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WO1996037192A1 - Compositions pharmaceutiques et cosmetiques contenant des sphingolipides et des glycolipides - Google Patents

Compositions pharmaceutiques et cosmetiques contenant des sphingolipides et des glycolipides Download PDF

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Publication number
WO1996037192A1
WO1996037192A1 PCT/IB1996/000493 IB9600493W WO9637192A1 WO 1996037192 A1 WO1996037192 A1 WO 1996037192A1 IB 9600493 W IB9600493 W IB 9600493W WO 9637192 A1 WO9637192 A1 WO 9637192A1
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Prior art keywords
water
pharmaceutical
group
cosmetic
soluble
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PCT/IB1996/000493
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English (en)
Inventor
Hans Georg Weder
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Vesifact Ag
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K8/11—Encapsulated compositions
    • 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
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4993—Derivatives containing from 2 to 10 oxyalkylene groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations

Definitions

  • compositions containing Sphingo- and Glycolipids containing Sphingo- and Glycolipids
  • the invention relates to pharmaceutical or cosmetic compositions for the topical, enteral or parenteral administration of sparingly soluble sphingolipids and glycolipids, a process for the preparation of these compositions and to the formulation base for the preparation of pharma ⁇ ceutical or cosmetic compositions.
  • Sphingolipids are lipid molecules of complex structure which are characterized in their skeletal structure by sphingosine or bases derived therefrom. Sphingolipids contain three characteristic structural embodiments: sphingosine or base derivatives thereof, a long chain fatty acid and a hydrophilic head group, which in some sphingolipids may assume considerable bulkiness and structural complexity, e.g. gangliosides. Sphingosine is a specific representative of a group consisting of 30 different amino alcohols which are present in sphingolipids of distinct biologi ⁇ cal species.
  • sphingosine 4-sphingenine
  • dihydrosphinganine sphinganine
  • phytosphingosine 4-hydroxysphinganine
  • the sphingosine base or the derivative thereof is bound at the amino group by an amide bond to a long chain, saturated or unsaturated fatty acid containing about 16-30 carbon atoms.
  • the corresponding compounds containing two non-polar long fatty acid chains are classified as ceramides. Ceramides of natural origin are charaterized by their optical activity and specific stereochemical confi ⁇ guration: IS, 2S, 3R for phytosphingosine and IS, 2S for sphingosine.
  • the hydroxy group in the 1 -position of the sphingosine base is substituted by three different hydrophilic head groups, the corresponding compounds can be classified in the following groups:
  • Sphingomyelins (the polar end is phosphatidylethanolamine or phosphatidylcholine); neutral glycosphingolipids (glycosyl ceramides, galactosyl ceramides; defined by the saccharide group which is attached to the ceramide group by beta-glycoside bonds); gangliosides, also defined as acidic gangliosides, which contain in their polar ends oligosaccharides (D-glucose, D- galactose, as well as N-acetyl-D-galactosamine groups) and which contain one or more sialic acid groups (N-acetylneuraminic acid).
  • Gangliosides are an important embodiment of the lipid structure present in human brain.
  • Ceramides and glycolipids have antiinflammatory efficacy and influence the differentiation and proliferation of epidermal tissue. Ceramides of different structure are present in stratum corneum of human epidermis, e.g. ceramide 1, 2, 3, 4, 5, 6 I and 6 II (D.C. Swarzendritger et al, Molecular Models, J. Invest. Derm. 92, 25 J (1989) ) in a percentage of more than 40%. Also present are cholesterol, cholesterol sulfate and free fatty acids. Ceramides function prima ⁇ rily as an epidermal barrier of the skin, which prevents transcutaneous loss of water and protects against environmental influences.
  • the stratum corneum layer consists of various keratinocytes (corneocytes) and other lipids of different structure. The latter ones are arranged intracellularly in multi-bilayer structures.
  • the "bricks and mortar" model describing the barrier to skin permeability defines the stratum corn ⁇ eum layer as a biphasic structure, wherein the continuous lipid phase consists of intracellular lamellae embedding corneocytes.
  • the sphingolipids and glycolipids mentioned above are in considerable amounts part of this continous lipid phase.
  • Liposomes as carrier systems have other drawbacks in view of their low loading capacity for sphingolipids and glycolipids.
  • the present invention intends to make available for therapeutic and cosmetic uses the im ⁇ portant group of sphingolipids and glycolipids and to enable the preparation of suitable topical and parenteral dosage forms.
  • the sparingly soluble therapeutic agent is encapsulated in lipid particles of a particle size of less than 1 ⁇ m.
  • the "loaded" lipid particles then form with the aqueous carrier liquid an aqueous phase of colloidally dispersed or, preferably, finely dispersed character, which differs from the true homogenous distribution of solutes at molecularly dispersed level but is, nevertheless, sufficiently homogenous for the preparation of intravenous and oral dosage forms.
  • Numerous publications suggest the incorporation of therapeutic agents of low solubility in micells, mixed micells, reversed micells, unilamellar or multilamellar liposomes, nanocapsules or nanoparticles.
  • sphingolipids and glycolipids are capable of forming finely dispersed systems having the homogeneity and stability necessary for topical and parenteral dosage forms. This is achieved by dispersing sparingly soluble sphingolipids and glycolipids in combination with phospholipids and a partial fatty acid ester of polyoxyethylene sorbitan.
  • the present invention relates to pharmaceutical or cosmetic compositions comprising: a) a sphingolipid or glycolipid of synthetic or natural origin of the formula:
  • OH H H R ⁇ is hydroxy, the phosphatidylcholine, the phosphatidylethanolamine group or hydroxy bound as ⁇ -glycoside to a mono- or oligosaccharide group or is an oligosaccharide group substituted by N-acetylneuraminic acid groups;
  • R 2 is Cie-so-acyl, Ci6- 3 o- ⁇ -hydroxyacyl or d ⁇ o-o-hydroxyacyl, which is optionally esterified by a linoleic acid group; b) a phospholipid of the formula
  • Ri is C ⁇ o- 2 oacyl
  • R 2 is hydrogen or C ⁇ o- 2 oacyl
  • R 3 is hydrogen, 2-trimethylamino- 1 -ethyl
  • Ri, R 2 und R 3 represent C 8 . 2 o-acyl; and g) water-soluble or lipid-soluble additives suitable for the intended pharmaceutical or cosmetic administration.
  • the pharmaceutical or cosmetic compositions defined above are distinguished by useful phase properties of the solubilised therapeutic agent. For example, where opalescence and trans ⁇ parency occur in incident light, only an extremely slight milky turbidity reveals that the dispersion formed still has physical differences vis-a-vis the ideal state of a true molecular solution. Electron microscope images show that a population of more than 95 % of the spa ⁇ ringly soluble active ingredient is present in the form of a colloid disperse system of particles having a particle size of approximately 5-20 nm (nanodispersion). However, these differences vis-a-vis a true solution are acceptable in view of some remarkable homogeneity properties of the dispersion. These properties can be made apparent in a high storage stability; for example there is no separation after storage for several months at 2-8°C (by extrapolation the expected stability is more than two years).
  • sphingolipid or glycolipid of synthetic origin defines lipids of the formula I, wherein segments of their molecular structure have been modified chemically, e.g. by hydration, transesterification, ester cleavage, esterification, substitution and other conventional process steps.
  • synthetic lipid also defines lipids of the formula I which are obtainable by total synthesis.
  • sphingolipid or glycolipid of natural origin defines lipids of the formula I, which have only been submitted to purification processes, e.g. chromatographic separation methods, but have not been submitted to chemical modifications of their molecular structure.
  • sphingolipid or glycolipid comprises lipids, which are defined by terms such as ceramides, sphingomyelines, cerebrosides, or gangliosides. Ceramides and sphingomyelines are classified together under the term sphingolipids, whereas cerebrosides and gangliosides are classified together under the term glycolipids.
  • ceramide of the formula I Ri is hydroxy.
  • Known ceramides are classified as ceramide 1, 2, 3, 4, 5, 6 I and 6 II.
  • the group of ceramides also comprises so-called synthetic questamides, e.g. questamide H, or so-called synthetic pseudo-ceramides, e.g. pseudo-ceramide SLE, and also lipids named ceramax.
  • ceramides which primarily occur in human skin are defined according to INCI rules (formerly CTFA) as ceramides 3.
  • 4-hydroxysphinganine phytosphingosin
  • 4-sphingenine sphingosine
  • a sphingomyeline of the formula I Ri is the the phosphatidylcholine or the phosphatidyl ⁇ ethanolamine group.
  • R 2 representing C i6-, C ⁇ 8 - and C 2 -acyl is preferably n-hexadecanoyl (palmitoyl), n-octa- decanoyl (stearoyl), n-tetracosanoyl (lignocerinoyl), 9-cis-octadecenoyl (oleoyl) or 9-cis- or 12-cis-octadecadienoyl.
  • R 2 representing d.6-3o-hydroxyacyl is preferably ⁇ -hydroxy-octadecanoyl or ⁇ -hydroxy- tetracosanoyl or a mixture thereof.
  • acid amides in this position formed with C 2 . ⁇ o- ⁇ -hydroxycarboxylic acids, e.g. hydroxyacetic acid (glycolic acid), 2- hydroxypropionic acid (lactic acid), 2-hydroxysuccinic acid (malic acid), ⁇ -hydroxy- phenylacetic acid (mandelic acid) or mixtures thereof.
  • R 2 representing d6- 3 o- ⁇ -hydroxyacyl, preferably in the sphigosine base phytosphigosine, is, e.g. 23-octadecanoyloxytricosanoyl or 23-octadecanoyloxy-heptacosanoyl.
  • a glycolipid (I) of the cerebroside type Ri represents hydroxy bound as ⁇ -glycoside to a mono- or oligosaccharide group which is optionally substituted by N-acetyl.
  • Representative monosaccharide groups are D-glucosyl and D-galactosyl, as well as N-acetyl- D-glucosamine and N-acetylgalactosamine.
  • a glycolipid (I) of the ganglioside-type Ri represents hydroxy, which is also bound as ⁇ - glycoside to an oligosaccharide group containing at least three hexosyl groups, which may be substituted by at least one N-Acetylneuraminic acid groups. These lipids are classified as gangliosides.
  • the compounds defined by the formula I are known and have been described in numerous textbooks and other references from biochemistry.
  • Ri and R 2 defined as C ⁇ o- 2 oacyl are preferably straight-chain C ⁇ o- 2 oalkanoyl having an even number of carbon atoms and straight-chain C ⁇ 0 . 2 oalkenoyl having from one to three double bonds and an even number of carbon atoms.
  • Straight-chain C ⁇ o-2oalkanoyl Ri and R 2 having an even number of carbon atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
  • Straight-chain C ⁇ o- 2 oalkenoyl Ri and R 2 having from one to three double bonds and an even number of carbon atoms are, for example, 6-cis-, 6-trans-, 9-cis- or 9-trans-dodecenoyl, -tetra- decenoyl, -hexadecenoyl, -octadecenoyl or -icosenoyl, especially 9-cis-octadecenoyl (oleoyl), and also 9,12-cis-octadecadienoyl or 9,12,15-cis-octadecatrienoyl.
  • a phospholipid (II), wherein R 3 is 2-trimethylamino-l -ethyl, is referred to by the trivial name lecithin and a phospholipid (II), wherein R 3 is 2-amino-l -ethyl, by the trivial name cephalin.
  • Suitable are, for example, naturally occurring cephalin or lecithin, for example cephalin or lecithin from soybeans or chicken eggs having different or identical acyl groups Ri and R 2 , or mixtures thereof.
  • the phospholipid (II) may also be of synthetic origin.
  • synthetic phospholipid is used to define phospholipids having a uniform composition in respect of Ri and R 2 .
  • Such synthetic phospholipids are preferably the above-defined lecithins and cephalins, wherein the acyl groups Ri and R 2 have a defined structure and are derived from a defined fatty acid having a degree of purity greater than approximately 95%.
  • Ri and R 2 may be identical or different and unsaturated or saturated.
  • Ri is saturated, for example n-hexadecanoyl
  • Naturally occurring defines a phospholipid (II) that does not have a uniform composition in respect of Ri and R 2 .
  • Such natural phospholipids are likewise lecithins and cephalins, wherein the acyl groups Ri and R 2 are structurally undefinable and are derived from naturally occurring fatty acid mixtures.
  • substantially pure defines a phospholipid (II) having a degree of purity of more than 90 % (by weight), preferably more than 95 %, which can be demonstrated by means of suitable determination methods, for example by paper chromatography, by thin-layer chromatography, by HPLC or by means of enzymatic colour testing.
  • R 3 defined as C ⁇ - alkyl is, for example, methyl or ethyl. Methyl is preferred.
  • R 3 defined as Ci-salkyl substituted by carboxy, d-salkyl substituted by hydroxy or d-salkyl substituted by carboxy or hydroxy is, for example, 2-hydroxyethyl, 2,3-dihydroxy-n-propyl, carboxymethyl, 1- or 2-carboxyethyl, dicarboxymethyl, 2-carboxy-2-hydroxyethyl or 3-carboxy-2,3-dihydroxy-n-propyl.
  • R 3 defined as C 2 -salkyl substituted by carboxy and amino is, for example, 3-amino-3-carboxy-n- propyl or 2-amino-2-carboxy-n-propyl, preferably 2-amino-2-carboxyethyl.
  • a phospholipid (I) having those groups may be in salt form, for example in sodium or potassium salt form.
  • Phospholipids (II) wherein R 3 is the inositol or the glyceryl group are known by the names phosphatidylinositol and phosphatidylglycerol.
  • acyl radicals in the phospholipids (II) and in the other components are also customarily known by the names given in brackets:
  • a salt of the phospholipid (II) is pharmaceutically acceptable. Salts are defined by the existence of salt-forming groups in the substituent R 3 and by the free hydroxy group at the phosphorus atom. The formation of internal salts is also possible. Alkali metal salts, especially the sodium salt, are preferred.
  • purified lecithin from soybeans for example of the LIPOID S 100 or S 100-35 types (partially hydrated lecithin), is used.
  • the above-mentioned partial fatty acid ester of polyoxyethylene sorbitan consists preferably of a substantially pure ester of sorbitan or a mixture of different esters of sorbitan in which the structure of the fatty acid groups and the length of the polyoxyethylene chains may vary.
  • the hydrophilic sorbitan is preferably etherified by three hydrophilic polyoxyethylene chains and esterified by a hydrophobic fatty acid group.
  • the sorbitan may, however, alternatively be etherified by only one or two polyoxyethylene chains and correspondingly esterified by two or three fatty acid groups.
  • the basic sorbitan structure is altogether substituted by a minimum of two and a maximum of three hydrophilic groups, the term "hydrophilic group" embracing the polyoxyethylene chains, whereas the fatty acid groups are hydrophobic.
  • the polyoxyethylene chain is linear and has preferably from 4 to 10, especially from 4 to 8, ethylene oxide units.
  • the ester groups on the basic sorbitan structure are derived from a satu ⁇ rated or unsaturated, straight-chain carboxylic acid having an even number of from 8 to 20 carbon atoms.
  • the ester group derived from that carboxylic acid is preferably straight-chained having 12, 14, 16 or 18 carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n- hexadecanoyl or n-octadecanoyl.
  • the ester group derived from an unsaturated carboxylic acid having an even number of from 8 to 20 carbon atoms is preferably straight-chained having 12, 14, 16 or 18 carbon atoms, for example oleoyl.
  • the mentioned esters of sorbitan are in conformity with the data given in the British Pharmacopoeia (specialised monograph) or Ph.Helv. VII.
  • Suitable partial fatty acid esters of polyoxyethylene sorbitan are commercially obtainable under the trademark Tween ® of ICI Corp. and known by the chemical names polyoxyethylene- (20 or 4)sorbitan monolaurate (TWEEN 20 and 21), polyoxyethylene(20)sorbitan mono- palmitate or monostearate (TWEEN 40 and 60), ⁇ olyoxyethylene(4 or 20)sorbitan mono- stearate or tristearate (TWEEN 61 and 65), polyoxyethylene(20 or 5)sorbitan monooleate (TWEEN 80 or 81) and polyoxyethylene(20)sorbitan trioleate (TWEEN 85).
  • polyoxyethylene(20)sorbitan monooleate (TWEEN 80) is used as component c).
  • the carrier liquid water is optionally admixed with a C 2 -C -alkanol, especially ethanol, and is present in the composition in the degree of purity necessary for the intended pharmaceutical or cosmetic administration.
  • a C 2 -C -alkanol especially ethanol
  • water has the degree of purity prescribed for injection formulations in accordance with the regulations of the national pharmacopoeias, such as the U.S. Pharmacopoeia (USP) or the Deutsches Arzneibuch (DAB) and is germ- and pyrogenfree. Water is germfree when topical dosage forms or cosmetic uses are intended.
  • the carrier liquid ethanol is optionally admixed as C 2 -C -alkanol when parenteral dosage forms are intended.
  • ethanol has the degree of purity (at least 96 %) prescribed for injection formulations.
  • the proportion of ethanol for injection formulations may vary within wide limits from about 1 % to about 10 %.
  • ethanol, isopropanol or mixtures thereof may be optionally admixed as C 2 -C 4 -alkanol.
  • the proportion of C 2 -C 4 -alkanol for topical formulations or cosmetic uses may vary within wide limits from about 0,1% to about 10 %, preferably 0.1 % to 2.0 %.
  • a therapeutic agent to be administered is any therapeutic agent or a combination of different therapeutic agents which is suitable for intended mode of administration, e.g. topical, parenteral, e.g. intramuscular in the form of injection dispersions, or oral, e.g. in the form of capsule fillings.
  • a preferred therapeutic agent is sparingly soluble in water and has a solubility in water of less than 500 mg/1000 ml, especially of less than 100 mg/1000 ml.
  • corticoids for dermal administration e.g. halogenated corticoids, e.g. amcinonide, dexamethasone, triamcinolone-16 ⁇ ,27 ⁇ -acetonide, betamethasone (17-valerate), flumetasone (21-pivalate), flupredniden-21 -acetate, clobetasol-17-propionate, mometasone-17- (2-furoate), diflorasone-17,21-diacetate, fluocinolone acetonide, clocortolone-21-pivalate or 21-hexanoate, diflucortolone-21-valerate, fludroxycortide, halometasone, fluocinonide, or fluocortinbutyl; or non-halogenated corticoids, e.g. prednisolone, methyl prednisolone ace- ponate, or hydrocortisone or derivatives
  • corticoids may also be combined with antimycotic, sulfonamides or estrogen derivatives.
  • Suitable for dermal formulations are also adstringents, anti-acne agents, antipsoriasis agents, or antipruriginosis agents.
  • antibiotics e.g. tetracyclin, erythromycin, fusidinic acid, framycetine sulfate, neomycin, meclocyclin, gentamycin, leucomycin, streptomycin, ganefromycin, rifamexil, ramoplanin, spiramycin, clindamycin, bacitracin, oxytetracyclin, sulfonamides, and other antibacterial and antiviral agents, e.g.
  • dermal antibiotics e.g. tetracyclin, erythromycin, fusidinic acid, framycetine sulfate, neomycin, meclocyclin, gentamycin, leucomycin, streptomycin, ganefromycin, rifamexil, ramoplanin, spiramycin, clindamycin, bacitracin, oxytetracyclin, sulfonamides, and other antibacterial and
  • antibiotics and antimycotic agents may be combined with other corticosteroids, antibiotics or antimycotic agents.
  • Particularly suitable for topical administration are also lipophilic vitamins, typically vitamin A (retinol, free acid or derivatives thereof), B (Bi: thiamine, B 2 : riboflavine, Be', pyridoxin, panthenol, pantothenic acid , vitamin B !2 and combinations thereof), vitamin C, D, E (tocopherol), biotin or vitamin K; also retinoids and carotinoids.
  • Suitable for topical, parenteral, eg. intramuscular, or oral administration, e.g. as capsule fillings are sparingly soluble therapeutic agents, e.g. immunosuppressants having a macrolide structure, typically cyclosporin A, cyclosporin G, rapamycin, tacrolimus, deoxyspergualin, mycophenolate-mofetil, gusperimus, non-steroidal antiphlogistic agents and salts thereof, typically acetylsalicylic acid, ibuprofen or S(+)-ibuprofen, indomethacin, diclofenac (Na and K- salt), piroxicam, meloxicam, tenoxicam, naproxen, ketoprofen, flurbiprofen, fenoprofen, felbinac, sulindac, etodolac, oxyphenbutazone, phenylbutazone, nabumetone; dihydro
  • the above-mentioned therapeutic agent may be present in the pharmaceutical composition in the form of a pharmaceutically acceptable salt, typically as hydrobromide, hydrochloride, mesylate, acetate, succinate, lactate, tartrate, fumarate, sulfate, maleate, and the like.
  • a pharmaceutically acceptable salt typically as hydrobromide, hydrochloride, mesylate, acetate, succinate, lactate, tartrate, fumarate, sulfate, maleate, and the like.
  • the concentration of the therapeutic agent or combination thereof is determined by the dosage to be administered and can be in the range from 1.0 to 30.0 % by weight, preferably from 5.0 to 20.0 % by weight, more particularly from 5.0 to 12.0 % by weight, based on the weight of the carrier composition.
  • Ri, 2 and R 3 are straight-chain C 8 - d -acyl having an even number of carbon atoms, especially n-octanoyl, n-dodecanoyl, n-tetra- decanoyl, n-hexadecanoyl, n-octadecanoyl, 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexa- decenoyl, 9-cis-octadecenoyl or 9-cis-icosenoyl.
  • Ri, R 2 and R 3 may be identical or different, whereas the individual groups Ri, R 2 and R 3 themselves are being defined by their uniform structure, which is characteristic of synthetic or semi-synthetic triglycerides. Ri, R 2 and R 3 may, however, alternatively consist of various acyl groups of different structures, which is characteristic of triglycerides of natural origin.
  • a triglyceride of formula III is a semi-synthetic or synthetic, substantially pure triglyceride or a pharmaceutically acceptable triglyceride of natural origin.
  • a triglyceride of natural origin is preferred, for example groundnut, sesame, sunflower, olive, maize kernel, soybean, castor, cottonseed, rape, thistle, grapeseed, fish or coconut oil.
  • a triglyceride having different acyl groups of different structure defined by the term "neutral oil” is used, for example a triglyceride of fractionated coconut C 8 -C ⁇ o fatty acids of the Miglyol ® type, e.g. MIGLYOL 812/
  • the optional component cholesterol is preferably purified cholesterol from lanolin (5-cholest- en-3 ⁇ -ol) and has a degree of purity of 96-97% in accordance with the regulations of The U.S. Pharmacopoeia National Formulary (USP. NF).
  • Typical additives may be present in the composition which are characteristic for the intended pharmaceutical dosage form or cosmetic uses. They have the degree of purity in accordance with the regulations of the national pharmacopoeias mentioned above. Depending on the intended use, additives may be water soluble or lipid soluble. Suitable additives are useful for the preparation of o/w, w/o, w/o/w emulsions, gels, ointments, creams, oils, lotions, foams, or sprays. The addition of preserving agents, antioxidants, stabilizers or softening agents is recommended.
  • a preferred additive in topical pharmaceutical and cosmetic compositions is cholesterol or a corresponding salt thereof, e.g. cholesterol sulfate in the degree of purity necessary for the intended cosmetic or pharmaceutical administration.
  • Suitable additives for pharmaceutical and particularly cosmetic compositions are also free fatty acids derived by conventional ester cleavage from the above-mentioned triglycerides (III), surfactants, e.g. anionic, cationic, or amphoteric, gel-forming agents, emulsifiers, e.g. ethoxylated fatty alcohols, hydrogenated ethoxylated castor oils, partial esters of fatty acids and modified fatty acids with glycerol, polycerol, and sorbitol, orthophosphoric acid esters, or silicone surfactants, lipophilic constituents, e.g.
  • surfactants e.g. anionic, cationic, or amphoteric
  • gel-forming agents emulsifiers, e.g. ethoxylated fatty alcohols, hydrogenated ethoxylated castor oils, partial esters of fatty acids and modified fatty acids with glycerol, polycerol, and sorbitol, ortho
  • solid, semisolid, and liquid hydrocarbons solid, semisolid, and liquid hydrocarbons, natural oils and waxes, silicone oil, guerbet alcohols, fatty acid esters, isostearic acid derivatives, co-emulsifiers, thickeners, gelling agents, foam stabilizers, fat-restoring substances, pearl-luster and turbidity agents, preservatives, dyes, colored pigments, perfume oils, and preferably light filters (sunscreens).
  • sunscreens are active agents such as UV-B filtering substances, e.g. 4-amino- benzoic acid, homosalate, oxybenzon, 3-imidazolyl-4-yl-acrylic acid and derivatives thereof, 2- phenylbenzimidazol-5-sulfonic acid and salts thereof; 2,3-dihydroxypropyl-4-amino-benzoate, 2-ethylhexyl-4-dimethyl-aminobenzoate, ethyl 4-[bis(2-hydroxypropyl)amino]benzoate, 2- ethylhexyl-4-methoxy-cinnamate, 2-ethylhexylsalicylate, ethylpoly(oxyethylene)-4- ⁇ bis-[(2- hydroxyethyl)-polyoxyethylene]amino ⁇ benzoate, 3-(4-imidazolyl)acrylic acid, isopentyl 4- methoxycinnamate, 4-isopropyl 4-
  • sunscreens are listed in P ⁇ egekosmetik: Ein Leitfaden, W.Ra ⁇ b, U.Kindl; Govi-Verlage, D-Frankfiirt 1991 and in Ullmann 's Encyclopedia of Industrial Chemistry, VCH Publishers, Fifth Complete Revised Edition, Volume A 24, Entry Skin Cosmetics.
  • a pharmaceutical or cosmetic composition comprising: a) a natural or synthetic ceramide or a derivative or mixtures thereof; b) purified lecithin from soy beans; c) at least one partial fatty acid ester of polyoxyethylene sorbitan; d) ethanol and water as carrier liquids; f) a triglyceride selected from the group of natural triglycerides; and as optional components: e) a therapeutic agent to be administered; g) cholesterol or a corresponding salt thereof; and other water-soluble or lipid-soluble additives suitable for the intended pharmaceutical or cosmetic administration.
  • a pharmaceutical or cosmetic composition comprising: a) a synthetic ceramide or a derivative thereof; b) purified lecithin from soy beans; c) polyoxyethylene(20)sorbitan monooleate; d) ethanol and water as carrier liquids; f) a triglyceride selected from the group of natural triglycerides; and as optional components: e) a therapeutic agent to be administered; g) cholesterol or a corresponding salt thereof; and other water-soluble or lipid-soluble additives suitable for the intended pharmaceutical or cosmetic administration.
  • a pharmaceutical or cosmetic composition comprising: a) N-(9-cis-Octadecenoyl)-phytosphingosine (Ceramide 3B); b) purified lecithin from soy beans; c) polyoxyethylene(20)sorbitan monooleate; d) ethanol and water as carrier liquids; f) a triglyceride selected from the group of natural triglycerides; and as optional components: e) a therapeutic agent to be administered; g) cholesterol or a corresponding salt thereof; and other water-soluble or lipid-soluble additives suitable for the intended pharmaceutical or cosmetic administration.
  • the invention relates also to the process known per se for the preparation of the pharma ⁇ ceutical or cosmetic composition, which process comprises preparing an aqueous dispersion by homogeneously mixing components a), b), c) and d) and the optional components e), f) and g) and subjecting the dispersion obtainable to the following subsequent operations: ⁇ ) addition of a further amount of water as carrier liquid and optionally further water-soluble excipients that are suitable for the intended pharmaceutical dosage forms or cosmetic compositions; filtration and optionally dialysis of the clear dispersion; or ⁇ ) filtration and optionally dialysis and subsequent conversion of the dispersion obtainable into a dry preparation, optionally with the addition of water-soluble excipients, and reconstitution of the dry preparation to form an injectable dispersion; or ⁇ ) further processing the dispersion obtained containing nanoparticles of the sparingly soluble sphingolipids and glycolipids (nanodispersion) to the intended pharmaceutical dosage forms or cosmetic compositions.
  • a pharmaceutical composition suitable for topical or dermal administration containing nanorparticles of the sparingly soluble sphingolipids and glycolipids is prepared.
  • a cosmetic composition containing ceramides and optionally sunscreens is prepared.
  • a formulation base is prepared as follows: To the phospholipid (II), component b, the carrier liquid ethanol, component d) then is added. To this dispersion, cholesterol, component g), the sparingly soluble sphingolipids and glyco ⁇ lipids (I), component a), a partial fatty acid ester of polyoxyethylene sorbitan, component c). a triglycerid (III), component f) and further lipophilic additives, component g), are added, which are suitable for the intended pharmaceutical dosage forms or cosmetic compositions.
  • the clear ethanolic dispersion containing the sparingly soluble sphingolipids and glycolipids (I), which may simply be defined as preparticular ceramide dispersion, is stable under normal storage conditions (room temperature, light protection) up to one year and more.
  • the dispersion containing nanoparticles of the sparingly soluble sphingolipids and glycolipids (I) is prepared by adding the formulation base consisting of the preparticular ceramide dispersion to the carrier liquid water. Further water-soluble additives, component g), are added, which are suitable for the intended pharmaceutical dosage forms or cosmetic compositions.
  • the invention also relates to the pharmaceuticla formulation base (preparticular ceramide dispersion) containing the components a), b), c), ethanol, and the optional components f) and
  • the invention also relates to an active agent free pharmaceutical formulation base containing the components a), b), c) and the carrier liquids ethanol and water, component d), and the optional components f) and g).
  • This formulation base is useful as placebo formulation or as precursor of the above-mentioned pharmaceutical composition to which a suitable active agent e) is added.
  • the invention also relates to a pharmaceutical composition, wherein the solubilisation of a sparingly soluble active ingredient is required, e.g. capsule fillings, drops, lotions, or emulsions form ointments, gels, creams etc.. Other excipients typical of such dosage forms may be added.
  • the invention also relates to a cosmetic composition containing the components a), b), c) and d), and the optional components f) and g), which is particularly suitable for the preparation of cosmetic sunscreen compositions.
  • the preparation of the formulation base and, in the alternative, of the cosmetic composition is performed in a manner analogous to the methods described above.
  • a process temperature of about 20° to room temperature is particularly preferred.
  • a process temperature of about 35- 45°C is preferred when cholesterol is added to the composition.
  • mixing can be effected by vigorous shaking using a dispersing machine, for example a Vortex mixer, or using dispersing machines of the POLYTRON type (Kinematica AG, Littau Switzerland) or dispersing machines produced by IKA (Staufen, Germany), a static mixer and conventional stirring machines having a propeller or paddle blade or using a magnetic stirrer or phase mixer.
  • stirring is carried out at moderate or high speed, for example using stirring machines produced by Polytron, for example Polytron PT 3000 or DH 30/30.
  • phase transition temperature gel-form/liquid crystalline
  • Dispersion is preferably effected at temperatures at which the phospholipid used is present in the liquid-crystalline state, that is to say above the so-called phase transition temperature.
  • the mixture obtainable can be defined as a dispersion of colloidal nanoparticles of the sparingly soluble sphingolipids and glycolipids, or, more simply, as a nanodispersion.
  • the colloidal particles present in the dispersion can be distinguished from other particles such as liquid crystals, micelles, inverse micelles or liposomes.
  • an average particle size of less than 30-50 nm is typical.
  • the necessary amount of water, which must be of the purity prescribed for injectables, can be added to the nanodispersion.
  • This nanodispersion can be directly administered after selecting the filtration method suitable for such types of dispersions, for example sterile gel filtration, for example using Sepharose ® or Sephacryl ® (Pharmacia) as carrier, or preferably sterile filtration (0.2 mm), for example with a PAL filter (Gelman), and optionally after adding further water- soluble excipients that can be used for intravenous dosage forms.
  • sterile-filtration is applicable to separate off all the relatively large particles in the dispersion having a diameter greater than about 200 nm, as well as floating and solid substances, and excess, dispersed lipids which may be present in high-molecular-weight aggregates. This yields a nanodispersion having a high proportion of hydrophilic particles of relatively uniform size.
  • the nanodispersion can be subjected to dialysis and/or ultrafiltration for the purpose of purification.
  • the subsequent purification steps described above may be carried out and the purified nanodispersion may be converted into a dry preparation, especially into a lyophilisate, which is reconstituted prior to administration by the addition of water.
  • An administrable nanodispersion is obtained again after reconstitution of the lyophilisate.
  • so-called builders such as lactose or mannitol, is customary. These excipients are added in such amounts that after reconstitution of the lyophilisate the nanodispersion to be administered has isotonic properties.
  • Measured amounts of nanodispersion are introduced, optionally in the form of a concentrate, into containers suitable for a unit dose, for example glass ampoules (vials)
  • the filled containers can be cooled, if desired, to about -40° to -50°C, especially to about -45°C, and then lyophilised at a pressure of about 0.2 to 0.6 mbar by slowly heating to a final temperature ofabout 25° to 35°C.
  • the sphingolipid- or glycolipid-containing compositions of the present invention are particularly suitable for topical application on skin and hair. Ceramides, for instance, are highly effective in maintaining, improving, restoring and protecting the water impermeabilty barrier of the skin.
  • ceramides have a high capacity for recovering diminished water- retaining properties of the skin.
  • pretreatment of the skin with the sphingolipid (ceramide) containing compositions of the invention shows a clear protecting effect against skin damage caused by external challenges. Also, on healthy skin the compsitions produce a clear moisturizing effect.
  • Example 1 Formulation for 1000 g ethanolic formulation base containing ceramide 3B in a concentration of 1.5 %.
  • Example 2 Formulation for 100 spray formulations for the dermal application a 30 ml and 45 mg Ceramide 3B.
  • the aqueous phase wherein the preparticular ceramide dispersion according to Example 1 is dispersed is prepared dissolving phenoxyethanol in water at room temperature.
  • the spray formulation is prepared from nine parts of the aqueous solution and one part of the preparticular ceramide dispersion according to Example 1. This dispersion is heated up to 45°. The aqueous solution is also heated up to 45°. The preparticular ceramide dispersion is then added to the aqueous solution. The dispersion is stirred for 30 min. at 45° with a magnetic stirrer at about 1000 rpm.
  • the nanodispersion is sterile-filtered (pore filter 0.2 ⁇ ) and introduced into containers under sterile conditions.
  • Example 3 Formulation for 100 dispensing units (nanosuspension lotion for dermal administration) a 30 ml and 60 mg Ceramide 3B.
  • Example 4 Formulation for 20 injection formulations a 5ml and 25 mg ceramide 3 B
  • LIPOID S 100-35 is dissolved in ethanol and stirred with a magnetic stirrer at about 40°. Cholesterol is then added and the mixture is again stirred at about 40°. Ceramide 3 B is given to the mixture, which is stirred for about 15 min. at about 40°. This batch is then mixed, in sequential order, with TWEEN 80 and MIGLYOL 812 and stirred for about 10 min. at 40° until the mixtures becomes clear.
  • the sodium chloride solution is heated to 40° and added under stirring to the reaction mixture.
  • the nanodispersion is then sterile-filtered (pore filter 0.2 ⁇ m) and introduced into containers under sterile conditions. The nanodispersion is stored at room temperature and protected against light.

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Abstract

L'invention concerne des compositions pharmaceutiques et cosmétiques destinées à l'administration locale, entérale et parentérale de sphingolipides et de glycolipides peu solubles. Ces compositions sont préparées par formation d'une dispersion homogène de nanoparticules.
PCT/IB1996/000493 1995-05-26 1996-05-24 Compositions pharmaceutiques et cosmetiques contenant des sphingolipides et des glycolipides WO1996037192A1 (fr)

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Cited By (22)

* Cited by examiner, † Cited by third party
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WO1997021428A1 (fr) * 1995-12-12 1997-06-19 Vesifact Ag Pulverisateur d'hydrocortisone pour administration topique
EP0852941A1 (fr) * 1996-12-13 1998-07-15 Vesifact Ag Composiotn cosmétique sous forme d'une nanodispersion
EP0868174A4 (fr) * 1995-09-12 1998-10-07
EP0956851A1 (fr) * 1998-05-11 1999-11-17 Ciba SC Holding AG Utilisation des nanotopes comme composants des produits cosmétiques
FR2779646A1 (fr) * 1998-06-15 1999-12-17 Epi France Extrait vegetal de cereales a base de lipides polaires et composition cosmetique comprenant un tel extrait vegetal
EP0956853A3 (fr) * 1998-05-11 2000-01-05 Ciba SC Holding AG Utilisation des nanodispersions dans des compositions pharmaceutiques
FR2792328A1 (fr) * 1999-04-19 2000-10-20 Lavipharm Lab Matiere huileuse comprenant des hydrocarbures paraffiniques et un compose riche en lipides d'origine vegetale, sa preparation et les compositions la contenant
FR2792327A1 (fr) * 1999-04-19 2000-10-20 Lavipharm Lab Matiere visqueuse stable, sa preparation et son utilisation dans des compositions cosmetiques
FR2792193A1 (fr) * 1999-04-19 2000-10-20 Lavipharm Lab Matiere de base pour la preparation de compositions cosmetiques et compositions cosmetiques la contenant
WO2001062222A3 (fr) * 2000-02-25 2002-04-25 Martin Albrecht Composition cosmetique
WO2002094221A1 (fr) * 2001-05-18 2002-11-28 Jupitar Pty Ltd Preparations et procedes pour emulsions et dispersions
EP1267798A4 (fr) * 2000-04-06 2004-01-28 Nicholas V Dr Perricone Traitement des lesions cutanees a l'aide de polyenylphosphatidylcholine
US6932963B2 (en) 2000-06-23 2005-08-23 Nicholas V. Perricone Treatment of skin wounds using polyenylphosphatidylcholine and alkanolamines
EP1534213A4 (fr) * 2002-03-13 2005-10-26 Collagenex Pharm Inc Systemes d'administration a base aqueuse
US6979459B1 (en) 2000-04-06 2005-12-27 Perricone Nicholas V Treatment of skin damage using polyenylphosphatidycholine
DE19952410B4 (de) * 1999-10-29 2007-03-29 Stada Arzneimittel Ag Lichtschutzzubereitungen umfassend feste Lipidnanopartikel
US7381423B2 (en) 1998-05-11 2008-06-03 Ciba Specialty Chemicals Corp. Use of nanodispersions in cosmetic end formulations
WO2008086953A1 (fr) * 2007-01-16 2008-07-24 Bayer Consumer Care Ag Solution colloïdale
EP1839644A3 (fr) * 2006-03-30 2009-09-30 Botica Comercial Farmacêutica Ltda. Nanoémulsion, procédé de fabrication correspondant et composition cosmétique et dermatologique la contenant
EP2301547A1 (fr) 2005-07-06 2011-03-30 Bayer Schering Pharma AG Utilisation d'activateurs de le guanylate cyclase pour favoriser la guérison des blessures
US9445975B2 (en) 2008-10-03 2016-09-20 Access Business Group International, Llc Composition and method for preparing stable unilamellar liposomal suspension
US10406088B2 (en) 2015-01-20 2019-09-10 TetraDerm Group LLC Versatile topical drug delivery vehicle and multifactorial tissue moisturizer that provides mucosal and skin barrier restoration

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EP0500437A1 (fr) * 1991-02-21 1992-08-26 L'oreal Céramides, leur procédé de préparation et leurs applications en cosmétique et en dermopharmacie
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Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0868174A4 (fr) * 1995-09-12 1998-10-07
WO1997021428A1 (fr) * 1995-12-12 1997-06-19 Vesifact Ag Pulverisateur d'hydrocortisone pour administration topique
US5997888A (en) * 1996-12-13 1999-12-07 Vesifact Ag Cosmetic preparations
EP0852941A1 (fr) * 1996-12-13 1998-07-15 Vesifact Ag Composiotn cosmétique sous forme d'une nanodispersion
US7871642B2 (en) 1998-05-11 2011-01-18 Ciba Specialty Chemicals Corporation Use of nanodispersions in pharmaceutical end formulations
EP0956853A3 (fr) * 1998-05-11 2000-01-05 Ciba SC Holding AG Utilisation des nanodispersions dans des compositions pharmaceutiques
EP0956851A1 (fr) * 1998-05-11 1999-11-17 Ciba SC Holding AG Utilisation des nanotopes comme composants des produits cosmétiques
CN1133414C (zh) * 1998-05-11 2004-01-07 西巴特殊化学品控股有限公司 毫微分散体在化妆品最终制剂中的用途
US7381423B2 (en) 1998-05-11 2008-06-03 Ciba Specialty Chemicals Corp. Use of nanodispersions in cosmetic end formulations
US7081253B2 (en) * 1998-05-11 2006-07-25 Ciba Specialty Chemicals Corporation Use of nanodispersions in pharmaceutical end formulations
US7008638B2 (en) 1998-05-11 2006-03-07 Ciba Specialty Chemicals Corporation Use of nanodispersions in cosmetic end formulations
AU764038B2 (en) * 1998-05-11 2003-08-07 Ciba Specialty Chemicals Holding Inc. Use of nanodispersions in cosmetic end formulations
AU767896B2 (en) * 1998-05-11 2003-11-27 Ciba Specialty Chemicals Holding Inc. Use of nanodispersions in pharmaceutical end formulations
FR2779646A1 (fr) * 1998-06-15 1999-12-17 Epi France Extrait vegetal de cereales a base de lipides polaires et composition cosmetique comprenant un tel extrait vegetal
WO1999065459A1 (fr) * 1998-06-15 1999-12-23 E.P.I. France Extrait vegetal de cereales a base de lipides polaires
FR2792328A1 (fr) * 1999-04-19 2000-10-20 Lavipharm Lab Matiere huileuse comprenant des hydrocarbures paraffiniques et un compose riche en lipides d'origine vegetale, sa preparation et les compositions la contenant
FR2792327A1 (fr) * 1999-04-19 2000-10-20 Lavipharm Lab Matiere visqueuse stable, sa preparation et son utilisation dans des compositions cosmetiques
FR2792193A1 (fr) * 1999-04-19 2000-10-20 Lavipharm Lab Matiere de base pour la preparation de compositions cosmetiques et compositions cosmetiques la contenant
DE19952410B4 (de) * 1999-10-29 2007-03-29 Stada Arzneimittel Ag Lichtschutzzubereitungen umfassend feste Lipidnanopartikel
US7001604B2 (en) 2000-02-25 2006-02-21 Kubs Kosmetik Gmbh & Co. Kg Cosmetic composition
WO2001062222A3 (fr) * 2000-02-25 2002-04-25 Martin Albrecht Composition cosmetique
US6979459B1 (en) 2000-04-06 2005-12-27 Perricone Nicholas V Treatment of skin damage using polyenylphosphatidycholine
EP1267798A4 (fr) * 2000-04-06 2004-01-28 Nicholas V Dr Perricone Traitement des lesions cutanees a l'aide de polyenylphosphatidylcholine
US6932963B2 (en) 2000-06-23 2005-08-23 Nicholas V. Perricone Treatment of skin wounds using polyenylphosphatidylcholine and alkanolamines
WO2002094221A1 (fr) * 2001-05-18 2002-11-28 Jupitar Pty Ltd Preparations et procedes pour emulsions et dispersions
US8029810B2 (en) 2002-03-13 2011-10-04 Thomas Skold Water-based delivery systems
EP1534213A4 (fr) * 2002-03-13 2005-10-26 Collagenex Pharm Inc Systemes d'administration a base aqueuse
EP2301547A1 (fr) 2005-07-06 2011-03-30 Bayer Schering Pharma AG Utilisation d'activateurs de le guanylate cyclase pour favoriser la guérison des blessures
EP1839644A3 (fr) * 2006-03-30 2009-09-30 Botica Comercial Farmacêutica Ltda. Nanoémulsion, procédé de fabrication correspondant et composition cosmétique et dermatologique la contenant
WO2008086953A1 (fr) * 2007-01-16 2008-07-24 Bayer Consumer Care Ag Solution colloïdale
RU2449776C2 (ru) * 2007-01-16 2012-05-10 Байер Конзюмер Кер АГ Коллоидный раствор
US9445975B2 (en) 2008-10-03 2016-09-20 Access Business Group International, Llc Composition and method for preparing stable unilamellar liposomal suspension
US10406088B2 (en) 2015-01-20 2019-09-10 TetraDerm Group LLC Versatile topical drug delivery vehicle and multifactorial tissue moisturizer that provides mucosal and skin barrier restoration

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