JPH0349887B2 - - Google Patents

Description

Claim 1: By locally or orally administering to a mammal an effective amount of a retinoid, or a pharmaceutically acceptable ester, ether, or salt thereof,
A hair growth promoter characterized by increasing the speed of hair growth and lengthening the growth phase of the hair cycle. 2. The retinoid according to claim 1, wherein the retinoid is all-trans retinoic acid, all-trans retinaldehyde, all-trans retinoyl acetate, or other suitable esters or salts of retinoic acid. Hair growth promoter. 3. The retinoid is a stereoisomer of vitamin A acid, or vitamin A _diacid , α-vitamin A acid,
γ-vitamin A acid, 5,6 epoxy-vitamin A
Hair growth promoter according to claim 1, characterized in that it is selected from the group consisting of acids, dehydrovitamin A acids or aldehydes, alcohols, esters, ethers or salts of said compounds. 4 The retinoid is 4-hydroxy retinoic acid, 4-keto retinoic acid, 4-oxo-
Retinoic acid, 5,8, oxo-retinoic acid or 7-cis-3 dehydroretinol or retinoic acid, 7-trans-9-cis-11-trans-13-trans-5'-hydroxy-retinoic acid, or 8- (2,6,6-trimethyl-3-
Naturally occurring vitamin A acids such as aldehydes or derivatives such as oxocyclohex-1-enyl)-2,6-dimethyl-6-hydroxyoctatrienal or stereoisomers of said compounds, or esters or salts thereof. The hair growth promoter according to claim 1, which is a metabolite. 5. Hair growth promoter according to claim 1, characterized in that the compound is a carotenoid such as crocetin, crocin or a naturally occurring metabolite thereof. 6. The hair growth promoter according to claim 1, wherein the hair is human hair. 7. The hair growth promoter according to claim 1, wherein the animal is a furry animal and the retinoid prevents shedding or hair loss. 8. Retinoid concentration in topical lotions, creams, ointments, conditioners, or shampoos
The hair growth promoter according to claim 1, wherein the hair growth promoter is in the range of 0.001 to 5% by weight. 9 The retinoid composition per kg of mammal
The hair growth promoter according to claim 1, which is orally administered in a dosage within the range of 0.25 to 20 mg. 10. The hair growth promoter according to claim 1, wherein the composition containing all-trans retinoic acid is locally applied to the human scalp. 11. The hair growth promoter according to claim 10, wherein the composition contains all-trans retinoic acid in a medium consisting of ethanol and propylene glycol. TECHNICAL FIELD This invention relates to the use of retinoids and their derivatives to increase the growth rate of human hair and of the fur growth of certain fur animals. BACKGROUND OF THE INVENTION A normal feature of hair growth in most people is that growth decreases with age, and both the rate of hair growth and the length of the growth cycle decrease. This condition is common to all people with rare exceptions, and in some people it is a clinically prominent condition associated with the production of the male hormone, testosterone and its derivatives, especially dihydrosterone. It must be distinguished from true androgenetic alopecia. Many factors influence the rate of hair growth, including race, gender, age, region, season, nutrition, and hormones (Myers and Hamilton, 1951;
Hamilton, 1958; Yano, 1936; Maeda,
1938; Troter, 1923; Pinkus, 1924; and Ono,
(see 1963). In the past, many attempts have been made to halt the progression of androgenetic alopecia by various treatments, but all have failed. The present invention does not intend to improve androgenetic alopecia.
The present invention relates to growing hair follicles and treatments for increasing the rate of hair growth and lengthening the growth phase of the hair cycle from the hair follicles of certain fur animals. In the past, compounds of vitamin A (hereinafter referred to as retinoids) have been shown to be effective in treating many diseases, including skin disease conditions such as acne and psoriasis. The inventors have discovered a new use of retinoids to increase the rate of hair growth and lengthen the anagen phase of the hair cycle. DISCLOSURE OF THE INVENTION The present inventors have discovered that retinoids, particularly all-trans retinoic acid (or retinoic acid) and its derivatives, promote hair growth in humans and in certain furry animals. discovered.
Administration options include topical applications such as lotions, ointments, creams, and the like. However, administration is not limited to these methods, and the effects can also be obtained by oral administration or systemic administration of the retinoid compound. DETAILED DESCRIPTION OF THE INVENTION The present invention provides the use of all-trans retinoic acid and its metabolites, as well as other retinoid compounds, to increase the rate of hair growth in humans and the growth rate of fur in certain fur animals. Regarding the use of retinoids, including. All-trans retinoic acid has been shown to result in high DNA synthesis in keratinocytes (specialized epidermal cells that synthesize keratin) in cell culture. It has also been proven that all-trans retinoic acid accelerates the turnover time of epidermal cells in cell culture experiments and in vivo experiments in human subjects. The inventors have discovered that cells of the hair follicle, including the dermal papilla, are stimulated by retinoids, including all-trans retinoic acid. When tested experimentally, retinoids inhibit tritiated thymidine by dermal papilla cells and root sheath cells.
It coalesced into DNA and regenerated from other hair follicles at a faster rate than untreated cells. This stimulation with retinoid compounds ultimately makes the entire hair follicle more active and increases the mitotic index, which is a measure of thymidine- _H3 incorporation into DNA. Therefore, a person's hair grows faster and has a longer growth phase. The main problem in influencing hair growth is achieving good transdermal absorption of the active compound. Another issue is accurate measurement of hair growth to substantiate test results. All-trans retinoic acid and its derivatives and other retinoid compounds provide excellent transdermal absorption and have been proven to be highly effective in keratinizing cells of the skin, including hair follicles. Additionally, relatively recent methods have been used to measure hair growth rate that give excellent results.
This method was devised by Saitoh, M.etal, and uses microcapillary tubes with 0.2 mm graduations. The term retinoid as used herein refers to retinol, retinal, retinyl esters, and retinoic acid and its esters, derivatives, and common metabolites. The terminal group can be oxidized, reduced,
It can be esterified, etc. Also included are salts of alkali metals (sodium, potassium, etc.) and alkaline earth metals (magnesium, calcium, etc.). The pharmaceutical, cosmetic or veterinary formulation of the invention comprises:
This can be done by conventional methods of formulating lotions, creams, conditioners or shampoos for human scalp, and by veterinary formulating for animal fur. Also included are orally administered preparations and compounds added to animal feed. In addition to the active retinoids of the present invention, the various formulations can include any conventional pharmaceutically or cosmetically acceptable inert or pharmaceutically active additives. For example, lotions are formulated using various forms of alcohol, solvents such as glycols, or esters. Conditioners are commonly accepted and industrially produced compounds such as cetyl alcohol, ateares-
5, -20 hydrantoin, hydrolyzed animal protein, glycol stearate, amodimethicone, paraffin, mineral oil, etc. (these are listed by way of example only and are not meant to be inclusive). Compounds of interest also include various oils, including essential fatty acids and other polyunsaturated fatty acids and their derivatives, and compounds such as hormones, including prodiesterone, estradiol, thyroids, and the like. Topically applied lotions, creams, conditioners, etc. are varied according to standard techniques with respect to the amounts of other hydrophilic and hydrophobic ingredients, including emulsifiers, so that oily, semi-oily or non-oily products are obtained. Shampoos include any of the commonly used detergents and soaps and other compounds used by those skilled in the art. Shampoo, which is oil-based, falls into these mixtures. Oral preparations can be in tablets, liquids, capsules, and the like. Pharmaceutically acceptable substances commonly used as preservatives, stabilizers, moisture retention agents, emulsifiers, etc. can also be included in these preparations. Commonly accepted antioxidants such as tocophenols, N-methyl alpha-tocopheramine, butylated hydroxyanisole and butylated hydroxytoluene can also be incorporated into the formulations of the invention. The dosage at which a retinoid is administered will vary depending on the route of administration and the requirements of the patient.
Topical treatments consist of lotions, creams, conditioners, shampoos, oil treatments, etc. containing 0.001-2% by weight of all-trans retinoic acid or its derivatives, or other retinoids, as desired dosages in the composition. Oral preparations are administered in amounts of 0.25 to 2 mg/kg body weight per day. These are mixed into the animal food in the case of furry animals or dogs, cats or other companion animals, and into the bird feed in the case of shedding birds. Several experiments were conducted to investigate the specific effects of retinoids on increasing the rate of hair growth. Hair growth rate was measured in each case using the microcapillary method. Table 1 shows the results of studies using male and female subjects. All-trans retinoic acid was administered topically or in the manner shown in the table, and hair growth rate was assessed by microcapillary techniques (see table on separate page). Table 1 shows the results of the study using male and female subjects. Ethyl ester of all-trans retinoic acid was administered topically or as indicated and a control untreated area was utilized for comparison. The growth rate, length, thickness, and shedding period of hair in fur-bearing animals is governed by many factors, including season, light (wavelength) periodicity, temperature, hormonal factors, and nutrition. Although it is not possible to control for all of these factors, animals were selected and their quadrants were shaved into a 2 inch diameter circle. In some animals, the area was treated topically with all-trans retinoic acid, and in others, the retinoid was mixed with the animal's diet and administered orally. Treated and untreated parts of some of the animals served as their controls. In fur animals, the undercoat and fur differ in thickness, length, and rate of growth. The average length of the undercoat in rabbits is 34.
mm and the length of the fur was 30 mm. Topical application of all-trans retinoic acid was effective in increasing the rate of new hair growth. The effect of topical treatment with all-trans retinoic acid in the form of a lotion on unshaved fur-covered areas was a reduction in hair loss or shedding. The average hair growth rate of the three rabbits in the shaved and treated areas was 0.3 mm/day, while the average growth rate in the shaved and untreated areas was 0.2 mm/day.
mm/day. This effect should also be demonstrated for domestic cats and dogs. A similar experimental method was adopted. The most significant effect in long-haired dogs and cats was a delay in shedding or shedding. Long-haired dogs and cats tended to retain more hair during the growth phase, and hair loss was reduced by 50% during the treatment period. Both dosing regimens were satisfactory. Topical lotions, cream treatments, or systemic treatments added to the animal's diet were all satisfactory. Daily administration to animals was 20 mg/kg body weight mixed in food or applied topically at 10-15 mg. Commercially important fur animals were also used in experiments.
The two male mink had their backs tightly clipped. These studies used the capillary method of measuring hair growth. The animals were given retinoids mixed in their diet or administered retinoids topically. Daily dose is 20 per kg of animal
mg/day mixed into food or applied topically at 5 mg/day. These experimental results indicate that the growth rate of new fur is approximately 30% by retinoid treatment.
% increase. Experiments in birds (canaries and parakeets) have shown that all-trans retinoic acid or ethyl-containing all-trans retinoic acid or all-trans retinoic acid
It was shown that adding 30mg of ester per kilogram of bird weight per day to the bird's diet slowed down the hair loss process. The following example illustrates the invention. Methods of administration include lotions, creams, ointments, pills, addition to food,
This includes how to apply it to bait seeds. These examples are for illustrative purposes only and are not intended to limit either the method of administration or the ingredients that may be incorporated into the present invention or the amounts used. Example Prescription ingredients for topical lotion Weight % Active ingredients: All-trans retinoic acid 0.1 Ethanol qs~100.0 Propylene glycol 5.0 Butylated hydroxytoluene 0.1 Safflower oil 1.0 α-tocopherol acetate 0.5 Example Cream conditioner for topical administration Ingredients Weight % Active ingredients: All-trans retinoic acid or all-trans retinoyl acetate 1.0 Distilled water qs~100.0 Cetrimonium chloride 5.0 Cetyl alcohol 4.0 Ethanol 4.0 Butylated hydroxytoluene 1.0 Hydrolyzed animal protein 0.5 Methylparaben, propylparaben 0.1 Example: 0.1 g of all-trans retinoic acid and 10 g of acetone.
ml, the solution is mixed with 90 g of UPS grade hydrophilic ointment to a uniform consistency and 1 g of butylated hydroxytoluene is added. The washable cream ointment thus prepared consists of 0.1% active ingredient. Example Tablet for oral administration Ingredients Weight % (mg) Active ingredients: All-trans retinoic acid, or all-trans retinoic acid ethyl ester or acetate 25 Lactose 52 Corn starch 20 Microcrystalline cellulose 40 Talc 2.5 Magnesium stearate 0.5 Activity as above The ingredients were mixed with lactose and granulated using cornstarch paste. The remainder of the above adjuvants were mixed therein and the powder was made into tablets. The tablets were then coated with a water-soluble or water-swellable lacquer. Small granules can also be made by adding gelatin to the same formulation. These small granules are then coated with lacquer. The small granules can be mixed with animal food to achieve the desired dosage level. The above formulation can also be used in powder form for mixing with bird feed (seed). And the bird food can be sprayed with latskar. Liquids, syrups or other mixtures may also be prepared consistent with pharmaceutical technology.

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