WO2007120868A2

WO2007120868A2 - Bioavailability enhancement of lipophilic drug by use solvent system

Info

Publication number: WO2007120868A2
Application number: PCT/US2007/009229
Authority: WO
Inventors: Stanley Kepka
Original assignee: Stanley Kepka
Priority date: 2006-04-14
Filing date: 2007-04-16
Publication date: 2007-10-25
Also published as: WO2007120868A3

Abstract

Compositions and methods for improving the efficacy and/or transdermal transport of topically administered pharmacologically active compounds are disclosed. Preferably, the pharmacologically active compound is incorporated in a carrier comprising an effective amount of a lipophilic pharmaceutically acceptable compound selected from the group consisting of alcohol, glycols, ethers and mixtures thereof, most preferably benzyl alcohol. In certain embodiments, compositions and methods of treatment for anti-fungal compositions are disclosed that exhibit enhanced permeation. In another embodiment and improved, stable topical composition of prostaglandin is disclosed.

Description

BIOAVAILABILITY ENHANCMENT OF LIPOPHILIC DRUG BY USE SOLVENT SYSTEM

This application is related to U.S. Provisional Patent Application 60/792,186 filed April 14, 2007.

FIELD OF THE INVENTION

This invention relates to a solvent for use in the topical administration of pharmaceutical or pharmacologically active compounds, in order to improve drug bioavailability.

BACKGROUND OF THE INVENTION

Although significant progress has been made in the development of antifungal drugs, nail fungal infection (e.g., onychomycosis) remains a disease most difficult to treat. The target sites for the treatment of onychomycosis reside in the nail plate, nail bed and nail matrix, or skin matrix. Topical treatment has not been effective because antifungal drugs cannot readily penetrate the nail plate to reach the infection site under nail. The most common means of treating onychomycosis is to remove the nail completely and topically apply medication to the underlying nail bed. An effective topical drug therapy for cutaneous disease requires drug uptake into a desired skin layer at sufficient concentrations over a particular period of time for maximal pharmacological activity. Transdermal drug delivery has become an important means of drug administration. It presents numerous advantages but it is still limited by the small number of drugs with a suitable profile. The use of solvents that affect the skin barrier function is one of the classic strategies of penetration enhancement. Some of these solvents have well characterized actions on the stratum corneum, but the majorities are still selected using empirical criteria. Dermato-pharmacokinetic analysis shows that time for reaching the pick of skin absorption was about six hours after topical application

Oral administration of antifungal drugs is the only effective way to treat onychomycosis, which has limited the use of some of the more potent antifungal drugs such as intraconazole and kethoconazole because of concern for possible side effects. It has been shown, however, that if nail barrier can be overcome or eliminated, topical antifungal drug treatment can be effective.

In order to deliver a sufficient amount of drug into the target tissue (the nail plate), the permeability of the drug need to be enhanced. Solvent assistance provides permeation enhancement and increase in the bioavailability of poorly water-soluble drugs.

As explained in International Patent Application PCT/AU03/00998 to West et al., when a drug is released from a formulation it will first partition into the outer lipids of the stratum corneum. The degree of absorption will depend primarily upon solubility of the drug into these lipids and partition co-efficient of the drug between the skin and the formulation. A simple method for maximizing this is to choose formulation components that allow the drug dose to reach its solubility limit. Ostrenga et al. demonstrated this principle by improving solubility and partition characteristics of two corticosteroids through manipulating the formulation ratio of water and propylene glycol, demonstrating that the most effective formulations were those that contained adequate propylene glycol to solubilize the maximum drug concentration in the finished pharmaceutical product (Ostrenga J. Steinmetz C, Poulsen B. Significance of vehicle composition 1. Relationship between topical vehicle composition, skin penetrability, and clinical efficacy. J. Pharm. Sci. 1971; 60:1175-1179).

It is also reported that supersaturated systems provide thermodynamic activity greater than unity that enhances skin penetration of drugs. A drug solvent system using a mixture of volatile and non- volatile solvents as vehicles, where the volatile compounds evaporate from the skin, can create a supersaturated solution on the skin surface and stimulate drug absorption. It is thought that some transdermal patch delivery systems have the ability to absorb water from the skin increasing thermodynamic activity of a drug creating a supersaturated solution thereby promoting its passage through the skin. One of the major problems with use of mixed volatile and non volatile delivery systems however, is the difficulty in creating systems that are reproducible, as the rate and degree of volatile evaporation will depend, to a large extent upon ambient conditions during application. Variability in absorption kinetics causes fluctuations in drug delivered and unreliable clinical efficacy.

Modern drugs typically do not have optimal solubility characteristics, and this is currently quantified by use of a solubility parameter. This has been estimated to be approximately for the skin, so drugs with solubility parameters similar to this may be expected to be freely soluble creating a large concentration gradient across the skin or high partition co-efficient. The importance of this is evident in an analysis of skin permeability data by Potts and Guy (Potts R O, Guy R H. Predicting skin permeability. Pharm. Res. 1992; 9:663-669) who examined the permeability of 90 compounds in aqueous solution and determined that permeability coefficient (K_p) through the skin was related to their octanol-water partition coefficient and the molecular weight in the following relationship: log (K_p) (cm s.sup.-l)=-6.3+0.71 log P-0.0061 MW(r.sup.2=0.69) This emphasizes the importance of solubility and partition coefficient, but like many mathematical structure activity relationships, results in a 2 dimensional answer to a three dimensional problem. For example, flux through the skin using this equation results in a parabolic dependency on the partition coefficient, which is still unclear. If a true linear concentration gradient existed then the higher the concentration gradient, the higher the drug absorption. The fact that the relationship is not linear suggests that physical limits exist, such as the number of pores in the skin or physiochemical forces other than solubility, dissolution and dispersion, which also act to facilitate membrane transport. It has been suggested that at high log P (a highly lipophilic compound), the transfer out of the stratum corneum is rate limiting or that drugs with high log P values generally have poor aqueous solubility. This means that lipid soluble drugs tend to stay in the phospholipid membrane because by nature they are lipophilic, that is, the drugs are trapped in the skin and not released to the target site.

Based on the equation and the accompanying assumption that drugs are transported across skin by virtue of a concentration gradient, it is suggested that drugs with log P in the range of 1 to 3 are more likely to diffuse through the skin. However, this simply serves to identify drugs that may move easily through the skin. This does not help to improve the transport of poorly soluble, highly lipophilic drugs.

BRIEF SUMMARY OF THE INVENTION

The invention provides a method for the treatment of fungal diseases in nail and if desired also to surrounding skin, of designed formula containing enhanced permeation (solvent and enhancer) administrated in amount sufficient to enhance the permeation of antifungal drugs through the membrane / nail tissue.

This invention provides a delivery means for topical treatment of fungal disease of the nail and skin, which delivers an effective dose of drug to a)the diseased nail plate ( and consequently, the underlying nail bed) and (b) surrounding skin tissue including nail bed and matrix via the eponychium and hyponychium skin route.

The invention further provides a film forming material to provide coating for treated zone. Bioavailability enhancement appears to have been mediated by way of improved drug solubility. It was shown by Franz that the use of different solvents had on influence on the drug uptake and penetration through keratin-based membrane.

In an attempt to increase the bioavailability of drug, we develop multifunctional solvent system, which provides enhancement. The uptake of drug and penetration through human nails was determined by soaking nail in formulation containing xx % of drug The uptake result was consistent with the results of drug penetration through the nail.

DETAILED DESCRIPTION OF THE INVENTION

As explained in United States Patent 7,018,649—Tavares ,et al., transdermal delivery of active agents is measured in terms of "relative release rate" or "flux," i.e., the rate of penetration of the active agent through the skin of an individual. Skin flux may be generally determined from the following equation: dm/dT =J=P*C where J is the skin flux, P is the permeability coefficient and C is the concentration gradient across the membrane, assumed to be the same as the donor concentration, m represents the amount of drug entering the blood stream. The variable dm/dT represent the change in amount of drug entering the blood stream and change over time.

It is well understood in the art of transdermal delivery systems that in order to maintain a desired flux rate for a desired dosing period, it is necessary to include an overage of active agent in the transdermal delivery system in an amount that is substantially greater than the amount to be delivered to the patient over the desired time period. For example, to maintain the desired flux rate for a three day time period, it is considered necessary to include much greater than 100% of a three-day dose of an active agent in a transdermal delivery system. This overage is necessary for creating a concentration gradient by means of which the active agent migrates through the layers of the transdermal delivery system to the desired site on a patient's skin. The remainder of the active agent remains in the transdermal delivery system. It is only the portion of active agent that exits the transdermal delivery system that becomes available for absorption into the skin.

The total amount of active agent absorbed into the patient's blood stream is less than the total amount available. The amount of overage to be included in a transdermal delivery system is dependent on these and other factors known to the skilled artisan.

Creating concentration gradient across membrane can be achieved by selecting solvent with sufficient drug solubility. For group of drugs, which suffer poor solubility, this becomes major step limiting drug application and new product development. It has been found that it is possible to treat onychomycosis according to the present invention by providing a transdermal delivery system containing a sufficient amount of solubilized intraconazol above currently known levels and reaching sufficient solubility level which allows to effectively deliver drug to infected area, to provide a desired relative release rate for at least about 3 days, and after single administration (application) of the transdermal dosage form, leaving the dosage form on the skin for approximately a 3 to 8 day time period, thereby resulting in the flux being maintained over the prolonged period and effective blood plasma levels and management of hypertension being maintained over the prolonged period. Preferably, the desired flux is maintained at least about 5, preferably at least about 7 days after application of the transdermal delivery system.

In certain preferred embodiments, the transdermal dosage forms used in accordance with the invention contain a polymer matrix layer. Generally, the polymers used to form the biologically acceptable polymer matrix are those capable of forming thin walls or coatings through which pharmaceuticals can pass at a controlled rate. A non-limiting list of exemplary materials for inclusion in the polymer matrix includes polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethylacrylate copolymers, ethylene vinyl acetate copolymers, silicones, rubber, rubber-like synthetic homo-, co- or block polymers, polyacrylic esters and the copolymers thereof, polyurethanes, polyisobutylene, chlorinated polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel), polyvinylidene chloride, poly(ethylene terephthalate), ethylene-vinyl alcohol copolymer, ethylene-vinyloxyethanol copolymer, silicones including silicone copolymers such as polysiloxane-polymethacrylate copolymers, cellulose polymers (e.g., ethyl cellulose, and cellulose esters), polycarbonates, polytetrafluoroethylene and mixtures thereof.

Preferred materials for inclusion in the polymer matrix layer are silicone elastomers of the general polydimethylsiloxane structures, (e.g., silicone polymers). Preferred silicone polymers cross-link and are pharmaceutically acceptable. Other preferred materials for inclusion in the polymer matrix layer include: silicone polymers that are cross-linkable copolymers having dimethyl and/or dimethylvinyl siloxane units which can be crosslinked using a suitable peroxide catalyst. Also preferred are those polymers consisting of block copolymers based on styrene and 1,3-dienes (particularly linear styrene-isoprene-block copolymers of styrene-butadiene-block copolymers), polyisobutylenes, polymers based on acrylate and/or methacrylate.

The polymer matrix layer may optionally include a pharmaceutically acceptable cross- linking agent. Suitable cross-linking agents include, e.g., tetrapropoxy silane.

Preferred transdermal delivery systems used in accordance with the methods of the present invention include an adhesive layer to affix the dosage form to the skin of the patient for a desired period of administration, e.g., about 3 to about 8 days. If the adhesive layer of the dosage form fails to provide adhesion for the desired period of time, it is possible to maintain contact between the dosage form with the skin by, for instance, affixing the dosage form to the skin of the patient with an adhesive tape, e.g., surgical tape. It is not critical for purposes of the present invention whether adhesion of the dosage form to the skin of the patient is achieved solely by the adhesive layer of the dosage form or in connection with a peripheral adhesive source, such as surgical tape, provided that the dosage form is adhered to the patient's skin for the requisite administration period.

The adhesive layer preferably includes using any adhesive known in the art that is pharmaceutically compatible with the dosage form and preferably hypoallergenic, such as polyacrylic adhesive polymers, acrylate copolymers (e.g., polyacrylate) and polyisobutylene adhesive polymers. In other preferred embodiments of the invention, the adhesive is a pressure-sensitive contact adhesive, which is preferably hypoallergenic.

The transdermal dosage forms, which can be used in accordance with the present invention, may optionally include a permeation-enhancing agent. Permeation enhancing agents are compounds, which promote penetration and/or absorption of the felodipine into the blood stream of the patient. A non-limiting list of permeation enhancing agents includes polyethylene glycols, surfactants, and the like.

Alternatively, permeation of drug may be enhanced by occlusion of the dosage form after application to the desired site on the patient with, e.g., an occlusive bandage. Removing hair from the application site by, e.g., clipping, shaving or use of a depilatory agent may also enhance permeation. Another permeation enhancer is heat. It is thought that heat enhancement can be induced by, among other things, using a radiating heat form, such as an infrared lamp, onto the application site after application of the transdermal dosage form. Other means of enhancing permeation of intracronazol such as the use of iontophoretie means are also contemplated to be within the scope of the present invention.

A preferred transdermal dosage form which may be used in accordance with the present invention includes a non-permeable backing layer made, for example, of polyester; an adhesive layer made, for example of a polyacrylate; and a matrix containing the felodipine and other desirable pharmaceutical aids such as softeners, permeability enhancers, viscosity agents and the like.

The active agent may be included in the device in a drug reservoir, drug matrix or drug/adhesive layer. Preferably, the active agent is intraconazol, taxol, or a pharmaceutically acceptable salt thereof.

Certain preferred transdermal delivery systems also include a softening agent. Suitable softening agents include higher alcohols such as dodecanol, undecanol, octanol, esters of carboxylic acids, wherein the alcohol component may also be a polyethoxylated alcohol, diesters of dicarboxylic acids, such as di-n-butyladiapate, and triglycerides particularly medium-chain triglycerides of the caprylic/capric acids or coconut oil, have proved to be particularly suitable. Further examples of suitable softeners are multivalent alcohols, for example, levulinic acid, cocprylic acids glycerol and 1,2-propanediol, which can also be etherified by polyethylene glycols.

An intraconazol solvent may also be included in the transdermal delivery systems of the present invention. Preferably, the solvents dissolve the intraconazol to a sufficient extent thereby avoiding complete salt formation. A non-limiting list of suitable solvents includes those with at least one acidic group. Particularly suitable are monoesters of dicarboxylic acids such as monomethylglutarate and monomethyladipate.

Other pharmaceutically acceptable compounds which may be included in the reservoir or matrix include: solvents, for example alcohols such as isopropanol; permeation enhancing agents such as those described above; and viscosity agents, such as cellulose derivatives, natural or synthetic gums, such as guar gum, and the like.

In preferred embodiments, the transdermal dosage form includes a removable protective layer. The removable protective layer is removed prior to application, and consists of the materials used for the production of the backing layer described above provided that they are rendered removable, for example, by a silicone treatment. Other removable protective layers, for example, are polyltetra-fluoroethylene, treated paper, allophane, polyvinyl chloride, and the like. Generally, the removable protective layer is in contact with the adhesive layer and provides a convenient means of maintaining the integrity of the adhesive layer until the desired time of application. The composition of the transdermal dosage forms used in accordance with the invention and the type of device used are not considered critical to the method of the invention, provided that the device delivers the active agent, e.g., intraconazol, for the desired time period and at the desired flux rate and/or the desired delivery rate of the transdermal dosage form.

Certain transdermal dosage forms for use in accordance with the present invention are described in U.S. Pat. No. 5,240,711 (Hille, et. al; assigned to LTS Lohmann Therapie- Systeme GmbH & Co.), hereby incorporated by reference. Such transdermal delivery systems may be a laminated composite having an impermeable backing layer containing felodipine, e.g., instead of buprenorphine, and optionally a permeation enhancer combined with a pressure-sensitive adhesive. A preferred transdermal dosage form in accordance with the 711 patent includes: (i) a polyester backing layer which is impermeable to the drug; (ii) a polyacrylate adhesive layer; (iii) a separating polyester layer; and (iv) a matrix containing felodipine, a solvent for the felodipine, a softener and a polyacrylate adhesive. The felodipine solvent may or may not be present in the final formulation. The transdermal delivery device described therein includes a backing layer, which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and optionally, a removable protective layer. Preferably, the reservoir layer includes about 10 to about 95%-wt polymeric material, about ,0.1 to about 40%-wt softener, about 0.1 to about 30%-wt felodipine. A solvent for the felodipine base or pharmaceutically acceptable salt thereof may be included as about 0.1 to about 30%-wt.

The transdermal delivery system may also be prepared in accordance with the disclosure of International Patent Application No. WO 96/19975 (Hille, et. al.; assigned to LTS Lohmann Therapie-Systeme GMBH), hereby incorporated by reference, where felodipine is substituted for buprenorphine as an active agent. In this device, the felodipine transdermal delivery device contains resorption-promoting auxiliary substances. The resorption-promoting auxiliary substance forms an under cooled mass. The delivery system contains 10% felodipine base, 10-15% acid (such as levulinic acid), about 10% softener (such as oleyoleate); 55-70% polyacrylate; and 0-10% polyvinylpyrollidone (PVP).

Alternatively, the transdermal device may be a reservoir system. A reservoir system transdermal drug delivery patch comprises several different components. An exemplary construction includes a backing layer, an active drug and optional permeation enhancing solvent gel, a membrane, a skin contact adhesive layer, and a protective release coated liner film. Characteristics of each component are set forth below:

Backing Film: This layer is exposed to the external environment when the system is worn on the skin surface. It is impervious to penetration of the active drug contained within the system preventing the escape of the active drug through the backing film. The backing film serves as barrier layer. Moisture, soaps, lotions and other elements are prevented from entering the system and diluting the active ingredients or altering the release characteristics of the system. The active drug and solvent are contained within the system to perform its designated function. The backing film also forms one half of the chamber, which contains the active drug reservoir. The backing film must be capable of being suitably attached to the membrane in order to form the reservoir chamber. Typical attachment methods include thermal, ultrasonic polymer heat seal or welding, and adhesive bonding. Necessary mechanical properties include a low compliance for conformability to the skin surface and elasticity to allow for movement with the skin surface. Typical thickness is in the range of 0.5-25.0 mil. Wide ranges of homogenous, woven, and non-woven polymer or composite materials are suitable as backing films.

Membrane: The membrane in combination with the backing film forms the chamber, which contains the active drug reservoir. The membrane is attached to the backing film, and provides a support surface for the skin contact adhesive. The membrane can be a homogenous polymer film, or a material with a porous structure. The membrane may also be designed to control the transport rate of the active drug and/or the permeation enhancing solvent. Necessary mechanical properties include a low compliance for conformability to the skin surface and elasticity to allow for movement with the skin surface. Typical thickness is in the range of 0.25-30.0 mil (1 mil=0.001 inch), and more preferably in the range of 0.5 to 25.0 mil. Wide ranges of homogenous, porous, woven, and non-woven polymer or composite materials are suitable as membranes and known in the art.

Active Drug Reservoir: The active drug is combined with a liquid vehicle to fill the reservoir chamber. A range of solvents can be used for the liquid vehicle. The solvents can be chosen to optimize skin permeation of the active (enhancers) or to optimize the permeation characteristics of the membrane or the adhesion of the skin contact adhesive. A viscosity-increasing agent is often included in the vehicle to aide in the handling and system manufacturing process. The composition of the vehicle must be compatible with the other components of the system. The vehicle may be in the form of a solution, suspension, cream, lotion, gel, physical mixture or emulsion. This list is not meant to be exhaustive.

Skin Contact Adhesive: The system is affixed to the skin with a skin contact adhesive. The adhesive may cover the entire surface of the system membrane, be applied in an intermittent pattern, or only to the perimeter of the system. The adhesive composition must be of materials suitable for skin contact without creating intolerable adverse effects such as excessive skin irritation or sensitization. Adequate adhesion to the membrane and skin are also necessary. The adhesive must also possess enough cohesive integrity to remain completely on the membrane upon removal of the system. The adhesive is applied in a thickness to provide a weight of 0.025 to 50.0 mg/cm², more preferably 0.25 to 5.0 mg/cm² and most preferably 0.3 to 0.6 mg/cm². Typical materials include silicone, polyisobutylene (PIB), and acrylates dissolved in organic solvents, aqueous emulsions, or directly applied by hot melt processing.

Release Coated Liner Film: The liner film is removed from the system before application to the skin surface. The liner film serves the function as a protective barrier to the skin contact adhesive prior to use. The coating on the liner provides a release capability for the adhesive, allowing separation of the liner from the adhesive. A coating is not necessary if the liner material is readily removed from the adhesive without disrupting the reservoir system. Typical thickness is in the range of 0.5-25.0 mil. A wide range of homogenous, woven, and non-woven paper, polymer or composite materials are suitable as liner films. Release coatings are typically composed of paraffin, polyethylene, silicone or fluorocarbons.

In other embodiments, the transdermal delivery system may be a plaster such as that described in U.S. Pat. No. 5,225,199 to Hidaka et al., hereby incorporated by reference. Such plasters include a film layer including a polyester film of about 0.5 to about 4.9 μm thickness, about 8 to about 85 g/mm strength, respectively in the two directions intersecting substantially at right angles, about 30 to about 150% elongation, in the two directions intersecting substantially at right angles and an elongation ratio of A to B of about 1.0 to about 5.0, wherein A and B represent data in two directions intersecting at right angles, and A is greater than B and wherein said polyester film includes about 0.01 to about 1.0% by weight, based on the total weight of the polyester film, of solid fine particles in which the average particle size is about 0.001 to about 3.0 μm and an adhesive layer which is composed of an adhesive containing transdermally absorbable drugs; wherein the adhesive layer is laminated on said film layer over the surface in about 2 to about 60 μm thickness. The average particle size is substantially not more than 1.5 times the thickness of the polyester film.

The transdermal delivery system used in the present invention may also be prepared in accordance with U.S. Pat. No. 5,879,701 issued Mar. 9, 1999 to Audett, et al., hereby incorporated by reference, wherein solubilization enhancer compositions are provided which facilitate transdermal administration of basic drugs from transdermal systems composed of nonpolar adhesive materials. The solubilization enhancing composition is particularly useful in facilitating the administration of basic drugs using transdermal systems worn for at least four days containing drug reservoirs comprised of nonpolar materials such as polyisobutylene adhesives or the like. The solubilizing enhancing composition itself is preferably a liquid, which is an isomeric acid mixture. Examples of suitable solubilizers include, but are not limited to, oleic acid dimer and neodecanoic acid, with oleic acid dimer particularly preferred. The solubilizer constitutes at least about 0.10 wt. % of the reservoir, and preferably represents on the order of 0.25 wt. % to 1.0 wt. % of the reservoir. The amount of enhancer composition present in the drug formulation will depend on a number of factors, e.g., the strength of the particular enhancer composition, the desired increase in skin permeability, and the amount of drug, which is necessary to deliver.

The pharmacokinetic information for felodipine is available in the literature. The adult oral dosage for felodipine is 10 mg/day. The bioavailability for the drug is approximately 20%, expressed as fraction, 0.20 of the oral dose made available to the blood stream from gastrointestinal absorption. A release rate for a felodipine transdermal delivery system was calculated from this data. 0.20 of the oral 10 mg daily dose provides 2.0 mg of felodipine available into the blood stream. Therefore, an equal dose is required to be delivered transdermally. 2.0 mg/day is converted to 2000 mcg/24 hours. This would require delivery of 83.3 meg/hour. The largest desirable surface area for a transdermal patch is about 40 cm². Dividing 83.3 mcg/hour/40 cm² by 40, yields a release rate of 2.1 mcg/hour/cm² of transdermal patch surface area. To account for drug elimination, further pharmacokinetic data and physiological data were required. The plasma concentration at steady state for felodipine is 0.002 mcg/ml. The physiological clearance rate is 48,000 ml/hour. The dosing rate is obtained from the product of the steady state concentration of felodipine and a representative clearance rate. This product is 96 meg/hour. The largest desirable surface area for a transdermal patch is about 40 cm². Dividing 96 mcg/hour/40 cm² by 40, yields a release rate of 2.4 mcg/hour/cm² of transdermal patch surface area. One of skill would expect a larger input rate or flux to maintain a steady state concentration in consideration of the loss of drug in the plasma due to elimination. A confirmatory calculation for flux requires further pharmacokinetic parameters. The volume of distribution for felodipine is 700,000 ml and the half-life is 14 hours. The elimination rate constant is 0.693/half-life. The product of steady state concentration, volume of distribution and steady state concentration yields a rate of 69.3 meg/hour. The largest desirable surface area for a transdermal patch is about 40 cm². Dividing 69.3 mcg/hour/40 cm² by 40, yields a release rate of 1.73 mcg/hour/cm² of transdermal patch surface area.

Any type of transdermal delivery system may be used in accordance with the methods of the present invention so long as the desired pharmacokinetic and pharmacodynamic response(s) are attained over at least 3 days, e.g., from about 5 to about 8 days. Preferable transdermal delivery systems include e.g., transdermal patches, transdermal plasters, transdermal discs, iontophoretic transdermal devices and the like

As explained in International Patent Application PCT/AU03/00998 to West et al., many modern drugs are highly lipophilic so skin enhancers and various formulation techniques have been developed to improve their absorption through the skin. Skin enhancers typically function to modify structure especially of the stratum corneum by dissolving or interfering with the lipid matrix to improve permeability of drug compounds. Examples include compounds like capric acid, oleic acid, azone, decylmethyl sulfoxide and hydroxy cinnamates. Dermal absorption of progesterone for example increases by 143% when the stratum corneum is delipidized. The enhancement increases to 843% when the stratum corneum is totally eliminated. With such aggressive modification, commonly reported problems with repeated use of such systems include contact dermatitis, reddening of the skin, itching and burning that requires movement of the patch or application of the drug, around the body to prevent local irritation. The reddening is said to disappear within hours of removing the patch. But concern has been raised with respect to long-term risk and safety of use of this type of transdermal delivery system, mainly because increased drug permeability is achieved at the cost of damaging a fundamentally important protective layer of the skin.

There have been a number of attempts to develop drug delivery systems that are less aggressive to the skin, however none of these attempts have provided commercially acceptable products. For example: U.S. Pat. No. 6,479,540 discloses use of a tocol based delivery system to solubilize charged amphophilic and water-soluble pharmaceutically active compounds. The patent teaches that the charged esters of tocopherol, such as phosphate, succinate, aspartate and glutamate form ion pairs with suitable drug substrates, which in turn associate with the tocol emulsion. The formulation thus renders the active compound to be much more lipophilic and incorporated in miscelles that may permit better transport through mucosal membranes. U.S. Pat. No. 5,583,105 discloses use of tocol and tocol derivatives including tocopherol polyethylene glycol 1000 succinate (TPGS) as solvents to dissolve certain drugs at high enough concentrations to be therapeutically useful. Emulsions and emulsification with solubilizers have a long history in drug delivery art. TPGS is used as a pharmaceutically acceptable water miscible solubilizer and there is no teaching regarding any other interaction between TPGS with lipophilic pharmaceuticals. International patent application WO 96/21440 discloses a method for improving bioavailability of a medicinal agent by covalent attachment of inositol phosphate and biphosphonate molecules. The resulting conjugates are said to have increased water solubility relative to the unconjugated agent.

The art of efficient topical drug delivery therefore requires that the drug be both soluble in the aqueous biological medium and in an appropriate form to permit transport of either individual drug molecules or very small aggregates of the drug molecules. This aim may be difficult to realize with drugs that are lipid soluble and not significantly water soluble, unless the delivery system is recognized by normal membrane transport systems. Such drug molecules have hydrophobic regions that form large aggregates in the high dielectric constant water rich medium where transport occurs.

A suitable carrier capable of topically delivering a broad range of pharmaceuticals or pharmacologically active compounds and improving absorption of the pharmaceutical or pharmacologically active compound in the targeted area without damaging the skin is therefore required.

It has surprisingly been found that a carrier composition comprising complexes of phosphates of lipophilic pharmaceutically acceptable compounds, such as tocopheryl phosphate, mixed with pharmaceuticals or their phosphorylated analogue allows rapid and efficient transport of the pharmaceuticals or pharmacologically active compounds.

Examples of suitable polymers are those selected from at least one of the group comprising polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, block copolymers of ethylene oxide and propylene oxide, and polyethylene glycol. Suitable surfactants include those of the anionic variety such as sodium lauryl sulfate, sodium laurate or dioctylsodium sulphosuccinate, and those of the cationic variety such as benzalkonium chloride, bis-2-hydroxyethyl oleyl amine or the like.

In another embodiment, the invention includes a method for treating mammals with said drugs by increasing the bioavailability of the drug following its administration using the composition of this invention. Still a further embodiment of this invention is a method of preparing compositions with increased bioavailability in mammals from a poorly soluble or water insoluble drug. The method includes the steps of:

(a) Forming a mixture or solution of a drug with a non-toxic, pharmacologically acceptable water-soluble polymer;

(b) drying the drug-polymer solution;

(c) mixing the dried drug-polymer mixture or solution with a surface wetting amount of wetting agent solution wherein said agent is selected from anionic and cationic surfactants; and

(d) drying the mixture of step (c).

The method for preparing these compositions is also useful as a method for preparing ultramicrocrystalline griseofulvin.

While the invention is illustrated with poorly soluble or water soluble drugs, and particularly grisefulvin, it will become apparent to those skilled in the art that the compositions and method of this invention are also suitable for other drugs which while relatively soluble have a tendency to agglomerate or crystallize in storage, or after formulation into pharmaceutical dosage forms.

Generally these polymers are commercially available over a broad range of average molecular weights. For example, polyvinylpyrrolidone (PVP) is a well known product produced commercially as a series of products having mean molecular weights ranging from about 10,000 to 700,000. Prepared by Reppe's process: 1,4-butanediol obtained in the Reppe butadiene synthesis is dehydrogenated over copper at 200.degree. forming .gamma. -butyrolactone; reaction with ammonia yields pyrrolidone. Subsequent treatment with acetylene gives the vinyl pyrrolidone monomer. Polymerization is carried out by heating in the presence of H.sub.2 O.sub.2 and NH.sub.3. DeBeIl et al., German Plastics Practice (Springfield, 1946); Hecth, Weese, Munch. Med. Wochenschr. 1 943, 11; Weese, Naturforschung & Medizin 62, 224 (Wiesbaden 1948), and the corresp vol. of FIAT Review of German Science. Monographs: General Aniline and Film Corp., PVP (New York, 1951); W. Reppe, Polyvinylpyrrolidon (Monographie zu "Angewandte Chemie" no. 66, Weinheim/Bergstr., 1954). Generally available commercial grades have average molecular weights in the range of 10,000 to 360,000, for example, General Aniline and Film Corporation (GAF) markets at least four viscosity grades available as K-15, K-30, K-60, and K-90 which have average molecular weights of about 10,000, 40,000, 160,000 and 360,000, respectively. The K- values are derived from viscosity measurements and calculated according to Fikentscher's formula (Kline, G. M., Modern Plastics 137 No. 1945). Similar commercial products are available from benzyl alcohol (BASF-Wyandotte).

Selection of a particular polymer with its characteristic molecular weight will in part depend on its ability to form suitable dosage forms with the particular drug. Thus, in preparing solid dosages, whether in powder, tablet or capsule units, the composition of this invention should be readily grindable or pulverizable, or in the form of free-flowing powders. A second consideration in the selection of a particular polymer derives from the limitations inherent in the use of specific equipment with polymers of increasingly higher viscosity. For example in forming the drug-polymer solution or mixture, complete dissolution or mixing could be inhibited utilizing blenders, mixer or the like, which are inadequate by reason of low shear or proper baffles to form a uniform and homogeneous drug-polymer solution or mixture. Depending on the process employed for forming of the drug-polymer mixture, another consideration in the selection of a particular polymer is that the polymer be mutually soluble in solvents for the particular drug.

In one preferred embodiment the present invention provides a benzyl alcohol drug delivery system. Benzyl alcohol has been evaluated by Scientific Communities for Food in 1981. The ability to metabolize benzyl alcohol is well-established and benzyl alcohol has been evaluated for use in the field of food as a carrier solvent for flavoring, and the data reviewed on compounds in this group are sufficient to demonstrate lack of carcinogenicity , or negative effect on developmental and reproductive potential.. Consequently, the group ADI of 0-5 mg /kg by weight as benzoic acid equivalent was maintained ( JECFA 1996). Later, JFCFA evaluated benzyl alcohol at 57-th meeting in 2001 and concluded that there was " "No safety concern " Benzyl alcohol is a natural constituent of a number of plants. It occurs, for example, in some edible fruits (up to 5 mg /kg) and in green and black tea ( 1-30 and 1-15 mg/kg, respectively. Benzyl alcohol is added as a flavoring substance to some foods and beverages at a level up to 400 mg/kg (chewing gum 1254 mg/kg). The quantity that is requested to be used as a carrier solvent for flavoring substance to food and beverages is up to 300 mg/kg in the final food as consumed. Additionally, benzyl alcohol is used as a local anesthetic, pharmaceutical aid, and in perfume. It is an indirect food additive, is used in wide variety of cosmetic formulations as a fragrance component, preservative and viscosity decreasing agent.. In 1998 , benzyl alcohol was reported by the US Food and Drug Administration to be used in 322 cosmetic formulations belonging to 43 cosmetic-product categories (CIR,2001).

Thus, it is established that benzyl alcohol is a safe and useful component for use in topical and non-topical medicaments. Upon application to intact skin, benzyl alcohol permeates or penetrates the skin, and takes a drug with it into the proximity of dermal pain receptor, and thus acts as a permeation enhancer. Benzyl alcohol has also been used lOmg/mL as a preservative in Innohep ( tinzaparin sodium injection). A commercial dose of Lupron contain 9 mg/mL benzyl alcohol, NF as preservatives for injection. Similarly, the vaginal cream Ccleocin ( clindamycin phosphate vaginal cream, USP) contain benzyl alcohol, as set forth in the FDA New Drug Application NDA 50-680/S- 004. Other known uses of benzyl alcohol in pharmaceutical compositions include:

CYPIONAX- contain benzyl alcohol for injection Mentax contain Benzyl alcohol ITCH-X gel (0495-33) Dual acting, Anti-itch Gel contain 10 % benzyl alcohol For the temporary relief of pain and itching associated with rashes, minor skin irritation, allergic itches, sunburns, insect bites, poison ivy , poison oak and poison sumac.

CANESTEN (1% BENZYL ALCOHOL as preservative) in unit dose 5 gram Canesten vaginal cream allows to apply 50 mg of benzyl alcohol in one dose unit.

Benzyl Alcohol is listed on FDA-CDER Inactive Ingredient Search for Approved Drug Products with s potency range for injection 1-14.4 % , as a topical gel 1-50 %, as a vaginal cream 1 % , as a topical ointment 2.2%, as a topical Solution 2 % and as a topical emulsion, cream 2.7% . Benzyl alcohol 10% v/v solutions also have some local anesthetic properties, which are exploited in some parenterals, cough products, ophthalmic solutions, ointments and dermatological aerosols sprays.

The compound (Benzoates) exhibits low acute toxicity as for the oral and dermal route. The LD 50 values are >2000 mg/kg by weight except for benzyl alcohol which needs to be considered as harmful by the oral route in view of an oral LD50 of 1610 mg/kg by weight. For these reasons, benzyl alcohol is included in the FDA Inactive Ingredients Guide ( injection, oral capsule, solutions and tablets, topical and vaginal preparations) and is included in parenteral and non-parenteral medicines licensed in the UK. As it can be seen benzyl alcohol can be seen as safe already applied in many pharmaceutical products as preservative agent. Although widely used as an antimicrobial preservative, benzyl alcohol has been associated with some reaction when administrated to neonates and should not be used in new born infants if at all possible.

The present invention recognizes and applies benzyl alcohol as solvent and enhancing agent. Benzyl alcohol has now been found to have useful application as solvent for many drug as a solubilizing agent as set forth below:

TABLE 1

Drug Solubility in Benzyl Alcohol

Different lines of therapy (antifungal, ED, anticancer) can be developed based on founding that Benzyl alcohol is a solvent for many different drugs. At the same time, it should be recognized as effective enhancer, therefore dual function of Benzyl alcohol should be translated as unique combination Having found solvent (Benzyl Alcohol) that produces concentrated solution of the various drug allows designing and implement new approach in drug delivery system. Benzyl alcohol offers very^' unique combination of performance; act as solubilizing agent, permeation enhancer agent and preserving agent and additionally can me metabolized by human body. Design of new multi-component solvent system that meets all FDA requirements and assures effective drug permeation also offers the opportunity to incorporate it into desired delivery vehicle. Certain preferred embodiments shown in Table 1 is well known as extremely difficult to solubilized, and this fact was major limiting factor in drug formulation. Based on this founding we can develop new delivery prototypes with superior performance because increased drug concentration in dose unit.

Compositions made in accordance with the present invention demonstrate:

• Higher concentration assure better permeation because higher concentration gradient

• Benzyl alcohol offers better permeation because permeate skin and is acting as enhancer for drugs. NTBD on each drug individually.

• Benzyl alcohol - eliminate not increase irritation

• Benzyl alcohol is safe in much application and is easy to metabolize.

• Benzyl alcohol is miscible with water / body fluid.

Stability of prostaglandin is very fundamental for product development with long shelf life (1-2 years).

Benzyl alcohol is miscible with water and also with physiological fluid, which assure high bio-availability of the drug for further adsorption into the tissue/ skin.

It also important to indicate that prostaglandin solution in Benzyl alcohol is significantly stable ( 14-16 month at room temperature). This allows designing room temperature stable Alprostadil formula. Removing all unwanted components, which trigger degradation chain reaction, is a basic concept to extend prostaglandin stability behind 14 -16 month up to 24 month. At this point we can declare we have reached destination point.

Benefits of design a multi component solvent system:

• Utilize a combination of volatile and non- volatile solvent to assure drug bioavailability

• Interaction with target tissue could be more diversified,

• Multiple enhancing effect could be utilized during permeation through tissue membrane

• Easy to over come FDA limit of application listed in CDER list TABLE 2

Selected components for room temperature stable Alprostadil

TABLE 3

Selected components to design stability kit for room temperature Alprostadil

A stability kit is in one embodiment applied directly to formulate drug product as well as for raw material preparation in order to remove unwanted component in raw material, mainly; water, oxygen, metal ion. Prepared solvent system is used for further product formulation process. Product formulated this way free of contaminates which trigger degradation process, offers significantly improved stability profile. This pretreatment of raw material is not obvious finding, we have identified this approach based on knowledge of diversified degradation mechanism and stability study for each component separately. Prostaglandin is solubilized by liquid carbon dioxide (CO₂) and remains stable in such condition for a long time (more then 2 years). There is no evidence of prostaglandin degradation under such conditions.

A preferred embodiment of lyophilized prostaglandin is created as follows, prostaglandin powder is solubilized in liquid carbon dioxide under pressure and mixed to assure complete solubilization of the active ingredient in a solvent system. Single or multiple solvent mixtures are available, as described above. Taking constant volume of prepared solution and dispensing it into a storage container/ applicator creates a uniform dose unit by applying automated dosing system. Several different version of the described processing technology can be created by those of skill in the art using known techniques and without undue experimentation. One factor in choosing the system would be to focus on the desired function. By addition of nonvolatile solvent a saturate solution of the drug can be obtained. By addition of reselected powder (which is not soluble in prepared solvent system) to the vessel and dispersed uniformly by mixing a condition for controlled reduction of pressure within the vessel that allows the volatile carbon dioxide to leave the system gradually, thereby reducing prostaglandin solubility. As a result, the prostaglandin gradually is deposited on surface of the selected powder. Maintaining mixing during this process assures uniform prostaglandin distribution in whole powder volume.

The process described above is modified in certain embodiments by the addition of a non-volatile solvent (benzyl alcohol, Propylene glycol, PEG 400) that allows to the solution to exceed prostaglandin solubility in given solvent and created saturated or supersaturated solution of prostaglandin in selected delivery system.

A property of lyophilized prostaglandin on polymeric solids will provide change in prostaglandin behaving, like rate of release, interaction with surrounding matrix system, interaction with water, surfactant, oxygen, and metal ions. In general the stability profile will be significantly improved, and therefore worth of extra cost of lyophilization.

Liquid crystal technology, organo-gel system - formation of gel without water benzyl alcohol can form water free gel with few different polymeric material like: HPMC, Carbopol, PVP and more. NTBD

Organized layer formation by benzyl alcohol and HPMC and prostaglandin assure creation of storage condition for prostaglandin with significantly improved storage stability.

Although certain embodiments of the present invention have been disclosed in great detail, the invention is not limited to the specific embodiments disclosed herein. Upon review of the foregoing, those of skill in the art will realize that numerous modifications, adaptations and alternate embodiments are readily created. In particular, the use of benzyl alcohol and similar solvents to enhance the behavior of various classes of pharmaceutically active ingredients can now be explored using the foregoing specific examples as a template, For this reason, the present invention is not limited by the foregoing specific examples and is instead defined by the appended claims.

Claims

What is claimed is:

1. A nail permeable composition for treatment of diseased conditions comprising: a medicament, a solvent; and an enhancer to facilitate permeation through a membrane chosen from the group consisting of skin and nail plate.

2. The nail-permeable composition of claim 1, wherein said medicament is chosen from the group consisting of an antibacterial, antifungal, anti- viral or antimicrobial drug.

3. The composition of claim 1 wherein the antifungal drug is selected from the group consisting miconazole, ketoconazole, itraconazole, econazole, ciclopirox, oxiconazole, clotrimazole, terbinafine, naftifine and pharmaceutically acceptable salts thereof and stereo-isomers thereof.

4. A method for improving the efficacy and/or transdermal transport of topically administered pharmacologically active compounds, said method comprising the step of incorporating said pharmacologically active compound in a carrier comprising an effective amount of a lipophilic pharmaceutically acceptable compound selected from the group consisting of alcohol, glycols, ethers and mixtures thereof.

5. The method according to claim 4, wherein the effective amount of pharmacologically active compounds is in range from 0.1 to 20 %.

6. The method according to claim 4 wherein the carrier further comprises one or more excipients that are selected from the group consisting of solvents, surfactants, emollients, preservatives, colorants, fragrances and mixtures thereof.

7. The method of claim 6, wherein the carrier comprises an effective amount of one or more phosphate derivatives of a lipophilic pharmaceutically acceptable compound.

8. The method of claim 4, further comprising the step of applying a patch delivery system device with resorption promoting auxiliary substances, containing skin contact adhesive to a subject.

9. The method of claim 4, wherein the lipophilic pharmaceutically acceptable compound is benzyl alcohol for intracronazol

10. A method of making a composition that enhances the bioavailability of a drug using a drug and solvent supersaturation system comprising the step of combining a mixture of a volatile and a non- volatile solvent, whereby a concentration gradient across a membrane by improved solvency power and creation necessary concentration gradient across a biological membrane.

,

11. The method of claim 10, wherein the solvent system comprises benzyl alcohol.

12. The method of claim 10, further comprising a polymer matrix with coating and film forming capacity, whereby the resultant composition is self-adhesive to affix a drug dosage to the membrane.

13. The method of claim 12, wherein the composition provides controlled release of a drug.

14. The method of claim 12, further comprising a compound of opposite charge selected from the group consisting of chitosan, CMC, and benzyl alcohol.