Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

• the present invention generally relates to a method of antifungal drug delivery, especially to the delivery of hydrophobic antifungal compounds such as terbinafine.
• the fingernails and toenails are susceptible to dematophytic infections caused by the invasion of fungi into the nails of human beings and other animals.
• fungi such as Trichophyton rubrum, Microsporum canis, T. mentagrophytes, T. interdigitale, and other known fungi that can cause such infections.
• Their treatment particularly when it involves the nails, requires the oral administration of one or more known antifungal agents, e.g. griseofulvin, ketoconazole, terbinafine, ciclopirox olamine, and other agents.
• the general rule is that if these infections are not treated early they become difficult to combat, and that even if oral administration results in clearing the disease, recurrence is common.
• many of these compounds because they are poorly absorbed from the gastrointestinal tract, have to be administered in relatively large amounts, and for prolonged periods of time, up to one year, to saturate the infected site and be effective.
• compositions for application to or treatment of nails including nail polishes, nail polish removers, nail oil emulsions, nail penetration enhancers, nail softeners, and the like have been developed. However, these have the problems described above.
• U.S. Patent No. 3,382,151 describes an aqueous-based, formaldehyde containing composition which can be applied to finger nails to strengthen them. The patent further discloses that the product has aseptic properties, curing fungi which occasionally infect nails, but which also causes some inflammation.
• U.S. Patent No. 4,820,724 describes a dual phase solvent carrier system for topically applying at least one pharmaceutically active compound comprised of the active compound dissolved in at least one delivery solvent and at least one fugitive solvent, with a particularly useful composition for topically treating dermatophytic infections comprised of griseofulvin, benzyl alcohol and at least one fugitive solvent.
• U.S. Patent No. 4,957,730 describes a nail varnish comprising a water insoluble film forming substance and a series of antimycotic compounds derived from a 1 -hydroxy-2-pyridone structure.
• U.S. Pat No. 6,495,124 describes a lacquer for treating or preventing fungal infections which includes several known antifungal agents entrapped in a water-insoluble film forming polymer, pentadecalactone, which also is claimed to act as a penetration enhancer.
• U.S. Patent 6,380,236 describes the use of a tissue softening composition containing urea and an antifungal composition concurrently or non- concurrently.
• the kit also includes the use of a protective gel-dressing for ready application.
• U.S. Patent No. 6,042,845 discloses a method for treating fungal diseases of the nail which includes the use of sulfhydryl containing amino acids and urea as permeation enhancers of antifungal drugs.
• U.S. Patent 5,889,039 describes the use of a topical antifungal preparation which contains either sulconazole or naftifine combined with an acetate penetration enhancer.
• an antifungal composition according to the invention for topical application to the skin and nails comprises: (1 ) an allylamine antifungal compound; (2) an aliphatic alcohol substituted with an aromatic substituent in which the allylamine antifungal compound is soluble to a degree that a therapeutically effective concentration of the allylamine antifungal compound can be applied topically in solution; (3) a lower aliphatic alcohol in which the aromatic alcohol is soluble; and (4) water or a water-compatible solvent mixture.
• the allylamine antifungal compound is terbinafine.
• the allylamine antifungal compound can be another allylamine such as naftifine or an analogue or derivative of terbinafine or naftifine.
• the aliphatic alcohol substituted with an aromatic substituent is benzyl alcohol.
• the aromatic alcohol is phenethyl alcohol or another aromatic alcohol.
• the lower aliphatic alcohol is selected from the group consisting of ethyl alcohol, isopropyl alcohol, and mixtures thereof.
• the lower aliphatic alcohol is ethyl alcohol. More preferably, the ethyl alcohol is absolute ethyl alcohol. Alternatively, the ethyl alcohol can be 95% ethyl alcohol. In another alternative, the lower aliphatic alcohol can be a mixture of ethyl alcohol and isopropyl alcohol.
• the concentration of the allylamine antifungal compound is from about 1% (w/v) to about 3% (w/v) in the final composition.
• the concentration of the allylamine antifungal compound is from about 1.5% (w/v) to about 2.5% (w/v) in the final composition. More preferably, the concentration of the allylamine antifungal compound is about 2% in the final composition.
• the concentration of the aliphatic alcohol substituted with an aromatic substituent is from about 3% (v/v) to about 10% (v/v) in the final composition.
• the concentration of the aliphatic alcohol substituted with an aromatic substituent is about 5% (v/v) in the final composition.
• the concentration of the lower aliphatic alcohol is from about 80% (v/v) to about 95% (v/v).
• concentration of the lower aliphatic alcohol is from about 82.5% (v/v) to about 87.5% (v/v). More preferably, the concentration of the lower aliphatic alcohol is about 85% (v/v).
• the concentration of water or the water-compatible solvent mixture is from about 1% (v/v) to about 15% (v/v).
• concentration of water or the water-compatible solvent mixture is from about 9% (v/v) to about 11 % (v/v). More preferably, the concentration of water or the water-compatible solvent mixture is about 10% (v/v).
• water is used; alternatively, a water-compatible solvent mixture can be used. This would comprise hydrophilic polar organic solvents.
• the invention comprises an additional antifungal compound.
• this embodiment comprises: (1) an allylamine antifungal compound; (2) an additional antifungal compound; (3) an aliphatic alcohol substituted with an aromatic substituent in which the allylamine antifungal compound and the at least one additional antifungal compound are soluble to a degree that a therapeutically effective concentration of the allylamine antifungal compound and of the additional antifungal compound can be applied topically in solution; (4) a lower aliphatic alcohol in which the aromatic alcohol is soluble; and (5) water or a water-compatible solvent mixture.
• the additional antifungal compound can be any of griseofulvin, ketoconazole, griseofulvin, miconazole, itraconazole, fluconazole, clotrimazole, econazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, cicloprox olamine, haloprogin, and tolnaftate.
• the additional antifungal compound is griseofulvin, miconazole, ketoconazole, both griseofulvin and ketoconazole, or both griseofulvin and miconazole.
• the compound or mixture of compounds should remain soluble in the presence of 10% to 20% water.
• the concentration of the allylamine antifungal compound is preferably about 2% (w/v).
• the concentration of the additional antifungal compound is typically from about 1 % (w/v) to about 3% (w/v), preferably from about 1.5% (w/v) to about 2.5% (w/v), more preferably about 2% (w/v).
• Other concentrations can be used depending on the specific additional antifungal compounds included.
• the volume of the lower aliphatic alcohol used is adjusted to take the concentration of the additional antifungal compound into account.
• Another embodiment of the invention is a method of treating a fungal infection of skin or nails, particularly onychomycosis.
• the method comprises topically administering a composition according to the present invention to the skin or nails in an amount therapeutically effective to treat the fungal infection.
• the fungal infection is an infection of the plantar or peri-plantar regions of the foot or of the subungual epithelium present above and around the nail bed.
• the fungal infection can be an infection caused by Trichophyton rubrum, Microsporum canis, T. mentagrophytes, T. interdigitale, or another fungal species.
• One embodiment of the present invention is an antifungal composition for topical application to the skin and nails.
• this embodiment of the composition comprises: (1) an allylamine antifungal compound; (2) an aliphatic alcohol substituted with an aromatic substituent in which the allylamine antifungal compound is soluble to a degree that a therapeutically effective concentration of the allylamine antifungal compound can be applied topically in solution; (3) a lower aliphatic alcohol in which the aromatic alcohol is soluble; and (4) water or a water-compatible solvent mixture.
• the allylamine antifungal compound is terbinafine.
• the allylamine antifungal compound can be another allylamine such as naftifine or an analogue or derivative of terbinafine or naftifine.
• the aliphatic alcohol substituted with an aromatic substituent is benzyl alcohol.
• the aromatic alcohol is phenethyl alcohol or another aromatic alcohol.
• the lower aliphatic alcohol is selected from the group consisting of ethyl alcohol, isopropyl alcohol, and mixtures thereof.
• the lower aliphatic alcohol is ethyl alcohol. More preferably, the ethyl alcohol is absolute ethyl alcohol. Alternatively, the ethyl alcohol can be 95% ethyl alcohol. In another alternative, the lower aliphatic alcohol can be a mixture of ethyl alcohol and isopropyl alcohol.
• the concentration of the allylamine antifungal compound is from about 1% (w/v) to about 3% (w/v) in the final composition.
• the concentration of the allylamine antifungal compound is from about 1.5% (w/v) to about 2.5% (w/v) in the final composition. More preferably, the concentration of the allylamine antifungal compound is about 2% in the final composition.
• the concentration of the aliphatic alcohol substituted with an aromatic substituent is from about 3% (v/v) to about 10% (v/v) in the final composition.
• the concentration of the aliphatic alcohol substituted with an aromatic substituent is about 5% (v/v) in the final composition.
• the concentration of the lower aliphatic alcohol is from about 80% (v/v) to about 90% (v/v).
• the concentration of the lower aliphatic alcohol is from about 82.5% (v/v) to about 87.5% (v/v). More preferably, the concentration of the lower aliphatic alcohol is about 85% (v/v).
• the concentration of water or the water-compatible solvent mixture is from about 1% (v/v) to about 12.5% (v/v).
• the concentration of water or the water-compatible solvent mixture is from about 9% (v/v) to about 11 % (v/v). More preferably, the concentration of water or the water-compatible solvent mixture is about 10% (v/v).
• water is used; alternatively, a water-compatible solvent mixture can be used. This would comprise hydrophilic polar organic solvents.
• the invention is directed at the delivery of drugs that have to act on the surface of the skin or under the nail, and that have to be retained for prolonged periods of time stored in the interstices of the epidermis, at the epidermal-dermal junction or sub-epidermal regions.
• drugs that have to act on the surface of the skin or under the nail, and that have to be retained for prolonged periods of time stored in the interstices of the epidermis, at the epidermal-dermal junction or sub-epidermal regions.
• antifungal agents that are required to act in the interstices of highly keratinized epithelium, such as that encountered on the plantar and peri- plantar regions of the foot and the subungual epithelium present above and around the nail bed (hyponychium, proximal nail fold, matrix and distal groove).
• a mixture of solvents which include benzyl alcohol as a primary carrier, combined with alcohols in an anhydrous phase, or mixed with various amounts of water, and which are still able to retain the highly hydrophobic antifungal agents in solution are used as carriers.
• This mixture is able to cross both the epidermal barrier working its way through the lipid phase encountered as the solvent migrates through the packed keratinocytes of the epidermis, as well as through the moist nail plate while continuing to carry the drugs in solution.
• tissue water begins to dilute the solution the drugs in question precipitate in the interstices of the cells and deposit in a microcrystalline form.
• the solutions prepared according the formulas described will hold the antifungal compounds until the water content reaches 40-60%, depending on the compound and the relative concentration of the solvents. Since the water content of the nail ranges between 10 and 30%, the solvent carrier with the terbinafine in solution is able to traverse the nail plate and reach the subungual region, or nail bed. The material, which then begins to precipitate, is deposited in the interstices of the soft tissue and nail plate. It has been shown clinically and experimentally to act as a slow release active principle, thus providing a long-term bioactive function.
• the rate of diffusion of water through the nail plate is 10 times greater than through abdominal skin, taken as an example.
• the permeability coefficient of nails to n- alkanols an indication of the ability of hydrophobic compounds to traverse a barrier, decreases as the compounds become increasingly hydrophobic. It is therefore apparent that for a compound to traverse the nail plate it has to be water-soluble. It has been postulated that if alkanol permeability could be extrapolated to other low molecular weight organics compounds, very polar compounds might be easily delivered through the nail plate to the underlying tissues (Walters), something that has never been achieved.
• This persistent and possible prophylactic response is attributed to the unique solubility characteristics of the compounds in question and to the ability of the selected solvents to deliver the drug to the subungual or keratin rich regions where the fungi accumulate, and to persist at such sites in a microcrystalline form after precipitation.
• the antifungal agent, terbinafine an allylamine compound used to treat infections of the nails and of the sub and peri-plantar regions of the foot (moccasin distribution) is dissolved in benzyl alcohol at room temperature with the aid of stirring.
• the solubility in this compound is very large (greater than 40% w/vol) and this accounts for the properties associated with such a solution.
• Two grams of terbinafine are therefore dissolved in 5 ml of benzyl alcohol.
• 85 ml of ethyl alcohol anhydrous and 10ml of distilled water are added.
• the final concentration of the active compound terbinafine is 2% and that of the preferred carrier, benzyl alcohol 5%.
• Alternative embodiments include increasing the benzyl alcohol concentration to 10%, using 95% ethanol instead of absolute ethanol, or replacing part of the ethanol with isopropyl alcohol.
• an antifungal composition comprising an allylamine antifungal compound and an additional antifungal compound.
• this embodiment of the composition comprises: (1) an allylamine antifungal compound; (2) an additional antifungal compound; (3) an aliphatic alcohol substituted with an aromatic substituent in which the allylamine antifungal compound and the additional antifungal compound are soluble to a degree that a therapeutically effective concentration of the allylamine antifungal compound and of the additional antifungal compound can be applied topically in solution; (4) a lower aliphatic alcohol in which the aromatic alcohol is soluble; and (5) water or a water-compatible solvent mixture.
• the additional antifungal compound can be any of griseofulvin, ketoconazole, griseofulvin, miconazole, itraconazole, fluconazole, clotrimazole, econazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, cicloprox olamine, haloprogin, and tolnaftate. More than one additional antifungal compound can be used. Typically, the additional antifungal compound is griseofulvin, miconazole, ketoconazole, both griseofulvin and ketoconazole, or both griseofulvin and miconazole. Although terbinafine works effectively on its own, therapeutic efficacy can be improved by combining it with other antifungal compounds that operate by different mechanisms (i.e., cell membrane synthesis inhibitors versus agents that operate by disrupting the cytoskeleton).
• the concentration of the allylamine antifungal compound is preferably about 2% (w/v).
• the concentration of the additional antifungal compound is typically from about 1% (w/v) to about 3% (w/v), preferably from about 1.5% (w/v) to about 2.5% (w/v), more preferably about 2% (w/v).
• Other concentrations can be used depending on the specific additional antifungal compounds included.
• the volume of the lower aliphatic alcohol used is adjusted to take the concentration of the additional antifungal compound into account. Thus, if one additional antifungal compound is used at a concentration of 2% (w/v), the volume of the lower aliphatic alcohol, such as ethyl alcohol, is reduced by 2%.
• compositions according to the present invention can be applied by conventional methods, including the use of a small brush with a nail-lacquer bottle, a roll-on applicator, or by a squeeze bottle with a small opening.
• a small brush with a nail-lacquer bottle was used.
• Another embodiment of the invention is a method of treating a fungal infection of skin or nails, particularly onychomycosis.
• the method comprises topically administering a composition according to the present invention to the skin or nails in an amount therapeutically effective to treat the fungal infection.
• the fungal infection is an infection of the plantar or peri-plantar regions of the foot or of the subungual epithelium present above and around the nail bed.
• the fungal infection can be an infection caused by Trichophyton rubrum, Microsporum canis, T. mentagrophytes, T. interdigitale, or another fungal species.
• the fungal infection can be tinea pedis (athlete's foot), typically caused by fungi such as T. mentagrophytes, T. rubrum, or Epidermophyton floccosum.
• an administered dose of a composition according to the present invention will vary with the severity and extent of the fungal infection. Further, the application dose and perhaps the application frequency, can also vary according to the age, body weight, and response of the individual patient, as well as other conditions affecting pharmacodynamic parameters such as liver and kidney function. This should be kept in mind even though systemic absorption of these drugs is relatively low and the total amount of medication used is orders of magnitude less than in the case of systemic administration.
• the present invention provides compositions and methods that are more efficient for treating fungal infections, particularly fungal infections of the skin and nails, by topical application of the compositions without need for systemic administration. Accordingly, the use of compositions and methods according to the present invention minimizes the risk of side effects that can occur with systemic administration of antifungal agents. Some of these side effects, particularly effects on the liver and on the hematopoietic system, can be serious and even life-threatening. At the very least, they can force discontinuance of therapy, leaving the patient without a cure for the fungal infection. The compositions and methods of the present invention avoid this problem. In addition, any recurrence following oral or topical therapy can be easily resolved due to the simplicity and safety of the method described herein.

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