WO1999049835A1 - An acidified composition for topical treatment of nail and skin conditions - Google Patents
An acidified composition for topical treatment of nail and skin conditions Download PDFInfo
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- WO1999049835A1 WO1999049835A1 PCT/US1999/006740 US9906740W WO9949835A1 WO 1999049835 A1 WO1999049835 A1 WO 1999049835A1 US 9906740 W US9906740 W US 9906740W WO 9949835 A1 WO9949835 A1 WO 9949835A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q3/00—Manicure or pedicure preparations
- A61Q3/02—Nail coatings
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- 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
- A61K31/415—1,2-Diazoles
-
- 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
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/20—Halogens; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
- A61K8/447—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof containing sulfur
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
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- 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
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- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
Definitions
- This invention relates to a method for topical treatment of human nail and skin diseases, including fungal infections, bacterial infections, and psoriatic infections.
- this invention relates to a method of treating the general condition of human nails including their strength, rate of growth and appearance. More particularly, the invention relates to an acidified composition and methods of using said composition. Still further the invention relates to an acidified lacquer useful in treating human nails and skin.
- Onychomycosis is a fungal disease of the human nail.
- the symptoms of this disease are a split, thickened, hardened, and rough nail plates. This is caused by any of a number of organisms and is particularly prevalent in the elderly.
- Typically fungal infections are treated by topical application of antifungal agents and/or oral administration of antifunal agents.
- there is no topical treatment for onchomycosis which is approved by the United States Food and Drug Administration. It is desirable to treat this disease topically due to the potential for side effects which have been associated with some of the oral treatment regimens.
- One reason for the absence of a topical treatment is that in this disease, the symptomatic thickened nail plate prevents topical agents from reaching the site of the infection.
- the target sites for the treatment of onychomycosis reside in the
- nail plate is thick, hard, dense, and represents a daunting barrier for drugs to be able to penetrate in a therapeutically required quantity.
- nail material is similar to the stratum corneum of the skin, being derived from epidermis, it is composed primarily of hard keratin, which is highly disulfide-linked, and is approximately 100-fold thicker than stratum corneum.
- the permeability of the nail plate to the drug must be enhanced. This is particularly true in fungal diseases where a common symptom of the disease is thickened nail plate.
- patients' small toe nails were 5 mm and their large toe nails were 9mm.
- Nail plates have a high sulphur content in the form of disulfide bonds.
- U.S. Patent 5,696,164 (Sun et al., 1997) discloses the use of thio-containing amino acids and its derivatives (i.e., sulfhydryl-containing amino acids), such as cysteine and N-acetyl cysteine, and urea to increase drug permeability in a nail plate, by breaking disulfide bonds in nail keratin to increase drug penetration into and through the nail. It was shown that a significant enhancement in topical drug delivery through nail was achieved.
- thio-containing amino acids and its derivatives i.e., sulfhydryl-containing amino acids
- cysteine and N-acetyl cysteine urea
- European Patent Application EP 503988 A1 (1992) discloses a composition to treat onychomycosis, comprising nail-penetration agents, such as glycols, glycol ethers, dimethyl sulfoxide, caprolactam, and other hydrophilic compounds to facilitate the penetration of allylamine fungicides into the nail.
- nail-penetration agents such as glycols, glycol ethers, dimethyl sulfoxide, caprolactam, and other hydrophilic compounds to facilitate the penetration of allylamine fungicides into the nail.
- Nail lacquer also known as nail coating, polish, enamel and/or varnish
- a drug-containing nail lacquer is the most convenient and most acceptable nail treatment method to treat nail diseases such as onychomycosis and psoriasis-affected nail.
- it is essential to have a drug-containing nail lacquer that is capable of delivering a drug or drugs into and through the nail in therapeutically sufficient quantity.
- the drug-containing lacquer should not be irritating to the skin tissue adjacent to the nail.
- the drug in the lacquer formulations should be stable enough to meet the normally required 2-year shelf life for a pharmaceutical product.
- Nail lacquers containing therapeutic agents have been known in the past.
- U.S. Patent 4,957,730 (1990) describes a nail varnish containing a water-insoluble film-forming substance and antimycotic compound.
- U.S. Patent 5,120,530 (1992) describes a antimycotic nail varnish containing amorolfine in quaternary ammonium acrylic copolymer.
- the water- insoluble film former is a copolymerizate of acrylic acid esters and methacrylic acid esters having a low content of quaternary ammonium groups.
- U.S. Patent 4,957,730 (1990) describes a nail varnish containing a water-insoluble film-forming substance and antimycotic compound.
- U.S. Patent 5,120,530 (1992) describes a antimycotic nail varnish containing amorolfine in quaternary ammonium acrylic copolymer.
- the water- insoluble film former is a copolymerizate of acrylic acid esters and methacrylic
- Patent 5,264,206 (1993) describes a nail lacquer with antimycotic activity, which contains an antimycotic agent and water-insoluble film formers including polyvinyl acetate, a copolymer of polyvinyl acetate and acrylic acid, copolymers of vinyl acetate and crotonic acid, monoalkyl maleate, etc.
- U.S. Patent 5,346,692 (1994) describes a nail lacquer for treating onychomycosis, comprised of a film-forming agent, an antimycotically active substance, and urea, wherewith the antimycotic agent and urea are liberated from the lacquer when the lacquer is applied.
- a preferred formulation comprises cellulose derivatives as film former, clotrimazole as the antimycotic agent, dibutyl phthalate as a plasticizer, and a mixture of acetone and ethanol as solvent.
- U.S. Patent 5,487,776 (1996) describes a nail lacquer composition which forms a water permeable film containing griseofulvin when the organic solvent system evaporates, wherein a portion of the griseofulvin is in solution and a portion of griseofulvin is present as a colloidal suspension.
- European Patent Application EP515312 A2 (1992) describes a nail lacquer containing terbinafine or its hydrochloric acid salt as an antimycotic agent, solvents, and a polymeric film former consisting of di-butyl phthalate, Paraloid A-21 acrylic resin, poly(vinyl acetate) etc.
- terbinafine or its hydrochloric acid salt as an antimycotic agent
- solvents solvents
- polymeric film former consisting of di-butyl phthalate, Paraloid A-21 acrylic resin, poly(vinyl acetate) etc.
- a topical product for nail disease treatment such as onychomycosis
- a topical product for nail disease treatment is not only efficacious in eliminating the fungi, but in shortening the waiting period for the healthy nail to grow.
- U.S. Patent 4,927,626 (1990) describes the topical application of minoxidil to increase the growth of unguis in animals, including human nail. However, it neither describes nor suggests how to deliver the minoxidil through the nail.
- onychomycosis The recurrence rate of onychomycosis is relatively high for the patients who have been treated and considered "cured". Because certain people are more prone to onychomycosis, prophylactic products, such as a drug- containing lacquer, are desirable to prevent the relapse of onychomycosis. Aside from the antifungal diseases associated with nails, there are antifungal diseases associated with human skin. One particular sight of infection is the feet where diseases associated with ring worm, commonly known as athlete's foot, are prevalent.
- a drug- containing composition which is capable of delivering a drug or drugs into and through human nails and skin in a therapeutically sufficient quantity.
- a composition which adheres to the nail and skin for a prolonged period of time Further it is an object of the invention to prepare a composition which is non-irritating to human skin.
- a lacquer containing said composition Further, the composition containing lacquer should not be irritating to the skin tissue adjacent to the nail. Further still, the composition and lacquer should have the shelf required of a pharmaceutical
- the present invention provides an acidified composition to treat nail and skin diseases such as onychomycosis, psoriatic nails, psoriasis of the skin, versicolor, ringworm, plantar tinea pedis, Jock itch, and athlete's foot.
- nail and skin diseases such as onychomycosis, psoriatic nails, psoriasis of the skin, versicolor, ringworm, plantar tinea pedis, Jock itch, and athlete's foot.
- the invention includes an acidified composition comprising at least one active agent, at least one acidifier, and at least one volatile solvent. Further, the invention includes a method of treating disease infected human nails or skin by topically applying 1 ) an acidified composition comprising at least one acidifier, at least one volatile solvent, and at least one active agent; or 2) an acidified lacquer composition comprising at least one acidifier, at least one volatile solvent, at least one active agent, and at least one polymeric film former.
- the invention includes a method of improving and promoting healthy human nails and skin by topically applying 1 ) an acidified composition comprising at least one acidifier, at least one volatile solvent, and at least one active agent; or 2) an acidified lacquer composition comprising at least one acidifier, at least one volatile solvent, at least one
- the invention contemplates an acidified lacquer composition comprising at least one active agent, at least one acidifier, at least one volatile solvent, and at least one polymeric film former.
- Figure 1 is a depiction of the target sites for the treatment of onychomycosis.
- Figure 2 is a graph of the drug partitioning results for miconazole nitrate lacquer formulations.
- Figure 3 is graph of the drug partitioning results for itraconazole lacquer formulations.
- Figure 4 is a graph of the permeation profiles for miconazole nitrate.
- Figure 5 is a graph of the permeation of miconazole nitrate lacquers.
- Figure 6 is a graph which compares the amount of miconazole nitrate retained on the skin using different miconazole nitrate formulations.
- Figure 7 shows the relative miconazole content in epidermis, dermis and receptor media.
- This invention relates an acidified composition
- an acidified composition comprising at least one active agent, at least one acidifier, at least one volatile solvent, and at least one active agent.
- the term "acidifier” refers to substances which are liquids having an apparent pH of ⁇ 1 , or solids having a pKa ⁇ 5. Apparent pH is the pH reading measured by a glass pH electrode.
- the preferred acidifiers are 37% HCI, 10% HCI, sulfuric acid, o-phosphoric acid, nitric acid, acetic acid, L (+)-lactic acid, salicylic acid, and glycolic acid.
- volatile solvent refers to liquid substances which evaporate more rapidly than water.
- the volatile solvent need not be anhydrous but should have less than 30%, preferably less than 10% with most preferably less than 2% water.
- examples of such solvents include but are not limited to ethyl alcohol, isopropyl alcohol, ethyl acetate, butyl acetate, acetone, and mixtures thereof.
- the preferred volatile solvents are ethyl alcohol, isopropyl alcohol, ethyl acetate, and butyl acetate. If the total weight of the acidified composition is 100 parts, preferably, the volatile solvent is 90-98 % w/w.
- active agents refers drugs for treating diseased nails, nutrients or nail conditioners which may be used to improve damaged nails or maintain healthy, and nail growth promoters which may be used on damaged or healthy nails. All of the aforementioned types of active agents may be used to treat the tissue surrounding the nail, and skin whether that tissue is healthy or diseased.
- the active agents include but are not limited to antifungal drugs used to treat onychomycosis and athlete's foot, antibiotics (or antiseptics) for bacterial infection of nails, tissue surrounding the nails and other human tissues, and antipsoriatic drugs for psoriatic nail and skin treatment.
- antifungal drugs include but are not limited to miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin,
- the preferred antifungal drugs are an azole, an allylamine, or a mixture thereof.
- Preferred azoles are selected from the group consisting of itraconazole, ketoconazole, miconazole, econazole, fluconazole, vo conazole, clotrimazole, butenafine, undecylenic acid, clioqinol, and their pharmaceutically acceptable salts.
- Preferred allylamines are selected from the group consisting of terbinafine, naftifine and mixtures thereof.
- antibiotics include but are not limited to mupirocin, neomycin sulfate, bacitracin, polymyxin B, /-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetrachcycline hydrochoride), clindamycin phsphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, and their pharmaceutically acceptable salts.
- Preferred antibiotics and antiseptics include mupirocin, neomycin sulfate, bacitracin, polymyxin B, /-ofloxacin, tetracyclines, benzalkonium chloride, benzethonium chloride, triclocarbon, and triclosan.
- antipsoriatic drugs include but are not limited to corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone verlerate, hydrocortisone butyrate, aclometasone dipropionte, flurandrenolide, mometasone furoate, methylprednisolone acetate), calcipotriene and anthraline.
- Preferred antipsoriatic drugs include betamethasone dipropionate, betamethasone valerate, and clobetasol propionate.
- the active agents are nail growth promoters
- such agents include but are not limited to minoxidil, minoxidil sulfate, retinoids, cysteine and acetyl cysteine, methionine, glutathione, biotin, finasteride and ethocyn, as well as pharmaceutically acceptable salts of these compounds.
- the preferred growth promoter are minoxidil, minoxidil sulfate, retinoids, cysteine and acetyl cysteine.
- the particularly preferred nail growth promoters are 2% minoxidil, 2% minoxidil sulfate, and 0.1% retinol.
- the active agents include nutrients, they include but are not limited to vitamins, amino acids, and their derivatives.
- vitamin B complex examples include but are not limited to vitamin B complex: thiamine, nicotinic acid, biotin, pantothenic acid, choline riboflavin, vitamin B 6 , vitamin B ⁇ 2 , pyridoxine, inositol, camitine; ascorbic acid, ascorbyl palmitate, vitamin A, vitamin K, vitamin E, vitamin D, cysteine and N-acetyl cysteine, herbal extracts, and their derivatives.
- vitamin B complex examples include but are not limited to vitamin B complex: thiamine, nicotinic acid, biotin, pantothenic acid, choline riboflavin, vitamin B 6 , vitamin B ⁇ 2 , pyridoxine, inositol, camitine; ascorbic acid, ascorbyl palmitate, vitamin A, vitamin K, vitamin E, vitamin D, cysteine and N-acetyl cysteine, herbal extracts, and their derivatives.
- the active agents include nail conditioners they include but are not limited to mineral-containing compounds, flavonoids and retinoids. These nail conditioners improve general nail conditions, such as strengthening the nails to prevent nail chipping and cracking, and to beautify the nails.
- retinoids examples include but are not limited to calcium pantothenate, calcium carbonate, and calcium gluconate.
- examples of retinoids include but not limited to retinol (Vitamin A alcohol), retinal (Vitamin A aldehyde), retinyl acetate, etinyl palmitate, retinoic cid, 9-cis-retinoic acid and 13-cis-retinoic acid.
- flavonoids include but not limited to naringenin, quercetin, catechins (e.g., epigallocatechin gallate), theaflavins, robustaflavone, hinokiflavone, amentoflavone, agathisflavone, volkensiflavone, morelloflavone, rhusflavanone, and succedangeaflavanone.
- catechins e.g., epigallocatechin gallate
- theaflavins robustaflavone, hinokiflavone, amentoflavone, agathisflavone, volkensiflavone, morelloflavone, rhusflavanone, and succedangeaflavanone.
- the preferred active agents are miconazole nitrate, itraconazole, econazole nitrate, ketoconzaole, clotrimazole, and terbinafine. If the total weight of the acidified composition is 100 parts, the active agent is present in about 0.05% to about 10% w/w, preferably, from about 0.1 % to about 5%, more preferably from about 0.5% to about 2%.
- compositions of this invention may include other substances, such as preservatives, cosmetic additives, antioxidants, chelating agents and pigment flakes.
- preservatives include but are not limited to benzoic acid, benzyl alcohol (as preservative), glycerol, propylene glycol as emollient, butylated hydroxyltoluene, butylated hydroxyanisole, ascorbic acid, ascorbyl palmitate, N-acetyl cysteine as antioxidant, citric acid, edetic acid and its sodium salts as chelating agent.
- An example of a typical acidified composition comprises 1 % clotrimazole as active agent, 0.1 % concentrated HCI (37% HCI by weight) as acidifier, and 98.7% ethyl alcohol as volatile solvent.
- An example of a topical formulation containing this composition comprises 1 % clotrimazole as active agent, 0.1 % concentrated HCI (37% HCI by weight) as acidifier, 0.1% butylated hydroxyltoluene as antioxidant, 0.1 % citric acid, and 98.7% ethyl alcohol as volatile solvent.
- the invention includes an acidified lacquer composition comprising at least one active agent, at least one acidifier, at least one volatile solvent, and at least one polymeric film former.
- the terms, active agent, acidifier, and volatile solvent have their aforementioned meanings.
- the acidifier should be present at about 0.05 to 10% w/w, preferably, from about 0.1 % to about 5%, more preferably form about 0.5% to about 2%.
- the volatile solvent should be present preferably, at about 70 to about 98 % w/w.
- the active agent should be present at about 0.05% to 10% w/w, preferably, from about 0.1 % to about 5%, more preferably from about 0.5% to about 2%.
- lacquer refers to a liquid substance which typically dries to form a continuous or a non-continuous film by evaporation of the solvent.
- polymeric film former is a polymer which may be added to a volatile solvent and other substances to form a polymeric solution which may be applied to the skin to form a film.
- polymeric film formers include but are not limited to acrylic copolymers/acrylic polymers, (such as Carboset® or Avalure® polymers, made by BF Goodrich); polymers of methacrylic acid and its esters (such as Eudragit® polymers.S, L, RS and RL series, made by Rohm Pharma); cellulose polymers, nitrocellulose, methyl cellulose, ethyl cellulose, cellulose acetates (such as cellulose triacetate, cellulose acetate butyrate); nylon, polyvinyl acetate, polyvinyl acetate phthalate, formaldehyde resin, and polymer blends of the aforementioned polymers.
- Preferred polymeric film formers are selected from the group consisting of acrylic copolymers/acrylic polymers, (such as Carb
- Lacquers may have different viscosities.
- the viscosity of the lacquer is related to the thickness of the film that will be left on a surface once the volatile solvent has evaporated. If one desires a thick and viscous lacquer, which will deposit a thick film on a surface, the concentration of the polymeric film former should be about 0.1 % to about 30%, preferably from about 0.5% to about 15% of the total composition. If one desires a thin lacquer which will deposit a thin film on a surface, the concentration of the polymeric film former should be about 0.1 % to about 15%, preferably about 0.5 % to about 5.0% of the total composition.
- the acidified lacquers of the invention may have other additives such as plasticizers (to maintain the pliability of the film formers), non-volatile drug solubilizers, cosmetic additives, and pharmaceutical additives.
- plasticizers and non-volatile drug solubilizers examples include but are not limited to phthalate esters (e.g., dibutyl phthalate), citrate esters, triacetin, isopropyl myristate, N-methyl- 2-pyrrolidone, fatty acids and fatty acid esters, propylene glycol, butylene glycol, hexylene glycol, propylene carbonate, poly-propylene glycol, methoxypolyethylene glycol, polyethylene glycol, glycerin.
- plasticizers are used they are preferably about 0.001 to about 10% by weight of the total composition.
- antioxidants include but are not limited to antioxidants and chelating agents.
- antioxidants include but are not limited to butylated hydroxyltoluene, butylated hydroxyanisole, ascorbic acid, ascorbyl
- a typical acidified lacquer composition comprises 1 % clotrimazole as active agent, 0.1 % concentrated HCI (37% HCI by weight) as acidifier, 15% acrylic polymer (Carboset® 525 or Avalure® AC 315) as film former, and 43% ethyl alcohol and 40% ethyl acetate as volatile solvents.
- the typical topical formulation containing the acidified lacquer composition comprises 1 % clotrimazole as active agent, 0.1 % concentrated HCI (37% HCI by weight) as acidifier, 15% acrylic polymer (Carboset® 525 or Avalure® AC 315) as film former, 0.7% isopropyl myristate as non-volatile drug solubilizer, 0.1 % butylated hydroxyltoluene as antioxidant, 0.1 % citric acid, and 43% ethyl alcohol and 40% ethyl acetate as volatile solvents.
- a typical formulation containing the acidifed lacquer composition which may be used to treat onychomycosis comprises from about 0.5 to about 3% of an antifungal drug as an active agent, from about 0.1% to about 1% concentrated HCI (37% HCI by weight) as an acidifier, about 15% acrylic polymer (Carboset® 525 or Avalure® AC 315) as a polymeric film former, 1 % isopropyl myristate as non-volatile solvent, 0.1 % butylated hydroxyltoluene as antioxidant, 0.1 % citric acid, and 37% ethyl alcohol and 42.3% - 42.7% ethyl acetate as volatile solvents.
- a typical formulation containing the acidifed lacquer composition which may be used to treat vesicolor, psoriasis, ringworm, plantar tinea pedis, Jock itch, and athlete's foot comprises from about 0.5 to about 3% an antifungal
- the anti fungal drugs in the above examples can be selected from at least one of the following: clotrimazole, miconazole, terbinafine, amorolfine, ciclopirox olamine, tolnaftate, fluconazole, econazole, ketocoanzole, itraconazole, butenafine, and their pharmaceutically acceptable salts.
- the invention includes a method of treating disease infected human nails or disease infected human skin by topically applying 1 ) an acidified composition comprising at least one acidifier, at least one volatile solvent, and at least one active agent; or 2) an acidified lacquer composition comprising at least one acidifier, at least one volatile solvent, at least one active agent, and at least one polymeric film former
- Fig. 1 is a schematic diagram showing the basic anatomic structure of human nail and its surrounding tissues.
- the treatment contemplated by this invention is intended to deliver an active agent to the nail plate (the stratum corneum unguis) and to the nail bed (the modified area of epidermis beneath the nail, over which the nail plate slides as it grows) through the nail plate.
- the active agent is also concurrently administered to the nail matrix (the proximal portion of the nail
- applying refers to any method of physically transferring the acidified composition to the nail and the skin. Such methods include but are not limited to painting the composition or lacquer on the surface of the nail; spraying the composition or lacquer using a spray pump, and combining the composition or lacquer with a propellant so that it sprayed on the skin as an aerosol.
- aerosol refers to systems consisting of "pressurized packages” with either compressed gases or liquefied gases as propellants. Examples of compressed gases are compressed nitrogen and air. Examples of liquefied gas propellants are propane, isobutane, n-butane, dimethyl ether, and mixtures thereof.
- the preferred propellants are dimethyl ether, and mixture of dimethyl ether and one or more hydrocarbon propellants.
- the preferred weight ratio of dimethyl ether to the hydrocarbon propellant(s) ranges from greater than or equal to about 3:2 (> 3.2) respectively.
- the composition or lacquer is initially applied for once or twice per day and may be reduced to once or twice a week depending upon the intensity and resilience of the underlying infection.
- disease refers to fungal diseases, bacterial diseases and psoriasis.
- the fungal diseases of the human nail that can be treated in accordance with the invention include but are not limited to "onychomycosis.” This disease is typically caused by an infection of Epidermophyton floccosum,
- Trichophyton such as T. rubrum and T. mentagrophytes
- yeast such as Candida albicans
- Fungal diseases of the human skin include but are not limited to the diseased portions of the skin surrounding a nail especially to the eponychium, i.e., the skin tissue above the nail matrix.
- This application allows antifungal drug and nail growth promoters to be absorbed into the eponychium and subsequently into the nail matrix. This is particularly beneficial, for when the nail growth is accelerated, some antifungal drug is incorporated into the growing healthy nail to prevent re-infection by fungi.
- fungal skin diseases such as versicolor, ringworm, psoriasis, athlete's foot, plantar tinea pedis, and Jock itch may be treated using the methods and compositions of this invention.
- these skin diseases are caused by funguses such as Trichophyton rubrum, T. mentagrophytes, and Epidermophyton floccosum.
- the treatment regimen for skin fungal infections using the acidified composition or acidified lacquer can be once or twice per day, preferably once per day, with a duration from less than a week to four weeks, preferably equal or less than two weeks.
- the topical treatment of the invention may be employed in combination with systemic treatment.
- an antifungal drug such as, itraconazole, terbinafine, griseofulvin or other antifungal drugs
- This time period may be concurrently during the entire topical treatment regimen, or concurrently during a portion (usually the latter phase) of the topical treatment regimen, or following the topical treatment.
- the invention includes a method of treating healthy human nails or skin by topically applying 1 ) an acidified composition comprising at least one acidifier, at least one volatile solvent, and at least one active agent; or 2) an acidified lacquer composition comprising at least one acidifier, at least one volatile solvent, at least one active agent, and at least one polymeric film former
- the acidified composition and the acidified lacquer of the invention are non-irritating they may be used prophylactically to prevent infection.
- the acidified lacquer and acidified composition may be applied once or twice per month.
- the prophylactic treatment regimen for fungal infections of the nail and skin using the acidified composition or acidified lacquer can vary from once or twice per week to once or twice per month, with the interval between treatments shorter for the skin and longer for the nail. In order to illustrate the invention, the following examples are included.
- the miconazole nitrate content of the nail clippings was analyzed by High Pressure Liquid Chromatography (HPLC), and the results were tabulated in Table 2. It can be seen that the nail uptake of miconazole nitrate from the acidified solutions was enhanced by approximately 9 fold using 1 % of hydrochloric acid or sulfuric acid; and 2-3 fold using the other acids tested.
- HPLC High Pressure Liquid Chromatography
- the nail lacquer formulations used in the drug partitioning studies are shown in the Table 3.
- the lacquer formulations contained either miconazole nitrate or itraconazole, with and without concentrate hydrochloric acid.
- the number on the bars in the figures are the enhancement ratio, which equals the nail drug content treated with a HCI-containing lacquer, divided by
- compositions of lacquer formulations containing either miconazole nitrate or itraconazole used in the nail uptake experiments and Primary Dermal Irritation Test (in weight %).
- Acidified lacquer formulations demonstrated enhanced drug uptake into human nail clippings.
- the drug concentrations in the nail were the average value (AVG) with corresponding standard deviation (STD).
- the enhancement ratio of nail uptake of a drug was calculated by dividing the nail drug content treated with the acidified lacquer formulation of a particular drug concentration, over the nail drug content treated with a non-acidified lacquer containing the same drug concentration.
- a standard test for skin irritation called “the Modified Draize Rabbit Primary Dermal Irritation Test” (PDI) was used to evaluate the acidified nail lacquers. The test procedures are described briefly as follows. The test skin sites of the New Zealand White albino rabbits were clipped free of fur. Skin abrasion was made at each test skin site using the barbed tip of a sterile 20 gauge hypodermic needle in a "tic-tac-toe" pattern. The nail lacquer was applied to the prepared test skin site.
- PDI Modified Draize Rabbit Primary Dermal Irritation Test
- the acidified nail lacquers were applied to the intact skin previously clipped free of fur (i.e., without previous skin abrasion) twice a week for two and one-half weeks. Prior to each lacquer application, the dried nail lacquer was first removed from the test skin using an alcohol swab containing 70% isopropyl alcohol.
- compositions of lacquer formulations containing either miconazole nitrate or itraconazole used in the Cumulative Skin Irritation Test (in weight
- Enhancers Nail penetration enhancers such as N-acetyl cysteine (NAC) have been shown to promote drug penetration through human nail when a drug formulation contained the penetration enhancer and the drug (see US patent 5,696,164).
- NAC N-acetyl cysteine
- the invention describes a new enhancement method using NAC for topical drug delivery to the nail.
- the essence of the new enhancing method is a nail pretreatment of nail penetration enhancer(s) prior to the application of an active-agent- containing formulation.
- the active agent may be of therapeutic or cosmetic value.
- the pretreatment formulation containing enhancer(s) is also comprised of active-agents for therapeutic and cosmetic purposes.
- the rank order of the enhancement with different pretreatment conditions are the following: urea alone ⁇ NAC alone ⁇ NAC plus urea.
- Pretreatment with urea alone showed rather limited enhancing effect on the drug uptake, whereas NAC alone was more effective.
- a combination of NAC and urea showed a definite synergistic effect in the enhancement of drug uptake.
- pretreatment with 20% urea alone resulted in 4.7 mg drug per gram nail
- pretreatment with 10% NAC alone resulted in 15.45mg drug per gram nail.
- pretreatment with 10% NAC and 20% urea resulted in 28.46mg drug per gram nail.
- the synergistic enhancement of two enhancers for drug uptake into the nail has an important and practical implication: it enable the use of a minimal amount of an enhancer which may be irritating to the skin at high concentration, such as NAC.
- Enhancement ratio is defined as: the drug content in the pretreated nail divided by the drug content in the non-pretreated nail after immersion in a nail lacquer of the same drug concentration.
- Example 6 Drug Permeation into and through Human Nail Plate Experiments were conducted to evaluate the drug penetration through human nails. The experimental procedures are briefly described as follows: (1 ) human nail plates were mounted in modified Franz diffusion cells. (2) A nail enhancer formulation containing 10% NAC and 20% urea was placed in the donor cells to pretreat the nail plate for 24 hours. (3) After the pretreatment formulations were removed from the donor cells, lacquer formulations containing 2% or 5% miconazole nitrate were applied to the nail plate in the donor cells. At the end of one week from the starting of the nail
- the nail lacquers were removed with ethanol swabs. Steps (2) & (3) were repeated for three more weeks.
- the effect of occlusive versus non-occlusive conditions was tested by covering selected donor cells with an occlusive polymer film after allowing the lacquer sufficient time to dry up.
- the occlusion test was used to mimic the condition often caused by the "over-coat" layers of another nail lacquer.
- the amount of drug permeated through the nail plate was determined by analyzing the receptor fluid with HPLC. The drug concentration in the nail plate was determined.
- the nail permeation results were tabulated in Table 7 and plotted in Figure 4.
- the permeation profiles in Figure 4 shows that miconazole nitrate from the nail lacquers permeated through the nail plate rather rapidly, especially for those nail plates which had been pretreated with nail penetration enhancers (i.e., comparing #1-4 with #5).
- the acidified nail lacquers delivered miconazole nitrate into and through the nail plates even without the help of nail penetration enhancers.
- Pretreatment with NAC and urea significantly increased the drug permeation through the nail.
- the lacquer containing a higher drug concentration delivered more drug through the nail. Occlusive condition further enhanced the drug permeation from the drug-containing lacquer.
- Occlusive conditions can be achieved easily by multiple coats of the drug- containing lacquer, or by "overcoats" of another lacquer, or by application of an occlusive cover, such as an adhesive-coated polymeric bandage of pre- determined properties, such as certain range of moisture and gas
- Enhancer 10%NAC & 20% urea Unoccluded 596.2 ⁇ 82.3 45.92 ⁇ 17.32 (8856.4 642.10 0.0567
- results in Table 9 and Figure 5 show that miconazole nitrate was indeed able to diffuse out of the lacquer layer and to penetrate through the human skin. All the miconazole nitrate- containing lacquers delivered more drug into the skin. A comparison of Formulation Nos. 7-3 with 7-4 show that a higher HCI content in the lacquer led to a higher skin permeation of the drug, indicating the acid acted like a penetration enhancer in this situation.
- the acidified formulations can be formulated as lacquer or spray and aerosol.
- a lacquer formulation contains relative high polymer content, and forms a polymer film upon application.
- a low-polymer-content formulation can be sprayed by a pump operated manually, or powered by compressed or liquefied gases, i.e., in the forms of liquid spray or aerosol.
- a pump operated manually or powered by compressed or liquefied gases, i.e., in the forms of liquid spray or aerosol.
- one of the formulations i.e., No. 4-3
- compositions of lacquer formulations containing miconazole nitrate used in the skin permeation study (in weight %).
- Control Micatin Cream conl taining 2% miconazole nitrate in a cream base.
- Example 8 Drug Stability in Acidified Lacquer
- accelerated drug stability tests were conducted at elevated temperatures over certain periods of time (a method widely applied in pharmaceutical industry).
- the stability results for the formulations tested e.g., Formulations 4-1 , 4-3, 3- 8, and 3-9 indicate that the drug formulations are stable in the acidified lacquers, and would satisfy the required two-year shelf life. This is a surprise since it is well known that the presence of a strong acid usually cause drug decomposition through acid-induced degradation reactions.
- Example 9 Increased Skin Substantivity of Miconazole Nitrate by the Present Invention
- the purpose of this experiment was to examine the skin substantivity of the antifungal drug miconazole nitrate from a liquid spray formulation as an example of the present invention.
- This liquid spray (hereto, the Spray Formulation) was compared to two commercial products for athlete's foot treatment, which contained the same drug and concentration as the Spray Formulation.
- topical antifungal products containing 2% miconazole nitrate for athlete's foot treatment require a regimen of twice-a-day
- a test formulation was applied to the skin surface to form a thin layer.
- a washing procedure was conducted to mimic normal shower/bath by washing the skin surface with 5 milliliters of warm water (32°C).
- miconazole nitrate retained on the skin surface was removed with methanol swabs, and the epidermis was separated from dermis.
- the drug content in wash liquids, methanol swabs, epidermis, dermis, and receptor media was analyzed by HPLC.
- Spray Formulation indeed provides superior drug substantivity to the skin, as opposed to the commercial cream and aerosol formulations.
- the significantly enhanced drug retention on the skin surface by the Spray Formulation should allow a less frequent dosing regimen than the current products, and thus improve patient compliance.
- Figure 7 shows the relative miconazole content in epidermis, dermis and receptor media.
- miconazole concentrations in the epidermis and dermis from the Spray Formulation were several fold higher than those from the Formula A cream and Formula B aerosol.
- Drug content in the receptor fluid was very low.
- Epidermis is the target tissue for athlete's foot treatment.
- a higher antifungal drug concentration in epidermis would assure complete elimination of the pathogenic dermatophytes, which should enable a reduction in dosing frequency (e.g., from twice a day to once a day) and treatment duration (e.g., from four weeks to one or two weeks).
- the unique moisture-triggering drug release from the Spray Formulation should be beneficial to the athlete's foot treatment.
- the newly developed miconazole nitrate Spray Formulation provides superior skin substantivity over the two commercial products tested (i.e., Formula A cream and Formula B spray liquid aerosol).
- the significantly enhanced drug retention on the skin surface by the Spray Formulation should allow a less frequent dosing regimen than the current products, and thus improve patient compliance.
- several fold more miconazole can be delivered into the skin by the Spray Formulation as opposed to the commercial products. Because epidermis is the target tissue for athlete's foot treatment, a higher antifungal drug concentration in epidermis would assure complete elimination of the pathogenic dermatophytes.
- Example 10 Aerosolized Acidified Lacquer Composition The "Spray Formulation" liquid composition in Example 9 (as shown in Table 10) was aerosolized following known procedures using dimethyl ether and a mixture of dimethyl ether with n-butane. The aerosol compositions and
- the aerosolized lacquer compositions 1 & 2 are preferable aersols with good content uniformity, where as the composition 3 is less desirable since the precipitation would likely cause non-uniform deposition of the drug during application, and would also likely to result in malfunction of the aerosol spray valve by clogging up the orifice.
- Example 11 Drug Partitioning Studies With Various Concentrations of Acidifiers
- Drug partitioning studies were conducted to evaluate formulation acidity on nail uptake of miconazole nitrate from nine nail lacquer formulations. All the formulations contain the same drug concentration (2% miconazole nitrate), but different amount of acidity modifiers, namely,
- the enhancement ratio refers to the ratio of a nail drug content from a lacquer containing an acidity modifier to that from a lacquer containing no acidity modifier (i.e., Formulation No. 5). It can be seen that both HCI and NaOH increased drug uptake into the nail. The extent of the increase in drug uptake is much greater with HCI. The highest drug uptake occurred with 0.5% concentrated HCI, followed by 1 % concentrated HCI.
- Formulation Cone HCI Cone. NaOH Miconazole Nitr in nail Enhancement Number. (37%) Added (10%) Added (mg drug/gm nail) Ratio
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
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AU32119/99A AU3211999A (en) | 1998-03-31 | 1999-03-29 | An acidified composition for topical treatment of nail and skin conditions |
BR9909324-3A BR9909324A (en) | 1998-03-31 | 1999-03-29 | Acidic composition for topical treatment of skin and nail conditions |
KR1020007010874A KR20010042324A (en) | 1998-03-31 | 1999-03-29 | An acidified composition for topical treatment of nail and skin conditions |
CA002326774A CA2326774A1 (en) | 1998-03-31 | 1999-03-29 | An acidified composition for topical treatment of nail and skin conditions |
JP2000540802A JP2002509867A (en) | 1998-03-31 | 1999-03-29 | Acidified composition for topical treatment of nails and skin |
EP99914224A EP1067897A1 (en) | 1998-03-31 | 1999-03-29 | An acidified composition for topical treatment of nail and skin conditions |
HK01104693A HK1034189A1 (en) | 1998-03-31 | 2001-07-09 | An acidified composition for topical treatment of nail and skin conditions. |
AU2003246031A AU2003246031A1 (en) | 1998-03-31 | 2003-09-10 | An acidified composition for topical treatment of nail and skin conditions |
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US8011698P | 1998-03-31 | 1998-03-31 | |
US60/080,116 | 1998-03-31 |
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US (1) | US6231875B1 (en) |
EP (1) | EP1067897A1 (en) |
JP (1) | JP2002509867A (en) |
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CN (1) | CN1198563C (en) |
AR (1) | AR015257A1 (en) |
AU (1) | AU3211999A (en) |
BR (1) | BR9909324A (en) |
CA (1) | CA2326774A1 (en) |
HK (1) | HK1034189A1 (en) |
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Also Published As
Publication number | Publication date |
---|---|
TWI225407B (en) | 2004-12-21 |
BR9909324A (en) | 2000-12-05 |
KR20010042324A (en) | 2001-05-25 |
CN1295456A (en) | 2001-05-16 |
AU3211999A (en) | 1999-10-18 |
US6231875B1 (en) | 2001-05-15 |
JP2002509867A (en) | 2002-04-02 |
EP1067897A1 (en) | 2001-01-17 |
AR015257A1 (en) | 2001-04-18 |
HK1034189A1 (en) | 2001-10-19 |
CA2326774A1 (en) | 1999-10-07 |
CN1198563C (en) | 2005-04-27 |
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