JP2008505914A - Gilsonite-derived pharmaceutical delivery compositions and methods: cosmetic and nail applications - Google Patents

Abstract

  Disclosed are pharmaceutical formulations comprising gilsonite oil for topical or transdermal application. Also provided is a method for transdermal administration of a bioactive agent with enhanced penetration, including topical administration of a composition comprising a transdermally effective amount of Gilsonite oil.

Description

Cross-reference to related applications This application is filed in U.S. Patent Application No. 10 / 887,466, filed July 7, 2004, and U.S. Patent Application No. 10 / 887,453, filed July 7, 2004 (both for all purposes). For the purpose of reference).

FIELD OF THE INVENTION This invention relates to pharmaceutical compositions for transdermal, transmucosal and topical delivery and methods for their use. More specifically, these compositions include a penetration enhancer and a bioactive agent.

  The transdermal route of parenteral delivery of drugs provides a number of advantages, and examples of transdermal systems for delivering a wide variety of drugs include U.S. Patents 3,598,122, 3,598,123, 3,731,683, 3,797,494 No. 4,286,592, No. 4,314,557, No. 4,379,454, No. 4,435,180, No. 4,559,222, No. 4,568,343, No. 4,573,999, No. 4,588,580, No. 4,645,502, No. 4,704,282, No. 4,816,258, No. 4,849,226, 27 No. 4,943,435, No. 5,004,610, No. 5,006,342, No. 5,314,694, No. 5,411,740, No. 5,629,019, No. 5,641,504, No. 5,686,097 (the disclosures of which are incorporated herein by reference) Has been. In many cases, a drug that appears to be an ideal candidate for transdermal delivery can be delivered in a therapeutically effective amount for intact skin permeability, with the application of a reasonably sized device or a reasonable amount of substance. It turns out to be so low.

  Pre-treating the skin with various chemicals or co-administering the drug in the presence of a penetration enhancer to enhance skin penetration so that the drug can be delivered transdermally in a therapeutically effective amount Is presented. U.S. Pat. No. 4,405,616, No. 4,568,343, No. 4,746,515, No. 4,764,379, No. 4,788,062, No. 4,820,720, No. 4,863,738, No. 4,863,970, No. 4,865,848, No. 4,900,555, No. 4,940,586, No. 4,973,405 , 5,059,426, 5,378,730 and WO 95/01167, the entire disclosures of which are hereby incorporated by reference, suggest various substances for this use. Yes. Williams et al. "Skin Absorption Enhancers" Critical Review in Therapeutic Drug Carrier Systems, pp. 305-353 (1992) and Santus et al. "Transdermal Enhancer Patent Literature", Journal of Controlled Release, pp. 1-20 (1993). A review of accelerators is given.

In order to be considered useful, penetration enhancers should have the ability to promote skin permeability to at least one, and preferably a significant number of drugs. More importantly, it should promote skin penetration so that the drug delivery rate from a reasonably sized system (preferably 5-60 cm ² ) is at a therapeutically effective level. Also, an ideal penetration enhancer when applied to the skin surface should be non-toxic, non-irritating in long-term exposure and closure, and non-sensitizing on repeated exposure. Preferably, it should be odorless and physiologically inert and capable of delivering the drug without causing tingling or tingling or other irritation. DMSO has been recommended as an effective penetration enhancer or carrier for transdermal drug delivery, but it is undesirable because of toxicity concerns.

  In addition to these penetration enhancer-skin interaction considerations, penetration enhancers should also be evaluated for possible interactions in the transdermal system itself (eg, a patch that adheres to the skin with an adhesive). is there. For example, penetration enhancers should be compatible with the drug to be delivered, the patch adhesive, and the polymer matrix or other reservoir that distributes the drug to the skin. Also, penetration enhancers should be chosen so as to provide an adequate balance between adhesive stickiness, adhesion and bond strength, or at best not improperly interfere with it.

  The use of co-solvents with penetration enhancers is also disclosed. Such co-solvents alone cannot clearly promote transdermal flux, but when used with other penetration enhancers can act synergistically to promote transdermal flux of the drug. One hypothesis is that these co-solvents act to enhance the availability of penetration enhancers on the skin surface and promote drug flux.

  For example, WO 95/09006 discloses lactic acid ester co-solvents such as lauryl lactate, ethyl lactate, cetyl lactate and myristyl lactate in combination with monoglycerides. However, these lactate esters can be irritating to the skin. WO 96/40259 discloses the use of lauryl acetate as a co-solvent for monoglyceride penetration enhancers such as glycerol monolaurate. This combination results in an enhanced flux compared to other monoglyceride / co-solvent combinations and is available in high purity. However, lauryl lactate has been found to be an undesirable co-solvent from a manufacturing standpoint. During the manufacture of transdermal delivery systems, it has been found that an undesirable amount of lauryl acetate evaporates due to its high vapor pressure, leaving only an insufficient amount of lauryl acetate in the system.

  Thus, despite these advances, due to problems related to skin irritation and recently discovered problems related to the processing and manufacture of films containing various co-solvents for monoglycerides, There remains a need for alternative penetration enhancing formulations.

US Pat. No. 5,312,122 also discloses the use of monoglycerides and fatty acid esters, alone or in combination, as penetration enhancing mixtures for synthetic progestogens. US Pat. No. 5,026,556 is selected from the group consisting of polar solvent materials selected from the group consisting of C ₃ -C ₄ diols, C ₃ -C ₆ triols and mixtures thereof, and fatty alcohol esters, fatty acid esters and mixtures thereof Disclosed is a composition for transdermal delivery of buprenorphine comprising an amount of buprenorphine in a carrier comprising a polar lipid substance. As a suitable polar lipid substance, ethyl palmitate is disclosed.

  US Pat. No. 5,352,456 discloses an initial pulse of drug followed by a transdermal delivery device that delivers the drug at a substantially lower continuous rate. The device includes a drug reservoir comprising a volatile penetration enhancer and a drug dissolved in a carrier. The volatile penetration enhancer is depleted from the reservoir by evaporation from the back layer, resulting in a decrease in drug delivery rate. The volatile penetration enhancer is described as having a vapor pressure greater than about 10 mmHg at 25 ° C.

  US Pat. No. 5,149,538 discloses transdermal delivery of opioids using preferred penetration enhancers including saturated and unsaturated fatty alcohols, fatty alcohol esters or fatty acids (having 8 to 18 carbon atoms). . U.S. Pat.No. 5,650,165 describes an acrylic acid copolymer, a fatty acid ester comprising a higher fatty acid having 12 to 16 carbon atoms and a lower monohydric alcohol having 1 to 4 carbon atoms, and 8 to 10 carbon atoms. Disclosed is a transdermally absorbable preparation containing monoglycerides containing higher fatty acids. US Pat. No. 5,747,069 discloses a transdermally absorbable preparation containing a penetration enhancer comprising a monoglyceride and a fatty acid and a drug. The entire disclosure of the above referenced patent is hereby incorporated by reference.

  In view of the above, it is clear that there is a need for new and improved systems for transdermal drug delivery.

SUMMARY OF THE INVENTION The present invention provides a pharmaceutical formulation for topical application of transdermal delivery of a bioactive agent comprising Gilsonite oil and the bioactive agent. The bioactive substance is a component of gilsonite oil or a substance added to the oil. Also provided is a method of transdermal administration of the bioactive agent with enhanced penetration comprising the topical administration of a composition comprising a transdermally effective amount of Gilsonite oil for transdermal delivery of the bioactive agent. . As used herein, “gilsonite oil” refers to a type of oil derived from uinterite material and is available from the American Gilsonite Company, San Francisco, California. Gilsonite oil is available in various grades with various physical properties (eg, viscosity). In accordance with the teachings of this disclosure, a suitable gilsonite oil for a formulation containing the desired bioactive agent and other ingredients that provides an effective transdermal delivery system of the present invention can be selected. While various characteristics of gilsonite oil can be used as a mixture in the present invention, the disclosure herein provides for a single gilsonite oil in each formulation to teach and illustrate the present invention. Described for use.

  In one embodiment of the composition, the invention comprises a bioactive substance and gilsonite oil, wherein the bioactive substance is a component of the gilsonite oil or a substance added to the oil. Compositions for administration are provided. Preferably, the composition further comprises one or more pharmaceutically acceptable selected from the group consisting of excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, anti-irritants and additional penetration enhancers. Pharmaceutically acceptable carriers optionally containing additives such as conventional oils, gels, creams, ointments, lotions, adhesives, polymers, basets or sprays. The bioactive agent component is present in an effective amount for the intended use, preferably at least about 0.01% by weight, preferably from about 0.1% to about 50%, and the bioactive agent is a component of gilsonite oil The other part of the gilsonite oil is preferably present at least about 0.01% by weight, preferably from about 0.1% to about 50%. In some formulations, the gilsonite oil component can be present as a major proportion component (and possibly even as the only component other than the bioactive agent), and thus penetration enhancers and carriers or diluents And can play both roles.

  Gilsonite oil itself is useful as a therapeutic agent for the treatment of skin and nail disorders. Such compositions can be manufactured by those skilled in the art and administered topically, for example, as a lotion or ointment.

  In another composition embodiment, the present invention is selected from the group consisting of gilsonite oil and excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, anti-irritants and additional penetration enhancers. Including a pharmaceutically acceptable carrier optionally containing one or more pharmaceutically acceptable additives such as ordinary oils, gels, creams, ointments, lotions, adhesives, polymers, basates or sprays. A penetration promoting system is provided. The carrier component is present at least about 0.1% by weight, preferably from about 1% to about 80%, more preferably from about 2% to about 50%, and the gilsonite oil component is at least about 0.1% by weight, preferably from about 1% to It is present at about 80%, more preferably from about 2% to about 50%. This composition of gilsonite oil and a pharmaceutically acceptable carrier represents the base material of the present invention that can be formulated with the desired bioactive substance.

  In yet another composition embodiment, the present invention provides a composition for topical or transdermal administration with enhanced penetration comprising a gilsonite oil and a bioactive substance, wherein the bioactive substance is gilsonite oil. A component or substance added to the oil, selected from the group consisting of gilsonite oil and excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, anti-irritants and additional penetration enhancers. A pharmaceutically acceptable carrier (eg, conventional oils, gels, creams, ointments, lotions, adhesives, polymers, basets or sprays) optionally containing one or more pharmaceutically acceptable additives; A composition is provided that is formulated with a penetration enhancing system comprising: The gilsonite oil-bioactive agent component and the gilsonite oil-carrier component can each be formulated as described above, and then these two components are about 1: 100 to about 100: 1, preferably They can be mixed or formulated in a weight ratio of about 10:90 to about 90:10, more preferably about 20:80 to about 80:20.

  In one of the method embodiments, the present invention provides a method for promoting the penetration of a bioactive substance through the skin or nails of a human or other animal, comprising the use of Gilsonite oil as described herein. There is provided a method comprising applying a composition comprising a penetration enhancing system and a bioactive substance to the skin or nails of the animal. Similarly, the present invention comprises applying a composition as described herein comprising a penetration enhancer system containing gilsonite oil and a bioactive substance to the surface or cutting opening of a plant part. A method for promoting the penetration of bioactive substances into plant systems.

  In another method embodiment, the present invention provides transdermal delivery of a bioactive agent by administering to the skin or nail of an animal a composition comprising gilsonite oil and a bioactive agent as described herein. By applying a composition comprising gilsonite oil and a bioactive substance, as described herein, to a surface or cutting opening of a plant part. A method for delivering an active agent is provided. The delivery method of this aspect of the invention includes direct application of the composition, application from an applicator device, time release application from an applicator device, and other methods adapted in accordance with the disclosure herein. Including.

  In another method embodiment, the present invention comprises mixing the bioactive agent and gilsonite oil in a ratio effective to obtain a composition for a desired application as described herein. A method for producing a bioactive agent delivery composition comprising: If desired, additional penetration enhancing additives, or other pharmaceutically acceptable additives such as those mentioned above, can be mixed with the ingredients or compositions described herein.

  In another embodiment, the present invention provides a composition comprising gilsonite oil and a bioactive agent, adapted for placement on animal skin or nails or plant parts or for delivering the composition. A device comprising an applicator device (eg, patch, strip or container) containing is provided.

  Another aspect of the present invention provides an applicator device adapted for placement on the skin or nail or plant part of an animal, comprising the Gilsonite oil and bioactive agent disclosed herein. There is provided a method of manufacturing a device for administration of a bioactive agent comprising including a composition comprising the applicator device.

DETAILED DESCRIPTION In the present invention, various methods are used to effectively achieve transdermal delivery of a drug and / or promote drug penetration through body surfaces (especially the skin and fingernails and toenails). Gilsonite oil can be used. First, the following terms used in this specification have the following meanings.

  The term “topical administration” refers to the application of a medicinal substance to the external surface or mucosa of the skin (including the surface membranes of the nose, lungs and mouth) and the substance enters the underlying tissue through the external surface or mucous membrane of the skin. Means that. Topical administration includes application of the composition to intact skin or mucous membranes or to the skin or mucous membranes of broken, open or open wounds. Topical administration of a medicinal substance can result in a limited distribution of the substance to the skin and surrounding tissues, and when the substance is removed from the treatment area by blood flow, the systemic distribution of the substance Can bring In a preferred topical dosage form, the pharmaceutical substance is delivered by transdermal delivery.

  The term “transdermal delivery” refers to the diffusion of a substance across a skin barrier resulting from topical administration or other application of the composition. The stratum corneum acts as a barrier, and most pharmaceutical substances cannot penetrate intact skin. In contrast, the epidermis and dermis are permeable to a number of solutes, and therefore drug absorption occurs more readily from skin that is scraped or exfoliated due to the stratum corneum peeling off. Transdermal delivery includes injection or other delivery through any part of the skin or mucous membrane, and absorption or penetration through other parts. Absorption through intact skin can be facilitated by placing the active agent in a suitable pharmaceutically acceptable vehicle prior to application to the skin. Passive topical administration may consist of applying the active agent in combination with a softener or penetration enhancer directly to the treatment site. The term transdermal delivery as used herein is intended to include delivery by penetration through the surfaces of fingers and toes.

  The term “transmucosal delivery” refers to the diffusion of a substance across a mucosal barrier. The epithelium acts as a barrier and many medicinal substances cannot penetrate the intact mucosa. Absorption through the intact mucosa can be facilitated by placing the active agent in a vehicle prior to application to the mucosa. Passive topical administration may consist of applying the active substance in combination with a penetration enhancer directly to the treatment site.

  The terms “promoting”, “promoting penetration” or “promoting permeation” mean that the penetration of the skin into the drug is promoted so that the rate of penetration of the drug through the skin is increased. The enhanced permeability provided by the use of such enhancers can be observed, for example, by measuring the rate of drug diffusion through animal or human skin using a diffusion cell device. The diffusion cell is described in Merritt et al., Diffusion Apparatus for Skin Penetration, J. of Controlled Release, 1 (1984) pp. 161-162.

  The term “penetration enhancer” or “permeation enhancer”, alone or in combination, refers to a substance or mixture of substances that act to promote skin permeability to a drug.

  The term “drug”, “bioactive substance” or “pharmaceutical substance” refers to any chemical substance, compound or composition suitable for transdermal administration that produces the desired biological, pharmacological or nutritional effect. Means. The terms “drug”, “bioactive substance” or “pharmaceutical substance” are also intended to include mixtures of two or more bioactive substances.

  The term “matrix” means a composition uniformly or gradiently combined in a biocompatible pressure sensitive adhesive in which the promoter is uniformly dissolved or suspended and may contain other components. To do. A matrix system is usually a closed adhesive patch having an impermeable film backing layer and a release liner on the surface of the adhesive opposite the film backing layer that is removed prior to transdermal application. Thus, the matrix system is a unit dosage form of the drug composition in an adhesive carrier, for the maintenance of the drug composition in the adhesive in the drug introduction relationship with the promoter and skin, skin or nails Also contains other ingredients to be blended. Unless otherwise noted, adhesive patches having a non-occlusive backing layer are also considered within the scope of this definition. The term “reservoir”, “reservoir patch” or “reservoir system” is contained within an occlusive device having an impermeable back surface and an opposing surface appropriately positioned with an osmotic membrane and an adhesive for transdermal administration. Means a pharmaceutical composition in a fluid of controlled viscosity. Thus, a reservoir system is a unit dosage form of a drug composition in a controlled viscosity fluid carrier, and the maintenance of the drug composition in the carrier in a drug-introducing relationship with the promoter and skin or skin. It also contains other ingredients that are formulated into the occlusive device.

  The term “controlled viscosity fluid” means a carrier in which the pharmaceutical formulation is contained in a single or phase separated fluid state. The fluid itself can act as a solvent, but it is also possible to add a solvent or a co-solvent. Such fluids can be based on water or organics and can contain a suitably gelled or concentrated liquid or solvent mixture. In other words, such fluids include, but are not limited to, solutions, suspensions, emulsions, gels, ointments, creams, basets, or any other similar that allows for outward diffusion of permeants and enhancers. In some cases, as well as optionally, solvents or other additives may be included.

  An “effective” amount of drug or penetrant means an amount of bioactive agent sufficient to produce the desired local or systemic effect. As used herein, an “effective” amount of penetration enhancer means an amount chosen to provide the desired enhancement in transdermal permeability and the corresponding desired penetration depth, administration rate and drug amount. By “therapeutically effective” amount or rate is meant the amount or rate of drug required to achieve the desired therapeutic effect.

  The term “drug delivery system”, “drug-promoting composition” or any similar term refers to such “pharmaceutically acceptable carrier” or “pharmaceutically acceptable vehicle”, penetration It means a formulated composition containing a drug to be delivered transdermally with an accelerator, excipient or any other additive.

  The term “pharmaceutically acceptable carrier or vehicle” provides for the proper delivery of an effective amount of a biologically active agent as defined herein without interfering with the effectiveness of the biological activity of the biologically active agent. By any formulation or carrier medium that is sufficiently nontoxic to the host or patient. Those skilled in the art will recognize the compositions of the present invention in a suitable manner and accepted practices (eg, Remington: The Science and Practice of Pharmacy, edited by Gennaro, Mack Publishing Co., Easton, Pa., 19th ed., 1995). It can be formulated according to what is disclosed.

  The term “pharmaceutically acceptable additive” is known or used in the field of pharmaceutical preparations and is sufficiently non-toxic to the host or patient without unduly impeding the effectiveness of the biological activity of the bioactive substance. Means preservatives, antioxidants, fragrances, emulsifiers, dyes and excipients.

  The term “excipient” is generally known to mean carriers, diluents and / or vehicles used in formulating drug compositions effective for the desired application.

Manufacture and formulation The specific gilsonite oils referred to herein, used in the examples described herein to illustrate the practice of the present invention, are gilsonite oils 1, 2, A, Described as B, C, X, Y and Q, materials available from American Gilsonite Corporation, San Francisco, California. Each oil has unique physical properties such as color and viscosity. Gilsonite oil is produced by the American Gilsonite Corporation by an exclusive method that produces a variety of individual gilsonite oil products having a variety of physical properties. Available gilsonite oils can be selected for use in the present invention by one of ordinary skill in the pharmaceutical arts in accordance with the teachings and disclosure herein. In general, gilsonite oils desirable for use in the present invention typically have a viscosity in the range of about 5 to about 5000 cps (25 ° C.), preferably about 5 to about 1000 cps, more preferably about 5 to about 100 cps. The specific gravity of gilsonite oil is usually less than 1.0 and most ranges from about 0.8 to about 0.95. Of course, the properties of the desired final pharmaceutical formulation for the desired use and function will determine which oil is selected for each formulation. Gilsonite oils selected for desired penetration and transport properties can be formulated into lotions, creams, gels or adhesive compositions, or they are very low for application to the skin or nails To obtain a composition of viscosity, it can be formulated into a liquid or spray composition containing a solvent or penetration enhancer.

  As mentioned above, Gilsonite oil has a range of physical properties that allow its isolation or purification. Such properties are determined by the composition of the oil, in particular the individual components and the respective composition rates. These various oils typically contain one or more of the following individual components or compounds: 6,10-dimethyl-2-undecanone, 2,6-dimethyl-2,5-heptadien-4-one, 2 -Butyl-1,1,3-trimethylcyclohexane, 2,6,10,14-tetramethylhexadecane, 1,6,7,8,9,9a-hexahydro-4-oxo4H-pyrido- [1,2- a] pyrimidine-3-carboxylic acid ethyl ester, 2-hydroxy-4,6-dimethylpyrimidine, transpinane, dihydroedulan, 1-pentyl-2-propylcyclopentane, 2,3,4-trimethyl 2 -Cyclopenten-1-one and N-formyl-2-phenylpiperidine.

  Preferably and conveniently, the Gilsonite oil composition of the present invention applied to the skin or nails uses a physiologically acceptable carrier and / or a bioactive substance (including both Gilsonite oil and the drug). To be formulated. However, if the drug is not a component of the oil, it is possible to apply gilsonite oil itself as a pretreatment agent before application of the drug, which is then formulated for transport through the skin or nails. Absorbs absorbed drugs. In such cases, a second application of gilsonite oil may be desired over the drug application for effective drug delivery. In such a method, it is possible to omit the pretreatment, first applying the drug, then applying gilsonite oil or oil formulation to the skin or nails. However, such in situ formulation or multi-step application is not preferred because it is inconvenient and complicated for the patient. It is preferred to formulate the composition of the present invention for one-step application. If the formulation includes a carrier, the carrier is described in a conventional topical formulation base (eg, Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa .: Mack Publishing Co., 1995)). Any of the above). Oils, lotions, solutions (solutions), creams, gels, ointments, polymers, adhesives, basates, aerosols, suppositories and spray formulations are representative examples of topical formulations of the present invention. Specific examples of suitable topical carriers for use in the present invention include water, alcohols and other non-toxic organic solvents, glycerin, mineral oil, silicone, petrolatum, lanolin, fatty acids, vegetable oils, parabens, waxes and the like. Particularly preferred formulations in the present invention are ointments, lotions, creams, adhesives and gels.

  Furthermore, it is contemplated that gilsonite oil functions as a carrier. An example of such a formulation is a composition comprising gilsonite oil and a bioactive substance, wherein the substance is a component of the oil or a substance added to the oil. The composition is preferably formulated for topical or transdermal application, although other routes of administration are possible, for example oral or intravenous routes. In formulations using gilsonite oil as a carrier, other pharmaceutically acceptable additives as described herein may optionally be included.

  Other additives for topical formulations are well known in the art and can be added to topical compositions as long as they are pharmaceutically acceptable and do not impair epithelial cells or their function. Furthermore, they should not adversely affect the epithelial penetration efficiency of gilsonite oil and should not compromise the stability of the composition. For example, inert fillers, anti-irritants, tackifiers, excipients, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, softeners, colorings known in the art Agents, preservatives, buffers, other penetration enhancers and other conventional components of transdermal delivery devices.

  Other penetration enhancing compounds are well known in the art, such as those described in US Pat. Nos. 4,424,210 and 4,316,893, the disclosures of which are incorporated herein by reference. Can be mentioned. Preferred penetration enhancing compounds include 1-dodecylazacycloheptan-2-one (AZONE.RTM.) (Stoughton, Arch. Dermatol., 1982, 118), DMSO, propylene glycol, oleyl alcohol and methylpyrrolidine. These additional penetration enhancing compounds can optionally be used in the compositions of the present invention in the usual range of from about 0.1 to about 10%, preferably from about 1.0% to about 5.0% by weight of the topical composition. .

  The formulations of the present invention are topically administered to the body and are adapted for use in specific treatments. For example, to treat pain, a formulation comprising an analgesic, gilsonite oil and a suitable carrier is preferred. In another example, a bioactive agent (eg, an antifungal or bioactive component of the oil), gilsonite, to treat fingernails or toenails diseases (eg, fungal infection and embrittlement) A formulation is prepared for transporting oil and a suitable carrier through the nail or through the skin under the nail. Furthermore, it is possible to produce a formulation for treating certain problems associated with the skin of an individual (eg, dryness or peeling of the skin).

  A number of nail disorders can be treated with the formulations of the present invention. Such disorders include nail infections, nail disorders associated with dermatological conditions, acquired nail disorders, peri-nail and sub-nail tumors, conditions requiring surgical treatment for nails, and generalized medical conditions Nail disorders associated with, but are not limited to. Infections that can affect the nails include onychomycosis (due to dermatophytes, candida or other fungi), peritonitis, certain bacterial infections (eg, due to pseudomononas aeruginosa or other bacteria), viral infections (For example, peri-nail or subnail warts) and HIV infection. Nail disorders associated with dermatological conditions include psoriasis, alopecia areata / roughened nails, eczema, lichen planus, contact dermatitis, 12-nail dystrophies and crimson erythema. Periungual and subnail tumors include superficial basal cell carcinoma and Bowen's disease (ie superficial squamous cell carcinoma). Nail surgical procedures include nail removal and nail biopsy. Nail disorders are often associated with a variety of systemic medical conditions including, but not limited to, connective tissue disease, kidney disease and chemotherapy.

  Nail disorders include embrittlement, embrittlement, splitting, bump formation, scarring, nail thickening (ie nail wing and nail thickening), loss of nail gloss, abnormal nail growth and nail discoloration It is. In order to treat such diseases, it is possible to use a gilsonite oil formulation in which the bioactive substance is a component of gilsonite oil. For example, it is possible to increase the strength of nails by at least 10, 20, 30, 40 or even 50% in the case of patients with embrittled or weakened nails, and in patients with thickened nails A decrease in nail thickness of at least 10, 20, 30, 40 or 50% can be observed. If loss of nail gloss is a problem, the gloss can be increased by at least 10, 20, 30 or 50%. It is possible to increase the nail growth rate in patients with abnormally slow nail growth by at least 10, 20, 30, 40 or 50%.

  As with nail disorders, skin problems are typically treated with a gilsonite oil formulation where the bioactive substance is a component of gilsonite oil. For example, application of the preparation can significantly reduce skin dryness, and can reduce or eliminate nail peeling.

  Various biologically active substances can be used to treat the nail disorders. Onychomycosis is typically treated with antifungal agents, urea or keratolytic agents. Antifungal agents include allylamine (eg, naftifine and terbinafine), azole (eg, bifonazole), clotrimazole, econazole, fluconazole, itraconazole. ), Ketoconazole, miconazole, oxiconazole, sulconazole, thioconazole and voriconazole), benzoic acid, benzylamine (eg, butenafine), cyclo Cicloprox olamine, polyenes (eg, nystatin), thiocarbamates (eg, tolciclate and tolnaftate) and undeci Include phosphate, salicylic acid is an example of a keratolytic agent.

  Nail psoriasis can be treated with corticosteroids, immunosuppressants, vitamin D derivatives, retinoids, 5-fluorouracil (ie, 5-FU), topical psoralen combined with UVA light, keratolytic agents, or urea. Corticosteroids include clobetasol proprionate, halobetasol proprionate, betamethasone, diproprionate, diflorasone diacetate, amcinonide, mometasone Mometasone fuorate, triamcinolone acetonide, fluticasone propionate, flucinolone acetonide, hydrocortisone valerate, flulandrenolide, flurandrenolide Hydrocortisone butyrate, aclometasone dipropionate desonide, betamethasone valerate, hydrocortisone acetate (hydrocortisone aceate) tate) and hydrocortisone. Cyclosporine, pimecrolimus and tacrolimus are examples of immunosuppressants. Vitamin D derivatives include calcipotriol. Specific examples of retinoids include tretinoin and tazarotene. The keratolytic agents include salicylic acid and α-hydroxy acid.

  Peritonitis and other infections are treated with antifungal agents, preferably azole antifungal agents, antibacterial agents, antiviral agents or sodium sulfacetamide, depending on the nature of the infection. Potential therapeutic agents for periungual and subnail warts include imiquimod, keratolytic agents, bleomycin or 5-FU. Substances used to treat alopecia areata and lichen planus include corticosteroids, immunosuppressants (eg, cyclosporine, pimecrolimus and tacrilumus), retinoids (eg, tretinoin) (Tretinoin) and tazarotene) and imiquimod. Inflammatory conditions such as eczema and contact dermatitis are usually treated with corticosteroids or topical immunosuppressants. Surgical procedures on the nails typically require the use of anesthetic agents such as xylocaine, lidocaine and tetracaine. Periungual and subnail tumors can be treated with imiquimod or 5-FU. Bacterial infections, yellow nail syndrome and nail ulcer disease are treated with sodium sulfacetamide, corticosteroids and TIMS, respectively.

  Ointments are semi-solid preparations and are typically based on petrolatum or other petroleum derivatives. As will be appreciated by those skilled in the art, the specific ointment base used is one that results in optimal delivery of the bioactive agent chosen for a given formulation and preferably other desired properties such as flexibility And so on. As with other carriers or vehicles, the ointment base should be inert, stable, nonirritating and non-sensitizing. As described in Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, Pa .: Mack Publishing Co., 1995) p. 1399-1404, ointment bases can be divided into four classes: : Oily base, emulsifying base, emulsion base and water-soluble base. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifying ointment bases are also known as absorbent ointment bases and contain little or no water, including, for example, hydroxystearate sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are made from polyethylene glycols of various molecular weights, again referring to Remington: The Science and Practice of Pharmacy (supra).

  Lotions are formulations that are applied to the skin surface without friction, and are typically liquid or semi-liquid formulations in which solid particles containing the bioactive substance are present in a water or alcohol base. Lotions are usually solid suspensions and preferably for this purpose comprise oil-in-water liquid oil emulsions. In general, it is necessary to break up the insoluble material in the lotion. Lotions are typically suspending agents to provide better dispersion and compounds useful for localizing and maintaining the active agent in contact with the skin (eg, methylcellulose, sodium carboxymethylcellulose). Etc.).

  Creams containing bioactive substances for delivery by the methods of the present invention are viscous liquids or semi-solid emulsions (either oil-in-water or water-in-oil). The cream base is washable with water and contains an oil phase, an emulsifier and an aqueous phase. The oil phase may also be referred to as the “inner” phase and is generally composed of petrolatum and a fatty alcohol, such as cetyl or stearyl alcohol, the aqueous phase usually being greater in volume than the oil phase (not necessarily) However, it generally contains a humectant. As explained in Remington: The Science and Practice of Pharmacy (supra), emulsifiers in creams are generally nonionic, anionic, cationic or amphoteric surfactants.

  A gel formulation can also be used in the present invention. As will be appreciated by those skilled in the field of topical medicine, gels are semi-solid suspension systems. Single phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but preferably also contain alcohol and optionally oil.

  Useful formulations of the present invention also include sprays. Sprays generally contain bioactive substances in aqueous and / or alcoholic solutions that can be sprayed onto the skin for delivery. Such sprays include those formulated to provide concentration of the bioactive agent solution at the site of administration after delivery. For example, the spray solution may consist primarily of alcohol or other similar volatile liquid in which the drug or bioactive substance can dissolve. Upon delivery to the skin, the carrier evaporates, leaving a concentrated bioactive substance at the site of administration.

  The pharmaceutical compositions of the present invention are also useful in devices such as patches, strips and containers adapted for topical or transdermal administration. Transdermal drug delivery (TDD) patches are designed to deliver a therapeutically effective amount of drug through the patient's skin. Transdermal patches typically include a liquid, gel, solid matrix or pressure sensitive adhesive carrier containing the drug. The first TDD system was a reservoir-type device that used a membrane to control the drug release rate. Currently, drugs are more commonly dispersed or dissolved in a pressure sensitive adhesive (PSA) matrix. Patch formulations and preparations are well known in the art. For example, "Dermatological and Transdermal Formulations" (Drugs and the Pharmaceutical Sciences, Vol 119) Kenneth A. Walters (ed), Marcel Dekker and "Transdermal Drug Delivery" (Drugs & the Pharmaceutical Sciences) Richard H. Guy (ed), Jonathan See Hadgraft (ed.) 2nd Rev & ex edition Marcel Dekker and "Mechanisms of Transdermal Drug Delivery" (Drugs & the Pharmaceutical Sciences, Vol 83), Russell O. Potts and Richard H. Guy (1997).

  The pharmaceutical formulation of the present invention can be provided, for example, as a patch containing a drug composition and a penetration enhancer in a laminate structure that serves as a drug delivery device applied to the skin. In such a structure, the pharmaceutical composition is contained within a delivery means, or “reservoir”, which is located below the top backing layer. The laminated structure can contain a single reservoir, or it can contain multiple reservoirs. Patches, ie, occlusive adhesive devices for transdermal delivery of drugs, are also taught in US Pat. Nos. 4,849,224, 4,983,395, 5,152,997 and 5,302,395. Such devices are generally patches for adhering to the skin surface and can be in matrix or reservoir form. Such patches may contain an occlusive backing layer.

  A delivery device suitable for use in the present invention can be formed using conventional techniques known in the art, for example, molding an adhesive, bioactive agent and carrier / vehicle fluid mixture onto a backing layer and then a release liner. Can be manufactured by laminating. Similarly, it is possible to mold the adhesive mixture onto a release liner and then laminate the backing layer. Alternatively, filling can be done by making the reservoir in the absence of a pharmaceutical formulation or excipient and then “dipping” into the drug / vehicle mixture.

  The backing layer in the laminate of the patch, which functions as the upper surface of the delivery device, functions as the main structural element of the laminated structure, giving the device the flexibility or rigidity required for individual applications. In order to prevent loss of components from the top surface of the device and prevent dehydration of the composition in the reservoir, the material selected as the backing material is such that it is substantially impermeable to the pharmaceutical formulation. Should be selected. The backing layer can be occlusive or non-occlusive, depending on whether it is desired that the skin be hydrated during drug delivery. Preferably, the backing layer is preferably composed of a flexible elastic sheet or film. Specific examples of polymers suitable for the backing layer include polyethylene, polypropylene, polyester, and the like.

  During storage and prior to use, the patch includes a release liner. Immediately prior to use, this layer is removed from the device to expose the skin contact surface of the device, which can be the reservoir itself or a separate contact adhesive layer, so that the system can be applied to the skin. The release liner is preferably composed of materials that are substantially impermeable to drugs and other ingredients in the formulation, such as polyethylene and silicone. These liners are well known in the art and are commercially available, for example from 3M Drug Delivery Systems (Minnesota).

  Adhesives useful in patches are well known in the art (eg, S. Venkatraman and R. Gale, “Skin Adhesives and Skin Adhesion, Part I: Transdermal Drug Delivery Systems,” Biomaterials 19, 1119-1136 ( 1998) and G. Auchter et al., "Acrylic Adhesives," in Handbook of Pressure Sensitive Adhesive Technology, edited by D. Satas, (Satas & Associates, Warwick, RI, 3d ed., 1999), pp. 444-514. Wanna) The pressure sensitive adhesive is preferably non-irritating, soft and tacky, has some ability to wet or dissolve or complex the additive and is stable (ie during storage or treatment time) Do not decompose in) and leave no residue on removal. The most common adhesives used in TDD systems are acrylic acid polymers and copolymers, silicones and polyisobutylene. The acrylic acid can be modified with appropriate additives to provide a wide range of performance with respect to various drugs, excipients and individual product requirements. Some specific examples of pressure sensitive adhesives include, but are not limited to, Duro-Tak® 87-2196, Duro-Tak® 87-2097.

  A broad class of bioactive substances that can be used with gilsonite oil or a mixture of gilsonite oil when the bioactive substance is not a component of gilsonite oil, typically delivered via body surfaces and membranes (including skin and nail surfaces) The drugs within are included. In general, this includes therapeutics in all major areas, including but not limited to: ACE inhibitors, pituitary hormones, adrenergic neuron blockers, corticosteroids, Inhibitors of corticosteroid biosynthesis, α-adrenergic agonists, α-adrenergic antagonists, selective α-2-adrenergic agonists, analgesics, antipyretics and anti-inflammatory drugs, androgens, local and general anesthesia Drugs, antiepileptic drugs, antiandrogens, antiarrhythmic drugs, antiasthma drugs, anticancer drugs, anticholinergic drugs, anticholinesterase drugs, anticoagulant drugs, antidiabetic drugs, antidiarrheals, antidiuretics, antiemetics, intestinal motility promotion Drugs, antiepileptic drugs, antiestrogens, antifungals, antihypertensives, antimicrobials, antimigraine, antimuscarinic, antitumor Anthelmintic, antiparkinson, antiplatelet, antiprogestin, antithyroid, antitussive, antiviral, atypical antidepressant, azaspirodecanedione, barbiturate, benzodiazepine, benzothiazide, beta-adrenergic Sex agonists, β-adrenergic antagonists, selective β-1-adrenergic antagonists, selective β-2-adrenergic agonists, bile salts, substances that affect volume and composition of body fluids, butyrophenone, lime Substances that affect aging, calcium channel blockers, cardiovascular drugs, catecholamines and sympathomimetics, cholinergic agonists, cholinesterase reactivating substances, dermatological drugs, diphenylbutylpiperidine, diuretics, ergot alkaloids, estrogens, Ganglion blocker, ganglion sting Drugs, hydantoins, substances for gastric acid control and treatment of peptic ulcers, hematopoietics, histamine, histamine antagonists, 5-hydroxytryptamine antagonists, hyperlipoproteinemia therapeutics, hypnotics and sedatives, immunosuppressants Laxatives, methylxanthines, monoamine oxidase inhibitors, neuromuscular blockers, organic nitrates, opioid analgesics and antagonists, pancreatic enzymes, phenothiazines, progestins, prostaglandins, psychiatric disorders, retinoids, sodium channel blockers, Drugs for convulsions and acute muscle spasms, succinimide, thioxanthine, thrombolytic drugs, thyroid drugs, tricyclic antidepressants, inhibitors of vascular transport of organic compounds, drugs affecting uterine motility, vasodilators, herbal extracts , Vitamins etc.

  Exemplary drugs include, but are not limited to, for example: bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine ), Nimodipine, nitredipine, verapamil, dobutamine, isoproterenol, carterolol, labetalol, levobunolol, nadolol , Penbutolol, pindolol, propranolol, sotalol, timolol, acebutolol, atenolol, betaxolol, esmolol, metoprolol Metoprolol, albuterol, bitolterol, isoetharine, metaproterenol, pirbuterol, ritodrine, terbutaline, alclometasone, osterolone ), Amcinonide, beclomethasone dipropionate, betamethasone, clobetasol, clocortolone, cortisol, cortisone, corticosterone, corticosterone desonide), desoximetasone, 11-desoxycorticosterone, 11-desoxycortisol, dexamethasone, difuro Diflorasone, fludrocortisone, flunisolide, fluocinolone, fluocinonide, fluorometholone, flurandrenolide, halcinonide, cortisone hydro , Medrisone, 6α-methylprednisolone (6.alpha.-methylprednisolone), mometasone, paramethasone, prednisolone, prednisone, tetrahydrocortisol, tetrahydrocortisol, triamcinolone, triaminolone Benoxinate, benzocaine, bupivacaine, chloroprocaine, cocaine, dibucaine, dyclonine ), Etidocaine, lidocaine, mepivacaine, pramoxine, prilocaine, procaine, proparacaine, tetracaine, alfentanil, alfentanil, alfentanil (Choroform), clonidine, cyclopropane, desflurane, diethyl ether, droperidol, enflurane, etomidate, fentanyl, halothane, isoflurane, Ketamine hydrochloride, meperidine, methohexital, methoxyflurane, morphine, propofol, sevoflurane, sufuflurane Sutantanil, thiamylal, thiopental, acetaminophen, allopurinol, apazone, aspirin, auranofin, aurothioglucose , Colchicine, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, gold sodium thiomalate, ibuprofen , Indomethacin, insulin, ketoprofen, meclofenamate, mefenamic acid, meselamine, methyl salicylate, nabumetone, naproxe (Naproxen), nicotine, oxyphenbutazone, phenacetin, phenylbutazone, piroxicam, salicylamide, salicylate, salicylic acid, salsalate ), Sulfasalazine, sulindac, tolmetin, acetophenazine, chlorpromazine, fluphenazine, fluphenazine, mesoridazine, perphenazine, thioridazine, thioridazine Trifluorperazine, triflupromazine, disopyramide, encainide, flecainide, indecainide, mexi Chin (mexiletine), moricizine, phenytoin, procainamide, propafenone, quinidine, tocainide, cisapride, domperidone, dronabinol (dronabin) ), Haloperidol, metoclopramide, nabilone, prochlorperazine, promethazine, thiethylperazine, trimethobenzamide, buprenorphine, buprenorphine butorphanol, codeine, dezocine, diphenoxylate, drocode, hydrocodone, hydromorphone, levalorfa (Levallorphan), levorphanol, loperamide, meptazinol, methadone, nalbuphine, nalmefene, nororphine, naloxone, naltrexone , Oxybutynin, oxycodone, oxymorphone, pentazocine, propoxyphene, isosorbide dinitrate, nitroglycerin, theophylline, phenylephrine, ephedrine (Ephidrine), pilocarpine, furosemide, tetracycline, chlorpheniramine, ketorolac, bromocriptine, guana Lens (guanabenz), prazosin (prazosin), doxazosin (doxazosin) and flufenamic acid (flufenamic acid).

  Other representative drugs include: benzodiazepines such as aiprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxeppam demoxepam), diazepam (diazepam), flumazenil (flumazenil), flurazepam (flurazepam), halazepam, lorazepam, lorazepam, midazolam, nitrazepam, nitrazepam, nordazepam, azepam prazepam), cruazepam, temazepam, triazolam, etc .; antimuscarinic agents such as anisotropine, atropine, clidinium, cyclopentole Cyclopentolate, dicyclomine, flavoxate, glycopyrrolate, hexocyclium, homatropine, ipratropium, isopropamide, mepenzometh, linen ), Oxyphencyclimine, pirenzepine, propantheline, scopolamine, telenzepine, tridihexethyl, tropicamide, etc .; estrogen such as chlorotrianisene, Ethylstilbestrol, methyl estradiol, estrone, estrone sodium sulfate, estron Estropipate, mestranol, quinestrol, sodium equilin sulfate, 17.beta.-estradiol (or estradiol), semi-synthetic estrogen derivatives, eg natural Esters of estrogen such as estradiol-17.β-enanthate, estradiol-17.β-valerate, estradiol-3-benzoate, estradiol-17.β-undecenoate, estradiol 16,17-hemisuccinate or estradiol-17.β -Cypionates, and 17-alkylated estrogens such as ethinyl estradiol, ethinyl estradiol-3-isopropyl sulfonate; androgens such as danazol, fluoxymesterone, meta Nandostenolone (methandrostenolone), methyltestosterone (methyltestosterone), nandrolone decanoate, nandrolone phenpropionate, oxandrolone, oxymetholone, stanozolol, test lactone ), Testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate; progestins such as ethinodiol diacetate, gestodene, hydroxyprogesterone caproate caproate, levonorgestrel, medroxy acetate Progesterone (medroxyprogesterone acetate), megestrol acetate, norethindrone, acetic acid Ruechindoron (norethindrone acetate), norethynodrel (norethynodrel), norgestrel (norgestrel), progesterone (Progesterone); immunosuppressants, e.g., cyclosporin (cyclosporins), etc..

  The amount of drug present in the formulation and the amount of drug required to obtain a therapeutic effect will depend on a number of factors, such as the minimum required dosage of the individual drug, usually the condition to be treated It will be determined by the physician in view of the relevant circumstances including route of administration, actual compound to be administered, individual patient age, weight and response, severity of patient symptoms, and the like.

  Appropriate dosage levels of bioactive substances without the use of penetration enhancers of the present invention are known to those skilled in the art. These normal dose levels correspond to the upper limit of the dose level for compositions containing bioactive substances and normal penetration enhancers. However, since the delivery of the active substance is facilitated by the gilsonite oil extract, the desired dosage level can be achieved with formulations containing significantly lower drug concentrations than the normal formulation. In general, the active agent is present in the composition in an amount of from about 0.0001% to about 60%, more preferably from about 0.001% to about 20% by weight of the total composition, depending on the particular material used. In general, however, the amount will range from about 0.01 to about 25% by weight of the total composition, with a level of about 0.05 to about 10% being preferred.

  The topical treatment regime of the practice of the present invention involves applying the composition directly to the skin or mucosa, ie the site of application, one to several times daily.

  The formulations of the present invention may be used to treat diseases and conditions, or symptoms associated with such diseases and conditions such as pain, psoriasis, dry skin, rosacea, irritation, sunburn, fungal infection, bacterial infection, baldness, hormonal dysfunction, etc. Can be used to treat, improve or prevent. The present invention can also be used in contraceptive formulations.

  The primary function of the epithelium, including the stratum corneum of the epidermis and keratinized mucosa, is to prevent excessive loss of fluid. When epithelial barrier function is impaired or disturbed, it stimulates various metabolic changes in the epidermis and mucous membranes, resulting in the repair of barrier defects. The barrier is beneficial in protecting against damage from UV radiation, dryness, chemical trauma, frictional trauma and blunt trauma, but it also transdermally and transmucosally penetrates locally administered drugs that are potentially beneficial to the host. Disturb. If bioactive substances are unable to penetrate the epithelium, their effective use to treat disease states and disorders is significantly limited not only in the skin and mucous membranes but also in the whole body. The composition of the present invention facilitates the delivery of both water-soluble and fat-soluble substances.

  As discussed above, various pharmaceutical formulations have been developed that enable transdermal treatment, but their successes vary. It is known to those skilled in the art that, among other things, there is a size dependence in the rate at which molecules are transported across the epithelial barrier. Typically, larger molecules have a lower flux across the barrier than small molecules. Examples 3-5 below show that Gilsonite oil is an effective penetration enhancer for small molecules, moderate molecules and larger molecules. Caffeine, hydrocortisone and a series of PEG molecules (molecular weights 502-766) were selected as small, medium and large molecule model compounds, respectively. The results obtained with a series of PEG molecules show a decrease in penetration with increasing molecular weight or size in the presence and absence of gilsonite oil. Pretreatment with gilsonite oil resulted in a substantial increase in flux for all PEG molecule studies.

  A pharmaceutical composition comprising gilsonite oil is included in and contained in the gilsonite oil composition as a pre-treatment before application of the gilsonite oil composition or as a post-treatment after application of the gilsonite oil composition Allows enhanced penetration compared to treatment with a drug combined with a prior art pretreatment agent (eg DMSO) as part of the drug or with the drug alone. Pharmaceutical formulations comprising gilsonite oil and a bioactive substance allow enhanced penetration compared to drugs without gilsonite oil or drugs including prior art penetration enhancers (eg, DMSO). The penetration enhancement of Gilsonite oil formulations is effective for such bioactive substances, regardless of whether the bioactive substance is a small molecule, a medium molecule or a large molecule.

  Initial screening of gilsonite preparations is performed using the normal Transepidermal Water Loss (TEWL) test using mice. For example, each oil sample can be topically applied to mice twice a day for 4 days. For samples that are liquid at room temperature, about 40 to about 80 μL of the oil sample is applied to the skin surface. For samples that are solid at room temperature, about 40 to about 60 mg of the oil is applied to the skin surface. TEWL and skin hydration are measured using techniques well known in the art using a Meeco device (Warrington, PA) and Corneometer (model CM-820, Courage & Khazak, Germany).

  Subsequent evaluation of the gilsonite oil formulation is done through skin penetration studies. Skin penetration studies can be performed using a flow-through diffusion cell (Laboratory Glass Apparatus, Berkeley, CA). The diffusion cell is maintained at a constant temperature using a circulating water bath. The skin is placed on the diffusion cell with the epidermis side facing the receiving chamber (receiver chamber). A peristaltic pump (Ismatec, Glattbrug-Zurich, Switzerland) is used to pump isotonic solution through the receiving compartment at 3-4 mL / hr. When pre-treating the external skin surface, the residual pre-treatment solution is removed and the skin surface is washed.

  A test solution containing an appropriate amount of radiolabeled test compound can be applied to the skin surface, and then the upper donor cell is sealed with parafilm. In a positive control experiment, the skin can be pretreated with dimethyl sulfoxide (DMSO) for 2 hours. The receiving fluid is agitated and samples are collected using the Retriever IV fraction collector (ISCO, Lincoln, NE) for approximately 12 hours at the indicated time intervals. Each fraction is mixed with Ready Safe® and analyzed on a Beckman LS 5000TA liquid scintillation counter. The flux through the skin is calculated from the slope of the linear part of the time versus osmotic drug accumulation curve.

  While the invention has been described in terms of its preferred embodiments, various changes and modifications will be apparent to those skilled in the art and the invention is intended to include such changes and modifications within the scope of the appended claims. Will be understood. The following non-limiting examples are set forth in order to further illustrate the invention.

In the examples below, the following abbreviations have the following significance. If an abbreviation is not defined, it has its generally accepted meaning.
cps = centipoise
EtOH = ethanol
h = time
HPLC = high performance liquid chromatography
M = molarity
mg = milligrams
min. = minutes
mL = milliliter
mm = millimeter
mM = millimolar concentration
mmol = mmol
N = normal
NS = normal saline
psi = pound per square inch
PEG = polyethylene glycol μm = micrometer μM = micromolar concentration μL = microliter% mol = mol percent
TEWL = Transepidermal water loss

  In the following examples and procedures, the usual compounds and reagents used in the procedures are commercially available from well known sources. Gilsonite oil identified and used in the examples was obtained from the American Gilsonite Company, San Francisco, California.

[Example 1]
Measuring the Effect of Gilsonite Oil on Transepidermal Water Loss (TEWL) and Skin Hydration Levels One of the primary functions of the skin is to retain water in the body. Thus, transepidermal water loss (TEWL) and skin hydration values are useful tools for assessing barrier function. In the experiments described herein, skin hydration and TEWL were measured in hairless mice after repeated application of the test oil.

Four mice were tested for each oil sample. The sample was administered topically to the mice twice daily for 4 days. For samples that were liquid at room temperature, 60 μL of the oil was applied to the skin surface. For samples that were solid at room temperature, about 60 mg of the oil was applied to the skin surface. TEWL was measured with a Meeco device (Warrington, PA) and skin hydration was measured with a Corneometer (model CM-820, Courage & Khazak, Germany). The results show a consistent decrease in hydration (Table 1) and an increase in TEWL (Table 2) with repeated oil treatment for all oils examined. When the last day measurements are compared to the pretreatment values obtained on day 0, the decrease in hydration and the increase in TEWL are statistically significant (T test, P> 0.95).

  These results show that all topically applied oils tested resulted in an increase in TEWL and a decrease in skin hydration consistent with promoting water transport through the treated skin.

[Example 2]
Effect of Gilsonite oil on PEG600 skin penetration Porcine abdominal skin was obtained from a nearby slaughterhouse. Immediately after obtaining the skin, the hair was cut and the skin was sectioned to a thickness of 500 μm with a dermatome. Skin slices sectioned with a dermatome were sandwiched between tissue papers soaked in normal saline (NS) and stored at -70 ° C. until use.

Skin penetration studies were performed using a flow-through diffusion cell (Laboratory Glass Apparatus, Berkeley, CA) with a diffusion area of 1 cm ² and a receiving volume of 3.6 mL. The diffusion cell was maintained at a constant temperature of 37 ° C. using a circulating water bath.

Oil samples for diffusion measurements were prepared by mixing an equal volume of the oil with ethanol (EtOH). After equilibration, the supernatant was used for skin pretreatment. The skin was placed on the diffusion cell with the epidermis side facing the receiving chamber (receiver chamber). A peristaltic pump (Ismatec, Glattbrug-Zurich, Switzerland) was used to deliver isotonic solution (pH 7.4, phosphate buffered saline-PBS) through the receiving compartment at 3-4 mL / hr. The external skin surface was pretreated with 500 μL of the oil / EtOH solution or a control solution of H ₂ O / EtOH (1: 1 volume ratio) for 24 hours. At the end of 24 hours, the residual solution was removed and the skin surface was washed twice with 200 μL EtOH and once with 200 μL NS.

  After skin pretreatment and washing, the outlet of each diffusion cell was connected to its own inlet and the receiving compartment was closed. A solution of 0.25M PEG600 in NS (500 μL) was applied to the skin surface and the upper feeding cell was sealed with parafilm. PEG 600 is a mixture of polyethylene glycol oligomers. The receiving fluid was stirred with a small Teflon coated magnet at 700 rpm. At the end of 12 hours, all receiving fluid was emptied and collected in a glass tube. In a positive control experiment, the skin was pretreated with dimethyl sulfoxide (DMSO) for 2 hours.

  Separation and quantification of individual oligomers within the PEG600 sample was performed using high performance liquid chromatography (HPLC). The HPLC system was a 717 plus autosampler (Waters) and Model 510 pump (Waters Co., Milford, MA) on a C8 reverse phase column (Microsorb-MVc, 5 μm, 4.6 × 250 mm, Ranin Instrument, Woburn, MA, USA). , USA). A mobile phase of methanol-water (volume ratio 40:60) was moved at a flow rate of 1 mL / min. A Series 200 refractive index detector (Perkin Elmer Co., Norwalk, CT, USA) was used to detect PEG oligomers eluted from the column. The refractive index detector was maintained at a constant temperature of 35 ° C.

At the end of 12 hours, the entire receiving fluid was emptied and collected in a 15 mL Pyrex tube for subsequent lyophilization and extraction. After lyophilization, the PEG was extracted by adding 10 mL of chloroform to the sample and then vortexing at high speed for 1 minute. The solvent was then contacted with the sample for at least 30 minutes. The sample was centrifuged at 3000 rpm for 10 minutes and the supernatant was transferred to a clean tube. Chloroform extraction was repeated again and the combined supernatants were evaporated to dryness at 50 ° C. under N ₂ stream. The residue was then dissolved in 1 mL of HPLC mobile phase. This sample was injected into the HPLC for analysis.

  Assay standards were prepared by lyophilizing 1 mL of PEG600 (concentration range 0.05-10 mg / mL) in PEG and then extracting as described above. After injection into the HPLC column, the refractive index peak area of each oligomer was plotted against the polymer concentration of the standard. A regression equation relating peak area to concentration was determined for each oligomer. The peak area of each oligomer in the unknown sample was determined and converted to the relative abundance of PEG using the regression equation. The largest peak from the chromatogram of the PEG600 standard was assigned to the oligomer with the molecular weight closest to the average, ie, the oligomer with a molecular weight of 590 Da. A total of 14 oligomers were detected in the PEG600 sample. However, in addition to the limited amount, the accompanying signal was low, so data for oligomers having a molecular weight of 502-766 Da could only be confirmed. Extraction recovery was about 60% to 103%.

As can be seen in the table below, oils B and Y showed a statistically significant increase in PEG flux compared to the control.

[Example 3]
Effect of Gilsonite Oil on Hydrocortisone Skin Penetration The experimental setup and skin pretreatment methods were the same as described in Example 2 above. At the end of the 24 hour pretreatment step, the residual solution was removed and the skin surface was washed twice with 200 μL EtOH and once with 200 μL NS. A solution (500 μL) of hydrocortisone (0.1 mg / mL in NS) containing an appropriate amount of radiolabeled compound ( ³ H-hydrocortisone) was applied to the skin surface and the upper donor cell was sealed with parafilm. In a positive control experiment, skin was pretreated with dimethyl sulfoxide (DMSO) for 2 hours. The receiving fluid was stirred with a small Teflon coated magnet at 700 rpm. Samples were collected for 12 hours at 1 hour intervals using a Retriever IV fraction collector (ISCO, Lincoln, NE). Each fraction was mixed with 10 mL Ready Safe® and analyzed on a Beckman LS 5000TA liquid scintillation counter. The flux through the skin was calculated from the slope of the linear portion of the time versus osmotic drug accumulation curve.

As can be seen in the table below, a statistically significant increase in flux, a decrease in lag time and an increase in 12-hour penetration compared to the controls were observed for oils 1, A, B, C, X, Y and Q. It was seen.

[Example 4]
Effect of Gilsonite Oil on Caffeine Skin Penetration The experimental setup and skin pretreatment methods were the same as described in Example 3 above. At the end of the 24 hour pretreatment step, the residual solution was removed and the skin surface was washed twice with 200 μL EtOH and once with 200 μL NS. A solution (500 μL) of caffeine (5.3 mg / mL in NS) containing an appropriate amount of radiolabeled compound ( ¹⁴ C-caffeine) was applied to the skin surface and the upper donor cell was sealed with parafilm. In a positive control experiment, skin was pretreated with dimethyl sulfoxide (DMSO) for 2 hours. The receiving fluid was stirred with a small Teflon coated magnet at 700 rpm. Samples were collected for 12 hours at 1 hour intervals using a Retriever IV fraction collector (ISCO, Lincoln, NE). Each fraction was mixed with 10 mL Ready Safe® and analyzed on a Beckman LS 5000TA liquid scintillation counter. The flux through the skin was calculated from the slope of the linear portion of the time versus osmotic drug accumulation curve.

As can be seen in the table below, a statistically significant increase in flux was seen in all but oil 2 when compared to the control. A statistically significant decrease in lag time and enhanced penetration for 12 hours was seen with all oils.

  The disclosure provided herein is a practicable and exemplary disclosure relating to the inventive concept of the present invention and is not intended to limit the scope of the invention as claimed.

Typical graph of transepidermal water loss (ie, “TEWL”) over time. The graph which shows the effect of Gilsonite oil with respect to skin hydration. Graph showing% penetration of polyethylene glycol (PEG) molecules over 12 hours as a function of molecular weight. Graph showing total hydrocortisone penetration from a hydrocortisone-containing gilsonite oil composition over 12 hours in a pig skin sample. Graph showing total caffeine penetration from a gyrsonite oil composition containing caffeine over a 12 hour period in a pig skin sample.

Claims (40)

  A composition for topical or transdermal administration comprising gilsonite oil. A composition for topical or transdermal administration comprising (i) a bioactive substance selected to treat nail disorders, and (ii) gilsonite oil.   3. The composition of claim 2, further comprising a pharmaceutically acceptable carrier.   The pharmaceutically acceptable additive further selected from the group consisting of excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, adhesives, polymers and additional penetration enhancers. Composition.   The composition of claim 2, wherein the bioactive agent is present from about 0.0001% to about 50% by weight.   The composition of claim 2, wherein the gilsonite oil is present from about 0.0001% to about 50% by weight.   A method for treating nail embrittlement in a patient, comprising treating the nail with the composition according to claim 1 or 2.   8. The method of claim 7, wherein the gilsonite oil composition further comprises a pharmaceutically acceptable carrier.   The gilsonite oil composition further comprises a pharmaceutically acceptable additive selected from the group consisting of excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, adhesives, polymers and additional penetration enhancers. 9. The method of claim 8, comprising.   8. The method of claim 7, wherein the treatment results in at least a 10% increase in patient nail strength.   8. The method of claim 7, wherein the treatment results in at least a 30% enhancement in the patient's nail strength.   8. The method of claim 7, wherein the treatment results in at least a 50% enhancement in the patient's nail strength.   A method for treating a thickened nail in a patient, comprising treating the nail with the composition according to claim 1 or 2.   14. The method of claim 13, wherein the gilsonite oil composition further comprises a pharmaceutically acceptable carrier.   The gilsonite oil composition further comprises a pharmaceutically acceptable additive selected from the group consisting of excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, adhesives, polymers and additional penetration enhancers. 15. The method of claim 14, comprising.   14. The method of claim 13, wherein the treatment results in a reduction of at least 10% in the patient's nail thickness.   14. The method of claim 13, wherein the treatment results in a reduction of at least 30% in the patient's nail thickness.   A method of treating abnormal nail growth in a patient, comprising treating the nail with a composition according to claim 1 or 2.   19. The method of claim 18, wherein the gilsonite oil composition further comprises a pharmaceutically acceptable carrier.   The gilsonite oil composition further comprises a pharmaceutically acceptable additive selected from the group consisting of excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, adhesives, polymers and additional penetration enhancers. 20. The method of claim 19, comprising.   19. The method of claim 18, wherein the treatment results in at least a 10% increase in the patient's nail growth rate.   19. The method of claim 18, wherein the treatment results in at least a 30% increase in the patient's nail growth rate.   19. The method of claim 18, wherein the treatment results in at least a 50% increase in the patient's nail growth rate.   A method of treating skin dryness in a patient, comprising treating the patient with a composition according to claim 1 or 2.   25. The method of claim 24, wherein the gilsonite oil composition further comprises a pharmaceutically acceptable carrier.   The gilsonite oil composition further comprises a pharmaceutically acceptable additive selected from the group consisting of excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, adhesives, polymers and additional penetration enhancers. 26. The method of claim 25, comprising. A nail of a human or warm-blooded animal comprising applying (a) a biologically active substance and (b) a penetration penetration system comprising (i) gilsonite oil and (ii) a pharmaceutically acceptable carrier to the body surface A method for promoting the penetration of biologically active substances through the body.   28. The method of promoting penetration according to claim 27, wherein the pharmaceutically acceptable carrier is selected from the group consisting of oil, lotion, gel, cream, adhesive and ointment.   28. The penetration enhancing method of claim 27, wherein the pharmaceutically acceptable carrier is suitable for use in a transdermal patch.   The gilsonite oil composition further comprises a pharmaceutically acceptable additive selected from the group consisting of excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, adhesives, polymers and additional penetration enhancers. 30. The penetration promoting method according to claim 29, comprising:   28. The method of promoting penetration according to claim 27, wherein the bioactive material is present at about 0.0001% to about 50% by weight.   28. The method of promoting penetration according to claim 27, wherein the gilsonite oil is present from about 0.0001% to about 50% by weight. (I) a bioactive agent selected to treat nail disorders; and (ii) a method for transdermally delivering a bioactive agent by administering a composition comprising gilsonite oil to an animal nail. .   34. A method for transdermally delivering a bioactive substance according to claim 33, further comprising a pharmaceutically acceptable carrier selected from the group consisting of oils, lotions, gels, creams and ointments.   34. A pharmaceutically acceptable additive selected from the group consisting of excipients, preservatives, antioxidants, fragrances, emulsifiers, dyes, adhesives, polymers and additional penetration enhancers. For transdermally delivering a bioactive agent of the present invention.   34. A method for transdermally delivering a bioactive agent according to claim 33, wherein the bioactive agent is present from about 0.0001% to about 50% by weight.   34. The method for transdermally delivering a bioactive agent according to claim 33, wherein the gilsonite oil is present from about 0.0001% to about 50% by weight.   A bioactive agent transdermal comprising mixing a bioactive agent selected to treat nail disorders and gilsonite oil in a ratio effective to obtain a composition for a desired application. A method for producing a delivery composition.   39. The method for producing a composition for transdermal delivery according to claim 38, further comprising mixing in a pharmaceutically acceptable carrier selected from the group consisting of oil, lotion, gel, cream, adhesive and ointment.   39. The method of claim 38, further comprising admixing with at least one pharmaceutically acceptable penetration enhancing additive, excipient, preservative, antioxidant, fragrance, emulsifier or pigment.

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