Title:  Compounds for treating fungal pathologies of the oral cavity

United States Patent:  6,780,838

Issued:  August 24, 2004

Inventors:  Lipton; James M. (Woodland Hills, CA); Catania; Anna P (Milan, IT)

Assignee:  Zengen, Inc. (Woodland Hills, CA)

Appl. No.:  774282

Filed:  January 29, 2001

Abstract

The broadest aspect of the invention is a composition and method of treatment of fungal pathologies of the oral cavity or fungal growth on the surface of dentures. A preferred embodiment of the is a pharmacologically effective amount of a peptide selected from the group of peptides with a C-terminal sequence consisting of KPV(SEQ ID NO: 1), HFRWGKPV(SEQ ID NO: 3), and SYSMEHFRWGKPV (SEQ ID NO: 4) in combination with a therapeutically effective amount of a fungicide selected from the group consisting of: itraconazole, econazole, ketoconazole, miconazole, imconazole and fluconazole. Another embodiment of the invention is a method for treating fungal pathologies of the oral cavity and dentures by application of a pharmacologically effective amount of a peptide selected from the group of peptides with a C-terminal sequence consisting of KPV (SEQ ID NO: 1), HFRWGKPV (SEQ ID NO: 3), and SYSMEHFRWGKPV (SEQ ID NO: 4) in combination with a therapeutically effective amount of a fungicide selected from the group consisting of: itraconazole, econazole, ketoconazole, miconazole and fluconazole. In yet another embodiment of the invention these peptides are used in combination with a therapeutically effective amount of gram positive and/or gram negative antibiotics.

SUMMARY OF THE INVENTION

The invention includes a composition and method of treatment of fungal pathologies of the oral cavity or fungal growth on the surface of dentures. In a preferred embodiment of the invention a therapeutically effective amount of one or more peptides selected from the group of peptides with a C-terminal sequence consisting of KPV (SEQ ID NO: 1), HFRWGKPV (SEQ ID NO: 3), and SYSMEHFRWGKPV (SEQ ID NO: 4) used in combination with a therapeutically effective amount of a fungicide selected from the group consisting of: itraconazole, econazole, ketoconazole, miconazole and fluconazole and dissolved into a carrier. More preferably still each peptide has the primary sequence of KPV (SEQ ID NO: 1) or VPK-Ac-CC-Ac-KPV (SEQ ID NO: 8)(Ac=Acetyl group). Pharmacologically effective concentrations may be as low as 10^-12 M but may be as high 10^-4 M. Pharmacologically effective concentration of these peptides may be incorporated into commercial formulations of creams, gels, mouthwashes, toothpastes, tablets, or atomized sprays.

In another preferred embodiment of the invention these peptides are topically or systemically applied to treat a candida infection of the oral cavity. In yet another embodiment of the invention these peptides are used in combination with a therapeutically effective amount of a gram positive or gram negative antibiotic to prevent or treat secondary bacterial infections of the oral cavity or on the surface of dentures.

DETAILED DESCRIPTION OF THE INVENTION

.alpha.-MSH is a 13 amino acid (SEQ ID NO: 4), fungicidal peptide with the primary sequence SYSMEHFRWGKPV (SEQ ID NO: 4). In addition to its fungicidal properties it also anti-pyretic and anti-inflammatory. The C-terminal trimer, KPV (SEQ ID NO: 1). appears responsible for these properties. Lipton, J. M., Antipyretic and Anti-inflammatory Lys-Pro-Val (SEQ ID NO: 1) Compositions and Methods of Use, U.S. Pat. No. 5,028,592, issued Jul. 2, 1991;Lipton, J. M., Antipyretic and Anti-inflammatory Lys-Pro-Val (SEQ ID NO: 1) Compositions and Methods of Use, U.S. Pat. No. 5,157,023, issued Oct. 20, 1992; Catania, A., Lipton J. M., .alpha.-Melanocyte Stimulating Hormone in the Modulation of Host Reactions, Endocr. Rev. 14, 564-576 (1993); Lipton, J. M., Catania, A., Anti-inflammatory Influence of the Neuroimmunomodulator .alpha.-MSH, Immunol. Today 18, 140-145 (1997). herein incorporated by reference. All references are hereby incorporated by reference in their entirety. The core .alpha.-MSH sequence (4-10) (SEQ ID NO: 2) has learning, memory and behavioral effects but little antipyretic and anti-inflammatory activity. Lipton, J. M., Catania, A., Anti-inflammatory Influence of the Neuroimmunomodulator .alpha.-MSH, immunol. Today 18, 140-145 (1997). .alpha.-MSH, the .alpha.-MSH core and its tripeptide C-terminal have very low toxicity. Lipton, J. M., Catania, A., Anti-inflammatory Influence of the Neuroimmunomodulator .alpha.-MSH, Immunol. Today 18, 140-145 (1997).

.alpha.-MSH is produced by the post translational processing of propriomelanocortin and shares the 1-13 primary sequence with adrenocortitrophic hormone (ACTH). Eberle, A. N., The Melanotropins, Karger, Basel, Switzerland (1988). It is secreted by a wide variety of cell types, including pituitary cells, monocytes, melanocytes, keratinocytes, epidermal cells and the epithelial cells of mucous membranes. Lipton, J. M., Catania, A., Anti-inflammatory Influence of the Neuroimmunomodulator .alpha.-MSH, Immunol. Today 18, 140-145 (1997); see also Catania et al., unpublished.

.alpha.-MSH reduces inflammation and fever by modulating the inflammatory cascade locally and systemically. Rajora, N., Ceriani, G., Catania, A., Star, R. A., Murphy, M. T., Lipton, J. M., .alpha.-MSH Production Receptors and Influence of Neopterin in a Human Monocyte/macrophage Cell Line, H.Leukoc. Biol. 59, 248-253 (1996); Star, R. A., Rajora, N. Huang, J., Stock, R. C., Catania, A., Lipton, J. M., Evidence of Autocrine Modulation of Macrophage Nitric Oxide Synthase by .alpha.-MSH, Proc. Natl. Acad. Sci. 92, 8016-8020 (1995); Lipton, J. M., Ceriani, G., Macaluso, A., McCoy, D., Carnes, K., Biltz, J., Catania, A., Anti-inflammatory Effects of the Neuropeotide .alpha.-MSH in Acute, Chronic and Systemic Inflammation, Ann. N.Y. Acad. Sci. 741, 137-148 (1994); Rajora, N., Boccoli, G. Burns, D., Sharma, S., Catania, A., Lipton, J. M., .alpha.-MSH Modulates Local Circulating Tumor Necrosis Factor A in Experimental Brain Inflammation, J. Neurosci, 17, 2181-2186 (1997); Richards, D. B., Lipton, J. M. Effect of .alpha.-MSH (11-13) (Lys-Pro-Val) (SEQ ID NO: 1) on Fever in Rabbits, Peptides 5, 815-817 (1984); Hiltz, M. E., Lipton, J. M., Anti-inflammatory Activity of a COOH-terminal Fragment of the Neuropeotide .alpha.-MSH. FASEB J.3, 2282-2284 (1989).

The broadest aspect of the invention is a composition and method of treatment of fungal pathologies of the oral cavity or fungal growth on the surface of dentures. In a preferred embodiment of the invention a therapeutically effective amount of one or more peptides selected from the group of peptides with a C-terminal sequence consisting of KPV (SEQ ID NO: 1), HFRWGKPV (SEQ ID) NO: 3), and SYSMEHFRWGKPV (SEQ ID NO: 4) is incorporated into a carrier. More preferably still, each peptide has the primary sequence of KPV (SEQ ID NO: 1) or VPK-Ac-CC-Ac-KPV (SEQ ID NO: 8) (Ac=Acetyl group). Pharmacologically effective concentrations may be as low as 10^-12 M but may be as high as 10^-4 M. A preferred embodiment of the invention utilizes peptide concentrations of 10^-12 M to 10^-10 M. Pharmacologically effective concentrations of these peptides may be incorporated into commercial formulations of creams, gels, mouthwashes, toothpastes, tablets, or atomized sprays.

Formulations of creams and gels are well known in the art. Harry's Comseticology (Chemical Publishing, 7^th ed. 1982); REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., 18^th ed. 1990).

Set forth below are examples of various formulations of the invention. As used below the term "Active ingredient" refers to one or more peptides selected from the group of peptides with a C-terminal sequence consisting of KPV (SEQ ID NO: 1), HRFWGKPV (SEQ ID NO: 3) and SYSMEHFRWGKPV (SEQ ID NO: 4). Preferably, the active ingredient is KPV (SEQ ID NO: 1) or VPK-Ac-CC-Ac-KPV (SEQ ID NO: 8).

An exemplary formulation of a gel based on the invention comprises:

An exemplary formulation of a cream comprises:

Formulations for toothpastes, and mouthwashes are well known in the art. U.S. Pat. Nos. 4,719,100; 4,314,990 and 4,151,271. An exemplary formulation of a toothpaste comprises:

An exemplary formulation of a mouthwash comprises:

In another preferred embodiment of the invention these compositions are topically or systemically applied to treat a candida infection of the oral cavity. Topical administration may be made with manual application of creams or gels, gargling of mouthwash, brushing with toothpaste, chewing on tablets, holding lozenges in the mouth or with an atomized spray. Systemic administration may be made by ingestion of hard tablets, soft tablets or capsules. In yet another preferred embodiment of the invention these peptides are used in combination with a therapeutically effective amount of a fungicide selected from the group consisting of: itraconazole, econazole, ketoconazole, miconazole and fluconazole. In yet another preferred embodiment of the invention these peptides are used in combination with a therapeutically effective amount of a gram positive or gram negative antibiotics selected from the group consisting of: aminglycosides, amoxicillin, ampicillin, azithramycin, erythromycin, nafcillin, penecillin, quinupuristin dalfopristin and vancomycin.

The formulation of tablets are well known in the art. An exemplary formulation of a hard gelatinous tablet comprises:

Claim 1 of 23 Claims

What is claimed is:

1. A pharmaceutical composition for the treatment of oral candidiasis comprising a therapeutically effective amount of a peptide selected from the group consisting of KPV (SEQ. ID. NO. 1), VPK-Ac-CC-Ac-KPV (SEQ. ID. NO. 8) and HFRWGKPV (SEQ. ID. NO. 3) in combination with a therapeutically effective amount of a fungicide.

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