Background of the Invention

1. Field of the Invention

The present invention relates to film-forming vehicles for deliver¬ ing medicaments to the nails of mammals. More particularly, this Invention relates to film-forming vehicles which are adapted to deliver one or more active ingredients to human nails in the treatment of vari¬ ous onychopathic conditions, such as onychomycosis. These vehicles provide a means for topical treatment of onychopathic conditions that is both effective and convenient. This Invention also relates to phar¬ maceutical compositions based on such vehicles and to a method of treating onychopathic conditions using these compositions.

2. Discussion of Related Art

Onychopathic conditions are very difficult to treat topically due to the poor delivery of drugs through the nails when the drugs are applied using conventional dosage forms, such as, creams, lotions, gels, solutions, and so on. This poor delivery is primarily attribut¬ able to the fact that the drugs are easily rubbed off, washed away or otherwise removed from the nails when applied via the conventional dosage forms mentioned above, and as a result may only be in contact with the nails for a very limited time.

Human nails are typically 100 to 200 times thicker than the stratum corneum. Because of this greater thickness, the time required for a given quantity of drug to penetrate the nail is much greater than the time required for the same quantity of drug to penetrate the stratum corneum. Thus, the drug must be in contact with the nail for a rela¬ tively long time (e.g., several hours) in order to achieve a thera¬ peutic concentration of drug in the affected tissue beneath the nail (i.e., the nail bed). The above-cited conventional dosage forms are generally ineffective because the drug is not kept in contact with the nail long enough to achieve a therapeutic concentration of drug in the nail bed.

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The prior art approaches to treating onychopathic conditions have generally fallen into one of three categories. Namely, these approaches have relied on either systemic (e.g., oral) administration of drugs; surgical removal of all or part of the nail followed by topi¬ cal application of drugs to the thus exposed tissue beneath the nail; or topical application of conventional creams, lotions, gels or solu¬ tions, frequently including the use of bandages to keep these dosage forms in place on the nails. All of these prior art approaches suffer from major drawbacks.

A major problem seen with systemic therapy is the considerable amount of time which is usually required to produce a therapeutic effect in the nail bed. For example, oral treatment of onychomycoses with the antifungal compound ketoconazole typically requires adminis¬ tration of a 200 to 400 mg daily dose for an average period of 20-25 weeks before any significant therapeutic effect is realized. The potential for side effects on major organ systems is a very significant danger associated with such long term, systemic therapy, since ketocon¬ azole has been reported to produce fatalities attributable to liver toxicity and to reduce testosterone levels in the blood due to an adverse effect on the testes. A further drawback seen with this type of therapy 1s the greater expense to the patient and consequent adverse affect on patient compliance.

A major drawback seen with the second type of therapy mentioned above, namely removing all or part of the nail prior to topical treat¬ ment of the condition, is the discomfort experienced by the patient, both during and subsequent to removal of the nail. A further problem with this approach is the undesirable cosmetic appearance of the nail or nail bed; this may represent a significant problem for some patients, particularly female patients.

A major problem seen with the third prior art approach to therapy has already been mentioned above; namely, conventional dosage forms such as creams, lotions, gels or solutions are easily removed from the nails. The use of bandages or similar means in an attempt to eliminate this problem has generally been met with poor patient compliance. The poor patient compliance is understandable, since such bandages are

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typlcally awkward and become very troublesome to keep in place over extended periods of several weeks or more. The use of a 2% miconazole cream together with occlusive bandages to treat onychomycosls is discussed 1n the following article: E. Helnke, "Clinical experiences with iconazol with special regard to a conservative treatment of the onychomycoses and paronychia", Mykosen, Vol. 15, pp.405-407 (1972). A 2% miconazole alcoholic solution 1s described in the following article: J. Vanderdonckt et al., "Miconazole alcoholic solution in the treatment of mycotlc nail infections", Mykosen. Vol. 19, pp.251-256 (1976). The solution is said to have the following formula:

Miconazole base 0.2 gram

Carbosept No. 525 0.475 gram

Carbosept No.515 0.025 gram

Propylene glycol USP 2 gram

Ethanol USP ad 10 mL

The article characterizes the above-identified solution as being a "film-forming alcoholic solution." (Emphasis added.) However, experi¬ ments conducted by the present inventors have shown that 1n fact the vehicle utilized by Vanderdonckt et al., (i.e., all of the ingredients listed above except for the miconazole) does not produce a continuous, self-supporting film, but rather leaves a deposit on the nails which may be more readily described as a residue than as a film. For pur¬ poses of the present specification, a film is considered to be self- supporting when it can be peeled from a nonstick surface such as glass or Teflon®. That is, a film is considered to be self-supporting when 1t can be removed from a nonstick surface and still retain the physical characteristics and form of a continuous film.

The experiments conducted by the present inventors have shown that the residue formed by the above-Identified solution takes several hours to dry and disintegrates if placed 1n water. In contrast, the film- forming vehicles of the present invention generally require only a few minutes to dry when placed on human nails and do not disintegrate readily when contacted with water. These properties of the film-

forming vehicles of the present invention are very significant with respect to the patient compliance and efficacy seen with compositions based on these vehicles.

The above-cited article also states that the solution was applied to the nails in drop form twice dally. This 1s a further indication that the alcoholic solution utilized by Vanderdonckt et al., is signi¬ ficantly different from the film-forming vehicles of the present inven¬ tion, which form a continuous film, adhere readily to the nail, and may be applied as infrequently as once or twice per week. Additional reports on the use of the above-identified 2% miconazole alcoholic solution are set forth in the following articles: G. Achten et al., "Treatment of onycho ycosis with a solution of miconazole 256 in alcohol," Mykosen, Vol. 20, pp. 251-256 (1976); and B. Bentley- Phillips, "The treatment of onychomycosis with miconazole tincture," South African Medical Journal, Vol. 62, pp. 57-58 (1982).

Japanese Patent Application No. 58-92926 (preliminary publication No. 59-216822) discloses film-forming, ender ic formulations. Those formulations differ from the film-forming vehicles of the present invention in that, among other things, the films formed are specially adapted to be flexible so as to remain on the skin after drying. A considerable amount (i.e., 5 to 1500 parts by weight) of a plasticizer (e.g., propylene glycol) is included in the formulations in order to provide this flexibility. It is believed that these formulations would require a considerable amount of time to dry if painted on human nails due to the relatively large amount of plasticizer contained therein. The film-forming vehicles of the present invention are specially adapted for use on nails rather than skin, and do not require the pre¬ sence of a plasticizer in order to provide flexibility. Thus, the film-forming vehicles of the present invention are designed to form films which are relatively inflexible compared to those of the type described in the Japanese Application.

The foregoing discussion demonstrates that a need exists for an effective, topical regimen for treating onychopathic conditions. More

spedfically, a need exists for an effective means of applying drugs topically to the nails in a manner which will, among other things, bring about:

(1) prolonged presence of drug on the nails;

(2) relatively rapid therapeutic concentrations of drug in the nail bed; and

(3) improved patient compliance based on convenience and cosmetic appearance.

This need has provided the stimulus for the present invention.

Summary of the Invention

A principal object of the present invention is the provision of film-forming vehicles adapted to deliver drugs to nails in an efficacious and cos etically acceptable manner.

A further object of this invention is the provision of film-forming vehicles which significantly enhance the delivery of drugs through nails by maintaining the drugs in contact with the nails.

A still further object of this invention is the provision of pharmaceutical compositions based on such film-forming vehicles, and a method of treating onychopathic conditions utilizing these compositions.

The foregoing objects and other general objects of the present invention are satisfied by the provision of a pharmaceutical vehicle adapted to deliver drugs to the nails which comprises from about 2% to about 0 by weight of a hydrophilic, film-forming resin, and a pharm¬ aceutically acceptable solvent for said resin, said vehicle being capable of forming a continuous, self-supporting film when applied to human nails, and pharmaceutical compositions based on such vehicles.

Description of Preferred Embodiments

The film-forming vehicles of the present invention are based on hydrophilic, film-forming resins. The film-forming resins utilized in this invention are polymeric materials which are at least partially soluble in water and/or polar organic solvents (e.g., methanol, ethanol, isopropanol, acetone, chloroform, methylene chloride, and so on), and which are capable of producing a continuous, self-supporting

film upon evaporation of the solvent. As mentioned above, the films formed by the vehicles of the present invention are considered to be self-supporting because it is possible to remove the films from a nonstick surface and still retain the physical characteristics and form of a continuous film. The film-forming resins are hydrophilic in the sense that they have an affinity for water or polar organic solvents, and are wettable by water. Examples of such film-forming resins include: cellulose resins, ethylene oxide resins, acrylic acid and acrylate resins, vinyl resins and vinyl pyrrolidone resins.

Examples of suitable cellulose resins include: methyl cellulose, carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose and hydroxyethylcellulose.

Examples of suitable ethylene oxide resins include polyethylene oxide polymers.

Examples of suitable acrylic acid and acrylate resins include: polyacrylamide, polyacrylic/polymethacrylic, poly ethacrylate/butyl- acrylate, polyacrylic/acr late and polyacrylic acid polymer.

Examples of suitable vinyl resins include: polyvinyl alcohol and poly (methyl vinyl ether/maleic anhydride).

Examples of suitable vinyl pyrrolidone resins include: polyvinyl pyrrolidone, polyvinyl pyrrolidone/vinyl acetate, and vinyl pyrrolidone/di ethylaminethyl methacrylate.

The above-described hydrophilic, film-forming resins are cornmercially available. The resins which may be utilized in the present invention are further illustrated by the specific examples set forth in Table 1 below.

Table 1

• Molecular

Weight

Class Subclass Tradename Manufacturer Range

Cellulose Resins Alkyl Cellulose Methocel A Dow Chemical 50,000 - 1,000,000

Hydroxyakyl Methocel E Dow Chemical

Alkyl Cellulose

Carboxymethyl CMC Industries of 50,000 -

Cellulose India 700,000

CMC-T Hercules Chemicals

Hydroxy Alkyl HEC Hercules 50,000 -

Cellulose HPC Chemicals 1,200,000

Klucel

Natrosol

Ethylene Oxide Polyethylene Oxide Polyox WSR N-10 Union Carbide 50,000 -

Resins Polymers Polyox WSR N-80 4,000,000 Polyox WSR N-750 Polyox WSR N-3000 Polyox WSR 205 Polyox WSR 1105 Polyox WSR 301

Continued . . .

Table 1 - Continued

Molecular Weight

Class Subclass Tradena e Manufacturer Range

Acrylic Acid and Poly (acrylic *Acrysol-l Rohm and Haas 50,000 - Acrylate Resins acid) *Acrysol-3 400,000 *Acrysol-5

Carbopol 910 B. F. Goodrich 400,000 - Carbopol 934 5,000,000 Carbopol 940 Carbopol 941

Polyacryl mide *Poly Trap 158 Wickhen 10,000 - *Poly Trap FML 205 Chemicals 1,000,000

Acrylyamide/ Reten-421 Hercules 10,000 - Sodium Acrylate Reten-423 Chemicals 1,000,000 Reten-425

Acrylic/Aerylate Carboset-514 B. F. Goodrich 7,000 - Copolymer Carboset-515 1,000,000 Carboset-525

Polymethacrylate/ Plastold A Rohm Pharm. 25,000 - Butyl Acrylate Plastoid B Co. 1,000,000 Copolymer

Vinyl Resins Polyvinyl Alcohol Gohsenol Nippon Gohesie 25,000 - ' Gelvatol Monsanto 300,000 El anol E. I. DuPont

Continued . . .

Table 1 - Continued

Molecular Weight

Class Subclass Tradename Manufacturer Range

Polyvinyl Polyvinyl PVP K-25 G. A. F. 15,000 -

Pyrrolidone Pyrrolidone PVP K-30 Chemicals 800,000

Resins Polymers PVP K-90

Polyvinyl **PVP/VA G. A. F. 50,000 - Pyrrolidone/ Chemicals 1,000,000 Vinyl Acetate Copolymers

Polyvinyl GAFQUAT G. A. F. 100,000 - Pyrrolidone/ Chemicals 1,000,000 Dimethylamino- ethyl Methacrylate Copolymers

^♦ These products are actually formulations containing the indicated type of resin rather than pure resin.

**A series of polyvinyl pyrrolidone/vinyl acetate copolymers containing the following ratios of PVP/VA: 70/30, 60/40, 50/50, 30/70, and 20/80.

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The above-identified film-forming, polymeric resins are further described In the following publications: Handbook of Water Soluble Gums and Resins. Davidson, R. L., McGraw-Hill Book Company (1980); and "Gum Technology in the Food Sciences," Food Science and Technology - A Series of Monographs. Glicksman, M., Academic Press (1969). The entire contents of these publications are incorporated herein by reference.

One or more of the above-described hydrophilic, film-forming resins are contained in the film-forming vehicles of this invention in an amount of from about 256 to about 40* by weight. The amount of poly¬ meric resin utilized in specific vehicles will vary depending on factors such as the molecular weight, viscosity and solubility of the resin; the type of solvent utilized; the inclusion of other components in the vehicles; and the type of active ingredient contained in the vehicles. The amount of polymeric resin contained in the vehicles will also depend to some extent on the particular type of resin utilized. The preferred ranges for each of the five classes of resins identified in Table 1 are as follows:

Class Preferred Range (wt %)

Cellulose Resins 5-15

Polyethylene Oxide Resins 10-30

Acrylic Acid and Acrylate Resins 5-35

Vinyl Resins 10-30

Polyvinyl Pyrrolidone 10-30

The film-forming vehicles described above are optionally used in combination with a layer of polymeric material which is applied to the nail after the film-forming vehicle has dried. The use of this second layer of material in effect creates a two coat system on the nail, with the first coat comprising the film-forming vehicle and drug and the second coat comprising the layer of polymeric material or overcoat.

The two coat system generally enhances the ability of drugs to penetrate the nail by modifying the hydration characteristics of the nails and the film-forming vehicles.

The two coat system 1s also advantageous in that it generally allows a greater concentration of drug to be contained in the film- forming vehicles. More particularly, when higher concentrations of drug are contained in the film-forming vehicles, the vehicles exhibit a greater tendency to deteriorate when submerged in water. The overcoat layer protects the film-forming vehicles from such deterioration, and thereby enables a greater concentration of drug to be contained in the vehicles.

The overcoat layer should preferably be waterproof, and must be capable of drying quickly (I.e., within 10 to 15 minutes, preferably within 1-2 minutes). Various types of materials meeting these require¬ ments may be utilized. For example, most comrnercially available nail lacquers and polishes can be utilized for this purpose. This is a distinct advantage in the treatment of many female patients, since the ability to use nail polishes for the overcoat layer in the two coat system may further contribute to good patient compliance by allowing the patient to maintain the normal cosmetic appearance of the nails while undergoing treatment.

Although comrnercially available nail lacquers and polishes may be utilized for the overcoat layer, the film-forming vehicles of the present invention and solutions containing pyroxylin resin (e.g., collodion USP and flexible collodion USP) may also be utilized for this purpose.

The film-forming vehicles of the present invention may further comprise one or more chemical agents to modify the physical and/or chemical properties of the vehicles and films formed from the vehicles. Examples of physical and chemical properties of the vehicles which may be modified include: solubility of the film-forming resins and drugs, viscosity, suspendability, clarity, light and UV absorption, and dry¬ ing. Examples of the physical properties of films which may be modi¬ fied include: elasticity, hardness, brittleness, appearance, adherence, drying and tackiness.

The classes of chemical agents which may be utilized to modify the above-described properties include: humidity controlling agents and tack controlling agents. Examples of suitable tack control agents include: carboxymethyl cellulose, cellulose, cellulose acetate pro- prionate, colloidal silica and shellac. Examples of suitable humidity controlling agents include glycerin and sorbitol.

The specific chemical agents utilized to modify the above-discussed properties and the amount of such agents required are dependent on numerous factors, but are primarily dependent on the desired drying time of the film. In general, it is desired that the film-forming vehicles of this invention be capable of forming a dry film within 15 minutes following application to the nails, preferably within 5 minutes. The films are deemed "dry" when tack free if touched lightly with a finger.

In addition to the above-described components, the film-forming vehicles of this invention may also include various adjuvants conven¬ tionally utilized in topically applied pharmaceutical dosage forms, such as, antioxidants, antimicrobial preservatives, chelating agents, buffering agents, pigments, ultra-violet absorbers, and so on.

The film-forming vehicles described above may be utilized to deliver a wide variety of drugs to the nails. Because of the hydro¬ philic properties of the resins, films formed from the resins support the diffusion of drugs contained in the film matrix. The only limita¬ tions with regard to the types of drugs which may be delivered are that the drug be physically and chemically compatible with the film-forming vehicle and be capable of permeating the nail. With regard to the latter requirement, it has been determined that drugs having a molecular weight of greater than about 550 can not effectively permeate the nail. Accordingly, the drugs which may be utilized in the compositions of the present invention must have a molecular weight less than about 550, and preferably have a molecular weight less than about 300. It has also been determined that drugs having a water solubility of greater than about 0.01 percent by weight generally permeate the nail more readily than drugs having a lesser degree of water

solubllity. Drugs having a water solubility of greater than about 0.01 percent by weight are therefore preferred in the present invention.

Two particularly important classes of drugs which are useful in the treatment of onychopathic conditions are antl-inflammatories and antl- ycotlcs. Other classes of drugs which may be delivered by the vehicles of the present invention include, for example, antibiotics, antineoplasties and antipsoriatlcs, such as methotrexate.

The antimycotics represent an especially important class of drugs, since fungal infections of nails and nail beds are typically very difficult to treat using conventional prior art therapies. The film- forming vehicles of the present Invention are particularly useful for delivering drugs having antimycotic activity to the nails. Specific examples of suitable drugs having antimycotic activity are miconazole, clotrimazole, ketoconazole, econazole, tioconazole, thiabendazole, bifonazole, chlormidazole, ciclopirox, sodium propionate, sodium pyrithione, and pharmaceutically acceptable salts thereof. These drugs are all known compounds which are further described, for example, in The Merck Index. Tenth Edition (1983).

The amount of drug contained in the compositions of the present invention will vary widely depending on the particular type of drug, severity of the condition, and other factors. In general, the composi¬ tions will contain from about 0.0156 to about 2556 by weight of one or more drugs as principal active ingredient.

The present invention is further illustrated by the following examples, but should not be interpreted as being limited in any way by. these examples.

Examples 1-2 The following formulations illustrate the film-forming vehicles of the present invention and compositions based on those vehicles which contain a drug having antimycotic activity. All percentages are by weight based on the total weight of the composition.

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Example 1

Ingredient _»

Carboset 525 18

Omadine (sodium pyrithione) 1

Purified Water 15

Alcohol (SD 40-2) QS 100

This composition was prepared by combining all of the ingredients except for the Carboset 525 resin to form a mixture, and then adding the Carboset 525 resin to that mixture. The resulting mixture was stirred with a paddle stirrer until the Carboset 525 resin was dissolved. The resulting product was a clear solution having a straw color. When painted on nails as a thin layer, this product provided a tack-free, transparent film within approximately three minutes following application.

Example 2

Ingredient %

Carboset 525 18.8

Miconazole Nitrate 1.0

Purified Water, USP . 15.6

Alcohol (SD 40-2) QS 100

This composition was prepared in the manner described in Example 1 above. When painted on nails as a thin layer, this composition provided a tack-free, transparent film within approximately five minutes following application.

Examples 3-4 The following formulations illustrate the film-forming vehicles of the present invention and compositions based on those vehicles which contain a drug having anti-inflammatory activity. All percentages are by weight based on the total weight of the composition.

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Example 3

Ingredient %

Carboset 525 18.0

Ibuprofen 5.0

Purified Water, USP 15.0

Alcohol (SD 40-2) QS 100

This composition was prepared in the manner described in Example 1 above. When painted on nails as a thin layer, this composition provided a tack-free, transparent film within approximately 3-1/2 minutes following application.

Example 4

Ingredient %

Carboset 525 18.8

Hydrocortlsone 1.0

Purified Water, USP 15.6

Alcohol (SD 40-2) QS 100

This composition was prepared in the manner described in Example 1 above. When applied on nails as a thin layer, this composition provided a tack-free, transparent film within approximately 5 minutes following application.

Examples 5-7 The following formulations further illustrate the film-forming vehicles of the present invention and compositions based on those vehicles. All percentages are by weight based on the total weight of the composition.

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Example 5 Ingredient %

Polyvinyl Alcohol 25.0

(Vinyl Resin) Sodium Propionate (Antifungal) 1.0

Water QS 100

This composition may be prepared by dissolving the polyvinyl alcohol in water with stirring and dissolving the sodium propionate in the resulting solution.

Example 6

Ingredient *

PVP/VA (Polyvinyl Pyrrolidone 20

Resin)

Ibuprofen (Anti-inflammatory) 5

Alcohol (SD 40-2) 20

Water QS 100

This composition may be prepared by dissolving the PVP/VA in the alcohol with stirring, and then slowly adding the ibuprofen and water with stirring.

Example 7 The following formulation illustrates a composition which is suitable for use as the overcoat layer. All percentages are by weight based on the total weight of the composition.

Ingredient %

Camphor 2

Castor Oil 3

Collodion USP QS 100

The ingredients are combined and shaken to form a solution.

Example 8

The following experimental results demonstrate the efficacy of the present compositions in treating onychopathic conditions, specifically onychomycoses.

A fifty-two year old, white male patient, afflicted with an onychomycotlc Infection of the big toe, had treated the infection topi¬ cally with applications of either Tinactln™ (tolnaftate) solution or Micatin™ (miconazole) cream twice daily for many months without producing any clinical signs of improvement. This patient was treated with a composition in accordance with the present invention containing 5.0 wt.56 sodium omadine (sodium pyrithione) and based on the vehicle illustrated in Example 1. The composition was applied to the affected toe by painting a single layer on the nail, and waiting approximately two minutes for the layer to form a dry, tack-free film. The composi¬ tion was applied in this manner two times per week beginning in October- 1984. By December 1984, obvious clinical improvement was apparent based on the growth of a normal appearing toe nail. By June 1985, the nail no longer exhibited any clinical signs of fungal infection.

The present invention has been described above in connection with certain preferred embodiments. However, as variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto.