WO2005044241A1

WO2005044241A1 - Transdermal firming serum

Info

Publication number: WO2005044241A1
Application number: PCT/US2003/031942
Authority: WO
Inventors: Myong Hun Chong
Original assignee: Hanna Isul Skin Therapy, Inc.
Priority date: 2003-10-08
Filing date: 2003-10-08
Publication date: 2005-05-19
Also published as: AU2003282503A1

Abstract

A transdermal formulation is shown which includes aloe vera and as well as Vitamins A, C and E as essential ingredients. The formulations penetrate the epidermis and act at the cellular level to aid in reducing pores, renewing the skin and create a smoother texture.

Description

TRANSDERMAL FIRMING SERUM

Description

Technical Field

The present invention relates to a system of skin care utilizing a unique product formulation which achieves transdermal delivery of active components to the living cells in the skin dermis, which system has particular applicability to pre and postoperative treatment of skin wounds such as those from laser surgery, facelifts, peals and microdermabrasion.

Background Art

Conventional treatment and preventative measures for tissue damage caused by, for example, UV radiation of the sun, over-exfoliated, peeled and lasered skin tissue, and the like, is currently confined to the application of bland moisturizing creams designed only to minimize infection to the damaged site or to prevent itching and subsequent scratching by the affected individual. Such treatment can at best only offer symptomatic relief and a barrier to assist prevention of secondary infection at the affected site.

Additionally, conventional creams or ointments are designed to deliver an active component only to the epidermal surface of the skin or, at best, to provide limited delivery through the surface skin layers. Because these existing formulations are presented to the epidermal surface in a form likely to penetrate only into the outer layer of the epidermis, they fail to provide a deep healing effect.

As a result, there exists a need for a system of skin care and for a product formulation which will treat all skin types deep beneath the surface layer of the epidermis to reduce pores, renew the skin and create a smoother texture.

A need also exists for such a formulation which will stimulate melatonin production and counteract sun damage to the skin, thereby promoting healing and returning the skin to a normal, healthy level. A need also exists for such a formulation which relieves itching and other discomforts suffered after laser or face lift surgery and glycolic or chemical peels which acts swiftly to aid the healing process immediately upon contact.

Disclosure of Invention

The present invention provides a system of skin care utilizing a unique product formulation which achieves transdermal delivery of active components to the living cells in the skin dermis in order to rejuvenate the appearance of human skin with reduced or minimal potential for skin irritation. The product formulation is delivered to the skin in the form of a lotion or serum, which includes as essential components aloe vera as well as vitamins A, C and E. The complete package of ingredients, including selected vitamins, antioxidants and alpha hydroxy acids, achieves transdermal delivery of the active components at a cellular level as compared to the topical treatments of the prior art. The composition has particular efficacy in treating thick, aging skin, enlarged pores and dehydrated or sun damaged skin and also has particular applicability to pre and postoperative treatment of skin wounds such as those from laser surgery, facelifts, peals and microdermabrasion.

Additional objects, features and advantages will be apparent in the written description which follows.

Best Mode for Carrying Out the Invention

The skin care system of the invention achieves a unique transdermal delivery of active components of the product formulation to the living cells in the human dermis. In order to explain the delivery system, it is helpful to briefly describe the nature of human skin. Skin is composed of four regions layered on top of each other. The outermost layer is the epidermis which overlays the basement membrane, dermis and subcutaneous tissue. The epidermis is the most superficial layer of the skin and provides the first barrier of protection from the invasion of foreign substances into the body. The principal cell of the epidermis is the keratinocyte, which makes up 95% of the cells. Other cells of the epidermis include melanocytes and Langerhans cells. The cells are embedded in an extracellular matrix (ECM), which is composed of proteins such as collagen and glycosaminoglycans such as hyaluronate.

The epidermis is subdivided into layers or strata: the stratum germinatum (SG), the stratum spinosum (SS), the stratum granulosum (SGR), and the stratum corneum (SC). The stratum germinatum (SG) provides the germinal cells necessary for the regeneration of the layers of the epidermis. These germinal cells of the SG are separated from the underlying dermis by a thin layer of basement membrane. After a keratinocyte in the SG undergoes cell division, the newly formed cells undergo a progressive maturation called keratinization as they migrate to the surface. The active ingredients of Applicant's formulations must enter these cells to promote their development and maturation. As will be described, Applicant's product formulations comprise "mixed micelles" which must reach this level and deposit the vitamins in the cells. This action is assisted in Applicant's skin care system by the exfoliating and cleansing action of alpha hydroxy acids, which removes much of the outer SC layer. As the keratinocytes mature and move toward the surface, they begin to accumulate many desmosomes on their outer surface which provide the characteristic "prickles" of the stratum spinosum (SS) - often called the prickle-cell layer. The progressive maturation of a keratinocyte is characterized by the accumulation of the protein keratin. This process is called keratinization. The cells of the stratum granulosum (SGR) also accumulate dense basophilic keratinohyalin granules. These granules contain lipids, which along with the desmosomal connections help to form a waterproof barrier, that functions to prevent fluid loss from the skin.

As a cell accumulates keratinohyalin granules, its lysosomal membranes eventually rupture and release lysosomal enzymes that eventually cause cell death. The dead and dying cells filled with mature keratin form the uppermost level of the stratum corneum (SC). The deeper cells of the stratum corneum retain their desmosomal junctions, but as they are pushed to the surface by newly forming cells of the stratum germinatum, the dead cells gradually break apart and are lost, a process called desquamation. It is this upper level that is removed in the process of exfoliation and cleansing by the alpha hydroxy acids of Applicant's product formulations, as will be described. Applicant's product formulations used in the skin care system of the invention are specifically formulated to reduce pores, renew the skin and create a smoother texture. The formulations of the invention are an excellent pre-op treatment for laser surgery, face lifts, glycolic and chemical peels. They are particularly recommended for thick, aging skin, enlarged pores and dehydrated or sun damaged skin. In the preferred form of a liquid or semi-liquid serum, the product formulations of the invention can be applied by saturating a cotton ball and using the ball to apply the formulation to the neck and face area. The transdermal formulations are also beneficial in treating the deleterious effects of glycolic or chemical peels, and relieve itching after laser surgery or face lift surgery immediately upon contact.

While other products cleanse and moisturize at the surface level, the formulations of the present invention restores, balances and hydrates the human epidermis at a deeper level, returning it to its normal healthy state. The transdermal formulations of the invention utilize pure botanical essences and vitamins to provide a gentle, fragrant and soothing composition which aids the skin's ability to heal itself. The formulations of the invention nurture and nourish the skin so that within a short period of time the skin appears younger, healthier, more firm and glowing.

The transdermal formulations of the invention include aloe vera as an essential component. Aloe vera is a well known extract from the aloe plant and occurs naturally in nature. The aloe leaf consists of three primary sections: the rind (photosynthesis) with sap contained in the pericyclic transport tubules (xylem and phloem), the mucilage (container) layer and the parenchyma or gel fillet (storage) layer. It is believed that the beneficial properties of the plant extract are the result of the synergistic actions of at least 75 known ingredients, including polysaccharides, steroids, organic acids, enzymes, antibiotic agents, amino acids and minerals. Glucomannan, one special complex polysaccharide composed largely of the sugar mannose, interacts with special cell-surface receptors on those cells which repair damaged tissues, called fibroblasts, stimulating them, activating their faster growth and replication. Plant hormones in aloe, called gibberellins, also accelerate healing by cell replication. Various other beneficial effects of the aloe vera plant extract are reported in the literature. The aloe vera component of Applicant's formulation is present in the range from about 1 5 to 25% by volume, most preferably about 20% by volume, based upon the total volume of the transdermal formulation.

Applicant's transdermal formulations present the positive healing properties of the aloe extract in combination with a synergistic active ingredient formulation which allows the active ingredients to penetrate more deeply into the epidermis to provide a deeper, longer lasting healing effect. The additional components of the formulation will be discussed in turn below.

The formulations of the invention include as one component, a commercially available multi-fruit blend comprising bilberry extract, sugar cane, sugar maple, orange and lemon extract. Bilberry concentrate is prepared to specifically contain at least 25% anthocyanosides. Anthocyanoside is one of the more effective antioxidants. In fact, it is generally ranked higher in anti-oxidant power than Vitamins E and C by some experts. The bilberry/fruit extract component of the formulations serves as a moisturizer and exfoliant as well as offering fruit anti- oxidant properties and is present in the range from about 5 to 1 5% by volume, most preferably about 1 2% by volume, based upon the total volume of the formulation.

Glycerine is an oily, viscous liquid, C₃H₅(OH)₃, colorless and odorless, and with a hot, sweetish taste, existing in the natural fats and oils as the base, combined with various acids, as oleic, margaric, stearic, and palmitic. It is a triatomic alcohol, and hence is also called glycerol. It is a commonly used moisture carrying vehicle and is used as a humectant in the formulations of the invention. It is present in the range from about 1 to 5% by volume, most preferably about 3% by volume, based upon the total volume of formulation.

Sodium hyaluronate is a sterile mixture made up mostly of natural, highly purified sodium hyaluronate that comes from rooster combs. It is available from a number of commercial sources and is present in the formulations of the present invention in the range from about 1 to 3% by volume, most preferably about 0.5% by volume, based upon the total volume of the formulation.

Ascorbic acid is a commercially available form of the anti-oxidant Vitamin C and is present in the range from about 1 to 5% by volume, most preferably about 2% by volume.

Hydroxyethylcellulose is one of several fibrous substances consisting of the chief part of the cell walls of plants. This family of materials is used as emulsifiers in creams and lotions and is resistant to bacterial decomposition and gives uniformity to the product. This component is present in the range from about 0.5 to 5 % by volume, most preferably about 1 .2% by volume, based upon the total volume of formulation.

Camomile is a well known herb which supplies an apple aroma as a fragrance to the transdermal formulations of the invention. Its extract also supplies anti- inflammatory properties to the formulations of the invention and it is present in the range from about 0.1 to 1 .0 % by volume, most preferably about 0.5% by volume.

Polysorbate-20 is a commercially available emulsifier associated with stearic acid. It is present in the formulations of the invention in the range from about 0.1 to

2.0% by volume, most preferably about 1 .0% by volume, based upon the total volume of the formulation.

Phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben and iosbutylparaben are widely used as preservatives in cosmetic formulations. A selected one of these preservatives or a combination of all can be utilized for purposes of the present invention. Preferably, a combination of these preservatives in approximately equal proportions is utilized. The preservative component of the formulations is present in the range from about 0.05 to 1 .5% by volume, most preferably about 0.7% by volume.

Tocopheryl acetate is a source of Vitamin E. It has known antioxidant properties and is present in the range from about 0.01 to 0.5% by volume, most preferably about 0.1 % by volume.

Retinyl palmitate is the ester of Vitamin A and palmitic acid. It also has known antioxidant properties and is present in the range from about 0.05 to 0.5% by volume, most preferably about 0.3% by volume.

In a particularly preferred form, the transdermal firming serum formulation of the invention comprises:

A unique aspect of the transdermal formulations of the invention is the use of the human skin tissue equivalent system developed and patented by the University of North Texas Health Science Center in Fort Worth, Texas (U.S. Patent No. 6,471 ,958, issued October 29, 2002, to Dimitrijevich and Gracy) . This human skin equivalent is constructed entirely from human skin cells grown into three-dimensional sheets of skin in the laboratory. This skin equivalent undergoes differentiation into the normal layers of skin and can be used for transplants (e.g. for burns patients). Tissue equivalents retain the properties of the parent tissues. They are ideally suited for assessment of topical medications and drugs and allow rapid and accurate assessment of formulations, dosages, toxicity and overall efficacy. The human skin tissue equivalent has allowed testing of many parameters including exfoliation, rehydration, collagen synthesis, delivery of vitamins and nutrients to underlying cells and new tissue growth. Similarly, it allows evaluation of antioxidants to prevent oxidative damage to the skin and the efficacy of products to enhance wound healing. The skin tissue equivalent was used in developing the transdermal firming formulations of the invention.

Through use of the human skin tissue equivalent system described above, the transdermal firming formulations of the invention have been found to function by four basic mechanisms. Each of these mechanisms begin to function immediately upon application to the skin surface, but their actions require different periods of time. The effects are seen in the order described below. Exfoliation and Cleansing the Skin: This is primarily the combined effect of the alpha hydroxy acids.

Synergistic Transdermal Delivery: Several of the components combine to bring about transdermal delivery (skin penetration) of the active components to the living cells in the dermis. This involves the delivery agents as well as the active ingredients. Cellular activity, wound healing and tissue repair: Biologically active components have specific effects on cells and tissue. For example, the vitamins promote cell growth, collagen synthesis, tissue remodeling. Antioxidant Protection: Specific antioxidants provide powerful protection against oxidative damage and in some cases may reverse oxidative damage to the skin. These function both within the cells as well as in the extracellular matrix (ECM).

I. Exfoliation and Cleansing the Skin: The transdermal firming formualtions of the invention are a viscous semi-transparent colloidal dispersion of micelles in which the aqueous component primarily contains the hydrophilic compounds, which include the alpha hydroxy acids. These agents are immediately presented to the comified epithelial layer of the skin and initiate exfoliation.

This process results in removal of the dead cells of the comified epithelium as well as cell remnants, debris and components of the extracellular matrix of the surface layers. This material, which is removed, contains oxidized collagen, and other extracellular matrix (ECM) materials such as hyaluronate derivatives.

Exfoliation by alpha hydroxy acids is widely recognized for its effective cleansing of the skin and the removal of dead cells of the comified epithelium. In addition to removing the dead cells from normal skin sloughing, this process removes oxidatively damaged proteins, glycosaminoglycans and other macromolecules of the ECM. This is particularly important in case of damaged skin (e.g. laser surgery, microdermabrasion, facelifts, sun damage etc).

A potential disadvantage of this process is that it leaves the upper layers of cells exposed, thinned and subject to damage from the environment such as increased sun sensitivity. However, in the case of the transdermal formulations of the invention, this does not occur. This is due to several different factors. First, the exfoliation takes place at a mild pH (always greater than 7.0) that minimizes trauma to the skin. Second, the ECM is immediately replaced with fresh hyaluronate. Third, the active components in extracts such as aloe vera and chamomile are well established to promote healing to the tissue and to minimize inflammation of the exfoliated skin.

II. Synergistic Transdermal Delivery of Vitamins A, C and E: The second component of the transdermal firming formulations of the invention is the delivery of the mixture of vitamins to the cells of the skin. Unless the vitamins are permitted entry into the cells they are of little value (except acting as general antioxidants). The mixed micelle delivery system permits the synergistic transport of the vitamins into the cells of the skin and also permits permeation of the material through the ECM. The surface of the cell has both hydrophobic and hydrophilic properties. Similarly, the mixed micelle has both hydrophobic and hydrophilic layers. Thus, at the cell surface there is enhanced interaction of the compatible components of the micelle with the cell membrane (e.g. allowing fusion of the lipid layer of the cell surface with the lipid layer of the delivery micelle and/or by the micelle acting as a transdermal enhancer). An additional important function of the delivery micelle is the protection of the vitamins from auto oxidation.

III. Cellular Activity wound healing and tissue repair: There are several active components of the transdermal firming formulations of the invention. Some of these have been mentioned above and function to minimize inflammation and promote healing of the cleansed tissue. These components (e.g. aloe vera and chamomile extracts) function by interacting with specialized cells of the skin that are involved in the immune system. A major portion of the active components of the present inventive formulations are the vitamins delivered to the cells via the synergistic transdermal delivery system described above. These vitamins act in independent metabolic pathways and function to promote cell growth, the synthesis and export of collagen to the ECM, and direct cellular, tissue and ECM tissue remodeling. The roles of these three essential vitamins are well established.

Ascorbic acid (Vitamin C) has several well-established roles in promoting health of the skin. It is the coenzyme essential for the synthesis of collagen the most abundant protein in skin. The extracellular matrix must be constantly replenished. Ascorbic acid also plays a very important role as a water-soluble antioxidant. It scavenges reactive oxygen species including free radicals produced from sun damage.

Tocopheryl acetate is the acetate ester of Vitamin E. The ester is used because it is more stable. Vitamin E is the major naturally occurring lipid-soluble antioxidant that protects skin from reactive oxygen species (such as free radicals). Vitamin E functions to maintain membrane integrity in virtually all cells of the body. This is because of its lipid nature, which allows it to reside in the membranes, and because of its potent antioxidant properties. It not only prevents oxidation of lipids but also proteins. It has recently been shown that the compound has additional mechanisms for protecting against membrane damage (in addition to antioxidant).

Retinyl palmitate is the ester of Vitamin A and palmitic acid. It is also an antioxidant with regenerating properties and also functions as a moisturizer and conditioner. It stimulates cell proliferation and synergistically increases the effects of other vitamins. Like vitamin E it is a lipid-soluble antioxidant. Transporting this component into cells may allow its conversion to all-trans retinoic acid, the active ingredient of Retin-A, with anti-wrinkle properties.

IV. Antioxϊdants: Oxidative damage is the primary cause of skin aging. It is promoted by photo oxidation from sunlight and other chemical oxidants that continually contact the skin. Also, the cells themselves produce some of these toxic compounds. Oxidation modifies proteins in the skin causing them to be cross-linked, cleaved or modified and unfolded. Oxidation also causes damage to lipids in the membranes of cells causing them to have different permeability, shapes and alters their physiological responses to environmental stresses. Oxidation also modifies DNA in the cells leading to, in some cases, malignant transformation (cancer). There are many types of oxidants encountered by the skin and in many locations inside and outside the cells. Thus, no single antioxidant is able to meet the challenge of scavenging and inactivating these potent reactive molecules. The formulations of the invention uniquely provide a combination of antioxidants (described above), which are delivered to the extracellular matrix as well as inside of the cells. These antioxidants are both water-soluble and lipid soluble - so they become distributed to every location throughout the skin. The resulting action minimizes oxidative damage.

An invention has been provided with several advantages. The formul ations of the invention contain primarily natural ingredients yet penetrate the epidermis to provide improved healing properties to reduce pores, renew the skin and create a smoother textured skin. The formulations provide improved healing properties and serve as excellent pre-op treatments for persons undergoing surgical skin procedures, face lifts, glycolic and chemical peels and similar procedures. The unique combination of Vitamins A,C and E with the other natural ingredients produces a synergistic effect in achieving the desired results mentioned above. The use of the human skin tissue equivalents testing allowed optimization of the component ingredients of the formulations and promoted the transdermal nature of the products. The formulation s of the invention contain no alcohol or drying agents. The products have a controlled pH. The products achieve exfoliation with immediate healing and use hyaluronate mediated hydration of the skin. The synergistic transdermal delivery properties of the formulations provide uniform delivery of high concentrations of vitamins A,C, E and other nutrients to deep layers of the dermis. The result is acccelerated collagen synthesis without the necessity of injections as well as uniform delivery to all components of the tissue. The products provide rapid soothing and comfort to wounded tissue and act to smooth, firm texture and lift the skin.

While the invention has been shown in only one of its forms, it is not thus limited but is susceptible to various changes and modifications without departing from the spirit thereof.

Claims

ClaimsWhat is claimed is:

1 . A method of providing transdermal delivery of active skin care ingredients to living cells in a patient's skin dermis, the method comprising the steps of:

preparing a transdermal formulation in the form of a serum comprising, as active ingredients, selected vitamins, antioxidants an alpha hydroxy acids;

applying the serum to an area of exposed skin of the patient, the formulation being effective to achieve transdermal delivery of the active ingredients at a cellular level as compared to topical treatments of the prior art;

wherein the serum is formulated to contain:

from about 1 5 to 25% aloe vera gel;

as additional ingredients, a selected amount of a source of each of the Vitamins A, C and E.

2. The method of claim 1 , wherein the aloe vera component of the formulation is present in an amount of at least about 20% by volume, based upon the total volume of the formulation.

3. The method of claim 1 , wherein the serum is formulated to further contain a combination exfoliant and fruit acid blend including bilberry extract, sugar can, sugar maple, orange and lemon extracts.

4. The method of claim 3, wherein the source of Vitamin C is ascorbic acid.

5. The method of claim 4, wherein the source of Vitamin E is tocopheryl acetate.

6. The method of claim 5, wherein the source of Vitamin A is retinyl palmitate.

7. The method of claim 6, wherein the serum is further formulated to contain glycerine, sodium hyaluronate, hydroxyethylcellulose and chamomile extract combined with selected preservatives.

8. The method of claim 7, wherein the selected preservatives are selected from the group consisting of phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben and isobutylparaben.

9. A method of providing transdermal delivery of active skin care ingredients to living cells in a patient's skin dermis, the method comprising the steps of:

preparing a transdermal formulation in the form of a serum comprising a viscous, semi-transparent colloidal dispersion of micelles having both hydrophilic and hydrophobic components, the serum comprising, as active ingredients, selected vitamins, antioxidants an alpha hydroxy acids;

applying the serum to an area of exposed skin of the patient, the hydrophilic and hydrophobic components of the micelles of the formulation being effective to achieve transdermal delivery of the active ingredients at a cellular level by permeation of the components through the patient's skin dermis to an extracellular matrix level;

wherein the serum is formulated to contain:

from about 1 5 to 25% by volume, based upon the total volume of formulation of aloe vera gel;

from about 10 to 1 5% by volume of commercially prepared extract of bilberry, sugar cane, sugar maple, orange and lemon extracts; from about 1 to 5% by volume of glycerine;

from about 1 to 5% by volume of ascorbic acid;

from about 0.1 to 1 .0% by volume of sodium hyaluronate;

from about 0.5 to 5% by volume of hydroxyethylcellulose;

from about 0.1 to 1 % by volume of Chamomile extract;

from about 0.05 to 1 .0% by volume of tocopheryl acetate;and

from about 0.05 to 1 .0% by weight of retinyl palmitate;and

the balance being selected preservatives and deionized water.

10. The method of claim 9, wherein application of the serum to the patient's skin initiates at least the following actions :

exfoliation and cleansing;

transdermal delivery of vitamins A, C and E;

cellular activity wound healing and tissue repair; and

delivery of antioxidants to the extracellular matrix of the patient's skin.

1 1 . The method of claim 10, wherein application of the serum to the patient's skin achieves immediate healing after exfoliation through the action of hyaluronate mediated hydration of the skin .

1 2. The method of claim 1 1 wherein the serum is further formulated to contain as emulsifiers and preservatives: from about 0.1 to 1 .0% by volume of polysorbate-20;

from about 0.1 to 1 .5% by volume of a mixture of preservatives selected from the group consisting of phenoxyethanol, methylparaben, ethylparaben, butylparaben, propylparaben and isobutylparaben.