Drug – bio-affecting and body treating compositions – Manicure or pedicure compositions
Reexamination Certificate
2002-06-27
2004-11-23
Dodson, Shelley A. (Department: 1616)
Drug, bio-affecting and body treating compositions
Manicure or pedicure compositions
C424S401000, C424S404000, C514S553000, C514S558000
Reexamination Certificate
active
06821508
ABSTRACT:
BACKGROUND OF THE INVENTION
Onychomycosis is a fungal disease of the human nail. The symptoms of this disease are 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 antifungal agents. The main challenge associated with developing topical treatments for nail disorders is to deliver the active compounds in therapeutically effective concentrations to the site of infection, which is often under the nail. If the nail barrier is modified, reduced, or eliminated, topical antifungal drug treatment is effective for onychomycosis. For example, both miconazole and ketoconazole have been demonstrated to be effective in topically treating onychomycosis after nail removal. However, most consumers would certainly prefer a less dramatic treatment of nail fungal infection than removal of the nail.
Nail psoriasis is another common nail disorder affecting up to 50% of patients with psoriasis. Characteristic nail psoriasis symptoms include pitting, which appears as punctuated or irregularly shaped depressions arranged on the surface of the body of the nail; discoloration of the nail bed; onycholysis or detachment of the body of the nail from the nail bed; subungual keratosis; or anomalies of the body of the nail. As with nail fungal infections, current methods of treatment are not satisfactory. One treatment method, the systemic method, consists of long-term administration of methotrexate, retinoids or cyclosporin A orally which can lead to intoxication. Another method consists of injecting intralesional corticosteroids. This method is naturally very painful and patients often refuse treatment. A further method consists of surgically removing the affected nails, but intervention is only temporary because within one week after regeneration of the body of the nail psoriasis may return. A fourth, gentler, method consists of treating the nails locally with specific, antipsoriatic substances such as dithranol, vitamin D analogs, or corticosteroids, however, as with nail infections, effective delivery of the active compounds is a problem.
The nail plate is thick, hard, dense, and represents a formidable barrier for drug penetration. Although 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. In order to deliver a sufficient amount of drug into the nail plate, 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.
Recent research efforts have focused on improving penetration by chemically modifying the nail keratin matrix (Kobayashi, et al. (1998)
Chem Pharm Bull
46(11):1797-1802). Examples of compounds which interact with keratin include mercaptan compounds, sulfites and bisulfites, keratolytic agents, and surfactants.
Mercaptan Compounds. The utility of compounds possessing sulfhydryl (SH) groups, i.e., mercaptan compounds, to enhance nail penetration has been reported (Soong (1991) Transport properties of drugs and model compounds across the human nail. Ph.D. Dissertation. University of Minnesota; U.S. Pat. No. 5,696,164). EP0440298 A1 discloses the use of sulfur-containing cysteine derivatives in topical preparations for treatment of nail diseases such as onychomycosis. Furthermore, U.S. Pat. No. 5,696,164 to Sun et al. discloses the use of sulfhydryl-containing cysteine and N-acetyl cysteine in combination with urea to increase drug permeability in a nail plate. Moreover, U.S. Pat. No. 6,123,930 provides a composition of sulphur-bearing amino acid together with sodium tetraborate for the treatment of nails. Mercaptan compounds reduce keratin in human hair via a sequence of two reversible, nucleophilic displacements (Robbins (1997) Chemical and physical behavior of human hair, 3rd ed. New York: Springer-Verlag. pp. 93-130; Wolfram (1981) In: Orfanos, et al, eds. Hair research: Status and future aspects. New York: Springer-Verlag. pp. 479-500). High concentrations of the mercaptan and alkaline pH favor the forward reaction due to the increased formation of the mercaptide anion required for reduction (Herrmann (1963)
Trans Farady Soc
59:1663-1671; Wickett (1983)
J Soc Cosmet Chem
34:301-316).
Pyrithione (2-mercaptopyridine-1-oxide, PTO) is a fungicidal and bactericidal agent. The zinc (ZnPTO) and sodium (NaPTO) derivatives of pyrithione possess fungicidal activity and ZnPTO is commonly used in antidandruff preparations. Compounds containing a SH group are themselves oxidized while reducing disulfide linkages in nail keratin (Robbins (1997) Chemical and physical behavior of human hair, 3rd ed. New York: Springer-Verlag. pp. 93-130; Wolfram (1981) In: Orfanos, et al, eds. Hair research: Status and future aspects. New York: Springer-Verlag. pp. 479-500). For PTO, such self-oxidation would result in the formation of the dipyrithione dimer which possesses antifungal activity.
Terpenes are also known to be effective skin penetration enhancers. Menthone, in particular, has been found to enhance penetration of several different drugs across skin (Kragh, et al. (1993)
STP Pharma Sci
3:499-506; Yamane, et al. (1995)
Int J Pharm
116:237-251). 1,4-Dithiothreitol, which contains two SH groups, has been shown to be a particularly effective reducing agent, because this molecule can undergo rapid autocleavage during the reduction process to form a sterically favored cyclic disulfide as the end product (Wolfram (1981) In: Orfanos, et al, eds. Hair research: Status and future aspects. New York: Springer-Verlag. pp. 479-500).
Sulfites and Bisulfites. Sulfites and bisulfites are known to be reducers of disulfide linkages in keratin, and thus are popularly used for permanent waving of hair (Robbins (1997) Chemical and physical behavior of human hair, 3rd ed. New York: Springer-Verlag. pp. 93-130).
Keratolytic Agents. Salicylic acid (SA), urea (U), and guanidine hydrochloride (GnHCl) are substances which may disrupt the tertiary structure, and possibly secondary linkages (such as hydrogen bonds) in keratin, thus promoting penetration through the nail. Compounds such as urea and guanidine hydrochloride are known to be denaturing agents, resulting in disruption of the water structure around proteins, decreasing the hydrophobic effect, and thereby promoting unfolding and dissociation of the protein molecules (Alber (1989) In: Fasman G D, ed. Prediction of protein structure and the principles of protein conformation. New York: Plenum Press. pp. 161-192; Manning, et al. (1989)
Pharm Res
6(11):903-918; Mathews and van Holde (1990) Biochemistry. Redwood City: The Benjamin/Cummings Publishing Co, pp. 213-215).
Surfactants. Surfactants, primarily of the anionic type, are known to be able to interact with keratin. Concentrated solutions of sodium lauryl sulfate are commonly used to solubilize proteins. These detergents are thought to form micelles around individual polypeptide chains and thus promote dissociation of protein molecules (Mathews and van Holde (1990) Biochemistry. Redwood City: The Benjamin/Cummings Publishing Co, pp. 213-215).
European Patent Application EP 503988 discloses other nail penetration agents including glycols, glycol ethers, dimethyl sulfoxide, caprolactam, and other hydrophilic compounds to facilitate the penetration of allylamine fungicides into the nail.
SUMMARY OF THE INVENTION
The present invention provides a composition which comprises sulfur-containing glycine residues and urea to increase the permeation of an active agent through nail tissue.
The invention further provides methods of applying the composition of the invention to a nail prior to, or in conjunction with, an active agent to increase the permeation of said active agent through the nail tissue.
DETAILED DESCRIPTION OF THE INVENTION
T
Malhotra Gouri G.
Zatz Joel L.
Dodson Shelley A.
Licata & Tyrrell P.C.
Rutgers, the State University
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