CA2584797C - Methods of delivering materials into the skin, and compositions used therein - Google Patents
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Abstract
The invention relates to a water-based volatile-alcohol-free cleanser composition comprising triclosan in an amount sufficient to kill microorganisms on skin; a non-irritating amount of a detergent; and at least one herbal extract and also to a composition of matter for application to the skin, said composition comprising macroporous ceramic hydroxyapatite particles and a physiologically and cosmetically acceptable vehicle other than water, wherein said vehicle is formulated for application to the skin.
Description
METHODS OF DELIVERING MATERIALS INTO THE SKIN, AND COMPOSITIONS
USED THEREIN
This application is a divisional application of Canadian Patent Application Number 2,510,933 filed June 13`", 1996 which itself is a divisional of Canadian Patent Application Number 2,199,993 filed on June 13th, 1996.
Field of the Invention The invention relates generally to a method of making skin care products and to methods of using such products. This invention also relates to skin care products which moisturize the skin and prevent excessive drying of the skin.
This invention further relates to skin care products which are antimicrobial and help prevent infection by pathogenic microorganisms, and which mitigate against the spread of such pathogens.
In particular, the invention is concerned with formulations for cleansing and moisturizing skin which are antimicrobial, have a water base, and comprise a micro-carrier to deliver materials into the skin. The formulations are free of alcohol, lanolin, fragrance, petroleum-based components or animal by-products.
This invention still further relates to skin cleaning products which are antimicrobial, and non-irritating and non-drying to the skin after frequent use. The instant invention further relates to skin moisturizing products which are antimicrobial, non-greasy, and which rapidly penetrate the outer layers of the skin, and which form a shield to prevent loss of moisture from the 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 surface.
Because the skin serves a key role as a physical barrier to the entry of parasites and pathogens, excessive drying can lead to a breach of the barrier and infection by pathogenic bacteria and fungi.
Thus cracks or openings in the skin serve as a portal of entry for pathogens and potential pathogens. Even organisms that are normally considered to be non-pathogens can result in opportunistic infection in immunologically 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 contiguous tissues, or by way of the lympahtics and ultimately by way of the bloodstream.
Thus, the frequent application of many prior art skin cleansing compositions contribute 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 invention of the parent application allow for frequent use of the products to protect the skin and prevent damage due to drying. In so doing, skin care products under the invention help to prevent infection of the skin itself and entry of pathogens through the skin where they may infect underlying tissues.
Skin cleansing products of the invention of the parent application are formulated not only to accommodate continued frequent use without causing drying and cracking of the skin but also, by the inclusion of one or more antimicrobial agents, to prevent the transmission and spread of pathogenic or potentially pathogenic microorganisms.
Skin care products of the invention of the parent application are formulated to implement the absorption of the composition by the skin. In particular, the skin care products comprise an absorption implementing micro-carrier material. The absorption implementing micro-carrier material of choice is a form of ceramic hydroxyapatite.
Ceramic hydroxyapatite is in the form of macroporous spheres of predetermined size range, and is chemically pure. It is formed by the agglomeration of crystals or hydroxyapatite, or 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 is exemplified by that manufactured by the Asahi Optical Company, Tokyo. Ceramic hydroxyapatite has been widely used as a chromatographic separation medium (see, for example R. Kasai et al. J.
Chromatography 407, 205 (1987); S. Tsuri et al. J Immunol. Methods 106, 169 (1988); T.
Kadoya et al. J. Liquid Chromatography 9,3543 (1986); T. Kadoya et al J.
Liquid Chromatography 11,2951 (1986)).
Apart from ceramic hydroxyapatite referred to above, hydroxyapatite has been produced in several other fornls, each with a characteristic particle morphology, size distribution and surface structure, as observed by scanning electron microscopy (T. Kadoya et al. J. Liquid Chromatography 9,3543 (1986).
Hydroxyapatite has also been ascribed various non-chromatographic applications including in a cosmetic material containing spherical hydroxyapatite, in a melanin-lightening composition including ethyl alcohol and sodium hydroxide, the use of hydroxyapatite for the selective removal of protein from the body surface, the use of hydroxyapatite as an abrasive, to assist in the cleaning of inanimate surfaces, and its use in a blending agent, comprising polystyrene beads coated with hydroxyapatite.
SUMMARY OF THE INVENTION
The invention of this application provides a composition of matter for application to the skin, said composition comprising: macroporous ceramic hydroxyapatite particles;
and a physiologically and cosmetically acceptable vehicle other than water, wherein said vehicle is formulated for application to the skin.
Skin moisturizing products of the present invention are formulated to protect the skin and maintain the skin in a healthy condition. Skin moisturizing products of the present invention are also formulated to be antimicrobial, thereby further reducing the risk of infection by pathogens. Furthermore, the antimicrobial properties of moisturizing products of the invention reduce the risk of transmission of pathogenic and potentially pathogenic microorganisms. Skin care products of the instant invention are further formulated to rapidly penetrate the skin, whereby ingredients of the formulation are more effective.
The compositions and methods of the instant invention may be used to protect the integrity of the skin. The compositions and methods of the instant invention may also be used to promote and maintain healthy skin. The skin cleansing compositions of the instant invention may be used frequently to prevent the spread of pathogenic or potentially pathogenic microorganisms. The skin cleansing compositions of the instant invention may also be used frequently on a continual basis with minimal risk of causing drying, irritation, inflammation, or damage to the skin. The antimicrobial skin moisturizing compositions of 3a the instant invention may be used to minimize the risk of irritation and infection. The skin cleansing and moisturizing products of the instant invention do not dissolve latex and are fully compatible with the use of latex gloves. Thus, the skin moisturizing compositions of the instant invention may be used with latex gloves without the risk of dissolution of the latex or other damage to the latex barrier.
The methods and compositions of the invention may further be used to implement the rapid absorption of biologically active components by the skin. In accordance with one embodiment of the invention, the skin moisturizing composition may be used as a single application, or application may be repeated periodically over an extended time period as needed.
In accordance with another method of the invention, a skin moisturizing composition, under the invention, may be applied specifically or preferentially to the point or area of a minor cut, crack, or abrasion of the skin. Such application may protect the epidermis and the dermis from further damage and promote healing, and/or prevent infection of the skin.
The invention of a related application relates to a moisturizing composition for applying to and leaving on human skin, the composition in the form of an antimicrobial lotion composition comprising: (a) an amount of triclosan effective to kill microorganisms present on the skin; (b) an emollient present in an amount effective to moisturize the skin;
and (c) a lotion base comprised of a, physiologically and cosmeceutically acceptable vehicle wherein said components of said lotion are present in amounts sufficient to provide an effective antimicrobial lotion.
The invention of a related application also relates to an antimicrobial lotion composition for application to skin, comprising: (a) approximately 0.1 to 1.0 wt. %
triclosan; (b) an emollient present in an amount effective to moisturize the skin, wherein the emollient is cetyl palmitate, dimethylpolysiloxane, glyceryl monoricinoleate, glycerin, glyceryl monostearate, isobutyl palmitate, isocetyl stearate, isopropyl palmitate, isopropyl stearate, butyl stearate, isopropyl laurate, hexyl laurate, decyl oleate, isopropyl myristate, lauryl lactate, octadecan-2-ol, caprylic triglyceride, capric triglyceride, polyethylene glycol, triethylene glycol, sesame oil, coconut oil, safflower oil, isoamyl laurate, nonoxynol-9, panthenol, hydrogenated vegetable oil, tocopheryl acetate, tocopheryl linoleate, allantoin, propylene glycol, arachis oil, castor oil, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, or a combination thereof; and (c) a lotion base comprised of a physiologically and cosmeceutically acceptable water-based vehicle, wherein said components of said lotion are present in amounts sufficient to provide an effective antimicrobial lotion, the lotion is free of volatile alcohol, petroleum-based ingredients and animal by-products and further wherein the lotion is compatible with latex gloves.
Compositions of this invention can be used to kill microorganisms on skin.
The invention of the parent application relates to a composition for delivering at least one active agent to the skin of a subject, the composition comprising at least one pharmaceutically active agent loaded into a chemically pure ceramic hydroxyapatite micro carrier and to uses of such a composition for healing of damaged skin.
In preferred embodiments:
(a) ceramic hydroxyapatite particles are macroporous;
(b) chemically pure ceramic hydroxyapatite is in the form of particles having a mean diameter of from about 1 to 10 micrometers; and (c) ceramic hydroxyapatite particles have pores of uniform size and regular shape, ranging from about 0.05 to 0.10 micrometers in diameter.
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 m2, and comprises about 10% of the total body mass, making it the largest organ of the human body. Functionally, the skin acts as an interface between the intemal and external environment, and fulfills 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.
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 keratinocytes 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 attained terminal keratinization constitute the cornified zone. Cells of the stratum corneum eventually become detached from the epidermal surface and are replaced from below.
Typically the time taken for a newly-formed keratinocyte to pass to the surface and be shed ranges from 45-75 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 cleansing and moisturizing the skin according to the invention comprise an antimicrobial agent, an emollient and a micro-carrier in combinations as described below.
i. Antimicrobial component The present invention provides skin cleansing and moisturizing compositions, comprising 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 TM.
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, etc. ..). Thus, the antimicrobial component of the composition is effective in both preventing infection via the skin and in preventing the 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.
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 may also comprise one or more micro-carriers.
Ceramic hydroxyapatite under the invention is in the form of macroporous spheres of predetermined size range and is chemically pure.
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 comified zone of the stratum lucidum and stratum comeum.
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 Ca1 o(PO4)6(OH)2), which is produced as spheres with a controlled diameter. Preferably the median diameter of ceramic hydroxyapatite under the invention is in the range of 1-10 micrometers, more preferably in the range of 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 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 materials. The carrier and absorption enhancing properties of ceramic hydroxyapatite is due to both its porosity and 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 volume of liquid-phase-bound materials.
Due to the small spherical nature of the ceramic hydroxyapatite particles, it may also act as a lubricant.
Conventional (i.e. 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. Hoppe-Seyler 372, 149 (1991); K.J. Primes et al.
J.
Chromatography, 236, 519 (1982); S. Hjerten, Biochim. Biophys. Acta, 31, 216 (1959);
G. Bemardi and W.H. Cook, ibid. 44, 96 (1960); R.K. Main et al..I. Am. Chem.
Soc. 81, 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 ceramic hydroxyapatite spheres are resistant to high temperature and pressure, and are much more physically stable than conventional hydroxyapatite. (T. Kadoya et al. J.
Liquid Chromatography, 9, 3543 (1986). This physical stability allows for the agitation or mixing of ceramic hydroxyapatite without disintegration of the particles. Ceramic hydroxyapatite is also more stable chemically 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, e.g. K.J. 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 also comprise a liquid, solid or semi-solid physiologically and cosmeceutically acceptable vehicle or carrier. A
suitable vehicle, under the invention, may act variously 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.
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 used singly or in combination. Suitable carriers may include, but are not limited to, the following examples:
castor oil, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, corn oil, dimethyl sulfoxide, ethylene glycol, isopropanol, soybean oil, glycerin, soluble collagen, zinc oxide, titanium dioxide, talc, 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.
vi. Humectant Compositions under the invention may optionally comprise one or more humectants, for example:
dibutyl phthalate, gelatin, glycerin, soluble collagen, sorbitol, sodium 2-pyrrolidone-5-carboxylate.
A preferred humectant, under the invention, is glycerin.
vii. Emollient Compositions under the invention may optionally comprise one or more emollients, for example:
butane-l,3-diol, cetyl palmitate, dimethylpolysiloxane, glyceryl monoricinoleate, glyceryl monostearate, isobutyl palmitate, isocetyl stearate, isopropyl palmitate, isopropyl stearate, butyl stearate, isopropyl laurate, hexyl laurate, decyl oleate, isopropyl myristate, lauryl lactate, octadecan-2-ol, caprylic triglyceride, capric triglyceride, palmitic acid, polyethylene glycol, propane-l,2-diol, stearic acid, triethylene glycol, sesame oil, coconut oil, safflower oil, isoamyl laurate, monoxynol-9, panthenol, hydrogenated vegetable oil, tocopheryl acetate, tocopheryl linoleate, allantoin, propylene glycol, arachis oil, castor oil, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myri state.
viii. Sun Blocking Agent The compositions, according to the invention, may optionally comprise a sun blocking agent. A preferred sun blocking agent under the invention is octyl palmitate.
ix. Anti-inflammatory Agent 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, panthenol, tocopheryl acetate, and tocopheryl linoleate.
X. Preservative Other than water activity depressants and antimicrobial components, such as triclosanTM, the compositions, according to the invention, may optionally comprise one or more preservatives such as polymethoxy bycyclic oxazolidine, methyl paraben, propyl paraben and DMDM hydantoin.
xi. Viscosity Enhancer or Thickening Agent The compositions, according to the invention, may optionally comprise a viscosity enhancer or thickening agent. Viscosity enhancers of various classes may be chosen, including microbial polysaccharides, such as xanthan gum; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose; and sorbitol.
xii. Emulsifier The compositions, according to the invention, may also comprise one or more emulsifiers. Preferred emulsifiers under the invention include: polysorbate-60Tm, sorbitol, and sorbitan stearate. Such emulsifiers may be incorporated into the instant compositions singly or in any combination.
xiii. Vitamins, Proteins and Derivatives Thereof The compositions, according to the invention, may also comprise one or more ingredients which are vitamins, proteins or derivatives thereof, other than those which 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 any combination. Examples of vitamins, proteins or derivatives thereof which may be included in the compositions under the invention include: tocopheryl acetate, tocopheryl linoleate, panthenol, wheat oligosaccharides and hydrolyzed wheat proteins.
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 The composition according to the invention may also comprise allantoin.
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 0.01-2% by weight.
xvii. 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 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 preferable 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.
ixx. 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 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 (C.J. Macalister (1936) Narrative of an Investigation Concerning an Ancient Medicinal Remedy and its Modern Utilities, Republished 1955, The Lee Foundation for Nutritional Research, Milwaukee, WI).
One constituent of comfrey considered to be responsible for its medicinal properties is allantoin.
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, eczema and inflammation.
Without being limited 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.
xx. pH
In the case of the skin cleanser composition, the preferred pH is in the range of 6.0 to 8.0, more preferably the pH is in the range of 6.5 to 7.5.
The preferred pH of the skin moisturizer composition is in the range of 5.0 to 8.0, more preferably the pH is in the range of 6.0 to 7Ø
In one embodiment, the composition of a skin moisturizer under the invention comprises for example, a humectant, an emollient, a carrier or micro-carrier, an antimicrobial agent, an antimicrobial function enhancer, an unbound/excess lipid remover, a vitamin, 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 following:
a humectant, such as glycerin;
a carrier or micro-carrier, such as hyaluronic acid or ceramic hydroxyapatite, 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 60;
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.
Formulation of Skin Moisturizer Composition a) Phase IM
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 1 M, comprising nonoxynol-9, Aloe vera extract and panthenol were then added, and the mixture was slowly heated to a predetermined temperature. Preferably Phase 1M
of the composition is heated to a predetermined temperature in the range of 30 to 95 C, more preferably in the range of 40 to 90 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 1M is in the range of 30 to 95 C, more preferably when the temperature of Phase 1M is in the range of 40 to 90 C, and most preferably when the temperature of Phase 1M is in the range of 50 to 80 C.
b) Phase 2M
The ingredients of Phase 2M, comprising glycerin and ceramic hydroxyapatite, were combined in a suitable second vessel and mixed thoroughly until completely homogeneous. Phase 2M was added to the first vessel when the predetermined temperature for Phase 1M had been attained.
c) Phase 3M
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, 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 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 turned 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 4M, comprising tocopherol linoleate, matricaria extract and comfrey 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 60 C, more preferably in the range of 35 to 55 C, and most preferably in the range of 40 to 55 C. When the temperature of the contents of the first vessel were at the same or a similar temperature as the predetermined temperature for Phase 4, the ingredients of Phase 4 were transferred from the fourth vessel to the first vessel with thorough mixing. Heating was discontinued and the mixture was allowed to cool.
When the mixture was at a suitable temperature, preferably in the range of 20-40 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, which is white or slightly off-white in color, and has a delicate scent of citrus fruit. At a temperature of 25 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 1Ø
In one embodiment, the composition of a skin cleanser under the invention comprises, for example, an antimicrobial agent, a viscosity enhancer, a carrier or micro-carrier, an antimicrobial function enhancer, and an unbound/excess lipid remover, a vitamin, protein or derivative thereof, plant extract, natural scent, and water.
In a preferred embodiment, the composition of a skin cleanser under the invention comprises, for example, the following:
an antimicrobial agent, such as Triclosan;
an antimicrobial function enhancer, such as ceramic hydroxyapatite, and an unbound/excess lipid remover, such as ceramic hydroxyapatite;
an emollient, such as propylene glycol, nonoxynol-9;
an anti-inflammatory agent, such as Aloe vera extract, panthenol;
a surfactant, such as cocamide DEA, sodium laureth sulfate;
an emulsifier, such as polysorbate 60, sorbitan stearate;
a preservative, such as propyl paraben, methyl paraben;
a sun block agent, such as octyl palmitate;
a vitamin or derivative thereof, such as tocopheryl linoleate or wheat oligosaccharides;
a protein or derivative thereof, such as hydrolyzed wheat protein;
a plant extract, such as comfrey extract, or matricaria extract;
a natural scent, such as oil of cucumber;
and water.
Methods, under the invention, for preparing the skin cleanser composition comprise 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 following Example.
Formulation of Skin Cleanser Composition a) Phase 1 C
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 1 C, 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 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 3 C 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 35 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.
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 matricaria extract, were added sequentially to the first vessel.
Finally, natural scent was added to the mixture in the first vessel, and the mixture 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 25 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 1Ø
A preferred embodiment of the skin moisturizer composition according to the invention comprises the constituents shown in the following Example.
Skin Moisturizer Composition Phase 1 comprises:
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.
Phase 2 comprises:
Glycerin, up to 10% w/w; and Ceramic hydroxyapatite, up to 5% w/w.
Phase 3 comprises:
Stearic acid, up to 10% w/w;
Tocopherol acetate, up to 5% w/w;
Octyl palmitate, up to 10% w/w;
Safflower 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.
Phase 4 comprises:
Plant extract - for example, extract of comfrey, matricaria, up to 5% w/w;
Tocopheryl lineate, 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 skin cleanser composition according to the invention comprises the constituents shown in the following Example.
Skin Cleanser Composition Phase 1 comprises:
Deionized water, to 100% w/w;
Panthenol, up to 10% w/w;
Aloe vera extract, up to 7% w/w; and Citric acid, up to 10% w/w.
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 methycellulose; and Wheat oligossacharides 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 by the embodiments presented above.
USED THEREIN
This application is a divisional application of Canadian Patent Application Number 2,510,933 filed June 13`", 1996 which itself is a divisional of Canadian Patent Application Number 2,199,993 filed on June 13th, 1996.
Field of the Invention The invention relates generally to a method of making skin care products and to methods of using such products. This invention also relates to skin care products which moisturize the skin and prevent excessive drying of the skin.
This invention further relates to skin care products which are antimicrobial and help prevent infection by pathogenic microorganisms, and which mitigate against the spread of such pathogens.
In particular, the invention is concerned with formulations for cleansing and moisturizing skin which are antimicrobial, have a water base, and comprise a micro-carrier to deliver materials into the skin. The formulations are free of alcohol, lanolin, fragrance, petroleum-based components or animal by-products.
This invention still further relates to skin cleaning products which are antimicrobial, and non-irritating and non-drying to the skin after frequent use. The instant invention further relates to skin moisturizing products which are antimicrobial, non-greasy, and which rapidly penetrate the outer layers of the skin, and which form a shield to prevent loss of moisture from the 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 surface.
Because the skin serves a key role as a physical barrier to the entry of parasites and pathogens, excessive drying can lead to a breach of the barrier and infection by pathogenic bacteria and fungi.
Thus cracks or openings in the skin serve as a portal of entry for pathogens and potential pathogens. Even organisms that are normally considered to be non-pathogens can result in opportunistic infection in immunologically 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 contiguous tissues, or by way of the lympahtics and ultimately by way of the bloodstream.
Thus, the frequent application of many prior art skin cleansing compositions contribute 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 invention of the parent application allow for frequent use of the products to protect the skin and prevent damage due to drying. In so doing, skin care products under the invention help to prevent infection of the skin itself and entry of pathogens through the skin where they may infect underlying tissues.
Skin cleansing products of the invention of the parent application are formulated not only to accommodate continued frequent use without causing drying and cracking of the skin but also, by the inclusion of one or more antimicrobial agents, to prevent the transmission and spread of pathogenic or potentially pathogenic microorganisms.
Skin care products of the invention of the parent application are formulated to implement the absorption of the composition by the skin. In particular, the skin care products comprise an absorption implementing micro-carrier material. The absorption implementing micro-carrier material of choice is a form of ceramic hydroxyapatite.
Ceramic hydroxyapatite is in the form of macroporous spheres of predetermined size range, and is chemically pure. It is formed by the agglomeration of crystals or hydroxyapatite, or 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 is exemplified by that manufactured by the Asahi Optical Company, Tokyo. Ceramic hydroxyapatite has been widely used as a chromatographic separation medium (see, for example R. Kasai et al. J.
Chromatography 407, 205 (1987); S. Tsuri et al. J Immunol. Methods 106, 169 (1988); T.
Kadoya et al. J. Liquid Chromatography 9,3543 (1986); T. Kadoya et al J.
Liquid Chromatography 11,2951 (1986)).
Apart from ceramic hydroxyapatite referred to above, hydroxyapatite has been produced in several other fornls, each with a characteristic particle morphology, size distribution and surface structure, as observed by scanning electron microscopy (T. Kadoya et al. J. Liquid Chromatography 9,3543 (1986).
Hydroxyapatite has also been ascribed various non-chromatographic applications including in a cosmetic material containing spherical hydroxyapatite, in a melanin-lightening composition including ethyl alcohol and sodium hydroxide, the use of hydroxyapatite for the selective removal of protein from the body surface, the use of hydroxyapatite as an abrasive, to assist in the cleaning of inanimate surfaces, and its use in a blending agent, comprising polystyrene beads coated with hydroxyapatite.
SUMMARY OF THE INVENTION
The invention of this application provides a composition of matter for application to the skin, said composition comprising: macroporous ceramic hydroxyapatite particles;
and a physiologically and cosmetically acceptable vehicle other than water, wherein said vehicle is formulated for application to the skin.
Skin moisturizing products of the present invention are formulated to protect the skin and maintain the skin in a healthy condition. Skin moisturizing products of the present invention are also formulated to be antimicrobial, thereby further reducing the risk of infection by pathogens. Furthermore, the antimicrobial properties of moisturizing products of the invention reduce the risk of transmission of pathogenic and potentially pathogenic microorganisms. Skin care products of the instant invention are further formulated to rapidly penetrate the skin, whereby ingredients of the formulation are more effective.
The compositions and methods of the instant invention may be used to protect the integrity of the skin. The compositions and methods of the instant invention may also be used to promote and maintain healthy skin. The skin cleansing compositions of the instant invention may be used frequently to prevent the spread of pathogenic or potentially pathogenic microorganisms. The skin cleansing compositions of the instant invention may also be used frequently on a continual basis with minimal risk of causing drying, irritation, inflammation, or damage to the skin. The antimicrobial skin moisturizing compositions of 3a the instant invention may be used to minimize the risk of irritation and infection. The skin cleansing and moisturizing products of the instant invention do not dissolve latex and are fully compatible with the use of latex gloves. Thus, the skin moisturizing compositions of the instant invention may be used with latex gloves without the risk of dissolution of the latex or other damage to the latex barrier.
The methods and compositions of the invention may further be used to implement the rapid absorption of biologically active components by the skin. In accordance with one embodiment of the invention, the skin moisturizing composition may be used as a single application, or application may be repeated periodically over an extended time period as needed.
In accordance with another method of the invention, a skin moisturizing composition, under the invention, may be applied specifically or preferentially to the point or area of a minor cut, crack, or abrasion of the skin. Such application may protect the epidermis and the dermis from further damage and promote healing, and/or prevent infection of the skin.
The invention of a related application relates to a moisturizing composition for applying to and leaving on human skin, the composition in the form of an antimicrobial lotion composition comprising: (a) an amount of triclosan effective to kill microorganisms present on the skin; (b) an emollient present in an amount effective to moisturize the skin;
and (c) a lotion base comprised of a, physiologically and cosmeceutically acceptable vehicle wherein said components of said lotion are present in amounts sufficient to provide an effective antimicrobial lotion.
The invention of a related application also relates to an antimicrobial lotion composition for application to skin, comprising: (a) approximately 0.1 to 1.0 wt. %
triclosan; (b) an emollient present in an amount effective to moisturize the skin, wherein the emollient is cetyl palmitate, dimethylpolysiloxane, glyceryl monoricinoleate, glycerin, glyceryl monostearate, isobutyl palmitate, isocetyl stearate, isopropyl palmitate, isopropyl stearate, butyl stearate, isopropyl laurate, hexyl laurate, decyl oleate, isopropyl myristate, lauryl lactate, octadecan-2-ol, caprylic triglyceride, capric triglyceride, polyethylene glycol, triethylene glycol, sesame oil, coconut oil, safflower oil, isoamyl laurate, nonoxynol-9, panthenol, hydrogenated vegetable oil, tocopheryl acetate, tocopheryl linoleate, allantoin, propylene glycol, arachis oil, castor oil, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, or a combination thereof; and (c) a lotion base comprised of a physiologically and cosmeceutically acceptable water-based vehicle, wherein said components of said lotion are present in amounts sufficient to provide an effective antimicrobial lotion, the lotion is free of volatile alcohol, petroleum-based ingredients and animal by-products and further wherein the lotion is compatible with latex gloves.
Compositions of this invention can be used to kill microorganisms on skin.
The invention of the parent application relates to a composition for delivering at least one active agent to the skin of a subject, the composition comprising at least one pharmaceutically active agent loaded into a chemically pure ceramic hydroxyapatite micro carrier and to uses of such a composition for healing of damaged skin.
In preferred embodiments:
(a) ceramic hydroxyapatite particles are macroporous;
(b) chemically pure ceramic hydroxyapatite is in the form of particles having a mean diameter of from about 1 to 10 micrometers; and (c) ceramic hydroxyapatite particles have pores of uniform size and regular shape, ranging from about 0.05 to 0.10 micrometers in diameter.
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 m2, and comprises about 10% of the total body mass, making it the largest organ of the human body. Functionally, the skin acts as an interface between the intemal and external environment, and fulfills 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.
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 keratinocytes 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 attained terminal keratinization constitute the cornified zone. Cells of the stratum corneum eventually become detached from the epidermal surface and are replaced from below.
Typically the time taken for a newly-formed keratinocyte to pass to the surface and be shed ranges from 45-75 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 cleansing and moisturizing the skin according to the invention comprise an antimicrobial agent, an emollient and a micro-carrier in combinations as described below.
i. Antimicrobial component The present invention provides skin cleansing and moisturizing compositions, comprising 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 TM.
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, etc. ..). Thus, the antimicrobial component of the composition is effective in both preventing infection via the skin and in preventing the 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.
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 may also comprise one or more micro-carriers.
Ceramic hydroxyapatite under the invention is in the form of macroporous spheres of predetermined size range and is chemically pure.
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 comified zone of the stratum lucidum and stratum comeum.
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 Ca1 o(PO4)6(OH)2), which is produced as spheres with a controlled diameter. Preferably the median diameter of ceramic hydroxyapatite under the invention is in the range of 1-10 micrometers, more preferably in the range of 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 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 materials. The carrier and absorption enhancing properties of ceramic hydroxyapatite is due to both its porosity and 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 volume of liquid-phase-bound materials.
Due to the small spherical nature of the ceramic hydroxyapatite particles, it may also act as a lubricant.
Conventional (i.e. 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. Hoppe-Seyler 372, 149 (1991); K.J. Primes et al.
J.
Chromatography, 236, 519 (1982); S. Hjerten, Biochim. Biophys. Acta, 31, 216 (1959);
G. Bemardi and W.H. Cook, ibid. 44, 96 (1960); R.K. Main et al..I. Am. Chem.
Soc. 81, 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 ceramic hydroxyapatite spheres are resistant to high temperature and pressure, and are much more physically stable than conventional hydroxyapatite. (T. Kadoya et al. J.
Liquid Chromatography, 9, 3543 (1986). This physical stability allows for the agitation or mixing of ceramic hydroxyapatite without disintegration of the particles. Ceramic hydroxyapatite is also more stable chemically 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, e.g. K.J. 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 also comprise a liquid, solid or semi-solid physiologically and cosmeceutically acceptable vehicle or carrier. A
suitable vehicle, under the invention, may act variously 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.
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 used singly or in combination. Suitable carriers may include, but are not limited to, the following examples:
castor oil, ethylene glycol monobutyl ether, diethylene glycol monoethyl ether, corn oil, dimethyl sulfoxide, ethylene glycol, isopropanol, soybean oil, glycerin, soluble collagen, zinc oxide, titanium dioxide, talc, 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.
vi. Humectant Compositions under the invention may optionally comprise one or more humectants, for example:
dibutyl phthalate, gelatin, glycerin, soluble collagen, sorbitol, sodium 2-pyrrolidone-5-carboxylate.
A preferred humectant, under the invention, is glycerin.
vii. Emollient Compositions under the invention may optionally comprise one or more emollients, for example:
butane-l,3-diol, cetyl palmitate, dimethylpolysiloxane, glyceryl monoricinoleate, glyceryl monostearate, isobutyl palmitate, isocetyl stearate, isopropyl palmitate, isopropyl stearate, butyl stearate, isopropyl laurate, hexyl laurate, decyl oleate, isopropyl myristate, lauryl lactate, octadecan-2-ol, caprylic triglyceride, capric triglyceride, palmitic acid, polyethylene glycol, propane-l,2-diol, stearic acid, triethylene glycol, sesame oil, coconut oil, safflower oil, isoamyl laurate, monoxynol-9, panthenol, hydrogenated vegetable oil, tocopheryl acetate, tocopheryl linoleate, allantoin, propylene glycol, arachis oil, castor oil, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myri state.
viii. Sun Blocking Agent The compositions, according to the invention, may optionally comprise a sun blocking agent. A preferred sun blocking agent under the invention is octyl palmitate.
ix. Anti-inflammatory Agent 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, panthenol, tocopheryl acetate, and tocopheryl linoleate.
X. Preservative Other than water activity depressants and antimicrobial components, such as triclosanTM, the compositions, according to the invention, may optionally comprise one or more preservatives such as polymethoxy bycyclic oxazolidine, methyl paraben, propyl paraben and DMDM hydantoin.
xi. Viscosity Enhancer or Thickening Agent The compositions, according to the invention, may optionally comprise a viscosity enhancer or thickening agent. Viscosity enhancers of various classes may be chosen, including microbial polysaccharides, such as xanthan gum; cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose; and sorbitol.
xii. Emulsifier The compositions, according to the invention, may also comprise one or more emulsifiers. Preferred emulsifiers under the invention include: polysorbate-60Tm, sorbitol, and sorbitan stearate. Such emulsifiers may be incorporated into the instant compositions singly or in any combination.
xiii. Vitamins, Proteins and Derivatives Thereof The compositions, according to the invention, may also comprise one or more ingredients which are vitamins, proteins or derivatives thereof, other than those which 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 any combination. Examples of vitamins, proteins or derivatives thereof which may be included in the compositions under the invention include: tocopheryl acetate, tocopheryl linoleate, panthenol, wheat oligosaccharides and hydrolyzed wheat proteins.
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 The composition according to the invention may also comprise allantoin.
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 0.01-2% by weight.
xvii. 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 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 preferable 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.
ixx. 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 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 (C.J. Macalister (1936) Narrative of an Investigation Concerning an Ancient Medicinal Remedy and its Modern Utilities, Republished 1955, The Lee Foundation for Nutritional Research, Milwaukee, WI).
One constituent of comfrey considered to be responsible for its medicinal properties is allantoin.
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, eczema and inflammation.
Without being limited 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.
xx. pH
In the case of the skin cleanser composition, the preferred pH is in the range of 6.0 to 8.0, more preferably the pH is in the range of 6.5 to 7.5.
The preferred pH of the skin moisturizer composition is in the range of 5.0 to 8.0, more preferably the pH is in the range of 6.0 to 7Ø
In one embodiment, the composition of a skin moisturizer under the invention comprises for example, a humectant, an emollient, a carrier or micro-carrier, an antimicrobial agent, an antimicrobial function enhancer, an unbound/excess lipid remover, a vitamin, 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 following:
a humectant, such as glycerin;
a carrier or micro-carrier, such as hyaluronic acid or ceramic hydroxyapatite, 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 60;
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.
Formulation of Skin Moisturizer Composition a) Phase IM
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 1 M, comprising nonoxynol-9, Aloe vera extract and panthenol were then added, and the mixture was slowly heated to a predetermined temperature. Preferably Phase 1M
of the composition is heated to a predetermined temperature in the range of 30 to 95 C, more preferably in the range of 40 to 90 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 1M is in the range of 30 to 95 C, more preferably when the temperature of Phase 1M is in the range of 40 to 90 C, and most preferably when the temperature of Phase 1M is in the range of 50 to 80 C.
b) Phase 2M
The ingredients of Phase 2M, comprising glycerin and ceramic hydroxyapatite, were combined in a suitable second vessel and mixed thoroughly until completely homogeneous. Phase 2M was added to the first vessel when the predetermined temperature for Phase 1M had been attained.
c) Phase 3M
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, 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 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 turned 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 4M, comprising tocopherol linoleate, matricaria extract and comfrey 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 60 C, more preferably in the range of 35 to 55 C, and most preferably in the range of 40 to 55 C. When the temperature of the contents of the first vessel were at the same or a similar temperature as the predetermined temperature for Phase 4, the ingredients of Phase 4 were transferred from the fourth vessel to the first vessel with thorough mixing. Heating was discontinued and the mixture was allowed to cool.
When the mixture was at a suitable temperature, preferably in the range of 20-40 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, which is white or slightly off-white in color, and has a delicate scent of citrus fruit. At a temperature of 25 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 1Ø
In one embodiment, the composition of a skin cleanser under the invention comprises, for example, an antimicrobial agent, a viscosity enhancer, a carrier or micro-carrier, an antimicrobial function enhancer, and an unbound/excess lipid remover, a vitamin, protein or derivative thereof, plant extract, natural scent, and water.
In a preferred embodiment, the composition of a skin cleanser under the invention comprises, for example, the following:
an antimicrobial agent, such as Triclosan;
an antimicrobial function enhancer, such as ceramic hydroxyapatite, and an unbound/excess lipid remover, such as ceramic hydroxyapatite;
an emollient, such as propylene glycol, nonoxynol-9;
an anti-inflammatory agent, such as Aloe vera extract, panthenol;
a surfactant, such as cocamide DEA, sodium laureth sulfate;
an emulsifier, such as polysorbate 60, sorbitan stearate;
a preservative, such as propyl paraben, methyl paraben;
a sun block agent, such as octyl palmitate;
a vitamin or derivative thereof, such as tocopheryl linoleate or wheat oligosaccharides;
a protein or derivative thereof, such as hydrolyzed wheat protein;
a plant extract, such as comfrey extract, or matricaria extract;
a natural scent, such as oil of cucumber;
and water.
Methods, under the invention, for preparing the skin cleanser composition comprise 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 following Example.
Formulation of Skin Cleanser Composition a) Phase 1 C
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 1 C, 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 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 3 C 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 35 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.
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 matricaria extract, were added sequentially to the first vessel.
Finally, natural scent was added to the mixture in the first vessel, and the mixture 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 25 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 1Ø
A preferred embodiment of the skin moisturizer composition according to the invention comprises the constituents shown in the following Example.
Skin Moisturizer Composition Phase 1 comprises:
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.
Phase 2 comprises:
Glycerin, up to 10% w/w; and Ceramic hydroxyapatite, up to 5% w/w.
Phase 3 comprises:
Stearic acid, up to 10% w/w;
Tocopherol acetate, up to 5% w/w;
Octyl palmitate, up to 10% w/w;
Safflower 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.
Phase 4 comprises:
Plant extract - for example, extract of comfrey, matricaria, up to 5% w/w;
Tocopheryl lineate, 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 skin cleanser composition according to the invention comprises the constituents shown in the following Example.
Skin Cleanser Composition Phase 1 comprises:
Deionized water, to 100% w/w;
Panthenol, up to 10% w/w;
Aloe vera extract, up to 7% w/w; and Citric acid, up to 10% w/w.
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 methycellulose; and Wheat oligossacharides 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 by the embodiments presented above.
Claims (14)
1. A composition of matter for application to the skin, said composition comprising:
macroporous ceramic hydroxyapatite particles in the form of spheres of a predetermined size range and chemically pure; and a physiologically and cosmetically acceptable vehicle other than water, wherein said vehicle is formulated for application to the skin.
macroporous ceramic hydroxyapatite particles in the form of spheres of a predetermined size range and chemically pure; and a physiologically and cosmetically acceptable vehicle other than water, wherein said vehicle is formulated for application to the skin.
2. The composition of matter according to Claim 1, wherein said composition is a solid.
3. The composition of matter according to Claim 1, wherein said composition is a powder.
4. The composition of matter according to Claim 1, wherein said composition is a liquid.
5. The composition of matter according to Claim 1, wherein said composition is a cream.
6. The composition of matter according to Claim 1, wherein said composition is a lotion.
7. The composition of matter according to Claim 1, wherein said composition is a gel.
8. The composition of matter according to Claim 1, wherein said composition is a paste.
9. The composition according to Claim 1, wherein said macroporous hydroxyapatite particles have a median diameter in the range of 1 to 10µm.
10. The composition according to Claim 1, wherein said macroporous hydroxyapatite particles are prepared by:
(a) agglomerating crystals of hydroxyapatite; and (b) sintering said agglomerated crystals.
(a) agglomerating crystals of hydroxyapatite; and (b) sintering said agglomerated crystals.
11. The composition according to Claim 10, wherein said crystals range in size from 50 to 100 nm.
12. The composition according to Claim 10, wherein said macroporous hydroxyapatite particles have a median diameter in the range of 1 to 10µm.
13. Use of a composition comprising macroporous ceramic hydroxyapatite particles in the form of spheres of a predetermined size range and chemically pure and a physiologically and cosmetically acceptable vehicle other than water as a skin cosmetic.
14. The use according to Claim 13, wherein said macroporous hydroxyapatite particles are manufactured by agglomerating crystals of hydroxyapatite ranging in size from 50 to 100 nm and sintering said agglomerated crystals.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/487,242 | 1995-06-13 | ||
| US08/487,242 US6096324A (en) | 1995-06-13 | 1995-06-13 | Methods of delivering materials into the skin, and compositions used therein |
| CA002510933A CA2510933C (en) | 1995-06-13 | 1996-06-13 | Methods of delivering materials into the skin, and compositions used therein |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002510933A Division CA2510933C (en) | 1995-06-13 | 1996-06-13 | Methods of delivering materials into the skin, and compositions used therein |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2584797A1 CA2584797A1 (en) | 1996-12-27 |
| CA2584797C true CA2584797C (en) | 2010-03-09 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002584797A Expired - Fee Related CA2584797C (en) | 1995-06-13 | 1996-06-13 | Methods of delivering materials into the skin, and compositions used therein |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2584797C (en) |
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1996
- 1996-06-13 CA CA002584797A patent/CA2584797C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CA2584797A1 (en) | 1996-12-27 |
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