AU7224200A - Methods of delivering materials into the skin and compositions used therein - Google Patents

Description

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Methods of delivering materials into the skin and compositions used therein The following statement is a full description of this invention including the best method of performing it known to us:- METHODS OF DELIVERING MATERIALS INTO THE SKIN, AND COMPOSITIONS USED THEREIN Field of the Invention The present invention relates generally to a skin care composition, and methods for delivering an active agent to skin.

Background of the Invention Excessive drying of the skin is a common problem which is often the result of exposure to wind, sun and low humidity, or a combination of these factors. Frequent washing of the hands can also result in excessive drying.

This is particularly true if abrasive soaps, alcohol-based products and other harsh chemicals are used for cleansing.

Skin that has been excessively dried is not only unsightly, but also tends to slough off excessively and to crack, leading to abrasions of the skin .i surface. Because the skin serves a key role as a physical barrier to the entry oo"* 20 of parasites and pathogens, excessive drying can lead to a breach of the .i barrier and infection by pathogenic barrier and fungi. Thus cracks or openings in the skin serve as a portal of entry for pathogens and potential oo pathogens. Even organisms that are normally considered to be nonpathogens can result in opportunistic infection in immunologically 25 comprised individuals. Infections may be mild or severe and may be localized to the initial site(s) of infection or may be systemic and spread throughout the body. Such spread may occur by direct extension to S: contiguous tissues, or by way of the lymphatics and ultimately by way of the bloodstream.

30 Thus, the frequent application of many prior art skin cleansing compositions contributes to skin damage, and therefore may indirectly increase the risk of skin infections. Many prior art skin moisturizers contain petroleum products which dissolve latex gloves as worn by workers in diverse fields, including the health care field.

Similarly, many prior art moisturizers contain animal-derived products, such as lanolin. It is known that certain animal-derived products may cause skin allergies and/or dermatitis.

Skin care products of the instant invention are preferably formulated to implement the absorption of the composition by the skin. In particular, skin care products of the instant invention comprise a absorption-implementing micro-carrier material. The absorption implementing micro-carrier material of choice under the invention is a form of ceramic hydroxyapatite. Ceramic hydroxyapatite under the invention is in the form of macroporous spheres of predetermined size range, and is chemically pure. It is formed by the agglomeration of crystals of hydroxyapatite, of 0.05 to 0.10 micrometer size range, into spherical particles which are then sintered at high temperature to provide mechanically-, physically- and chemically-stable spheres. Ceramic hydroxyapatite which is useful in the practice of the instant invention is exemplified by that manufactured by the Asahi Optical Company, Tokyo.

Ceramic hydrozxyapatite has been widely used as a chromatographic separation medium (see, for example, R. Kasai et al. J. Chromatography 407, 205(1987); S. Tsuru, et al. J. Immunol. Methods 106, 169 (1988); T. Kadoya et al. J. Liquid Chromatography 9,3543 (1986); T Kadoya et al. J. Liquid 20 Chromatography 11,2951 (1986)).

Apart from ceramic hydroxyapatite referred to above, hydroxyapatite i has been produced in several other forms, each with a characteristic particle *e morphology, size distribution and surface structure, as observed by scanning electron microscopy Kadoya et al J. Liquid Chromatography 9,3543 (1986).

25 Hydroxyapatite has also been ascribed various non-chromatographic applications. For example, JP 254415 discloses cosmetic materials containing Sspherical hydroxyapatite. JP 266066 teaches a melanin-lightening composition including ethyl alcohol and sodium hydroxide. JP 007409 teaches the use of hydroxyapatite for the selective removal of protein from the 30 body surface. JP 179074 discloses the use of hydroxyapatite as an abrasive, to Sassist in the cleaning of inanimate surfaces. JP 238429 discloses a blending agent, comprising polystyrene beads coated with hydroxyapatite.

Summary of the Invention In a first aspect, the present invention provides a composition for delivering at least one active agent to the skin of a subject, said composition comprising: at least one active agent loaded into a micro carrier selected from the group consisting of hyaluronic acid and chemically pure ceramic hydroxyapatite.

Preferably, the active agent is selected from the group consisting of charged molecules, lipids, proteins, peptides, water and nucleic acids.

Further, it is preferred that the chemically pure ceramic hydroxyapatite is in the form of particles having a mean diameter of from 1 to 10 micrometers.

It is also preferred that the chemically pure ceramic hydroxyapatite particles have pores of uniform size and regular shape, ranging from 0.05 to 0.10 micrometers in diameter.

In a second aspect, the present invention provides a method for promoting healing of damaged skin comprising applying to said skin a composition according to the first aspect.

In a third aspect, the present invention provides a method for delivering an active agent to skin, said method comprising, topically applying to said skin a composition comprising at least one active agent loaded into a micro carrier selected from the group consisting of hyaluronic acid and chemically pure ceramic hydroxyapatite.

a fourth aspect, the present invention provides a method for delivering in active agent to skin, said method comprising: topically applying to said skin the composition according to the first aspect.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the .:eeo) exclusion of any other element, integer or step, or group of elements, integers or steps.

Detailed Description of the Invention The skin or integumentary system is an essential, physiologically and anatomically specialized boundary lamina. It covers the entire external surface of the body. The total area of skin in an adult is between 1.2 to 2.2 m 2 and comprises about 10% of the total body mass, making it the largest organ of the 4 human body. Functionally, the skin acts as an interface between the internal and external environment, and fulfils thermoregulatory, sensory, and other functions, as well as playing a key role as a highly effective physical barrier against infectious agents and dehydration. The skin also acts as a barrier against mechanical, chemical, osmotic, thermal and photic damage.

The condition of the skin is generally considered, by medical practitioners and lay people alike, to reflect the state of health, age and other aspects of life of an individual.

o Histologically, three major tissue layers are identified. The uppermost layer, the epidermis, is a relatively thin stratified squamous epithelium which is itself composed of five strata. Subjacent to the epidermis is the dermis, a dense fibroelastic connective tissue stroma. The third layer, lying beneath the dermis is the subcutaneous layer composed of areolar and fatty connective tissue.

There are three basic cell types in the epidermis: keratinocytes which produce keratin, melanocytes which are involved in pigmentation, and Langerhans cells which aid the immune system by intercepting foreign bodies in the skin. In the epidermis a mitotic layer at the base provides keratinocytes which continuously replace those shed at the skin surface.

The epidermis can be divided into layers according to the stage of maturation of kerainocytes within it. These layers are, from deep to superficial, as follows: stratum basale, stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum. The first three of these layers are metabolically active, while the two upper layers which have 15 attained terminal keratinization constitute the cornified zone. Cells of the stratum comeum eventually become detached from the epidermal surface and are replaced from below.

S.

Typically the time taken for a newly-formed keratinocyte to pass to the surface and be shed ranges from 75 days. However, under certain pathological conditions of the skin, turnover rates are much higher. As a result keratinization is incomplete and the normal barrier functions of the skin are lost.

The dermis comprises a strong yet flexible layer which consists primarily of collagen. This layer, which contains nerves, blood vessels, hair follicles, sebaceous glands and apocrine glands, fulfills vital roles in thermoregulation and sensory perception. The sebaceous glands produce sebum, a natural lipid material which helps to prevent drying, cracking and excessive shedding of the outer layers of the skin.

Compositions for delivering at least one active agent to the skin of a subject according to the invention are described below.

i. Antimicrobial component The present invention provides compositions which may comprise an antimicrobial agent which functions to inhibit the growth of pathogenic or potentially pathogenic bacteria and fungi, or to kill such organisms. Thus the antimicrobial agent may be bacteriostatic, bacteriocidal, fungistatic or fungicidal in its action.

A preferred antimicrobial agent for use under the invention is Triclosan. This agent used in the formulation has been found effective against the whole genera of microorganisms, (for example: bacteria, fungi, Pseudomonas aeruginosa, Pseudomonas capacia, Staphylococcus aureus, Escherichia coli, Candida albicans, Aspergillus niger, Salmonella typhimurium, Thus, the antimicrobial component of the composition is effective in both preventing infection via the skin and in preventing the 20 spread and transmission of pathogenic microorganisms. The antimicrobial agent is normally present in an amount of from 0.001-5% by weight, preferably from 0.05-2% by weight, and more preferably from 0.1-1% by weight.

25 ii. Water activity depressant Compositions according to the invention may also comprise one or more water activity depressants, the function of which is, in part, to inhibit the growth of microorganisms during product storage and to preserve the product. Water activity depressants, with or without the inclusion of an antibiotic chemical, help to prevent the growth of spoilage organisms. Examples of water activity depressants include sorbitol, propylene glycol, sugars, and alkali metal salts, including carboxylates, halides, and sulfates. A preferred water activity depressant is sorbitol. The sorbitol component of the composition is preferably present in a concentration of from 1-20% by weight, more preferably from 1-10% by weight, and most preferably from 1-2% by weight.

iii Micro-carrier Compositions under the invention comprise one or more microcarriers. The function of such a micro-carrier is, in part, to implement the uptake of the product by the skin. Uptake of the product prevents excessive loss of moisture from the skin surface and promotes product contact with the metabolically active cells of the dermis and epidermis beneath the cornified zone of the stratum lucidum and stratum corneum.

A preferred micro-carrier is ceramic hydroxyapatite. Ceramic hydroxyapatite also functions as an unbound/excess lipid remover and antimicrobial function enhancer. Ceramic hydroxyapatite used under the invention is a form of chemically pure calcium phosphate (molecular formula Cato(PO 4 which is produced as spheres with a controlled diameter. Preferably the median diameter of ceramic hydroxyapatite under 20 the invention is in the range of 1-10 micrometers, more preferably in the range of 2-6 micrometers. Ceramic hydroxyapatite spheres are manufactured by the agglomeration of small crystals (50-100 nm size range) followed by sintering at high temperature. As a result of this process, each sphere is porous and can act as a miniature sponge. This characteristic of ceramic 25 hydroxyapatite spheres allows it to absorb, carry and subsequently release components of the composition to which it has been bound.

Ceramic hydroxyapatite having a mean particle diameter in the range of 2-6 micrometers can act as an efficient absorption implementing agent for liquid phase 8 materials. The carrier and absorption enhancing properties of ceramic hydroxvapatite is due to both its porosity anid its affinity for various substances. For example, ceramic hydroxyapatite has the ability to bind water, charged molecules, lipids, proteins, and nucleic, acids. The porous nature of ceramic hydroxyapatite allows it to bind and then slowly release a relatively large volumne of liquid-phase-bound materials.

Due to the small spherical nature of the ceramic hydroxyapalite particles, it may also act as a lubricant.

Conventional non-ceramic) hydroxyapatite is known to bind to biological molecules, including proteins, lipoproteins, lipids and nucleic acids ((see, for example, D.

Josic et al. BioL Chem. 1-ioppe-Seyler 3 72, 149 (199 K.3 Primes et al. J ChromatogrcTphy, 236, 519 (1982); S. I~jerten, Biochim. Biophys. Acta, 31, 216 (1959); G.

B erardi and W.H. Cook, ibid. 44, 96 (1960); R.K. Main et al. J Am. Chem. Soc. 8 1, 6490 ((1959); A. Tiselius et al. Arch. Biochem. Biophys. Acta 65, 132 (1956)). However, in comparison to ceramic hydroxyapatite, conventional hydroxyapatite is produced as particles which are more irregular in shape and in size, and also more fragile. Ceramic hydroxyapatite is also superior to conventional hydroxyapatite in that cerarnic hydroxyapatite spheres are resistant to high temperature and pressure, and are much more physically stable than conventional hydroxyapatite. KadoYa et i. J1. Liquid Chromatographry, 9, 3 543 (1986). This physical stability allows for the agitation or mixing of ceramic hydroxyapatite without disintegration of the particles. Ceramic hydroxyapazite 0 is also more stable chemnically than conventional hydroxyapatite, being stable for at least **.five years when stored at room temperature in dry or hydrated form.

Because hydroxyapatite binds lipids. see, K.i. Primes et al. J Chromatography, 236, 519 (1982)), ceramic hydroxyapatite, under the invention, may bind to lipid constituents of the instant compositions, as well as to lipid components of the skin. Ceramic hydroxyapatite has the additional advantage in the context of the present invention of binding to proteins much more strongly than does conventional hydroxyapatite. In binding to proteins of the skin, ceramic hydroxyapatite under the invention can act as a bridge between the proteins of skin cells and bound lipids. The resulting layer of bound lipid molecules can serve as an effective protective film to prevent dehydration of, and damage to, the skin.

Finally, ceramic hydroxyapatite, due to its propensity to bind to biological molecules, may bind to various surface components of microbial cells and promote the immobilization and inactivation of microorganisms.

Ceramic hydroxyapatite is preferably present in compositions under the invention at a concentration of from 0.001-10%, by weight, more preferably 0.01-5% by weight, and even more preferably from 0.05-1% by weight.

iv. Vehicle or Delivery System The compositions according to the invention may also comprise a liquid, solid or semi-solid physiologically and cosmeceutically acceptable 0 .s vehicle or carrier. A suitable vehicle, under the invention, may act variously 20 as a solvent, diluent or dispersant for the constituents of the composition, and allows for the uniform application of the constituents into the skin at an appropriate dilution. It will be apparent to the skilled artisan that the range of possible vehicles is very broad. In general, compositions according to this invention may comprise at least one physiologically and cosmeceutically acceptable vehicle.

sees Vehicles that can be used in compositions under the invention may be liquids or solids, including emollients, various solvents, powders, and humectants. Carriers may be o used singly or in combination. Suitable carriers may include, but ame not limited to, the following examples: castor oil, ethylene glycol monobutyl ether, diethylene glycol rnonoethyl ether, corn oil, dimethyl sulfoxdde, ethylene glycol, isopropanol.

soybean oil, glycerin, soluble collagen, zinc oxide, titanium dioxide, Kaolin, hyaluronic acid.

The active constituents of the skin care compositions according to the invention may be soluble or insoluble in a liquid carrier. If the active constituents are soluble in the carrier, the carrier acts as solvent for the active ingredient. If the active constituents are :insoluble in the carrier, they are dispersed in the carrier by means of for example, a suspension,- emulsion, gel, cream or paste, and the like. Various oils, such as vegetable oils obtained from any of corn, sunflower, safflower, soybean, canola, and the like, may also be used as a vehicle, either alone or in combination. Various oils may also be used in combination with water following emulsification.

v. Water In general, compositions according to this invention may comprise water. When water is used in the invention, preferably the water is deionized. Water is a preferred solvent and/or diluent for the active constituents in the compositions of the present invention. Water may be used singly or in combination with another solvent and/or diluent.

Ai. Humectant Compositions under the invention may Optionally comprise one or more humectats, for example: dibutyl phthalate, gelatin, glycerin, soluble collagen, .sorbitol, sodium A preferred humectant under the invention, is glycerin.

vii. Emollient Compositions under the invention may optionally comprise one or more **~emollients, for example, butane- 1,3-diol, cetyl palmitate, dimethylpolysiloxane, 12 glyceryl monoricinoleate, glyceryl monosteatC.

isobutyl palmitate, isocetyl stearate.

s isopropyl palmitate, isopropyl stearate, butyl stearate, isopropyl Iaiirate, hexyl laurate, decyl oleate, isopropyl. myristate, lauryl lactate, octadecan-2-ol, :caprylic triglyceride, capric triglyceride, palmitic acid, polyethylene glycol, propane- 1,2-diol, stearic acid, 1riethylene glycol, sesame oil coconut oil, safflower oil.

isoarnyl laurate, 13 nonoxynol-9.

panthenol, hydrogenated vegetable oil, tocopheryl acetate, tocopheryl linoleate, allantoin, propylene glycol, arachis oil, castor oil, isostearic acid, paliritc acid, isopropyl linoleate, lauryl lactate, rnyristyl lactate, decyl oleate, myristyi myristate.

viii. Sun Blockinf Aeent The compositions, according to the invention, may optionally comprise a sun blocking agent. A preferred sun blocking agent under the invention is octyl paintitate.

iL Anti-inflamnmatory Apent The compositions, according to the invention, may optionally comprise an anti-inflammatory agent. Preferred anti- inflammatory agents, under the invention, include extracts of Aloe vera, parithenol, tocopheryl acetate, and tocopheryl linoleate.

14 zL Preservative Other than water activity depressants and antimricrobial components, such as Triclosan, the compositions, according to the invention, may optionally comprise one or more preservatives such as polymethoxy bycyclic oxazofidine, methyl paraben, propyl paraben and DMDM hydantoin.

ii. Viscosity Enhancr or Thicken in! Avent The compositions, according to the invention, may optionally comprise a viscosity enhancer or thickening agent. Viscosity enhancers of' vairious classes may be chosen,* including microbial polysaccharides, such as xanthan gum; cellulose derivatives, such. as' inethylcellulose, carboxyrnethylceilulose, hydroxypropylmethylcellulose and hydroxyethylceoulose; and sorbitol.

iii. Emlirier The compositions, according to the invention, may also comprise one or more emulsifiers. Preferred emulsiiers under the invention include: polysorbate-60, sorbitol, *is and sorbitan stearate. Such emiulsifiers may be incorporated into the instan compositions singly or in any combination.

xiii. Vitamins. Proteins and Derivatives Thereor The compositions, according to the invention, may also comprise one or more ingredients which are vitamins, proteins or derivatives thereof& other than those which .20 may be present in other components of the instant compositions. Vitamins, proteins or derivatives thereof may be incorporated into the compositions of the invention either singly or in an combination. Examples of vitamins, proteins or derivatives thereof which may be included in the compositions under the invention include: tocopheryl acetate, toohey linoleate, patenl wheat oligosaccharides and hyrlye wheat prtis xiv. Surfactant The compositions, according to the invention, may optionally comprise one or more surfactants. Surfactants used under the invention are preferably mild or very mild detergents. Preferred surfactants under the invention include: sodium laureth sulfate and cocamide DEA.

xv. Citric acid The compositions according to the invention may also comprise citric acid, a naturally occurring compound present in both plant and animal cells as an intermediate of the Tricarboxylic acid cycle and in relatively high concentrations in citrus fruit. It is preferred that only plant and no animal byproducts are used. Under the invention, citric acid is preferably present in a concentration of from 0-10% by weight, more preferably from 0-5% by weight, and most preferably from 0 to about 2% by weight. The concentration of citric acid may be adjusted slightly to provide a suitable pH.

xvi. Allantoin 15 The composition according to the invention may also comprise allantoin.

P

Allantoin is a natural product which occurs in both plants and animals, plants being preferable here. Allantoin is considered to stimulate cell proliferation and promote healing of the skin. The allantoin component of the composition is preferably present in a concentration of from 0-5% by weight, preferably from 0.01-2% by weight.

xviL Aloe vera components The composition according to the invention also comprises a cosmetically and physiologically acceptable preparation obtained from the Aloe vera plant. Constituents of this plant are reported to prevent infection, promote wound healing, and to have antifungal properties. The gel obtained from Aloe vera leaves are said to be useful for dry 16 skin conditions. The Aloe vera gel has also been recommended for treating fungal skin infections. The Aloe vera component of the composition is preferably present in a concentration of from 0. 1-10% by weight, more preferably from 0.2-5% by weight, and most preferably from 0.5-1.5% by weight.

xviii. Natural Scents The composition according to the invention also comprises one or more natural scents. Natural scents added to the skin care compositions under the invention impart a pleasant, mild scent, and are formulated to avoid any negative impact on the skin such as drying, irritation or allergies. For example, natural scents may be obtained from plant materials in the form of essential oils by the process of fractional distillation, thus avoiding extraction procedures involving organic solvents.

ix. Other Plant or Herbal Extracts The compositions according to the invention also comprise one or more natural plant or herbal extracts, including matricaria extract, comfrey extract, and cucumber 15 extract. Under the invention, natural plant extracts are preferably present in a concentration of from 0-5% by weight, more preferably from 0-2% by weight, more preferably from 0 to about 0.8% by weight.

Medicinal use of the herb known as comfrey dates back at least to the time of the Ancient Egyptian civilization, and it has been widely used as a herbal remedy for hundreds if not thousands of years (see, for example, P. Ody (1993) The Complete Medicinal Herbal, Dorling Kindersley, London, New York, Stuttgart). Nicholas Culpeper, an Elizabethan herbalist listed comfrey as being amongst the most effective natural healing *agents. The English physician Charles J. Macalister, M.D. used comfrey topically to treat "serious skin lesions with remarkable results J. Macalister (1936) Narrative ofan 17 hinwstigazon Conicerning anAnciet Mcdici flt medv wad its Airern Ulilities.

Republished 1955, The Lee Foundation for Nutritional Research, Milwaukee, WI). Ode constituent of comafrey considered to be responsible for its medicinal properties is allatoin.

Matricaria is another herb that has been used medicinally since antiquity. Among the skin conditions for which Matricaria has been recommended are: various sores and wounds, eczem and inflamnmation.

Without being limnited by any theory of mode of action of any of these constituents, it is believed that topical use of the instant skin care compositions not only, helps to maintain treated skin in a healthy condition, but also promotes healing of dry, cracked sore, or damaged skin.

XL~f In the case of the sin cleanser composition, the preferred pH is in the range of to 8.0; more preferably the pH is in the range of 6.5 to 0 00S* 15 The preferred pH of the skin moisturizer composition is in the range of 5.0 to ~more preferably the pH is in the range of 6.0 to In one embodiment, the composition of a skin moisturizer under the invention comprises for example, a humectant, an emollient, a carrier or mnicro-carrier, an antimicrobial agent, an antimicrobial function enhancer, an unbound/excess lipid remrover.

a vitamnin, protein or derivative thereof, plant extract, natural scents, and water.

:In a preferred embodiment, the composition of a skin moisturizer under the invention comprises, for example, the folowinga humnectant, such a's glycerin; 18 a carrier or micro-crier, such as hyaluronic acid or ceramic hydroxyapaite, an antimicrobial function enhancer, such as ceramic hydroxyapatite, an unbound/excess lipid remover, such as ceramic hydroxyapatite; an emollient, such as glyceryl stearate, allantoin, or nonoxynol-9; an antimicrobial agent, such as Triclosan; an anti-inflammatory agent, such as Aloe vera extract, or panthenol; an emulsifier, such as polysorbate a preservative, such as DMDM hydantoin; a sun block agent, such as octyl palmitate, a vitamin or derivative thereof, such as tocopheryl acetate or wheat oligosaccharides; a protein or derivative thereof, such as hydrolyzed wheat proteins; a plant extract, such as comfrey extract, or Matricaria extract; a natural scent, such as oil of citrus fruit; and water.

Methods, under the invention, for preparing a skin moisturizer composition comprise the steps of formulating the constituents of each composition as four separate Phases, and subsequently combining each Phase.

The skin moisturizer composition may be formulated according to the following Example.

*SS

e.

e• 19 EXAMPLE 1 Formulation of Skin Moisturizer Composition Phase M A suitable volume of deionized water at ambient temperature was metered into a first stainless steel vessel or tank, and the mixer was turned on. Ingredients of Phase 1M, comprising nonoxynol-9, Aloe vera extract and panthenol were then added, and the mixture was slowly heated to a predetermined temperature. Preferably Phase IM of the composition is heated to a predetermined temperature in the range of 30 to 95 more preferably in the range of 40 to 900 C, and most preferably in the range of 50 to 80* C. In a preferred embodiment, methyl paraben is added after heating has begun, when the temperature of Phase IM is in the range of 30 to 950 C, more preferably when the temperature of Phase IM is in the range of 40 to 900 C, and most preferably when the temperature of Phase IM is in the range of 50 to 800 C.

b) Phase 2M •15 The ingredients of Phase 2M comprising glycerin and ceramic hydroxyapaite, were combined in a suitable second vessel and mixed thoroughly until completely homogeneous.

o Phase 2M was added to the first vessel when the predetermined temperature for Phase IM had been attained.

c) Phase M The constituents of Phase 3M, comprising stearic acid, octyl palmitate, tocopheryl acetate, safflower oil, and hydrogenated vegetable oil, were combined in a stainless steel third vessel, S and the mixture was heated towards a predetermined temperature. Preferably the predetermined temperature for Phase 3M is in the range of 30 to 95° C, more preferably in the range of 40 to 90 0 C. and most preferably in the range of 50 to 80° C.

When most of the solid constituents had melted the mixer for the third vessel was tunied on. When the temperature of the contents of both the third and first vessels attained their respective predetermined temperatures, Phase 3M was added to the first or main vessel, and the contents were mixed well.

After thorough mixing, heating was discontinued and the contents of the first vessel were allowed to cool.

d) Phase 4M The ingredients of Phase 4K, comprising tocopherol linoleate, matricaria. extract and comnfrey extract, were combined in a suitable fourth vessel, and heated to a predetermined temperature. Preferably the predetermined temperature for Phase 4M is in the range of 30 to 600 C. more preferably in the range of 3 5 to 5 50 C, and most preferably in the range of 40 to 550 C. When the temperature of the contents of the first vessel were at the same or a similar temperature as the predetermnined temperature for Phase 4, the ingredients of Phase 4 were transferred from the fourth vessel to the first vessel with thorough mixing. Heating was 0 0 15 discontinued and the mixture was allowed to cool.

When the mixture was at a suitable temperature, preferably in the range of 20.400 C, *.:more preferably in the range of 25-35* C, natural scent was added, and the mixture was thoroughly stirred until homogeneous.

The skin moisturizer composition of the current invention provides a smooth moisturizer, wvhich is white or slightly off-white in cooanda a dlcate scent ofcitus ftit. At a temperature of 250 C, it has a pH in the range of 6-7, a viscosity in the range of 3500-6500 and preferably 4,400-5, 100 centipoise, and a specific gravity near *e In one embodiment. the composition of a sin cleanser under the invention comprises, for example, an antimicrobial agent, a viscosity enhancer, a carrier or micro-carrier, an 21 antimicrobial funcuion enhancer, and an unboundlexcess lipid remover, a vitamin, protein or derivative thereo& plant extract, natural scent, and water.

In a preferred embodiment. the composition of a skib cleansr under the invention comprises, for example, the following: an antimicrobial agent, such as Triclosan; an antimicrobial finction enhancer. such as ceramic hydroxyapatite, and an unbound/excess lipid remover, such a~s ceramic hydroxyapatite; an emollient, such as propylene glycol, nonoxynol4,; an anti-inflammatory agent, such as Aloe vera extract, paxnthenol; a surfactant, such as cocamide DEA. sodium laureth sulfate; an emulsifier, such as polysorbate 60, sorbitan stearate;, a preservative, such as propyt paraben, methyl paraben., a sun block agent, such as octyl palmitate; a vitamin or derivative thereof such as tocopheryl linoleate or wheat ollgosaccharides; 4. .15 a protein or derivative thereo such as hydrolyzed wheat protein; :a plant extract, such as comnfrey extract, or matricaria. extract, natural scent, such as oil of cucumber; and water.

Methods, under the invention, for preparing the skin cleanser composition comnprise the steps of formulating the constituents of each composition as four Phases, and subsequently combining each Phase sequentially.

The skin cleanser composition may be formulated according to the foi~lowing Example.

22 EXAMPLE 2 Formulation of Skin Cleanser Composition a) Phase 1C A suitable volume of deionized water at ambient temperature was metered into a first stainless steel vessel or tank, and the mixer was turned on. Ingredients of Phase IC, comprising sodium laureth sulfate, Aloe vera extract, citric acid and panthenol were then added, and the mixture was thoroughly stirred.

b) Phase 2C The ingredients of Phase 2, comprising sorbitol and ceramic hydroxyapatite, were combined in a suitable second vessel and mixed thoroughly until completely homogeneous.

Phase 2 was added to the first vessel.

c) Phase 3C The constituents of Phase 3C, comprising propylene glycol, Polymethoxy Bycyclic Oxazolidine and Triclosan, were combined in a suitably sized third vessel, and the contents 15 were thoroughly mixed. Mixing was continued and the mixture was heated until the mixture was homogeneous and it attained a predetermined temperature. Preferably the predetermined temperature for Phase 3C is in the range of 35 to 95° C, more preferably in the range of 45 to 85° C, and most preferably in the range of 55 to 75* C. Heating was discontinued and the mixture was allowed to cool. When the temperature of Phase 3C in the third vessel was in the range of 15 to 350 C, and preferably in the range of 18 to 25* C, Phase 3C was transferred to the first vessel, and the contents were mixed well.

*o° e, 06 **eo 23 d) Phase 4C Mixing of the contents of the first vessel was continued while the ingredients of Phase 4C at ambient temperature, comprising nonoxynol-9, cocamide DEA, comfrey extract, and matricarii extract, were added sequentially to the first vessel.

Finally, natural scent was added to the mixture in the first vessel, and the ixture was thoroughly stirred until homogeneous.

The skin cleanser composition of the current invention provides a smooth, viscous liquid which is clear to slightly opaque, and has a slight scent of cucumber. At a temperature of C, it has a pH in the range of 6.5-7.5, a viscosity in the range of 3,000-4,000, even more preferably in the range of 3200-3800 centipoise, and a specific gravity near approximately A preferred embodiment of the skin moisturizer composition according to the invention comprises the constituents shown in the following Example.

EXAMPLE 3 Skin Moisturizer Composition S. 15 Phas.I comprises: ,00* Deionized water, to 100% w/w; Panthenol, up to 10% w/w; Methyl paraben, up to 5% w/w, and Aloe vera extract, up to 7% w/w.

*20 Phase 2 comprises: Glycerin, up to 10% w/w, and Ceramic hydroxyapatite, up to 5% w/w.

Eal comprises: Staic acid, up to Stearic acid, up to 10% w/w; 24 Tocopherol acetate, up to 5% w/w, Octyl palmitate, up to 10% w/w; Saffower oil, up to 10% w/w; Hydrogenated vegetable oil, up to 10% w/w; Propyl paraben, up to 5% w/w; and Triclosan, up to 1% w/w.

EhasA 4 comprises: Plant extract for example. extract of comfrey, matricaria up to 5% w/w; Tocopheryl linoleate, up to 5% w/w; Allantoin, up to 5% w/w; and Oligosaccharides and Hydrolyzed wheat protein.

A further constituent of a preferred embodiment of the skin moisturizer composition is natural oil of citrus in the range of 0.01-0.1% w/w.

A preferred embodiment of the sldkin cleanser composition according to the invention 15 comprises the constituents shown in the following Example.

EXAMPLE 4 Skin Cleanser Composition

OS

Phase I comprises: Deionized water, to 100% w/w; 0@SO 20 Panthenol, up to 10% w/w; Aloe vera extract, up to 7% w/w; and Citric acid, up to 10% wlw.

**Phase 2 comprises: Sorbitol, up to 10% w/w; and Ceramic hydroxyapatite, up to 5% w/w.

Phase 3 comprises: Methyl paraben, up to 5% w/w; Propyl paraben, up to 5% w/w; Propylene glycol, up to 10% w/w; Disodium ethylenediaminetetraacetic acid, up to 2% w/w; and Triclosan, up to 1% w/w.

Phase 4 comprises: Plant extract for example, extract of comfrey, Matricaria up to 5% w/w; Nonoxynol-9; Hydroxypropyl methylcellulose; and Wheat Oligosaccharides and Hydrolyzed wheat protein.

A further constituent of a preferred embodiment of the skin cleanser composition is natural oil of cucumber in the range of 0.01-0.1% w/w.

The present invention having been described in various embodiments, it will be apparent to one of ordinary skill that many modifications can be made thereto which nevertheless utilize the methods and compositions of the invention as disclosed. The scope of the invention is defined by the appended claims rather than the embodiments presented above.

20 Any discussion of prior art documents, acts, materials, devices, articles or the like which has been included in the present specification has been so solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior *art base or were common general knowledge in the field relevant to the present 25 invention as it existed before the priority date of each claim of this application.

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Claims (7)

1. A composition for delivering at least one active agent to the skin of a subject, said composition comprising: at least one active agent loaded into a micro carrier selected from the group consisting of hyaluronic acid and chemically pure ceramic hydroxyapatite.

2. The composition according to claim 1 wherein said active agent is selected from the group consisting of charged molecules, lipids, proteins, peptides, water and nucleic acids.

3. The composition according to claim 1 or claim 2 wherein said chemically pure ceramic hydroxyapatite is in the form of particles having a mean diameter of from 1 to 10 micrometers.

4. The composition according to claim 3, wherein said chemically pure ceramic hydroxyapatite particles have pores of uniform size and regular shape, ranging from 0.05 to 0.10 micrometers in diameter. 20

5. A method for promoting healing of damaged skin comprising applying to said skin a composition according to any one of claims 1 to 4.

6. A method for delivering an active agent to skin, said method comprising, topically applying to said skin a composition comprising at least one active agent 25 loaded into a micro carrier selected from the group consisting of hyaluronic acid and chemically pure ceramic hydroxyapatite.

7. A method for delivering in active agent to skin, said method comprising: topically applying to said skin the composition according to any one of claims 1 30 to 4. Dated this twelfth day of December 2000. ZAHRA MANSOURI Patent Attorneys for the Applicant: F B RICE CO