THE USE OF RETINOIDS AND THEIR DERIVATIVES TO INCREASE THE RATE OF GROWTH OF HUMAN SCALP HAIR AND TO INCREASE THE RATE OF GROWTH OF FUR IN CERTAIN FUR-BEARING ANIMALS

Abstract: This invention involves the use of retinoids to increase the rate of hair growth and to prolong the anagen phase of the hair cycle.

Description: Title: The Use of Retinoids and Their-Derivatives to Increase tha Rate of Growth of Human Scalp Ξair and to Increase the Rate - of Growth of Fur in Certain Fur Bearing Animals. Background of the Invention 1. Field of i±e Invention This invention relates to the-use of retinoids and their deri¬ vatives in order to increase the rate of growth of human scalp hair and to increase the rate of growth of fur in certain fur bearing animals. 2. Description σf the Prior Art A ι_xaιaal"cha_racteristic of human hair ' growth in most individuals is that it diminishes with age. Both the rate of.growth of the hair and i±e length of the growing cycle are reduced. This condition is cαπron to all individuals with rare exception and must be differ¬ entiated from true male pattern alopecia, which is a distinct clini¬ cal entity associated in certain individuals with the prcx ction of the male sex hormone, testosterone and its derivatives, particularly dihydrotestosterone. ϊ-feny factors may influence i±e rate of hair growth including race, sex, age, region, season of the year, nutrition and hαπrones (Myers " and Hamilton, 1951, Hamilton, 1958, Yano, 1936, Maeda, 1938, Troter, 1923, Pinkus, 1924, and Ono, 1963) . In the past, many at¬ tempts have been made to altar the course of male pattern alopecia through numerous types of treatmen s r all of which have proven ucr: successful. Bias invention does not purport to reverse total male - pattern alqcecia. This invention describes a trea-fxπeπt to increase the rate of growth of hair from growing hair follicles and frαn the hair follicles of certain fur bearing animals, and to prolong the growing phase of the hair cycle. In the past. Vitamin A cαπpσπcds, hereafter referred to as retinoids have been shown to be effective in treating many types αf disorders including de__πιatolcgical conditions such as acne and psoriasis. I have now found a usa use for the retinoids in increa¬ sing the rate of hair grc-wth and prolonging i±e anagen phase of the hair cycle. In the past, VitamijiA. αnponrris, hereafter referred to as retinoids have been sh__wn to be effective in treating many types of disorders including dermatolpgical conditions such as acne and psoriasis. I have new found a new use for the retinoids in increasing the rate of hair growth. Suπmary of the Invention I have discovered that, retinoids particularly al trans refcinoic acid and its der±vativies can increase the rate of scalp hair growth in humans and that it- can also be used to increase the rate of growth of fur in certain fur bearing animals and to retard molting. Bie choice of administration is topically by use of lotions, ' ointments, creams, etc. However, adadni tration is not limited to these means, i±e effect can also be obtained by the oral or systemic administration of the retinoid compounds. Detailed Description of the Invention This invention concerns the use of retinoids, including all trans retinoic acid and its metabolites ≤ 1 *** other retinoid cαππαunds in order to increase the rate of scalp hair growth in humans and to increase the rate of pelt (fur) growth in certain fur bearing animals. All trans retinoic acid has been shown to cause elevated DNA synthesis in eratinocytes in cell culture. All. i_rans-~ret.___x.ic acid has been shown to cause elevated DNS. synthesis in kej-stinocytes in cell culture. All t__ans-retinoic acid can also be shown to increase the turnover time of epidermal cells in cell culture experiments as well as i ±n vivo experiments with human subjects. I have discovered that the cells of the hair follicle including the papillae can be stimu¬ lated by retinoids including all trans retinoic acid. When tested experimentally, i±e retinoids caused the cells of i±e dermal papillae and the cells of i±e rcot sheath to incorporate more tritiated thy- midine into DNΑ. and to reproduce at a more rapid rate than untreated calls frαn other hair follicles. This stimulation by the retinoid cαrtgσunds ultimately causes the entire hair follicle to become mare activated and the mitotic index as measured by thymidine-Ξ^ incorp¬ oration into OIOA to rise. Therefore the individual scalp hairs can be shewn to grow at an increased rate and the anagen phase is prolonged. A major problem in influencing hair growth is to obtain good percutaneous absorption of the active cαn ounds. Jtoother problea is the accurate measurement of hair growth to substantitats the results of t±e testing. AH i_zans-retinoic acid and its derivatives and the other retinoid cαucound≤ have been shown to give excellent percutaneous absorption and to be very active on the keratirύzing cells of i±e skin, including i±e hair follicle. Furtheπnore, a re¬ latively recent method which, gives excellent results has been used to- measure the rate σf hair growth. This method was devised by Saitoh, M. et al and utilizes micrccapi 1ary tubes which are gradu¬ ated using 0.2an graduations. ( a reproduction of the photograph of the instruments utilized for this method is enclosed.) As used herein, the term retinoid denotes retinal, -retinal, retixyi esters as well as retinoic acid, and its esters, deravatives and normal metabolites. The terminal group may be oxidized, reduced est≤rified, etc. The alkali metal (sodium, potassium, etc} and alkaline eart± metal (magnesium, clacium, etc ) salts are also inclu¬ ded herein. The pharmaceutical or cosmetic cr veterinary preparations of • i±e present invention can be prepared by the conventional techniques for the preparation of lotions, crearns, conditioners or shaεrcos for i±e scalp or veterinary preparations for pelts. Included also are preparations which can be administered orally and compounds which can be added to animal feeds. In addition to the active retinoids of this invention, the various preparations can contain any conventional pharmaceatically acceptable cr cosnetically acceptable inert or pha____τaccdynamically active additives. For example, the lotions may be prepared using various forms of alcohols or other solubiϋzers such as glycols, or esters. The conditioners may contain i±e norrπally acceptable ccra- merically produced σccrpσunds .such as σetyl alcohol, ceteareth-5,-20 hydrantoins, hydrolyzed animal protein, glycol stearate, aπx-xiimethi- ccne, paraffin, mineral oil, etc. (These are only given as examples, and are not meant to be inclusive.) The topical compounds may also contain various oils including essential -fatty acids and other pclyunsaturated fatty acids and their derivatives, and cαπpσunds suc± as hormones, including progesterone, estradiols, thyroid, etc. The topically applied lotions, creams, and conditioners, etc will vary according to the standard art with regard to the amounts of other hydrcphilic and hydrophobia containing ingredients ' includ¬ ing emuls fiers, so that either an oily, seπi-oily or oil. free product may be obtained. The shampoos may contain any of the con¬ ventionally used detergents or soaps and any other cαitpαunds used by i±ose familiar with the art- Oil based shamπocs are included in these formulations. The oral preparations may be tablets, liquids, capsules, etc. The pharmaceutically acceptable substances cαrmonly used as preser¬ vatives, stabi izers, noisture retainers, emulsifiers, etc. can be present in these preparations. Conventionally acceptable antioxid- ants such as tccopherols, N-mεthyl a-tocopheramine, butylatad hydro- xyanisole and butylated hydrcxytoluene, can be also incorporated in the preparations described in this invention. The dosages in which the retinoids are administered can be varied eit± i±e route of administration and i±e requirement s of the subjects. Bie topical treatments may consist of lotions, creams, conditioners, shampoos, oil treatments, etc with from 0.001 to 2% by weight of all trans-retinoic acid cr derivatives, or other retinoids, as the preferred dosages in i±e described cαπpositions. The oral phazmacesitical preparations may be*adπιininstered at a daily dose of from 0.25 g to 2 mg per kilogram of bcdy weight. These can be also incorporated into animal chow in i±e case of fur bearing animals ,in the case of dogs or cats cr other pet food,or in i±e case of bird seed for moulting bidrds. In order to examine the specif c action of the retinoids in in¬ creasing the rate of hair grc-jwth, several types of experiments were performed. 1-he micrccappi 11ery method was used in each case to measure i±e rate of hair grαwth. Ih. Table I is described the results of studies using male and female subjects. The all trans-retinoic acid was applied topically cr as described in the table asά. the micrccappi11ary method was used to assess hair growth rates, (see separate pages for TABLES) . In Table H is described the results of studies using male and feπale subjects. The ethyl ester of all i____ansreti_noic acid was applied topic¬ ally or as described in the table and a control non-treated area was utilized for comparisor In fur bearing animals, the rate of fur growth, length of hair, thickness of hair and molting season are controlled by many factors including season, light (wavelength) periodicity, i__aroerature, hormcnal factors and nutrition. Controlling, all of these variables is impossible however, animals were selected and areas over the hind quarters were shaved in 2 inch diameter circular areas. In seme of the animals the areas were treated topically with all-t_rans-retinoic acid and in other animals the retinoid was administered erally in animal chow. Same of i±e animals served as their ouwn controls, using treated and non-treated areas. Λ In fur bearing animals, the guard hairs and the pile hairs differ in thickness, length and growth rate. In the rabbits studied, the guard hairs averaged 34 urn and the pile hairs 30 ιτm in length. The effect of topical application of all trans-retinoic acid was to increase the rate of new hair_ growth. &-, - effect on the non-shaved fur bearing areas treated with topical all trans retinoic acid- in lotion form, was a decrease in the sheadin cr molting of fur. The mean rate of hair (fur) growth frcm treated shaved areas was 0.3 mπ day for 3 rabbits (meajl while in non-treatment shaved areas it averaged 0.2 irm per day (mean of 3 rabbits) . The effect could also be demonstrated in domestic cats and dogs; the same type of experimental procedures were used. The most striking effect in long haired degs and cats was the retardation of molting or hair sheading. Long haired dogs and cats tended to retain more hair in the aπagen phase and there was approximately 50 % less sheading during the treatment periods. 3oth methods of administration were satisfactory. Either topical lotion or cream treatment or systanic treatment by inclusion in animal chow was satis¬ factory. The daily dosage for animals was 2 ( fog per kilogram per day in chow or 10 to 15 mg applied topically. Ccπmerically -important fur bearing animals were also used for experi¬ mentation. T o male minks were closely clipped over the back hind quarters The animals were treated an one hind quarter and the other was used a the control. The cappillary method for measuring hair growth was used for thes str-dies. The animals were treated by two different methods- The animals were either fed the retino in theas chew or they were administered the retinoid topically . The daily dosewas 2D mg per kg body weight per day in animal chow or 5 mg. pe -day applied topically. „ The results of these experiments shewed that the rate of growth of new pelt was increased approximately 30 % by t±e retinoid treatment. • Experiments losing birds (canaries and parakeets )shewed that inclusion of the all trans retinoic acid or the ethyl ester of all trans retinoic acid in bird feed at a dosage of 30mg. per kilogram bird weight per day retarded t±e molting process. The following Examples illustrate the present invasticn. The methods of administration may vary by lotion, cream, ointment, pill, supplement to chow,coating for seeds, etc. These Examples are only meant to be illustrat and do not limit the mode of adπunistration nor the ingredients which can b admixed to the present invention* nor the amounts which may be used. Example I Lotion femulation for the topical adπunistration % wt to wt Active ingredient: all trans retinoic acid 0.1 Ξthanol q.s. to 100 Eropylene glycol' 5.0 Butylatad 3_ιydrαxytoluene 0.1 Safflower oil 1.0 α-tocopherol acetate 0.5 Example U Cream Conditioner for Topical A iiinistratiαn Active ingredient: All i_rans-retinoic acid cr 1.0 all fcrans-retinoyl acetate Distilled water q.s. to 100.0 Cetrimonium Chloride 5.0 cetyl alcohol 4.0 Ethanol 4.0 Butylatad hydrαxytoluene 1.0 hydrolyzed animal protein 0.5 methylparaben, propylparaben 0.1 Bcample HI All trans retinoic acid 0.1 gram is dissolved in 10 ml of acetone, and i±e solution admixed with 90 g of USP grade hydro- philic ointment to a uni orm consistency one gram of butylatad hydrαxytoluene is added. The water washable cream ointment thus prepared consists of 0.1 % active __ g edien*__ s- -~ ^ _ . JLU Example 17 Tablets for oral aππππistration Active ingredient all trans retinoic acid or 25 mg. all trans retinoic acid ethyl ester or acetate lactose 52 mg <_krnstarch 20 mg M-i.-r-f -T-yyhan-in-a cellulose 40 g T&ic - 2.5 mg J&gnesium steaxate 0.5 mg The active ingredient was mixed with lactose and granulated using a corn starπh paste. The remainder of the above adjuvants was then admixed t±erei the mass was tableted- The.-tablets ware then tablet≤d. The tablets were then coated with a water-soluble or water-T.- y *!! ble lacquer. The same fαππulatiαn can also be used and gelatin can be added to make beadlets- These beadlets are then coated with a lacquer. The beadlets and animal chow can be mixed to the desired dosage level. The above fermulation can also be used in the powdered farm far mixing with bird seed and the bird seed can then be sprayed with lacquer. Liquids, syrups or other fαππulations can be made consistent with the pharmaceutical art. RESULTS USING ALL TRANS RETINOIC ACID TABLE I mm/day mm day Subject Dosage Form of Treatment Control Treatment Dosage Time Sate 33ate of Growth Sex Age M 36 10 mg/ Topical 21 days 0.3 0.45 day Lotion 38 βσMg/ oral 14 days 0.21 0.25 day . 24 10 mg Topical 10 days 0.35 0.49 F 35 10 mg Topical 30 days 0.39 0.50 F 41 60 mg Oral 28 days 0.36 0.39 F 63 10 mg Topical 21 days 0.28 0.38 RESULTS USING ALL TRANS RETINOIC ACID ETHYL ESTER - B Ξ H mm/day mm/day Subject Dosage Form of Trffrt.71'lent Control Treaii'-ient Sex JS e per day Dosage Time Rate Rate of Growth M 31 10 mg Topical 21 days 0.25 0.31 M 68 10 mg Topical 20 days 0.21 0.29 M 38 70 mg Oral 21 days 0.30 "~ 0.32 F 36 10 g Topical 22 days 0.34 0.46 F 42 10 mg Topical Cream 19 days 0.31 0.40 F 66 50 mg Oral 20 days 0.28 0.29 ■ ^ j E T - Table III RESULTS USING ALL TRANS SEXINA DEHSDE (Commerically available- for synthesis see Merc .Index) mm/day mm/day Subject Dosage Form of Treatment Control Treatment Dosage Time -Rate Hate of Growth Sex Age M 36 10 ng/ Topical 21 days 0.30 0.35 day M 38 •10 Mg/ Topical 14 days 0.23 0.32 day M 24..- 10 mg Topical. 10 days * - 0.35 0.40 F 35 10 mg Topical 30 α ya 0.39 0.45 F " 41 ~ lθ mg Topical . 28 days.-.--. 0.31 : ■ 0.35 F : 63 ---- 10 ng- - Topical 21 days - 0.28. 0.41 ' TABLE " .-..IV i.e. RESUL-TS USING -RETINOIC ACID METABOLITES- <-4-hydτoxy and 4-keto)"-- (Can be prepared;by enzymatic methods; synthesis known) Ref: Archives-of Biochemistry and Biophysics, 199 p.374-383( Subject Dosage Foππ of Treatment Control Trea±ment Sex iftge per day Dosage . Time Rate Bate of Growth M 31 10 mg Topical 21 days 0.25 0.-31 M 68 10 mg Topical 20 days 0.21 0.28 M 38 10 g Topical 21 days 0.34 0.35 F 36_ 10 mg Topical 22 days 0.34 0.41 F 42 10 mg ToDical 19 days 0.39 0.48 F 66 ID mg Topical 20 days 0.28 0.36 i.e. 8-(2,6^-tr_unethyl*-3-oxocyclohex-l-βnyl)-2,6- dimethyl -6- hydroxoctatrienal prepared by ' enzymatic methods ( Biochimica Biophysica Acta, 627; 270-275 (1980) Subject Dosage Form of Treatment Control Treatment Dosage Time Hate of Growth Sex Age mm day mm αay M 36 10 mg/ Topical 21 days 0.30 0.35 day M 38 10 Mg/ Topical 14 days 0.21 0.24 day 24 10 πg- Topical ..- 10 " days . 0.35 0.35 F 35 10in -. Topical.:.: 30 " days 0.39- F • 41.i 10 mg..- Topical -. • 28 -days -.- 0.36- 0.38 F 63 • " 10 mg Topical 2 ' days 0.28 0.27 TABLE VI EXTRACTED- R0M~. ' RESULTS* USING.DEHYDRORETTNOIS (PIKE .IVEE. -OIL)._AND_ - THEI'T- . STERIΪOISOMERS ' (SEE MERCK -INDEX" FOR SPECIFICATIONS) AND-OXIDATION -PRODUCTS INCLUDING ALDEHYDES .AND ACIDS mm/day mm/day Subject Dosage Form of Treaiment Control Treatment Sex Age per day Dosage Time Pate Kate of Growth 31. 10 mg Topical 21 days 0.25 0.41 M 68 10 mg. Topical 20 days 0.21 0.25 M 38 • ^Q mg Topical 21 days 0.30 0. 4 ' F 36 10 mg Topical 22 days 0.34 0.34 F 42 10 mg Topical 19 days 0.31 0.32 F 66 10 πg T p_ical 20 days 0.28 0..29 • RESULTS USING ALL TRANS RETINOΣL ACETATE TABIS- VII mm/day ma/ ay Subject Dosage Fom of Treatment Control Treaimant Dosage Time Hate Fata of Growth Sex _?_ge M 36 10 mg T pical 21 days 0.30 0.45 day Totion M 38 60 Mg/ oral ..4 days 0.21 0.2 0 day M * 24 -- • 10 mg -- TV-^πr-wl 10 cays; 0.35 0.4.1.. F r 35 ™ 10 g Topical 1 30 days_ ; . 0.39 -.-. 0.39 .. . F . 41.: 60 mg ---- Oral " : 2 days - - 0.3?..- 0.30 . F • 63 ' 10 mg — Topical ' 21 days 0.28 ■ 0. 5 ' TABLE VIII RESULTS -5S ϊG- . -* __i--ΗlΔNS-- E T Atfl: &.*=π -*.- ~- mm/day m/day Subject Dosage Form of Treatment Control Treatment Sex Age per day Dosage .Time ate- Rate of Growth M 31 10 mg Topical 21 days 0.25 0.30 M 68 10 mg . cπical 20 days 0.21 0.2-3 RESULTS USING ^RETINOIC ACID AND CRETINOIC ACID F 36 10 mg Itopical 22 days 0.34 0.40 F 42 10 mg % Topical Crsa 19 days 0.31 0.41

Claims: What is claimed is: 1. A method for increasing the rate of growth of hair and prolonging the anagen phase of the hair cycle by topically or orally administering to a mammal, a retinoid or a pharmaceutically acceptable ester, ether, or salt thereof, in an amount effective for the purpose. 2. The method of Claim 1 wherein the retinoid is all trans retinoic acid, or all trans retinaldehyde, or all trans retinoyl acetate, or other suitable esters or salts of retinoic acid. 3. The method of Claim 1 wherein the retinoid is selected from the group consisting of the stereoiso ers of vitamin. A acid, or * vitamin A2 acid, vita¬ min A acid, vitamin A acid, 5,6 epoxy-vitamin A acid, - dehydrovitamin A acid or the aldehydes, alcohols, esters, ethers or salts of the above mentioned compounds. 4. The method of Claim 1 wherein the retinoid is a naturally occuring metabolite of vitamin -A acid such as 4-hydroxy retinoic acid, 4-ket ' o retinoic acid, 4-oxo-retinoic acid, 5,8,oxy-retinoic acid or 7-cis 3 dehydroretinol or retinoic acid,- y-trans-θ-c-Ls-ll-trans-lS-trans-S'-hydroxy-retinoic-acid^ or 8-(2,6,6-trimethyl-3-oxocyclohex-l-anyl)-2,6-dimethyl-6-hydroxyoctatrienal or ' stereoisomers of the above mentioned compounds, or aldehydes or derivatives such as esters or salts thereof. 5. The method of Claim 1 wherein the compound is a carotenoid such as crocetin or crocin or its naturally occuring metabolites. 6. The method of Claim 1 wherein the mammal is a human and the hair is scalp hair. 7. -The method of Claim 1 wherein the animal is a fur bearing animal and the retinoids also prevent or retard molting or shedding. 8. The method of Claim 1 wherein the retinoid concentration in the topi¬ cal lotion, cream, ointment, conditioner or shampoo is between 0.001 to 5% by- weight- 9: The method of Claim 1 wherein the retinoid compositions are given orall i a d

Inventors: BAZZANO GAIL SANSONE
Applicants: BAZZANO GAIL SANSONE
Application year: 1981
Main classification: A61K7
IPC codes: A61K8, A61K31, A61Q7