WO2000072883A2

WO2000072883A2 - Pharmaceutical transdermal compositions

Info

Publication number: WO2000072883A2
Application number: PCT/US2000/015289
Authority: WO
Inventors: Vanaja V. Ragavan
Original assignee: Aviana Biopharm
Priority date: 1999-06-02
Filing date: 2000-06-02
Publication date: 2000-12-07
Also published as: WO2000072883A3; AU5460800A; WO2000072883A9

Abstract

The compositions described herein allow for the delivery of substances to the organs of the skin such as hair follicles and sebaceous glands, to the tissues under the skin such as muscles, joints and related tissues and to the systemic circulation. The compositions can be used to treat a variety of skin disorders as well as disorders of deeper tissue or disorder distant to the site of application through absorption through the skin. The formulations include pharmaceutical compositions with or without enhancers for delivery of active ingredients to the skin and organs of the skin to treat common disorders of the skin and its organs, as well as areas distant from the skin, i.e., regional or systemic delivery via transdermal administration. Preferred enhancers combine a diol and a cell-envelope disrupting agent. Examples of dermatologic conditions which can be treated include sunburn prevention and treatment, minor and major burns, agents toxic to the skin such as poison ivy, chemical and non-chemical such as radiation that disrupt the normal epidermis, conditions of the skin organs such as hirsutism, acne, infections such as bacterial and viral infection, inflammatory processes such as after application of facial peels, lasers, tanning agents, drug reactions, muscular and joint inflammation and pain such as arthritis and sports injuries, hormone deficiencies, menopause, and contraception.

Description

PHARMACEUTICAL TRANSDERMAL COMPOSITIONS

Background of the Invention

The present invention is generally in the area of transdermal and dermal formulations including non-steroidal anti-inflammatories and hormones, for treatment of skin disorders as well as disorders at more distant locations. The invention describes formulations for delivery of active substances through the intact skin and through compromised skin to heal diseases related to skin and deeper tissues. Normal skin is an active barrier to the penetration of therapeutic products.

Furthermore, many pharmaceuticals may not penetrate the skin because they may precipitate or be poorly soluble or be absorbed. The skin consists of three layers: the stratum corneum (S.C), the epidermis, and the dermis. The stratum corneum represents the rate-limiting step in diffusion of chemical through the skin. The S.C. is composed of dead, keratinized, metabolically inactive cells which are closely packed together, and consists of an amorphous matrix of mainly lipoid and nonfibrous protein within which keratin filaments are distributed. The cells of the S.C. generally contain 20% water, while the cells below, in the stratum germinativum, contain 70% water. The S.C. does not become hydrated readily. Thus, transdermal permeation is primarily controlled by diffusion through the S.C. first-pass metabolism in the liver; this is extremely important for drugs with short half-lives, or with potential unwanted actions on the liver.

There appear to be at least two pathways for transport across the skin: a polar pathway and a non-polar pathway. The polar pathway is conducted through the protein component of the stratum corneum and the transport takes place through aqueous channels. The non-polar pathway, which comprises the majority of delivery, is through the lipid component.

The existence of these various pathways allows for development of products that take advantage of the skin transport pathways by using vehicles that alter the permeability of skin via different pathways. The development of a two-component system based on the knowledge of their behavior in skin transport can enhance the transport of active moieties with efficacy in a variety of skin disorders. There are advantages to delivery of substances through the skin, including avoiding the disadvantages associated with oral delivery of drugs which results in metabolism, elimination or decrease in systemic availability during passage through the liver and bypassing the portal circulation; uncertainties of absorption from, and irritation to, the gastrointestinal tract arising from drugs given orally; elimination of the need for frequent or daily dosing, higher levels needed to overcome metabolism, and irregular blood levels. Transdermal delivery can be used to decrease the frequency of dosing (daily, weekly or longer) for certain drugs; stabilize blood levels and increase ease of use and thereby patient compliance. A number of formulations have been described for topical delivery. There is a need, however, for improved formulations for transdermal delivery of different compounds such as hormones, steroids and non-steroidal anti-inflammatory compounds. For example, U.S. Patent No. 5,093,133 describes an aqueous alcoholic gel for the percutaneous delivery of Ibuprofen. The gel contains, by weight of the total formulation, about 1 to 15% S-Ibuprofen, 0 to 20% propylene glycol; about 40 to 60% alcohol; about 2.0 to 5.0% gelling agent and pH modifier to obtain an acidic pH in the range of 3.5 to 6.0. The rate of delivery of Ibuprofen is stated to be pH dependent. U.S. Patent No. 5,863,560, refers to an microparticulate form of active ingredients formulate in a mixture of carbomer, water, ethoxydiglycol, and methylparaben.

There are many conditions and diseases of the skin in which the epidermis, the normal protective coating of the skin, is compromised and in these circumstances, formulations for delivery of active ingredients do not necessarily require an enhancer. Formulations for these applications are described in this invention and relate to providing active substances in the presence of a compromised skin. Such conditions include burns, skin resurfacing procedures, sunburn, poison ivy and other agents that can injure the skin, inflammatory conditions and infections, among others.

Summary of the Invention The compositions described herein allow for the delivery of substances to the organs of the skin such as hair follicles and sebaceous glands, to the tissues under the skin such as muscles, joints and related tissues and to the systemic circulation.

The compositions can be used to treat a variety of skin disorders, as well as disorders of deeper tissue or disorders distant to the site of application through absorption through the skin. The formulations include pharmaceutical compositions with or without enhancers for delivery of active ingredients to the skin and organs of the skin to treat common disorders of the skin and its organs, as well as areas distant from the skin, i.e., regional or systemic delivery via transdermal administration.

Preferred enhancers combine a diol and a cell-envelope disrupting agent. Examples of dermatological conditions which can be treated include sunburn prevention and treatment, minor and major burns, poison ivy, hirsutism, acne, bacterial and viral infection, inflammatory processes such as after application of facial peels, lasers, tanning agents, drug reactions, muscular and joint inflammation and pain such as arthritis and sports injuries, hormone deficiencies, menopause, and contraception.

Brief Description of the Figures Figure 1 is a graph of the transdermal penetration of flutamide alone and in combination with a formulation containing enhancer, oleic acid, over time. Figure 2 is a graph of the transdermal penetration of ibuprofen alone and in combination with a formulation containing enhancer, oleic acid, over time.

Detailed Description of the Invention The compositions described herein are drawn to combinations of an active ingredient and a carrier(s), preferably consisting of well known and generally regarded as safe (GRAS) components. In embodiments for application to intact skin, the formulation contains enhancers to deliver pharmaceutical agents to skin organs in the dermis and distally. The formulations without enhancer are used to treat compromised skin. I. Formulations A. Active Ingredients

Exemplary pharmaceutically active agents include hormones such as estrogens and their derivatives, progestogens and their derivatives, androgens and their derivatives and metabolites of all these hormones and their antihormones, anti- androgens such as spironolactone, cyproterone acetate, finasteride, flutamide, sex steroid hormones such estrogen and its derivatives, progesterone and its derivatives, androgens and its derivatives, and other non-corticosteroid such as danazol, acyclovir and other anti-viral agents and cyclooxygenase inhibitors (COX-2 inhibitors), such as celecoxib and rofecoxib. Other active agents include phosphodiesterase enzyme inhibitors, both specific and non-specific, ICAM-1 inhibitors, and substances which affect the formation and aggregation of melanin granules by shading the nucleus of the cell from the sun's rays. Also included are inhibitors of enzymes that participate in the cascade of reactions responsible for cell death, prominent among them are enzymes such as caspasine.

Active ingredients for pharmaceutical preparations not including enhancers which are to be administered for the treatment of acute skin inflammation, for example, after skin resurfacing procedures, include non-steroidal anti-inflammatory agents and their enantiomers, such as ibuprofen, declofenac, naproxyn, piroxican, phenybutazone, etfenamate, fulindac, among others, salicylic acid and indomethacin.

Additional pharmaceutically active agents are described with reference to specific conditions to be treated.

B. Enhancers

Formulations containing enhancers can be used to deliver pharmaceutical agents to skin organs in the dermis and distally through intact skin. Formulations do not need to include enhancers when the epidermis has been compromised due to external procedures or acute inflammatory responses.

A large number of enhancers are known, although preferred formulations have now been developed to deliver agents to the skin organs, local tissues and systemic circulation. Cooper, ER. J. Pharm. Sci., 73:1153-56 (1984) reports on the use of the combination of oleic acid and other solvents for penetration of the stratum corneum. See also, U.S. patent Nos. 4,552,872; 4,557,934; and 4,954,487. In U.S. patent Nos. 4,983,396; 4,885,174; and 4,764,381, Bodor et al utilized the teachings of Cooper to develop a specific agent 2-ethly-l ,3,hexandediol used in conjunction with oleic acid to enhance the delivery of nitroglycerin and estrogens. Enhancers have been shown previously to deliver corticosteroids and a limited number of non- steroidal anti-inflammatories directly into the systemic circulation, as noted in U.S. patent Nos. 4,552,872; 4.557,934; and 4,954,487.

Newly developed enhancer formulations include a diol compound and a cell- envelope disordering compound, alone or in combination with a carrier such as propylene glycol and 1, 2 butanediol. Representative carriers include polyethylene glycol. Other enhancing compounds which can be added to the composition include oleic acid, methyl laureate, oleyl alcohol, monolein, and other such compounds. Additives in addition to carrier include lauryl alcohol, ethyl alcohol, TWEEN™, CARBOPOL™ and water.

Useful diol compounds include 1 ,2-propanediol, 1,3-propanediol, 1 ,2- butanediol, 1,3-butanediol, 1 ,4-butanediol, and mixtures of these diol compounds. 1 ,2-propanediol and 1 ,2-butanediol are preferred diol compounds. 1 ,2-propanediol is an especially preferred diol compound.

Useful "cell-envelope" disordering compounds include methyl laurate, oleic acid, oleyl alcohol, monoolein, and myristyl alcohol. Mixtures of these "cell- envelope" disordering compounds may also be employed. Preferred cell-envelope disordering compounds include methyl laurate, oleic acid and myristyl alcohol. Methyl laurate is a particularly preferred cell-envelope disordering compound.

Binary mixtures of any of the foregoing diol compounds and cell-envelope disordering compounds, in a weight ratio of diol compound ell-envelope disordering compound of from about 1 :1 to about 500:1, provide significant enhancement of penetration for pharmaceutically active agents, especially corticosteroids. A ratio of diol compound:cell-envelope disordering compound of from about 5:1 to about 100:1 is preferred, and the penetrating components are most preferably present in a ratio of about 10: 1 to about 100:1. In a highly preferred embodiment, the penetrating components are present in a ratio of about 10:1 to about 50:1.

C. Carriers

The pharmaceutically active agent can be formulated in carriers, such as water, oil (such as mineral oil), lotions (emulsions of oil and water, typically further including surfactant), hydrogels, and petrolatum jelly. The compositions may optionally contain a cosmetically acceptable solvent.

The solvent, if used, should not significantly interfere with the penetration action of the binary combination, and should preferably evaporate rapidly and completely to leave only the active components of the composition at the site of application. Preferred solvents include ethanol and isopropanol. Water may be used as a solvent or component. However, simple addition of water to these compositions may cause some or all of the penetration-enhancing compounds to precipitate out, which may significantly reduce the overall effectiveness of the system. In order to prevent this, if water is used, it is preferred that it be in the form of an emulsion or gel. Since these compounds themselves, used alone, do not form a stable emulsion or gel, emulgents or gelling agents should therefore be employed. Such solvents, i.e., water, ethanol or 2-propanol (isopropanol; isopropyl alcohol), may comprise from 0% to about 80% of the total composition by weight. Ethanol and 2-propanol are preferably present at a level of between 0% to about 70%.

However, certain solvents, cosolvents, excipients, lipid materials and other generally acceptable components conventionally found in topical pharmaceutical compositions (other than the cell-envelope disordering compounds) should be avoided in the formulation. It is thought that such compounds compete in some fashion for the role the cell-envelope disordering compounds play, or the site these compounds occupy, in the stratum corneum. This competition prevents the disruption or disordering of the lipids of the stratum corneum by the cell-envelope disordering compounds. Some of these compounds may also compete with the lipids of the stratum corneum for the cell-envelope disordering compound and the cell-envelope disordering compound will preferentially partition into such lipid-like compounds in the vehicle rather than the lipids of the stratum corneum. Such selective competition will also prevent lipid disordering or disruption by the cell- envelope disordering compound and, accordingly, penetration of the pharmaceutically active agent will not be enhanced. If used, such compounds should generally be used as sparingly as possible, far below art-established levels. For example, hydrocarbons such as liquid petrolatum (mineral oil, liquid paraffin, paraffin oil), white petrolatum, yellow petrolatum, paraffin, microcrystalline wax, and ceresin are all known to be useful as hydrophobic vehicles or structural matrix formers in topical pharmaceutical formulations. However, all of these excipients are capable of significantly interfering with enhancement of penetration. It is thought that these compounds inhibit the ability of the cell- envelope disordering compound to effectively disrupt the intercellular lipid structure of stratum corneum by preventing the cell-envelope disordering compound from effectively reaching the lipids of the stratum corneum, possibly by selective competition for the cell-envelope disordering compound. While a certain level of such ingredients can be tolerated in a system which is otherwise particularly effective, in a preferred embodiment of the present compositions described herein such ingredients are limited to less than about 10%, and more preferably less than about 5%.

Certain straight chain, saturated C\₆ -C₂₀ normal fatty alcohols should also be avoided. Cetyl alcohol and stearyl alcohol are extremely common ingredients in topical formulations. Both of these alcohols are capable of significant interference with the penetration enhancement of the combination of diol and cell disruption agent. These alcohols, as well as the Cι₈ saturated alcohol, are likely to decrease the level of enhancement of penetration. Accordingly, in a preferred embodiment, the compositions are substantially free of such compounds, i.e., any particular compound should be present at a level of less than 3.5%, and more preferably at a level less than 1% by weight of the entire composition. In a highly preferred embodiment the compositions of the present compositions described herein contain less than 0.5% of any specific member of this alcohol group.

Certain fatty acids are also capable of gross interference with penetration. These acids include the straight chain C₄ -C₂₀ saturated monocarboxylic and dicarboxylic acids. Octanoic and decanoic acid are particularly harmful. In a preferred embodiment, the formulation is substantially free of these acids, i.e., contain less than about 3.5% of any particular member of C₄ -C ₀ saturated monocarboxylic and dicarboxylic acid, and more preferably less than about 1% of the acids by weight of the entire composition. In a highly preferred embodiment the formulation contains less than 0.5% of any specific member of the acid group.

The formulation may additionally contain other adjunct components conventionally found in pharmaceutical compositions, not recited above, at their art- established usage levels. Thus, for example, the formulation may contain additional compatible pharmaceutically-active materials for combination therapy (such as antimicrobials, antipruritics, astringents, local anesthetics, or non-steroidal anti- inflammatory agents), or may contain materials useful in physically formulating various dosage forms, such as excipients, dyes, perfumes, fragrances, preservatives, anti-oxidants, opacifiers, thickening agents and stabilizers. Such materials, when added, should not unduly interfere with the penetration enhancers. Such formula modifications to improve cosmetic acceptability are well within the skill of workers in the cosmetic and dermatological arts. All optional components should be selected to prevent substantial interference with the penetration ability of the formulation. The formulations may further include active agents which also exert a pharmaceutical effect, such as Vitamin C, A and E, aloe vera, and bovine collagen. For example, vitamin E is useful as an antioxidant, but also has advantages properties when administered to the skin. Wound healing involves a phase where inflammatory cells release proteases and reactive oxygen species, such as superoxide, hydrogen peroxide and other free radical forms. These molecules have potential adverse effects on the tissue. Antioxidants, such as Vitamin A and E, may diminish the activity of reactive oxygen species and this limit post-procedure inflammation. Vitamin E is known to prevent peroxidases from accumulating and stabilizes lysosomes and cell membranes. Topical Vitamin E has accelerated the healing of chemotherapy-induces mucositis Vitamin C may be used to enhance collagen growth. Vitamins and other such ingredients may be added in the weights of 100 micrograms to 50 grams per application tube. D. Formulations The pharmaceutically active agents are typically formulated with a carrier, alone or in further combination with enhancer. As noted above, when the epidermis has been compromised due to external forces such as chemical and laser peeling, or when there is an acute inflammatory response rendering the epidermis more permeable, a formulation of agents without enhancer could be used to treat these conditions.

The formulations typically contain from about 10% to about 99.9%, and preferably about 15% to about 99.9%, by weight, of the penetration enhancing binary mixture of the diol compounds and cell-envelope disordering compounds, employing the ratios described above. In a highly preferred embodiment the binary mixture is present at a level of about 50% to about 99.9% by weight.

In certain topical formulations, however, aesthetic and cosmetic qualities may be of equal or even paramount importance. Accordingly, ranges other than those described above may be preferred. In general, a composition employing a weight:weight ratio of about 1 :1 to about 10: 1 will not demonstrate the same degree of penetration enhancement as a system employing the same components at a weight ratio of about 10: 1 to about 50: 1. However, such ratios (1 :1-10: 1) may be preferred for certain vehicles or systems because they frequently produce better aesthetic qualities. It should be noted that while not generally providing maximum penetration, such aesthetically pleasing compositions nonetheless demonstrate a dramatic enhancement of penetration when compared to conventional or art- disclosed vehicles or systems. Compositions comprising a binary mixture at a level of about 25% to about 45% of the overall composition and employing weight: weight ratios of about 4: 1 to about 6: 1 provide an excellent compromise or balance of cosmetic acceptability and enhanced penetration and are accordingly preferred.

Various proportions of the above compounds may be utilized to provide optimal delivery across the skin. Typical examples are:

1) 1-50% Ibuprofen 35% Propylene glycol

10% Lauryl alcohol

5% Ethyl alcohol

2% TWEEN™ 30

0.25% CARBOPOL™ 934 32.75% Water

2) l-50% Naproxyn 40% Propylene glycol 10% Oleyl alcohol

5% Ethyl alcohol 2% TWEEN™ 80

0.25% CARBOPOL™ 934 32.75% water

3) 1% Estrogen

II. Types of Conditions to be Treated Harrison's Textbook of Medicine, 14^lh Edition and Novak's Gynecology,

12^th edition and Clinical Dermatology by J. Hunter, 2^nd Edition is referred to for additional details.

A. Skin Disorders

Almost everyone suffers from a dermatologic ailment at some point in his or her life. These ailments can range from mild, acute conditions such as small burns, cuts or insect bites to life-long and sometimes debilitating, conditions such as psoriasis, pemphigus and hirsutism. Although a wide variety of products are available to treat dermatologic conditions, there are many conditions for which no adequate treatment is yet available.

There are a variety of conditions, both of the skin and of deeper tissues, for which the compositions described herein described can be useful. Some examples of, but not limited to, the conditions are described below. B. Treatment of Antihirsutism and Acne

Hirsutism, or excess hair growth, is a common problem encountered by women for which there are no effective treatments that medically treat the increased hair growth. This is a difficult problem for most women to cope with. The most common cause of hirsutism in reproductive age women is due to polycystic ovarian disease, a disease characterized by several endocrine abnormalities, including higher than normal circulating levels of androgens. These women may also suffer from an increased incidence of acne. It is well known that hair follicles and the sebaceous glands contain androgen receptors and will be stimulated by the higher levels of circulating androgens. The hair follicles of the face and other parts of the body then respond to the higher androgens by growing a coarser hair more typically found in men, also called male type hirsutism.

Hirsutism also becomes a problem to older women in menopause when estrogen secretion by the ovaries has ceased. At this time, women tend to make both estrogen and androgens in fat cells. The ratio of estrogen to androgens, which are also secreted by adrenal changes, in the menopause and the relative androgenicity is thought to be responsible for the increase in hirsutism seen in older women.

Polycystic ovarian disease may be treated with oral contraceptives, which can sometimes correct hirsutism. Spironolactone is an anti-androgen that is given to treat hirsutism. In Europe, cyproterone acetate, a progestogen with anti-androgenic properties, is also used for acne and hirsutism. Flutamide, a potent anti-androgen currently marketed for prostate cancer, has been shown to be effective when given orally and is more effective that Finestride. a 5α reductase inhibitor.

Recent studies have shown that anti-androgens may be effective in treating hirsutism of Polycystic Ovarian Syndrome (PCO), a condition in which the normal menstrual cycle is disrupted and the woman does not ovulate normally. The ovaries of these women also secrete a larger than normal amounts of androgens. which can lead to hirsutism or abnormal hair growth on the face and sometimes, even the chest and abdomen. A recent study found that a topical anti-androgen, cyproterone acetate, was effective in treating acne, another skin condition aggravated by androgen receptors in the sebaceous glands. See, Gruber, et al. Archives of Dermatology. 134:459-63 (1998). Cyproterone acetate is not available in the U.S., but flutamide, the product of choice for development, has been approved and used in the US for many years, with a large database of safety and efficacy. A recent study compared finestride and flutamide for the treatment of idiopathic hirsutism. In this study, patients were given 5 mg of finestride daily or 250 mg of flutamide twice daily for 12 months. 46 women were treated with either drug for a period of 12 months and both antiandrogens were found to be effective in the treatment of hirsutism. but flutamide was more effective than finestride. See Falsetti & Gambera Fertil. Steril. 72:41 -46 (1999). The reason given for flutamide's superior efficacy is it acts as an anti-androgen, while finasteride acts by suppressing the type 2 5- αreductase. Type 2 is typically found in hair follicles.

Antiandrogens have been shown to be effective when given systemically because they bind to the androgen receptors found in the hair follicle and suppress their growth. Although these drugs were effective, there are side effects associated with taking them by mouth, including gastrointestinal side effects, liver problems and decrease in libido. These could be avoided by the use of topically administered products, and with enhanced formulations, pharmaceutical products can penetrate and bind to the androgen receptors found in the hair follicle.

C. Local, Non-Dermatologic Conditions to be Treated with the Enhanced Formulations A variety of local, tissue conditions can be treated. Examples include local muscle injury due to sports or to falls, inflammation, osteoarthritis, other forms of arthritidis, and other tissue injuries and diseases. Other conditions include local infections, bacterial or viral, requiring high local levels of anti-infectives.

D. Systemic Conditions to be Treated with the Enhanced Formulations

To treat systemic conditions, pharmaceuticals and other therapeutic agents must be able to penetrate the skin and enter the systemic circulation. However, drugs must be given with enhancers to penetrate the skin and enter the systemic circulation. Conditions for consideration include hormone replacement therapy, contraception, angina, hypogonadism due to testosterone deficiency, among others. E. Conditions to be Treated with the Unenhanced Formulations Examples of conditions that can be treated with formulations not including enhancers include acute inflammations of the skin with compromise of the epidermis, for example, inflammation occurring from skin resurfacing procedures, sunburns, any type of minor or major burns, infective inflammation, and inflammation due to toxic substances such as poison ivy and other irritative agents. The cause of dermal inflammation that results from external injury, whether it is ultraviolet radiation or other types of burns is thought to have a complex mechanism of action. One of the major mechanisms includes the formation of prostaglandins, which are known to cause the release of the inflammatory agents. The actual mechanism that leads to activation of the prostaglandins and other inflammatory agents are not well understood. See, Hruza & Pentland, "Mechanisms of UV- induced inflammation" J. Invest. Dermatol. 100:35S-41 S (1993), and Soter NA. Semin. Dermatol. 9:11-5 (1990). Prostaglandin E2 levels have been shown to be increased to approximately 150 percent of control levels 24 hours after UV exposure and then diminishes gradually. In addition, there are increased levels of arachidonic acid and of prostaglandin D2, E2 and 12 that peak in the dermis within 5-9 hours post-exposure and subside thereafter before peak redness occurs. See, David R. Bickers: Photosensitivity and other Reactions to Light. Harrisons Textbook of Medicine, pages 329-330 (14^th edition, McGraw Hill, New York, 1996).

Skin resurfacing procedures are described here as a typical example of a compromised epidermis situation. Skin resurfacing procedures are performed on tens of thousands of patients every year and consist of chemical peels, laser resurfacing and dermabrasion. (American Society for Dermatologic Surgery: Information booklet entitled "Chemical Peeling". 1999). Skin resurfacing procedures are currently being used to treat a number of conditions such as pigmentary dyschromias. actinic keratoses, and rhytids (wrinkles), depressed scarring and in some cases, irradiation dermatitis. Skin resurfacing involves the removal of the epidermis and the upper dermal layer, leaving intact the deeper or reticular layer. Post resurfacing, the reticular layer will regenerate and create a smoother and more even skin. Furthermore, some studies have shown that the amount of collagen can even increase, creating a tighter skin after the peel.

Superficial peels are less invasive procedures, but must be repeated often. For those desiring a more permanent effect for aging skin, there are two methods more commonly used. They are medium depth chemical peels and the increasingly popular laser resurfacing using a CO? laser or the newer Er/Yag laser. Studies have shown that these two methods can result in long-term effectiveness. Manuskiatti, W et al. "Long term effectiveness and side effects of carbon dioxide laser resurfacing for photoaged skin" J. Am. Acad. Dermatol. 40:401-1 1 (1999). The immediate reaction to all these agents is very similar to sunburn, with the intensity and length of the acute reaction dependant on the length and depth of chemical or laser exposure. This acute reaction is followed by a longer erythema, and this erythema is considered part of the healing process.

Chemical peels are accomplished by the application of one or more chemical solutions — such as glycolic acid, tricholoroacetic acid, salicyclic acid, lactic acid or carbolic acid. For removal of fine wrinkles, glycolic acid is the most commonly used product. The most commonly used procedure is the superficial peeling. Superficial peels work by removing the epidermal layer of skin and can be applied every 4-6 weeks. This procedure is followed by redness or local inflammation followed by scaling that ends within three to five days. These peels are administered using low concentration glycolic acid or Jessneris solution (combination of resorcinol. salicylic acid lactic acid and ethanol), 50% salicylic acid ointment, alpha- hydroxy acid, or solid carbon dioxide. Tretinoin can be pre-applied to enhance the action of TCA. Tricholoroacetic acid can be used if the concentration is kept between 10 and 35%. Multiple weekly or monthly applications of superficial peels are usually performed. Patients can usually return to normal activities after a superficial peel. There will be mild erythema, which are currently covered with cosmetics. A milder version of superficial peel is the application of retinen cream, which can also be associated with erythema. Medium depth chemical peels are most often rendered with 70% or higher

TCA (trichloroacetic acid), phenol and/or Jessner's solution (combination of the above two ingredients). In this procedure, 40-60% trichloroacetic acid (40-60%) is used. 35% TCA provides a medium depth peeling if used after the use of superficial peeling agent such as Jessner's solution. The first few days after application, the patient will feel some pain and experience erythema. Ninety days after therapy, an expanded papillary zone of the dermis is seen, the deeper the wounding agent, the thicker the zone. Deeper peels can be rendered with a Baker's solution. Deep peels are used to treat deep rhytids and require significantly more effort and time. When used over the whole face, an anesthetic may be needed. Phenol formulas result in a deeply stained elastotic dermal band. The new subepidermal horizontally arranged collagen band is responsible for lessening of wrinkles. Deep wounding compares favorably to CO resurfacing laser. The depth of the peel is determined to some extent by factors such as length of administration, dosing and concentration.

Included also are pre-and post peel care. Some researchers and practitioners have tried different combinations with success. See. Brody HJ J. Dermatol. S rg. Oncol. 15:953-63 (1989); Stone PA. Clin. Plast Surg. 25:21 -44 (1998); Tse Y et al. Dermatol. Surg. 22:781-6 (1996). This procedure is usually performed as single procedure to remove actinic keratosis, mild rhytids or pigmentary dyschromias and to depress scars.

Laser resurfacing is another method to render a peel. In this procedure, a laser beam is focused on areas of interest. Laser resurfacing is also being more commonly used to treat acne scars and wrinkles. The mode of action is the conversion of light energy to heat based on the absorption of the water content of skin. The heat then causes local thermal injury and skin rejuvenation. The depth of effect is based on the number of passes. The results with laser resurfacing can be impressive. This treatment is universally associated with erythema, which can last up to 12 weeks. Newer laser technology includes Er: YAG laser, which allows for a wider range of use and depth of peeling. Following the laser procedure, an inflammatory response develops, resulting in sloughing of old skin and the formation of new skin without wrinkles. Some studies have shown that the effect of laser resurfacing, the deepest of the peels usually administered, can be long-lasting. Weinstein Clin. Plast. Surg. 25:109-30 (1998). Peels are associated with acute and longer-term side effects. Following the peel, a reaction similar to sunburn occurs. Superficial peels have the least side effects — scaling that ends within three to five days follows redness. Medium depth and deep peeling can sometimes result in swelling and blisters that may form and break over a period of seven to 14 days. Laser resurfacing can result in a variable period of healing, lasting from a few weeks to months. Again, the acute process is followed by prolonged erythema. Typically, cosmetics are applied after the first 7 to 14 days. After the initial reaction, there can be erythema for a longer period of time, which is considered part of the healing process and is associated.

The same treatments are generally applicable to treatment of other conditions, for example, for skin resurfacing (or a burn situation). Prior to the procedure, typically, antibiotics (and sometimes antivirals) are given usually starting a few days before and following up for a few days afterwards. It seems patients do get infections and sometimes herpes simplex can flare up. The epidermis is removed, yielding a minor burn type of situation. Also, some physicians apply tretinoin cream prior to the procedure to stimulate the healing process. These products are used prior to the procedure. After the procedure, wound care is applied, typically a suave type agent is applied. These treatments vary from center to center, but may be used in combination with the formulations described herein as a topical analgesic.

1. Semiocculsive Hydrogel dressings: Serves as a barrier to microorganism while absorbing exudates and absorptive hydrogels have been found to help in minor burn situations. See Alvarez et al., J. Surg. Res. 35:142-8 (1983). Resurfacing wounds are very exudative, similar to a burn. It is not clear how long to keep the hydrogel— if its kept too ling, it could be nidus for infection. See Feldman et al., Surg. Gynecol. Obstet. 173:1-5 (1991). Some examples include Second Skin, Duderm, Biobrane, Xeroform, Flexzan, Vigilon, Cetrix. See Duke & Grevelink, Derm. Surgery. 24:201-6 (1998). 2. Semi-occlusive ointments are also used, and these are thought to be equivalent or slightly worse than hydrogels. See Alsbjorn et al., Acta. Chir. Scand. 156:21 1-3 (1990). These agents do not absorb the exudate from the wound, but petrolatum is cheaper, readily available and better tolerated by some patients.

3. A lotion containing propylene glycol without petrolatum can also increase wound healing, in one study. See Eaglstein et al., J. Invest. Dermatol. 74:90-1 (1980). 4. Vitamin E and Vitamin C may also be helpful in skin resurfacing and burn situations. Vitamin E has antioxidant characteristics and Vitamin C may help collagen growth.

The present invention will be further understood by reference to the following non-limiting examples:

Example 1: Enhanced Delivery of Products through intact epidermis A study was conducted to investigate the topical delivery of two drug molecules as examples of enhanced delivery utilizing the pharmaceutical compositions. Two pharmaceutical products were utilized to evaluate the efficacy of the enhancers described. The specific objectives of the studies were to investigate the in vitro flux of two drugs, ibuprofen and flutamide, to traverse across human cadeveric epidermis in formulations with and without enhancer.

Human cadaver skin obtained from a skin/tissue bank was used. The skin was stored at -80 °C and then thawed just before use. Skin obtained from four different donors was selected so that each n =4 experiment used skin from different donors. This results in high S.D. but makes the data comparable across different experiments. This way, each different experiment uses the same skin source so that results can be compared since transdermal studies have so much variation inherent to the skin. For separation of epidermis, full thickness human skin was placed in a beaker containing water heated to 60 °C, stirring occasionally and gently with a spatula. The skin was rubbed between spatula and the epidermis was removed carefully after 45 sec. Franz (vertical) diffusion cells were used for the in vitro permeation studies. The donor half was exposed to room temperature (25 °C) while the receptor half was maintained at 37 °C. Receptor compartment was filled with buffer and continuously stirred. The epidermis was mounted on the vertical diffusion cells, and then 100 μL of the formulation was placed on the skin. Samples taken at different time points were analyzed by HPLC assay described below.

The different formulations are utilized as shown below. Each formulation is spread to cover the donor surface completely. The donor cell was then clamped in place. Samples were taken from the receptor cell at various times as outlined in the results. The results of the permeation experiments were plotted as cumulative amounts of drug permeated versus time. Analysis was conducted on HPLC assay with a UV detector. A standard curve was completed with the active ingredient with the peak noted from USP monographs for both active ingredients. The results of the two studies are shown below.

A. Topical Delivery of Flutamide to Skin.

The topical delivery of Flutamide for treatment of acute inflammatory response of skin was studied. The specific objective of these experiments was to investigate the in vitro flux of flutamide across human epidermis. The composition of the donor solution was as follows: Table 1: Composition of Flutamide Samples

The methods were as described above. After the experiments were analyzed, an interfering peak was identified in the chromatograph very close to the drug peak. Changes in the composition of the mobile phase shifted this peak from one side of the drug peak to another but it was still too close and was interfering. The column was then switched, changing from a 10 cm to a 25 cm column. The samples were reanalyzed, at which time no interference was observed. The standard curve was linear with an r^" of 0.99.

Figure 1 compares the transdermal penetration of flutamide with no enhancer to that with enhancer (oleic acid) (same data plotted to show only oleic acid results). The difference is statistically significant at the 20 and 24 hr time points (ANOVA).

B. Topical Delivery of Ibuprofen to Skin.

Using the same method described above, ibuprofen was also tested for in vitro skin flux utilizing human cadaveric skin. The specific objective of these experiments was to investigate the in vitro flux of ibuprofen across human epidermis. The composition of the donor solution was as follows: Table 2. Composition of Ibuprofen Samples

Figure 2 compares the transdermal transfer of ibuprofen with no enhancer to that with enhancer (oleic acid) (same data plotted to show only oleic acid results). The difference is statistically significant at the 20 and 24 hr time points (ANOVA). Example 3: Topical Ibuprofen formulation not including enhancer

These formulations are particularly useful for application to compromised skin. The formulation is prepared as follows. Mix ibuprofen and mineral oil or silicone oil in w/w ratio of 1 : 1 or such that the ibuprofen is saturated in the oil. Add sufficient TWEEN™ 80 or other surfactant to an aqueous solution containing parabens as a preservative and homogenize the liquid (containing from 5% to 10% ibuprofen) from step 1 to form an emulsion. Add approximately 0.1% CARBOPOL™ 940 and adjust pH until a gel is formed.

Active ingredients can also be formulated in hydrogel matrices, petrolatum jelly, and other soothing agents among others.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The references cited herein are hereby incorporated by reference as appropriate.

Claims

We claim:

1. A topical formulation comprising a penetration enhancer, the penetration enhancer consisting essentially of a diol and a cell envelope disrupting agent.

2. The formulation of claim 1 wherein the diol is selected from the group consisting of 1 ,2-propanediol, 1 ,3-propanediol, 1 ,2-butanediol, 1,3-butanediol, 1,4- butanediol, and mixtures of these diol compounds.

3. The formulation of claim 1 wherein the cell envelope disordering agent is selected from the group consisting of methyl laurate, oleic acid, oleyl alcohol, monoolein, myristyl alcohol, and mixtures thereof.

4. The formulation of claim 1 wherein the weight ratio of diol compound: cell-envelope disordering compound is from about 1 :1 to about 500: 1.

5. The formulation of claim 1 comprising a pharmaceutically active agent to be delivered selected from the group consisting of hormones, anti-hormones, corticosteroids, anti-viral agents, phosphodiesterase enzyme inhibitors, ICAM-1 inhibitors, substances which affect the formation and aggregation of melanin granules, inhibitors of enzymes that participate in the cascade of reactions responsible for cell death, and non-steroidal antiinflammatories.

6. The formulation of claim 5 wherein the pharmaceutically active agent is selected from the group consisting of caspasine, estrogens, progestogens, androgens, metabolites of estrogens, progestogens, androgens, anti-androgens, celecoxib, rofecoxib. danazole, acyclovir, ibuprofen, declofenac, naproxyn, piroxican, phenybutazone, etfenamate, fulindac, salicylic acid and indomethacin.

7. The formulation of claim 6 wherein the pharmaceutically active agent is selected from the group consisting of spironolactone, cyproterone acetate, finasteride, flutamide, casodex and other substances known to inhibit androgen activity by binding to the androgen receptor or inhibit post-receptor events and transformation of testosterone to active androgens.

8. A topical formulation for transdermal administration comprising a pharmaceutically active agent to be delivered selected from the group consisting of hormones, anti-hormones, corticosteroids, anti-viral agents, phosphodiesterase enzyme inhibitors, ICAM-1 inhibitors, substances which affect the formation and aggregation of melanin granules, inhibitors of enzymes that participate in the cascade of reactions responsible for cell death, and non-steroidal antiinflammatories, in combination with a pharmaceutically active carrier for transdermal transport of the pharmaceutically active agent through compromised skin.

9. The formulation of claim 8 wherein the pharmaceutically active agent is selected from the group consisting of caspasine, estrogens, progestogens, androgens, metabolites of estrogens, progestogens, androgens, anti-androgens, celecoxib, rofecoxib. danazole, acyclovir, ibuprofen, declofenac, naproxyn, piroxican, phenybutazone, etfenamate, fulindac, salicylic acid and indomethacin.

10. The formulation of claim 8 wherein the pharmaceutically active agent is selected from the group consisting of spironolactone, cyproterone acetate, finasteride, and flutamide.

1 1. A method for transdermal administration of a pharmaceutically active agent comprising administering to the skin any one of the formulations of claims 1- 10 when there is a compromise of normal skin.

12. The method of claim 1 1 for treatment of skin disorders.

13. The method of claim 12 wherein the skin disorder is a burn, cut or insect bite, including minor and major burns and sunburns.

14. The method of claim 12 wherein the skin disorder is psoriasis, pemphigus or hirsutism.

15. The method of claim 12 wherein the skin disorder is a burn with loss of epidermis and/or part of the dermis, such as in skin resurfacing procedures through chemical, laser and other agents.

16. The method of claim 12 wherein the skin disorder is due to the action of toxic agents such as poison ivy, radiation therapy, chemotherapy or other chemical and non-chemical skin disrupting agents.

17. The method of claim 11 for treatment of a local, tissue condition.

18. The method of claim 15 wherein the local tissue condition is local muscle injury, inflammation, arthritis, or infection.

19. The method of claim 1 1 for treatment of compromised skin.