GB2150433A - Topical pharmaceutical compositions of phospholipid emulsions - Google Patents

Abstract

Pharmaceutical compositions for application to the skin comprise the following ingredients: (1) an ester of a fatty acid and fatty alcohol, (2) a sterol, (3) a phospholipid, (4) a carbohydrate, (5) a protein or hydrolysed protein and (6) water, in the form of an emulsion. The composition may be applied by itself or may be used as a vehicle for a pharmaceutically active agent e.g. hydrocortisons to augment skin penetration.

Description

SPECIFICATION Membrane analogue emulsions The treatment of skin with various agents has been undertaken for many years with the goal being to keep the skin in a smooth and supple condition. Skin tends to dry out when exposed to conditions of low humidity or when exposed to prolonged contact with detergents. The reason for this being the removal of skin surface lipids, horny layer lipids and the dissolution of the hygroscopic water soluble components of the stratum corneum. Modern analytical techniques have allowed detailed identification of these corneal materials and attempts have previously been made to re-assemble these constituents in emulsified form for skin treatment in the belief that such emulsions would display superior conditioning properties and be more compatible with skin physiology.Such previous attempts have not been noticeably successful consisting as they have done of a piecemeal assemblage of skin surface lipids without considering their morphology. The presence of triglycerides in skin surface lipids has been particularly misleading as they arise solely from sebaceous secretions. Sebaceous secretions have been pronounced vestigial by Kligman their function having been to condition the copious body hair now replaced with stratum corneum in man. Horny layer lipids however arise from the breakdown of the membrane surrounding each keratinised cell of the corneum and are therefore of fundamental importance to maintaining a supple moisturised corneum.

The present invention therefore relates to the production of emulsions based on the known structure of corneal membranes that show complete compatibility with skin physiology, excellent usability and stability with cosmetic and pharmaceutical acceptability. The emulsions of this invention have excellent affinity with skin and by nature of their construction make it possible to apply to the skin substances which are naturally present in the epidermis. The emulsions of this invention also display superior skin penetration properties and may be used as vehicles or excipients for therapeutically active substances.

Corneal membranes are concerned primarily with structural functions rather than metabolic functions and therefore contain much less integral protein than membranes involved in active metabolism. They contain proportionately more lipids than other membranes and are unusual in that esters are present. Corneal membranes have been found to consist of approximately 70% lipids, 25% proteins and up to 5% carbohydrate. The lipids are amphipathic molecules which form closely packed bi-layers whose strength depends on the exclusion of water from their hydrophobic core, further integrity deriving from the interactions of protein at the periphery. These lipids have been identified as sterols, phospholipids and esters which are held together by non covalent forces thus allowing a high degree of flexibility and fluidity whilst at the same time maintaining structural integrity and solid properties.The lipids are able to undergo twisting and flexing motion as well as being highly mobile within the plane of the membrane. These fundamental properties are the result of Van Der Vaals forces of attraction between the acyl chains of the phospholipids esters and sterols and the non covalent forces of hydrogen bonding and polar headgroup interactions at the periphery of the membrane.

The component fatty acids of human phospholipids have been found to be: C1 Palmitic 66%, Stearic 26%, Others 8% C2 Oleic 22%, Linoleic 47%, Others 23% Approximately 50% of these acids are unsaturated with approximately 40% saturated and 10% branched.

The possibility of two phases therefore exists for such acyl chains, a solid phase in which all trans configurations occur or a liquid phase in which all cis configurations occur. Phase transition is governed by the following parameters :- length of acyl chain, number and type of double bonds, nature of headgroup, and paticipation of sterol. Solid and liquid phases co-exist at the transition temperature which can be greatly extended or smeared by the participation of cholesterol. Cholesterol increases the fluidity of the solid phase by restricting the closeness of packing of the acyl chains and preventing the all trans configuration, at the same time it reduces the fluidity of the liquid phase as its rigid puckered ring restricts motion of adjacent acyl chains.These properties are strictly confined to sterols with a 3 beta hydroxyl group capable of hydrogen bonding to the carboxyl group of the phospholipid fatty acids. Geometric considerations show that bonding with the C2 unsaturated fatty acids is strongly favoured. Such bonds are constantly breaking and reforming at a rate of 107 per second however it is sufficient to define the geometric alignment of the cholesterol molecule with the phospholipids. The rigid cholesterol molecule interacts with adjacent acyl chains along the first 1 .2nm. of or the membrane whilst the branched C17 terpenoid tailgroup confers motility to the remaining portion of the acyl chains thus a microviscosity gradient is established within the membrane.

The associated carbohydrates are covalently bound to both lipids and proteins and they perform both structural and functional roles. For the purposes of this invention only the structural role need be considered.

The carbohydrate associated with lipid is to be found as ganglioside headgroups, phosphatidyl inositol, and glycosyl diacylglycerol. Mono, Di and Oligo saccharides predominate with glucose, galactose, n-acetyl d-glucosamine, and terminal sialic acid groups favoured. This bound carhobydrate therefore functions as non-ionic hydrophilic solubilisers. A seperate role may be ascribed to the glycosaminoglycans that are to found associated with membranes in minute quantities. Apart from forming the intercellular connective substance these acidic polysaccharides confer integrity at the interface in the same way as macromolecular stabilisers.

The role of the associated protein in corneal membranes is largely structural and by binding with the polar headgroups of the phospholipids at the periphery this protein confers integrity to the membrane at the same time bending water to the outer surface of the membrane.

The essential features which must be copied in the successful production of corneal membrane analogue emulsions are therefore : 1 ) Saturated, Unsaturated, Polyunsaturated and branched hydrocarbon chains of from 14 to 24 carbon atoms which can form a motile hydrophobic core.

2) Participation of between 16% and 33% (molar) sterol in the fatty phase said sterol characterised by a 3 beta hydroxyl group and a C77 branched acyl tail preferably of terpenoid derivation.

3) Headgroup interactions at the periphery between polar headgroups and water soluble protein and each other.

4) Carbohydrate hydrophilic groups solubilising lipid at the interface, solubilising protein in the aqueous phase, conferring integrity of the interface and binding water molecules to the periphery.

The emulsions of this invention have therefore been composed to comply with the preceding requirements and provide a lipid film the constituents of which closely resemble those of a corneal membrane, the process of emulsification having arranged the constituent molecules in the most favourable thermodynamic configuration. This invention therefore provides the means whereby a lipid film with properties closely analogous to a corneal membrane may be applied to the skin providing a superior method of conditioning and moisturising the skin whilst not interfering with the processes of natural transpiration.

As the percutaneous absorption of molecules must take place through membranes the ability of such a film to equilibriate with membranes and hence for the exchange of molecules to take place means that the emulsions of this invention represent a more ideal vehicle or excipient for the topical administration of therapeutically or biologically active substances than conventional emulsions.

The emulsions of this invention may be prepared by any of the standard methods of preparing emulsions using any of the normal equipment as described in a standard text on the subject such as "EMULSiONS THEORY AND PRACTICE" by PAUL BECHER and published by LONGMANS. Essentially such methods comprise mixing fatty phase ingredients seperately and holding in a suitable container, mixing aqueous ingredients seperately and holding, then adding one phase to the other with agitation at an appropriate temperature. Emulsions of water in oil, oil in water, mixtures of the two, multiple emulsions and microemulsions may all be prepared according to the end use required of the emulsions. Such emulsions are well known to those skilled in the art and are described in detail in the same text.The emulsions of this invention are characterised in that they comprise a fatty phase and an aqueous phase comprising : Fatty phase ?) Esters of fatty acids and fatty alcohols The ester component of this invention has the structure

wherein R1 is a hydrocarbon chain of length C6 to C36 but preferrably of C12 to C24. R7 may be saturated, unsaturated or branched according to the final properties required of the emulsion by the formulator. R1 may also be an hydroxy acid as in lanolin esters and castor wax esters. R2 is a hydrocarbon chain as defined for R1 or a triterpenoid or steroid if required. R1 and R2 may be identical or not.The ester component of this invention may consist of one ester or a mixtures of several the actual choice being determined by the requirements of the final formulation. For example it might be desired that a composition according to this invention containing hydrocortisone showed a sustained release profile over many hours and predominantly saturated esters would be appropriate. In the absence of such considerations the esters should ideally comprise about 40% saturated hydrocarbons of length C14 to C24, about 50% unsaturated hydrocarbons of length C14 to C24 and about 10% branched hydrocarbon of the same length. Esters suitable for use in this invention may be of natural or synthetic origin and include but are not limited to : Lanolin Waxes, Carnauba Wax, Candellila Wax, Spermaceti, Jojoba Waxes, Isomerised Jojoba Waxes, Isocetyl Stearate, Myristyl Myristate, Decyl Oleate, Isodecyl Oleate, Hexyl Laurate, Cetyl Palmitate, 2-Ethyl-Hexyl Palmitate, Lanolin Linoleate, Octyl Palmitate and the like.

2) Phospholipids The phospholipid component of the present invention has the structure:

Wherein R1 and R2 are saturated or unsaturated hydrocarbons having from 8 to 40 carbon atoms and R2 is Choline, Ethanolamine, Serine, Inositol, Glycerol, N-Methylethanolamine, NN-Dimethylethanolamine, or the like. Representative phospholipids include but are not limited to: Egg Lecithin, Soy Lecithin, Phosphatidyl Serine, Phosphatidyl Choline, Phosphatidyl Inositol, Dipalmitoylphosphatidylcholine, Distearoylphosphatidylethanolamine and the like. Phospholipids of non glyceryl base may be included and indeed are usually present in the Lecithins of commerce and examples include Cerebrosides and Gangliosides.Ideally Phospholipids wherein R1 is a C16 saturated hydrocarbon and C2 is a C18.20 unsaturated hydrocarbon such as Oleic, Linoleic, Linolenic or Arachidonic, and the like are preferred.

3) Sterols The sterol component of this invention must feature a 3 Beta Hydroxyl and a C17 branched hydrocarbon chain. Examples include but are not limited to :- Cholesterol, Cholestanol, Sitosterol, Campesterol, Stigmasterol, Phytostanol, Ergosterol, Brassicasterol, Spinasterol, Fucosterol and various sterol mixtures contained in the unsaponifiable matter of Lanolin and the like.

The emulsions of the present invention may be composed of a great variety of combinations and proportions of the aforementioned fatty materials however the following limits are recommended to be observed : Proportion ofphospholipid to sterol The proportion of Phospholipid to Sterol may be from 10; 1 to 1; 10 but ideally should be from 2; 1 to 1; 2.

Proportion of esters to combined phospholip id and sterol The proportion of Esters to combined Phospholipid and Sterol may be from 10; 1 to 1; 10 but ideally should be from 2; 1 to 1; 2.

Proportion of fatty phase to aqueous phase The emulsions of the present invention may be presented in a wide variety of compositions containing from 2% to 98% fatty phase however it is preferrable to employ a fatty phase of from 4% to 40%.

Aqueous phase The emulsions of the present invention also comprise an aqueous phase made up of :1) Protein our protein derivative The Protein component of the present invention may comprise of Simple Protein, Conjugated Protein or the products of acid, base or enzymatic hydrolysis of such. The Protein or Protein Derivative should be cosmetically and pharmaceutically acceptable and should be soluble in water. Protein from plant, animal or microbial derivation may be used and examples include but are not limited to :- Simple or Conjugated Proteins, Denatured Proteins, Primary Proteoses, Secondary Proteoses, Peptones, Polypeptides, Peptides and Amino Acids. Particularly suited to cosmetic use are Collagen and its Hydrolysates, Elastin and its Hydrolysates, Silk Protein, Soya Protein, Oat Protein, Casein and the like.

2) Carbohydrate Carbohydrates are usually found with biological membranes at levels of up to 10%. A dual role exists for such carbohydrates which are found co-valently bound to Lipids and Proteins as they perform both structural and functional roles. As the emulsions of the present invention are concerned with structural functions this role only is considered. The majority of carbohydrate is present in the form of glycolipid and is to be found as Ganglioside headgroups, Phosphatidyl Inositol, and Glycosyl Diacylglycerol.

Predominant headgroup sequences of Glucose, Galactose, N Acetyl D Glucosamine and terminal Sialic Acid are to be found performing the function of non-ionic hydrophilic headgroup. For the purposes of the present invention commercial Lecithin provides a convenient source of such glycolipids. It is of course possible to add unbound carbohydrate however the role of such carbohydrate is best considered under the categories of humectants and moisturisers.

A seperate role exists for the minute amounts of glycosaminoglycans to be found in association with membranes. Apart from forming the intercallular connective substance these acidic polysaccharides also confer integrity at the interface in much the same way as amacromolecular stabiliser. Glycosaminoglycans may be obtained from Umbilical Cord extract, Rooster Comb extract, Bovine Trachea and the like and include but are not limited to Hyaluronic Acid. Chondroitin Sulphate, Dermatan Sulphate and the like.

3) Water The water employed in the emulsions of the present invention should be free from microbiological contamination and may be buffered to physiological pH and iso-osmosticity with serum if required. A pH of between 5 and 6 buffered with Lactic Acid and Sodium Lactate and an iso-osmotic electrolyte content comprising the Chlorides of Sodium, Potassium, Calcium and Magnesium would be appropriate for many applications. Some formulations however preclude the use of such electrolytes however and their use is not essential.

Optional components It will be readily appreciated that the emulsions of the present invention admit of the use of optional components both functional and active. They must be chosen so as not to impair the desirable properties of the composition and must add to the total cosmetic or pharmaceutical performance of the composition.

Such formulae modifications are well within the skill of workers in the cosmetic and dermatological arts and by themselves constitute no part of this invention.

A uxilliary stabilisers Emulsified products stabilised with Lecthin and Cholesterol have been known since antiquity and have usually included auxilliary stabilisers to improve keeping properties. Auxilliary stabilisers may also be added to the emulsions of the present invention in order to improve shelf life, however such stabilisers should be chosen so as not to interfere with the properties of the emulsion and it is preferred that they should not be present in amounts exceding the combined proportion of Phospholipid and Sterol. Macromolecular stabilisers are particularly suitable for use in the present invention as they may considered closely analogous to the natural ground substance of living cells.Polysaccharide stabilisers are thus an appropriate choice and include :- Alginates, Guar Gum, Carrageenan, Celluose Derivatives, Chitin Derivatives, Mucopolysaccharides, Xanthan Gum and the like. Colloidal dispersions and Organically Modified Colloids may also be suitable choices for promoting long term stability in emulsions of the present invention.

Amphipathic stabilisers may also be used to promote long term stability and are particularly suitable if it is desired to produce an emulsion with droplets of a specific charge. Dicetyl Phosphate or Stearylamine may be used to produce negatively or positively charged droplets and a wide variety of anionic, cationic, non-ionic and amphoteric emulsifiers of the appropriate HLB may be used. Examples of appropriate auxilliary emulsifiers suitable for use in this invention include but are not limited to :- Homo and Co Polymers of Acrylic, Maleic, Vinyl and Pyrollidone derivation, Polyglycols, Carbomers, Clathrates, Polyalanines, Silicone Glycol Co-Polyols, Bentonites, Organically Modified Bentonites, Magnesium Aluminium Silicates, Mono and Di-Acyl Glycerides, Polyglycerols, Glucoside and Sucrose Derivatives, Propoxylated Glycerides and the like.

Emollients Emulsions of the present invention may also contain additional emollients to the aforementioned fatty phase components. Volatile non-polar emollients are particularly suitable as they can be expected to have little or no adverse interaction at the interface with amphipathic components of the invention. Any cosmetically acceptable volatile non polar hydrophobic oil may be used at levels up to about 85% of the fatty phase and examples include but are not limited to Volatile Silicone Pentamers and Tetramers, Deodorised Kerosene and the like.

Hydrocarbon emollients may also be used in emulsions of this invention up to a level of about 35% of the fatty phase and examples include but are not limited to :- Squalane, Sqalene, Perhydrosqualene, Polyisobutene, Mineral Oils, Mineral Waxes, Microcrystalline Waxes, Branched Hydrocarbon Oils, Silicone Oils, Organosilicone Oils and the like.

Vegetable Oils, Isopropyl Esters of Fatty Acids, Fatty Acids and Fatty Alcohols may also be employed as emollients in the present invention however as they have potential for participation at the interface their use should be kept to levels below 10% of the fatty phase.

Functional adjuncts The emulsions of the present invention may also contain functional adjuncts for further controlling the properties of a cosmetic or pharmaceutical composition containing the emulsion. Functional adjuncts include but are not limited to :-Antioxidants, Propellants, Solvents, Humectants, Fillers, Preservatives, Thickeners, Fragrances and the like. The use of such adjuncts is well known to those skilled in the art and their use at art established levels forms no part of this invention.

Applications The emulsions of the present invention may be employed as vehicle or excipientfor a wide variety of cosmetically, therapeutically and biologically active substances particularly substances that have a beneficial effect when applied to the skin. The emulsions of the present invention therefore provide a means whereby such active ingredients may be diluted, preserved conveyed to and distributed upon the skin at an appropriate concentration.

Cosmetically active adjuncts Examples of cosmetically active ingredients suitable for inclusion in compositions based upon the emulsions of this invention include but are not limited to the categories listed below. The use of such active ingredients at art established levels is well known and comprehensively described in HARRY'S COSMETI COLOGY published by GEORGE GODWIN and such use constitutes no part of the present invention.

Mo is turisers Such as Sodium PCA, Sodium Lactate, Sodium and Potassium Chlorides, Saccharides, Glycosaminoglycans, Magnesium and Calcium Chlorides, Urea, Amino Acids or a mixture of the aforementioned which may be referred to as "Natural Moisturising Factor", and the like.

Sunscreens Such as Para Amino Benzoic Acid and its derivatives, Camphor and its Derivatives, Benzophenones, Cinnamates, Salicylates and the like.

Germicides Such as Bronopol, Bezalkonium Chloride, Thiomersal, Cetrimide and the like.

Deodorants Such as Zinc Oxide, 2 Ethyl 1,3 Hexane Diol and the like.

Antiperspirants Such as Aluminium Chlorohydrate, Zirconyl Chlorohydrate and the like.

Healing Agents Such as Allantoin, Azulene, Placenta Extract and the like.

Astringents Such as Menthol, Camphor, Ethanol, Tannins and the like.

Herbal extracts Such as Aloe Vera, Camomile, Cucumber Gentian mixtures of such and the like.

Vitamins Such as Tocopherols, Retinoids, Ascorbic Acid mixtures of same and the like.

Exfoliatives Such as Bezoyl Peroxide, Salicylic Acid, Retinoid Derivatives and the like.

The emulsions of the present invention may be present in a variety of forms such as Creams, Lotions, Gels, Sticks and the like for the purpose of applying a conditioning, moisturising, protective or emollient cosmetic composition. Examples of the form such compositions may take are well known to those skilled in the art and are described in detail in HARRY'S COSMETICOLOGY, SUCH EXAMPLES INCLUDE BUT ARE NOT LIMITED TO : Cleansing Creams and Lotions, Moisturising Creams and Lotions, Hand and Body Creams and Lotions, Barrier Creams and Lotions, Sunscreen Creams and Lotions, Moisturising Foundations, Tinted Creams and Lotions, Moisturising Rouge, Cosmetic Sticks, Sprays, Gels and the like.

The emulsions of the present invention may also be used with other skin conditioning compositions and may be used consecutively, conjointly or as a single composition. When used as a single composition the emulsions of this invention are incorporated into a second composition useful as a skin conditioner. In the case of the second composition taking the form of an emulsion care must be taken not to break down either emulsion or cause homogenisation of the two, admixture must therefore take place at room temperature or below with a minimum amount of shear. The ratio for incorporation can be from 99 1 to 1 : 99 emulsion of the present invention : second composition, preferably from 20: 1 to 1: 20 and ideally from 10:1 to 1:10.

Therapeutically active ingredients The emulsions of the present invention are also ideally suited for use as vehicles or excipients of therapeutically active substances of either Hydrophobic or Hydrophilic nature. Examples of such ingredients follow and are well known to those skilled in the Pharmaceutical Arts and are described in detail in "THE PHARMACOLOGICAL BASIS OF THERAPEUTICS" 4th. edition by GOODMAN AND GILMAN published by MACMILLAN.

Classes of therapeutically active substances include but are not limited to :- Local Anaesthetics, Non Steroidal Anti-l nfla mmatories, Antibiotics, Anti-Vira Is, Oestrogens, Progestogens, Androgens, Anti Androgens, Anti-Neoplastic Agents, Glucocorticoids, Mineralocorticoids, Anti-Keratolytics, Rubefacients, Antihistamines and the like.

Biologically active substances Classes of biologically active substances that may be compounded in the emulsions of the present invention include but are not limited to :- Bioactive Macromolecules, Biological Response Modifiers, Immunogenic Determinants, Antibodies, Antigens, Genetic Material, Enzymes, Enzyme Inhibitors, Diagnostic Agents, Radiolabled Tracers, Glycosides and the like.

The emulsions of the present invention also offer the means whereby the Bio-Availability of the aforementioned active ingredients may be regulated within precise and reproducible limits. Control of Bio-Availability may be achieved by controlling the following variables : Affinity of the vehicle for the active agent The rate of diffusion of an active substance from emulsions of this invention may be controlled by adjusting the solubility of said active substance in the emulsion. Greater solubility of the active substance in or greater affinity with the emulsion will result in a slower diffusion of the active substance out of the emulsion and hence a slower rate of absorption.In the case of steroidal anti-inflammatories such as Hydrocortisone the affinity of the emulsion for the steroid may be greatly increased by employing esters and auxilliary emulsifiers with C12 hydroxyl groups such as Castor Oil derivatives. Similar adjustments of affinity may be made for individual active ingredients on an ad hoc basis and such formula modifications form no part of the present invention representing as they do existing techniques well known to those skilled in the pharmacodynamic arts.

Alterations to the fluidity of the lipid phase The rate of release of lipophilic active ingredients from oil in water emulsion of this invention and the rate of release of both lipophilic and hydrophilic active ingredients from water in oil emulsions of this invention may be further controlled by adjusting the fluidity of the Lipid Phase and hence altering the rate of exchange of molecules between the Lipid Phase and host membranes. Methods of adjusting this fluidity are well known and include 1) Variation of proportion of branched and straight chain acyl chains.

2) Variation of proportion of saturated and unsaturated acyl chains.

3) Variation of proportion of sterol in lipid phase.

4) Variation of proportion of peripheral protein.

5) Addition of high melting point waxes including hydrocarbon waxes.

6) Variation in size of droplet in the emulsion and control of droplet size distribution (homogenisation).

Enhancement of penetration and absorption of active substances Although the emulsions of the present invention display marked transepidermal delivery of an incorporated active ingredient when compared with other compositions at equal chemical potential, their performance may be enhanced further by the following means : 1 ) Inclusion of penetration enhancers such as N-Methyl Pyrollidine, Propylene Glycol, Salicylic Acid, Urea, Dimethyl Sulphoxide, and the like.

2) Inclusion of membrane disrupting agents such as Local Anaesthetics, Cholate, Divalent Cations, Saponins, Barbiturates, Eucalyptol, 1-0-Alkyl-Acetyl-sn.Glyceryl-3-Phosphoryl choline, 1-Substituted Aza cycloalkan-2-ones.

3) Use of pro-drugs based on Pyrollidone or Dinitroglycerol.

4) Inclusion of ionophore forming antibiotics such as Amphotericin and Valinomycin.

5) Inclusion of enzyme systems such as Acyl Carnitine transport system or Phospholipid Exchange Protein /ATP/KOH system.

Pharmaceutical preparations The emulsions of this invention have so far been discussed with reference to topically applied compositions, however their use is not limited to topical application and it is possible to employ them in any Pharmaceutical Composition employing emulsified material. Examples of such non topical compositions include but are not limited to : Aerosols, Applications, Bougies, Douches, Plasters, Emulsions, Enemas, Gargles, Drops, Injections, Milks, Lamellae, Mixtures, Mucillages, Nebulae, Oleoresins, Stili, Suppositories, Vapores, and the like.

The emulsions of the present invention may be characterised by reference to the diagram following which depicts the ideallized orientation of the amphipathic constituents of Example No. 1 in association with the globular protein therein. It should be noted that the diagram depicts a state of statistical probability that the amphipaths will assume such an orientation of thermodynamic equilibrium as the continual breakdown of hydrogen bonds followed by immediate formation of others admits of tremendous variation of molecular arrangements within this general optimal thermodynamic orientation. The diagram may be regarded as representing 10-7 seconds in the life of the emulsion.The amphipathic molecules have been fixed within this dynamic framework as a result of the process of emulsification, and it should further be appreciated that Example No. 1 represents an emulsion the internal phase of which approaches the maximum possible for spherical droplets. As the fatty phase in Example No. 1 is composed of about 80% volatile silicone it may be predicted that the depicted orientation of amphipaths has a high level of probability and indeed it is possible to calculate precisely the optimal molar concentration of amphipaths required to produce spherical droplets of internal phase surrounded by monolayers of amphipaths. With reference to the diagram analogous membrane characteristics are as follows : 1) Molecule of Globular Protein peripherally bound to polar headgroup 2) The Choline Headgroup which is the predominant Headgroup in Lecithin.

3) and 4) represent the predominant Ester of Jojoba Oil Erucyl Eicosenoate featuring cis unsaturation at C11 and C13, Hydrogen Bonding with 5) The Oleate chain of Glyceryl Monooleate a Water in Oil Co-emulsifier.

6) Represents a molecule of Cholesterol fixed in position through Hydrogen Bonding of its 3 Beta Hydroxyl with the carboxyl group of 7) The C2 Linoleate chain of Phosphatidylcholine the predominant Phospholipid of Lecithin. It can be seen that geometric considerations favour such an association.

8) Represents the C1 Palmitic Acid chain which predominates in Lecithin.

9) Represents an iso branched free fatty alcohol Hydrogen Bonding with 8.

10) Represents a glycerol group which forms an anchoring structure at the interface.

It can thus be seen that the essential features reponsible for the properties of corneal membranes have been closely reproduced in Example No. 1. It may also be seen that the emulsions of this invention admit of considerable variation as long as the critical features referred to are present.

Examples The embodiments of this invention which follow are given only by way of iilustration and may be modified in any of the ways referred to herein within the parameters hitherto defined. As an example of the versatility of this invention Examples No. 5 and 6 have been taken directly from suppliers literature with modification to the fatty phase in order to comply with the parameters herein defined. Further modifications are well within the skill of workers in the cosmetic, dermatological and pharmaceutical arts and by themselves constitute no part of this invention.

1) Water in volatile silicone Fatty Phase Aqueous Phase Volatile Silicone Tetramer 19.0 Sodium Lactate 1.5 Silicone Glycol Co-Polyol 1.0 Lactic Acid 0.5 Jojoba Esters 2.0 Oat Protein 1.0 Squalane 1.0 Pentavitin* 1.0 Glyceryl Monooleate 0.1 Propylene Glycol 3.0 Glyceryl Monostearate 0.1 Kathon C G 0.1 Isostearyl Alcohol 0.2 Hyaluronic Acid 0.1 Lecithin 0.4 Iso-Osmotic Water To 100.0 Cholesterol 0.4 *Pentavitin is a proprietory blend of saccharides from PENTA of Switzerland.

Oil in Water Fatty Phase Aqueous Phase Jojoba Esters 5.0 Carbopol 940 1.0 Avocado Oil 1.0 TEA 1.0 Essential Fatty Acids 1.0 Ethomeen C 25 2.0 Sqalane 1.0 Phytelline 3.0 Cholesterol 0.4 Glucam E 10 3.0 Cholesterol POE 24 0.4 Pentavitin 2.0 Lecithin 0.8 Soluble Collagen 5.0 Water in volatile silicone Fatty Phase Aqueous Phase Glyceryl Monolinoleate 0.2 Euxyl 0.1 Glyceryl Monostearate 0.2 Water To 100.0 Phytellines are herbal extracts, Glucam E10 a humectant, Euxyl a preservative, and Ethomeen C 25 a PEG Coco-Amine.

3) Water in Oil Fatty Phase %age Aqueous Phase %age Cholesterol 1.5 Hyaluronic Acid 0.2 Lecithin 1.5 Sodium PCA 3.0 Perhydrosqualene 3.0 Arginine 1.0 Liquid Paraffin 3.0 Hydrolysed Silx Protein 3.0 Lanolin Linoleate 1.0 Pentavitin 1.0 Isocetyl Stearate 1.0 Kathon CG 0.1 Isodecyl Oleate 1.0 IsoosmoticWater To 100.0 Cetyl Palmitate 1.0 Myristyl Myristate 1.0 Jojoba Esters 1.0 4) Water in Oil Fatty Phase %age Aqueous Phase /Oage Volatile Silicone 19.0 Sodium Lactate 1.5 Silicone Glycol Copolyol 1.0 Sodium Citrate 1.0 Isocetyl Stearate 1.0 Hydrolysed Silk Protein 3.0 Lanolin Linoleate 1.0 Propylene Glycol 3.0 Jojoba Esters 1.0 Kathon CG 0.1 Castor Oil 1.0 Water To 100.0 Avocado Oil 1.0 Cholesterol 0.4 Lecithin 0.8 Glyceryl Monoricinoleate 0.2 Polyglyceryl 3 Oleate 0.2 Hydrocortisone 0.1 The above Water in Volatile Silicone formulation demonstrates the use of 12 hydroxy esters in the solubilisation of Hydrocortisone and the use of predominantly unsaturated esters to promote fluidity and hence facilitate penetration and absorption.

The formulations to follow have been taken from suppliers literature and the oil phase modified to comply with the criteria herein defined. The formulations containing "VEEGUM" have been take from Cosmetics and Toiletries Formulary published by R.T. Vanderbilt, Inc. The other formulation has been adapted from Personal Care products published by B.F. Goodrich.

Examples Water in Oil Fatty Phase Aqueous Phase Squalane 10.0 Veegum 1.3 Cetyl Palmitate 5.0 Magnesium Sulphate 0.5 Jojoba Oil 5.0 Umbilical Cord Extract 2.0 Isocetyl Stearate 5.0 Ster-O-Pro* 2.0 Tocopherols 0.3 Pentavitin 2.0 Cholesterol 4.0 Propylene Glycol 3.0 Lecithin 4.0 Water To 100.0 Oleamide D E A 2.0 *Ster-O-Pro is a Proprietory Oat Protein product.

6) Oil in Water Fatty Phase Aqueous Phase Sqalane 5.0 Collagen Hydrolysate 5.0 Cetyl Palmitate 2.5 Pentavitin 2.0 Jojoba Oil 2.5 Rooster Comb Extract 2.5 Tocopherols 0.3 Carbopol 934 1.0 Cholesterol 2.0 Ethomeen C 25 1.0 Lecithin 2.0 TEA 1.0 Euxyl 0.1 Water 100.0 In the above formulations Rooster Comb and Umbilical Cord extracts have both been used as a source of glycosaminoglycans. Tocopherols are both antioxidants and natural Vitamin E.

All the above embodiments have shown excellent stability and cosmetic acceptability.

Claims (31)

1. An emulsion comprising a fatty and an aqueous phase composed of : Fatty phase Esters of Fatty Acids and Fatty Alcohols Sterols Phospholipids Aqueous phase Protein or Protein Derivative Carbohydrate Water.

2. An emulsion as in claim 1 wherein the acyl chains of the esters are from Ce to Ce in length and comprise saturated, unsaturated, polyunsaturated or branched hydrocarbons or any combination of these.

3. An emulsion as in claims 1 - 2 wherein the acyl chains of the esters are comprised of from 35% - 45% saturated hydrocarbons of from C14 - C22 in length, from 45% - 55% unsaturated and polyunsaturated hydrocarbons of from C14 - C22 in length and from 5% - 15% iso or ante-iso branched hydrocarbons of from C14- C22 in length.

4. An emulsion as in claims 1 - 3 wherein the fatty alcohol portion of the esters is of steroid or triterpenoid derivation.

5. An emulsion as in claims 1 - 4wherein the Phospholipid component has the structure

wherein R, and R2 are saturated, unsaturated, polyunsaturated or branched hydrocarbons having from 8 to 40 carbon atoms and R3 may be Choline, Ethanolamine, Serine, Inositol, Glycerol, N-Methylethanolamine NN-Dimethylethanolamine or the like.

6. An emulsion as in claims 1 - 5 wherein the Phospholipid component includes but is not limited to Egg Lecithin, Soy Lecithin, Dipalmitoylphosphatidylcholine, Distearoylphosphatidylethanolamine, and the like.

7. An emulsion as in claims 1 - 6 wherein the Sterol component is characterised by a 3 - Beta Hydroxyl group and a C17 branched acyl chain. Examples include but are not limited to :- Cholesterol, Cholestanol, Phytosterols, Phytostanol, Ergosterol, Brassicasterol, Spinasterol, Fucosterol and the like.

8. An emulsion as in claims 1 - 7 wherein the ratio of Phospholipid to Sterol is from 10:1 to 1:10 and preferably from 2:1 to 1: 2.

9. An emulsion as in claims 1 - 8 wherein the ratio of Esters to combined Sterol and Phospholipid is from 10:1to1 :10andpreferablyfrom4:1to1 :4.

10. An emulsion as in claims 1 - 9 wherein the Aqueous Phase contains a Protein or Protein derivative as defined in ORGANIC CHEMISTRY VOL 2 by l.L. FINAR LONGMANS 1968, present at a level of up to 20% of the total emulsion.

11. An emulsion as in claims 1 - 10 wherein a carbohydrate as defined in the same volume is present in the Aqueous Phase either in the free form or covalently bonded to either Lipid or Protein at a level of up to 10% of the total emulsion.

12. An emulsion as in claims 1 - 11 wherein a macromolecularstabiliser is present at a level of up to 10% of the Fatty Phase.

13. An emulsion as in claims 1 - 12 wherein an auxilliary emulsifier of HLB from 1.0 to 40.0 according to the emulsion type, of anionic, non-ionic, cationic, or amphoteric character is present within a range of Auxiliiary Emulsifier to combined Sterol and Phospholipid from 2; 1 to 1; 2.

14. An emulsion as in claims 1 -13 wherein the auxilliary emulsifier is characterised by being a Mono or Di-Acyl Glyceride, Polyglyceryl or Polypropoxylated Fatty Acid or Fatty Alcohol, Mono, Di or Oligo Saccharide Acyl Glyceride or the like.

15. An emulsion as in claims 1 - 14 wherein a Colloidal or Organically Modified Colloidal stabiliser is present at a level of up to 2% of the total emulsion.

16. An emulsion as in claims 1-15 wherein the Aqueous Phase is buffered to a pH of from 4.5 to 6.5 and also where the Aqueous Phase is adjusted to iso-osmotic pressure with Human Serum.

17. An emulsion as in claims 1 - 16 wherein a Volatile Silicone is present at a level of up to 85% of the Fatty Phase.

18. An emulsion as in claims 1 -17 wherein a hydrocarbon emollient is present at a level of up to 35% of the Fatty Phase.

19. An emulsion as in claims 1 - 18 wherein a polar fatty emollient is present at a level of up to 10% of the Fatty Phase.

20. An emulsion as in claims 1 - 19 wherein any of the following functional additives well known to those skilled in the art and described in HARRY'S COSMETICOLOGY 7th. Edition published by GEORGE GODWIN are present at art established levels : Antioxidants, Solvents, Propellants, Humectants, Preservatives, Thickeners, Fillers, Fragrances and the like.

21. An emulsion as in any preceding claim belonging to any of the following emulsion types well known to those skilled in the art and described in EMULSIONS THEORY AND PRACTICE by PAUL BECHER published by REINHOLD PUBLISHING CORP., and prepared by any of the methods and employing any of the equipment referred to therein:- Water in Oil, Oil in Water, Multiple Emulsions, Microemulsions or any combination thereof.

22. A composition as in any preceding claim for conditioning, moisturising, protecting or providing emollience to the skin taking the form of a moisturising cream or lotion, sun cream or lotion, hand and body cream or lotion, cleansing cream or lotion, sports cream or lotion, moisturising foundation, tinted moisturising cream or lotion, cosmetic stick, rouge, gel or the like.

23. An emulsion as in any preceding claim used consecutively, conjointly, or as a single composition with other skin conditioning compositions.

24. A composition as in any preceding claim wherein any of the following cosmetically active ingredients well known to those skilled in the art and described in HARRY'S COSMETICOLOGY are present at art established levels :- Moisturisers, Sunscreens, Germicides, Deodorants, Astringents, Antiperspirants, Exfoliatives, Depilatories, Herbal Extracts, Vitamins and the like.

25. A composition as in any preceding claim wherein a therapeutically active substance or precursor of same belonging to the following categories is present at art established levels : Loacal Anaesthetic, Non Steroidal Anti-Inflammatory; Rubefacient, Oestrogen, Androgen, Progestogen, Anti-Androgen, Mineralocorticoid, Glucocorticoid, Anti-Viral, Anti-Microbial, Anti-Neoplastic, Anti-histamine and the like.

26. A composition as in any preceding claim wherein a biologically active substance belonging to any of the following categories is included at art established levels :- Bioactive Macromolecules, Biological Response Modifiers, Immunogenic Determinants, Enzymes, Enzyme Inhibitors, Antibodies, Antigens, Genetic Material, Glycosides, Placenta and Umbilical Cord extracts, Diagnostic Agents, Radiolabled Tracers and the like.

27. A method by which the Bio-Availability of a topically applied cosmetically, biologically, or therapeutically active substance may be controlled within definable and reproducible limits by the formulator consisting of either varying the affinity of the composition of this invention for said active substance or by controlling the fluidity of the lipid film compositions of this invention deposit upon the skin.

28. A method of enhancing the penetration or absorption of active substances by including in compositions of this invention membrane disrupting agents, enzyme systems and the like.

29. A method by which a therapeutically, biologically or cosmetically active substance may be delivered percutaneously in such a way that a safe and effective amount of a composition according to any preceding claim is topically applied to the skin of a human or lower animal.

30. A composition comprising an emulsion according to the present invention presented in the form any of the Pharmaceutical Preparations aforementioned.

31. An emulsion as in any preceding claim wherein the fatty phase comprises from 2% to 98% of the total emulsion but preferrably from 4% to 40%.