/00A AU3980400A (en) 1999-04-12 2000-04-11 Lipid aggregate forming compositions and their uses

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9908309.9A GB9908309D0 (en) 1999-04-12 1999-04-12 Lipid aggregate forming compositions and their use
GB9908309.9 1999-04-12

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WO2000061113A1 true WO2000061113A1 (fr) 2000-10-19

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Cited By (13)

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WO2002026211A1 (fr) * 2000-09-27 2002-04-04 Chemeq Ltd Emulsion antimicrobienne polymere topique
WO2003042392A1 (fr) * 2001-11-15 2003-05-22 Phares Pharmaceutical Research N.V. Melanges de phospholipides normalises
WO2003049701A3 (fr) * 2001-12-10 2003-10-30 Spherics Inc Procedes et produits utiles dans la formation et l'isolation de microparticules
WO2004037216A1 (fr) * 2002-10-28 2004-05-06 Phares Pharmaceutical Research N.V. Microdispersion et procede de production associe
US6746635B2 (en) 2001-08-08 2004-06-08 Brown University Research Foundation Methods for micronization of hydrophobic drugs
WO2004054540A3 (fr) * 2002-12-12 2004-09-30 Micelle Lab Inc Formulations solides a ecoulement facile presentant une biodisponibilite amelioree de medicaments faiblement solubles dans l'eau et leur procede de fabrication
WO2005105040A3 (fr) * 2004-04-26 2006-10-19 Micelle Products Inc Preparation hydrosoluble de vitamines liposolubles, agents pharmaceutiques et leurs applications
FR2956320A1 (fr) * 2010-02-17 2011-08-19 Commissariat Energie Atomique Nanoemulsion pour la delivrance d'au moins deux agents d'interet
CN102526753A (zh) * 2011-12-15 2012-07-04 成都师创生物医药科技有限公司 一种以磷脂为基质的原位相变凝胶缓释系统及其制备方法
EP1728505B1 (fr) * 2004-03-24 2014-06-04 Takeda Pharmaceutical Company Limited Préparation en teneur élevée
EP2997957A1 (fr) * 2014-09-17 2016-03-23 theranovis GmbH & Co. KG Nouvelle composition pour l'hygiene buccale
CN110636863A (zh) * 2017-05-18 2019-12-31 丘比株式会社 具有自乳化性的组合物及其制造方法及纳米乳液及其制造方法
US11655475B2 (en) 2010-07-06 2023-05-23 Glaxosmithkline Biologicals Sa Immunisation of large mammals with low doses of RNA

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WO2005105040A3 (fr) * 2004-04-26 2006-10-19 Micelle Products Inc Preparation hydrosoluble de vitamines liposolubles, agents pharmaceutiques et leurs applications
WO2011101602A1 (fr) * 2010-02-17 2011-08-25 Commissariat à l'énergie atomique et aux énergies alternatives Nanoémulsion pour la délivrance d'au moins deux agents d'intérêt
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CN110636863A (zh) * 2017-05-18 2019-12-31 丘比株式会社 具有自乳化性的组合物及其制造方法及纳米乳液及其制造方法
EP3626271A4 (fr) * 2017-05-18 2021-02-24 Kewpie Corporation Composition auto-émulsifiante ainsi que procédé de fabrication de celle-ci, et nanoémulsion ainsi que procédé de fabrication de celle-ci
US11571385B2 (en) 2017-05-18 2023-02-07 Kewpie Corporation Self-emulsifiable composition, production method therefor, nanoemulsion, and production method therefor

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