WO1994017778A1 - Method of enhancing hair growth and hair revitalizing compositions comprising lutzomyia protein - Google Patents
Method of enhancing hair growth and hair revitalizing compositions comprising lutzomyia protein Download PDFInfo
- Publication number
- WO1994017778A1 WO1994017778A1 PCT/US1994/001202 US9401202W WO9417778A1 WO 1994017778 A1 WO1994017778 A1 WO 1994017778A1 US 9401202 W US9401202 W US 9401202W WO 9417778 A1 WO9417778 A1 WO 9417778A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- maxadilan
- hair
- composition
- hair growth
- amount
- Prior art date
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Classifications
-
- 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
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/91—Injection
Definitions
- the present invention relates to a hair revitalization composition having excellent hair revitalizing effects, such as the prevention of epilation, and excellent trichogenous effects.
- the invention is particularly useful in the preparation of drugs, quasi-drugs, and in the field of cosmetics.
- the composition comprises a peptide found in the sand fly Lutzomyia longipalpis .
- vitamins such as B vitamins and vitamin E
- amino acids such as serine and methionine
- vasodilators such as swertiae extract and acetylcholine derivatives
- anti-inflammatory agents such as lithosperiradix extract and hinokitiol
- skin-hyperactive agents such as cepharanthine
- compositions containing chemical inhibitors for glycanases have been disclosed in U.S. Patent No. 5,015,470
- compositions containing growth factors such as transforming growth factors alpha and beta have been disclosed in U.S. Patent No. 5,037,643
- compositions containing mixtures of nicotinates and hydrochloride have been disclosed in U.S. Patent No. 5,043,162. These compositions have a certain efficacy in promoting hair growth.
- hair growth enhancement or revitalization could be used in the cosmetic industry for increasing hair growth rates, in the pharmaceutical industry for the treatment of baldness, and in the animal breeding industry for stimulating wool growth and fur growth in commercially important animals, such as sheep and rabbits.
- the present inventors have researched substances effective for the treatment of epilation and possessing othe excellent hair revitalizing effects, such as the prevention of trichogenous effect. As a result, it has been discovered that specific peptides that can be found in the salivary glands of the sand fly Lutzomyia longipalpis exhibit characteristics useful for revitalizing hairs, thereby makin this invention possible.
- this invention aids in fulfilling the need in the art by providing a hair revitalizing composition
- a hair revitalizing composition comprising, as effective components, peptides that can be found in the salivary glands of the sand fly Lutzomyia longipalpis.
- the peptides exhibit vasodilation activity in mammals.
- the hair revitalizing composition according to the present invention provides excellent trichogenous effects an hair revitalization effects by topical application and subcutaneous injection.
- this invention provides a method for inducing, maintaining or increasing hair growth in a mammal.
- the method comprises administering a hair growth inducing, maintaining or increasing amount of Lutzomyia protein to the skin or hair of the mammal.
- the Lutzomyia protein is topically applied to the mammal.
- a preferred Lutzomyia protein is maxadilan.
- This invention also provides a composition suitable for topical application to mammalian skin or hair.
- the composition comprises Lutzomyia protein in a hair growth inducing, maintaining or increasing amount in a pharmaceutically acceptable vehicle.
- the present invention is useful for the enhancement of hair growth utilizing compounds belonging to a category different from the group of substances hitherto used.
- the present invention is also useful for increasing production o wool or fur in animal breeding industries. The invention is thus beneficial for inducing, maintaining or increasing hair growth in mammals.
- the Figure shows a graph in which the hair growth of organ cultures of mouse whiskers is plotted against cultivation day to show the action of Lutzomyia longipalpis on these cultures.
- the present invention resulted from research efforts directed to the identification of substances which effectively prevent epilation and the trichogenous effect. Applicants' efforts led to the discovery that specific peptides that can be found in the salivary glands of the san fly Lutzomyia longipalpis exhibit strong effects, which result in the enhancement of hair growth. 1. Lutzomyia Proteins.
- Peptides from salivary gland lysates of the sand fly were previously identified and shown to be capable of vasodilation and of temporary immune suppression in mammals. (See, International Patent Publication No. WO91/00293 of Lerner E. A., et al.; and Ribeiro et al.. Science, Vol. 243 pp. 212-214 (1989)). These peptides are exemplified by the "Lutzomyia protein" (LP), which, in one embodiment, has been referred to as "maxadilan” .
- LP Lutzomyia protein
- Maxadilan has a molecular weigh of about 6800 daltons, and elutes prior to calcitonin gene- related peptide in an acetonitrile-H 2 0-trifluoracetic acid- reverse phrase column. (See, International Patent Pub ⁇ lication No. WO91/00293 of Lerner E. A., et al.).
- LP can be obtained by conventional purification chromatography from surgically excised salivary glands of Lutzomyia longipalpis .
- One pair of salivary glands contains about 10-15 ng LP.
- the Lutzomyia protein constitutes about 1% of the total protein in the salivary glands of the sand fly Lutzomyia longipalpis.
- Applicants have discovered new properties possessed by Lutzomyia protein, exemplified by maxadilan. In addition to their vasodilator activity and their ability to suppress the immune system of mammals, percutaneous injection or topical administration of the protein results in the enhancement of hair growth.
- Peptides suitable for use in the methods and compositions of the present invention include those peptides extracted and purified from the lysate of salivary glands of sand fly, active analogs and active fragments thereof, described in International Patent Publication No. W091/00293, or recombinantly produced peptides.
- Lutzomyia protein as used herein refers to all such peptides, active analogs, and active fragments. Maxadilan or active fragments thereof are examples of suitable Lutzomyia proteins for use in the present invention. Maxadilan will be used as a representative peptide in the following description of the invention.
- nucleotide sequence of the cDNA and the deduced amino acid sequence of one form of mature Lutzomyia protein is as follows:
- the genomic Lutzomyia protein DNA sequence is as follows:
- the genomic Lutzomyia protein DNA sequence varies somewhat from the Lutzomyia protein cDNA sequence and is believed to represent a variant Lutzomyia protein gene.
- the genomic Lutzomyia protein DNA sequence includes the DNA sequence and deduced amino acid sequence of a 17 amino acid leader peptide.
- the signal sequence of Lutzomyia protein is also given in the genomic DNA sequence (nucleotides 1-51).
- compositions rich in Lutzomyia protein or its active analogs and fragments can be used in carrying out this invention.
- the active analogs and fragments of Lutzomyia protein are typically proteins or peptides comprising an amino acid sequence sufficiently duplicative of the sequence of the active portion of the Lutzomyia protein such that the proteins or peptides are capable of inducing, maintaining or increasing hair growth in a mammal.
- the peptides of the present invention need not be identical to those disclosed in International Patent Publication No. WO91/00293. Variations can be attributable to local mutations, which do not substantially detract from the hair revitalizing properties of the peptide. Such variations can be found in peptides isolated from lysates as well as chemically or recombinantly constructed peptides.
- Lutzomyia protein sequence enables the skilled artisan to produce large quantities of the protein for therapeutic use.
- the Lutzomyia protein can be synthesized using conventional chemical solid or solution phase peptide synthesis techniques.
- knowledge of the sequence permits expression of the DNA encoding Lutzomyia protein in various types of host cells, including both prokaryotes and eucaryotes, to produce large quantities of the protein.
- Lutzomyia protein suitable for use in this invention can be characterized by its chemical and biological properties. Specifically, the Lutzomyia protein suitable for use in this invention is capable of inducing vasodilation or temporary immune suppression in a mammal.
- the vasodilatory activity o the Lutzomyia protein is shown by relaxation of at least about 100% of a constricted rabbit aortic ring as described in International Patent Publication No. WO91/00293.
- Temporary immune suppression using salivary gland extract is demonstrated by the assay of H ⁇ C production by macrophages as a marker of immune stimulation as described in International Patent Publication No. WO91/00293 such that H 0 2 production is depressed by at least about 75% in the assay.
- the Lutzomyia protein has a molecular weight of about 6839 daltons as determined by mass spectrometry.
- the Lutzomyia protein employed in this invention is characterize by reference to calcitonin gene-related peptide (CGRP). Tha is, the Lutzomyia protein is characterized by elution prior to CGRP in an acetonitrile-H 2 0-trifluoroacetic acid elution in a reverse-phase high performance liquid chromatography column.
- the Lutzomyia protein can also be characterized as having vasodilation activity as measured by erythema induction in animal skin of at least about 80-100 times that of CGRP as measured by the assay described in International Patent Publication No. WO91/00293.
- the present invention also provides a method for inducing, maintaining or increasing hair growth comprising administering Lutzomyia protein at the desired site of hair growth.
- the Lutzomyia protein can be applied to the desired site by topical application or by subcutaneous injection.
- the Lutzomyia protein can be applied to the hair of a mammal, the skin of a mammal, or both the hair and the skin to induce, maintain, or increase hair growth in the mammal.
- the subject is a human, although the compositions and method of the invention can be employed with hair and fur bearing animals, such as sheep, rabbits, mice, rats and other mammalia.
- the composition of the invention can be applied to a location proximate hair pellicles in order to obtain the beneficial effects of the invention.
- compositions for Topical Application can be formulated into a form suitable for topical application by incorporating the Lutzomyia protein in a suitable vehicle.
- vehicle can be a solid, semi-solid or liquid vehicle that is cosmetically acceptable, pharmaceutically acceptable, or physiologically acceptable, and which enables the Lutzomyia protein to be conveyed to the skin at an appropriate dilution.
- the nature of the vehicle will depend upon the method chosen for topical administration of the composition.
- the vehicle can itself be inert or it can impart physiological or pharmaceutical benefits to the composition.
- the vehicle for topical application is a substance that acts as a diluent, dispersant, or solvent for the Lutzomyia protein and other reagents in the composition so that the composition can be applied to and distributed substantially evenly over the hair, the scalp or both the hair and scalp at an appropriate concentration.
- the vehicle is preferably one that aids penetration of the Lutzomyia protein into the skin to reach the immediate environment of hair pellicles.
- the vehicle for topical application of the composition of this invention can be based on water or at least one cosmetically acceptable vehicle other than water. It will be understood that non-aqueous cosmetically acceptable vehicles can also be combined with water to provide a composition suitable for topical application.
- Vehicles that can be employed in the composition of the invention include solids or liquids, such as emollients, solvents, humectants, thickeners, and powders.
- Lutzomyia protein can be utilized in the methods and compositions of the present invention either alone, or in combination with other known treatment agents.
- peptides of the present invention can be used in combination with one or more of the following agents: vasodilators, such as carpronium chloride, swertiae extract and acetylcholine derivatives; amino acids, such as serine and methionine; vitamins, such as vitamin B ⁇ , vitamin E and derivatives thereof, and biotin, pantothenic acid and derivatives thereof; glycyrrhetinic acid and derivatives thereof; nicotinates, such as benzyl nicotinate; skin-hyperactive agents, such as female sex hormones, such as estradiol; cepharanthine and minoxidil.
- vasodilators such as carpronium chloride, swertiae extract and acetylcholine derivatives
- amino acids such as serine and methionine
- vitamins
- anti-inflammatories such as hinokitiol, hexachlorophene, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarbanilide, and bithionol
- refrigerants such as menthol
- agents such as salicylic acid, zinc, and derivatives thereof, lactic acid and alkyl esters thereof, organic acids (such as citric acid), amino acids (such as arginine), oils (such as olive oil), squalene, liquid paraffin, isopropyl myristate, higher fatty acids and higher alcohols, polyhydric alcohols (such a glycerol) , propylene glycol, as well as surfactants, perfumes, antioxidants, ultraviolet absorbers, pigments, ethanol, water, humectants, propellants, and
- the hair revitalizing composition according to the present invention can be incorporated with an extremely low level of the Lutzomyia protein, generally, the protein i
- the hair revitalizing composition according to the invention can be either directly applied or sprayed on the skin or applied by percutaneous injection.
- the dosage of th hair revitalizing composition according to the invention varies depending on age, individual differences, symptoms, etc., but in the case of an adult, it is generally in the range of 500 fg to 500 mg, and preferably in the range of 10 pg to 100 mg, Lutzomyia protein per kg of body weight per day.
- maxadilan can be applied to humans i an amount ranging from 100 fg to 100 mg, and preferably in the range from 100 pg to 100 mg, per square cm of surface area.
- Maxadilan is present in the topical composition of th present invention in an amount of about 5.0 x 10 " to about 5.0 x 10— " 1 percent by weight, preferably about 5.0 x 10—8 to
- composition is administered to an adult in an amount of about 100 fg to about 100 mg, preferably about 100 pg to about 100 mg, per kg of host body weight per day.
- the hair pellicle of the mammal is treated daily between 1 and 4 times per day.
- the exact regime used will depend on several factors such as the condition of the individual, but are readily determinable by the treating physician. Treatment should be continued at least until the desired effect is achieved.
- composition of this invention can be in any form that it can be applied to the hair pellicle.
- the composition can be formulated as a shampoo, a conditioner, a hair spray, a hair gel product, or a moisturizing lotion.
- composition for Subcutaneous Injection In addition to topically applying the composition of this invention to the subject, the composition of the invention can also be administered to the subject by subcutaneous injection to induce, maintain or increase hair growth.
- Lutzomyia protein has an extremely good hair revitalizing effect so that it has an efficacy dose in animals of at least 1 pg per kg of host body weight per day by subcutaneous injection. The Lutzomyia protein will not be used in an amount exceeding about 1 mg per kg of body weight per day.
- Maxadilan was found, to be an effective hair revitalizin agent preventing epilation and trichogenous effects. Both i vitro and in vivo results showed that maxadilan enhances hai growth. Organ cultures of hair follicles from mouse whisker were used to demonstrate the effectiveness of the present invention in vitro. Topical application on mice and humans, and subcutaneous injections of maxadilan, demonstrated the effectiveness of the present invention in vivo.
- L.P. represents Lutzomyia Protein, which was maxadilan in each Ex. ** The formulation made to 100% by deionized water.
- Example I The hair growth-stimulating effects of compositions prepared as described in Example I were determined in a test termed a trichogenous test.
- the trichogenous tests for the hair revitalizing compositions of Example I were carried out using C3H/HeNCrJ mice whose hair cycle was at a resting stage. The method used was that of Ogawa et al. ("Normal and Abnormal Epidermal Differentiation", M. Seiji and I.A. Berstein eds. (1982) pp. 159-170, Todal Press.)
- each test group was comprised of 10 mice.
- One test group received no application, while other groups were treated with the formulations of Ex. 1 to 5 and Comparative E . 1.
- the backs of the mice were shaved by means of a pair of hair clippers and a shaver.
- Each sample in an amount of 0.1 ml was daily topically applied.
- the trichogenous (hair growth) portions at the backs of the mice were measured, and the trichogenous effects of respective samples were compared with each other by means of proportion of area.
- the time required for 50% trichogenous rate in eac sample is shown in Table 2.
- the “number of accelerated days” in Table 2 is the difference between the number of days confirming 50% trichogenous action for "no application” and the measured value for the respective Ex., and is a measure of the hair growth-stimulating effect of the composition.
- the stimulation of hair growth was the same in test groups in which no application was made and in the Comparative Ex. 1 using a composition that did not contain Lutzomyia protein.
- the hair roots of removed hairs were microscopically observed before and after the use of the hair revitalizing compositions, and the number of hair roots at the resting stage was counted by observing the form of the hair roots.
- the hair revitalizing activities of the compositions were compared by the increase or decrease in the rate of growth.
- the "hair roots" at the resting stage are hair roots of the hairs whose growth has stopped, and the proportion of the hair roots at the resting stage is confirmed to be higher in the person suffering from epilation than in a person not suffering from epilation.
- phase A An emulsion hair tonic was prepared from phase A, phase B, phase C, phase D, and phase E having the following compositions: Phase A
- Phase A and phase B were separately and thermally melted at 60°C and then mixed with the homomixer to produce a gel.
- Phase D was gradually added thereto and dispersed by means of the homomixer.
- phase A A cream hair tonic was prepared from phase A and phase having the following compositions: Phase A
- Phase A and phase B were each separately and thermally dissolved and were then mixed together.
- the mixture was emulsified by means of a homomixer to obtain a creamy hair tonic.
- a practical test was carried out on a person as described in Example II.
- the hair tonic was confirmed to have excellent hair revitalizing effects .
- Phase A A cream hair tonic was prepared by mixing two phases having the following compositions: Phase A
- Phase A and phase B were separately and thermally dissolved. After combining the phase A and the phase B, the mixture was emulsified by means of a homomixer to obtain a creamy hair tonic. Using this hair tonic, a practical test was carried out for person as described in Example II. The hair tonic was confirmed to have excellent hair revitalizing effects.
- a hair gel was prepared by combining five phases having the following compositions: Phase A
- Phase A and phase B were separately and thermally melted at 60°C and then mixed with homomixer to produce a gel.
- Phase D was gradually added thereto and dispersed by means of homomixer.
- the dispersed phase C was added thereto, and finally phase E was added followed by the homomixer treatment to obtain an oil-in-water type emulsion hair tonic.
- Example II Using this hair tonic, a practical test was carried out for person as described in Example II. The hair tonic was confirmed to have excellent hair revitalizing effects.
- mice The backs of 58 days old C3H mice were shaved by means of a pair of hair clippers. Each test group was comprised of 5 animals. The samples to be tested were intradermally or percutaneously injected daily in an amount of 0.05 ml per day, and similar injections were continued over a period of 20 days (except for Saturdays and Sundays). Thereafter, the hair growth on the mice was observed every week over a period of about 40 days.
- MOLECULE TYPE DNA (genomic)
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP94909527A EP0683660A1 (en) | 1993-02-12 | 1994-02-10 | Method of enhancing hair growth and hair revitalizing compositions comprising lutzomyia protein |
JP6518194A JPH09500090A (en) | 1993-02-12 | 1994-02-10 | Method for promoting hair growth and hair activating composition containing rutozomia protein |
AU62346/94A AU6234694A (en) | 1993-02-12 | 1994-02-10 | Method of enhancing hair growth and hair revitalizing compositions comprising lutzomyia protein |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1706193A | 1993-02-12 | 1993-02-12 | |
US08/017,061 | 1993-02-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994017778A1 true WO1994017778A1 (en) | 1994-08-18 |
Family
ID=21780501
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1994/001202 WO1994017778A1 (en) | 1993-02-12 | 1994-02-10 | Method of enhancing hair growth and hair revitalizing compositions comprising lutzomyia protein |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0683660A1 (en) |
JP (1) | JPH09500090A (en) |
AU (1) | AU6234694A (en) |
CA (1) | CA2155866A1 (en) |
WO (1) | WO1994017778A1 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991000293A1 (en) * | 1989-06-29 | 1991-01-10 | The President And Fellows Of Harvard College | Vasodilatory and immune suppressant peptides |
-
1994
- 1994-02-10 AU AU62346/94A patent/AU6234694A/en not_active Abandoned
- 1994-02-10 JP JP6518194A patent/JPH09500090A/en active Pending
- 1994-02-10 EP EP94909527A patent/EP0683660A1/en not_active Withdrawn
- 1994-02-10 CA CA002155866A patent/CA2155866A1/en not_active Abandoned
- 1994-02-10 WO PCT/US1994/001202 patent/WO1994017778A1/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991000293A1 (en) * | 1989-06-29 | 1991-01-10 | The President And Fellows Of Harvard College | Vasodilatory and immune suppressant peptides |
Also Published As
Publication number | Publication date |
---|---|
JPH09500090A (en) | 1997-01-07 |
CA2155866A1 (en) | 1994-08-18 |
AU6234694A (en) | 1994-08-29 |
EP0683660A1 (en) | 1995-11-29 |
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