Colloidal Solution

The present invention relates to a composition which is a colloidal solution comprising at least one active ingredient, at least one membrane-forming molecule and at least one foaming component, its process for preparation and its cosmetically or pharmaceutical use.

Pharmaceutical and cosmetic compositions for skin care exist in various forms of preparation e.g. as gels, lotions, foams, sprays, ointments, pastes, creams, etc.. Due to their adhesion to the epidermis and their penetration properties, such compositions are helpful for wound healing, compensation for loss of moisture or fat form the skin, and regeneration and protection of the skin in connection with environmental influences, weather, UV radiation from sunlight etc..

In order to reach the desired effect the active ingredient has to be transported to the respective site, for example to the skin surface, mucosa, nails, hair, epidermal and dermal areas of the skin by means of carrier or transport vehicles. Therefore the active ingredients must be sufficiently soluble in the formulation base or at least adequately solubilized and must be compatible with the other excipients of the formulation. In many cosmetics the active ingredients, for example water soluble vitamins or melanines, or amino acids, are encapsulated in liposomes. The composition comprising the active ingredient, the formulation base and other excipients should be homogenous, must be adequately stable and must not tend to e.g. chemical reactions or separation effects. In particular nanodispersions, a dispersion of nanoparticles, on a liposome basis shows advantageous properties in this regard.

EP 0 852 941, EP 0 956 851 and EP 0 956 853 describe stable nanodispersions comprising an oil- soluble active ingredient e.g. vitamin A, vitamin E or dexpanthenol, a specific phospholipid and a partial fatty acid ester of polyoxyethylene sorbitan as an emulsiiϊer.

Field of invention

The present invention relates to a colloidal solution comprising at least one active ingredient, at least one membrane-forming molecule and at least one foaming component.

A colloidal solution according to the invention is an especially finely dispersed system of a lipophilic phase in an aqueous or aqueous-alcoholic phase based on nanoparticles having a particle size less equal than 100 nm.

A colloidal solution according to the invention has opalescence and transparency in back lighting, which hints that the colloidal solution is physically identical to the ideal state of a true molecular solution. Electron-microscopic images show a homogenous dispersion of particles with a particle

size of less than about 100 run, so called nanoparticles. To characterize the available colloidal solution, methods known in the art are suitable, e.g., optical evaluation: weak to strong opalescence, dynamic light scattering (e.g. Photon Correlation Spectroscopy) and electron microscopy. Laser light scattering measurements and electron microscopic analysis confirm the very small size and excellent homogeneity of the nanoparticles present in the composition. Such colloidal solution is sometimes called as nanodispersion.

The colloidal solution according to the invention shows surprisingly a long shelf life, i.e. no separation and high stability of the particle size after storage for several weeks at temperatures up to 50 ⁰ C.

According to the invention the active ingredients can be a water-soluble and/or an oil-soluble compound preferably suitable for skin preparations.

Examples of water-soluble ingredients include but are not limited to dexpanthenol, pantothenic acid, folic acid, vitamin C, enzymes, extracts of plants, or mixtures thereof. Preference is given to dexpanthenol.

Further examples for active ingredients include but are not limited to oil-soluble vitamins, allantoin, azulene, cosmetic and therapeutic oils, oil-soluble sunblocks or mixtures thereof.

Examples of oil-soluble ingredients include but are not limited to vitamin A, retinol in the form of free acid or its derivatives, vitamin E, essential fatty acids, or mixtures thereof.

Example of sunblocks include but are not limited to anthranilic acid derivatives, salicylic acid derivatives, cinnamic acid ester derivatives, coumarin derivatives, o-aminobenzoic acid derivatives, benzophenone, benzylidene camphor or mixtures thereof. Preference is given to 4- aminobenzoic acid, 2-ethylhexyl-4-methoxy-cinnamate, 2-ethylhexylsalicylate, benzophenone-4, benzophenone-3, benzophenone- 10 and mixtures thereof. Furthermore suitable sunblocks are described in Pflegekosmetik: Ein Leitfaden [Cosmetics: A Manual], W. Raab, U. Kindl, Govi- Verlag, Frankfurt 1991 and in Ullmann's Encyclopaedia of Industrial Chemistry, VCH, Sedition,

Vol. A24, entry skin cosmetics.

The active ingredient is present in the colloidal solution according to the invention in a concentration of e.g. from 0.1 up to 20%, preferably from 1 up to 10% by weight, based on the total weight of the colloidal solution. Preference is given to dexpanthenol as active ingredient in a concentration of preferably from 1 up to 10 %, more preferably from 1.5 up to 7 % by weight based on the total weight of the colloidal solution.

Examples of membrane-forming molecules include but are not limited to phospholipids such as lecithin which can be a mixture of different phospholipids, hydrogenated or partially hydrogenated phospholipids, lysophospholipids, ceramide or mixtures thereof. Preference is given to lecithin as a membrane-forming molecule. Most preferably the phospholipid phosphatidylcholine is used as membrane-forming molecule.

The phosphatidylcholine or lecithin can stem for example from egg yolk or soy beans. The phosphatidylcholine stemmed from egg yolk contains for example C16-fatty acid (16:0) in an amount of around 33%, fatty acid (18:0) in an amount of around 14%, fatty acid (18:1) in an amount of around 30%, fatty acid (18:2) in an amount of around 14% and fatty acid (20:4) in an amount of around 4% by weight. The phosphatidylcholine stemmed from soy beans contains for example fatty acid (16:0) in an amount of around 14%, fatty acid (18:0) in an amount of around 4%, fatty acid (18: 1) in an amount of around 12%, fatty acid (18:2) in an amount of around 65% and fatty acid (18:3) in an amount of around 5% by weight. The phosphatidylcholine stemmed from soy beans is preferred.

The membrane-forming molecule is present in the colloidal solution according to the invention in a concentration of e.g. from 0.05 up to 15%, preferably from 0.1 up to 5%, more preferably from 0.2 up to 1 % by weight based on the total weight of the colloidal solution. Preference is given to phosphatidylcholine as active ingredient in a concentration of preferably from 0.1 up to 2 %, more preferably from 0.2 up to 0.8% by weight based on the total weight of the colloidal solution.

The foaming component according to the invention is selected from the group consisting of oleate, cocoamphoacetate, capryl/capramidopropyl betaine, a mixture of PEG-5 laurylcitrate / sulfosuccinat / laureth sulphate, a mixture of lauryl glucose carboxylate / lauryl glucoside, or a mixture thereof. Preference is given to sodium oleate, sodium cocoamphoacetate, capryl/capramidopropyl betaine, a mixture of disodium PEG-5 laurylcitrate / sulfosuccinat / sodium laureth sulphate, a mixture of sodium lauryl glucose carboxylate / lauryl glucoside, or a mixture thereof. More preferably cocoamphoacetate, capryl/capramidopropyl betaine, a mixture of lauryl glucose carboxylate / lauryl glucoside or a mixture thereof are used as foaming component. Most preferably sodium cocoamphoacetate, capryl/capramidopropyl betaine, the mixture of sodium lauryl glucose carboxylate / lauryl glucoside or a mixture thereof are used as foaming component. The foaming agents according to the invention can also be understood as surfactants.

The foaming component is present in the colloidal solution according to the invention in a concentration of e.g. from 0.5 up to 10%, preferably from 1 up to 4% by weight based on the total weight of the colloidal solution.

In addition the colloidal solution according to the invention can comprise sodium oleate as surfactant e.g. in a concentration of from 0.01 up to 0.1%, preferably from 0.01 up to 0.05% by weight based on the total weight of the colloidal solution.

Surprisingly the colloidal solution according to the invention remains stable in the presence of the foaming agent.

Furthermore the colloidal solution according to the invention can include one or more solvent, solubilizer, buffering agent, chelating agent, cooling agent and/or preservative.

Examples of solvents include but are not limited to water, preferably purified water, C ₂ -Cg alcohol, preferably ethanol or propylene glycol, or mixtures thereof. Preference is given to water as solvent.

The solvent can be present in the colloidal solution according to the invention in a concentration of e.g. from 50 up to 95%, preferably from 70 up to 92% by weight based on the total weight of the colloidal solution. Preference is given to water in a concentration of from 80 up to 95% based on the total weight of the colloidal solution.

Examples of solubilizers include but are not limited to C ₂ -C ₈ alcohol, preferably ethanol or propylene glycol, or mixtures thereof. Preference is given to ethanol as solubilizer.

The solubilizer can be present in the colloidal solution according to the invention in a concentration of e.g from 0.1 up to 2%, preferably from 0.2 up to 0.8 %, more preferably from 0.35 up to 0.55% by weight based on the total weight of the colloidal solution.

Examples of buffering agents include but are not limited to sodium dihydrogen phosphate, disodium phosphate, or a mixture thereof. Preference is given to sodium dihydrogen phosphate, disodium phosphate or a mixture thereof.

The buffering agent can be present in the colloidal solution according to the invention in a concentration of e.g. from 0.01 up to 1% by weight based on the total weight of the colloidal solution.

Sodium dihydrogen phosphate as buffering agent can be used in a concentration of e.g. from 0.05 up to 0.2%, preferably from 0.1 up to 0.15% by weight based on the total weight of the colloidal solution.

Disodium phosphate as buffering agent can be used in a concentration of e.g. from 0.01 up to 0.1%, preferably from 0.01 up to 0.05% by weight based on the total weight of the colloidal solution.

Preference is given to a mixture of sodium dihydrogen phosphate and disodium phosphate in a ratio of e.g. 10: 1 up to 1 :1, preferably 7: 1 up to 3: 1 in the colloidal solution according to the invention.

Examples of chelating agents include but are not limited to sodium edetate. Preference is given to sodium edetate.

The chelating agent can be present in the colloidal solution according to the invention in a concentration of e.g. from 0.01 up to 1%, preferably from 0.02 up to 0.08% by weight based on the total weight of the colloidal solution.

Examples of preservatives include but are not limited to phenoxyethanol. Preference is given to phenoxyethanol .

The preservative can be present in the colloidal solution according to the invention in a concentration of e.g. from 0.1 up to 1% by weight based on the total weight of the colloidal solution.

Examples of cooling agents include but are not limited to isobutane and isopentane, or a mixture thereof. Preference is given to a mixture of isobutane and isopentane.

The cooling agent can be present in the colloidal solution according to the invention in a concentration of e.g. from 0.1 up to 10%, preferably from 0.5 up to 5%, more preferably from 1 up to 2.5% by weight based on the total weight of the colloidal solution.

A preferred embodiment is a colloidal solution comprising dexpanthenol as active ingredient, a membrane-forming molecule, a water as solvent, ethanol as solubilizer, and a foaming component selected from the group consisting of sodium cocoamphoacetate, capryl/capramidopropyl betaine, the mixture of sodium lauryl glucose carboxylate / lauryl glucoside or a mixture thereof.

Most preferred is a colloidal solution comprising dexpanthenol as active ingredient, phosphatidylcholine as membrane-forming molecule, water as solvent, ethanol as solubilizer and a foaming component selected from the group consisting of sodium cocoamphoacetate, capryl/capramidopropyl betaine, the mixture of sodium lauryl glucose carboxylate / lauryl glucoside or a mixture thereof, wherein the ratio of water and ethanol is for example from 120 : 1 up to 250 : 1.

The colloidal solution of the present invention can be used as foam or spray. Therefore propellants known to the skilled person can be added. Preference is given to compressed nitrogen.

Moreover, the colloidal solution according to the invention can contain further excipients e.g. stabilizers, pH-adjuster, wetting agents, colorants, flavorants, fragrances, viscousifying agents, salts for varying the osmotic pressure, masking agents and antioxidants. It can also contain still other therapeutically valuable substances, such as further vitamins, minerals, sun filters, phytotherapeutic extracts, etc..

Excipients for pharmaceuticals and cosmetically compositions to the skilled person are also described for example in the following handbook: "Handbook of Pharmaceutical Excipients", Wade, A. & Weller, P. J., American Pharmaceutical Association, Washington, 2nd edition 1994.

Cosmetic or pharmaceutical composition

The colloidal solution according to the invention is a pharmaceutical and/or a cosmetic preparation, in particular a preparation for skin care, which preferably can be used as a foam, foam-spray or spray formulation.

The colloidal solution according to the invention includes but is not limited to a liquid composition before producing a foam, a liquid composition before spraying, the foam itself or the atomized spray itself.

Use of the composition

The colloidal solution according to the invention can be used for treating dermatological disorders which involve the degranulation process of the mastocytes, such as atopic dermatitis, psoriasis, contact eczema, skin allergies, skin inflammation due to insect bites, skin allergies, senile pruritus, minor burns and sunburns, irritated skin.

Furthermore the colloidal solution according to the invention can be used for moisturization, for regeneration or repair of barrier function of the horny layer, for cooling, and/or for soothing.

Preference is given to a colloidal solution that can be applied dermal or topically one or more times per day.

Process for manufacture

The colloidal solution according to the invention can be produced by mixing the buffering agent, the preservative and the chelating agent into the solvent, preferably water, at temperature from optionally room temperature up to 50 ⁰ C, preferably 35 to 40 ⁰ C. The mixture is stirred until it is dissolved. A part of the active ingredient is then added optionally dissolved in a solvent, preferably in water, more preferably in a concentration of 50 to 80% by weight, most preferably as a 65% by

weight aqueous solution. The mixture is stirred and homogenized until dissolution and the temperature can be decreased to 15°C up to room temperature, preferably to 20 ⁰ C. In the next step a solution comprising at least parts of the active ingredient, at least one membrane-forming molecule, water as solvent, ethanol as solubilizer and a surfactant is added. Preferably a solution comprising dexpanthenol, more preferably in a concentration of 10 to 50%, most preferably in a concentration of 25 to 35 % by weight, water as solvent, ethanol as solubilizer, preferably in a concentration of 6 to 12%, most preferably in a concentration of 8 to 10% by weight, phosphatidylcholine as membrane-forming molecule, preferably in a concentration of 8 to 16%, most preferable in a concentration of 1 1 to 13% by weight and sodium oleate as surfactant, preferable in a concentration of 0.2 to 0.8%, most preferably in a concentration of 0.4 to 0.6 % by weight is added and the mixture is stirred and homogenized until homogeneously dispersed. Finally the foaming component is added, preferable in a concentration of 0.5 to 5%, most preferably in a concentration of 1 to 3 % by weight.

The mixing is carried out by using a standard homogenization apparatus equipped with stirring and homogenization device.

Examples:

Example 1 : (Foam Spray)

Example 2: (Foam Spray)

Example 3: (Foam Spray)

Stability test:

Examples 1 to 3 and the colloidal solution concentrate are stored at 5O ⁰ C for 3 month. Analysis of the colloidal solutions show that they remain stable and are not separated or agglomerate to bigger aggregates, i.e. the particle size is less or equal than 100 nm.

Manufacturing process:

Examples 1 to 3 are prepared following the same protocol, e.g. for a batch of 2.000 kg: The buffering agents, the preservative and the chelating agent are added into 1772 kg water. The mixture is stirred at 35-40 ⁰ C until a solution is formed. 1 13,5 kg of an about 65% by weight aqueous solution of dexpanthenol is then added. The mixture is homogenized and stirred until dissolution and the temperature is decreased to 20 ⁰ C. In the next step 100 kg of a colloidal solution concentrate comprising 30 kg dexpanthenol, sodium oleate, phosphatidylcholine, ethanol and water is added and the mixture is homogenized and stirred until homogeneously dispersed. Finally the foaming component is added and the solution is stirred untii a homogenousiy dispersed colloidal solution is achieved.