CA2633489A1 - Compositions and methods for treating dermatological conditions - Google Patents

Abstract

The present invention is drawn to solidifying adhesive formulations, methods of drug delivery, and solidified layers for dermal delivery of a drug which can treat various dermatological conditions, such as a bacterial infection, a virus infection, a fungal infection, alopecia, dermatitis, psoriasis, or photo damaged skin. The formulation can include a drug, a solvent vehicle, and a solidifying agent. The solvent vehicle can include a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system including at least one non-volatile solvent. The non-volatile solvent system can facilitate the delivery of the drug at therapeutically effective rates for sustained period of time. The non-volatile solvent system can also act as a plasticizer for the solidifying agent. The formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvents system. When applied to the skin, the formulation can form a solidified layer after at least a portion of the volatile solvent system is evaporated.

Description

COMPOSITIONS AND METHODS FOR TREATING
DERMATOLOGICAL CONDITIONS

FIELD OF THE INVENTION

The present invention relates generally to systems and methods for treating various dermatological conditions. More particularly, the present invention relates to solidifying adhesive formulations having a viscosity suitable for application to skin areas afflicted with a dermatological condition, and which form a sustained drug-delivering solidified adhesive layer on the skin.

BACKGROUND OF THE INVENTION

Skin or dermatological conditions affect millions of people across the world. Such conditions include infections from fungal, bacterial, and viral sources, alopecia, photo or sun damaged skin, dermatitis, and psoriasis.
Treatments are generally available for each of these treatments, but current treatments have some pronounced drawbacks. For example, one type of viral infection is a herpes infection. Herpes infections often occur on lips, e.g.
cold sores, and on the genitals. There are two common dosage forms available.for treating cold sores and genital. herpes, namely topical and ora1. Both delivery forms have certain drawbacks. For example, oral delivery of acyclovir, an anti-viral drug, can cause undesirable side effects such as upset stomach, loss of appetite, nausea, vomiting, diarrhea, headache,dizziness, or weakness. One drawback of current topical anti-cold sore formulations, iri the form of ointments and creams such as Zovirax ointment and cream , is that they are often inadvertently wiped off from the treatment site when the subject eats, drinks, or licks his/her lips, etc. This is believed to be a reason why topical cold sore formulations often need to be applied many times a day, which is very inconvenient and frequently results in poor patient compliance: When a topical anti-herpes formulation is applied on the genitals, the drug is often subject to inadvertent removal by underwear and adjacent healthy skin/mucosal surface contact. In addition, some topical. formulations usually contain volatile solvent(s), such as water and ethanol, which tend to evaporate shortly after application. The complete evaporation of such solvents can cause a significant decrease or even termination of dermal drug delivery, thereby prematurely ending treatment. Additionally, semisolid formulations.are often "rubbed'into"
the skin, which does not necessarily mean the drug formulation is actually delivered into the skin. Instead,"this phrase often means that a very thin layer of the drug formulation is applied onto the surface of the skin. Such thin layers of traditional topical semisolid formulations may not contain suffioient quantity of active drug to achieve sustained delivery over long periods of time.
Another example is photo damaged skin. It is believed that topical application of immune activators.such as imiquimod can be used to treat photo damages and=premature aging of the skin, which are characterized by fine lines, -wrinkles, roughness, dryness, laxity, and/or ii-reguiar pigmentation. For example, treatment of visible signs of photo aging-with an imiquimod over several weeks can improve the morphology and appearance of photo damaged skin. However, the only commercially available dosage form of imiquimod, Aldara Cream from 3M, was not designed or approved fo,r treating photo damaged 'skin, i.e. it was approved for treating genital warts and basal cell carcinoma: After the cream is applied on and rubbed "into" the skin, most of the drug does not really get into the skin. Instead, most of the drug stays on the surface of the skin for a long duration during which= it is subject to unintentional removal. For example, the cream applied on a subject's face and forehead before bedtime can be removed by the pillow or blanket during the riight.
Similar drawbacks can be found with many of the available treatments for the other above mentioned dermatological conditions.
In view of the shortcomings of current dermal formulations=for treating dermatological disorders, it would be desirable to provide systems, formulations, and/or methods that i) provide more sustained drug delivery over long periods of time, ii) are not vulnerable to unintentional removal by contact with clothing, iii) provide a protective physical barrier that is beneficial in certain disease treatment, and/or iv) are easily removed after application and use.

SUMMARY OF THE INVENTION

It has been recognized that it would be advantageous to provide Jormulations and related methods for treating' dermatological conditions which are capable of providing sustained release of drug and do not suffer from the drawback of unintentional removal. In accordance with this, the present invention is drawn generally to a formulation for treating dermatolological conditions, comprising a drug that is effective for treating a dermatological condition, a,solvent vehicle, and a solidifying agent. The solvent vehicle can comprise a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system including at least one non-volatile solvent, wherein the non-volatile solvent system is capable of facilitating delivery of the drug at therapeutically effective rates over a sustained period of time. The formulation can haveI a viscosity suitable for application and adhesiori to a skin surface prior to evaporation of the volatile solvent'system. The formulation applied to the skin surface can form a soft, coherent; solidified layer after at-least partial evaporation of the volatile solvent system. Further,'the drug-can continue to be delivered after the volatile solvent system is at least substantially evaporated.
The elermatological conditions which can be treated include a bacterial-infection, a virus infection, a fUngal infection, alopecia, dermatitis, psoriasis, photo damaged skin, and combinations thereof In another embodiment, a method of treating dermatological conditions can comprise applying a solidifying adtfesive formulation to an infected skin surface: The formulation can be a formulation as described-in the previous embodiment. Additional steps include solidifying the formulation to form a soft, coherent, solidified layer on the infected skin surface by at least partial evaporation of the volatile solvent system, and dermally delivering.the drug from , the solidified, layer to the infected skin site at therapeutically effective rates over a sustained period of time.

In another embodiment, a soft, coherent, solidified layer for treating dermatological conditions an infection can comprise a drug that is effective for treating the dermatological condition; a non-volatile solvent system including at least one non-volatile solvent, wherein the non-volatile solvent system facilitates the delivery of the drug at therapeutically effective rates over a sustained period of time; and a solidifying agent. The solidified layer can preferably be stretchable by 5% (or even 10%) in one direction withotit cracking, breaking, and/or separating from a skin surface to which the layer is applied.
Additional features and advantages of the invention will be apparent from the following detailed description and figure which illustrate, by way of example, features of the invention.

. BRIEF DESCRIPTION OF THE DRAWING .

FIG. 1 is a graphical representation of the cumulative amount of acyclovir delivered transdermally over time from two separate formulations in accordance with embodiments of the present invention compared to the marketed product Zovirax cream. .

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S) Before particular embodiments of the present invention are disclosed and described, it is to be understood that this invention is not limited to the particular process and materials disclosed herein as -such may vary to some degree. It is=
also to be understood that the terminology used herein is used for the purpose of describing particular embodirrients only and is not'intended to be limiting, as the scope of the present invention will be defined only by the appended claims and equivalents thereof. In describing and claiming the present invention, the following terminology will be used.

The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a drug"
includes reference to one or more of such compositions.
"Skin" is defined to include human skin (intact, diseased, ulcerous, or 5 broken), finger and toe nail surfaces; and mucosal surfaces that are usually at least partially exposed to air such as lips,.genital and anal mucosa, and nasal and oral mucosa.
The phrase "dermatological condition" refers to any skin condition, or combination of skin conditions, including bacterial infection, viral infection, fungal infection, alopecia, psoriasis, dermatitis, or photo damaged skin.
Wheri referring to skin that is "photo damaged," both acute photo damage and chronic photo damage is included herein. Acute photo damage can be manifest as a sunburn, and chronic photo damage can be seen as gradual changes in the skin caused by an accumulation of sun exposure throughout a period of months, but more typically years. Thus, photo damage includes human skin having experienced photo damage of some type, which can be manifest as premature aging, fine lines, wrinkles, roughness, dryness, laxity, irregular pigmentation, pre-cancerous lesions and/or skin cancers.
Similarly, "skin damage" can be defined to include photo damage, premature aging, fine lines, wrinkles, roughness, dryness, laxity, and/or irregular pigmentation of the skin.
The term "drug(s)" refersto any bioactive agent or agents which can be used to effectiveiy treat dermatological conditions. For example when the dermatological condition is a fungal infection antifungal drugs can be used.
Examples of antifungal drugs which can be used in the present invention .include, but are not limited.to, amorolfine, butenafine, naftifine, terbinafine, fluconazole, itraconazole, ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, butoconazole , econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, caspofungin, micafungin, anidulafingin, amphotericin B, AmB, nystatin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, and undecylenate, or combinations thereof.

When the dermatological condition is a viral infection anti-viral drugs including, but not limited to, acyclovir, penciclovir, famciclovir, valacyclovir, behenyl alcohol, trifluridine, idoxuridine, cidofovir, gancyclovir, podofilox, podophyllotoxin, ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine,.zanamivir, or combinations thereof can be used.
When the dermatological condition is. a bacterial infection, antibacterial drugs can be used include, but are not limited= to; erythromycin, clindamycin, te,tracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones such as ciproflaxin, or combinations thereof: The active drug in the formulations and methods of the present invention for treating skin infections can also include immune modulating agents, including but is not limited to imiquimod When the dermatological condition is photo damaged skin, drugs which can be used include, but are not limited to immune modulating agents or immune activators which are capable of increasing immunity of the human skin mucosa. Non-limiting examples of such drugs include imiquimod, rosiquimod, or combinations thereof.
When the dermatological condition is alopecia, generally any drug which is capable of stimulating hair growth when dermal.ly delivered can be. used.
This includes compositions that are traditionally identified as drugs, as well other bioactive agents that are not always considered to be "drugs" in the classic sense. Examples of drugs wtiich can be used in the present invention include corticosteroids such as betamethasone dipropionate, halobetasol propionate, diflorasone diacetate, triamcinolone acetonide, desoximethasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, atclometasone dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone acetate, and combinations thereof. Other drugs can also be used. Other examples include drugs which can irritate the skin to stimulate hair growth such as minoxidil, spironolactone, finasteride, anthralin, tretinoin topical immunotherapeutic agents such as dinitrochlorobenzene, squaric acid dibutyl ester, diphenylcyclopropenone, other hair growth stimulants, or combinations thereof.
When the dermatological condition is psoriasis or dermatitis, drugs which can be used include, but are not limited to, agents selected from the drug ciasses of corticosteroids, immune modulators, vitamin D3 and its analogs, retinoic acids and their pharmaceutically active derivatives, or combinations thereof. Specific non-limiting examples of such drugs include betamethasone dipropionate, clobetasol propionate, halobetasol propionate, diflorasone diacetate, amcinonide, desoximethasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alclometasone dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone acetate, tacrolimus, picrolimus, tazarotene, isotretinoin,-cyclosporin, anthralin, vitamin D3, cholecalciferol, calcitriol, calcipotriol, tacalcitol, calcipotriene, or combinations thereof.
When referring generally to a "drug," it is understood that there are various forms of a given drug, and those various forms are expressly included.
In accordance with this, various drug forms include polymorphs, salts, hydrates, solvates, and cocrystals. This includes compositions that are traditionally' identified as drugs, as well other bioac#ive agents that are not always considered to be "drugs" in the classic sense, but which can provide a therapeutic effect for certain conditions. In one embodiment, a single agent can be effective in treating multiple dermatological conditions. In another embodiment, multiple drugs for treating a single dermatological condition can be concurrently present and delivered from the same solidified formulation. In another embodiment, multiple. drugs targeting separate dermatological conditions can be delivered from the same solidified formulation. -The term "emollient," "moisturizing agent," "moisturizer," and "humectant"
can be used interchangeably and refer to a substance capable of softening, soothing, or enhancing a skin's ability to retain moisture in or on the surface thereof. Non-limiting examples of such compounds include glycerol, propylene glycol, dipropylenen glycol, butylene glycol, sorbitol, honey and honey derivatives such as honeyquat, urea and urea derivatives such as hydroxyethyl.
urea, ammonium lactate, sodium lactate, potassium lactate, pyroglutamic acid and its salts, sodium malates, polydextrose, triacetin, mannitol, oxidised polyethylene, isomalt, maltitol and maltitol syrup, lactitol, xylitol, erythrit, and combinations thereof.
The phrases "topical -delivery" or "topical delivery of drugs" shall mean the delivery of a drug to a skin tissue, and subsequent absorption into the skin that may occur.
The phrases "dermal drug delivery" or "dermal delivery of drug(s)" shall include both transdermal and topical drug delivery, and includes the delivery of drug(s) to, through, or into the skin. "Transdermal delivery" of drug can be targeted to skin tissues just under the skin, regional tissues or organs under the skin, systemic circulation, and/or the central nervous system.
The term "flux" such as in the context of "dermal flux" or "transdermal flux," respectively, refers to the quantity of the drug permeated into or across skin per unit area per unit time. A typical unit of flux is microgram per square centimeter per hour. One way to measure flux is to place the formulation on a known skin area of a human volunteer and measure how much drug can permeate into or across skin.within certain time constraints. Various methods (in vivo methods) might be used for the measurements as well. The method described in Example 1 or other similar method (in vitro methods) can also be used to measure flux. Although an in vitro method uses human epidermal membrane obtained from a cadaver, or freshly separated skin 'tissue from hairless mice rather than measure drug flux across the skin using human volunteers-,'it is generally accepted by those skilled in the art that results from a properly designed and executed in vitro test can be used to estimate or predict the results of an in vivo test with reasonable reliability. Therefore, "flux"
values referenced ih this patent application can mean that measured by either in vivo or in vitro methods.

The term "flux-enabling" with respect to the non-volatile solvent system (or solidified layer including the same) refers to a non-volatile solvent system (including one or more non-volatile solvents) selected or formulated specifically to be able to provide therapeutically effective flux for a particular drug(s).
For topically or regionally delivered drugs, a flux enabling non-volatile solvent .system is defined as a non-volatile solvent system which, alone without the help of any other ingredients, is capable of delivering therapeutic effective levels of the drug across, onto or into the subject's skin when the non-volatile solvent system is saturated with'the drug. For systemically targeted drugs, a flux enabling non-volatile solvent system is a non-volatile'solvent system that can provide therapeutically effective daily doses over 24 hours when the non-volatile solvent system is saturated with the, drug and is in full contact with the subject's skin with no more than 500 cm2 contact area. In one embodiment, the contact area for the non-volatile solvent system is no more than 100 cm2. Testing using this saturated drug-in-solvent state can be used to measure the maximum flux-generating ability of a non-volatile solvent systern.To determine flux, the drug=
solvent mixture needs to be kept on the skin for a clinically sufficient amount of time. In reality, it may be difficult to keep a liquid solvent on the skin of a human volunteer for an extended period of time. Therefore, an alternative method to determine whether a solvent system is "flux-enabling" is to measure the in -eitro drug permeation across the hairless mouse skin or human cadaver skin using the apparatus and method described in Example 1. This and similar methods are commonly used by those==skilled in the art to evaluate permeability and feasibility of formulations. Alternatively, whether a non-volatile solvent system is flux-enabling can be tested on the skin of a live human subject with means to maintain the non-volatile solvent system with saturated drug on the skin, and such means may not be practical for a product. For example, the non-volatile solvent system with satiurated drug can'be soaked into an absorbent fabric material which is then applied on the skin and covered with a protective membrane. Such a system is not practical as a pharmaceutical product, but is appropriate for testing whether a non-volatile solvent system. has the intrinsic ability to provide sufficient drug flux, or whether it is flux-enabling.

It is also noted that once the formulation forms a solidified layer, the solidified layer can also be "flux enabling" for the drug while some of the non-volatile solvents remain in the solidified layer, even after the volatile solvents (including water) have been substantially evaporated.
5 The phrase "effective amount," "therapeutically effective amount,"
"therapeutically effective rate(s)," or the like, as it relates to -a drug, refers to sufficient amounts or delivery rates of a drug which achieves any appreciable level of therapeutic results in treating a condition for which the drug is being delivered. It is understood that "appreciable level of therapeutic results"
may or 10 may not meet any government agencies' efficacy standards for approving the commercialization of a product. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an "effective amount," "therapeutically effective amount," or "therapeutically effective rate(s)" may be. dependent in some instances on such biological factors to some degree. However, for each drug, there is usually a corisensus among those skilled in the art on the range of doses or fluxes that are sufficient in most subjects. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a subjective decision. The determination of a therapeutically effective amount or delivery rate is well within the ordinary skill in the art of pharmaceutical sciences and medicine.
"Therapeutically effective flux" is defined as the permeation fiux of the selected drug that delivers sufficient amount of. drug into or across the skin to be clinically beneficial. It does not necessarily mean that most of the subject population can obtain some degree of benefit or'the benefit is high enough to be deemed "effective" by relevant government agencies or the medical profession.
More specifically, for drugs that target skiri or regional tissues or organs close to the skin surface (such as joints,.certain muscles, or tissues/organs that are at least partially within 5 cm of the skin surface), "therapeutically effective flux"
refers to the drug flux that can deliver a sufficient amount of the drug into the target tissues within a clinically reasonable amount of time. For drugs that target the systemic circulation, "therapeutically effective flux" refers to drug flux that, via clinically reasonable skin contact area, can deliver sufficient amounts of the selected drug to generate clinically beneficial plasma or blood drug concentrations within a clinically reasonable time. Clinically reasonable skin contact area is defined as a size of skin application area that most subjects would accept. Typically, a skin contact area of 400 cm2 or. less is considered reasonable. Therefore, in order to deliver 4000 mcg of a drug to the systemic circulation via a 400 cm2 skin contact area over 10 hours, the flux needs to be at least*4000 mcg/400cm2/10 hour, which equals 1 mcg/cm2/hr. By this definition, different drugs have 'different "therapeutically effective flux."
Therapeutically effective flux" may be different in different subjects and or at different times for even the same subject. However, for each drug, there is usually a consensus among the skilled in the art on the range of doses or fluxes that are sufficient in most subjects at most times. The following are estimates of flux for sbme drugs that are therapeutically effective or more than sufficient:

Table A - In vitro steady state flux values of various drugs -Estimaied Drug Indication Therapeutically effective flux ' mc lcm2lh Ro ivacaine** Neuropathic pain 5 Lidocaine Neuropathic pain 3U
Ac -clovir Herpes simplex virus 3 Ketoprofen Musculoskeletal pain 16 Diclofenac Musculoskeletal pain 1 Clobetasol Dermatitis, psoriasis, 0,05 eczema Betamethasone Dermatitis, psoriasis, 0.01 eczema Testosterone Hypogonadal men, 0.8 Testosterone Hormone treatment for 0.25 postmenopausal women Imiguimod Warts, basal cell 0.92 carcinorria * Flux determined using an in vitro method described in Example 1.
** Estimated flux based on known potency relative to lidocaine.

The therapeutically effective flux values in Table A (with the exception of ropivacaine) represent the steady state flux values of marketed products through hairless mouse or human epidermal membrane in an in vitro system described in Example 1. These values are meant only to be estimates and to provide a basis of comparison for formulation development and optimization.
The therapeutically effective flux for a selected drug could.be very different for different diseases to be treated for, different stages of diseases, and different individual subjects. It should be noted that the flux listed may be more than therapeutically effective.
The following examples listed in Table B illustrate screening of non-- vo#atile solvent's flux enabling ability for some of the drugs specifically stiidied.
Experiments were carried out as described in Example 1 below and the results are further discussed in the subsequent Examples 2-9.

Table B - !n vitro steady state flux values of various drugs from non-volatile solvent systems Drug Non-Volatile Solvent Average Flux*
mc /cm2/hr Betamethasone Oleic acid 0.009 t 0.003 Dipropionate Sorbitan Monolaurate 0.03 t 0.02 Clobetasol Propionate Propylene Glycol PG . 0.0038 -0.0004 Li ht Mineral Oil 0.031 0.003 Isostearic acid (ISA) 0.019.t 0.003 Ropivacaine Glycerol 1:2 0.7 Mineral Oil 8.9 0.6 Ketoprofen Pol eth lene glycol 400 5 t 2 S an20 15t3 Acyclovir Pol eth lene glycol 400. 0 lsostearic acid + 10% 2,7 ~ 0.6 trolamine ' Each value represents the mean and st. dev of three determinations.

The in vitro steady state flux values in Table B from non-volatile solvents show surprising flux-enabling and non flux-enabling solvents. This information can be used to guide formulation development.
The term "plasticizing" in relation to flux-enabling non-volatile solvent(s) is defined as a flux-enabling non-volatile solvent that acts as a plasticizer for the solidifying agent. = A"plasticizer" is an agent which is capable of increasing the percentage elongation of the formulation after the volatile solvent system has at least substantially evaporated. Plasticizers also have the capability to reduce the brittleness of solidified formulation by making it more flexible and/or elastic.
For example, propylene glycol is a "flux-enabling, plasticizing rion-volatile solvent" for the drug ketoprofen with polyvinyl alcohol as the selected solidifying agent. However, propylene glycol in a formulation of ketoprofen with Gantrez S-97 or Avalure UR 405 as solidifying agents does not provide the same plasticizing effect. The combination of propylene glycol and Gantrez S-97 or Avalure UR 405 is less compatible and results in less desirable formulation for topical applications. = Therefore, whether a given non-volatile solvent is "plasticizing" depends on which solidifying agent(s) is selected.
Different drugs often have different matching flux-enabling non-volatile solvent systems which provide particularly good results, Examples of such -are noted in Table C. Experiments were carried out as described in Example 1 below and the results are further discussed in the subsequent Examples 2-9.
Table C - In vitro steady state =flux values of various drugs from particularly high flux-enabling non-volatile solvent s stems Drug High flux-enabling non- Avg. Flux*
volatile solvent mc lcm2/h Ropivacaine ISA . 11 t=2 S an20 26:t 8 Ketoprofen Propylene glycol (PG) 90 t 50 Acycolvir ISA + 30% trolamine 7 t 2 Betamethasone Propylene Glycol 0.20 t 0.07 Di ro ionate Clobetasol PG+ISA (Ratio of PG:ISA 0.8 :h 0.2 Propionate ranging from 200:1 to 1:1) * Each value represents the mean and st. dev of three determinations.

It should be noted that "flux-enabling non-volatile solvent," "flux-enabling, plasticizing non-volatile solvent," or "high flux-enabling non-volatile solvent" can be a single chemical substance or a mixture of two or more chemical substances.. For example, the steady state flux value for clobetasol propionate in Table C is a 9:1 for propylene glycol : isostearic acid mixture that generated much higher clobetasol flux than propylene glycol or ISA alone (see Table B).
Therefore, the 9:1 propylene glycol:isostearic acid mixture is a "high flux-enabling non-volatile solvent" but propylene glycol or isostearic acid alone is not.
The term "adhesion" or "adhesive" when referring to a solidified layer herein refers to sufficient adhesion between the solidified layer and the skin so that the layer does not fall off the skin during intended use on most subjects.
Thus, "adhesive" or the like when used to describe the solidified layer means the solidified layer is adhesive to the body surface to which the initial formulation layer was originally applied (before the evaporation of the volatile solvent(s)). In one embodiment, it does not mean the solidified layer is adhesive on the opposing side. In addition, it should be noted that whether a solidified layer can adhere to-a skin surface for the desired exterided period of time partially ' depends on the condition of the body surface. For exampie, excessively sweating, or.oily skin, or oily substances on the skin surface may make~ the' solidified layer less adhesive to the skin. Therefore, the adhesive solidified layer of the current invention may not be able to maintain perfect contact with the body surface and deliver the drug over a sustained period of time for every subject under any conditions on the body surface. A standard is that it maintains good contact with most of the body surface, e.g. 70% of the total area, over the specified period of time for most subjects under normal conditions of the body surface, and external environment.
The terms "flexible," "elastic," "elasticity," or the like, as used herein refer to sufficient elasticity of the solidified layer so that it -is not broken if it is stretched in at least one direction by up to about 5%, and often to about 10%
or even-greater. For example, a solidified layer that exhibits acceptably elasticity and adhesion to skin can be attached to human skin over a flexible skin location, e.g., elbow, finger, wrist, neck, lower back, Iips, knee, etc., and will remain substantially intact'on the skin upon stretching of the skin. It should be noted that the solidified layers of the present invention do not necessarily have 5 to have any elasticity in some embodiments.
The term "peelable," when used to describe the solidified layer, means the solidified layer can be lifted from the skin surface in one large piece or few to several large pieces, as opposed to many small pieces or crumbs.
The term "sustained" relates to therapeutically effective rates of dermal drug 10 delivery for a continuous period of time of at least 30 minutes, and in some embodiments, periods of time of at least about 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, or longer. -.
"Volatile solvent system" can be a single solvent or a mixture of solvents that are volatile, including water and solvents that are more volatile than water.

15 Non-limiting examples of volatile solvents that can be used in the present invention include iso-amyl acetate, denatured alcohol, methanol, ethanol, isopropyl alcohol, water,.propanol, C4-C6 hydrocarbons, butane, isobutene, pentane, hexane, acetone, chlorobutanol, ethyl acetate, fluro-chloro-hydrocarbons, turpentine, methyl ethyl ketone, methyl ether, hydrofluorocarbons, ethyl ether, 1,1,1,2 tetrafluorethane 1;1,1,2,3,3,3-heptafluoropropane,.1,1,1,3,3,3 hexafluoropropane, or combinations thereof. .
"Non-volatile solvent system" can be a single solvent or mixture of solvents that are less volatile than water. It can also contain substances that are solid or liquid at room temperatures, such as pH or ion-pairing agents.
After evaporation of the volatile- solvent system, most of the non-volatile solvent system should remain in the solidified layer for an amount of time sufficient to dermally delivery,a given drug to, into, or through the skin of a subject at a sufficient flux for a period of time to provide a therapeutic effect. In some ' embodiments, in order to obtain desired permeability for an active drug and/or compatibility with solidifying agents or other ingredients of the formulation, a mixture of two or more non-volatile solvents can be used to form the non-volatile solvent system. In one embodiment, the combination of two or more non-volatile solvents to form a solvent system provides a higher transdermal flux for a drug than the flux provided for the drug by each'of the non-volatile solvents individually. The non-volatile solvent system may also serve as a plasticizer of the solidified layer, so that the solidified. layer is elastic and flexible.
The term "solvent vehicle" describes compositions that inciiade both a volatile solvent system and non-volatile solvent system. The volatile solvent system is chosen so as to evaporate from the adhesive formulation quickly to form a solidified layer, and the non-volatile solvent system is formulated or chosen to substantially remain as part of the solidified layer after volatile solvent system evaporation so as to provide continued delivery of the drug. Typically, the drug can be partially or completely dissolved in the solvent vehicle or formulation as a whole. Likewise, the drug can also be partially or completely solubilizable in the non-volatile solvent system once the volatile solvent system is evaporated. Formulations in which the drug is only partially dissolved in the non-volatile solvent system after the evaporation of the volatile solvent system have the potential to maintain longer duration of sustained delivery, as the undissolved drug can dissolve into the non-volatile solvent system as the dissolved drug is being depleted from the solidified' layer during drug delivery..
"Adhesive solidifying formulation" or "solidifying formulation" refers to a composition that has a viscosity suitable for application to a skin surface.prior to evaporation of its volatile solvent(s), and which can become a solidified layer after evaporation of at least a portion of the volatile solvent(s). The solidified layer, once formed, can be very durable. In one embodiment, once solidified on a skin surface, the formulation can form a peel. The peel can be a soft, coherent solid that can be removed b.y peeling large pieces from the skin relative to the size of the 'applied formulation, and often, can be peeled from the skin as a single piece. The application viscosity is typically more viscous than a water-like liquid, but less viscous than a soft solid. Examples of preferred viscosities include materials that have consistencies similar to pastes, gels, ointments, and the like, e.g., viscous liquids that flow but are not subject to spilling. Thus, when a composition is said to have a viscosity "suitable for application" to a skin surface, this means the composition has a viscosity that is high enough so that the composition does not substantially run off the skin after being applied to skin, but also has a low enough viscosity so that it can be easily spread onto the skin. A viscosity range that meets this definition can be from about 100 cP to about 3,000,000 cP (centipoises), and more preferably from about 1,000 cP to about 1,000,000 cP.
,In some embodiments of the present invention, it may be desirable to add an additional agent or substance to the formulation so as to provide enhanced or increased adhesive characteristics. The additional adhesive agent or substance can be an additional non-volatile solvent or an additional solidifying agent. Non-limiting examples of substances which might be used as additional adhesion enhancing agents include copolymers of methylvinyl ether and maleic anhydride (Gantrez polymers), polyethylene glycol, and polyvinyl. pyrrolidone, gelatin, low molecular weight polyisobutylene rubber, copolymer of acryisan alkyl/octylacrylamido (Dermacry179), and/or various aliphatic resins and aromatic resins.
The terms "washable," "washing" or "removed by washing" when used with respect to the adhesive formulations of the present invention refers to the ability of the adhesive formulation to be removed by the.application of a washing solvent using a normal or medium amount of washing force. -The required force to remove-the formulations by washing should not cause significant skin irritation or abrasion. Generally, gentle washing force accompanied by the application of an appropriate. washing.solvent is sufficient to remove the adhesive formulations disclosed herein. The solvents which can be used for rerrioving by washing the formulations of the present invention are numerous, but preferably are chosen from commonlyacceptable solvents including the volatile solvents listed herein. Pref.erred washing solvents do not significantly irritate human skin and are generally available to the average subject.
Examples of washing sofvents include but are not limited to water, ethanol, methanot, isopropyl alcohol, acetone, ethyl acetate, propanol; or combinations thereof. In aspect of the invention the washing solvents can be selected from the group consisting of water, ethanol, isopropyl alcohol, or combinations thereof. Surfactants can also be used in some embodiments.
An acceptable length of time for a "drying time" refers to the time it takes for the formulation to form a non-messy solidified surface after application on skin under standard skin and ambient conditions, and with standard testing procedure. It is noted that the word "drying time" as used herein does not mean the time it takes to completely evaporate off the volatile solvent(s).
Instead, it means the time it takes to form the non-messy solidified surface as described above..
,"Standard skin" is defined as dry, healthy human skin with a surface 'temperature of between about 30 C to about 36 C. Standard ambient conditions are defined by the temperature range of from 20 C to 25 C and a relative humidity range of from 20% to 80%. The term "standard skin".in no way limits the types of skin or skin conditions on which the formulations of the present invention can be used. The formulations of the present inventiori can be used to treat all types of "skin," including undamaged (standard skin), diseased skin, or damaged skin. Although skin conditions having different characteristics can be treated using the formulations of the present invention, the use of the term "standard skin" is used merely as a standard to test the compositions of the varying embodiments of the present invention. As a practical matter, formulations that perform well (e.g:, solidify, provide therapeutically effective flux, etc.) on standard skin can also perform well diseased or damaged skin. .
The "standard testing procedure" or "standard testing condition" is as follows: to standard skin at standard ambient conditions is applied an approximately 0.1 mm layer of the adhesive solidifying formulation,and the drying time is measured. The drying time is defined as the time it takes for the formulation to form a non-messy surface such that the formulation does not lose mass by adhesion to a piece of 100% cotton cloth pressed onto the formulation surface with a pressure of between about 5 and about 10 g/cm2 for 5 seconds.
"Solidified layer" describes the solidified or dried layer of an adhesive solidifying formulation -after at least a portion of the volatile solvent system has evaporated. The solidified layer remains adhered to the skin, and is preferably capabie, of maintaining good contact with the subject's skin for substantially the entire duration of application under standard skin and ambient conditions. The solidified layer also preferably exhibits sufficient tensile'strength so that it can be peeled off the skin at the end of the application in one piece or several large pieces (as opposed to a layer with weak tensile strength that breaks into many small pieces or crumbles when removed from the skin).
. The use of the term "substantially" when referring to the evappration of the volatile solvents means that a majority of the volatile solvents which were included in the initial formulation have evaporated. Similarly, when a solidified layer is said to be "substantially devoid" of volatile solvents, including water, the solidified layer has less than 10 wt%, and preferably less than 5 wt%, of the volatile solvents in the solidified layer as a whole.
Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should'be interpreted flexibly to include not only the numerical values explicitly recited as the lirnits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as.if each numerical value and sub-range is explicitly recited. As anillustration, a numerical range of "about 0.01 to -2.0 mm" should be interpreted to include not only the explicitly recited values of about b.01 mm to about 2.0 mm, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range -are individual values such as 0.5, 0.7, and 1.5, and sub-ranges such as from 0.5 to 1.7, 0.7 to 1.5, and from 1.0 to 1.5, etc. This same principle applies to ranges reciting only one numerical value. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described. As used herein, a plurality of drugs, compounds, and/or solvents may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is iridividually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
With these definitions in mind, the present invention is drawn generally to 5 a formulation for treating an infection, comprising a drug that is effective for treating an infection, a solvent vehicle, and a solidifying agent. The solvent vehicle can comprise a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system including at least one non-volatile solvent, wherein the non-volatile solvent system is capable of facilitating delivery 10 of the drug at therapeutically effective rates over a sustained period of time.
The formulation can have a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system. The formulation applied to the skin surface can form a solidified layer after at least partial evaporation of the volatile solvent system. Further, the drug can continue to be 15 delivered after the volatile solvent system is at least substantially evaporated.
In another embodiment, a method of treating a skin infection can comprise applying a solidifying adhesive formulation to an infected skin surface.
The solidifying adhesive formulation can comprise a drug that is. effective for treating a skin infection, a solvent vehicle, and a solidifying agent. The solvent 20 system can comprise a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system including at least one non-volatile solvent. The non-volatile solvent system can.be capable of facilitating the delivery of the drug at therapeutically effective rates over a sustained period of time. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system.
Additional steps include solidifying the formulation to form a solidified layer on the infected skin surface by at least partial evaporation of the volatile solvent system, and dermally delivering the drug from the solidified layer to the infected skin site at therapeutically effective rates over a sustained period of time. .
In another embodiment, a solidified layer for treating an infection can comprise a drug that is effective for treating a skin infection; a non-volatile solvent system including at least one non-volatile solvent, wherein the non-volatile solvent system facilitates the delivery of the drug at therapeutically effective rates over a sustained period of time; and a solidifying agent. The solidified layer can be stretchable by 5% (or even 10%) in one direction without cracking, breaking, and/or separating from a skin surface to which the layer is applied.
In still another embodiment, a formulation for treating an infection can comprise a drug selected from the group consisting of acyclovir, valacyclovir, pencyclovir, or combinations thereof; a solvent vehicle comprising a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system comprising a non-volatile solvent; and a solidifying agent. The non-volatile solvent can be selected from the group consisting of oleic acid, isostearic acid, olive oil, or combinations thereof. The solidifying agent can be selected from the group consisting of ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymers, butyl and methyl methacrylate copolymers, ethyl cellulose, and mixtures and copolymers thereof.
The formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvent system, can form a solidified, coherent, flexible, and continuous layer after at least partial evaporation of the volatile solvent system, and the drug can be continued to be delivered at a therapeutically effective rate after the volatile solvent.system is at least substantially all evaporated. In another embodiment, a formulation for treating an infection can comprise a drug selected from the groupp consisting of econazole, terbinafine, or.
*combinations thereof; a solvent vehicle comprising a volatile solvent system including at least one volatile solvent and a non-volatile solvent system comprising at least one non-volatile solvent, and a solidifying agent. The non-volatile solvent can be selected from the group consisting of tetrahydroxypropyl ethylenediamine, oleic acid, isostearic acid, olive oil, or combinations thereof.
The solidifying agent can be selected from the group consisting of ethyl acrylate-methyl methacrylate-trimethylammonioethyi methacrylate chloride copolymers, butyl and methyl methacrylate copolymers, ethyl cellulose, and mixtures and copolymers thereof. The formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvent system, can form a solidified, coherent, flexible, and continuous layer after at least partial evaporation of the volatile solvent system, and the drug can be continued to be delivered at a therapeutically effective rate after the volatile solvent system is at least substantially all evaporated.
In another embodiment, an adhesive solidifying formulation for treating-a nail infection can comprise a drug that is effective for treating a nail infection, a solvent vehicle, and a solidifying agent. The solvent vehicle can comprise a volatile solvent system including at least one volatile solvent, and a non-volatile solvent systern,including at least one non-volatile solvent; wherein the non-volatile solvent system is capable of facilitating delivery of the drug at a therapeutically effective rate over a sustained period*of time. The formulation-has a viscosity suitable for application and adhesion to a nail surface prior to evaporation of the volatile solvent system, and when applied to the nail surface, it forms a solidified layer after at least partial evaporation of the volatile solvent system. Further, the drug continues to be delivered to the hail after the volatile solverit system is at least substantially evaporated. -In another embodiment, a method of treating nail fungal infection can comprise applyirig to a nail surface with a fungal infection, and optionally surrounding skin, a layer of an adhesive solidifying formulation. The formulation can comprise an anti-fungal drug,-a solvent vehicle including a volatile solvent._ system comprising at least one volatile solvent, and a non-volatile solvent system. comprisingat least one non-volatile solvent, and a solidifying agent.
The non-volatile solvent system can'be capable of facilitating delivery of the anti-fungal drug at a therapeutically effective rate over a sustained period of time, and can have a viscosity suitable for application and adhesion to a nail surface prior to evaporation of the volatile solvent system. Further, the formulation -applied to the nail surface can form a solidified layer after at least partial evaporation of the volatile solvent system, and the drug can continue to be delivered from the solidified layer to the nail after the volatile solvent system is at least substantially evaporated. Additional steps can include keeping the solidified layer on said nail surface for a treatment period of at least 4 hours, and removing the solidified layer after the treatment period.
In another embodiment, a formulation for treating dermatitis or psoriasis (such as hand dermatitis) can comprise a drug, a solvent vehicle, and a solidifying agent. The drug can include at least one member selected from the group, consisting of clobetasol propionate, clobetasol, derivatives thereof, or combinations thereof. The volatile solvent system can include at least one volatile solvent, and a non-volatile solvent system including propylene glycol and/or glycerol, and another non-volatile solvent including isostearic acid and/or oleic acid. The solidifying agent can include at least one member selected from the group consisting of polyvinyl alcohol, fish gelatin, zein, or combinations thereof. The formulation can have a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system.
The formulation applied to the skin surface can form a solidified, coherent, flexible, and continuous layer after at least partial evaporation of the voiatile solvent system. Additionally, the drug can continue to be delivered at the therapeutically effective rate after the volatile solvent system is at least substantially all evaporated While the formulations, methods, and solidified layers of the current invention can be used to treat dermatitis (eczema) or psoriasis of skiri areas anywhere on the human body, the special characteristics -of tlie formulatioris and methods of the current invention are expected to be particularly beneficial for treating hand dermatitis and psoriasis. .
In still another embodiment, a solidified layer for treating alopecia can comprise a drug for treating alopecia, a non-volatile solvent system, and a solidifying agent. The non-volatile solvent system can be flux-enabling*. The solidified layer itself can also be flux-enabling (meaning the 'drug can be topically delivered to the skin at therapeutically rates from the solidified layer). Further, the solidified layer can have sufficient flexibility and adhesion to the skin surface so that it can maintain good contact with the skin surface to which it was originally applied for.
at least most of the intended duration of the application..

In an alternative embodiment, a method of treating alopecia can comprise applying a layer of an adhesive formulation to a skin surface suffering from alopecia (hair loss). The formulation can comprise a drug capable of stimulating hair growth when delivered -to a hair follicle of a subject suffering from alopecia, a solvent vehicle, and a solidifying agent. The solvent vehicle can comprise a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system including at least one non-volatile solvents, wherein the non-volatile solvent system is preferably capable of facilitating topical delivery of the drug at a therapeutically effective rate over a sustained period of time. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. Other steps include solidifying the forrnulation to form a-solidified layer on the skin surface by at least partial evaporation of the volatile solvent system; and topically delivering the drug from the solidified layer to the skin at therapeutically effective rates over.a sustained period of time.

In another embodiment, a solidified layer for delivering a drug for treating alopecia.can comprise a drug capable of stimulating hair growth when delivered to a hair follicle of a subject suffering from alopecia, a non-volatile solvent system including at least dne non-volatile solvent, wherein the non-volatile solvent system is capable of facilitating the delivery of the drug at therapeutically effective rates over a sustained period of time, anda solidifying agent: The solidified layer can have sufficient flexibility and adhesion to the skin surface so that it can maintain good contact with the skin surface to which it was originally applied for at least most of the intended duration of the application:
In another embodiment, a formulation for treating a subject suffering from alopecia can comprise a drug, a solvent vehicle,-and a solidifying agent. The drug can include a member selected from the group consisting of clobetasol propionate, clobetasol, derivatives thereof, and combinations- thereof. The solvent vehicle can comprise a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system comprising at least one solvent selected from the group consisting of propylene glycol, glycerol, and, combinations thereof, and at least one solvent selected from the group consisting of isostearic acid, oleic acid, and combinations thereof. The solidifying agent can include a member selected from the group consisting of polyvinyl alcohol, fish gelatin, gluten, casein, zein, and combinations thereof.
The formulation can have a viscosity suitable for application and adhesion to a 5 skin surface 'prior to evaporation of the volatile solvent system, and, after being appiied to a skin surface as a layer, can form a solidified, coherent, flexible, and continuous layer after at least partial evaporation of the volatile solvent system.
The continues to be topically delivered at the therapeutically effective rate after the volatile solvent system is at least substantially all evaporated.
10 In another embodiment, a method for treating alopecia can comprise applying to a skin area of a' subject suffering from alopecia a 0.01 mm to 2 mm thick layer of an adhesive solidifying formulation. The formulation can comprise a drug including at least one.member selected from the group consisting of clobetasol propionate, clobetasol, and combinations thereof, a volatile solvent 15 system including at least one volatile solvent. Other ingredients can comprise a non-volatile solvent system including at least one solvent selected from the group consisting of propylene glycol, glycerol, and combinations thereof, and at least one solvent selected from the group consisting of isostearic acid, oleic acid, and combinations thereof. A solidifying agent can also be present can 20 include at least one member selected from the.group consisting of polyvinyl alcohol, fish gelatiri, gluten, casein, zein, and combinations thereof. The formulation can have a viscosity suitable for application and adhesion to the palm skin surface prior to evaporation of the volatile solvent system, and can form*a solidified, coherent and flexible layer after at least partial evaporation of 25 the volatile solvent system. The drug can continue to, be topically delivered at the therapeutically effective rate after the volatile zolvent system is.at least substaiitially all evaporated. Other steps include leaving the 'formulation on the skin surface for an intended application period of at least 2 hours, and removing the solidified, coherent and flexible layer from the skin surface after the intended .
application period.
In another embodiment, an adhesive solidifying formulation for treating photo damaged human skin can comprise an immune modulating agent, and at least one member selected from .the group consisting of isostearic acid, triacetin, sorbitan monolaurate, and combinations thereof.
!n another embodiment, a solidified layer for treating photo damaged human skin can comprise an immune modulating agent, a non-volatile solvent system, 'and a solidifying agent. The non-volatile solvent system can comprise at least one non-volatile solvent, and the system can be capable of facilitating the delivery of the immune modulating agent at a therapeutically effective rate over a sustained period of time. The solidified layer can be capable of adhering to a human skin surface for at least two hours.
. In further detail, the present invention is related to a formulation comprising an immune activator, a volatile solvent system comprising at least one volatile solvent (defined as water or solvents more volatile than water), a non-volatile solvent system comprising one or more non-volatile solvent (defined as less volatile than water), and a solidifying agent. Before application to the skin, the formulation is in its initial, less-than-soiid form, such as cream;
gel, .
paste, or ointment. After applying a layer of such a formulation on the skin area to be treated, the evaporation of the volatile solvent(s), with -the help from the solidifying agent, can convert the formulation layer into a soft, flexible, coherent solid layer that is optionally peelable. The non-volatile solvent system stays in the formulation for substantially-the entire duration of the application and serves as* vehicle solvent for delivering the drug into the skin (a fraction of the non- volatile solvent(s) may be absorbed by skin during the application). The soft, flexible, coherent solid layer is designed to adhere to the skin for a substantial duration, preferably longer than 2 hours. Optionally, an emollient and/or a moisturizing substance can be included in the formulation for providing beneficial moisturizing effect as well as soothing the skin and minimizing the possible irritation caused by the immune activator. .

The. formulations of the present invention provide several advantages over the Aldara cream. First, the immune activating agent in the formulations of the present invention is "anchored" on the skin surface to be treated, and thus is not as susceptible to unintentional removal. The optional emollient and/or moisturizing agent(s) can moisturize and sooth the.skin to provide additional treatment benefits. The optional emollient and/or moisturizing agent(s) may also offset the possible irritation caused by the immune activating agent.
Furthermore, the physical barrier provided by the solidified layer and water retention property of the moisturizing agent can help maintain moisture in and/or on the surface of the skin. This is believed to be valuable because hydration of the skin is believed to increase th.e permeability of the skin, which in turn can increase the absorption of the immune activating agent. Therefore, formulations containing both immune activator and moisturizing agent can be synergistic.

Thus, the present invention is related to formulations that are typically in the initial form of semi-solids (including creams, gels, pastes, ointments, and other viscous liquids), which can be easily applied onto the skin as a layer, and can, after evaporation of at least some of the volatile solvent(s), quickly (from 15 seconds to about 5 minutes under standard skin and ambient conditions as set forth above) to moderately quickly (from about 4 to about 15 minutes under standard skin and ambient conditions) change into a solidified layer (which is optionally also peelable), e.g., a coherent and soft solid layer, for drug delivery.
The solidified layer thus formed is capable of delivering drug over a sustained period of time, e.g., hours to tens of hours, so that most of the drug absorption occurs after the solidified layer is forrned.
Additionally, the solidified layer typically adheres to the skin, but has a solidified, minimally-adhering, outer surface which is formed relatively soon after application and which does not substantially transfer to or otherwise soil clothing or other objects that a subject is wearing or that the solidified layer may inadvertently contact. The solidified _layer can also be formulated such that it is highly flexible and stretchable, and thus, is capable of maintaining good contact with a skin surface, even if the skin is stretched during normal daily activities.
The formulations of the present invention can be applied. and used-on various types =of human body or skin surfaces. In one embodiment, the skin surface being treated can be what is traditionally referred to as "skin." The skin surface can be an epidermal layer of the skin. In another embodiment, the skin surface that can be treated is a mucosal surface, such as lips, oral mucosal, genital mucosa, nasal mucosa, or anal mucosa. In another embodiment, the skin surface being treated can be a finger or toe nail surface. In yet another embodiment, the skin surface being treated is a wounded skin surface. in yet another embodiment, the skin surface is a bed sore or a skin surface with one or more lesions or open sores. , In selecting the various components that can be used, e.g., drug, solvent vehicle of volatile solvent system and non-volatile solvent system, solidifying agent(s), etc., many variations can be considered. For example, the volatile solvent system may be one or more volatile solvents (at least as volatile as water, including water). In one embodiment of the present invention, the volatile solvent system can include a member of ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane,.propane, isobutene, 1,1, difluoroethane, 1,1,1,2 tetrafluorethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone, or combinations thereof. In another embodiment of the present invention, the volatile solvent system can include iso-amyl acetate, denatured alcotiol; methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclomethicone, methyl ethyl ketone, or combinations thereof. The volatile solvent system can include a mixture or combination of any of the volatile solvents set forth in the embodiments above. These volatile solvents should be chosen to be compatible with the'rest of the formulation. * It-is desirable to use an appropriate, weight percentage of the volatile-solvent(s) in the formulation. Too much of the volatile solvent system prolongs the drying time. Too little of the volatile solvent system can make it difficult to spread the formulation on the skin. For most .25 formulatioris, the weight percentage of the volatile solvent(s) can be from about 10 wt% to about 85 wt%, and more preferably from about 20 wt% to about 50 wt%.
The non-volatile solvent system can also be chosen or formulated to be compatible with the solidifying agent, the drug, the volatile solvent, and any other ingredients that may be present. For example, the solidifying agent can be chosen so that it is dispersible or soluble in the non-volatile solvent.system.
Most non-volatile solvent systems and solvent vehicles as a whole can be formulated appropriately after experimentation. For instance, certain drugs have good solubility in poly ethylene glycol (PEG) having a molecular weight of 400 (PEG 400, non-volatile solvent) but poor solubility in glycerol (non-volatile solvent) and water (volatile solvent). However, PEG 400 cannot effectively dissolve poly vinyl alcohol (PVA), and thus, is not very compatible alone with PVA as the only solidifying agent. In order to dissolve sufficient amount of an active drug and use PVA as a solidifying agent at the same time, a non-solvent system including PEG 400 and-glycerol (compatible with PVA) in an appropriate ratio can be formulated, achieving a compatibility compromise. As a further example of compatibility, non-volatile solvent/solidifying agent incompatibility is observed when Span 20 is formulated into a formulation containing PVA. With this combination, Span 20 can separate out of the formulation and form an oily -layer on the surface of the solidified layer. Thus, appropriate solidifying agent/non-volatile solvent selections are desirable in developing a viable formulation and compatible combinations.
Non-volatile solvent(s) that can be used alone or in combination to form non-volatile solvent systems can be selected from a variety of pharmaceutically acceptable liquids. -In one embodiment of the present invention, the non-volatile solvent system can inciude glycerol, propylene glycol, isostearic acid, oleic acid, propylerie glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, butanol, or combinations thereof.
In another embodiment the non-volatile solvent system can include benzoic acid, butyl alcohol, dibutyl sebecate, diglycerides, dipropylene glycol, eugenol, fatty acids such as coconut oil, fish oil, palm oil, grape seed oil, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan.fatty acid surfactants, triethyl citrate, or combinations thereof. In a further.embodiment, the non-volatile solvent system can include 1,2,6-hexanetriol, alkyltriols, alkyldiols, acetyl monoglycerides, tocopherol, alkyl dioxolanes, p-propenyianisole, anise oil; apricot oil, dimethyl isosorbide, alkyl glucoside, benzyl alcohol, bees wax, benzyl benzoate, butylene glycol, caprylic/capric triglyceride, caramel, cassia oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglycerides, coriander oil, corn oil, coriander oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglycerides, diethanolamine, dietthylene glycol monoethyl ether, diglycerides, ethylene glycol, eucalyptus oil, fat, fatty alcohols, flavors, liquid sugars ginger extract, glycerin, high fructose corn syrup, hydrogenated castor 5 oil, IP paimitate, lemon oil, lime oil, limonene, milk, monoacetin, monoglycerides, nutmeg oil, octyidodecanol, olive alcohol, orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, vegetable shortening, vinyl acetate, wax, 2-(2-(octadecyloxy)ethoxy)ethanol, 10 benzyl benzoate, butylated hydroxyanisole, candelilla wax, carnauba wax, ceteareth-20, cetyl alcohol, polyglyceryl, dipolyhydroxy stearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG Fatty acid esters such as PEG- stearate, PEG - oleate, PEG- laurate, PEG fatty acid diesters such as PEG-dioleate, 'PEG- distearate, 15 PEG-castor oil, glyceryl behenate, PEG glycerol fatty acid esters such as PEG
glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate, hexylene glycerol, lanolin, lauric diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, methacrylic acid, multisterol extract, myristyl alcohol, neutral oil, PEG-octyl phenyl ether, PEG -alkyl ethers such as PEG-cetyl ether, PEG-stearyl ether, 20 PEG- sorbitan fatty acid esters such as PEG-sorbitan diisosterate, PEG-sorbitan monostearate, propylene glycol fatty acid esters such as propylene glycol stearate, propylene glycol, caprylate/caprate, sodium pyrrolidone carboxylate, sorbitol, squalene, stear-o-wet, triglycerides, alkyl aryl polyether alcohols, polyoxyethylene derivatives of sorbitan-ethers, saturated polyglycofyzed.C8-25 glycerides, N-methyl pyrrolidone, honey, polyoxyethylated glycerides, dimethyl sulfoxide, azone and related compounds, dimethylformamide, N-methyl formamaide, fatty acid esters, fatty alcohol ethers, alkyl-amides (N,N-dimethylalkylamides), ,N-methyl pyrrolidone related compounds, ethyl oleate, .
polyglycerized fatty acids, glycerol monooleate, glyceryl monomyristate, glycerol 30 esters of fatty acids, silk amino acids, PPG-3 benzyl ether myristate, Di-myreth 1 0-adipate, honeyquat, sodium pyroglutamic acid, abyssinica oil, dimethicone, macadamia nut oil, limnanthes alba seed oil, cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice, phenyl trimethicone, hydrolyzed wheat protein, or combinations thereof. In yet a further embodiment the non-volatile solvent system can include a combination or mixture of non-volatile solvents.set forth in the any of the above discussed embodiments.
Certain volatile and/or non-volatile solvent(s) that are irritating to the skin may be desirable to use to achieve the desired solubility and/or permeability of the drug. It is also desirable to add compounds that are both capable of preventing or reducing skin irritation and are compatible with the formulation.
For example, in a formulation where the solvent (either non-volatile or volatile) is capable of irritating the skin, it would be helpful to use a non-volatile solvent that is capable of reducing skin -irritation. Examples of solvents that are known to be capable of preventing or reducing skin irritation include, but are not limited to, glycerin, honey, and propylene glycol, although other irritation reducing solvents may also be used.
The formulations of the current invention may also contain two or more non-volatile solvents that independently are not adequate non-volatile solvents for a drug but when formulated together become an adequate non-volatile solvent. One possible reason for these initially non adequate non-volatile solvents to become adequate non-volatile solvents when formulated together may be due to the optimization of the ionization state of the drug to a physical form which has higher flux or the nori-volatile solvents act in some other synergistic manner. One further benefit of the mixing of the non-volatile solvents is that it may optimize the pH of the formulation or the skin tissues under the formulation layer to minimize irritation. Examples of suitable combinations of non-volatile solvents that result in an adequate non-volatile.
solvent system include but are not limited to isostearic acid /trolamine, isostearic acid/diisopropyl amine, oleic acid/trolamine, and propylene glycol/isostearic acid.
The selection of the solidifying agent can also be carried out in consideration of the other components present in the solidifying adhesive formulation. An appropriate solidifying agent is compatible with the formulation such that the.formulation is in liquid or semi-liquid state, e.g. cream, paste, gel, ointment, etc., before any evaporation of the volatile solvent(s) and becomes a soft, coherent solid after the evaporation of at least some of the volatile solvent(s). The solidifying agent can be selected or formulated to be compatible with the drug and the solvent vehicle (including the volatile solvent(s) and the non-volatile solvent system), as well as provide desired physical properties to the solidified layer once it is formed. Depending on the drug, solvent vehicle, and/or other components that may be present, the solidifying agent can be selected from a variety of agents. In one embodiinent, the solidifying agent can include polyvinyl alcohol with a MW range of 20,000-70,000 (Amresco), esters of polyvinylmethylether/maleic anhydride copolymer (ISP Gantrez ES-425 and Gantrez ES=225) with a MW range of 80,000-160,000, neutral copolymer of butyl methacrylate and methyl -methacrylate.(degussa Plastoid B) with a MW-range of 120,000-180,000, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (degussa Eudragit E100) with a MW range of 100,000-200,000, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer with a MW greater than 5,000 or similar MW to Eudragit RLPO (Degussa), Zein (prolamine) with a MW greater than 5,000 (Zein, MW around 35,000, Freeman industries), pregelatinized starch having a MW similar to Instant Pure-Cote B793 (Grain Processing Corporation), ethyl -20 cellulose with a MW greater than 5,000 or a MW similar to Aqualon EC N7, N10, N14, N22, N50, or N100 (Hercules),.fish gelatin having a MW range of 20,000-250,000 (Noriand Products), gelatin, other animal sources with a MW range greater than 5,000, acrylates/octylacrylamide copolymer with a MW range greater than 5,000 or a MW similar to National Starch and Chemical Dermacryl 79. .
In another embodiment, the solidifying agent can include ethyl cellulose, hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxy propyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose;
polyether amides, corn starch, 'pregelatinized corn starch, polyether amides, shellac, polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate phthalate, or combinations thereof. In a further embodiment, the solidifying agent can include ammonia methacrylate, carrageenan, cellulose acetate phthalate aqueous such as CAPNF from Eastman, carboxy polymethylene, cellulose acetate (microcrystalline), cellulose polymers, divinyl benzene styrene, ethylene vinyl acetate, silicone, guar gum, guar rosin, gluten, casein, calcium caseinate, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate, PEG/PVP, xantham gum, trimethyl siloxysilicate, maleic acid/anhydride colymers, polacrilin, poloxamer, polyethylene oxide, poly glactic acid/poly-l-lactic acid, turpene resin, locust bean gum, acrylic copolymers, polyurethane dispersions, dextrin, polyvinyl alcohol-polyethylene glycol co-polymers, 1.0 methyacrylic acid-ethyl acrylate copolymers such as BASF's Kollicoat polymers, methacrylic acid and methacrylate based polymers such as poly(methacrylic acid), or combinations thereof. In yet a further embodiment, the solidifying agent can include a combination of solidifying agents set forth in the any of the above discussed embodiments. Other polymers may also be suitable as the solidifying agent, depending on the solvent vehicle components, the drug, and the specific functional requirements of the given formulation.
In one embodiment of the present invention, the solidifying agent includes a methacrylic polymer or copolymer such as methyacrylic acid-ethyl acrylate copolymer, butyl and methyl methacrylate copolymer, aminoalkyl methacrylate copolymer, and/or an ammonioalkyl methacrylate copolymer. In another embodiment, the solidifying .agent includes polyvinyl alcohol or a polyvinyl alcohol copolymer such as polyvinyl alcohol-polyethylene glycol copolymer.
The non-volatile solvent system and the solidifying agent are preferably compatible with one other. Compatibility can be defined as i) the solidifying agent does not substantially negatively influence the function of the non-volatile solvent system; ii) the solidifying agent can hold the non-volatile solvent system in the solidified layer so that substantially no non-volatile solvent oozes out of the layer, and iii) the solidified layer formed with the selected non-volatile solvent system and the solidifying agent has acceptable flexibility, rigidity, tensile strength, elasticity, and adhesiveness. The weight ratio of the non-volatile solvent system to the solidifying agent.can be from about 0.1:1 to about 10:1, or more preferably from about 0.5:1 to about 2:1. In some embodiments, the non-volatile solvent system makes up about 20-60% of the total weight of the formulation, The thickness of the formulation layer applied on the skin should also be appropriate for a given formulation and desired drug delivery considerations.
If the layer is too thin, the amount of the drug may not be sufficient to support sustained delivery over the desired length of time. If the layer is too thick, it may take too long to form a non-messy outer surface of the solidified layer. If the drug is very potent and the solidified layer has very high tensile strength, a layer as thin as 0.01 mm may be sufficient. If the drug has rather low potency and the solidified layer has low tensile strength, a layer as thick as 2-3 mm may be desirable. Thus, for most drugs and formulations, the appropriate thickness can be from about 0.01 mrri to about 3 mm, 0.1 mm to about 2 mm, or from about 0.2 mm to about 0.4 mm. In one embodiment, the formulations of the present invention can have sufficient gas volatile solvents such that the formulation can be contained in a pressurized container and applied to the skin by spraying.
In another embodiment, the formulation can be sprayed on a skin surface of a subject experiencing alopecia.
The formulations of the present invention can be applied over a variety of skin surfaces of subjects suffering from alopecia. Generally, tlie 'skin surface can be any size; however, in one embodiment, it can be desirable to limit the area to no more than 100 cm2, and often, no more than 20 cm2, .particularly if the active drug is a corticosteroid. The desirability of limiting the skin area is based on fact that though the corticosteroid is delivered topically, a good portiorn of the delivered drug may enter the systemic circulation which, if at high enough quantities, can cause undesirable side effects. Therefore, it can be desirable to achieve a balance of good topical effect and minimum systemic drug absorption.
Since the acting site of:the corticosteroids is the hair follicles which exist somewhat deep.under the skin surface, the drug needs to travel along a relatively long.path through the skin, and thus, the subject can experience some systemic uptake. This -being stated, a significant number of alopecia subjects only have relatively small skin area where they are experiencing alopecia.

Therefore, a limitation on the skin treatment area can stratify the treatment need of those subjects, white minimizing systemic side effects. Even for subjects who alopecia skin areas are larger, a limitation on treatment skin area may still make sense as it altows the alopecia skin areas to be treated portion by portion with 5 minimized potential of systemic side effects. Treating large alopecia skin areas portion by portion is possible because the treatment of each portion is expected to be periodical instead of continuous.
The flexibility and stretchability of a solidified layer, optionally in the form of a peel, can be desirable in some applications. High flex and stretch are 10 particularly advantageous when the area being treated is involved in frequent stretching or movement, such as the lips or corners of the mouth. Traditional ointments, creams, gels, pastes or the like are often not suitable for treatment of these areas because they are easily removed by licking the lips or. through contact with food during eating. In contrast, the solidifying compositions of the 15 present invention can be formulated so as to provide adequate flexibility and stretching while not being easily licked, rubbed, or scraped off. It is also worth noting that the solidified layers of the present invention do not always need to be stretchable, though some elasticity is preferred.
A further feature of a formulation is related to the drying time. If a 20 formulation dries too quickly, the user may not have sufficient time to spread the formulation -into a thin layer on the skin surface before the formulation is solidified, leading to poor skin contact. If the formulation dries too slowly, the subject may have to wait a long time'before resuming' normal activities (e.g.
putting clothing on, eating, talking, etc) that may remove un-solidified 25 formulation. Thus, it is desirable for the drying time to be longer than about 15 seconds but shorter than about 15 minutes, and preferably from about 0.5 minutes to about 5 minutes.
One way for conveniently using the formulations of the present invention is to apply the formulation on the skin to be treated within an hour of sleeping 30 and remove the solidified layer within an hou'r after waking.
Another way is to apply the formulation within an hour after waking and remove the solidified layer within an hour of sleeping.

When using the formulations of the present invention to treat the dermatological condition of photo damaged skin, it can be advantageous to apply the formulation so as to cover a skin area slightly beyond the damaged skin area. Therefore, one embodiment of the current invention is to apply the formulation at least 1-2 mm beyond the damaged skin area.
Other benefits of the solidified layers of the present invention include the presence of a physical barrier that can be formed by the.material itself. This physical barrier can protect the infected area against contacting objects or sources which cause irritation, pain, or further infections. For example, the solidified layer can act as a barrier against friction with a diaper, or as a protective barrier against urine and/or fecal matter. Additionally, upon volatile solvent system evaporation, the dosage form is relatively thick and can contain much more active drug than a typical layer of.traditional cream,'gel, lotion, ointment, paste, etc., and furthe'r; is not as subject to unintentional removal.
These and other advantages can be summarized by the following non-limiting application embodiments. The solidified layers of the present invention can be prepared in an initial form that is easy to apply as a semisolid dosage form. Additionally, upon volatile solvent evaporation, the formulation layer applied to the skin is relatively thick and can contain much more active drug than a typical layer of traditional cream, gel, lotion, ointment, paste, etc., and further, is resistant to unintentional removal. After the evaporation of the volatile solvent(s) and the formatiori of the solidified layer, the.drug in the solidified layer can be delivered at therapeutically effective rates over sustained periods of time. Further, as the solidified layer remains adhesive to skin and, easy removal of the solidified layer can occur, usually without the aid of a solvent or surfactant. In some embodiments, the adhesion to skin and elasticity of the material is such that the solidified layer will not separate from the skin upon skin stretching at. highly stretchable skin areas, such.as over joints and muscles. For example, in one embodiment, the solidified iayer can be stretched by 5% or even 10% or greater in at least one direction without cracking, breaking, and/or separating form a skin surface to , which the layer is applied.

As a further note, it is a unique feature that the solidified layers of the present invention can keep a substantial amount of the non-volatile solvent system, which is optimized for delivering the drug, on the body surface. This feature can provide unique advantages over existing products. For example, Penlac is a product widely used for treating nail fungal infections. It contains the drug ciclopirox, volatile solvents (ethyl acetate and isopropyl), and a polymeric substance. After being applied on the nail surface, the volatile solvents quickly evaporate and the formulation layer solidifies into a hard lacquer. The drug molecules are immobilized in the hard lacquer layer and'are substantially unavailable for delivery into the nail. As a result, it is believed that the delivery of the drug is not sustained over a long period of time. As a result, without being bound by any particular theory, it is believed that this is at least one of the reasons why Penlac, while widely used, has an efficacy rate of only about 10%.
Conversely, in the solidified layer of the present invention, the drug molecules are quite mobile in the non-volatile solvent system which is in contact with the skin surface, e.g., skin; nail, mucosal, etc., surface, thus ensuring sustained delivery: EXAMPLES

The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. 'Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present.invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present.invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

Example 1 Hairless mouse skin (HMS) or human epidermal membrane (HEM) is used as. the model membranes as noted for the in vitro flux studies described in herein. Hairless mouse skin (HMS) is used as the model membrane for the in vitro flux studies described in herein. Freshly separated epidermis removed from the abdomen of a hairless mouse is mounted carefully between the donor and receiver chambers of a Franz diffusion cell. The receiver chamber is filled with pH 7.4 phosphate buffered saline (PBS). The experiment is initiated by placing test formulations (of Examples 2-5) on the stratum corneum (SC) of the skin sample. Franz'cells are placed in a heating block maintained at 37 C and the HMS temperature is maintained at 35 C. At predetermined time intervals, 800 L aliquots are withdrawn and replaced with fresh PBS solution. Skin flux ( g/cm2%h) is determined from the steady-state slope of a plot of the cumulative amount of permeation versus time. It is to be noted that human cadaver skin -can be used as the model membrane for the in vitro flux studies as well. The mounting of the skin and the sampling techniques 'used as the same as described above for the HMS studies.

Example 2 Formulations of acyclovir in various non-volatile solvent systems are evaluated. Excess acyclovir is present. The transdermal flux of acyclovir from the test formulations through HMS is presented in Table 1 below.
Table 1 Non-volatile solvent system Skin Fi Zx*
~ mc /cm /h Isostearic Acid 0.1 0.09 Isostearic Acid + 10% Trolamine 2.7 t 0.6 Isostearic Acid + 30% Trolamine 7 f 2 Olive Oil 0.3 t 0.2 Olive Oil + 11 % Trolamine 3 t 3 Olive Oil -+ 30% Trolamine 0.3 t 0.2 Oleic Acid '0.4 t 0.3 Oleic Acid + 10% Trolamine 3.7 t 0.5 Oleic Acid + 30% Trolamine 14 t 5 Ethyl Oleate 0.2 t 0.2 Ethyl Oleate + 10% Trolamine 0.2 0.2 ~ Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be'between 4-8 hours.
As indicated, significant enhancement of acyclovir skin flux is achieved with isostearic acid or oleic acid mixed with trolamine. Relatively significant flux enhancement (e.g., 10 fold) is observed when trolamine is added to olive oil, oleic acid, and isostearic acid and no appreciable flux enhancement is observed when trolamine is added to ethyl oleate. This surprising result may be the result of an additive or even synergistic enhancement effect of trolamine/fatty acid combination resulting in much higher acyclovir flux values.

Examples 3-6 Prototype adhesive solidifying formulations are prepared as follows.
Several acyclovir solidifying formulations are prepared in accordance with embodiments of the present invention in accordance with Table 2, as follows:
Table 2 Exam le 3 4 5 6 % b wei ht Ethanol 21 25 28 29.5 Eudragit RL- 15 18 20 PO'' = 21.0 -Isostearic Acid 31 36 39 42.0 Trolamine 30 18 10 4.7 Ac yclovir 3 3 3 2.8.
~ degussa polymer.
In Examples 3-6, the compositions in Table 2 are prepared as follows. Eudragit RL-PO and ethanol are combined in a glass-jar.and heated with stirring until the -RL-PO is dissolved. The isostearic 'acid and trolamine is added to the RL-PO/ethanol mixture and the mixture is vigorously stirred. Once a uniform mixture is obtained, acyclovir'is added to the mixture and the formulation is vigorously mixed.

Examples 7-8 Two acyclovir adhesive solidifying formulations are prepared in accordance with embodiments of the present invention in accordance with Table 3, as follows:
5 Table 3 Example 7 8 % b wei ht Ethanol 26 21 Eudragit RL-PO 44 15 Isostearic Acid 26 31 Diiso ro anol Amine 2 --Neutrof TE Polyol -- 30 Acyclovir 2 3 The compositions of Examples 7 and 8 as shown in Table 3 are prepared as follows. Eudragit RL-PO and ethanol are combined in a glass jar and heated with stirring until the RL-PO is dissolved. The isostearic acid and diisopropanol 10 amirie or Neutrol TE Polyol (BASF) is added to the RL-PO/ethanol mixture and the mixture is vigorously stirred. Once 'a uniform mixture is obtained, acyclovir is added to the mixture and the formulation is vigorously'mixed.

Examples 9-10 15 Two acyclovir solidifying forrrmulations are prepared in accordance with embodiments of the present invention in accordance with Table 4, as follows:
Table 4 Example 9 10 %b wei ht Ethanol 59.6 58 Ethyl cellulose . --ECN7* 19.9 Ethyl cellulose 19 ECN100* --Trolamine 7.6 9 lsostearic Acid 7.7 9 Ac clovir 5.2 5 * Hercuies Aqualon N type ethyl cellulose.
In Examples 9-10.the compositions in Table 4 are prepared as follows. EC7 or 20 E01 00 and ethanol are combined in a glass jar and heated with stirring until the solid cellulose is dissolved. The isostearic acid and trolamine is added to the cellulose/ethanol mixture and the mixture is vigorously stirred. Once a uniform mixture is obtained, acyclovir is added to the mixture and the formulation is vigorously mixed.
Example 11 The formulations of Examples 3-10 are tested in a hairless mouse skin (HMS) in vitro model described in Example 1. Table 5 shows data obtained using the experimental process outlined above.
Table 5- Steady-state flux (J) of Acyclovir through HMS
Formulation J* Ratio to cm2/h Control Exam le 3 12 5 6 Exam le4 19 1 8 Exam le 5 8 1 4 Exam le. 6 1 1 0.5 Example 7 0.7 0.3 0.35 Example 8 1:1-_ 0.9 0.5 Exam le '9 2 1 1 Example 10 19 t7 8 Zovirax Cream 2 t 0.4 1 * Skin flux measurements represent the mean and standard deviation of three 'determinations. Flux measurements reported were determined.from the linear region of the cumulative amount versus time =plots. The. linear region was observed to be between 4-8 hours. If experimental conditions allowed the steady'state flux would extend beyond the 8 hours measured.

The formuiations of the invention shown above generally provide tor significant *20 penetration of the active ingredient, and further, the formulations of Examples 3-5 and 10 are found to be much greater in permeability than the marketed product Zovirax Cream (control). The quantity of acyclovir that permeated across the HMS stratum corneum over time for Examples 3, 4, and Zovirax Cream are shown in FIG. 1. Each value shown indicates the mean t SD of at least three experiments.
Examples 3-6 show the impact of the trolamine to isostearic acid (ISA) ratio on acyclovir flux enhancement. The optimal ISA:trolamine ratio is 1:1 to 2:1 and ratio greater than 4:1 show a significant decrease in the acyclovir skin flux. Additions of diisopropanol amine and Neutrol in place of trolamine (Examples 7 and 8) in the formulation show a significant decrease in acyclovir .
flux values. This may be due to a specific chemical interaction between trolamine and ISA creating an environment within the formulation which facilitates higher skin flux. Examples 9 and 10 utilize a different solidifying agent to evaluate the impact of the solidifying agent on acyclovir flux.
Surprisingly, Example 9 shows a significant decrease in acyclovir skin flux, but Example 10, which differed from Example 9 only by the molecular weight of the solidifying -agent, shows no *impact on acyclovir skin flux compared to a similar ISA:trolamine ratio in Example 3.
As can be seen from FIG. 1, Examples 3 and 4 show sustained delivery of acyclovir up to 8 hours, it is reasonable to assume based on the drug load and the continued presence of the non volatile solvent that the delivery of acyclovir would continue at the reported flux values for as long as the subject desires to leave the adhesive solidifying formulation affixed to the skin.
Example 12 A formulation similar to Example 4 (with no acyclovir) is applied onto a human skin surface, resulting in a thin; transparent, flexible, and-stretchable-fitm. After a few minutes of-evaporation of the volatile solvent (ethanol), a solidified adhesive layer that is peelable is formed. The stretchable film has good adhesion to the skin and did not separate from the skin, and could easily be peeled away from the skin. The absence of acyclovir is expected to'have minimal to no impact on the physical and wear properties of the; coherent solid because it is present at such low concentration, when present.

Examples 13-14 Anti-fungal formulations are prepared and a qualitative assessment of - 30 peel flexibility and viscosity are evaluated. The formulation components are presented in Table 6 below.
Table 6 ' Example 13 14 Com =onents Parts b Weight Eudra it RL-PO 3.8 4.2 Isostearic Acid 2 2.2 Ethanol 5.3 3.8 Neutrol TE Polyol 1 1 Econazole 0.09 0.1 The formulation in Example 13 has a low viscosity that was lower than may be desirable for application on a nail or skin surface. The time to form a solidified peel with this formulation is longer than the desired drying time. The formulation' in Example 14 had an increase in the amount of solidifying agent (Eudgragit RL-PO) and decrease in amount of ethanol, which improves the viscosity and drying time. Example 14 has a viscosity suitable for application and an improved drying time.

Example 15 Formulations of betamethasone dipropionate (BDP) in various non-volatile solvent systems are evaluated following procedure described in Examplel. Excess BDP is present. The permeation of BDP from the test formulations through HEM is presented in Table 7 below.
Table 7- Non volatile solvents for betamethasone dipropionate Non-volatile solvent Skin Flux*
system n /cm2/h Propylene Glycol 195.3 t 68.5 Triacetin 4.6 t 2.8 Li ht Mineral Oil 11.2 t 3.1 Oleic Acid 8.8 t 3.3 Sorbitan Monolaurate 30.0 15.9 Labrasol 12.2t6.0 * Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 6-28 hours. If the experiment was continued it is anticipated the steady state would continue.

Active enzymes in the skin convert BDP to betamethasone. The steady state flux values reported in Table 7 are quantified using external betamethasone standards and are reported as amount of betamethasone permeating per unit area and time. As seen from the results triacetin, labrasol, oleic acid, and light mineral oil have flux values close to 10 ng/cm2/hr. Addition of solidifying agents and other components could possibly decrease the flux and therefore the above mentioned solvents would not be an ideal non-volatile solvent'. However, sorbitan monolaurate and propylene glycol have average.flux of 30 ng/cm2/hr and 195 ng/cm2/hr, respectively, and.therefore are good candidates for non-volatile solvent.
Example 16 Formulations of clobetasol propionate in various non-volatile solvent systems are evaluated. All solvents have 0.1 % (w/w) clobetasol propionate.
The permeation of clobetasol from the test formulations through HEM is presented in Table 8 below.

Table 8- Non volatile solvents for clobetasol propionate Non-volatile solvent Skin Flux*
system n cm2/h Propylene Glycol 3.8 0.4 GI cerol= 7.0 4.1 Light Mineral Oil 31.2 f 3.4 lsostearic Acid (ISA) 19.4 ~ 3.2 Ethyl Oleate 19.4 t 1.6 Olive Oil 13.6t3.3 Propylene G! cof/ISA 9:1 764.7 t 193.9 Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of.the cumulative amount versus time plots. The linear region was observed to be between 6-28 hours. If the -experiment was continued it is anticipated the steady state would continue. ' All the pure non=volatile solvents studied have an average flux of less than ng/cm2/hr over the 30 hour time period. Propylene glycol and. glycerol have the lowest permeation for clobetasol propionate. A mixture of propylene glycol and isostearic acid in weight ratio of 9:1 have significantly higher flux than either of the solvents alone or the other solvents tested. The average flux is 20 times higher than that with light mineral oil which is the best non-mixed solvent.
Hence, for clobetasol propionate propylene glycol/isostearic acid combination is 5 an ideal non-volatile solvent.

Examples 17-22 Adhesive solidifying formulations containing 0.05% (w/w) clobetasol propionate with propylene glycol and isostearic acid as non volatile solutions 10 and various solidifying agents are prepared. The formulations are prepared from the ingredients as shown in Table 9.

Table 9 - Solidifying formulation components Percent Percent Percent Percent Percent Example Polymer Polymer Ethano.l Propylene Isostearic Water GI col Acid 17 Polyvinyl 20 30 19.6 0.4 30 Alcohol 18. Shellac 50 30 19.6 0.4 0 19 Dermacryl 65.76 21.16 12.76. 0.26 0 20 Eudragit 50 30 19.6 0.40 0 21 Eudragit 50 30 19.6 0.40 0 RLPO, 22 Gantrez 14.3 57.1 28 0.6 0 15 Each ofthe compositions shown above are studied for flux of clobetasol propionate as shown in Table 10 as follows:

Table 10 - Steady state flux of clobetasol propionate through human cadaver skin at 35 C
Formulation Skin FI2 x*
n cm/h Example 17 87.8 t 21.4 , Example 18 9.7 t 2.4 Example 19 8.9 t 0.8 Example 20 3.2 :t 1.7 Example 21 20.2 t 18.6 Example 22 147.5 :t 38.8 ~ Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 6-28 hours. If the experiment was continued it is anticipated the steady state would continue.

As seen frorim-Table 10 formulation described in Example 17 that contains polyvinyl alcohol as solidifying agents has high flux of clobetasol propionate.
Polyvinyl alcohol is known to form stretchable films (if formulated with appropriate plasticizer) and it is likely that this formulation will have acceptable wear properties. The toughness of the resulting film can be modified by adding appropriate plasticizers if needed. Tackiness can also be modified by adding appropriate amounts of tackifier or by adding appropriate amounts of another solidifying.agent such as dermacryl 79.
Regarding formulation described in Example 22, a higher percentage of ethanol is needed to dissolve the polymer. However, the polymer used in Example 22 provides the highest flux of clobetasol propionate arriong the solidifying agents studied. The wear properties of this formulation can be modified by adding appropriate levels of other ingredients including but not limited to plasticizers, tackifiers, non-volatile solvents and or solidifying agents.
Example 23-25 Placebo formulations containing Gantrez ES 425 as a tackifier were prepared for wear studies by volunteers. The formulations are shown as examples in Table 11. All the formulations have Polyvinyl alcohol as the solidifying agent. The amount of propylene glycol in the formulations was decreased from 19.6% (w/w) to 8.7% (w/w), and the amount of glycerol was increased by the same amount to keep the total non-volatile ratio constant.
Keeping the non-volatile ratio constant'is. important as it determines the drying time and the duration of delivery. The placebo formulations are worn on the palms of hand and percentage adherence of the film formed after evaporation of volatile solvents was observed after 5-6 hours.

Table 11 - Placebo formulations (%w/w ingredients) Ingredient Example 23 Example 24 Example 25 Pol vin I Alcoho( 21.7% 21.7% 21.7%
Water 32.6% 32.6% 32.6%
GI cero( 8.7% 13.0% y 9:6%
Propylene Glycol 19.6% 15.2% 8.7%
Gantrez ES 425 4.3% 4.3% 4.3%
Ofeic acid 4.3% 4.3% 4.3%
Ethanol 8.7% 8.7% 8.7%
Wear study results on 3 volunteers show that 70-80% of solidified layer as described in Example 23 stayed on palms after a duration of 5-6 hours.
However, greater than 90% of solidified layer as shown in Example 25 stayed on palms of the volunteers. These examples demonstrate that glycerol is a better plasticizer that propylene glycol for the polyvinyl alcohol polymer. It also shows that the ratio of non-volatile solvent is critical in selecting the formulation for treatment of hand dermatitis.
Example 26 A formulation with the following composition: 10.4% polyvinyl alcohol, 10.4% polyethylene glycol 400, 10.4% polyvinyl pyrrolidone K-90, 10.4%
glycerol, 27.1 % water, and 31.3% ethanol was applied ontO a human skin surface at an elbow joint and a finger joint, resulting in a thin, transparent, flexible, and stretchable film. * After a few minutes of evaporation of the volatile solvents (ethanol and water), a solidified peelable layer that was peelable was formed. The stretchable film had good adhesion to the skin and did not separate from the skin on joints when bent, and could easily be peeled away from the skin.
Examples 27-28 Adhesive peelable formulations containing 0..05% (w/w) clobetasol propionate and 0.15% (w/w) clobetasol prppionate with polyvinyl alcohol as 25' solidifying polymer are prepared for in-vitro flux evaluation. Propylene glycol and oleic acid are the non volatile solvents selected for facilitation of clobetasol propionate delivery. As shown in Example 12, glycerol is added as the non r . .

volatile solvent for its plasticizing properties. Ratios of ingredients used in the two formulations are shown in Table 12.
Table 12 - Clobetasol Propionate peel formulations*
Ingredient Exam le 27 Example 28 Pol vin I Alcohol 22.7% 22.7%
Water 34.1% 34.0%
Glycerol 17.3% 17.2%
Propylene Glycol 7.7% 7.7%
Gantrez ES 425 4.5% 4.5%
Oleic acid 4.5% 4.5%
Ethanol 9.1% 9.1%
Clobetasol Propionate 0.05% 0.15%
* Numbers do not add to 100% because of rounding irl the second decimal.
Both of the compositions shown above are studied for flux of clobetasol propionate on cadaver skin from three donors. The permeation results are as shown in Table 13. Commercial clobetasol ointment (0.05% w/w) was used as a control formulation.
Table 13 - Steady state flux of clobetasol propionate through human cadaver skin at 35 C
Control Example 27 Example 28 Skin Donor J* ~ng/. J* ~ng/ J* ~ng/
cm /h) cm /h cm /h .
Donor 1 22.4t2.1 8.8:t 1.9 29.2t8.2 Donor2 20.0t2.5 7.6:t 2.5 18.5t6.4 Donor3 35.0t4.7 19.3t5.9 24.8t7.7 Mean +/- SD n=3. donors 25.8 7.5 1'i .9 6.5 24.2 t 8.0 * Skin flux measurements represent the mean and standard deviation of three determinations. Fluz measurements reported are determined from the linear region of the cumulative ainount versus time plots. The linear region are observed to be between 6-28 hours. If the experiment is continued, it is anticipated the steady state would continue.

As seen from Table 13 formulation described in Example 27 that contained polyvinyl alcohol as a solidifying ageint and 0.05% clobetasol propionate had 46% flux of clobetasol propionate when compared to the control formulation.
Increasing the clobetasol propionate concentration drug concentration to 0.15%
(w/w) increased the steady state flux and the flux values were 94% of the control formulation. It is expected that longer duration of application with the peel formulation would increase cumulative delivery in-vivo resulting in effective treatment of dermatitis.

Example 29 Adhesive solidifying formulations containing 0.05% (w/w) clobetasol propionate with fish gelatin as solidifying agent are prepared for in-vitro flux evaluation. Propylene glycol, isostearic acid, and oleic acid are used as non-volatile solvents to facilitate delivery of clobetasol. Talc is added as a filler to reduce the drying time the formulation. Ratio of irigredients used in the formulation is shown in Table 14.
Table 14: Clobetasol Propionate formulations*
Ingredient Example 29 Fish Gelatin 29.4%
Water 22.0%
Ethanol 14.7%
Pro lene GI col 17.6%
Isostearic acid = 2.2%
Oleic acid 2.2%
Talc 11.8%
Clobetasol Propionate 0.05%
~ Numbers do not add to 100% because of rounding in the second decimal.
Uniike the polyvinyl based formulations shown in previous examples, the fish gelatin based formulation shown in Example 29 is a water washable formulation and can be easily removed by subjects suffering from hand dermatitis. Steady state flux across human cadaver skin from 3 donors with formulation as described in Example 29 is compared to the commercial clobetasol ointment.
The permeation results are shown in Table 15.

Table 15 - Steady state flux of clobetasol propionate through human cadaver skin at 35 C
Skin Donor * Control. 2 Example 29 J (ng/ cm /h J ri / cm /h Donor =1 39.2 9.2 46.1 14.3 Donor 2 35.6 t 2.1 52.9 22.3 Donor 3 35.6 :t 5.7 79.7 18.4 Mean +/- SD (n=3 donors) 36.8 t 5.8 59.6 t 22.3 *Skin flux measurements represent the mean and standard*
deviation of three determinations. Flux measurements reported are determined from the linear region of the cumulative amount versus time plots. The linear region are observed to be between 6-28 hours. If the 5 experiment is continued, it is anticipated the steady state would continue.
As seen from Table 15, formulation described in Example 29 has 62% higher steady state flux when compared to the commercial ointment. Higher steady 10 state flux would is expected to reduce inflammation in difficult to treat dermatitis and psoriasis cases.

Example 30 Adhesive solidifying formulations containing 0.05% (w/w) clobetasol 15 propionate with fish gelatin as solidifying polymer are prepared for in-vitro flux evaluation. Propylene glycol, and isostearic acid are used as non-volatile solvents to facilitate delivery of clobetasol. Fumed silica is added as a filler to reduce the drying time the formulation. Ratio of ingredients used in the formulation is shown in Table 16. .
20 Table 16: Clobetasol Propionate formulations*
1n redient - Example 30 Fish Gelatin 32.2%
Water ' 24.2%
Ethanol 16.1%
Propylene GI col 19.3%
lsostear.ic- acid 4.8%
Fumed Silica 3.2%
Clobetasol Pro ionate . 0.05%
* NLirnbers do not add to 100% because of rounding in the second. decimal.
The fish gelatin based formulation shown in Example 30 is a wate'r washable formulation and can be easily removed by subjects suffering from hand 25 dermatitis. Steady state flux across human cadaver skin from 4 donors=with formulation as described in Example 30 is compared to the commercial ctobetasol ointment. The permeation results are shown in Table 17.

Table 17 - Steady state flux of clobetasol propionate through human cadaver skin at'35 C
Skin Donor * Control 2 Example 30 J (ng/ cm /h J (ng/ cm /h Donor 1 28.2 t 7.8 20.7 12.8 Donor2 30.1 14.9 30.6t13.8 Donor3 36.2:i- 6.2 93.4 7.5 Donor4 33.6t3.9 101.4 8.5 Mean +/- SD (n=3 donors) 32.0 8.5 61.5 38.9 *Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported are .5 determined from the lineer region of the cumulative amounY versus time plots. The linear region are observed to be between 6-28 hours. If the experiment is continued, it is anticipated the steady state would continue.

As seen from Table 17, on an average, formulation described in Example 30 has at-least similar or better steady state flux when to compared to the steady state flux with the commercial ointment. Unlike talc used in Example 29, fumed silica had a low density and is expected.to have a less potential to separate frorin the formulation.
Examele 31 Example 29 and 30 indicate that'fish gelatin, a protein based solidifying agent (polymer) based formulations is preferred polymer of choice fdr delivery of corticosteroid drugs. However, fish.gelatin based forniulations take a longer time to dry. Alternate adhesive formulations containing 0.05% (w/w) clobetasol propionate with zein, a.corn based protein, as solidifying polymer are, prepared for in-vitro flux evaEuation. Propyierie glycol, and isostearic acid are used as non=volatile solvents to facilitate delivery of clobetasol. Unlike fish gelatin, which has poor solubility in ethanol, zein, is soluble in ethanol, and hence zein based formulations have a lower drying time. Ratio of ingredients used iri the formulation is shown in Table 18. . .
Table 18: Clobetasol Propionate formulations with zein'' Ingredient Example 31 Zein 36.3%
Propylene Glycol 21.8%
Isostearic acid 5.5%' Ethanol 36.3%

Clobetasol Propionate 0.05%
" Numbers do not add to 100% because of rounding in the second decimal.
Steady-state flux across human cadaver skin with formulation as described in Example 31 is compared to the skin flux with a commercial clobetasol ointment.
The permeation results are shown in Table 19.

Table 19 - Steady state flux of clobetasol propionate through human cadaver skin at 35- C
Control Example 31 J* n/ cm2/h) J* (ng/ cm2/h ' Cadaver skin 17.2 4.1 14.8 1Ø
*Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported are determined from the linear region of the cumulative amount versus time plots. The linear region are observed to be between 6-28 hours. If the experiment is continued, it is anticipated the steady state would continue.
As seen from Table 19, the formulation described in Eicample 31 has comparable steady state flux to the commercial ointment (Ratio 86%). This ratio is significantly .higher than the ratio of formulation in Example 27, a polyvinyl alcohol based formulation, which has a ratio of 46%. This example demonstrates that formulations with-protein based solidifying agents preserve -flux of corticosteroids better than polyvinyl based formulations. The wear properties of formulation in Example 31 can be improved by the addition of plasticizers and fillers.

Example 32' = .
To demonstrate the ability of the solidified solidifying formulations to ' reduce the transepidermal water loss (TEWL) the following experiment was conducted. ' .
Placebo PVA formulation similar.to #he formulation'described in Example '28 was applied to the top of the hand and the TEWL was measured on a site immediately adjacent to the solidified layer and on top of the solidified peel. The TEWL measurement of the site covered by the solidified layer was 33% lower than the untreated skin site.
Placebo Plastoid B formulation similar to the formulation described in Example 20 was applied to the top of the hand and the TEWL was measured on a side immediately adjacent to the solidified layer and on top of the solidified peel. The TEWL measurement on the site covered by the solidified layer was 30% lower than the untreated skin site.

Example 33-36 Adhesive solidifying formulations containing the following components are made:
Table 20 - Imi uimod eelable formulation ingredients Ingredients* Exam le PVA 10.1 Plastoid B** 17.5 Eudra it RL PO 16.2 24.8 Pemulen TR-2 0.3 Water 52.9.
Iso ro anol 35.1 Ethanol 32.4 38.6 ISA Isostearic Acid) 16.8 23.4 23.1 27.6 Salicylic Acid 15.2 16.4 16.2 Trolamine 1.7 Triacetin 3.5 3.5 4.1 lmiguimod 3.0 4.1 4.0 4.8 'tngredients are noted as weight percent.
** Polymer from Degussa These formulations are applied to HMS skin as described in Example 1, and the imiquimod flux is measured. A summary of the results from in vitro flux studies carried out with the formulations in,Examples 33-36 are listed in Table 21.

Table 21 - Steady-state flux of lmiquimoci through hairless mouse skin from various adhesive peelable formulations at 35 C
Average flux Ratio to Formulation mc /cm2/h* Control**
Example 33 1J:1 1.1 Example 34 4.5 zt: 0.4 5 Example 35 3.8 t 0.5 4.2 Example 36 0.8 t 0.2 0.9 Aldara 0.9 0.02 1 ~ The flux values represent the mean and SD of three determinations ** Ratio to control calculated by dividing the flux value for each Example by the flux value for Aldara control flux.

In vitro flux of Examples 33-36 is substantially higher than that of the Aldara control.

While the invention has been described with reference to certain preferred embodiments, those skilled in the art will appreciate that various 'modifications, changes, omissions, and substitutions can be made without departing from the spirit of the invention. It is therefore intended that the invention be limited only by the scope of the appended claims:

Claims (121)

1. An adhesive solidifying formulation for treating a dermatological condition, comprising:
a) a drug for treating a dermatological condition;
b) a solvent vehicle, comprising:
i) a volatile solvent system including at least one volatile solvent, and ii) a non-volatile solvent system including at least one non-volatile solvent, wherein the non-volatile solvent system is capable of facilitating delivery of the drug at a therapeutically effective rate over a sustained period of time; and c) a solidifying agent, wherein the formulation has a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system, the formulation applied to the skin surface forms a solidified layer after at least partial evaporation of the volatile solvent system, and the drug continues to be dermally delivered after the volatile solvent system is at least substantially evaporated.

2. A formulation as in claim 1, wherein the non-volatile solvent system acts as a plasticizer for the solidifying agent.

3. A formulation as in claim 1, wherein the non-volatile solvent system is flux-enabling for the drug.

4. A formulation as in claim 1, wherein the formulation further comprises an additional agent which is added to increase adhesion of the formulation when applied to a body surface.

5. A formulation as in claim 4, wherein the additional agent includes a member selected from the group consisting of copolymers of methylvinyl ether and maleic anhydride, polyethylene glycol and polyvinyl pyrrolidone, gelatin, low molecular weight polyisobutylene rubber, copolymer of acrylsan alkyl/octylacrylamido, aliphatic resins, aromatic resins, and combinations thereof.

6. A formulation as in claim 1, wherein the volatile solvent system comprises water.

7. A formulation as in claim 1, wherein the solvent vehicle is substantially free of water.

8. A formulation as in claim 1, wherein the volatile solvent system includes at least one member selected from the group consisting of ethanol, isopropyl alcohol, and combinations thereof.

9. A formulation as in claim 1, wherein the volatile solvent system includes at least one solvent more volatile than water, and includes at least one member selected from the group consisting of ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1, difluoroethane, 1,1,1,2 tetrafluorethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone, and combinations thereof.

10. A formulation as in claim 1, wherein the volatile solvent system includes at least one solvent more volatile than water, and includes at least one member selected from the group consisting of iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclomethicone, methyl ethyl ketone, and combinations thereof.

11. A formulation as in claim 1, wherein the volatile solvent system comprises a volatile solvent whose boiling point is below 20°C.

12. A formulation as in claim 11, wherein the volatile solvent with the boiling point below 20°C is completely dissolved in the formulation.

13. A formulation as in claim 11, wherein the volatile solvent with the boiling point below 20°C is included in the formulation as a propellant for pressurized spray-on application.

14. A formulation as in claim 11, wherein the volatile, solvent with the boiling point below 20°C is a hydrofluorocarbon.

15. A formulation as in claim 11, wherein the at least one solvent whose boiling point is below 20 C is selected from the group consisting of dimethyl ether, butane, 1,1, difluoroethane, 1,1,1,2 tetrafluorethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, or a mixture thereof.

16. A formulation as in claim 1, wherein the non-volatile solvent system includes multiple non-volatile solvents admixed together.

17. A formulation as in claim 1, wherein the non-volatile solvent system includes at least one solvent selected from the group consisting of isostearic acid, oleic acid, olive oil, trolamine, and combinations thereof.

18. A formulation as in claim 1, wherein the non-volatile solvent system comprises at least one member selected from the group consisting of sorbitan monolaurate, isostearic acid, triacetin, benzoic acid, and combinations thereof.

19. A formulation as in claim 1, wherein the non-volatile solvent system includes at least one solvent selected from the group consisting of glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, butanol, and combinations thereof.

20. A formulation as in claim 1, wherein the non-volatile solvent system includes at least one solvent selected from the group consisting of benzoic acid, butyl alcohol, dibutyl sebecate, diglycerides, dipropylene glycol, eugenol, fatty acids, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan fatty acid surfactants, triethyl citrate, and combinations thereof.

21. A formulation as in claim 1, wherein the non-volatile solvent system includes at least one solvent selected from the group consisting of 1,2,6-hexanetriol, alkyltriols, alkyldiols, acetyl monoglycerides, tocopherol, alkyl dioxolanes, p-propenylanisole, anise oil, apricot oil, dimethyl isosorbide, alkyl glucoside, benzyl alcohol, bees wax, benzyl benzoate, butylene glycol, caprylic/capric triglyceride, caramel, cassia oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglycerides, coriander oil, corn oil, coriander oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglycerides, diethanolamine, dietthylene glycol monoethyl ether, diglycerides, ethylene glycol, eucalyptus oil, fat, fatty alcohols, flavors, liquid sugars, ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, limonene, milk, monoacetin, monoglycerides, nutmeg oil, octyldodecanol, olive alcohol, orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil; vegetable shortening, vinyl acetate, wax, 2-(2-(octadecyloxy)ethoxy)ethanol, benzyl benzoate, butylated hydroxyanisole, candelilla wax, carnauba wax, ceteareth-20, cetyl alcohol, polyglyceryl, dipolyhydroxy stearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG fatty acid esters, PEG-stearate, PEG-oleate, PEG laurate, PEG fatty acid diesters, PEG- dioleate, PEG-distearate, PEG-castor oil, glyceryl behenate, PEG glycerol fatty acid esters, PEG glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate, hexylene glycerol, lanolin, lauric diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, methacrylic acid, multisterol extract, myristyl alcohol, neutral oil, PEG-octyl phenyl ether, PEG-alkyl ethers, PEG-cetyl ether, PEG-stearyl ether, PEG-sorbitan fatty acid esters, PEG-sorbitan diisosterate, PEG-sorbitan monostearate, propylene glycol fatty acid esters, propylene glycol stearate, propylene glycol, caprylate/caprate, sodium pyrrolidone carboxylate, sorbitol, squalene, stear-o-wet, triglycerides, alkyl aryl polyether alcohols, polyoxyethylene derivatives of sorbitan-ethers, saturated polyglycolyzed C8-glycerides, N-methyl pyrrolidone, honey, polyoxyethylated glycerides, dimethyl sulfoxide, azone and related compounds, dimethylformamide, N-methyl formamaide, fatty acid esters, fatty alcohol ethers, alkyl-amides (N,N-dimethylalkylamides), N-methyl pyrrolidone related compounds, ethyl oleate, polyglycerized fatty acids, glycerol monooleate, glyceryl monomyristate, glycerol esters of fatty acids, silk amino acids, PPG-3 benzyl ether myristate, Di-PPG2 myreth 10-adipate, honeyquat, sodium pyroglutamic acid, abyssinica oil, dimethicone, macadamia nut oil, limnanthes alba seed oil, cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice, phenyl trimethicone, hydrolyzed wheat protein, and combinations thereof.

22. A formulation as in claim 1, wherein the solidifying agent includes at least one member selected from the group consisting of polyvinyl alcohol, esters of polyvinylmethylether/maleic anhydride copolymer, neutral copolymers of butyl methacrylate and methyl methacrylate, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymers, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymers, prolamine (Zein), pregelatinized starch, ethyl cellulose, fish gelatin, gelatin, acrylates/octylacrylamide copolymers, and combinations thereof.

23. A formulation as in claim 1, wherein the solidifying agent includes at least one member selected from the group consisting of ethyl cellulose, hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxy propyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amides, corn starch, pregelatinized corn starch; polyether amides, shellac, polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate phthalate, and combinations thereof.

24. A formulation as in claim 1, wherein the solidifying agent includes at least one member selected from the group consisting of ammonia methacrylate, carrageenan, cellulose acetate phthalate aqueous, carboxy polymethylene, cellulose acetate (microcrystalline), cellulose polymers, divinyl benzene styrene, ethylene vinyl acetate, silicone, guar gum, guar rosin, gluten, casein, calcium caseinate, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate, PEG/PVP, xantham gum, trimethyl siloxysilicate, maleic acid/anhydride colymers, polacrilin, poloxamer, polyethylene oxide, poly glactic acid / poly-I-lactic acid, turpene resin, locust bean gum, acrylic copolymers, polyurethane dispersions, dextrin, polyvinyl alcohol-polyethylene glycol co-polymers, methyacrylic acid-ethyl acrylate copolymers, methacrylic acid and methacrylate based polymers such as poly(methacrylic acid), and combinations thereof.

25. A formulation as in claim 1, wherein the solidifying agent includes a methyacrylic polymer.

26. A formulation as in claim 1, wherein the solidifying agent includes a methyacrylic acid-ethyl acrylate copolymer.

27. A formulation as in claim 1, wherein the solidifying agent includes a polyvinyl alcohol-polyethylene glycol copolymer.

28. A formulation as in claim 1, wherein the solidifying agent-includes a polyvinyl alcohol-polyethylene glycol copolymer.

29. A formulation as in claim 1, wherein the solidifying agent includes a member selected from the group of a methyacrylic acid copolymer, an aminoalkyl methacrylate copolymer, an ammonioalkyl methacrylate copolymer, and combinations thereof.

30. A formulation as in claim 1, wherein the drug includes multiple pharmaceutically active agents.

31. A formulation as in claim 1, wherein the dermatological condition is a viral infection and the drug is an anti-viral agent.

32. A formulation as in claim 31, wherein the anti-viral agent includes a member selected from the group consisting of acyclovir, penciclovir, famciclovir, valacyclovir, behenyl alcohol, trifluridine, idoxuridine, cidofovir, gancyclovir, podofilox, podophyllotoxin, ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, and combinations thereof.

33. A method as in claim 31, wherein the viral infection is a herpes infection and the drug is a steroid for treating the herpes infection.

34. A formulation as in claim 33, wherein the herpes infection is a cold sore and the drug is for treating the cold sore.

35. A formulation as in claim 33, wherein the herpes infection is genital herpes and the drug is for treating the genital herpes infection.

36. A formulation as in claim 1, wherein the dermatological condition is a nail infection and the drug is for treating nail infection.

37. A formulation as in claim 1, wherein the dermatological condition is a fungal infection and the drug is an antifungal agent.

38. A formulation as in claim 37, wherein the antifungal agent includes a member selected from the group consisting of amorolfine, butenafine, naftifine, terbinafine, fluconazole, itraconazole, ketoconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, butoconazole, econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazole, caspofungin, micafungin, anidulafingin, amphotericin B, AmB, nystatin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, and undecylenate, and combinations thereof.

39. A formulation as in claim 1, wherein the dermatological condition is photo damaged skin and the drug is an immune modulating agent.

40. A formulation as in claim 39, wherein the immune modulating agent includes multiple immune modulating agents.

41. A formulation as in claim 39, wherein the immune modulating agent includes imiquimod.

42. A formulation as in claim 39, wherein the immune modulating agent includes rosiquimod.

43. A formulation as in claim 1, wherein the formulation further includes a protectant comprising a member selected from the group consisting of allantoin, calamine, cod liver oil, dimethicone, kaolin, lanolin, mineral oil, petrolatum, talc, topical starch, white petrolatum, zinc oxide, and combinations thereof.

44. A formulation as in claim 1, which comprises a moisturizing agent.

45. A formulation as in claim 45, wherein the moisturizing agent includes at least one member selected from the group consisting of: glycerol, propylene glycol, dipropylenen glycol, butylene glycol, sorbitol, honey and honey derivatives such as honeyquat, urea and urea derivatives such as hydroxyethyl urea, ammonium lactate, sodium lactate, potassium lactate, pyroglutamic acid and its salts, sodium malates, polydextrose, triacetin, mannitol, oxidised polyethylene, isomalt, maltitol and maltitol syrup, lactitol, xylitol, erythrit, and combinations thereof.

46. A formulation as in claim 1, wherein the solidified layer provides a mechanical barrier against external sources of irritation.

47. A formulation as in claim 1, wherein the solidified layer provides a barrier against urine or fecal matter.

48. A formulation as in claim 1, wherein the solidified layer provides a barrier against friction with a diaper.

49. A formulation as in claim 1, wherein the dermatological condition is a bacterial infection and the drug is an antibacterial agent.

50. A formulation as in claim 49, wherein the antibacterial agent includes a member selected from the group consisting of erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones such as ciproflaxin, and combinations thereof.

51. A formulation as in claim 1, wherein the dermatological condition is a skin infection.

52. A formulation as in claim 1, wherein the dermatological condition is alopecia and the drug includes a corticosteriod.

53. A formulation as in claim 52, wherein the drug is a corticosteroid including a member selected from the group consisting of steroids including betamethasone dipropionate, halobetasol propionate, diflorasone diacetate, triamcinolone acetonide, desoximethasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alclometasone dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone acetate, and combinations thereof.

54. A formulation as in claim 1, wherein the dermatological condition is alopecia and the drug includes a hair growth stimulant.

55. A formulation as in claim 1, wherein the dermatological condition is alopecia and the drug is a substance which irritates the skin to stimulate hair growth, and includes a member selected from the group consisting of minoxidil, spironolactone, finasteride, anthralin, tretinoin topical, immunotherapeutic agents such as dinitrochlorobenzene, squaric acid dibutyl ester, diphenylcyclopropenone, and combinations thereof.

56. A formulation as in claim 1, wherein the dermatological condition is alopecia and the drug includes clobetasol or a clobetasol derivative.

57. A formulation as in claim 56, wherein the clobetasol derivative is clobetasol propionate.

58. A formulation as in claim 56, wherein the concentration of clobetasol or clobetasol derivative is greater than about 0.03%.

59. A formulation as in claim 56, wherein the concentration of clobetasol or clobetasol derivative is greater than 0.14%.

60. A formulation as in claim 56, wherein the concentration of clobetasol or clobetasol derivative is greater than 0.29%.

61. A formulation as in claim 56, wherein the drug is clobetasol or a clobetasol derivative and the solidifying agent includes a member selected from the group consisting of gelatin, zein, gluten, polyvinyl alcohol, and combinations thereof.

62. A formulation as in claim 1, wherein the dermatological condition is dermatitis or psoriasis and the drug includes at least one member of a class of drugs selected from the group consisting of corticosteroids, immune modulators, analogs of vitamin D3, retinoic acids, pharmaceutically active derivatives thereof, and combinations thereof.

63. A formulation as in claim 1, the dermatological condition is dermatitis or psoriasis and the drug includes at least one member selected from the group consisting of betamethasone dipropionate, clobetasol propionate, halobetasol propionate, diflorasone diacetate, amcinonide, desoximethasone; fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alclometasone dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone acetate, tacrolimus, picrolimus, tazarotene, isotretinoin, cyclosporin, anthralin, vitamin D3, cholecalciferol, calcitriol, calcipotriol, tacalcitol, calcipotriene, and combinations thereof.

64. A formulation as in claim 1, the dermatological condition is dermatitis or psoriasis and the solidified layer is capable of adhering to the palm skin of human hands.

65. A formulation as in claim 1, wherein dermatological condition is alopecia and the non-volatile solvent system comprises propylene glycol and isostearic acid in the weight ratio of from 19:1 to 4:1.

66 66. A formulation as in claim 1, wherein the solidified layer is sufficiently flexible and adhesive to the skin such that when applied to the skin at stretchable skin surface, the solidified layer will remain substantially intact on the skin upon stretching of the skin.

67. A formulation as in claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 2 hours following the formation of the solidified layer.

68. A formulation as in claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 4 hours following the formation of the solidified layer.

69. A formulation as in claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 8 hours following the formation of the solidified layer.

70. A formulation as in claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 12 hours following the formation of the solidified layer.

71. A formulation as in claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 24 hours following the formation of the solidified layer.

72. A formulation as in claim 1, wherein the solidifying agent is dispersed in the solvent vehicle.

73. A formulation as in claim 1, wherein the solidifying agent is solvated in the solvent vehicle.

74. A formulation as in claim 1, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.1:1 to about 10:1.

75. A formulation as in claim 1, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.5:1 to about 2:1.

76. A formulation as in claim 1, wherein the non-volatile solvent system is capable of causing human skin irritation and at least one non-volatile solvent of the non-volatile solvent system is capable of reducing the skin irritation.

77. A formulation as in claim 76, wherein the non-volatile solvent capable of reducing the skin irritation includes a member selected from the group consisting of glycerin, propylene glycol, and honey, and combinations thereof.

78. A formulation as in claim 1, wherein the solidified layer is formed within about 15 minutes of application to the skin surface under standard skin and ambient conditions.

79. A formulation as in claim 1, wherein the solidified layer is formed within about 5 minutes of the application to the skin surface under standard skin and ambient conditions.

80. A formulation as in claim 1, wherein the solidified layer is removable from a skin surface by washing.

81. A formulation as in claim 1, wherein the formulation has an initial viscosity prior to skin application from about 100 to about 3,000,000 centipoises.

82. A formulation as in claim 1, wherein the formulation has an initial viscosity prior to skin application from about 1,000 to about 1,000,000 centipoises.

83. A formulation as in claim 1, wherein the weight percentage of the volatile solvent system is from about 10 wt% to about 85 wt%.

84. A formulation as in claim 1, wherein the weight percentage of the volatile solvent system is from about 20 wt% to about 50 wt%.

85. A formulation as in claim 1, wherein the non-volatile solvent system includes multiple non-volatile solvents and at least one of the non-volatile solvents improves the compatibility of the non-volatile solvent system with the solidifying agent.

86. A formulation as in claim 1, wherein the solidified layer is coherent, flexible, and continuous.

87. A formulation as in claim 1, wherein the solidified layer, upon formation, is a soft, coherent sold that is peelable from a skin surface as a single piece or as only a few large pieces relative to the application size.

88. A formulation as in claim 1, wherein the solidified layer, upon formation, is a soft, coherent sold that is removable by gentle washing.

89. A formulation as in claim 1, wherein the solidified layer is formulated to transdermally deliver the drug.

90. A formulation as in claim 1, wherein the dermatological condition is a bacterial infection, a virus infection, a fungal infection, alopecia, dermatitis, psoriasis, or photo damaged skin.

91. A method of treating a dermatological condition, comprising:
a) applying an adhesive solidifying formulation as in one of claims 1 to 90 to a skin surface affected with the dermatological condition;

b) solidifying the formulation to form a soft, coherent, solidified, layer on the skin surface by at least partial evaporation of the volatile solvent system;
and c) dermally delivering the drug from the solidified layer to the infected skin site at therapeutically effective rates over a sustained period of time.

92. A method as in claim 91, wherein the skin site is epidermal skin.

93. A method as in claim 91, wherein the skin site is a mucosal site.

94. A method as in claim 91, wherein the skin site is a nail with a fungal infection.

95. A method as in claim 91, wherein the skin site is wounded skin.

96. A method as in claim 91, wherein the skin site is a bed sore, a skin lesion, or an open sore.

97. A method as in claim 91, wherein the step of applying includes applying the formulation at a thickness from about 0.01 mm to about 3 mm.

98. A method as in claim 91, wherein the thickness of the formulation applied on the skin is between about 0:05 mm to about 3 mm.

99. A method as in claim 91, wherein the step of applying includes applying the formulation at a thickness from about 0.05 mm to about 1 mm.

100. A method as in claim 91, wherein the formulation is applied on the.
skin of the subject within an hour of sleeping and removed within an hour after waking.

101. A method as in claim 91, wherein the formulation is applied on the skin of the subject after waking and removed before sleeping.

102. A method as in claim 91, wherein the solidified layer is left on the skin surface for at least 2 hours following the formation of the solidified layer.

103. A method as in claim 91, wherein the solidified layer is left on the skin surface for at least 12 hours following the formation of the solidified layer.

104. A method as in claim 91, wherein the formulation is applied in combination with a sunscreen, either applied separately or included within the formulation.

105. A method as in claim 91, wherein the dermatological condition is alopecia and the human skin covered by the formulation has an area of no more than 100 cm2.

106. A method as in claim 91, wherein the dermatological condition is alopecia and the human skin covered by the formulation has an area of no more than 20 cm2.

107. A method as in claim 91, wherein the application of the formulation comprises spraying the formulation on the skin.

108. The method of claim 91, wherein the dermatological condition is dermatitis or psoriasis and the skin surface is the palm skin of the hand.

109. A method as in claim 91, wherein the dermatological condition is a bacterial infection, a virus infection, a fungal infection, alopecia, dermatitis, psoriasis, photo damaged skin, and combinations thereof.

110. A soft, coherent solidified layer for treating a dermatological condition, comprising:
a) a drug that is for treating a dermatological condition;
b) a non-volatile solvent system including at least one non-volatile solvent, wherein the non-volatile solvent system facilitates the delivery of the drug at a therapeutically effective rate over a sustained period of time; and c) a solidifying agent, wherein the solidified layer is capable of adhering to a skin surface to which the layer is applied.

111. A solidified layer as in claim 110, wherein the non-volatile solvent system acts as a plasticizer for the solidifying agent.

112. A solidified layer as in claim 110, wherein the non-volatile solvent system is flux-enabling for the drug.

113. A solidified layer as in claim 110, wherein the solidified layer is sufficiently adhesive and flexible to remain substantially intact on a standard skin surface under the standard testing condition for at least about 2 hours.

114. A solidified layer as in claim 110, wherein the solidified layer can be stretched in at least one direction by 5% without breaking or separating from a skin surface.

115. A solidified layer as in claim 110, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.5:1 to about 2:1.

116. A solidified layer as in claim 110, wherein the solidified layer is removable by washing with water, surfactant, an alcohol solvent, or a combination thereof.

117. A solidified layer as in claim 110, wherein the solidified layer is a peel and can be removed by peeling from a skin surface as a single piece or as only a few large pieces relative to the application size.

118. A solidified layer as in claim 110, wherein the solidified layer is flux-enabling for the drug.

119. A solidified layer as in claim 110, wherein the solidified layer is adhesive to a skin surface on one surface, and is non-adhesive on an opposing surface.

120. A solidified layer as in claim 110, wherein the solidified layer is formulated to deliver a majority the drug that is dermally deliverable therefrom while the solidified layer is substantially devoid of water and any solvent more volatile than water.

121. A solidified layer as in claim 110, wherein the dermatological condition a bacterial infection, a virus infection, a fungal infection, alopecia, dermatitis, psoriasis, or photo damaged skin.