DK150967B - DISPERSION OF TASTE BALLS AND PROCEDURE FOR ITS MANUFACTURING - Google Patents

DISPERSION OF TASTE BALLS AND PROCEDURE FOR ITS MANUFACTURING Download PDF

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DK150967B
DK150967B DK291376AA DK291376A DK150967B DK 150967 B DK150967 B DK 150967B DK 291376A A DK291376A A DK 291376AA DK 291376 A DK291376 A DK 291376A DK 150967 B DK150967 B DK 150967B
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dispersion
lipid
group
solution
phase
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DK291376A (en
DK150967C (en
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Guy Vanlerberghe
Rose-Marie Handjani
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Oreal
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    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
    • C09K23/34—Higher-molecular-weight carboxylic acid esters
    • 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—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • 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—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/04—Preparations for care of the skin for chemically tanning the skin
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K19/00—Liquid crystal materials
    • C09K19/52—Liquid crystal materials characterised by components which are not liquid crystals, e.g. additives with special physical aspect: solvents, solid particles
    • C09K19/54—Additives having no specific mesophase characterised by their chemical composition
    • C09K19/542—Macromolecular compounds
    • C09K19/544—Macromolecular compounds as dispersing or encapsulating medium around the liquid crystal
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K19/00—Liquid crystal materials
    • C09K19/52—Liquid crystal materials characterised by components which are not liquid crystals, e.g. additives with special physical aspect: solvents, solid particles
    • C09K2019/523—Organic solid particles
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K19/00—Liquid crystal materials
    • C09K19/52—Liquid crystal materials characterised by components which are not liquid crystals, e.g. additives with special physical aspect: solvents, solid particles
    • C09K2019/528—Surfactants

Description

150967150967

Det er velkendt, at visse lipoider er i stand til i nærværelse af vand at danne mesomorfe faser, hvis tilstandsform er midt imellem den krystallinske tilstand og den flydende tilstand. Blandt de lipoider, der er i stand til at danne mesomorfe faser, er det allerede vist, at visse kan kvælde i vandig opløsning, hvorved der dannes små kugler, der er dispergeret i det vandige miljø.It is well known that certain lipoids are capable of forming in the presence of water mesomorphic phases, the state of which is between the crystalline state and the liquid state. Among the lipoids capable of forming mesomorphic phases, it has already been shown that some can swell in aqueous solution, forming small spheres dispersed in the aqueous environment.

Disse kugler består af multimolekylære lag og fortrinsvis af bimolekylære lag, der har en tykkelse på ca. 30 til 100 Å (se især artiklen af Bangham, Stadish og Watkins, J. Mol. Biol., 13,238 (1965)).These spheres consist of multimolecular layers and preferably bimolecular layers having a thickness of approx. 30 to 100 Å (see, in particular, the article by Bangham, Stadish and Watkins, J. Mol. Biol., 13,238 (1965)).

Indtil nu har det kun været muligt at opnå lipoidkugler, der har bestået af koncentriske lag, ved at anvende lipoider, der indeholder en hydrofil iongruppe og en lipofil gruppe, og de fremstillingsmåder, som man har beskrevet, 2 150967 medførte at man opnåede kugler, der havde en middeldiameter, der var mindre end 1000Å. Fremgangsmåden til fremstilling af dise kugler består i at frembringe en dispersion, hvor dispersionsfasen indeholder den lipoide forbindelse, der er i stand til at danne kuglerne, og at underkaste denne dispersion en ultralydbehandling. For at frembringe den dispersion, der skal underkastes ultralydbehandling, kan man først ved fordampning frembringe en tynd film af den lipoidforbin-delse, der skal dispergeresjpå en skærm, dernæst kan man bringe den således dækkede skærm i kontakt med den kontinuerte fase af den dispersion, der skål fremstilles og endelig for det tredie omrøre for at opnå den dispersion, der skal behandles med ultralyd.Up to now, it has only been possible to obtain lipid balls made up of concentric layers using lipoids containing a hydrophilic ion group and a lipophilic group, and the methods described have resulted in balls being obtained, which had a mean diameter less than 1000Å. The method of producing these spheres consists in producing a dispersion, the dispersion phase containing the lipoid compound capable of forming the spheres, and subjecting this dispersion to ultrasound treatment. In order to produce the dispersion to be subjected to ultrasound treatment, one can first produce, by evaporation, a thin film of the lipoid compound to be dispersed on a screen, then contact the screen thus covered with the continuous phase of the dispersion. bowl is prepared and finally for the third stir to obtain the dispersion to be treated with ultrasound.

I tysk offentliggørelsesskrift nr. 2249552 beskrives en fremgangsmåde til fremstilling af småkugler bestående af koncentriske blade eller lameller, hvilke småkugler betegnes liposomer. Til dette formål anvendes lipidforbindel-ser, der som hydrofile grupper har en phosphat-, carboxyl-, sulfat-, amino-eller cholingruppe, og som hydrofobgruppe en alkyl-, alkenyl- eller alkinyl-gruppe. Disse liposomer er ionogene forbindelser, og liposomernes diameter er begrænset til højst 1000 Å og er fortrinsvis mellem 200 og 500 Å. Som det overraskende er blevet påvist ved nedenstående nærmere beskrevne sammenligningsforsøg er dispersionen ifølge opfindelsen væsentligt overlegen i forhold til det i nævnte offentliggørelsesskrift beskrevne produkt med hensyn til evnen til at optage et aktivt stof, som skal indkapsles, samt med hensyn til stabiliteten og permeabilitetsforhold.German Patent Publication No. 2249552 describes a process for producing concentric leaves or lamellae, which are called liposomes. For this purpose, lipid compounds are used which have as a hydrophilic group a phosphate, carboxyl, sulfate, amino or choline group and as a hydrophobic group an alkyl, alkenyl or alkinyl group. These liposomes are ionic compounds and the diameter of the liposomes is limited to a maximum of 1000 Å and is preferably between 200 and 500 Å. As has been surprisingly demonstrated in the comparative experiments described below, the dispersion according to the invention is substantially superior to the product described in said disclosure in terms of its ability to absorb an active substance to be encapsulated, as well as its stability and permeability conditions.

Man har allerede foreslået at anvende liposomer til at indeslutte vandige opløsninger indeholdende aktive forbindelser i de vandige rum, der findes mellem de dobbelte lipoidlag for på denne måde at beskytte de indkapslede forbindelser mod de ydre påvirkninger, (se især artiklen af Sessa og Weismann, J. Lipid Res., 9,310 (1968) og artiklen af Magee og Miller, Nature, Vol 235 (1972). Liposomerne kan være af varierende størrelse i området mindre end 1000 A. Man kan variere deres indtrængningsevne i det menneskelige legeme, hvilket tillader utallige anvendelser inden for pharmacien, ligesom deres elektriske ladning tillader en udvælgelse af deres fastgørelsessted (Biochem. J. (1971), 124p.58P). Anvendelsen" e af kugler med en diameter mindre end 1000 A er inden for det kosmetiske omrade tilbøjelig til at frembyde visse ubehageligheder på grund af risikoen for at produktet trænger gennem huden. Det er således klart, at i det mindste til dette anvendelsesformål ville det være ønskeligt at kunne frembringe kugler med kon- a centriske lipoidlag; med en diameter, der er større end 1000 A.It has already been proposed to use liposomes to enclose aqueous solutions containing active compounds in the aqueous compartments found between the double lipoid layers in order to protect the encapsulated compounds from the external influences, (see, in particular, the article by Sessa and Weismann, J. Lipid Res., 9,310 (1968) and the article by Magee and Miller, Nature, Vol. 235 (1972) The liposomes can be of varying size in the range of less than 1000 A. Their penetration into the human body can be varied, allowing countless applications in the field of pharmacy, just as their electric charge allows for a selection of their point of attachment (Biochem. J. (1971), 124p.58P). The use of spheres with a diameter less than 1000 A is prone to cosmetic use. present some unpleasantness due to the risk of the product penetrating the skin, so it is clear that at least for this purpose it would be desirable to nne produce spheres with con centric lipoid layers; with a diameter greater than 1000 A.

Yderligere har de hidtil kendte fremgangsmåder til opnåelse af liposomer, der indeslutter aktive forbindelser mellem deres koncentriske lipoidlag, betyde 3 150967 lige ulemper: for det første er den aktive forbindelse, der befinder sig i den kontinuerte dispersionsfase, som man underkaster ultralydbehandling, kun indkapslet mellem liposomernes lipoidlag for en meget lille dels vedkommende, da en meget lille del af den kontinuerte dispersionsfase befinder sig indkapslet mellem disse lag. Dersom man ønsker at isolere indkapslingsliposomerne er det nødvendigt at lade dispersionen, som man har underkastet ultralydbehandling, passere gennem en separationskolonne af typen "Sephadex”, i hvilket tilfælde liposomerne udvindes som en stærkt fortyndet dispersion. Dette resulterer på den ene side i, at det med den hidtil kendte teknik er bogstavelig talt umuligt at opnå en kraftig koncentration af liposomer, og at på den anden side den aktive forbindelse kun er indesluttes for en lille del og tabes ved elueringen i separationskolonnen uden at det er praktisk muligt at genvinde den på en enkel måde. Dette medfører en betydelig forøgelse af fabrikationsprisen for de aktive forbindelser, der er indkapslet i liposomerne. Det er derfor ønskeligt at råde over en fabrikationsmetode til fremstilling af kugler af koncentriske lag, der muliggør, at man kan få en dispersion med stor koncentration af kugler med et reduceret tab af det produkt, der er indkapslet mellem kuglernes lag.Furthermore, the known methods of obtaining liposomes that enclose active compounds between their concentric lipoid layers have equal disadvantages: first, the active compound which is in the continuous dispersion phase undergoing ultrasonic treatment is encapsulated only between the lipoid layers of the liposomes for a very small part, since a very small part of the continuous dispersion phase is encapsulated between these layers. If one wishes to isolate the encapsulation liposomes, it is necessary to allow the dispersion that has been subjected to ultrasound to pass through a separation column of the type "Sephadex", in which case the liposomes are recovered as a highly diluted dispersion. with the prior art, it is literally impossible to achieve a high concentration of liposomes and, on the other hand, the active compound is only contained to a small extent and lost by elution in the separation column without being practically recoverable on a This results in a significant increase in the fabrication cost of the active compounds encapsulated in the liposomes, so it is desirable to have a fabrication method for producing concentric layer spheres which allows a high concentration dispersion to be obtained. of bullets with a reduced loss of the product encapsulated between the layers of the balls.

Endelig har de fabrikationsmetoder for liposomer, der er beskrevet indtil nu, angivet, at man kun kunne anvende visse særlige kategorier af lipoider: indtil nu har man inden for teknikken nævnt anvendelsen af phosphorlipoider, lipoider, der bærer en hydrofil iongruppe og en lipofil gruppe, og fede umættede syrer.Finally, the manufacturing methods for liposomes described so far have indicated that only certain specific categories of lipoids could be used: so far, the use of phosphorus lipoids, lipoids carrying a hydrophilic ion group and a lipophilic group has been mentioned in the art. and fatty unsaturated acids.

Det er ved opfindelsen tilsigtet at tilvejebringe en dispersion af små-kugler af den art, som er angivet i indledningen til krav 1, samt en fremgangsmåde til dens fremstilling som angivet i indledningen til krav 2, i hvilken dispersion der foreligger en forøget koncentration af småkugler, hvorved det er muligt at opnå at småkuglerne indkapsler de aktive stoffer som skal indesluttes, med stort udbytte ved indeslutningsprocessen, således at der kan indkapsles en forøget mængde aktivt stof, hvilken dispersion er stabil og udviser gunstige permeabilitetsforhold.It is an object of the invention to provide a dispersion of pellets of the kind set forth in the preamble of claim 1, and a process for its preparation as set forth in the preamble of claim 2, in which dispersion is present in an increased concentration of pellets whereby it is possible to obtain that the beads encapsulate the active substances to be encapsulated in high yield in the containment process so that an increased amount of active substance can be encapsulated which is stable and exhibits favorable permeability conditions.

Det tilsigtede opnås ved de foranstaltninger som er anført i de kendetegnende dele af kravene henholdsvis 1 og 2.The intention is achieved by the measures set out in the characterizing parts of claims 1 and 2, respectively.

X en foretrukken udførelsesform er vægtforholdet mellem den vandige fase, der skal indkapsles, og som er bragt i kontakt med lipoiderne»og lipoiderne, der udgør den lamellære fase, mellem ca. 0,1 og ca. 3. Den vandige fase, der skal indkapsles, kan være vand eller en vandig opløsning-af den aktive forbindelse. Vægtforholdet mellem dispersionsfasen, som man tilsætter, og den lamellære fase, som man dispergerer, kan være mellem ca. 2 og ca. 100. Dispersionsfasen og den vandige fase, der skal indkapsles, er fortrinsvis isoosmotiske. Dispersionsfasen kan fordelagtig være en vandig opløsning.X is a preferred embodiment, the weight ratio of the aqueous phase to be encapsulated which is brought into contact with the lipoids and the lipoids constituting the lamellar phase is between ca. 0.1 and approx. 3. The aqueous phase to be encapsulated may be water or an aqueous solution of the active compound. The weight ratio of the dispersion phase that is added to the lamellar phase which is dispersed can be between about 2 and approx. 100. The dispersion phase and the aqueous phase to be encapsulated are preferably isoosmotic. The dispersion phase may advantageously be an aqueous solution.

4 1509674 150967

Omrøringen, der er det sidste trin af fremgangsmåden, opnås ved rystning i et rysteapparat. Fremgangsmåden udføres ved stuetemperatur eller ved en højere temperatur, dersom lipoiderne er faste ved stuetemperatur. Dersom man ønsker, at de opnåede kugler skal have en middeldiameter, der er mindre end 1000 Å, kan man underkaste kugledispersionen en ultralydbehandling.Stirring, which is the last step of the process, is achieved by shaking in a shaker. The process is carried out at room temperature or at a higher temperature if the lipoids are solid at room temperature. If you want the spheres obtained to have a mean diameter of less than 1000 Å, you can subject the spherical dispersion to ultrasound treatment.

For at danne den lamellære fase kan man anvende et enkelt lipoid eller en blanding af lipoider. Lipoidet/erne, som man anvender, bærer en lang lipofil kæde, der indeholder 12 til 30 carbonatomer, hvilken kæde er mættet eller umættet forgrenet eller lineær· . Man kan specielt vælge olein-, lanolin-, tetradecyl-, hexadecyl-, isostearyl-, lauryl- eller alcoylphenylkæder. Medens lipoidets hydrofile gruppe, der danner den lamellære fase, er en ikke-ionisk gruppe, kan man fordelagtigt som hydrofil gruppe vælge en polyoxyethylen, en polyglycerol, en evei tuelt oxyethyleneret polyolssfeer og £.eks. en polyoxyethylene ret . sorbitaleatat·-To form the lamellar phase, a single lipoid or a mixture of lipoids can be used. The lipoid (s) used carry a long lipophilic chain containing 12 to 30 carbon atoms, which chain is saturated or unsaturated branched or linear ·. In particular, one may select olein, lanolin, tetradecyl, hexadecyl, isostearyl, lauryl or alcoylphenyl chains. While the hydrophilic group of the lipoid forming the lamellar phase is a nonionic group, one may advantageously select as a hydrophilic group a polyoxyethylene, a polyglycerol, an even oxyethylenated polyol sphere, and the like. a polyoxyethylene ret. sorbitaleatat · -

Man kan anvende en vandig fase til indkapsling indeholdende aktive forbindelser af alle arter og især sådanne forbindelser, der er af farmaceutisk eller levnedsmiddelmæssig interesse eller forbindelser, der har kosmetisk virkning.An aqueous phase can be used for encapsulation containing active compounds of all species and especially such compounds which are of pharmaceutical or food or cosmetic effect.

De aktive forbindelser kan f.eks. være, når det drejer sig om kosmetik: forbindelser, der er egnet til hudens eller hårets pleje f.eks. fugtighedsbevarere som glycerin, sorbitol, pentaerythritol, inositol, pyrrolidoncarboxylsyren og dens saltej midler til kunstig bruning som f.eks. dihydroxyacetone, erythrulosQ, glyceraldehyd, ft-dialdehyder såsom tartaraldehyd (forbindelserne kan eventuelt være associeret med farvestoffer): vandopløselige solbeskyttende forbindelser, antiperspirationsmidler, deodoranter, astringenter, svalende forbindelser, tonika, ardannende midler, keratolyserende midler, afhåringsmidler, parfumerede vande, ekstrakter af animalske eller vegetabilske celler såsom proteiner, poly-saccharider, amnionvæsker, vandopløselige farvestoffer, skælhænmende midler, antiseboroiske midler, oxideringsmidler,(affarvningsmidler) såsom hydrogenper-oxid, reduktionsmidler som f.eks. thioglycolsyren og dens salte. Som aktive farmaceutiske forbindelser kan nævnes: vitaminer, hormoner, enzymer (f.eks. per-oxiddismutase) vacciner, anti-inflammatoriske midler (f.eks. hydrocortison), antibiotika, baktericider.The active compounds may e.g. be when it comes to cosmetics: compounds that are suitable for skin or hair care e.g. humectants such as glycerine, sorbitol, pentaerythritol, inositol, pyrrolidone carboxylic acid and its salts for artificial browning, e.g. dihydroxyacetone, erythrulosic acid, glyceraldehyde, β-dialdehydes such as tartaraldehyde (the compounds may optionally be associated with dyes): water-soluble sun-protecting compounds, antiperspirants, deodorants, astringents, coolants, tonics, scars, scintillating agents, keratolysing agents, keratolysing agents or vegetable cells such as proteins, polysaccharides, amniotic fluids, water-soluble dyes, scavengers, antiseboroic agents, oxidizing agents, (decolorizing agents) such as hydrogen peroxide, reducing agents, e.g. thioglycolic acid and its salts. Active pharmaceutical compounds include vitamins, hormones, enzymes (eg, peroxide dismutase) vaccines, anti-inflammatory agents (eg hydrocortisone), antibiotics, bactericides.

Det er klart, at man vil vælge, afhængig af den aktive substans indeholdt i den vandige fase, der skal indkapsles, de lipoider,der er i stand til på stabil måde at indkapsle den vandige fase, det drejer sig om. For at de lipoider, der udgør den lamellære fase, giver stabile kugler, er det nødvendigt, at der findes en tilstrækkelig gensidig lateral påvirkning mellem lipoidets kæder som, anbragt side om side, udgør lagene eller bladene af. kuglerne, dvs. at de Van der Waalske kræfter mellem kæderne sikrer en tilstrækkelig cohæsion af bladene. Denne betingelse er tilfredsstillet for de lipoider, der har de karakte- 5 150967 ristika, der er angivet i den generelle beskrivelse for fremgangsmåden, der er angivet nedenfor, Lipoiderne kan anvendes ved fremgangsmåden ifølge opfindelsen, dersom de hører til den kategori af emulsionsdannere af typen vand i olie.Obviously, depending on the active substance contained in the aqueous phase to be encapsulated, one will choose the lipoids capable of stably encapsulating the aqueous phase in question. In order for the lipoids constituting the lamellar phase to produce stable spheres, it is necessary that sufficient mutual lateral action exists between the chains of the lipoid which, placed side by side, constitute the layers or leaves. the bullets, i.e. that the Van der Waals forces between the chains ensure a sufficient cohesion of the leaves. This condition is satisfied for the lipoids having the characteristics set forth in the general description of the process set forth below. The lipoids may be used in the process of the invention if they belong to the category of emulsion formers of the type water in oil.

Fremgangsmåden ifølge opfindelsen tilvejebringer dispersioner af kugler, der består af amfifile ikke-ioniske lipoidforbindelser, og som af den grund danner hidtil ukendte forbindelser, der tillader en indkapsling af aktive forbindelser, der kan anvendes f.eks. i farmacien, inden for levnedsmiddelområdet eller inden for kosmetikken. Anvendelsen af ikke-ioniske forbindelser til dannelse af indkapslingskuglerne frembyder en ikke ringe interesse, når man ønsker at undgå, at kuglerne har en ydre overflade, der er elektrisk ladet.The process of the invention provides dispersions of spheres consisting of amphiphilic non-ionic lipoid compounds, which, for that reason, form novel compounds which allow the encapsulation of active compounds which can be used e.g. in pharmaceuticals, in the food field or in cosmetics. The use of non-ionic compounds to form the encapsulating beads presents little interest in avoiding the balls having an electrically charged outer surface.

De ikke-ioniske lipoidforbindelser er fortrinsvis valgt blandt gruppen bestående af; lineære eller forgrenede polyglycerolethere med formlerneThe nonionic lipoid compounds are preferably selected from the group consisting of; linear or branched polyglycerol ethers of the formulas

R- ( och2chohch2-}^— OHR- (och2chohch2 -} ^ - OH

elleror

R-4)CH2CH -4 OHR-4) CH 2 CH -4 OH

I CH2Olj]n hvori n betegner et helt tal mellem 1 og 6, R betegner en lineær eller forgrenet alifatisk kæde, der er mættet eller umættet,med 12 til 30 carbonatomer, carbon-hydridgrupperne af lanolinalkoholer, eller hydroxy-2-alkylgrupper af Ot -dioler med lang kæde; polyoxyethylenerede fede alkoholer; eventuelt oxyethylenerede polyolestre specielt polyoxyethylenerede sorbitolestre; glycolipoider af naturlig eller syntetisk oprindelse f.eks. cerebrosider.In CH 2 O, where n represents an integer between 1 and 6, R represents a linear or branched aliphatic chain saturated or unsaturated having 12 to 30 carbon atoms, the hydrocarbon groups of lanolin alcohols, or hydroxy-2-alkyl groups of Ot long chain diols; polyoxyethylenated fatty alcohols; optionally oxyethylenated polyol esters especially polyoxyethylenated sorbitol esters; glycolipoids of natural or synthetic origin e.g. cerebrosides.

Dispersionens kontinuerte fase, der omgiver kuglerne, er en vandig fase. Den vandige fase, der er indkapslet i kuglerne, er en vandig opløsning af en virksom forbindelse, fortrinsvis isoosmotisk med dispersionens kontinuerte fase.The continuous phase of the dispersion surrounding the spheres is an aqueous phase. The aqueous phase encapsulated in the spheres is an aqueous solution of an effective compound, preferably isoosmotic with the continuous phase of the dispersion.

Forskellige additiver kan være knyttet til de ikke-ioniske lipoidforbindelser for at modificere permeabiliteten eller overfladeladningen af kuglerne.Various additives may be attached to the nonionic lipoid compounds to modify the permeability or surface charge of the spheres.

Til dette formål kan nævnes eventuel tilsætning af langkædede alkoholer og dioler, steroler f.eks. cholesterol, langkædede aminer og deres kvaternære ammoniumderivater, dihydroxyalkylaminer, polyoxyethylenerede fede aminer, estere af aminoalkoholer med lang kæde, af deres salte og kvaternære ammoniumderivater phosphorestere af fede alkoholer f.eks. natriuradicetylphosphat, alkylsulfater f.eks. natriumcetylsulfat, visse polymere såsom polypeptider og proteiner.To this end may be mentioned possible addition of long chain alcohols and diols, sterols e.g. cholesterol, long chain amines and their quaternary ammonium derivatives, dihydroxyalkylamines, polyoxyethylenated fatty amines, long chain amino alcohol esters, of their salts and quaternary ammonium derivatives phosphorus esters of fatty alcohols e.g. sodium diacetyl phosphate, alkyl sulfates e.g. sodium cetyl sulfate, certain polymers such as polypeptides and proteins.

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Anvendelsen af de omhandlede vandige dispersioner inden for kosmetikken, frembyder store fordele sammenlignet med den hidtil kendte anvendelse af emulsioner. Det er i virkeligheden sådan, at dersom man ønsker at anvende præparater,der på én gang indeholder fede materialer og vand, er det nødvendigt for at sikre emulsionens stabilitet at anvende amphifile emulgeringsmidler. Det er velkendt, at visse emulgeringsmidler kan fremkalde nogen irritation, dersom de påføres huden. Man har under arbejdet med de omhandlede forbindelser fundet, at denne virkning af emulgeringsmidler, for en given kemisk opbygning, i høj grad afhænger af, hvordan de anvendes. Man har således kunnet vise, at en emulsion olie/ vand bestående af 42% perhydrosqualen, 8% emulgeringsmiddel og 50% vand er særdeles irritationsfremkaldende, medens en vandig dispersion af 8% af det samme emulgeringsmiddel udviser en irritationspåvirkning, der er praktisk taget ubetydelig, og at perhydrosqualenet er fuldstændigt uskadeligt. Det fremgår heraf, at der er en irritationssynergi, når man har et emulgeringsmiddel og en oliefase til stede. De omhandlede vandige dispersioner muliggør at undgå samtidig anvendelse af et emulgeringsmiddel og en olie, hvilket er et afgørende fremskridt inden for kosmetikken.The use of the present aqueous dispersions in cosmetics offers great advantages over the prior art use of emulsions. In fact, if one wishes to use preparations containing at once fatty materials and water, it is necessary to ensure the stability of the emulsion to use amphiphilic emulsifiers. It is well known that certain emulsifiers can cause some irritation if applied to the skin. It has been found during the work of the compounds in question that this effect of emulsifiers, for a given chemical structure, depends to a large extent on how they are used. Thus, it has been shown that an oil / water emulsion consisting of 42% perhydrosquale, 8% emulsifier and 50% water is highly irritant, while an aqueous dispersion of 8% of the same emulsifier exhibits an irritant effect which is practically negligible. and that the perhydrosqualene is completely harmless. It is clear from this that there is an irritant synergy when an emulsifier and an oil phase are present. The aqueous dispersions at issue make it possible to avoid the simultaneous use of an emulsifier and an oil, which is a crucial advance in the cosmetics industry.

Det bør bemærkes, at man til de omhandlede dispersioner af kugler kan tilsætte forskellige hjælpestoffer for at forandre udseendet eller den organo-leptiske karakter, såsom uklarhedsdannende midler, geleringsmidler, aromastoffer, parfumer eller farvestoffer.It should be noted that various dispersions of spheres may be added to the auxiliary substances to change the appearance or organoleptic nature, such as cloud-forming agents, gelling agents, flavoring agents, perfumes or dyes.

Det bemærkelsesværdige ved de omhandlede dispersioner er, at de muliggør indførslen af hydrofile forbindelser i et fuldstændigt lipofilt miljø. Dette bevirker under disse forhold, at disse befinder sig maskerede eller beskyttede over for forskellige midler, der kan påføre mulige ændringer: oxideringsmidler, fordøjelsessafter og mere generelt reaktive forbindelser over for de indkapslede forbindelser. Penetrationen og/eller fixeringen af de aktive forbindelser kan ændres ved at forandre kuglernes størrelse og deres elektriske ladning. Deres virkning kan ligeledes være forskellig (protraheret virkning). Det, at de er maskerede, gør, at man i vid udstrækning kan undertrykke eller forandre deres organoleptiske karakter, især deres smag. Endelig besidder lipoiderne i disse præparater i sig selv en gavnlig virkning f.eks. blødgørende, smørende, glatte rende .The remarkable feature of the present dispersions is that they allow the introduction of hydrophilic compounds in a completely lipophilic environment. Under these conditions, this causes them to be masked or protected against various agents that may cause possible changes: oxidizing agents, digestive juices and, more generally, reactive compounds against the encapsulated compounds. The penetration and / or fixation of the active compounds can be changed by changing the size of the balls and their electrical charge. Their effect may also be different (protected effect). The fact that they are masked can greatly suppress or alter their organoleptic character, especially their taste. Finally, the lipoids in these compositions themselves have a beneficial effect e.g. emollient, lubricating, smooth gutter.

Opfindelsen beskrives nærmere i de efterfølgende eksempler, 7 150967The invention is further described in the following Examples, 7 150967

Eksempel 1 I en rundbundet kolbe på 50 ml sammenbringes 500 mg sorbitoltrioleat, der er oxyethyle,neret med 20 mol oxyethylen (forbindelse "Ttøeen 85” solgt af selskabet ICI Atlas) og 0,335 ml af en 0,7 molær opløsning af sorbitol, og man homogeniserer blandingen. Forsøget udføres ved stuetemperatur.Example 1 In a 50 ml round bottom flask 500 mg of sorbitol trioleate, which is oxyethyl, are combined with 20 moles of oxyethylene (compound "Ttoe" 85 sold by the company ICI Atlas) and 0.335 ml of a 0.7 molar solution of sorbitol. The test is carried out at room temperature.

Man tilsætter herefter 3 ml af en vandig opløsning på 1% af en forbindelse, der kendes under sit handelsnavn "Carbopol 934” (polyacrylsyre netdannet med polyallylsucrose, solgt af selskabet "Goodrich”). Kolben, der er anbragt i et rysteapparat, omrystes energisk i 1 time.Then, 3 ml of an aqueous solution of 1% of a compound known by its trade name "Carbopol 934" (polyacrylic acid formed with polyallylsucrose, sold by the company "Goodrich") is added. The flask placed in a shaker is shaken vigorously for 1 hour.

Den opnåede dispersion er geleret. Kuglernes diameter er større end 1 mikron.The dispersion obtained is gelled. The diameter of the balls is greater than 1 micron.

Eksempel 2 I en rundbundet kolbe på 50 ml blander man grundigt 250 mg oleylalkohol, der er oxyethyleneret med 10 mol (forbindelse ”Brij 96” forhandlet af selskabet ICI Atlas), og 250 mg oleylalkohol, der er oxyethyleneret med 2 mol (forbindelse "Brij 92” forhandlet af selskabet ICI Atlas). Herefter bringer man den opnåede blanding i kontakt med 1 ml af en 0,5 molær opløsning af glycerol,og blandingen homogeniseres. Forsøget udføres ved stuetemperatur.Example 2 In a 50 ml round bottom flask, thoroughly mix 250 mg oleyl alcohol oxyethylene with 10 moles (compound "Brij 96" marketed by ICI Atlas) and 250 mg oleyl alcohol oxyethylene with 2 moles (compound "Brij 92 "(marketed by the company ICI Atlas), then the resulting mixture is contacted with 1 ml of a 0.5 molar solution of glycerol and the mixture is homogenized. The test is carried out at room temperature.

Herefter tilsætter man 20 ml af en 0,245 molær opløsning (NaCl, KCl). Kolben anbringes på et rysteapparat, hvorefter man omryster energisk i 1 time.Then 20 ml of a 0.245 molar solution (NaCl, KCl) is added. Place the flask on a shaker and shake vigorously for 1 hour.

Den opnåede dispersion er flydende og mælkeagtig. Kuglernes diameter er ca. 1 mikron.The dispersion obtained is liquid and milky. The diameter of the balls is approx. 1 micron.

Eksempel 3 I en rundbundet kolbe på 50 ml sammenbringes 500 mg af en forbindelse med den almene formel:Example 3 In a 50 ml round bottom flask 500 mg of a compound of the general formula are combined:

R-fOCH2-CH j OHR-fOCH 2 -CH 2 OH

\ CHo0H J— 2 n hvor R betegner alkoylgruppen af hydrogenerede lanolinalkoholer, og ή har en statistisk værdi, der er mindre end 3, og 220 ml af en 0,5 molær opløsning af pen-taerythritol. Herefter homogeniserer man blandingen. Forsøget udføres ved stuetemperatur.Where CH represents the alkoyl group of hydrogenated lanolin alcohols and ή has a statistical value of less than 3 and 220 ml of a 0.5 molar solution of pentaerythritol. The mixture is then homogenized. The experiment is carried out at room temperature.

Herefter tilsætter man 4 ml vand. Kolben anbringes på et rysteapparat, og man omryster energisk i 30 minutter.Then add 4 ml of water. Place the flask on a shaker and shake vigorously for 30 minutes.

Den opnåede dispersion har et mælkeagtigt udseende. Kuglernes diameter er større end 1 mikron.The dispersion obtained has a milky appearance. The diameter of the balls is greater than 1 micron.

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Eksempel 4 I en rundbundet kolbe på 50 ml sammenbringes 500 mg af en forbindelse med den almene formelExample 4 In a 50 ml round bottom flask, 500 mg of a compound of the general formula is combined

R —0CH2-CH j OHR-OCH 2 -CH 2 OH

\ CH„0H / 2 n hvor R betegner gruppen tetradecyljOg n er lig med 2, med 0,75 ml af en 0,4 molær opløsning af sorbitol. Herefter homogeniserer man blandingen. Forsøget udføres ved 40°C.Where CH represents the tetradecyl group and n is equal to 2, with 0.75 ml of a 0.4 molar solution of sorbitol. The mixture is then homogenized. The test is carried out at 40 ° C.

Herefter tilsætter man 4 ml vand. Kolben anbringes på et rysteapparat, og man omryster energisk i 30 minutter.Then add 4 ml of water. Place the flask on a shaker and shake vigorously for 30 minutes.

Den opnåede dispersion er klar efter gennemledning af ultralyd. Kuglernes diameter er mindre end 1 mikron.The obtained dispersion is ready after ultrasound penetration. The diameter of the balls is less than 1 micron.

Eksempel 5 I en rundbundet kolbe på 50 ml sammenbringes 500 mg af en forbindelse med den almene formelExample 5 In a 50 ml round bottom flask 500 mg of a compound of the general formula are combined

R—A-0CH2-CH J OHR-A-OCH 2 -CH J OH

\ CH_ OH / 2 n hvor R betegner gruppen hexadecyl, og n er lig med 2, og 0,335 ml af en 0,3 molær opløsning af cysteinchlorhydrat. Herefter homogeniserer man blandingen. Forsøget udføres ved 55°C.\ CH_ OH / 2 n where R represents the group hexadecyl and n is equal to 2 and 0.335 ml of a 0.3 molar solution of cysteine chlorohydrate. The mixture is then homogenized. The test is carried out at 55 ° C.

Herefter tilsætter man 4,1 ml af en 0,145 molær opløsning (NaCl, KCl). Kolben anbringes på et rysteapparat, og man omryster kraftigt i 3 timer.Then, 4.1 ml of a 0.145 molar solution (NaCl, KCl) is added. Place the flask on a shaker and shake vigorously for 3 hours.

Den opnåede dispersion er næsten gennemsigtig ved 55°C. Kuglernes diameter er ca. 2 mikron. Ved langsom afkøling af dispersionen til stuetemperatur, opnår man en hvid uklar gel.The dispersion obtained is almost transparent at 55 ° C. The diameter of the balls is approx. 2 microns. By slowly cooling the dispersion to room temperature, a white cloudy gel is obtained.

Dispersionen, der holdes ved 55°C, kan eventuelt fortyndes med en isoos-motisk opløsning, der indeholder et fortykkelsesmiddel såsom gummier eller polymere. Herved opnår man en let uklar opløsning. Fortyndingsforholdet vælges alt efter, hvilken opløsning man Ønsker at opnå.Optionally, the dispersion maintained at 55 ° C may be diluted with an iso-motic solution containing a thickening agent such as gums or polymers. This results in a slightly cloudy solution. The dilution ratio is chosen according to the solution you want to obtain.

Eksempel 6 I. en rundbundet kolbe på 50 ml, der er anbragt i et vandbad på 55°C bringer man 500 mg af en forbindelse med den almene formel 9 150967Example 6 In a 50 ml round bottom flask placed in a 55 ° C water bath, 500 mg of a compound of the general formula 9 is added.

R-| OGH2-CH ] OHR | OGH2-CH1 OH

\ CH-CH/ z n hvor R betegner en hexadecylgruppe, og n er lig 2, i kontakt med 10 ml af en 0,3 molær opløsning af methionin. Man homogeniserer blandingen. Forsøget udføres ved 55°C.\ CH-CH / z n where R represents a hexadecyl group and n equals 2, in contact with 10 ml of a 0.3 molar solution of methionine. The mixture is homogenized. The test is carried out at 55 ° C.

Kolben anbringes på et rysteapparat, og man omryster energisk i 3 timer ved 55°C.Place the flask on a shaker and shake vigorously for 3 hours at 55 ° C.

Den opnåede dispersion er gennemsigtig. Kuglernes diameter er ca. 1 mikron. Ved afkøling til stuetemperatur får man en hvid gel«The dispersion obtained is transparent. The diameter of the balls is approx. 1 micron. Cooling to room temperature gives a white gel «

Eksempel 7 I en rundbundet kolbe på 50 ml bringer man 500 mg af en forbindelse med den almene formel R-f 0CH2-CH I OH \ CH„0H /- hvor R betegner alkylgruppen af isostearylalkohol, n har en statistisk værdi, der er mindre end 2, i kontakt med 5 ml vand. Man homogeniserer blandingen. Forsøget udføres ved stuetemperatur.Example 7 In a 50 ml round bottom flask, 500 mg of a compound of the general formula Rf OCH2-CHI OH \ CH2 OH / - where R represents the alkyl group of isostearyl alcohol, n has a statistical value of less than 2 , in contact with 5 ml of water. The mixture is homogenized. The experiment is carried out at room temperature.

Man anbringer kolben på et rysteapparat og omryster kraftigt i 4 timer.Place the flask on a shaker and shake vigorously for 4 hours.

Den opnåede dispersion er mælkeagtig. Kuglernes diameter er ca. 5 mikron. Dispersionen kan underkastes ultra lydbehand ling, hvorved man reducerer kuglernes størrelse betydeligt.The dispersion obtained is milky. The diameter of the balls is approx. 5 microns. The dispersion can be subjected to ultra sound treatment, thereby reducing the size of the balls considerably.

Eksempel 8 I en rundbundet kolbe på 50 ml opløser man 83,2 mg (200 y^-mol) af en forbindelse med den almene formelExample 8 In a 50 ml round bottom flask, dissolve 83.2 mg (200 µl) of a compound of the general formula

R-f 0CH9-CH λ OHR-f OCH9-CH λ OH

v Km)„ hvor R betegner alkylgruppen af oleylalkohol, og n er lig med 2, i 2 ml af en blanding af chloroform-methanol i forholdet 2:1. Man afdamper opløsningsmidlet ved hjælp af en roterende fordamper, og man fjernes de sidste spor af opløsningsmiddel ved hjælp af en vingepumpe i 1 time.v Km) where R represents the alkyl group of oleyl alcohol and n is equal to 2 in 2 ml of a 2: 1 chloroform-methanol mixture. The solvent is evaporated by means of a rotary evaporator and the last traces of solvent are removed by means of a wing pump for 1 hour.

10 15096710 150967

Man bringer 10 ml af en 0,3 molær opløsning af glucose i kontakt med li-poidet. Kolben, der er anbragt på et rysteapparat, rystes kraftigt i 4 timer. Forsøget udføres ved stuetemperatur.10 ml of a 0.3 molar glucose solution is contacted with the lipid. The flask placed on a shaker is shaken vigorously for 4 hours. The experiment is carried out at room temperature.

Dispersionen underkastes ultralydbehandling i 20 minutter. Herefter er kuglernes diameter reduceret til en værdi, der er mindre end 0,5 mikron. Man filtrerer herefter dispersionen på en gelkolonne nSephadex G 50 grov**, der er kvældet i en opløsning af 0,145 molær (NaCl, KCl). Den opnåede opløsning er let blålig.The dispersion is subjected to ultrasound treatment for 20 minutes. Subsequently, the diameter of the balls is reduced to a value less than 0.5 microns. The dispersion is then filtered on a gel column nSephadex G 50 coarse ** which is swollen in a solution of 0.145 molar (NaCl, KCl). The solution obtained is slightly bluish.

Eksempel 9 I en rundbundet kolbe på 50 ml blander man grundigt 58 mg af en forbindelse med den almene formelExample 9 In a 50 ml round bottom flask, thoroughly mix 58 mg of a compound of the general formula

R-/ 0CH2-^H \ OHR- / OCH2- ^ H \ OH

\ CHo0H J- hvor R betegner alkylgruppen af isostearylalkohol, n er lig med 2, med 58 mg af en forbindelse med den almene formelWhere CH represents the alkyl group of isostearyl alcohol, n is equal to 2, with 58 mg of a compound of the general formula

R-j och2-ch I OHR-j and 2-ch in OH

\ CH„ OH /- 2 n hvor R betegner alkoylgruppen af "isostearyP'-alkohol, n er lig med 6, og herefter bringer man den opnåede blanding i kontakt med 10 ml af en 1 molær opløsning af glucose. Forsøget udføres ved stuetemperatur. Kolben anbringes på et rysteapparat, og man omryster kraftigt i 4 timer.Where CH represents the alkoyl group of "isostearyP" alcohol, n is equal to 6, and then the resulting mixture is contacted with 10 ml of a 1 molar solution of glucose. The experiment is carried out at room temperature. Place the flask on a shaker and shake vigorously for 4 hours.

Den opnåede dispersion er meget findelt. Kuglerne har en diameter på ca.The dispersion obtained is very finely divided. The balls have a diameter of approx.

1 mikron. Man kan underkaste dispersionen ultralydbehandling i 30 minutter, hvorved kuglernes størrelse sænkes til en værdi, der er mindre end 0,5 mikron.1 micron. The dispersion can be subjected to ultrasound treatment for 30 minutes, thereby reducing the size of the spheres to a value less than 0.5 microns.

Den opnåede dispersion, dels med kugler med en diameter, der er større end 1 mikron, dels med kugler, der har en diameter, der er mindre end 1 mikron, filtreres på en gelkolonne "Sephadex G 50 grov", der er kvældet i en opløsning af 0,475 molær (NaCl, KCl).The obtained dispersion, partly with spheres having a diameter greater than 1 micron, and partly with spheres having a diameter less than 1 micron, is filtered on a gel column "Sephadex G 50 coarse" swollen in a solution of 0.475 molar (NaCl, KCl).

Eksempel 10 I en rundbundet kolbe på 50 ml bringer man 500 mg af monolauryletheren af tetraethylenglycol i kontakt med 0,4 ml af en 0,3 molær opløsning af glucose. Man homogeniserer blandingen. Forsøget udføres ved stuetemperatur.Example 10 In a 50 ml round bottom flask, 500 mg of the tetraethylene glycol monolauryl ether is contacted with 0.4 ml of a 0.3 molar glucose solution. The mixture is homogenized. The experiment is carried out at room temperature.

11 15096711 150967

Herefter tilsætter man 5 ml af en opløsning af 0,145 molær (NaCl, KC1). Kolben anbringes i et rysteapparat, og man omryster kraftigt i 15 minutter.Then 5 ml of a solution of 0.145 molar (NaCl, KCl) is added. Place the flask in a shaker and shake vigorously for 15 minutes.

Den opnåede dispersion er gennemsigtig. Kuglernes diameter er ca. 1 mikron.The dispersion obtained is transparent. The diameter of the balls is approx. 1 micron.

Eksempel 11 I::en rundbundet kolbe på 50 ml bringer man 500 mg af en forbindelse med den almene formel R-/0CH2-CH j OH \ CH„0H /- hvor R er en hexadecylgruppe, og n har en statistisk værdi, der er mindre end 3, i kontakt med 0,5 ml af en opløsning af 50 mg/ml af "Crotéine C" (protein med en molvægt på ca. 10000, solgt af selskabet "CRCDA”)·Example 11 In a 50 ml round bottom flask, 500 mg of a compound of the general formula R - / OCH 2 - CH 2 OH \ CH 2 OH - where R is a hexadecyl group and n has a statistical value which is less than 3, in contact with 0.5 ml of a solution of 50 mg / ml of "Crotéine C" (protein with a molecular weight of about 10000 sold by the company "CRCDA") ·

Man homogeniserer blandingen. Forsøget udføres ved 60°C.The mixture is homogenized. The test is carried out at 60 ° C.

Herefter tilsætter man 4 ml af en opløsning på 0,145 molær (NaCl, KCl). Kolben anbringes i et rysteapparat,og man omryster kraftigt i 3 timer.Then 4 ml of a solution of 0.145 molar (NaCl, KCl) is added. Place the flask in a shaker and shake vigorously for 3 hours.

Den opnåede dispersion er gennemsigtig. Kuglernes diameter er ca. 1 mikron. Ved langsom afkøling til stuetemperatur får man en hvid uigennemsigtig gel.The dispersion obtained is transparent. The diameter of the balls is approx. 1 micron. Slow cooling to room temperature results in a white opaque gel.

Eksempel 12 I en rundbundet kolbe på 50 ml bringer man 300 mg sphingomyelin i kontakt med 0,350 ml af en 0,3 molær opløsning af glucose. Man homogeniserer blandingen. Forsøget udføres ved stuetemperatur.Example 12 In a 50 ml round bottom flask, contact 300 mg of sphingomyelin with 0.350 ml of a 0.3 molar solution of glucose. The mixture is homogenized. The experiment is carried out at room temperature.

Herefter tilføjer man 5 ml af en opløsning på 0,145 molær (NaCl, KCl).Then 5 ml of a solution of 0.145 molar (NaCl, KCl) is added.

Man anbringer kolben i et rysteapparat og omryster kraftigt i 2 timer.Place the flask in a shaker and shake vigorously for 2 hours.

Den opnåede dispersion er mælkeagtig. Kuglernes diameter er ca. 2 mikron. Dispersionen kan underkastes ultralydbehand ling i 2 timer, hvorved kuglernes diameter formindskes.The dispersion obtained is milky. The diameter of the balls is approx. 2 microns. The dispersion can be subjected to ultrasound treatment for 2 hours, thereby reducing the diameter of the balls.

Eksempel 13 I en rundbundet kolbe på 50 ml blander man grundigt 300 mg af en forbindelse opnået ved moldestillation med den almene formelExample 13 In a 50 ml round bottom flask, thoroughly mix 300 mg of a compound obtained by mold distillation with the general formula

R—( 0CH2-CH \ OHR - (OCH 2 -CH \ OH

\ CH. OH/ 2 · n 12 150967 hvor R betegner alkylgruppen af oleylalkohol, og n er lig med 2j 150 mg cholesterol; 50 mg af en amin med den almene formel c2h5 RC00(CH,CH,0)-CH,CH,N l L η i i v c2h5 hvor RC00 betegner kokusoliegruppen, og n er et tal mellem 2 og 5, og man bringer den opnåede blanding i kontakt med 0,5 ml af en 0,3 molær opløsning af sorbitol. Man homogeniserer blandingen. Forsøget udføres ved stuetemperatur.\ CH. OH / 2 · n 12 where R represents the alkyl group of oleyl alcohol and n is equal to 2j 150 mg of cholesterol; 50 mg of an amine of the general formula c2h5 RC00 (CH, CH, O) -CH, CH, N1 L η iiv c2h5 where RC00 represents the coconut oil group and n is a number between 2 and 5 and the mixture obtained is obtained. in contact with 0.5 ml of a 0.3 molar solution of sorbitol. The mixture is homogenized. The experiment is carried out at room temperature.

Herefter tilsætter man 4 ml af en opløsning af 0,145 molær (NaCl, KC1). Kolben anbringes på et rysteapparat,og man omryster kraftigt i 4 timer.Then 4 ml of a solution of 0.145 molar (NaCl, KCl) is added. Place the flask on a shaker and shake vigorously for 4 hours.

Den opnåede dispersion er opaliserende diameteren af kuglerne er ca.The dispersion obtained is opalescent diameter of the spheres is approx.

2 mikron.2 microns.

Eksempel 14 I en rundbundet kolbe på 50 ml bringer man 425 mg af en forbindelse med den almene formelExample 14 In a 50 ml round bottom flask, 425 mg of a compound of the general formula is charged.

R-/ 0CH2-CH \ OHR- / OCH2-CH \ OH

\ Km)n hvor R betegner alkylradikalet af oleylalkohol, og n er et tal lig med 2, og 75 mg af en amin med den almene formel i \ R- 0CH„-CH -0CHoCH0H-CHoN 0Where Km represents the alkyl radical of oleyl alcohol and n is a number equal to 2 and 75 mg of an amine of the general formula in \ R-OCH2 -CH-CHOCHOH-CHON 0

V kon/- WV could / - W

2 n hvor R betegner oleylgruppen, og ή betegner en statistisk værdi mindre end 1, 1 kontakt med 0,5 ml af en 0,3 molær opløsning af glucose. Man homogeniserer blandingen. Forsøget udføres ved stuetemperatur.2 n where R represents the oleyl group and ή represents a statistical value less than 1, 1 contact with 0.5 ml of a 0.3 molar solution of glucose. The mixture is homogenized. The experiment is carried out at room temperature.

Herefter tilsætter man 4 ml af en 0,145 molær opløsning (NaCl, KCl).Then, 4 ml of a 0.145 molar solution (NaCl, KCl) is added.

Kolben anbringes i et rysteapparat, og man omryster energisk i 4 timer.Place the flask in a shaker and shake vigorously for 4 hours.

Den opnåede dispersion er uigennemsigtig. Kuglernes diameter er større end 2 mikron.The dispersion obtained is opaque. The diameter of the balls is greater than 2 microns.

Dispersionen kan underkastes ultralydbehandling. Herved bliver kuglernes størrelse mindre i mikron.The dispersion can be subjected to ultrasound treatment. This makes the size of the balls smaller in microns.

13 15096713 150967

Eksempel 15 I en rundbundet kolbe på 50 ml bringes 300 mg sphingomyelin i kontakt roed 0,350 ml af en 0,3 molær opløsning af ascorbinsyre. Man homogeniserer blandingen. Forsøget udføres ved stuetemperatur.Example 15 In a 50 ml round bottom flask, contact 300 mg of sphingomyelin red 0.350 ml of a 0.3 molar solution of ascorbic acid. The mixture is homogenized. The experiment is carried out at room temperature.

Herefter tilsætter man 2,650 ml af en opløsning på 0,145 molær (NaCl, KCl). Kolben anbringes i rysteapparatet, og man omryster energisk i 4 timer.Then 2.650 ml of a solution of 0.145 molar (NaCl, KCl) is added. Place the flask in the shaker and shake vigorously for 4 hours.

Den opnåede dispersion er mælkeagtig. Kuglernes diameter er ca. 2 mikron. Dersom det ønskes, kan dispersionen filtreres på en gelkolonne "Sephadex G 50 grov”, der er kvældet i en opløsning af 0,145 molær (NaCl, KCl).The dispersion obtained is milky. The diameter of the balls is approx. 2 microns. If desired, the dispersion may be filtered on a gel column "Sephadex G 50 coarse" swollen in a solution of 0.145 molar (NaCl, KCl).

Eksempel 16 2 I en rundbundet kolbe på 50 ml opløses 142 mg af natriumsaltet af N -(al-koylolein)-N-dodecyl-N(N',N'-diethylaminoethyl)-asparagin i 2 ml af en blanding af chloroform-methanol i forholdet 2:1. Man afdamper opløsningsmidlet ved hjælp af en roterende afdamper. Herefter fjerner de sidste spor af opløsningsmiddel ved at underkaste produktet i 1 time for reduceret tryk, der frembringes med en vingepumpe.Example 16 2 In a 50 ml round bottom flask, 142 mg of the sodium salt of N - (alkoylolein) -N-dodecyl-N (N ', N'-diethylaminoethyl) asparagine is dissolved in 2 ml of a mixture of chloroform-methanol in a 2: 1 ratio. The solvent is evaporated by means of a rotary evaporator. Thereafter, the last traces of solvent are removed by subjecting the product for 1 hour to reduced pressure generated by a wing pump.

Man bringer 10 ml af en opløsning af 0,3 molær glucose i kontakt med li- poidet.10 ml of a solution of 0.3 molar glucose is contacted with the lipid.

Kolben anbringes på et rysteapparat, og man ryster kraftigt i 4 timer. Forsøget udføres ved stuetemperatur. Kuglernes størrelse er ca. 1 mikron. Dispersionen filtreres herefter på en gelkolonne "Sephadex G 50 grov", der er kvældet i en opløsning af 0,145 molær (NaCl, KCl).Place the flask on a shaker and shake vigorously for 4 hours. The experiment is carried out at room temperature. The size of the balls is approx. 1 micron. The dispersion is then filtered on a gel column "Sephadex G 50 coarse" swollen in a solution of 0.145 molar (NaCl, KCl).

Eksempel 17 I en kolbe på 50 ml opløser man 80 mg af en forbindelse med den almene formelExample 17 In a 50 ml flask, 80 mg of a compound of the general formula is dissolved

R—J 0CH2-CH j OHR-J OCH 2 -CH 2 OH

V GH2QH/n hvor R betegner en hexadecylgruppe, og n er lig med 2, 10 mg cholesterol og 10 mg dicetylphosphat i 2 ml af en blanding af chloroform/methanol i forholdet 2/1.V GH2QH / n where R represents a hexadecyl group and n is equal to 2, 10 mg of cholesterol and 10 mg of dicetylphosphate in 2 ml of a 2/1 chloroform / methanol mixture.

Man afdamper opløsningsmidlet ved hjælp af en roterende afdamper,og derefter fjerner man de sidste spor af opløsningsmiddel ved hjælp af en vingepumpe i 1 time.The solvent is evaporated by means of a rotary evaporator and then the last traces of solvent are removed by means of a wing pump for 1 hour.

Herefter bringer man 10 ml af en 0,15 molær opløsning af natriumsaltet af pyroglutaminsyre i kontakt med lipoiderne. Kolben anbringes i et rysteapparat, 14 150967 og man omryster kraftigt i 2 timer på et vandbad ved 55°C. Herefter afkøler man langsomt, til man når til stuetemperatur.Then, 10 ml of a 0.15 molar solution of the sodium salt of pyroglutamic acid is brought into contact with the lipoids. The flask is placed in a shaker, shaken vigorously for 2 hours on a water bath at 55 ° C. Then slowly cool until you reach room temperature.

Dispersionen underkastes ultralydbehand ling i en time ved en temperatur, tæt på stuetemperatur. Herefter filtrerer man dispersionen på en gelkolon ne "Sephadex G 50 grov", der er kvældet i destilleret vand.The dispersion is subjected to ultrasound treatment for one hour at a temperature close to room temperature. The dispersion is then filtered on a gel column "Sephadex G 50 coarse" which is swollen in distilled water.

Den opnåede dispersion er flydende og klar efter behandling med ultralyd. Kuglernes diameter er mindre end 1 mikron.The dispersion obtained is fluid and clear after ultrasonic treatment. The diameter of the balls is less than 1 micron.

Eksempel 18 I en rundbundet kolbe på 50 ml blander man grundigt 240 mg af en forbindelse med den almene formelExample 18 In a 50 ml round bottom flask, thoroughly mix 240 mg of a compound of the general formula

R—/ 0CH2-CH \ OHR— / OCH₂-CH \OH

\ k0H/n hvor R betegner en alkoylgruppe af hydrogenerede lanolinalkoholer, og n har en statistisk værdi mindre end 3, og 60 mg cholesterol.where R represents an alcohol group of hydrogenated lanolin alcohols and n has a statistical value less than 3 and 60 mg of cholesterol.

Man bringer den opnåede blanding i kontakt med 0,4 ml af en 0,15 molær opløsning af natriumsaltet af pyroglutaminsyre, og herefter homogeniserer man blandingen. Forsøget udføres ved 45°C. Herefter tilsætter man 4,6 ml af en 9 °/oo opløsning af natriumchlorid.The resulting mixture is contacted with 0.4 ml of a 0.15 molar solution of the sodium salt of pyroglutamic acid, and then the mixture is homogenized. The test is carried out at 45 ° C. Then 4.6 ml of a 9 ° / oo solution of sodium chloride is added.

Kolben, der er anbragt på et vandbad, omrystes energisk ved hjælp af et rysteapparat i 2 timer ved 45°G, herefter afkøler man gradvis indtil stuetemperatur.The flask placed on a water bath is shaken vigorously by means of a shaker for 2 hours at 45 ° G, then gradually cooled to room temperature.

Den opnåede dispersion er flydende og mælkeagtig. Kuglernes diameter er større end 1 mikron.The dispersion obtained is liquid and milky. The diameter of the balls is greater than 1 micron.

Eksempel 19 I en rundbundet kolbe på 50 ml blander man grundigt 200 mg af en forbindelse med den almene formel:Example 19 In a 50 ml round bottom flask, thoroughly mix 200 mg of a compound of the general formula:

R—/0CH2-CH \ OHR— / OCH₂-CH \OH

\ hvor R betegner en hexadecylgruppe, og n er lig med 2, 25 mg cholesterol og 25 mg dicetylphosphat. Man bringer den opnåede blanding i kontakt med 0,3 ml af en 1C% opløsning af tartaraldehyd og homogeniserer blandingen. Forsøget udføres ved 55°C. Herefter tilsætter man 4,7 ml af en opløsning af 0,145 molær (NaCl, KCl).where R represents a hexadecyl group and n is equal to 2, 25 mg of cholesterol and 25 mg of dicetyl phosphate. The obtained mixture is contacted with 0.3 ml of a 1% C solution of tartaraldehyde and the mixture is homogenized. The test is carried out at 55 ° C. Then 4.7 ml of a solution of 0.145 molar (NaCl, KCl) is added.

15 15096715 150967

Kolben anbringes på vandbad og omrøres kraftigt ved hjælp af et rysteapparat i 2 timer ved 55°G. Herefter afkøler man gradvis til stuetemperatur.Place the flask on a water bath and stir vigorously with a shaker for 2 hours at 55 ° G. Afterwards, cool gradually to room temperature.

Den opnåede blanding er geleret og har et let blåligt udseende.The resulting mixture is gelled and has a slightly bluish appearance.

Samtidig påførsel på huden af denne dispersion af niosomer og en vandig opløsning med samme s lutkoncentration af tartaraldehyd bevirker, at man opnår to virkninger af niosomerne, idet de tydeligt forstærker den udviklede farve og klart forbedrer holdbarheden af farven ved vask med vand eller med detergenter.Simultaneous application to the skin of this dispersion of niosomes and an aqueous solution with the same s t concentration of tartaraldehyde results in two effects of the niosomes, clearly enhancing the color developed and clearly improving the durability of the dye by washing with water or with detergents.

De ovenfor nævnte udførelseseksempler skal på ingen måde betragtes som begrænsende for opfindelsen. Man kan foretage alle ønskelige modifikationer, uden at gå uden for den foreliggende opfindelses rammer.The above-mentioned exemplary embodiments are in no way considered as limiting the invention. All desirable modifications can be made without departing from the scope of the present invention.

16 15096716 150967

SAMMENLIGNINGSFORSØGCOMPARISON TRIALS

A. Sammenligningsforsøg med permeabilitet af ioniske og ikke-ioniske liposom-dispersioner.A. Comparative experiments with permeability of ionic and non-ionic liposome dispersions.

Ved den klassiske omrøringsmetode kan man med phospholipider såvel som med ikke-ioniske lipider opnå dispersioner af blærer med flere lag, som har en gennemsnitlig diameter større end eller lig med 1 mikron.In the classical stirring method, dispersions of multi-layer vesicles having an average diameter greater than or equal to 1 micron can be obtained with phospholipids as well as with nonionic lipids.

Ved anvendelse af ultralyd kan man kraftigt formindske størrelsen af blærerne og opnå sådanne med en diameter på ca. 500 Å.By using ultrasound one can greatly reduce the size of the bladders and obtain those with a diameter of approx. 500 Å.

Størrelsen af med ultralyd behandlede blærer (250-1000 Å) kan måles ved iagttagelse under elektronmikroskop, idet man anvender en passende fremkalder, f.eks. natriumsaltet af phosphorwolframsyre.The size of ultrasonically treated blisters (250-1000 Å) can be measured by observation under an electron microscope using a suitable developer, e.g. the sodium salt of phosphorus tungsten acid.

Permeabiliteten af blærerne før og efter ultralydsbehandlingen blev målt ved enzymatisk mikrobestemmelse af glukose.The permeability of the bladders before and after the ultrasound treatment was measured by enzymatic glucose determination.

Dispersionen blev fremstillet som følger:The dispersion was prepared as follows:

Lipiderne forenes, idet de sættes til en chloroform-methanol-opløsnings-middelblanding 2:1.The lipids are combined by adding to a 2: 1 chloroform-methanol-solvent mixture.

Man fremstiller en 3%'s dispersion af lipidblandingen i en 0,3 m-glukose-opløsning.A 3% dispersion of the lipid mixture is prepared in a 0.3 m glucose solution.

Temperaturen af dispersionen indstilles til en temperatur over krystallisationspunktet for hovedlipidet, hvorpå dispersionen afkøles til stuetemperatur under omrøring.The temperature of the dispersion is adjusted to a temperature above the crystallization point of the main lipid, whereupon the dispersion is cooled to room temperature with stirring.

Man behandler i 30 minutter med ultralyd ved direkte kontakt med mikrosonden, idet dispersionen holdes under nitrogenatmosfære, hvis den indeholder oxyderbare liposomer. Temperaturen holdes over krystallisationstemperaturen for hovedlipidet.Ultrasound is treated for 30 minutes by direct contact with the microsonde, keeping the dispersion under a nitrogen atmosphere if it contains oxidizable liposomes. The temperature is kept above the crystallization temperature of the main lipid.

Derpå filtreres over en søjle med gel af modificeret dextran, med partik-kelstørrelsen "grov" (anvendt i en 97Js kogesaltsopløsning.Then filter over a column of modified dextran gel, with the particle size "coarse" (used in a 97 J boiling solution).

Forsøgsresultaterne med hensyn til optagelsesevnen for liposomerne overfor aktive opløsninger (her glukose) og permeabiliteten af liposomerne er sammenfattet i følgende tabeller 1 til 3: 17 15096; to I t)0 tuo o-ι oThe experimental results regarding the uptake capacity of the liposomes against active solutions (here glucose) and the permeability of the liposomes are summarized in the following Tables 1 to 3: 17 15096; to I t) 0 tuo o-ι o

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Ultralydsbehandlixig af den ioniske liposom-dispersion:Ultrasonic treatment of the ionic liposome dispersion:

Sammensætning: Æggelecithin 85%Composition: Egg Lecithin 85%

Cholesterol 10%Cholesterol 10%

Natriumdicetylphosphat 5% TABEL 2Sodium dicetyl phosphate 5% TABLE 2

Varighed af ultralyds- Opkvældning % tab efter 1 døgn behandlingen, minutter 0 76 0,6 5 44 0,5 20 33 1,0 60 21 1,0Duration of ultrasonic swelling% loss after 1 day of treatment, minutes 0 76 0.6 5 44 0.5 20 33 1.0 60 21 1.0

Ultralydsbehandling af ikke-ioniske liposom-dispersioner (Niosomer):Ultrasound Treatment of Non-Ionic Liposome Dispersions (Niosomes):

Sammensætning:composition:

Produkt med den almene formel / \ R--U0CHo-CH--OH 70% \ i \ CH20H / ^ hvori R = alkyl fra hydrerede lanolinalkoholer og ir svarer til statistisk middelværdi på 3Product of the general formula / R - UOCHo-CH - OH 70% \ in \ CH2 OH / R in which R = alkyl from hydrated lanolin alcohols and ir corresponds to statistical mean of 3

Cholesterol 20%Cholesterol 20%

Natrium-dicetylphosphat 10% TABEL 3Sodium dicetyl phosphate 10% TABLE 3

Varighed af ultralyds- Opkvældning % tab efter 1 døgn behandlingen, minutter 0 80 0,0 20 53 0,1 19 150967Duration of ultrasonic swelling% loss after 1 day of treatment, minutes 0 80 0.0 20 53 0.1 19 150967

Analyse af forsøgsresultater:Analysis of test results:

Forsøgsresultaterne i Tabel 1 viser, at ved liposomerne (diameter >1000Å og ^1000Å) er en formindskelse af blærenes størrelse i alle tilfælde forbundet med en forøgelse af en øget gennemtrængelighed for det opløste stof. Permeabili-teten af de ikke-ioniske liposomer tiltager dog mindre stærkt med diameterens formindskelse ved de ikke-ioniske liposomer, end ved de toniske liposomer.The experimental results in Table 1 show that in the case of the liposomes (diameter> 1000Å and ^ 1000Å) a decrease in the size of the bladder is in all cases associated with an increase in increased permeability of the solute. However, the permeability of the nonionic liposomes increases less strongly with the diameter decrease in the nonionic liposomes than in the tonic liposomes.

Forsøgsresultaterne i Tabel 1 viser endvidere, at de ikke-ioniske liposomer med størrelser ^1000Å er overlegne i forhold til de kendte liposomer af tilsvarende størrelse, også med hensyn til mængden af optaget glukoseopløsning.The experimental results in Table 1 further show that the nonionic liposomes of sizes ^ 1000Å are superior to the known liposomes of similar size, also with respect to the amount of glucose solution taken up.

De optager, om det kan ses af opkvældningsdata, ca. den tredobbelte mængde opløst stof.They record whether it can be seen by swelling data, approx. the triple amount of solute.

Forsøgsresultaterne i Tabel 2 og 3 viser, at tabet af indesluttet glukose hos de ikke-ioniske liposomer (se Tabel 2), dvs. permeabiliteten af disse liposomer, forøges med varigheden af ultralydsbehandlingen. Permeabiliteten synes her at være sammenknyttet med størrelsen af blærerne, således at blærer med mindre diametre er mere gennemtrængelige end blærer med store diametre.The experimental results in Tables 2 and 3 show that the loss of trapped glucose in the nonionic liposomes (see Table 2), ie. the permeability of these liposomes increases with the duration of the ultrasound treatment. The permeability here seems to be associated with the size of the blisters, so that blisters with smaller diameters are more permeable than blisters with large diameters.

I modsætning hertil udviser de ikke-ioniske liposomer (se Tabel 4) også ved en ultralydsbehandling i 20 minutter og en dermed forbundet formindskelse af diameteren kun en særdeles ringe forøgelse af permeabiliteten.In contrast, the non-ionic liposomes (see Table 4) also show a very slight increase in permeability by ultrasonic treatment for 20 minutes and a consequent decrease in diameter.

B. Sammenligningsforsøg vedrørende stabiliteten af de ioniske og ikke-ioniske liposom-dispersioner.B. Comparative experiments on the stability of the ionic and nonionic liposome dispersions.

I. Ioniske liposom-dispersioner.I. Ionic Liposome Dispersions.

Formuleringen omfatter 75% æggelecithin, 20% cholesterol og 5% dicetyl-phosphat.The formulation comprises 75% egg lecithin, 20% cholesterol and 5% dicetyl phosphate.

Fremstilling af den ioniske liposom-dispersion.Preparation of the Ionic Liposome Dispersion.

I en 50 ml rundbundet kolbe opløses 375 mg æggelecithin, 100 mg cholesterol og 25 mg natriumdicetylphosphat i 3 ml af en blanding af chloroform og methanol (2:1).In a 50 ml round bottom flask, dissolve 375 mg of egg lecithin, 100 mg of cholesterol and 25 mg of sodium dicetyl phosphate in 3 ml of a mixture of chloroform and methanol (2: 1).

Opløsningsmidlet fjernes ved hjælp af en rotationsfordamper, og de sidste spor af opløsningsmiddel fjernes ved at blandingen holdes en time under reduceret tryk.The solvent is removed by means of a rotary evaporator and the last traces of solvent are removed by keeping the mixture under reduced pressure for one hour.

Den opnåede lipidfilm tilsættes ved 40°C 8 ml af en vandig 9natrium-chloridopløsning. Kolbeindholdet røres to timer ved 40 °C og afkøles derpå langsomt til omgivelsernes temperatur. Kolben befinder sig under omrøringen på et rysteapparat.The resulting lipid film is added at 40 ° C to 8 ml of an aqueous 9 sodium chloride solution. The flask contents are stirred for two hours at 40 ° C and then slowly cooled to ambient temperature. The flask is placed on a shaker during stirring.

Man underkaster derpå dispersionen ultralydsbehandling i en time ved direkte kontakt med en lydsonde. Den under nitrogen stående dispersion holdes ved hjælp af et vandbad ved en ydertemperatur på 50°C.The dispersion is then subjected to ultrasound treatment for one hour by direct contact with a sound probe. The nitrogen dispersion is maintained by means of a water bath at an outside temperature of 50 ° C.

20 15096720 150967

Efter ultralydsbehandlingen filtreres dispersionen over en søjle med agarosegel i perleform, opkvældet i en 9^-natriumchloridopløsning (egnet størrelse for søjlen: diameter 2,6 cm, længde 30 cm).After the ultrasonic treatment, the dispersion is filtered over a bead-shaped agarose gel column, swollen in a 9 ° sodium chloride solution (suitable size for the column: diameter 2.6 cm, length 30 cm).

Eluatet optages i fraktioner på 10 ml.The eluate is taken up in 10 ml fractions.

Elektronmikroskopisk undersøgelse viser, at de sidste af fraktionerne indeholder liposomet.Electron microscopic examination shows that the last of the fractions contain the liposome.

Den fraktion, som skal undersøges, fortyndes med samme volumen af en vandig 2%'s opløsning af ammoniumsaltet af phosphorwolframsyre mindst 30 minutter før målingen.The fraction to be examined is diluted with the same volume of an aqueous 2% solution of the ammonium salt of phosphorous tungsten acid at least 30 minutes before the measurement.

Man anbringer 10 mikroliter af fortyndingen på et gitter af guld, som er overtrukket med en kollodiumfilm.Ten microliters of the dilution is applied to a gold lattice coated with a collodium film.

Efter en indvirkningstid på 30 sekunder tørres gitteret med filtrerpapir, og præparatet er herefter færdigt til undersøgelse.After an impact time of 30 seconds, the grating is dried with filter paper and the preparation is then ready for examination.

Trin 1:Step 1:

Felt af blærer, dispersion med adskilte blærer, størrelse 150 til 300Å.Field of blisters, dispersion with separate blisters, size 150 to 300Å.

Trin 2:Step 2:

Forekomst af blæreophobninger.Occurrence of bladder accumulation.

Trin 3 og 4:Steps 3 and 4:

Sammensmeltning af blærerne.Merging of the blisters.

Trin 5:Step 5:

Tilbagevending til ordnet lamelfase.Return to ordered lamella phase.

Overgangen fra trin 1 til trin 4, dvs. spredning af disse liposomer, sker hurtigt (i løbet af 24 timer).The transition from step 1 to step 4, ie. The spread of these liposomes occurs rapidly (within 24 hours).

I den klare, blålige udgangsdispersion viser liposomernes adskillelse sig i makroskopisk målestok ved forekomst af spiraler eller ruller og derpå ved dannelse af sammensmeltede blæreophobninger.In the clear bluish initial dispersion, the separation of the liposomes is shown on a macroscopic scale by the presence of coils or rolls and then by the formation of fused bladder accumulations.

II. Ikke-ionisk liposom-dispersion (Niosom) .II. Nonionic Liposome Dispersion (Niosome).

Formuleringen omfatter 80% niosom, 10% cholestantriol og 10% dicetyl-phosphat.The formulation comprises 80% niosome, 10% cholestanetriol and 10% dicetyl phosphate.

Fremstilling af den ikke-ioniske liposom-dispersion.Preparation of the Nonionic Liposome Dispersion.

I en 50 ml rundbundet kolbe opløses 400 mg af produktet med formlen I \In a 50 ml round bottom flask, dissolve 400 mg of the product of formula I

R--h OCfL-— ~CH-\-------OHR - h OCfL-— ~ CH - \ ------- OH

II!II!

' CH 0H/SCH 2 OH / S

Claims (4)

21 150967 50 mg cholestantriol og 50 mg natriumdicetylphosphat i 3 ml af en 2:1-blanding af chloroform og methanol. Opløsningsmidlet afdampes ved hjælp af en rotationsfordamper, og de sidste spor heraf fjernes, idet blandingen holdes en time under reduceret tryk. Den opnåede lipidfilm tilsættes 8 ml af en vandig 0,3 molær glukoseopløsning. Forsøget gennemføres ved en temperatur på 70°C. Kolben stilles på e rysteapparat og røres 2 timer kraftigt ved 70°C, hvorpå den afkøles til omgivelsernes temperatur. Derpå underkaster man dispersionen behandling med ultralyd i 20 minutter ved en temperatur, som ved hjælp af et is-vandbad holdes under stuetemperatur, idet behandlingen sker ved direkte kontakt med lydsonden. Den med ultralyd behandlede opløsning fortyndes derpå i destilleret vand til en lipidkoncentration på 1% og fortyndes derpå atter i et volumenforhold på 1:1, mindst 30 minutter før målingen, med en 2%'s opløsning af ammoniumsaltet af phosphorwolframsyre. Man anbringer 10 mikroliter af denne fortynding på et guldgitter, som er dækket med en kollodoniumfilm. Efter en indvirkningstid på 30 sekunder tørres gitteret med et filtrerpapir. 8 dage efter fortynding af dispersionen i opløsningen af ammoniumsaltet af phosphorwolframsyren konstateres det, at der foreligger en dispersion af nio-somer med ringe størrelse (300Å). Der iagttages hverken aggregation eller strukturforandringer af blærerne ved henstand, i adskillige dage. Dispersionen er stabil i flere måneder. Forsøg viser, at de ikke-ioniske liposomdispersioner (her liposom-dia-meter f.eks. 300Å) er væsentligt stabilere end de kendte ioniske liposomer med en diameter på op til 1000Å, specielt 500Å (jvf. tysk offentliggørelsesskrift nr. 22 49 552).50 mg of cholestantriol and 50 mg of sodium dicetyl phosphate in 3 ml of a 2: 1 mixture of chloroform and methanol. The solvent is evaporated by means of a rotary evaporator and the last traces thereof removed, keeping the mixture under reduced pressure for one hour. The resulting lipid film is added to 8 ml of an aqueous 0.3 molar glucose solution. The test is carried out at a temperature of 70 ° C. Place the flask on a shaker and stir vigorously for 2 hours at 70 ° C and then cool to ambient temperature. The dispersion is then subjected to ultrasound treatment for 20 minutes at a temperature which is kept below room temperature by means of an ice-water bath, the treatment being by direct contact with the sound probe. The ultrasonically treated solution is then diluted in distilled water to a lipid concentration of 1% and then diluted again in a volume ratio of 1: 1, at least 30 minutes before the measurement, with a 2% solution of the ammonium salt of phosphorus tungstic acid. 10 microliters of this dilution is applied to a gold lattice covered with a collodonium film. After an impact time of 30 seconds, the grating is dried with a filter paper. Eight days after dilution of the dispersion in the solution of the ammonium salt of the phosphorous tungsten acid, a small size dispersion (300Å) is found. Neither aggregation nor structural changes of the blisters are observed upon standing for several days. The dispersion is stable for several months. Experiments show that the nonionic liposome dispersions (here, liposome diameters, for example, 300Å) are substantially more stable than the known ionic liposomes with a diameter of up to 1000Å, especially 500Å (cf. German Publication No. 22 49 552 ). 1. Dispersion af småkugler, som består af molekulare lag af lipidforbin-delser, som omslutter en vandig fase, kendetegnet ved, at lipidfor-bindelseme er ikke-ioniske forbindelser med den almene formel X-—·Υ hvori X betegner en hydrofil polyoxyethylengruppe, polyglycerolgruppe eller oxy-ethyleret eller ikke-oxyethyleret polyolestergruppe, og Y betegner en lipofil-gruppe, hvilke kugler har en diameter fra 100 til 50.000Å.Dispersion of pellets consisting of molecular layers of lipid compounds enclosing an aqueous phase, characterized in that the lipid compounds are nonionic compounds of the general formula X X wherein X represents a hydrophilic polyoxyethylene group, polyglycerol group or oxyethylated or non-oxyethylated polyol ester group, and Y represents a lipophilic group having spheres of 100 to 50,000Å in diameter. 2. Fremgangsmåde til fremstilling af dispersionen ifølge krav 1, kendetegnet ved, at man blander i det mindste en i vand dispergerbar ikke-ionisk lipidforbindelse med den almene formel 150967 X-Y hvori X betegner en hydrofil polyoxyethylengruppe, polyglycerolgruppe eller oxyethyleret eller ikke-oxyethyleret polyolestergruppe, og Y betegner en lipo-fil gruppe, og den vandige fase, som skal indesluttes i kuglerne, idet lipidets lipofil/hydrofil-forhold vælges således, at lipidet kvældes i den vandige fase, som skal indesluttes, under dannelse af en lamelagtig fase, hvorpå man tilsætter en dispergeringsvæske i overskydende mængde til den lamelagtige fase, som opnås og ryster kraftigt i fra 15 minutter til 3 timer.Process for preparing the dispersion according to claim 1, characterized in that at least one water-dispersible nonionic lipid compound of general formula 150967 XY wherein X represents a hydrophilic polyoxyethylene group, polyglycerol group or oxyethylated or non-oxyethylated polyol ester group, is mixed. and Y represents a lipophilic group and the aqueous phase to be enclosed in the spheres, the lipophilic / hydrophilic ratio of the lipid being selected such that the lipid is swollen into the aqueous phase to be enclosed to form a lamellae phase, upon which an excess liquid dispersant is added to the lamella phase which is obtained and shaken vigorously for from 15 minutes to 3 hours. 3. Fremgangsmåde ifølge krav 2, kendetegnet ved, at man benytter et vægtfbrhold'mellem den vandige fasé, der skal indesluttes og det eller de lipider, som danner den lamelagtige fase. på fra 0,1 til 3.A method according to claim 2, characterized in that a weight ratio is used between the aqueous phase to be enclosed and the lipid (s) forming the lamella-like phase. of from 0.1 to 3. 4. Fremgangsmåde ifølge krav 2 eller 3,kendetegnet ved, at man arbejder ved en temperatur, som i det mindste er så høj som smeltetemperaturen af det eller de lipider, hvormed der arbejdes.Process according to claim 2 or 3, characterized in that it operates at a temperature which is at least as high as the melting temperature of the lipid (s) used.
DK291376A 1975-06-30 1976-06-29 DISPERSION OF TASTE BALLS AND PROCEDURE FOR ITS MANUFACTURING DK150967C (en)

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ATA470376A (en) 1980-09-15
JPS588287B2 (en) 1983-02-15
JPS526375A (en) 1977-01-18
DE2629100B2 (en) 1979-11-29
BE843300A (en) 1976-12-23
DE2661108C2 (en) 1993-12-16
GB1539625A (en) 1979-01-31
DE2629100C3 (en) 1980-08-14
CH623236A5 (en) 1981-05-29
BR7604270A (en) 1977-04-05
CA1063908A (en) 1979-10-09
AU505843B2 (en) 1979-12-06
AU1539376A (en) 1978-01-05
AT361893B (en) 1981-04-10
NL168715C (en) 1982-05-17
FR2315991A1 (en) 1977-01-28
DK291376A (en) 1976-12-31
JPS6156016B2 (en) 1986-12-01
DK150967C (en) 1988-02-15
FR2315991B1 (en) 1977-12-02
IT1062389B (en) 1984-10-10
DE2660069C2 (en) 1990-09-13
ES449312A1 (en) 1977-08-16
CH616087A5 (en) 1980-03-14
JPS56108528A (en) 1981-08-28
DE2629100A1 (en) 1977-01-20

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