Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Liposomes
  • A61K9/1277—Processes for preparing; Proliposomes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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

Definitions

• the present invention relates to a method for producing liposomes.
• the present invention further relates to the cosmetic, medical or pharmaceutical use of such structures.
• this term is understood to mean a group of water-insoluble molecules which are distinguished by at least one pronounced hydrophilic molecular region and at least one pronounced lipophilic molecular region.
• the phosphoric acid esters of acylated glycerols, the so-called “phospholipids” and other compounds belong to this group, which is quite inhomogeneous overall, of chemical compounds.
• lipids do not usually form real molecular solutions in vitro, for example in a mixture with water, but rather they either form colloids, they usually combine to form so-called micelles, in which the lipophilic molecular areas of the lipid molecules are located inside the micelle are located and the hydrophilic regions of the lipid molecules represent the outer region of the micelles, as described in FIG. 1, or else they form liquid-crystalline phases.
• the lipid molecules have a hydrophilic area (h) and a lipophilic area (I).
• the micelle (M) shown in FIG. 1 represents a sphere of lipid molecules, the interior of which is covered by the lipophilic residues of the it is obvious that the outer shell of the micelle is formed by the hydrophilic groups of the lipid molecules.
• Lipid membranes can, for example, be linear, curved (cubic phases, LrPhases) or self-contained (vesicles, LrPhases).
• the individual lipid molecules attach to one another in such a way that two monomolecular layers of lipid molecules arranged in parallel come to lie on one another at their lipophilic regions.
• the lipid molecules have a hydrophilic area (h) and a lipophilic area (I).
• the lipid bilayer (L) shown in FIG. 2 represents a membrane made of lipid molecules, the interior of which is filled by the lipophilic residues of the lipid molecules. Since the lipid bilayer is present in an aqueous environment (W), it is obvious that the outer shell of the lipid bilayer is formed by the hydrophilic groups of the lipid molecules.
• the lipid bilayers shown represent membranes made of lipid molecules which have a hydrophilic region (h) and a lipophilic region (I). The inside of the membranes is filled with the lipophilic residues of the lipid molecules.
• the lamellar structure is created by “stacking” the membranes, the interlamellar spaces between the individual membranes being filled with water.
• Vesicles or liposomes are spherically closed microscopic objects which are delimited on the outside by a lipid bilayer and which contain a water phase inside. This is shown in Fig. 3.
• the lipid molecules have a hydrophilic area (h) and a lipophilic area (I).
• the center of the vesicles is filled with an aqueous phase.
• the diameter of liposomes usually ranges from a few (typically about 25) nanometers to about 1 ⁇ m.
• M multilamellar vesicle
• lipid double membranes consisting of lipid molecules with a hydrophilic region (h) and a lipophilic region (I).
• a thin layer of a polar, in particular aqueous phase (w) is generally arranged between the lipid double membranes.
• a polar phase inside the multilamellar vesicle is another polar, usually aqueous phase, which can also be loaded with active substances (here: Q)).
• Q active substances
• liposomes for example, is well known to the person skilled in the art.
• One method is, for example, an ultrasound treatment of a lipid water system, with the liposomes obtained only having to be filtered off when choosing suitable lipids.
• vesicle extrusion of suitable lipids through a membrane filter with a pore size of typically about 100 nm also leads to the formation of liposomes.
• the basic components of the lipid double-membrane covering the liposomes are normally selected from the group of phospholipids, often lecithin. Occasionally, especially with the so-called niosomes, non-ionic surfactants are also used as the covering material.
• niosomes non-ionic surfactants are also used as the covering material.
• empty liposomes which consist of a shell and an aqueous interior
• loaded liposomes the interior of which represents an aqueous phase which is provided with water-soluble active substances, or whose shell is provided with lipophilic active substances.
• Microorganisms can be encapsulated in a liposomal manner, "transfersomes" should penetrate the epidermis intact, in contrast to "normal" liposomes.
• liposomes do not penetrate intact, but adsorb on or in the uppermost layers of the stratum co eum. There is much to suggest that liposomes are endocytotically absorbed into the body cell. In addition to the topical administration of preparations containing liposomes, intravenous administration is also possible.
• the phospholipids in particular are of the highest biological interest since they represent the basic substance of the cell membranes of all living cells or their cell organelles.
• phospholipids are important components of the plasma membrane, the myelin, the endoplasmic reticulum and certain organelles, for example the chloroplast photosynthetic organisms.
• R 1 and R 2 typically represent unbranched aliphatic radicals having 15 or 17 carbon atoms and up to 4 cis double bonds.
• Lecithins are not only important in the living cell, they are also preferably used as a basic component for the outer layer of the most common commercially available liposomes.
• the basic structure of the sphingolipids is sphingosine or phytosphingosin, which are characterized by the following structural formulas:
• R 1 and R 3 independently represent saturated or unsaturated, branched or unbranched alkyl radicals of 1 to 28 carbon atoms
• R 2 is selected from the group: hydrogen atom, saturated or unsaturated, branched or unbranched alkyl radicals of 1 to 28 carbon atoms, sugar radicals, with organic radicals esterified or unesterified phosphate groups, with organic radicals esterified or unesterified sulfate groups and Y either a represents hydrogen atom, a hydroxy group or another hetero-functional radical.
• sphingolipids include the naturally occurring ceramides, cerebrosides, gangliosides, sphingophospholipids, of which in particular the sphingomyelins, sphingosulfatides and glycosphingosides as well as analogues obtainable by chemical synthesis, examples of which are listed below:
• Ri and R 3 represent alkyl radicals
• R 4 represents an organyl radical
• Sphingomyeline are organylphosphorylated sphingolipids of the type
• R 2 is selected from the group of sugar residues in the structural formula of the ceramides, a distinction is usually made between whether monoglycosylceramides or di, tri or generally oligoglycosylceramides are present.
• Monoglycosylceramides are commonly called cerebrosides:
• Oligoglycosylceramides are mostly called gangliosides.
• Frequent sphingolipids are ceramide I, II, III and IV, glucosylceramide, lactosylceramide and the gangliosides GM 1, 2 and 3.
• a mixture of phospholipids is dispersed in water and then evaporated in a glass flask.
• a lipid film forms on the wall, which is moistened with a buffer solution, whereby liposomes spontaneously form.
• Multilamellar vesicles usually develop.
• a phospholipid mixture dispersed in water is crushed by ultrasound, producing liposomes.
• a phospholipid mixture dispersed in water is converted into liposomes by pressure in an extruder.
• the lipids in particular phospholipids, are dissolved in an organic solvent such as ether, methanol and injected into warm water in which the substance to be enclosed is present in solution. After removal of the solvent in vacuo, mostly unilamellar vesicles are formed.
• organic solvent such as ether, methanol
• the Detergent Method An aqueous mixed micelle solution of phospholipids, a detergent and the substance to be encapsulated is prepared and then the detergent is removed by dialysis or column chromatography.
• a water-in-oil emulsion is prepared in a buffer, the phospholipids and the substances to be enclosed, and the volatile organic phase is then evaporated off in vacuo. At the end of the evaporation process, a suspension of large unilamellar vesicles is formed.
• lipid mixtures can result in liposome dispersions without using the methods described above.
• This so-called "spontaneous formation of vesicles” is selected by selecting the lipids, pH changes (Proc. Natl. Acad. Sci. USA, Vol 79, p. 1683, 1982) dilutions from ethanol-containing fatty alcohol and fatty acid mixtures (Biochemistry, Vol 17, No.18, p.3758, 1978) or from ethanol-containing phospholipid solutions (J. Pharm. Pharmacol. 43, p. 154, 1991) .Mixtures of phosphatidylcholine and lysophosphatidylcholine (Chemistry and Physics of Lipids, 43, p.
• EP 0 211 647 discloses liposome preparations which, by mixing a C 8 -C 24 carboxylic acid (or an amine) with a compound which contains two ionizable groups (dicarboxylic acid, diamine, ⁇ -amino- ⁇ -carboxylic acid) material and water to be encapsulated. It is disclosed that a proliposome gel is produced for production, which is then mixed with water. is thinning. The concentrate consists of the liposome-forming ingredient and the compound that contains two ionizable groups. The gel consists of a hydrated complex, which is in the form of a liquid crystal.
• the liposomal dispersion is obtained from the gel by dilution in a phosphate buffer solution.
• the process for producing this liposome dispersion therefore requires two steps.
• a paste is prepared with the exclusion of water from phospholipids and oleic acid, which is then mixed with a second compound, such as arginine, to be dissolved in water to form the gel, which then spontaneously forms liposomes with water.
• EP 707847 presents a process which allows liposomes to be spontaneously produced from ketoprofen and phospholipids or nonionic amphiphiles.
• First the pH of the mixture is adjusted to 6-8, and liposomes are spontaneously obtained by lowering the pH below pH 6.
• DE 69214552 describes a method for producing vesicles for hair care preparations that contains at least one lipid (amphiphilic, ionic), a silicone and water.
• the process described for the production is complex because it requires several steps.
• a high pressure homogenizer is also used.
• the lipid vesicles described in DE 69600008 are also produced by ultrasound or high-pressure homogenization.
• liquid crystalline preparations can be produced from phospholides (lamellar phases, for example).
• the lamellar phase arises when suitable lipids are mixed with water.
• the water absorption capacity for liquid crystals is limited since the spacing of the water channels and thus also the spacing of the lipid bilayers become so large that the liquid crystal becomes unstable due to the addition of large amounts of water.
• H mean a hexagonal phase
• C a cubic phase
• L a lamellar phase
• H an inverse hexagonal phase
• the state K 2 (corresponding to a temperature ⁇ 3 ) in the region L ⁇ can be achieved by lowering the temperature, in which liposomes form.
• the state l ⁇ (corresponding to a temperature ⁇ 3 ) in the region L ⁇ can be achieved by lowering the temperature , in which liposomes form.
• the state Ke (corresponding to a temperature ⁇ 3 ) in the range can be reached by increasing the concentration P of a component (here water as an example) in which liposomes form.
• the state Ks can be increased by increasing the concentration P of a component (here as an example water) (corresponding to a temperature ⁇ 3 ) in the region U, in which liposomes form.
• phospholipids in particular those as described at the beginning of the background, as lipids (a).
• the basic structures based on lipid double membranes can advantageously be chosen on all common lipids of natural, synthetic or partially synthetic origin.
• Particularly advantageous are the phospholipids such as phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, cardiolipins (diphosphatidylglycerols) and sphingomyelines, and also glycolipids or glycerolipids.
• lecithins sphingolipids such as sphingosine or phytosphingosine, ceramides, cerebrosides, gangliosides, sphingophospholipids, of which in particular the sphingomyelins, sphingosulfatides and glycosphingosides, and analogues obtainable by chemical synthesis.
• lipids which can be used according to the invention are, for example, dimethyldioctadecylammonium chloride, dimethyldioctadecylammonium bromide, 1-palmitoleyl-2-oleyl-sn-glycero-3-phosphatidylcholine, dimyristoleylphosphatidylcholine, 1-palmitoleyl-2-oleyl-3-phosphatidylglycerol.
• Process step (IV) can be carried out with water at a temperature which is within, above or below the temperature interval [ ⁇ ], particularly advantageously with water at a temperature of at most 35 ° C.
• the lamellar phases can occur at room temperature or only at a higher temperature or over larger temperature ranges.
• the preparation of the liposomes can therefore depend on the selected surfactant system both at room temperature and at a higher temperature (for example 85 ° C.) and, when diluted with water, lead to liposomes according to the invention.
• Surfactants are amphiphilic substances that can dissolve organic, non-polar substances in water. Due to their specific molecular structure with at least one hydrophilic and one hydrophobic part of the molecule, they ensure a reduction in the surface tension of the water, wetting of the skin, facilitating the removal and removal of dirt, easy rinsing and, if desired, foam regulation.
• hydrophilic parts of a surfactant molecule are mostly polar functional groups, for example -COO ' , -OSO 3 2' , -SO 3 " , while the hydrophobic parts generally represent non-polar hydrocarbon residues.
• surfactants are generally of type and charge of the hydrophilic part of the molecule. There are four groups:
• B + any cation, eg Na +
• Non-ionic surfactants do not form ions in an aqueous medium.
• acylglutamates for example sodium acylglutamate, di-TEA-palmitoylaspartate and sodium caprylic / capric glutamate,
• acyl peptides for example palmitoyl-hydrolyzed milk protein, sodium cocoyl-hydrolyzed soy protein and sodium / potassium cocoyl-hydrolyzed collagen,
• Sarcosinates for example myristoyl sarcosin, TEA-lauroyl sarcosinate, sodium lauroyl sarcosinate and sodium cocoyl sarcosinate,
• taurates for example sodium lauroyl taurate and sodium methyl cocoyl taurate
• carboxylic acids for example lauric acid, aluminum stearate, magnesium alkanolate and zinc undecylenate,
• ester carboxylic acids for example calcium stearoyl lactylate, laureth-6 citrate and sodium PEG-4 lauramide carboxylate,
• ether carboxylic acids for example sodium laureth-13 carboxylate and sodium PEG-6 cocamide carboxylate,
• Phosphoric acid esters and salts such as, for example, DEA-oleth-10-phosphate and di-laureth-4 phosphate,
• Sulfonic acids and salts such as 1.
• acyl isethionate for example sodium / ammonium cocoyl isethionate,
• alkyl sulfonates for example sodium coconut monoglyceride sulfate, sodium C IM4 olefin sulfonate, sodium lauryl sulfoacetate and magnesium PEG-3 cocamide sulfate,
• Sulfosuccinates for example dioctyl sodium sulfosuccinate, disodium laureth sulfosuccinate, disodium lauryl sulfosuccinate and disodium undecylenamido MEA sulfosuccinate
• sulfuric acid esters such as
• alkyl ether sulfate for example sodium, ammonium, magnesium, MIPA, TIPA laureth sulfate, sodium myreth sulfate and sodium C 12 . ⁇ 3 pareth sulfate,
• Alkyl sulfates for example sodium, ammonium and TEA lauryl sulfate.
• Quaternary surfactants contain at least one N atom that is covalently linked to 4 alkyl or aryl groups. Regardless of the pH value, this leads to a positive charge.
• Alkyl betaine, alkyl amidopropyl betaine and alkyl amidopropyl hydroxysulfain are advantageous.
• the cationic surfactants used in the invention can be also preferably selected from the group of quaternary ammonium compounds, especially benzyltrialkylammonium chlorides or bromides, for example benzyldimethylstearylammonium chloride, also trialkylammonium alkyl, such as, for example, Cetyltrimethylammoniumchlo- chloride or bromide, alkyldimethylhydroxyethylammonium chlorides or bromides, dialkyl or kyldimethylammoniumchloride bromides, alkylamidethyltrimethylammonium ether sulfates, alkylpyridinium salts, for example lauryl or cetylpyrimidinium chloride, imidazoline derivatives and compounds with a cationic character, such as amine oxides, for example alkyldimethylamine oxides or alkylaminoethyldimethylamine oxides. Cetyltrimethylammonium salts are particularly advantageous
• acyl- / dialkylethylenediamine for example sodium acylamphoacetate, disodium acylamphodipropionate, disodium alkylamphodiacetate, sodium acylamphohydroxypropylsulfonate, disodium acylamphodiacetate and sodium acylamphopropionate,
• N-alkylamino acids for example aminopropylalkylglutamide, alkylamino propionic acid, sodium alkylimidodipropionate and lauroamphocarboxyglycinate.
• alkanolamides such as cocamides MEA / DEA / MIPA
• amine oxides such as cocoamidopropylamine oxide
• esters which are formed by esterification of carboxylic acids with ethylene oxide, glycerol, sorbitol or other alcohols,
• ethers for example ethoxylated / propoxylated alcohols, ethoxylated / propoxylated esters, ethoxylated / propoxylated glycerol esters, ethoxylated / propoxylated cholesterols, ethoxylated / propoxylated triglyceride esters, ethoxylated propoxylated lanolin, ethoxylated / propoxylated polysiloxanes, propoxylated POE ethers and Lauryl glucoside, decyl glycoside and cocoglycoside.
• the liposome size can be controlled via the relative ratio of surfactants (for example anionic surfactant) to phospholipid, ie the more (for example anionic) surfactant is present, the smaller the total liposome, the lower the proportion of (for example anionic) surfactants automatically lead to larger lipids with the same total content of phospholipid and (eg anionic) surfactants.
• surfactants for example anionic surfactant
• phospholipid ie the more (for example anionic) surfactant is present, the smaller the total liposome, the lower the proportion of (for example anionic) surfactants automatically lead to larger lipids with the same total content of phospholipid and (eg anionic) surfactants.
• the liposome size can also be controlled in an analogous manner even with nonionic (e.g. glyceryl stearate citrate) or cationic surfactants (e.g. cetyltrimethylammonium bromide).
• nonionic e.g. glyceryl stearate citrate
• cationic surfactants e.g. cetyltrimethylammonium bromide
• glycerol esters e.g. glycerol monocaprylate, caprinate, laurate
• glycerol ether (2-ethylhexylglycerol ether
• the size of the vesicles can be controlled by
• the concentration of the added cosurfactant / coemulsifier anionic / non-ionic / amphoteric
• c) surface-active agents as cosurfactant or coemulsifier e.g. ascorbyl palmitate
• concentration and type of oil component to be encapsulated e) Use of curvature-inducing polymers (including hydrophobically modified polymers)
• the vesicles can be further diluted without disintegrating (eg in micelles).
• the oil phase can advantageously be selected from the following group of substances: mineral oils, mineral waxes
• Oils such as triglycerides of capric or caprylic acid, but preferably castor oil;
• Fats, waxes and other natural and synthetic fat bodies preferably esters of fatty acids with alcohols of low C number, e.g. with isopropanol, propylene glycol or glycerin, or esters of fatty alcohols with low C number alkanoic acids or with fatty acids; Alkyl benzoates;
• Silicone oils such as dimethylpolysiloxanes, diethylpolysiloxanes, diphenylpolysiloxanes and mixed forms thereof.
• the oil phase is advantageously selected from the group of esters of saturated and / or unsaturated, branched and / or unbranched alkane carboxylic acids with a chain length of 3 to 30 carbon atoms and saturated and / or unsaturated, branched and / or unbranched alcohols with a chain length of 3 to 30 carbon atoms, from the group of esters of aromatic carboxylic acids and saturated and / or unsaturated, branched and / or unbranched alcohols with a chain length of 3 to 30 carbon atoms.
• ester oils can then advantageously be chosen from the group of isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononylisononanoate, 2-ethyl-2-ethylhexyl, ethyl-2-ethylhexyl, ethyl-2-ethylhexyl 2-octyldodecyl palmitate, oleyl oleate, olerlerucate, erucyl oleate, erucylerucate as well as synthetic, semisynthetic and natural mixtures of such esters, for example Jojoba oil.
• the oil phase can advantageously be selected from the group of branched and unbranched hydrocarbons and waxes, the silicone oils, the dialkyl ethers, the group of saturated or unsaturated, branched or unbranched alcohols, and also the fatty acid trigiycerides, especially the triglycerol esters of saturated and / or unsaturated, branched and / or unbranched alkane carboxylic acids with a chain length of 8 to 24, in particular 12 - 18 carbon atoms.
• the fatty acid triglyce Rides can, for example, advantageously be selected from the group of synthetic, semi-synthetic and natural oils, for example olive oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil and the like.
• any mixtures of such oil and wax components can also be used advantageously for the purposes of the present invention. It may also be advantageous to use waxes, for example cetyl palmitate, as the sole lipid component of the oil phase.
• the oil phase is advantageously selected from the group consisting of 2-ethylhexyl isostearate, octyldecanol, isotridecyl isononanoate, isoeicosane, 2-ethylhexyl cocoate, C 2 .i 5 alkyl benzoate, caprylic capric acid triglyceride, dicaprylyl ether.
• C 12 Mixtures of C 12 are particularly advantageous. 15 alkyl benzoate and 2-ethylhexyl isostearate, mixtures of C ⁇ 2 . 15 alkyl benzoate and isotridecyl isononanoate and mixtures of C ⁇ 2 . 15 alkyl benzoate, 2-ethylhexyl isostearate and isotridecyl isononanoate.
• hydrocarbons paraffin oil, squalane and squalene
• hydrogenated polyisobutene can advantageously be used for the purposes of the present invention.
• the oil phase can advantageously also contain cyclic or linear silicone oils or consist entirely of such oils, although it is preferred to use an additional content of other oil phase components in addition to the silicone oil or the silicone oils.
• Cyclomethicone (octamethylcyclotetrasiloxane) is advantageously used as the silicone oil to be used according to the invention.
• other silicone oils can also be used advantageously for the purposes of the present invention, for example hexamethylcyclotrisiloxane, polydimethylsiloxane, poly (methylphenylsiloxane).
• aqueous phase of the preparations according to the invention optionally advantageously contains
• Alcohols, diols or polyols with a low C number, and their ethers preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products, furthermore low C-number alcohols, e.g.
• thickening agents which one or which can advantageously be selected from the group consisting of silicon dioxide, aluminum silicates, polysaccharides or their derivatives, e.g. Hyaluronic acid, xanthan gum, hydroxypropylmethyl cellulose, particularly advantageously from the group of polyacrylates, preferably a polyacrylate from the group of so-called carbopoles, for
• active ingredients can be selected very advantageously from the group of antioxidants. It is advantageous to use antioxidants as the only class of active ingredient, for example when cosmetic or dermatological application is in the foreground, such as combating the oxidative stress on the skin. However, it is also advantageous to provide the preparations according to the invention with one or more antioxidants if the preparations are to serve another purpose, e.g. as deodorants or sunscreens.
• Amino acids eg histidine, tyrosine, tryptophan
• imidazoles eg urocanic acid
• peptides such as D, L-carnosine, D-carnosine, L-carnosin and their derivatives (eg anserine), carotenoids, carotenes (eg ⁇ -carotene, ⁇ -carotene, lycopene) and their derivatives
• lipoic acid and their derivatives eg dihydroliponic acid
• aurothioglucose propylthiouracil and other thiols
• glutathione cysteine, cystine, cystamine and their glycosyl- , N-acetyl, methyl, ethyl, Propyl, amyl, butyl and lauryl, palmitoyl, oleyl, ⁇ -linoleyl, cholesteryl and g
• buthionine sulfoximines in very low tolerable dosages (e.g. pmol to ⁇ mol / kg), also (metal) - chelators (e.g. ⁇ -hydroxy fatty acids, ⁇ -Hydroxypalmitic acid, phytic acid, lactoferrin), ⁇ -hydroxy acids (e.g.
• citric acid citric acid, lactic acid, malic acid
• humic acid bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and their derivatives
• unsaturated fatty acids and their derivatives e.g. ⁇ -linolenic acid, linoleic acid, linoleic acid Oleic acid
• folic acid and its derivatives ubiquinone and ubiquinol their derivatives
• vitamin C and derivatives e.g. ascorbyl palmitates, Mg - ascorbyl phosphates, ascorbylacetates
• Tocopherols and derivatives e.g.
• vitamin E - acetate vitamin E - acetate
• vitamin A and derivatives vitamin A - palmitate
• coniferyl benzoate of benzoic resin ruinic acid and its derivatives, ferulic acid and its derivatives, butylated hydroxytoluene, butylated hydroxyanisole, nordihydroguajakh resinic acid, nordihydroguajroenon acid, trihydric acid Uric acid and its derivatives, zinc and its derivatives (e.g. ZnO, ZnSO 4 ) selenium and its derivatives (e.g. selenium methionine), stilbenes and their derivatives (e.g. stilbene oxide, trans-stilbene oxide) and the derivatives suitable according to the invention (salts, esters, ethers, sugar) , Nucleotides, nucleosides, peptides and lipids) of these active ingredients.
• zinc and its derivatives e.g. ZnO, ZnSO 4
• Oil-soluble antioxidants can be used particularly advantageously for the purposes of the present invention.
• the amount of the antioxidants (one or more compounds) in the preparations is preferably 0.001 to 30% by weight, particularly preferably 0.05 to 20% by weight, in particular 1 to 10% by weight, based on the total weight of the preparation .
• vitamin E and / or its derivatives represent the antioxidant (s)
• vitamin A or vitamin A derivatives or carotenes or their derivatives represent the antioxidant or antioxidants, it is advantageous to have their respective concentrations in the range from 0.001-10% by weight, based on the total weight of the formulation, to choose.
• vitamin Bi very cheap the vitamin Bi, the vitamin B 12, the vitamin D L but also salicylic acid, sodium salicylate, enzymes, DNA, bisabolol, unsaturated fatty acids, especially the essential fatty acids (often called vitamin F), especially the ⁇ - Linolenic acid, oleic acid, eicosapentaenoic acid, docosahexaenoic acid and its derivatives, chloramphenicol, caffeine, prostaglandins, thymol, camphor, extracts or other products of plant and animal origin, e.g. evening primrose oil, borage oil or currant seed oil, fish oils, cod liver oil as well as ceramides and similar compounds .
• vitamin F especially the ⁇ - Linolenic acid, oleic acid, eicosapentaenoic acid, docosahexaenoic acid and its derivatives, chloramphenicol, caffeine, prostaglandins, thymol, camphor, extracts or other products
• hydrophilic active substances are also favored according to the invention
• a further advantage of the preparations according to the invention is that even oil-soluble or iipophilic active substances with particularly great effectiveness are made bioavailable.
• the lipid (s) (again advantageous: phospholipids, glycerol esters, ethers) is or are at room temperature (if desired with the ingredients to be encapsulated) in a solvent, in particular a polar solvent (for example a polyol such as glycerol, erythritol, dipropylene glycol, propylene glycol , Sorbitol or ethanol).
• a polar solvent for example a polyol such as glycerol, erythritol, dipropylene glycol, propylene glycol , Sorbitol or ethanol.
• a surfactant (dissolved in water) is added until the liquid crystal appears and the mixture is diluted with water and other water-soluble additives to form liposomes according to the invention.
• the lipid (s) (again advantageous: phospholipids, glycerol esters, ether) is or will be in the heat (25-85 ° C) (if desired with the ingredients to be encapsulated) in a solvent, in particular a polar solvent (for example a polyol such as Glycerin, erythritol, dipropylene glycol, propylene glycol, sorbitol or also ethanol) dissolved.
• a surfactant (dissolved in water) is added until the liquid crystal appears and the mixture is diluted with water and other water-soluble additives to form liposomes according to the invention.
• lipid (s) (again advantageous: phospholipids, glycerol esters, ethers) is or are heated (25-85 ° C) with a surfactant and, if desired, with ingredients to be encapsulated in a solvent, in particular a polar solvent (e.g. a Polyol such as glycerin, erythritol, dipropylene glycol, propylene glycol, sorbitol or also ethanol) dissolved. Water is added until the liquid crystal appears and the mixture is diluted with water and other water-soluble additives to form liposomes according to the invention.
• a polar solvent e.g. a Polyol such as glycerin, erythritol, dipropylene glycol, propylene glycol, sorbitol or also ethanol
• the lipid (s) (again advantageous: phospholipids, glycerol esters, ethers) is or are at room temperature with a surfactant, one or more oil components and, if desired, with ingredients to be encapsulated in a solvent, in particular a polar solvent (for example a polyol such as glycerol , Erythritol, dipropylene glycol, propylene glycol, sorbitol or ethanol). Water is added until the liquid crystal appears and the mixture is diluted with water and other water-soluble additives to form liposomes according to the invention.
• a surfactant for example a polyol such as glycerol , Erythritol, dipropylene glycol, propylene glycol, sorbitol or ethanol.
• Water is added until the liquid crystal appears and the mixture is diluted with water and other water-soluble additives to form liposomes according to the invention.
• the lipid (s) (again advantageous: phospholipids, glycerol esters, ethers) is or will be heated (25-85 ° C) with a surfactant, one or more oil components and, if desired, with ingredients to be encapsulated in a solvent, especially one polar solvent (for example a polyol such as glycerol, erythritol, dipropylene glycol, propylene glycol, sorbitol or ethanol). Water is added until the liquid crystal appears and the mixture is diluted with water and other water-soluble additives to form liposomes according to the invention.
• a surfactant for example a polyol such as glycerol, erythritol, dipropylene glycol, propylene glycol, sorbitol or ethanol.
• 188 mg lecithin (Phopholipon 90) and 49 mg polyglycerol dipalmitostearate (Polydermanol GE-14-DA) are dissolved in 1670 mg propanediol. At 80 ° C 1500 mg of water are added. A lamellar liquid-crystalline phase is formed, which is retained even at room temperature. Dilution with water leads to a vesicle suspension (156 nm radius).

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