WO2006106528A1 - Novel peptides useful for treatment of alopecia - Google Patents
Novel peptides useful for treatment of alopecia Download PDFInfo
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- WO2006106528A1 WO2006106528A1 PCT/IN2005/000453 IN2005000453W WO2006106528A1 WO 2006106528 A1 WO2006106528 A1 WO 2006106528A1 IN 2005000453 W IN2005000453 W IN 2005000453W WO 2006106528 A1 WO2006106528 A1 WO 2006106528A1
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- pharmaceutical composition
- hair growth
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- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 84
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- 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
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- 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
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to novel peptides of formula (I) and its pharmaceutically acceptable salts thereof and a method of in vitro and in vivo bioassay of the said peptides for promotion and stimulation of hair growth and thereby their usefulness for treatment of alopecia.
- the present invention also relates to a method for preparation of the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof as well as a pharmaceutical composition comprising an effective amount of one or more of the novel peptides for promotion and stimulation of hair growth.
- Alopecia commonly known as baldness is indicative of deficiency of hair, either normal or abnormal.
- Alopecia is primarily cosmetic in nature found in human beings, although it could be psychological as well (C. H. Mortimer et. al., Clin. Exp.
- Alopecia is associated with a change in hair type from terminal to vellus as well as alteration in the cycle of hair growth, viz. anagen, catagen and telogen. As baldness progresses, there is a shift in the percentage of hair follicles in each phase, with majority shifting from anagen to telogen.
- alopecia Different types of alopecia are known, with androgenetic alopecia accounting for about 95 % of hair loss in both men and women, however, being more ⁇ prevalent in males. Androgenetic alopecia affects more than one-third of the population having a strong family history of hair loss. (W. F. Bergfield, Clin. Dermatol. 1998, 6, 102-107). The onset of alopecia is determined by the presence of sufficient circulating androgens and the degree of genetic predisposition (Ellis et. al., Expert Rev in MoI. Med., 2002, 1-
- Alopecia areata, (iv) Traumatic alopecia, and (v) Anagen effluvium.
- Chemotherapy induced alopecia is a frequent and emotionally distressing side effect of cancer therapy (V.J.Dorr, Semin. Oncol., 1998, 25, 562 and K. Munstedt, N. Manthey, et.al., 1997, 75, 303) for which there is currently no effective preventive therapy (G. Chen et.al., Int.J.Cancer, 1998, 75, 303 and M. Duvic et.al, JAm. Acad. Dermatol, 1996, 35, 74).
- Type II 5 ⁇ reductase enzyme is a key enzyme linked to the development of Androgenetic Alopecia, it is present in abundance in genital skin, prostate, inner root sheath and dermal papilla (Xui Li et. al., Steroids, 1995, 430-441), exists as two isozymes, I and II that share 50 % homology. In balding scalp the level of expression of 5 ⁇ reductase and androgen receptor are elevated as compared to non-balding scalp.
- Finasteride currently marketed as Propecia ® for the treatment of hair loss is a specific inhibitor of type II 5 ⁇ reductase, whereas Dutasteride, a molecule under clinical investigation for the treatment of hair loss is a dual inhibitor of both isoforms and is currently under clinical investigation.
- Propecia ® may have specific peripheral toxicity and hence cannot be Used by women.
- Minoxidil as disclosed in US 4,596,812, which is marketed as Rogaine ® is a topical pharmaceutical composition for stimulation of hair growth. Minoxidil originally was developed as an antihypertensive drug and hypertrichosis was seen as a toxic effect.
- Fluridil which acts as an antiandrogen by suppressing the expression of androgen receptor is another hair growth promoter as disclosed in WO 01/58854.
- the androgen receptor belongs to steroid receptor superfamily.
- the androgen-receptor gene, expressing the receptor was the first gene to have been associated with alopecia.
- the androgen-receptor complexes dimerize in nucleus and bind to a hormone response element or regulatory DNA sequence in or near a target gene.
- Amino acids like arginine/ L-arginine, cysteine/ L-cysteine have been proposed to stimulate hair growth.
- Biotin and folic acid in diet are claimed to promote hair growth.
- Zinc sulphate limits availability of reduced cofactor NADPH required for 5 alpha reductase activity and thus was found to be an inhibitor of DHT. (Semin Cutan, Med Surg. 1998, 17(4), 276-83).
- alopecia is also addressed through hair transplantation, which, however is costly, time consuming, painful, and meets with only limited success.
- Minoxidil and Finasteride are effective in only select population and hence not universal.
- loss of hair or baldness is a social stigma, especially in men, which not only affects the psyche but also the quality of life of such individuals.
- the present invention is a step forward in this direction and provides novel peptides, hitherto not reported, which exhibit significant potential in addressing the need.
- An object of the present invention is to provide novel peptides useful for promotion and stimulation of hair growth.
- Another object of the present invention is to provide novel peptides useful for treatment of alopecia.
- Yet another object of the present invention is to provide novel peptides and a method of in vitro and in vivo bioassay of the said peptides for promotion and stimulation of hair growth.
- Still another object of the present invention is to provide novel peptides and a method of in vitro and in vivo bioassay of the said peptides for treatment of alopecia.
- a further object of the present invention is to provide novel peptides for promotion and stimulation of hair growth in a mammal treated with a chemotherapeutic agent.
- Yet further object of the present invention is to provide novel peptides for promotion and stimulation of hair growth in a human treated with a chemotherapeutic agent.
- object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for treatment of alopecia.
- a further object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for promotion and stimulation of hair growth in a mammal treated with a chemotherapeutic agent.
- Yet further object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for promotion and stimulation of hair growth in a human treated with a chemotherapeutic agent.
- Another object of the present invention is to provide a pharmaceutical composition comprising the- novel peptides for treatment of alopecia in a mammal treated with a chemotherapeutic agent.
- Yet another object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for treatment of alopecia in a human treated with a chemotherapeutic agent.
- peptides both small and large have been disclosed for promotion of hair growth/ treatment of alopecia.
- all the peptides disclosed so far are comprised of amino acids, selected from among the twenty common amino acids.
- a small tripeptide comprising an uncommon amino acids viz. ⁇ , ⁇ - dialkylated amino acids linked through peptide bond, with a basic amino acid on one side i.e., at the amino terminal and either glycine or a basic amino acid on the other side i.e., at the carboxyl terminal, exhibits remarkable in vitro and in vivo bioassay for promotion and stimulation of hair growth in mammals and thereby useful for the treatment of alopecia.
- The, uncommon amino acids viz ⁇ , ⁇ dialkylated amino acids are known for inducing conformational constraint.
- the incorporation of these uncommon amino acids restricts the rotation of ⁇ , ⁇ angles, within the molecule, thereby stabilizing a desired peptide conformation.
- the prototypic members of ⁇ , ⁇ dialkylated amino acids viz. ⁇ aminoisobutyric acid (Aib) or ⁇ ⁇ , dimethylglycine has been shown to induce ⁇ -turn or helical conformation when incorporated in a peptide sequence (B.V.V. Prasad et. al., 1984, CRC Crit Rev.Biochem., 16, 307-347; LL. Karle et. al.
- the present invention exploits the known conformational properties of ⁇ , ⁇ - dialkylated amino acids and hydrophobicity of the side chain, for design of the peptides of formula (I) of this invention, which as mentioned hereinbefore, exhibits remarkable in vitro and in vivo bioassay for promotion and stimulation of hair growth.
- the present invention provides novel peptides of formula (I) and its pharmaceutically acceptable salts thereof,
- Ri & R 2 are alkyl or Y represents a carbocycle of 3-8 carbon atoms; Z is a residue of an amino acid selected from Arginine, Histidine, Ornithine or Lysine or its amino protected derivatives thereof, forming the amide linkage with the amino group adjacent to group Y.
- the present invention provides methods for preparation of the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof.
- the present invention provides a method of in vitro and in vivo bioassay of the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a mammal.
- the present invention provides a method of in vitro and in vivo bioassay of novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the promotion and stimulation of hair growth in a human.
- the present invention provides a method of in vitro and in vivo bioassay of novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the promotion and stimulation of hair growth in depilated and telogen skin.
- the present invention provides a method of in vitro and in vivo bioassay of novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the treatment of alopecia in a mammal.
- the present invention provides a method of in vitro and in vivo bioassay of novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the treatment of alopecia in a human.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a mammal.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a human.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in depilated and telogen skin.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the treatment of alopecia in a mammal.
- the present invention is to provide pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the treatment of alopecia in a human.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a mammal treated with a chemotherapeutic agent.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a human treated with chemotherapeutic agent.
- the present invention provides a pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for treatment of alopecia in a mammal treated with a chemotherapeutic agent.
- present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for treatment of alopecia in a human treated with a chemotherapeutic agent.
- Fig 1 Effect of Compound No.l of table 1 on length of the hair follicle in whole organ cultures in vitro.
- Fig 2 Effect of Compound No.l of table 1 on length of the hair shaft in whole organ cultures in vitro.
- Fig 3 Effect of Compound No.4 of table 1 on length of the hair follicle in whole organ cultures in vitro.
- Fig 4 Effect of Compound No.4 of table 1 on length of the hair shaft in whole organ cultures in vitro.
- Fig 5 Establishment of in vivo model for chemotherapy induced alopecia irp adult
- Fig 6 Effect of compound No. 1 in Table I on chemotherapy induced alopecia in model in adult Swiss albino mice.
- Fig 7 Effect of compound No 1 (200 ⁇ g/4cm 2 ) of Table I on Chemotherapy induced alopecia model in adult C57/BL6 mice.
- Fig 8 Effect of compound No 1 (400.. ⁇ g/4cm 2 ) of Table I on Chemotherapy induced alopecia model in adult C57/BL6 mice.
- Fig 9 Effect of compound No 3 of Table I on Chemotherapy induced alopecia model in adult C57/BL6 mice.
- Fig 11 Effect of compound No 1 (concentration 3.2mg/15cm 2 ) of Table I on hair promotion/Anagen induction in C57/BL6 mice in vivo.
- Fig 12 (A)(I), (A)(2) and (A)(3): Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with compound No. 1
- Fig 12 (B)(I), (B)(2) and (B)(3) Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with Vehicle 1.
- Fig 13 Effect of compound No 1 (concentration 1.6mg/15cm 2 ) of Table I on hair promotion/Anagen induction in C57/BL6 mice in vivo.
- X is a residue of an amino acid selected from Arginine, Histidine, Lysine, Ornithine or Glycine forming the amide linkage with carboxylic acid group adjacent to group Y;
- Y is a group of formula,
- Ri & R 2 are alkyl or Y represents a carbocycle of 3-8 carbon atoms; Z is a residue of an amino acid selected from Arginine, Histidine, Ornithine or Lysine or its amino protected derivatives thereof, forming the amide linkage with the amino group adjacent to group Y.
- amino acids which constitutes the group X are those in which the terminal amino group forms the peptide bond with the carboxylic acid of the uncommon amino acid represented by the group Y.
- the carboxy terminal of those amino acids constituting the group X are free i.e. the hydroxy group is either not protected or substituted by any group.
- amino acids which constitute the group Z are those in which the terminal carboxylic acid forms the peptide bond with the amino group of the uncommon amino acid represented by the group Y.
- the terminal amino group of the amino acid constituting the group Z is however, either free or protected.
- the suitable amino protective groups include acetyl, n-butanoyl, n-hexanoyl, n- octanoyl, lauroyl, myristoyl, palmitoyl, isohexanoyl, cyclohexanoyl, cyclopentylcarbonyl, n-heptanoyl, n-decanoyl, n-undecanoyl, 3,7-dimethyloctanoyl etc.
- Pharmaceutically acceptable salts of the peptides of formula (I) refer to non-toxic salts of the said compounds.
- Representative salts of the peptides of formula (I) include but are not limited to: acetate, ascorbate, benzoate, citrate, oxalate, stearate, trifluoroacetate, succinate, tartarate, lactate, fumarate, gluconate, glutamate, phosphate/diphosphate, valerate.
- Other salts include those with group I and II metals such as Ca, Li, Mg, Na, and K salts formed with halides, salts with amino acids like lysine or arginine; salts with guanidine or ammonium/ substituted ammonium salts or aluminium salts.
- novel peptides of formula (I) and its pharmaceutically acceptable salts thereof can be prepared exclusively by solid phase techniques or by solution phase procedures.
- the peptides were synthesized using the Fmoc solid phase strategy, either manually, or on a semi-automatic peptide synthesizer (CS Bio, Model 536). The peptides were assembled from C-terminus to N-terminus procedure on solid phase.
- the peptides were assembled from C-terminus to N-terminus using Wang Resin (4-Benzylobenzyl alcohol resin of 100-200 mesh substitution 1.2 raM/g, 1% DVB).
- Swelling of the resin was typically carried out in dichloromethane (10-40 ml/g resin) for 10 minutes.
- the first amino acid was loaded on the Wang Resin.
- the loading of first Fmoc protected amino acid on the resin was mediated by excess of Diisopropylcarbodiimide (DIPCDI), 4-Dimethylaminopyridine (DMAP) and N-Hydroxybenzotriazole (HOBt).
- DIPCDI Diisopropylcarbodiimide
- DMAP 4-Dimethylaminopyridine
- HOBt N-Hydroxybenzotriazole
- the coupling reaction was carried out in Dimethyl formamide, Dichloro methane or N-N dimethyl pyrrolidone or a mixture of these solvents and the reaction was monitored by weight gain. If the observed weight of the resin and peptide comes less than the expected weight, then capping is done by adding a solution mixture of 80% DMF, 10% acetic anhydride and 10% DIPEA.
- Fmoc group was deprotected and coupled to the second amino acid.
- the third amino acid was also coupled after deprotection of Fmoc group.
- the ami ⁇ o-terminal Fmoc group was removed and peptide-resin was washed with methanol, dried and cleaved from the resin support by treatment with trifluoroacetic acid and de-ionized water for lhr at room temperature.
- the crude peptide was obtained by precipitation with cold dry ether, filtered, dissolved, and lyophilized. On a 1.0 g scale of resin, 1.56 g of peptide-resin was obtained.
- the invention also provides pharmaceutical composition comprising an effective amount of at least one peptide of formula (I) and its pharmaceutically acceptable salts intended for promotion and stimulation of hair growth/ treatment of alopecia.
- the pharmaceutical composition comprising peptide of formula (I) may be administered in any convenient manner such as oral, parenteral or topical. However the preferred route of administration is topical.
- the peptide of formula (I) may be orally administered, for example, with inert diluents or with an edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
- the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- the peptide of formula (I) may also be administered parenterally or intraperitoneally.
- Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils.
- the peptide of formula (I) and its pharmaceutically acceptable salts thereof are formulated for topical administration.
- Suitable topical formulations include one or more peptides of formula (I) and its pharmaceutically acceptable salts thereof in the form of a liquid, lotion, cream or and gel.
- Topical administration may be accomplished by application directly on the treatment area. For example, such application may be accomplished by rubbing the formulation (such as a lotion or gel) onto the skin of the treatment area, or by spray application of a liquid formulation onto the treatment area.
- the amount of hair growth peptide can vary widely, depending upon the needs of the subjects.
- the preferred amount of hair growth peptides of formula (I) in such compositions comprises from about 0.01 % to about 10 % by weight more preferably between 0.5 % to 2 % by weight.
- the cosmetic composition according to the invention are applied to the alopecic regions of the scalp and the hair of a mammal or human individual, and is optionally maintained in contact for a number of hours, and is optionally rinsed there from. It is possible, for example, to apply a composition containing an effective amount of peptide of formula (I) to the hair and ' scalp in evening, to maintain the composition in contact overnight and optionally to shampoo in, the morning.
- the balance of the topically applied pharmaceutical preparations comprise peptides of formula (I) and an inert, physiologically acceptable carrier.
- the physiologically acceptable medium may contain other adjuvant commonly used in the cosmetic or pharmaceutical field, such as surface-active agents, thickening or gelling agents, cosmetic "agents, preservatives, or basifying or acidifying agents, which are well known in the art and in amount which are sufficient to obtain the desired form of presentation.
- the pharmaceutical compositions may contain pharmaceutically acceptable additives known in the art such as carriers, diluents etc. Typical carriers that can be employed include a disintegrant, lubricant and diluents. Disintegrants and lubricants are well known in the pharmaceutical sciences. Suitable disintegrants include starch, croscarmellose sodium, crospovidone, sodium starch glycolate, croscarmellose calcium, microcrystalline cellulose and polacrilin potassium, and the like.
- Suitable lubricants include magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated cottonseed oil, stearic acid, calcium stearate, colloidal silicon dioxide and the like.
- Suitable diluents may include RPMI 1649, buffered saline, isotonic NaCl 5 Ringer's solution, water, distilled water, polyethylene glycol, 2% Tween in water, 50% dimethylsulfoxide in water (v/v), propylene glycol, phosphate buffered saline, balanced salt solution, glycerol, and other conventional fluids that are suitable for intravenous administration.
- the composition can contain other additives, such as suspending agents, thickening agents, sweeteners, preservatives, bulking agents and flavouring agents.
- suspending agents examples include xanthan gum, hydroxypropyl methylcellulose, methylcellulose, carageenan, sodium carboxymethyl cellulose, microcrystalline cellulose mixes, thixotropic suspending agents such as xanthan, carageenan and sodium carboxymethyl cellulose/microcrystalline cellulose mixes and mixtures thereof. More preferred of these are xanthan gum and guar gum.
- the thickening agents found suitable in the present formulation include silicon dioxide and the like.
- the sweeteners that can be used include sugars such as fructose, sucrose, glucose, maltose, or lactose as well as non caloric sweetener such as aspartame, which can be used alone OF in combination with another non-caloric or low caloric sweetener known to have synergistic sweetening properties with aspartame, e.g. saccharin, acesulfame, thaumatin, chalcone, cyclamate, stevioside and the like.
- the water soluble preservatives found useful in the present invention include sodium benzoate, sodium citrate and.benzalkonium chloride, the preferred one being sodium benzoate and the like.
- Suitable bulking agents are lactose, manitol, isomalts, polydextrose, starch, microcrystalline cellulose, sorbitol, calcium sulphate, calcium phosphate, acacia and the like.
- Representative flavouring liquids include, artificial, natural or synthetic fruit flavours such as lemon, orange, banana, grape, lime, apricot and grapefruit oils and fruit essences including apple, strawberry, cherry, orange, pineapple and so forth; bean and nut derived flavours such as coffee, cocoa, cola, peanut, almond and so forth; and root derive flavours such as licorice.
- artificial, natural or synthetic fruit flavours such as lemon, orange, banana, grape, lime, apricot and grapefruit oils and fruit essences including apple, strawberry, cherry, orange, pineapple and so forth
- bean and nut derived flavours such as coffee, cocoa, cola, peanut, almond and so forth
- root derive flavours such as licorice.
- the topically applied pharmaceutically preparation of the peptides of formula (I) and its pharmaceutically acceptable salts thereof comprise peptides, tris buffer (pH ⁇ 8), isopropanol, and propylene glycol.
- a typical topical composition comprising the peptides of formula (I) is described in Example -10 given hereinbelow.
- the peptide of formula (I) 1.0 gm Tris buffer (pH ⁇ 8) 60.0 gm Isopropanol 10.0 gm Propylene glycol 24.0 gm Glycerine 5.0 gm
- the in-vitro model for evaluating hair growth promoting molecules is based on whole organ hair culture (Toshikazu Kamiya, Akio Shirai et. Al. J. Dermatol. Science, 1998, YT 1 54-60). Quantitation of hair growth is based on the cumulative increase in hair shaft and hair follicle in the presence of the compound.
- the studies carried out are described in the non-limiting examples given hereinbelow: Example-11 Establishment of Whole Organ Hair Cultures for Evaluation of Efficacy of the Hair Growth Promoting Peptides of formula (I) in vitro
- mice Male Swiss Albino mice (age- ⁇ weeks old) were purchased from National Institute of Nutrition Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. The whiskers were shaved off carefully using sterile scalpel blade. On 10 th day whiskers at anagen/proliferative phase of hair growth cycle, were decapitated. Whisker pads were dissected out carefully and transferred to ice cold transport medium (DMEM, NaCl (8.0g/L), KCl (0.4g/L), NaHCO 3 (3.7g/L), KH 2 PO 4 (0.06g/L), NaH 2 PO 4 (0.12g/L), pH-7.4).
- DMEM ice cold transport medium
- Whisker pads were washed in vertical Laminar hood for 5 -10 minutes in antibiotic solution containing streptomycin (lOO ⁇ g/mL to 500 ⁇ g/mL), penicillin (100U/mL to 500U/mL). Finally the Whiskers pads were washed in defined culture medium constituted with Williams E Medium to which were added Hydrocortisone (lO ⁇ g/mL), mixture of Insulin selenium and transferrin (lO ⁇ g/mL), L-glutamine (ImM) and Phenol red (10 mg/mL). Single hair follicles were dissected using dissecting microscope while carefully removing extra dermal tissues using sterile forceps. Each 35 mm petriplate was coated with 50 ⁇ L of sterile collagen.
- mice Male Swiss Albino mice (age- 6weeks old) were purchased from National Institute of Nutrition, Hyderabad India. Mice were observed in Quarantine for one week prior to initiation of the study. The whiskers were shaved off carefully using sterile scalpel blade. On 10 th day whiskers at anagen phase of hair growth cycle, were decapitated. Whisker pads were dissected out carefully and transferred to ice cold tansport medium (DMEM 5 NaCl (8.0g/L), KCl (0.4g/L), NaHCO 3 (3.7g/L), KH 2 PO 4 (0.06g/L), NaH 2 PO 4 (0.12g/L), pH-7.4).
- DMEM 5 NaCl (8.0g/L), KCl (0.4g/L), NaHCO 3 (3.7g/L), KH 2 PO 4 (0.06g/L), NaH 2 PO 4 (0.12g/L), pH-7.4 ice cold tansport medium
- Whisker pads were washed in vertical laminar hood for 5 -10 minutes in antibiotic solution containing streptomycin (lOO ⁇ g/mL to 500 ⁇ g/mL) penicillin (lOOU/mL to 500U/mL).
- the Whiskers pads were washed in defined culture medium constituted with Williams E Medium to which were added Hydrocortisone (lO ⁇ g/mL), mixture of Insulin selenium and transferrin (10 ⁇ g/mL) 5 L- glutamine (ImM) and Phenol red (10 mg/mL).
- Single hair follicles were dissected using dissecting microscope while carefully removing extra dermal tissues using sterile forceps. Each 35 mm petriplate was coated with 50 ⁇ L of sterile collagen. Two hair follicles were seeded in each petriplate.
- the organ cultures were maintained for 7 days in culture media in CO 2 incubator at 37° C and used for evaluating hair growth promoting peptides of formula (I) in vitro.
- the organ cultures were treated with Compound No.l of Table-I concentration ranging from 1OnM to 100OnM or with the Vehicle alone.
- the Compound No.l of Table-I was dissolved in sterile water (pH 7.1).
- the cumulative increase in the length of hair shaft and hair follicle was evaluated on 7 th day of the experiment using phase contrast microscope (NIKON) fitted with a measuring graticule.
- NIKON phase contrast microscope
- Figure- 1 represents effect of concentration of Compound No.l of Table-I on cumulative increase of length of hair follicle in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 100 nM.
- Figure-2 represents effect of concentration of Compound No.l of Table-I on cumulative increase of length of hair shaft in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM.
- Example-13 represents effect of concentration of Compound No.l of Table-I on cumulative increase of length of hair shaft in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM.
- Example-13 represents effect of concentration of Compound No.l of Table-I on cumulative increase of length of hair shaft in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM.
- Example-13 represents effect of concentration of Compound No.l of Table-I on cumulative increase of length of hair shaft in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM.
- mice Male Swiss Albino mice (age- ⁇ weeks old) were purchased from National Institute of Nutrition Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. The whiskers were shaved off carefully using sterile scalpel blade. On 10 th day whiskers at anagen phase of hair growth cycle, were decapitated. Whisker pads were dissected out carefully and transferred to ice cold transport medium [DMEM, NaCl (8.0g/L), KCl (0.4g/L), NaHCO 3 (3.7g/L), KH 2 PO 4 (0.06g/L), NaH 2 PO 4 (0.12g/L), pH-7.4].
- DMEM ice cold transport medium
- Whisker pads were washed in vertical Laminar hood for 5 -10 minutes in antibiotic solution containing streptomycin (lOO ⁇ g/mL to 500 ⁇ g/mL) penicillin (100U/mL to 500U/mL) .
- the Whiskers pads were washed in definite culture medium constituted with Williams E Medium to which were added Hydrocortisone (lO ⁇ g/mL), mixture of Insulin selenium and transferrin (lO ⁇ g/mL), L-glutamine (ImM) and Phenol red (10 mg/mL).
- Single hair follicles were dissected using dissecting microscope while carefully removing extra dermal tissues using sterile forceps. Each 35 mm petriplate was coated with 50 ⁇ L of sterile collagen. Two hair follicles were seeded in each petriplate. The organ cultures were maintained for 7 days in culture media in CO 2 incubator at 37° C and used for evaluating hair growth promoting peptides in vitro.
- Figure-3 represents effect of concentration of Compound No.4 of Table-I on cumulative increase of length of hair follicle in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM.
- Figure-4 represents effect of concentration of Compound No.4 of Table-I on cumulative increase of length of hair shaft in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM. in vivo Studies on Peptides of Formula (J) in vivo models used for evaluating hair growth promoting molecules are Sprague Dawley rats, C3H mice and C57BL6 mice.
- mice cycles in a wave like pattern from head to tail as opposed to mosaic pattern in humans (www.keratin.com/aa/aaOO8.shtml).
- C57/BL6 mice are widely used for hair growth promoting studies, due to the difference in pigmentation corresponding to different phases of hair growth cycle.
- the skin colour of mice is pink in telogen, which changes to grey to black in active anagen phase (Sven Muller-Rover et. al. Journal of Investigative Dermatology, 2001, 117, 3-15).
- mice Male Swiss Albino mice (age- ⁇ weeks old) were purchased from National Institute of Nutrition, Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer. On 10 th day the hair regrown were at Anagen phase of hair growth.
- Vehicle 1 represents the following: Vehicle 1: Vehicle of Etoposide injection.
- Table-Ill shows that the treatment of Group III animals with Etoposide, induce 100% visible Alopecia. Onset of Alopecia was seen in all the animals in Group III on 18 th day of the experiment, whereas hair growth is seen to be normal in Group I and in Group II animals on days 18 th 19 th , 20 th , 21 st .
- mice Male Swiss Albino mice (age- ⁇ weeks old) were purchased from National Institute of Nutrition, Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body Jiairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer. On 10 th day the hair regrown were at Anagen phase of hair growth.
- Vehicle 1 and Vehicle 2 represent the following: Vehicle 1: Vehicle of Etoposide injection Vehicle 2: Vehicle of Compound No. 1 ofTable-I The Composition of the Vehicle 2 is
- Vehicle 1 and Vehicle 2 represent the following: Vehicle 1: Vehicle of Etoposide injection Vehicle 2: Vehicle of Compound No. 1 of Table-I The Composition of the Vehicle 2 is
- mice Male C57/BL6 mice (age- ⁇ weeks old) were purchased from National Institute of Nutrition, Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer. On 10 th day the hair regrown were at Anagen phase of hair growth.
- Vehicle 1 and Vehicle 2 represent the following: Vehicle 1: Vehicle of Etoposide injection Vehicle 2: Vehicle of Compound No. 1 ofTable-I The Composition of the Vehicle 2 is
- composition Tris buffer(pH ⁇ 8) 66.0 g Propylene glycol 30.0 g Glycerine 3.0 g
- the quantitation of alopecia/ hair growth was done as percentage of shaved area covered by new hair growth, scored by blinded observer on scale of 0 (no growth) to 5 (complete hair growth) as described in US 20020198250.
- the quantitation of alopecia/ hair growth was done by weighing the hairs regrown after shaving.
- mice Male Swiss Albino mice (age- ⁇ weeks old) were purchased from National Institute of Nutrition Hyderabad- India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer. On 10 th day the hair regrown were at Anagen phase of hair growth. Treatment given to six different groups of animals is shown in Table-X. The study was conducted in six groups of six animals each. In Table-VI Vehicle 1 and Vehicle 2 represent the following: Vehicle 1: Vehicle of Etoposide injection
- Vehicle 2 Vehicle of Compound No. 3 of Table-I The Composition of the vehicle is
- composition Component . weight of composition
- mice Male C57/BL6 mice (42 day old) were purchased from National Institute of Nutrition, Hyderabad, India. Mice were observed in quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer.
- Vehicle 1 represents the following: Vehicle 1: Vehicle of Compound No. 1 of Table-I The Composition of the vehicle 1 is
- Component weight of composition Tris buffer (pH ⁇ 8) 66.0 g Propylene glycol 30.0 g Glycerine 3.0 R Compound No. 1 or the Vehicle was applied to 50-day-old mice (telogen hair growth phase) on depilated skin of the dorsal back using a syringe plunger (30 strokes for each applications) each day to the respective groups for 10 continuous days.
- Hair growth was quantitated by the percent of the shaved area covered by new hair growth a scored by a blinded observer on a scale of 0 (no growth) to 5 (complete hair growth).
- Hair growth was evaluated on 5 th day to 10 th day after initiation of the treatment. After five applications, the first visual sign i.e. darkening of skins is observed in Compound No. 1 of Table-I treated group. After seven applications, 90% of the animals in Group II showed intense follicular pigmentation. After 10 applications all the animals in the Group II showed visual hair growth as compared to the animals in Vehicle treated group.
- Table-XII shows observation and evaluation of hair growth as scored by blinded observer whereas figure 8 is visual observation of hair growth on C57/ BL6 mice on 10 th day of treatment.
- Animals in group II, which received Compound No. 1 of Table-I exhibits increased hair growth, indicative of promoting hair growth in depilated skin.
- Vehicle 1 represents the following: Vehicle 1: Vehicle of Compound No. 1 of Table- 1 The Composition of the Vehicle 1 is
- composition Tris buffer (pH ⁇ 8) 66.0 g Propylene glycol 30.0 g Glycerine 3.0 g
- Figure 12(A) is the Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with
- Compound No.l. Figure 12(B) is Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with Vehicle 1. A marked increase in number and density of hair follicles accompanied by an increase in the thickness of skin in animals treated with Compound No. 1 of Table-I is observed histopathologically. This was more than that observed for animals in group I, suggesting the potential of Compound No. I for induction of Anagen in hair follicles in the resting telogen phase of hair growth.
- Vehicle 1 represents the following: Vehicle 1: Vehicle of Compound No. 1 of Table-1
- the Composition of the vehicle is Component weight of composition
- Glycerine 3.0 g Compound No. 1 of Table-I or the Vehicle was applied to 50-day-old mice (telogen hair growth phase) on dorsal back using a syringe plunger (30 strokes for each applications) each day in respective group for seven continuous days.
- Figure 14 (A) is the Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with Compound No.l.
- Figure 14 (B) is Histopathological data of hair follicle and skin thickness as observed visually in Group I animals treated with Vehicle.
- a marked increase in number and density of hair follicles accompanied by an increase in the thickness of skin in animals treated with Compound No. 1 of Table-I is observed histopathologically. This was more than that observed for animals in group I, suggesting the potential of Compound No. 1 for induction of Anagen in hair follicles in the resting telogen phase of hair growth.
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Abstract
The invention provides novel peptides of formula (I) and its pharmaceutically acceptable salts thereof and a method of in vitro and in vivo bioassay of the said peptides for promotion and stimulation of hair growth and thereby their usefulness for treatment of alopecia. The invention also provides a method for preparation of the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof as well as a pharmaceutical composition comprising an effective amount of one or more of the novel peptides for promotion and stimulation of hair growth.
Description
NOVEL PEPTIDES USEFUL FOR TREATMENT OF ALOPECIA
FIELD OF THE INVENTION
The present invention relates to novel peptides of formula (I) and its pharmaceutically acceptable salts thereof and a method of in vitro and in vivo bioassay of the said peptides for promotion and stimulation of hair growth and thereby their usefulness for treatment of alopecia.
The present invention also relates to a method for preparation of the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof as well as a pharmaceutical composition comprising an effective amount of one or more of the novel peptides for promotion and stimulation of hair growth.
BACKGROUND OF THE INVENTION
Alopecia, commonly known as baldness is indicative of deficiency of hair, either normal or abnormal. Alopecia is primarily cosmetic in nature found in human beings, although it could be psychological as well (C. H. Mortimer et. al., Clin. Exp.
Dermatol, 1984, 9, 342-350).
Alopecia is associated with a change in hair type from terminal to vellus as well as alteration in the cycle of hair growth, viz. anagen, catagen and telogen. As baldness progresses, there is a shift in the percentage of hair follicles in each phase, with majority shifting from anagen to telogen.
Different types of alopecia are known, with androgenetic alopecia accounting for about 95 % of hair loss in both men and women, however, being more^prevalent in males. Androgenetic alopecia affects more than one-third of the population having a strong family history of hair loss. (W. F. Bergfield, Clin. Dermatol. 1998, 6, 102-107). The onset of alopecia is determined by the presence of sufficient circulating androgens and the degree of genetic predisposition (Ellis et. al., Expert Rev in MoI. Med., 2002, 1-
11). In men with androgenetic alopecia, endogenous androgen cause progressive miniaturization of scalp hair follicles, leading to a steady decline in visible scalp hair density and, eventually baldness. In addition to androgenetic alopecia mentioned hereinbefore, there exist other forms of alopecia, viz. (i) Chemotherapy induced alopecia (ii) Telogen effluvium, (iii)
Alopecia areata, (iv) Traumatic alopecia, and (v) Anagen effluvium.
Chemotherapy induced alopecia (CIA) is a frequent and emotionally distressing side effect of cancer therapy (V.J.Dorr, Semin. Oncol., 1998, 25, 562 and K. Munstedt, N.
Manthey, et.al., 1997, 75, 303) for which there is currently no effective preventive therapy (G. Chen et.al., Int.J.Cancer, 1998, 75, 303 and M. Duvic et.al, JAm. Acad. Dermatol, 1996, 35, 74). CIA is thought to arise when anticancer drugs ablate the proliferating epithelium and block normal maturation of precursor epithelial cells to the final hair strand product (R.Paus, G Cotsarelis, N. Engl. J. Med. 1999, 341, 491).
Type II 5 α reductase enzyme is a key enzyme linked to the development of Androgenetic Alopecia, it is present in abundance in genital skin, prostate, inner root sheath and dermal papilla (Xui Li et. al., Steroids, 1995, 430-441), exists as two isozymes, I and II that share 50 % homology. In balding scalp the level of expression of 5 α reductase and androgen receptor are elevated as compared to non-balding scalp.
Several treatments are available for alopecia primarily targeting 5 α reductase enzyme, androgen receptor, potassium channels, superoxide dismutase etc.
Finasteride, currently marketed as Propecia® for the treatment of hair loss is a specific inhibitor of type II 5 α reductase, whereas Dutasteride, a molecule under clinical investigation for the treatment of hair loss is a dual inhibitor of both isoforms and is currently under clinical investigation. Propecia® may have specific peripheral toxicity and hence cannot be Used by women.
Unlike finasteride, which is an oral pharmaceutical composition, Minoxidil, as disclosed in US 4,596,812, which is marketed as Rogaine® is a topical pharmaceutical composition for stimulation of hair growth. Minoxidil originally was developed as an antihypertensive drug and hypertrichosis was seen as a toxic effect.
Fluridil, which acts as an antiandrogen by suppressing the expression of androgen receptor is another hair growth promoter as disclosed in WO 01/58854. The androgen receptor belongs to steroid receptor superfamily. The androgen-receptor gene, expressing the receptor was the first gene to have been associated with alopecia. The androgen-receptor complexes dimerize in nucleus and bind to a hormone response element or regulatory DNA sequence in or near a target gene.
Chidsey in US 4,139,619, disclosed a topical composition of minoxidil and related iminopyrimidines to stimulate the conversion of vellus hair to terminal hair and increase the rate of growth of terminal hair.
However, despite its popularity, minoxidil has not performed in a completely satisfactory fashion in promoting hair growth in all target population. Skin toxicity are
seen at times with application of Rogain®, including irritation, itch, contact dermatitis, hives, swelling, and sensitivity.
Other novel agents such as Lamin, Polysorbate 80, Folligen, Extract of Serenoa repens are in the process of emergence to gain protection and approval for various forms of alopecia.
Amino acids like arginine/ L-arginine, cysteine/ L-cysteine have been proposed to stimulate hair growth. Biotin and folic acid in diet are claimed to promote hair growth. Zinc sulphate limits availability of reduced cofactor NADPH required for 5 alpha reductase activity and thus was found to be an inhibitor of DHT. (Semin Cutan, Med Surg. 1998, 17(4), 276-83).
In addition to the above treatments, alopecia is also addressed through hair transplantation, which, however is costly, time consuming, painful, and meets with only limited success.
Further, several peptides, both small and large have been disclosed/ tested for alopecia. A summary of such disclosures is given herein below: i) Mahe in US 5,739,111 and in US 6,001,812 have disclosed a method and composition for inducing growth of hair by administering an effective amount of Lys-Pro-Val tripeptide. Kronholm et. al. in US 5,252,559 disclosed the use of a composition consisting of His-Gly-Gly peptides and its derivatives for hair growth. ii) Buultijens et. al. in US 5,068,315 have disclosed the application of purified hair growth regulating peptides (HGRP) to stimulate hair growth. l iii) Pickard in US 5,177,061 has disclosed the topical application of glycyl-L- histidyl-L-lysine: copper (II) (GHL-Cu) and its derivatives to promote hair growth in warm-blooded animals. iv) Pickard in US 5,550,183 and in US 5,120,831 has disclosed a method for stimulating the growth of hair in warm blooded animals by administering topically or by injection to the animal a stimulatory effective amount of glycyl-
L-histidyl-L-lysine: copper (II). v) Pallenberg et. al. in US 5,538,945 and in US 6,017, 888 have disclosed the stimulation of hair growth on an animal by administering topically or by injection to the animal an effective amount of a peptide-copper complex. .
From the foregoing, while various drugs and therapies are available for promotion and stimulation of hair growth and for treatment of alopecia, however, the
existing drugs and therapies suffer from various limitations. For instance, Minoxidil and Finasteride are effective in only select population and hence not universal.
Also, new entities including peptides are reported for the treatment of alopecia, which are expected to hold promise in treatment of the said condition. However, invariably such peptides are complexes with a metal, which not only makes the manufacture of such peptides costly but also raises safety concerns.
Further, loss of hair or baldness is a social stigma, especially in men, which not only affects the psyche but also the quality of life of such individuals.
Because of the aforementioned reasons and moreover, because of the importance of this indication i.e. loss of hair or alopecia, a need therefore, exists for better drugs or more potent molecules which would not only be clinically safe but also would minimize the limitations associated with the existing therapies. .
The present invention is a step forward in this direction and provides novel peptides, hitherto not reported, which exhibit significant potential in addressing the need.
OBJECTS OF THE INVENTION
An object of the present invention is to provide novel peptides useful for promotion and stimulation of hair growth.
Another object of the present invention is to provide novel peptides useful for treatment of alopecia.
Yet another object of the present invention is to provide novel peptides and a method of in vitro and in vivo bioassay of the said peptides for promotion and stimulation of hair growth.
Still another object of the present invention is to provide novel peptides and a method of in vitro and in vivo bioassay of the said peptides for treatment of alopecia.
A further object of the present invention is to provide novel peptides for promotion and stimulation of hair growth in a mammal treated with a chemotherapeutic agent.
Yet further object of the present invention is to provide novel peptides for promotion and stimulation of hair growth in a human treated with a chemotherapeutic agent.
Still further object of the present invention is to provide novel peptides for treatment of alopecia in a mammal treated with a chemotherapeutic agent.
Yet further object of the present invention is to provide novel peptides for treatment of alopecia in a human treated with a chemotherapeutic agent.
Another object of the present invention is to provide a method for preparation of the novel peptides and its pharmaceutically acceptable salts thereof. Yet another object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for promotion and stimulation of hair growth.
Still another, object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for treatment of alopecia. A further object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for promotion and stimulation of hair growth in a mammal treated with a chemotherapeutic agent.
Yet further object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for promotion and stimulation of hair growth in a human treated with a chemotherapeutic agent.
Another object of the present invention is to provide a pharmaceutical composition comprising the- novel peptides for treatment of alopecia in a mammal treated with a chemotherapeutic agent.
Yet another object of the present invention is to provide a pharmaceutical composition comprising the novel peptides for treatment of alopecia in a human treated with a chemotherapeutic agent.
SUMMARY OF THE INVENTION
As mentioned hereinbefore, several peptides both small and large have been disclosed for promotion of hair growth/ treatment of alopecia. However, all the peptides disclosed so far are comprised of amino acids, selected from among the twenty common amino acids.
In their endeavor to meet the objective, the present inventors have found to their surprise that a small tripeptide comprising an uncommon amino acids viz. α, α - dialkylated amino acids linked through peptide bond, with a basic amino acid on one side i.e., at the amino terminal and either glycine or a basic amino acid on the other side i.e., at the carboxyl terminal, exhibits remarkable in vitro and in vivo bioassay for
promotion and stimulation of hair growth in mammals and thereby useful for the treatment of alopecia.
The, uncommon amino acids, viz α, α dialkylated amino acids are known for inducing conformational constraint. The incorporation of these uncommon amino acids restricts the rotation of φ,φ angles, within the molecule, thereby stabilizing a desired peptide conformation. The prototypic members of α, α dialkylated amino acids, viz. α aminoisobutyric acid (Aib) or α α, dimethylglycine has been shown to induce β-turn or helical conformation when incorporated in a peptide sequence (B.V.V. Prasad et. al., 1984, CRC Crit Rev.Biochem., 16, 307-347; LL. Karle et. al. Biochemistry, 1990, 29, 6747-6756). The conformational properties of the higher homologs of a, a dialkylated amino acids such as di-ethylglycine (Deg), di-n-propylglycine (Dpg) and di-n- butylglycine (Dbg) as well as the cyclic side chain analogs of α, α dialkylated amino acids such as 1-aminocyclopentane carboxylic acid (Ac5c)5 1-aminocyclohexane carboxylic acid (Ac6c), 1-aminocycloheptane carboxylic acid (Ac7c) and 1- aminocyclooctane carboxylic acid (Ac8c) have also been shown to induce folded conformation (S. Prasadt et. al., Biopolymer, 1995, 35, 11-20 ; LL. Karle, et. al., J. Amer. Chem.Soc, 1995, 117, 9632-9637) . Further, α,α Dialkylated amino acids have been used in the design of highly potent chemotactic peptide analogs (S. Prasad et. al., IntJ.Peptide Protein Res., 1996, 48, 312-318) The present invention exploits the known conformational properties of α, α- dialkylated amino acids and hydrophobicity of the side chain, for design of the peptides of formula (I) of this invention, which as mentioned hereinbefore, exhibits remarkable in vitro and in vivo bioassay for promotion and stimulation of hair growth.
In one aspect, the present invention provides novel peptides of formula (I) and its pharmaceutically acceptable salts thereof,
N TT
H O (I) wherein X is a residue of an amino acid selected from Arginine, Histidine, Lysine, Ornithine or Glycine forming the amide linkage with carboxylic acid group adjacent to group Y; Y is a group of formula,
C
/ \ wherein Ri & R2 are alkyl or Y represents a carbocycle of 3-8 carbon atoms; Z is a residue of an amino acid selected from Arginine, Histidine, Ornithine or Lysine or its amino protected derivatives thereof, forming the amide linkage with the amino group adjacent to group Y.
In another aspect, the present invention provides methods for preparation of the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof.
In yet another aspect, the present invention provides a method of in vitro and in vivo bioassay of the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a mammal.
In a further aspect, the present invention provides a method of in vitro and in vivo bioassay of novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the promotion and stimulation of hair growth in a human.
In yet further aspect,.the present invention provides a method of in vitro and in vivo bioassay of novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the promotion and stimulation of hair growth in depilated and telogen skin.
In another aspect, the present invention provides a method of in vitro and in vivo bioassay of novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the treatment of alopecia in a mammal. ' In yet another aspect, the present invention provides a method of in vitro and in vivo bioassay of novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the treatment of alopecia in a human.
In still another aspect, the present invention provides a pharmaceutical composition comprising the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a mammal.
In a further aspect, the present invention provides a pharmaceutical composition comprising the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a human.
In yet further aspect, the present invention provides a pharmaceutical composition comprising the novel peptides of formula (I) and its pharmaceutically
acceptable salts thereof for promotion and stimulation of hair growth in depilated and telogen skin.
In another aspect, the present invention provides a pharmaceutical composition comprising the novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the treatment of alopecia in a mammal.
In yet another aspect, the present invention is to provide pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for the treatment of alopecia in a human.
In still another aspect, the present invention provides a pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a mammal treated with a chemotherapeutic agent.
In a further aspect, the present invention provides a pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for promotion and stimulation of hair growth in a human treated with chemotherapeutic agent.
In yet further aspect, the present invention provides a pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for treatment of alopecia in a mammal treated with a chemotherapeutic agent.
In another aspect, present invention provides a pharmaceutical composition comprising novel peptides of formula (I) and its pharmaceutically acceptable salts thereof for treatment of alopecia in a human treated with a chemotherapeutic agent. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS The present invention will now be described in greater detail with reference to the accompanying drawings wherein:
Fig 1: Effect of Compound No.l of table 1 on length of the hair follicle in whole organ cultures in vitro.
Fig 2: Effect of Compound No.l of table 1 on length of the hair shaft in whole organ cultures in vitro.
Fig 3: Effect of Compound No.4 of table 1 on length of the hair follicle in whole organ cultures in vitro.
Fig 4: Effect of Compound No.4 of table 1 on length of the hair shaft in whole organ cultures in vitro.
Fig 5: Establishment of in vivo model for chemotherapy induced alopecia irp adult
Swiss albino mice.
Fig 6: Effect of compound No. 1 in Table I on chemotherapy induced alopecia in model in adult Swiss albino mice. Fig 7: Effect of compound No 1 (200 μg/4cm2) of Table I on Chemotherapy induced alopecia model in adult C57/BL6 mice.
Fig 8: Effect of compound No 1 (400..μg/4cm2) of Table I on Chemotherapy induced alopecia model in adult C57/BL6 mice.
Fig 9: Effect of compound No 3 of Table I on Chemotherapy induced alopecia model in adult C57/BL6 mice.
Fig 10: Effect of compound No 1 of Table I on hair promotion/Anagen induction in
C57/BL6 mice in vivo.
Fig 11: Effect of compound No 1 (concentration 3.2mg/15cm2) of Table I on hair promotion/Anagen induction in C57/BL6 mice in vivo. Fig 12 (A)(I), (A)(2) and (A)(3): Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with compound No. 1
Fig 12 (B)(I), (B)(2) and (B)(3): Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with Vehicle 1.
Fig 13: Effect of compound No 1 (concentration 1.6mg/15cm2) of Table I on hair promotion/Anagen induction in C57/BL6 mice in vivo.
Fig 14 (A)(I) and (A)(2): Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with compound No. 1 (
Fig 14 (B)(I) and (B)(2): Histopathological data of hair follicle and skin thickness as observed visually in Group I animals treated with Vehicle 1. DETAILED DESCRIPTION OF THE INVENTION
The invention which is detailed herein below provides novel peptides of formula (I) and its pharmaceutically acceptable salts thereof,
wherein X is a residue of an amino acid selected from Arginine, Histidine, Lysine, Ornithine or Glycine forming the amide linkage with carboxylic acid group adjacent to group Y;
Y is a group of formula,
R1 R2
\ / C
/ \ wherein Ri & R2 are alkyl or Y represents a carbocycle of 3-8 carbon atoms; Z is a residue of an amino acid selected from Arginine, Histidine, Ornithine or Lysine or its amino protected derivatives thereof, forming the amide linkage with the amino group adjacent to group Y.
It has to be understood that the amino acids which constitutes the group X are those in which the terminal amino group forms the peptide bond with the carboxylic acid of the uncommon amino acid represented by the group Y. The carboxy terminal of those amino acids constituting the group X are free i.e. the hydroxy group is either not protected or substituted by any group.
Similarly, it should be understood that the amino acids which constitute the group Z are those in which the terminal carboxylic acid forms the peptide bond with the amino group of the uncommon amino acid represented by the group Y. The terminal amino group of the amino acid constituting the group Z, is however, either free or protected.
The suitable amino protective groups include acetyl, n-butanoyl, n-hexanoyl, n- octanoyl, lauroyl, myristoyl, palmitoyl, isohexanoyl, cyclohexanoyl, cyclopentylcarbonyl, n-heptanoyl, n-decanoyl, n-undecanoyl, 3,7-dimethyloctanoyl etc. Pharmaceutically acceptable salts of the peptides of formula (I) refer to non-toxic salts of the said compounds. Representative salts of the peptides of formula (I) include but are not limited to: acetate, ascorbate, benzoate, citrate, oxalate, stearate, trifluoroacetate, succinate, tartarate, lactate, fumarate, gluconate, glutamate, phosphate/diphosphate, valerate. Other salts include those with group I and II metals such as Ca, Li, Mg, Na, and K salts formed with halides, salts with amino acids like lysine or arginine; salts with guanidine or ammonium/ substituted ammonium salts or aluminium salts.
The representative peptides of formula (I) as per this invention are summarized in Table-I The preferred Compounds are Compound No. 1, 3 and 4
Table-I
Representative Peptides of Formula (I)
Synthesis of the Peptides of Formula (I)
The novel peptides of formula (I) and its pharmaceutically acceptable salts thereof can be prepared exclusively by solid phase techniques or by solution phase procedures. In a preferred embodiment the peptides were synthesized using the Fmoc solid phase strategy, either manually, or on a semi-automatic peptide synthesizer (CS Bio, Model 536). The peptides were assembled from C-terminus to N-terminus procedure on solid phase.
Synthesis of various peptides of formula (I) is described in detail in Examples 1-9 given in the experimental section. The description given in the examples should however not be construed as limiting the scope of the invention. Example-l
Synthesis of Compound No. 1 of Table-I
The peptides were assembled from C-terminus to N-terminus using Wang Resin (4-Benzylobenzyl alcohol resin of 100-200 mesh substitution 1.2 raM/g, 1% DVB).
Swelling of the resin was typically carried out in dichloromethane (10-40 ml/g resin) for 10 minutes.
The first amino acid was loaded on the Wang Resin. The loading of first Fmoc protected amino acid on the resin was mediated by excess of Diisopropylcarbodiimide (DIPCDI), 4-Dimethylaminopyridine (DMAP) and N-Hydroxybenzotriazole (HOBt). The coupling reaction was carried out in Dimethyl formamide, Dichloro methane or N-N dimethyl pyrrolidone or a mixture of these solvents and the reaction was monitored by weight gain. If the observed weight of the resin and peptide comes less than the expected weight, then capping is done by adding a solution mixture of 80% DMF, 10% acetic anhydride and 10% DIPEA. After loading, Fmoc group was deprotected and coupled to the second amino acid. The third amino acid was also coupled after deprotection of Fmoc group. On completion of assembly of the amino acids, the amiηo-terminal Fmoc group was removed and peptide-resin was washed with methanol, dried and cleaved from the resin support by treatment with trifluoroacetic acid and de-ionized water for lhr at room temperature. The crude peptide was obtained by precipitation with cold dry ether, filtered, dissolved, and lyophilized. On a 1.0 g scale of resin, 1.56 g of peptide-resin was obtained. After cleavage and lyophilization, 400 mg of the crude peptide was obtained. The resulting crude peptide was purified by preparative HPLC (high performance liquid chromatography) using a C-18 reverse phase column system (gradient: 0.1% TFA in acetonitrile and water). The eluted fractions were reanalyzed on analytical HPLC system using a C-18, reverse- phase column. Acetonitrile was evaporated and fractions were lyophilized to obtain the pure peptide. It was further characterized by NMR (Nuclear Magnetic resonance) and Mass spectra. The pure peptide was then used for biological activity. 1HNMR (DMSO-d6, δ) : 8.93 (IH, s, NH Aib,), 8.61 D (IH, s, 2CH His), 8.13 (IH, t, NH GIy), 7.42 (IH, s, 4CH His), 4.1 (IH, t, CΗ His), 3.7 (IH, d, CαH GIy), 3.6 (IH, d, CΗ2 GIy), 3.23 (2H, t, C βH His), 1.35 (6H, d, CβH3 Aib)
Mass Spectrum: Calculated Mass: 297; Observed Mass (M+1): 298
Exaraple-2
Synthesis of Compound No. 2 ofTable-I
The synthesis of Compound No. 2 of Table-I was carried out using 1.0 g of resin. On 1.0 g of resin, 1.53 g of peptide-resin was obtained. After cleavage and lyophilization, 345 mg of the crude peptide was obtained. The crude peptide was purified as described in Example- 1. The peptide was characterized by Mass Spectrum.
Mass Spectrum: Calculated Mass: 326.2 ; Observed Mass (M+1):327.2
Example-3 Synthesis of Compound No. 3 of Table-I
The synthesis of Compound No. 3 of Table-I was carried out using 1.0 g of resin. On 1.0 g of resin, 1.34 g of peptide-resin was obtained. After cleavage and lyophilization, 200 mg of the crude peptide was obtained. The crude peptide was purified as described in Example-1. The Peptide was characterized by Mass Spectrum. Mass Spectrum: Calculated Mass: 354.5; Observed Mass (M+1):355.2
Example-4
Synthesis of Compound No. 4-of Table-I
The synthesis of the Compound No. 4 of Table-I was carried out in the same way as described in example 1. On a 1.0 g scale of resin, 1.6 g of peptide-resin was obtained. After cleavage and lyophilization, 333 mg of the crude peptide was obtained which was further purified by HPLC as described in Example-1. The Peptide was characterized by Mass Spectrum.
Mass Spectrum: Calculated Mass: 382.9; Observed Mass (M+1): 383.3
Example-5 Synthesis of Compound No. 5 of Table-I
The synthesis of Compound No. 5 of Table-I was carried out in the same way as described in examplel. On a 1.0 g scale of resin, 1.65 g of peptide-resin was obtained.
After cleavage and lyophilization, 280 mg of the crude peptide was obtained which was further purified as per the method described in Example-1. The Peptide was characterized by Mass Spectrum.
Mass Spectrum: Calculated Mass: 323.7; Observed Mass (M+1): 324.3
Example-6
Synthesis of Compounds No. 9, 11, 12 and 13 of Table-I
The synthesis of Compounds No. 9, 11, 12, and 13 of Table-I was carried out in the same way as described in Example-1. On a 2.0 g scale of resin, 2.9 g of peptide- resin was obtained. Thus obtained peptide-resin was divided the into 4 equal parts of approximately 700 mg each. A. Synthesis of Compound No. 9 of Table-I
700 mg of peptide-resin was taken and coupled with Acetic anhydride. After cleavage and lyophilization, approximately, 100 mg of the crude peptide was obtained. Purification of crude peptide was carried out as per the method described in Example-1. The Peptide was characterized by Mass Spectrum. Mass Spectrum: Calculated Mass: 339.2; Observed Mass (M+1): 340.19
B. Synthesis of Compound No. 11 of Table-I
700 mg of peptide-resin was taken and coupled with Octanoic acid. After cleavage and lyophilization, approximately, 100 mg of the crude peptide was obtained. Purification of crude peptide was carried out as per the method described in Example-1. The Peptide was characterized by Mass Spectrum.
Mass Spectrum: Calculated Mass: 367.5; Observed Mass (M+1): 368.3
C. Synthesis of Compound No. 12 of Table-I
700 mg of peptide-resin was taken and coupled with Myristic acid. After cleavage and lyophilization, approximately, 125 mg of the crude peptide was obtained. Purification of crude peptide was carried out as per the method described in Example-1. The Peptide was characterized by Mass Spectrum. Mass Spectrum: Calculated Mass: 507.7; Observed Mass (M+1): 508.4
D. Synthesis of Compound No. 13 of Table-I
Fourth part of peptide-resin (i.e., 700 mg) as described above was taken and coupled with Palmitic acid. After cleavage and lyophilization, approximately, 185 mg of the crude peptide was obtained. Purification of crude peptide was carried out as per the method described in Example-1. The Peptide was characterized by Mass Spectrum.
Mass Spectrum: Calculated Mass: 535.4; Observed Mass (M+1): 536.5
Example-7 Synthesis of Compound No. 14 of Table-I
On a 1.0 g scale of resin, 1.48 g of peptide-resin was obtained. After cleavage and lyophilization, 207 mg of the crude peptide was obtained. Purification of crude peptide was carried out as per the method described in Example-1.
Example-8
Synthesis of Compound No. 15 ofTable-I
On a 1.0 g scale of resin, 1.48 g of peptide-resin was obtained. After cleavage and lyophilization, 150 mg of the crude peptide was obtained. Purification of crude peptide was carried out as per the method described in Example- 1. Example-9 Synthesis of Compound No. 16 ofTable-I
On a 1.0 g scale of resin, 1.37 g of peptide-resin was obtained. After cleavage and lyophilization, 260 mg of the crude peptide was obtained. Purification of crude peptide was carried out as per the method described in Example- 1.
Pharmaceutical Composition Comprising Peptides of Formula (I)
The invention also provides pharmaceutical composition comprising an effective amount of at least one peptide of formula (I) and its pharmaceutically acceptable salts intended for promotion and stimulation of hair growth/ treatment of alopecia. The pharmaceutical composition comprising peptide of formula (I) may be administered in any convenient manner such as oral, parenteral or topical. However the preferred route of administration is topical.
The peptide of formula (I) may be orally administered, for example, with inert diluents or with an edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The peptide of formula (I) may also be administered parenterally or intraperitoneally. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. The peptide of formula (I) and its pharmaceutically acceptable salts thereof are formulated for topical administration. Suitable topical formulations include one or more peptides of formula (I) and its pharmaceutically acceptable salts thereof in the form of a liquid, lotion, cream or and gel. Topical administration may be accomplished by application directly on the treatment area. For example, such application may be
accomplished by rubbing the formulation (such as a lotion or gel) onto the skin of the treatment area, or by spray application of a liquid formulation onto the treatment area.
The amount of hair growth peptide can vary widely, depending upon the needs of the subjects. The preferred amount of hair growth peptides of formula (I) in such compositions comprises from about 0.01 % to about 10 % by weight more preferably between 0.5 % to 2 % by weight.
The cosmetic composition according to the invention are applied to the alopecic regions of the scalp and the hair of a mammal or human individual, and is optionally maintained in contact for a number of hours, and is optionally rinsed there from. It is possible, for example, to apply a composition containing an effective amount of peptide of formula (I) to the hair and 'scalp in evening, to maintain the composition in contact overnight and optionally to shampoo in, the morning.
The balance of the topically applied pharmaceutical preparations comprise peptides of formula (I) and an inert, physiologically acceptable carrier. The physiologically acceptable medium may contain other adjuvant commonly used in the cosmetic or pharmaceutical field, such as surface-active agents, thickening or gelling agents, cosmetic "agents, preservatives, or basifying or acidifying agents, which are well known in the art and in amount which are sufficient to obtain the desired form of presentation. The pharmaceutical compositions may contain pharmaceutically acceptable additives known in the art such as carriers, diluents etc. Typical carriers that can be employed include a disintegrant, lubricant and diluents. Disintegrants and lubricants are well known in the pharmaceutical sciences. Suitable disintegrants include starch, croscarmellose sodium, crospovidone, sodium starch glycolate, croscarmellose calcium, microcrystalline cellulose and polacrilin potassium, and the like.
Suitable lubricants include magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated cottonseed oil, stearic acid, calcium stearate, colloidal silicon dioxide and the like.
Suitable diluents may include RPMI 1649, buffered saline, isotonic NaCl5 Ringer's solution, water, distilled water, polyethylene glycol, 2% Tween in water, 50% dimethylsulfoxide in water (v/v), propylene glycol, phosphate buffered saline, balanced salt solution, glycerol, and other conventional fluids that are suitable for intravenous administration.
In addition, the composition can contain other additives, such as suspending agents, thickening agents, sweeteners, preservatives, bulking agents and flavouring agents.
Examples of suitable suspending agents include xanthan gum, hydroxypropyl methylcellulose, methylcellulose, carageenan, sodium carboxymethyl cellulose, microcrystalline cellulose mixes, thixotropic suspending agents such as xanthan, carageenan and sodium carboxymethyl cellulose/microcrystalline cellulose mixes and mixtures thereof. More preferred of these are xanthan gum and guar gum.
The thickening agents found suitable in the present formulation include silicon dioxide and the like.
The sweeteners that can be used include sugars such as fructose, sucrose, glucose, maltose, or lactose as well as non caloric sweetener such as aspartame, which can be used alone OF in combination with another non-caloric or low caloric sweetener known to have synergistic sweetening properties with aspartame, e.g. saccharin, acesulfame, thaumatin, chalcone, cyclamate, stevioside and the like.
The water soluble preservatives found useful in the present invention include sodium benzoate, sodium citrate and.benzalkonium chloride, the preferred one being sodium benzoate and the like.
Suitable bulking agents are lactose, manitol, isomalts, polydextrose, starch, microcrystalline cellulose, sorbitol, calcium sulphate, calcium phosphate, acacia and the like.
Representative flavouring liquids include, artificial, natural or synthetic fruit flavours such as lemon, orange, banana, grape, lime, apricot and grapefruit oils and fruit essences including apple, strawberry, cherry, orange, pineapple and so forth; bean and nut derived flavours such as coffee, cocoa, cola, peanut, almond and so forth; and root derive flavours such as licorice.
The topically applied pharmaceutically preparation of the peptides of formula (I) and its pharmaceutically acceptable salts thereof comprise peptides, tris buffer (pH~8), isopropanol, and propylene glycol. A typical topical composition comprising the peptides of formula (I) is described in Example -10 given hereinbelow. Example-10 Topical Composition for Regulating Hair Growth
Component Weight of composition
The peptide of formula (I) 1.0 gm Tris buffer (pH~8) 60.0 gm Isopropanol 10.0 gm Propylene glycol 24.0 gm Glycerine 5.0 gm
in vitro Studies on Peptides of Formula (I)
The in-vitro model for evaluating hair growth promoting molecules is based on whole organ hair culture (Toshikazu Kamiya, Akio Shirai et. Al. J. Dermatol. Science, 1998, YT1 54-60). Quantitation of hair growth is based on the cumulative increase in hair shaft and hair follicle in the presence of the compound. The studies carried out are described in the non-limiting examples given hereinbelow: Example-11 Establishment of Whole Organ Hair Cultures for Evaluation of Efficacy of the Hair Growth Promoting Peptides of formula (I) in vitro
Male Swiss Albino mice (age- όweeks old) were purchased from National Institute of Nutrition Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. The whiskers were shaved off carefully using sterile scalpel blade. On 10th day whiskers at anagen/proliferative phase of hair growth cycle, were decapitated. Whisker pads were dissected out carefully and transferred to ice cold transport medium (DMEM, NaCl (8.0g/L), KCl (0.4g/L), NaHCO3 (3.7g/L), KH2PO4 (0.06g/L), NaH2PO4 (0.12g/L), pH-7.4). Whisker pads were washed in vertical Laminar hood for 5 -10 minutes in antibiotic solution containing streptomycin (lOOμg/mL to 500μg/mL), penicillin (100U/mL to 500U/mL). Finally the Whiskers pads were washed in defined culture medium constituted with Williams E Medium to which were added Hydrocortisone (lOμg/mL), mixture of Insulin selenium and transferrin (lOμg/mL), L-glutamine (ImM) and Phenol red (10 mg/mL). Single hair follicles were dissected using dissecting microscope while carefully removing extra dermal tissues using sterile forceps. Each 35 mm petriplate was coated with 50μL of sterile collagen. Two hair follicles were seeded in each petriplate. The organ cultures were maintained for 7 days in culture media in CO2 incubator at 37° C and used for evaluating hair growth promoting peptides of formula (I) in vitro. ■ '
Example-12
Effect of Compound No. 1 of Table-Ion Length of Hair Follicle and Hair Shaft in Whole Organ Hair Cultures in vitro
Male Swiss Albino mice (age- 6weeks old) were purchased from National Institute of Nutrition, Hyderabad India. Mice were observed in Quarantine for one week prior to initiation of the study. The whiskers were shaved off carefully using sterile scalpel blade. On 10th day whiskers at anagen phase of hair growth cycle, were decapitated. Whisker pads were dissected out carefully and transferred to ice cold tansport medium (DMEM5 NaCl (8.0g/L), KCl (0.4g/L), NaHCO3 (3.7g/L), KH2PO4 (0.06g/L), NaH2PO4 (0.12g/L), pH-7.4). Whisker pads were washed in vertical laminar hood for 5 -10 minutes in antibiotic solution containing streptomycin (lOOμg/mL to 500μg/mL) penicillin (lOOU/mL to 500U/mL). The Whiskers pads were washed in defined culture medium constituted with Williams E Medium to which were added Hydrocortisone (lOμg/mL), mixture of Insulin selenium and transferrin (10μg/mL)5 L- glutamine (ImM) and Phenol red (10 mg/mL). Single hair follicles were dissected using dissecting microscope while carefully removing extra dermal tissues using sterile forceps. Each 35 mm petriplate was coated with 50μL of sterile collagen. Two hair follicles were seeded in each petriplate. The organ cultures were maintained for 7 days in culture media in CO2 incubator at 37° C and used for evaluating hair growth promoting peptides of formula (I) in vitro.
On day 1st, the organ cultures were treated with Compound No.l of Table-I concentration ranging from 1OnM to 100OnM or with the Vehicle alone. The Compound No.l of Table-I was dissolved in sterile water (pH 7.1). The cumulative increase in the length of hair shaft and hair follicle was evaluated on 7th day of the experiment using phase contrast microscope (NIKON) fitted with a measuring graticule.
Figure- 1 represents effect of concentration of Compound No.l of Table-I on cumulative increase of length of hair follicle in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 100 nM.
Figure-2 represents effect of concentration of Compound No.l of Table-I on cumulative increase of length of hair shaft in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM.
Example-13
Effect of Compound No.4 of TaUe-I on Length of Hair Follicle and Hair Shaft in Whole Organ Hair Cultures in vitro
Male Swiss Albino mice (age- όweeks old) were purchased from National Institute of Nutrition Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. The whiskers were shaved off carefully using sterile scalpel blade. On 10th day whiskers at anagen phase of hair growth cycle, were decapitated. Whisker pads were dissected out carefully and transferred to ice cold transport medium [DMEM, NaCl (8.0g/L), KCl (0.4g/L), NaHCO3 (3.7g/L), KH2PO4 (0.06g/L), NaH2PO4 (0.12g/L), pH-7.4].
Whisker pads were washed in vertical Laminar hood for 5 -10 minutes in antibiotic solution containing streptomycin (lOOμg/mL to 500μg/mL) penicillin (100U/mL to 500U/mL) .The Whiskers pads were washed in definite culture medium constituted with Williams E Medium to which were added Hydrocortisone (lOμg/mL), mixture of Insulin selenium and transferrin (lOμg/mL), L-glutamine (ImM) and Phenol red (10 mg/mL). Single hair follicles were dissected using dissecting microscope while carefully removing extra dermal tissues using sterile forceps. Each 35 mm petriplate was coated with 50μL of sterile collagen. Two hair follicles were seeded in each petriplate. The organ cultures were maintained for 7 days in culture media in CO2 incubator at 37° C and used for evaluating hair growth promoting peptides in vitro.
On day 1st, the organ cultures were treated with Compound No.4 of Table-I in concentrations ranging from 1OnM to 100OnM or the Vehicle alone. Compound No.4 of Table-I was dissolved in sterile water (pH 7.1). The cumulative increase in the length of hair shaft and hair follicle was evaluated on 7th day of the experiment using Phase contrast microscope (NIKON) fitted with measuring graticule.
Figure-3 represents effect of concentration of Compound No.4 of Table-I on cumulative increase of length of hair follicle in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM. Figure-4 represents effect of concentration of Compound No.4 of Table-I on cumulative increase of length of hair shaft in whole organ culture. The concentration varied from 10 nM to 1000 nM. Maximum increase in hair follicle was observed at the concentration of 1000 nM.
in vivo Studies on Peptides of Formula (J) in vivo models used for evaluating hair growth promoting molecules are Sprague Dawley rats, C3H mice and C57BL6 mice. The hair in mice cycles in a wave like pattern from head to tail as opposed to mosaic pattern in humans (www.keratin.com/aa/aaOO8.shtml). C57/BL6 mice are widely used for hair growth promoting studies, due to the difference in pigmentation corresponding to different phases of hair growth cycle. The skin colour of mice is pink in telogen, which changes to grey to black in active anagen phase (Sven Muller-Rover et. al. Journal of Investigative Dermatology, 2001, 117, 3-15). Example-14
Establishment of in vivo model for Chemotherapy Induced Alopecia in Adult Swiss Albino Mice for Evaluating the Efficacy of Hair Growth Promoting Peptides
Male Swiss Albino mice (age- όweeks old) were purchased from National Institute of Nutrition, Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer. On 10th day the hair regrown were at Anagen phase of hair growth.
The study was conducted in three groups of six animals each. Treatment given to three different groups of animals is shown in Table-II, wherein Vehicle 1 represents the following: Vehicle 1: Vehicle of Etoposide injection.
Table-II Treatment modalities in different Groups of animals
The progression of alopecia was quantitated as described by Jimenez et. al. (Joaquin J.Jimenez et. al., FASEB J., 1991, 5^.2456-2458).
Observation of alopecia/ hair growth is shown in Table-Ill and Figure-5. Table- Ill shows that the treatment of Group III animals with Etoposide, induce 100% visible Alopecia. Onset of Alopecia was seen in all the animals in Group III on 18th day of the experiment, whereas hair growth is seen to be normal in Group I and in Group II animals on days 18th 19th, 20th, 21st.
Table-Ill
Observation of Alopecia/ hair growth after initiation of treatment as given in
Table-II
Example-15
Effect of Compound No. 1 ofTable-Ion Chemotherapy Induced Alopecia model in- vivo in Adult Swiss Albino Mice
Male Swiss Albino mice (age- όweeks old) were purchased from National Institute of Nutrition, Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body Jiairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to
cause nick or abrasion to the underlying dermal layer. On 10th day the hair regrown were at Anagen phase of hair growth.
The study was conducted in six groups of six animals each. Treatment given to six different groups of animals is shown in Table-IV. In Table-IV, Vehicle 1 and Vehicle 2 represent the following: Vehicle 1: Vehicle of Etoposide injection Vehicle 2: Vehicle of Compound No. 1 ofTable-I The Composition of the Vehicle 2 is
Component weight of composition
Tris buffer(pH~8) 66.0 g
Propylene glycol 30.0 g
Glycerine 3.0 g
Table-IV Treatment modalities in different Groups of animals
The progression of alopecia was quantitated as described by Jimenez et. al. (Joaquin JJimenez et. al., FASEB J., 1991, 5^.2456-2458).
On 30th day the quantitation of alopecia/ hair growth was done as percentage of shaved area covered by new hair growth, scored by blinded observer on scale of 0 (no growth) to 5 (complete hair growth) as described in US 20020198250.
Observation and evaluation of hair growth after initiation of treatment is shown in Table-V and Figure-6. Increased hair growth was observed in Group V animals, treated with Compound 1 of Table-I as compared to Groups IV and VI, indicating the stimulation of hair growth in skin treated with Chemotherapeutic agents like Etoposide but not limited to it. All the animals in Groups I, II, III showed similar hair growth as observed for that in the animals of Group V.
Table-V
Observation and Evaluation of hair growth after initiation of treatment as given in
Table-IV
Effect of Compound No. 1 (200 μg/ 4cm2 ) of Table-Ion Chemotherapy Induced Alopecia model in-vivo in Adult C57/BL6 Mice Male C57/BL6 mice (age- όweeks old) were purchased from National
Institute of Nutrition, Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer. On 10th day the hair regrown were at Anagen phase of hair growth.
The study was conducted in six groups of seven animals each. Treatment given to six different groups of animals is shown in Table- VI. In Table-VI, Vehicle 1 and Vehicle 2 represent the following: Vehicle 1: Vehicle of Etoposide injection Vehicle 2: Vehicle of Compound No. 1 of Table-I The Composition of the Vehicle 2 is
Component weight of composition
Tris buffer(pH~8) 66.0 g
Propylene glycol 30.0 g Glycerine 3.0 g
Table- VI
Treatment modalities in different Groups of animals
The progression of alopecia was quantitated as described by Jimenez et. al. (Joaquin
JJimenez et. al., FASEB J., 1991, 5^2456-2458).
On 30th day the quantitation of alopecia/ hair growth was done as percentage of shaved area covered by new hair growth, scored by blinded observer on scale of 0
(no growth) to 5 (complete hair growth) as described in US 20020198250.
On 30th day the quantitation of alopecia/ hair growth was done by weighing the hairs regrown after shaving.
Observation and evaluation of hair growth after initiation of treatment is shown in
Table-VII and Figure-7. Increased hair growth was observed in Group V animals,
treated with Compound 1 of Table-I as compared to Groups IV and VI, indicating the stimulation of hair growth in skin treated with Chemotherapeutic agents like Etoposide but not limited to it. All the animals in Groups I, II, III showed similar hair growth as observed for that in the animals of Group V.
Table-Vπ
Observation and Evaluation of hair growth after initiation of treatment as given in
TaUe-Vl
Effect of Compound No. 1 (400 μg/ 4cm2) of Table-Ion Chemotherapy Induced Alopecia model in-vivo in Adult C57/BL6 Mice
Male C57/BL6 mice (age- όweeks old) were purchased from National Institute of Nutrition, Hyderabad, India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer. On 10th day the hair regrown were at Anagen phase of hair growth.
The study was conducted in six groups of six animals each. Treatment given to six different groups of animals is shown in Table- VIII .In Table-VIII, Vehicle 1 and Vehicle 2 represent the following: Vehicle 1: Vehicle of Etoposide injection Vehicle 2: Vehicle of Compound No. 1 ofTable-I The Composition of the Vehicle 2 is
Component weight of composition Tris buffer(pH~8) 66.0 g Propylene glycol 30.0 g Glycerine 3.0 g
Table-Viπ
Treatment modalities in different Groups of animals
The progression of alopecia was quantitated as described by Jimenez et. al. (Joaquin J.Jimenez et. al., FASEB J., 1991, 1.2456-2458).
On 30th day the quantitation of alopecia/ hair growth was done as percentage of shaved area covered by new hair growth, scored by blinded observer on scale of 0 (no growth) to 5 (complete hair growth) as described in US 20020198250.
On 30th day the quantitation of alopecia/ hair growth was done by weighing the hairs regrown after shaving.
Observation and evaluation of hair growth after initiation of treatment is shown in Table-IX and Figure-8. Increased hair growth was observed in Group V animals, treated with Compound 1 of Table-I as compared to Groups IV and VI, indicating the stimulation of hair growth in skin treated with Chemotherapeutic agents like Etoposide but not limited to it. All the animals in Groups I, II, III showed similar hair growth as observed for that in the animals of Group V.
Table-IX
Observation and Evaluation of hair growth after initiation of treatment as given in
Table-VIII
Example-18 Effect of Compound 3 ofTable-I on Chemotherapy Induced Alopecia model in vivo in Adult Swiss Albino Mice
Male Swiss Albino mice (age- βweeks old) were purchased from National Institute of Nutrition Hyderabad- India. Mice were observed in Quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer. On 10th day the hair regrown were at Anagen phase of hair growth. Treatment given to six different groups of animals is shown in Table-X. The study was conducted in six groups of six animals each. In Table-VI Vehicle 1 and Vehicle 2 represent the following: Vehicle 1: Vehicle of Etoposide injection
Vehicle 2: Vehicle of Compound No. 3 of Table-I The Composition of the vehicle is
Component . weight of composition
Tris buffer (pH~8) 66.0 g Propylene glycol 30.0 g
Glycerine 3.0 g
Table- X
Treatment modalities in different Groups of animals
The progression of alopecia was quantitated as described by Jimenez et. al. (Jimenez et al., FASEBJ., 1991, 5^2456-2458).
On 30th day the quantitation of Hair growth was done as percentage of shaved area covered by new hair growth, scored by blinded observer on scale of 0 (no growth) to 5 (complete hair growth) as described by Steiner, Joseph P et. al. in US 20020198250.
Observation and evaluation of hair growth after initiation of treatment is shown in Table-XI and Figure-9. Onset of Alopecia was seen in all the animals in group IV, V and VI on 18th day of the experiment.
Increased hair growth was observed in Group V animals, treated with Compound No. 3 of Table-I as compared to Groups IV and VI, indicating that Compound No. 1 of Table-I stimulates the hair growth in skin treated with Chemotherapeutic agents like Etoposide but not limited to it. All the animals in Groups I, II, III showed similar hair growth as observed for that in the animals of Group V.
Table-XI
Observation and Evaluation of hair growth after initiation of treatment as given in
Tahle-X
Example 19
Effect of Compound No. 1 of Table-Ion Hair Promotion in depilated skin in C57/BL6 Mice in vivo
Male C57/BL6 mice (42 day old) were purchased from National Institute of Nutrition, Hyderabad, India. Mice were observed in quarantine for one week prior to initiation of the study. On day zero, not more than 10% of the body hairs from dorsal back were shaved off using sterile scalpel blade and care was taken not to cause nick or abrasion to the underlying dermal layer.
Treatment given to two groups of animals is shown in Table-XII. In Table- XII, Vehicle 1 represents the following: Vehicle 1: Vehicle of Compound No. 1 of Table-I The Composition of the vehicle 1 is
Component weight of composition Tris buffer (pH~8) 66.0 g Propylene glycol 30.0 g Glycerine 3.0 R
Compound No. 1 or the Vehicle was applied to 50-day-old mice (telogen hair growth phase) on depilated skin of the dorsal back using a syringe plunger (30 strokes for each applications) each day to the respective groups for 10 continuous days.
Table-XII Treatment modalities in different Groups of animals
Hair growth was quantitated by the percent of the shaved area covered by new hair growth a scored by a blinded observer on a scale of 0 (no growth) to 5 (complete hair growth).
Hair growth was evaluated on 5th day to 10th day after initiation of the treatment. After five applications, the first visual sign i.e. darkening of skins is observed in Compound No. 1 of Table-I treated group. After seven applications, 90% of the animals in Group II showed intense follicular pigmentation. After 10 applications all the animals in the Group II showed visual hair growth as compared to the animals in Vehicle treated group.
Evaluation of hair growth after initiation of treatment was carried out on the 10th day and is shown in Table-XII and in Figure-10. Table- XIII shows observation and evaluation of hair growth as scored by blinded observer whereas figure 8 is visual observation of hair growth on C57/ BL6 mice on 10th day of treatment. Animals in group II, which received Compound No. 1 of Table-I exhibits increased hair growth, indicative of promoting hair growth in depilated skin.
Table-Xπi Observation and Evaluation of hair growth after initiation of treatment
Effect of Compound No. 1 (Concentration: 3.2mg/15cm2) ofTable-lonAnagen
Induction in C57/BL6 mice in Telogen Phase of Hair Growth Male C57/BL6 mice (42 day old) were purchased from National Institute of Nutrition Hyderabad, India. Mice were observed in quarantine for one week prior to initiation of the study. The animals were grouped and each group had 10 animals. Treatment given to two groups of animals is shown in Table- XIV. In Table-XIV Vehicle 1 represents the following: Vehicle 1: Vehicle of Compound No. 1 of Table- 1 The Composition of the Vehicle 1 is
Component weight of composition Tris buffer (pH~8) 66.0 g Propylene glycol 30.0 g Glycerine 3.0 g
Compound No. 1 of Table-I or the Vehicle was applied to 50-day-old mice (telogen hair growth phase) on dorsal back using a syringe plunger (30 strokes for each applications) each day in respective group for seven continuous days. Table- XIV
Treatment modalities in different Groups of animals
Evaluation and analysis: After five applications the first visual signs i.e. darkening of skin (Anagen induction) is observed in animals of group II which were treated with Compound No. 1 (3.2mg/15cm2) of Table-I. Animals of the Group II treated with compound
No.l showed intense follicular pigmentation indicative of induction of Anagen phase of hair growth.
Animals were sacrificed on day 8th of the study; 8 mm punch biopsies were centrally taken from the resected skin (15 cm2 dorsal skin which received the topical application). The efficacy of Compound No. 1 of Table-I as a hair growth promoter is shown in Figure 11. Animals in group II showed higher follicular pigmentation indicative of anagen induction and hair growth.
Further the skins resected from animals in group I and group II were evaluated histopathologically for evidence of hair growth as reflected in Anagen induction in resting Telogen skin. Figure 12(A) is the Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with
Compound No.l. Figure 12(B) is Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with Vehicle 1. A marked increase in number and density of hair follicles accompanied by an increase in the thickness of skin in animals treated with Compound No. 1 of Table-I is observed histopathologically. This was more than that observed for animals in group I, suggesting the potential of Compound No. I for induction of Anagen in hair follicles in the resting telogen phase of hair growth.
Example 21
Effect of Compound No. 1 (Concentration: 1.6mg/15cm2) of Table-I on Anagen Induction in C57/BL6 mice in Telogen Phase of Hair Growth v
Male C57/BL6 mice (42 day old) were purchased from National Institute of Nutrition Hyderabad, India. Mice were observed in quarantine for one week prior to initiation of the study. The animals were grouped and each group had 8 animals. Treatment given to two groups of animals is shown in Table- XV. In Table-XV Vehicle 1 represents the following: Vehicle 1: Vehicle of Compound No. 1 of Table-1
The Composition of the vehicle is Component weight of composition
Tris buffer (pH~8) 66.0 g
Propylene glycol 30.0 g
Glycerine 3.0 g
Compound No. 1 of Table-I or the Vehicle was applied to 50-day-old mice (telogen hair growth phase) on dorsal back using a syringe plunger (30 strokes for each applications) each day in respective group for seven continuous days.
Table- XV Treatment
Evaluation and analysis:
After five applications the first visual signs i.e. darkening of skin (Anagen induction) is observed in animals of group II which were treated with Compound No. 1 (concentration 1.6mg/15cm2) of Table-I treated group. Animals of the Group II treated with compound No.l showed intense follicular pigmentation indicative of induction of Anagen phase of hair growth.
Animals were sacrificed on day 8th of the study; 8 mm punch biopsies were centrally taken from the resected skin (15 cm2 dorsal skin which received the topical application). The efficacy of Compound No. 1 of Table-I as a hair growth promoter is shown in figure 13. Animals in group II showed higher follicular pigmentation indicative of anagen induction and hair growth.
Further the skin's resected from animals in group I and group II were evaluated histopathologically for evidence of hair growth as reflected in Anagen induction in resting Telogen skin. Figure 14 (A) is the Histopathological data of hair follicle and skin thickness as observed visually in Group II animals treated with Compound No.l. Figure 14 (B) is Histopathological data of hair follicle and skin thickness as observed visually in Group I animals treated with Vehicle. A marked increase in number and density of hair follicles accompanied by an increase in the thickness of skin in animals treated with Compound No. 1 of Table-I is observed histopathologically. This was more than that observed for animals in group I, suggesting the potential of Compound No. 1 for induction of Anagen in hair follicles in the resting telogen phase of hair growth.
Claims
1. A peptide of formula (I) and its pharmaceutically acceptable salts thereof,
wherein X is a residue of an amino acid selected from Arginine, Histidine, Lysine, Ornithine or Glycine forming the amide linkage with carboxylic acid group adjacent to group Y; Y is a group of formula
R1 R2
\ /
C
/ \ wherein Ri & R2 are alkyl or Y represent carbocycle of 3-8 carbon atoms; Z is a residue of an amino acid selected from Arginine, Histidine, Ornithine, or Lysine forming the amide linkage with the amino group adjacent to group Y, wherein the amino group of the amino acid represented by Z is free or protected.
2. A peptide according to claim 1 wherein alkyl is of 3-8 carbon atoms.
3. A peptide according to claim 1 wherein the amino acids represented by group Y are uncommon amino acids.
4. A peptide according to claim 3, wherein the uncommon amino acid is an α, α- ' dialkylated amino acid.
5. A peptide according to anyone of claims 3 and 4 wherein the oc, α-dialkylated amino acids differ in hydrophobicity.
6. A peptide according to anyone of claims 4 and 5 wherein the α, α-dialkylated amino acids are selected from α-aminoisobutyric acid, α, α diethyl glycine, α,α dipropyl glycine, α,α di-n-butyl glycine.
7. A peptide according to claim 1 wherein the amino protective groups are selected from acetyl, n-butanoyl, n- hexanoyl, n-octanoyl, lauroyl, myristoyl, pajmitoyl,
isohexoyl, cyclopentylcarbonyl, n-heptanoyl, n-decanoyl, n- undecanoyl and 3,7-dimethyloctanoyl.
8. A peptide according to claim 1 wherein pharmaceutically acceptable salts are selected from acetate, ascorbate, benzoate, citrate, oxalate, stearate, trifluoroacetate, succinate, tartarate, lactate, fumarate, gluconate, glutamate, phosphate/diphosphate, valerate; Ca, Li, Mg, Na, and K salts; halides; salts with amino acids selected from lysine or arginine; guanidine; ammonium, or substituted ammonium salts; and aluminium salts.
9. A method of in vitro and in vivo bioassay for promotion and stimulation of hair growth in a mammal comprising administration of one or more peptides of formula (I).
10. A method of in vitro and in vivo bioassay for promotion and stimulation of hair growth in depilated and telogen skin in a mammal comprising administration of one or more peptides of formula (I).
11. A method of in vitro and in vivo bioassay according to anyone of claim 9 and 10 wherein the mammal is a human.
12. A method of in vitro and in vivo bioassay for treatment alopecia in a mammal comprising administration of one or more peptides of formula (I).
13. A method of in vitro and in vivo bioassay according to claim 12 wherein the mammal is a human.
14. A pharmaceutical composition comprising an effective amount of one or more peptides of formula (I).
15. A pharmaceutical composition according to claim 14 further comprising one or more pharmaceutically acceptable carriers.
16. A pharmaceutical composition according to anyone of claims 14 and 15 wherein the pharmaceutically acceptable carriers include a disintegrant, a lubricant, and a diluent.
17. A pharmaceutical composition according to anyone of claims 14 to 16 further comprising one or more suspending agents, thickening agents, sweeteners, preservatives, bulking agents, and flavouring agents.
18. A pharmaceutical composition according to claim 16 wherein the disintegrant is selected from starch, croscarmellose sodium, crospovidone, sodium starch glycolate, croscarmellose calcium, microcrystalline cellulose and polacralin potassium.
19. A pharmaceutical composition according to claim 16 wherein the lubricant is selected from magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, hydrogenated castor oil, hydrogenated cottonseed oil, stearic acid and calcium stearate, and colloidal silicon dioxide.
20. A pharmaceutical composition according to claim 16 wherein the diluent is selected from RPMI 1649; buffered saline; isotonic NaCl; Ringer's solution; water, distilled or undistilled; polyethylene glycol, Tween, dimethylsulfoxide, propylene glycol, or mixtures thereof with water; phosphate buffered saline, balanced salt solution and glycerol.
21. A pharmaceutical composition according to claim 17 wherein the suspending agent is selected from xanthan gum; hydroxypropyl methylcellulose; methylcellulose; carageenan; sodium carboxymethyl cellulose; macrocrystalline cellulose mixes; thixotropic suspending agents such as xanthan, carageenan and sodium carboxymethyl cellulose/microcrystalline cellulose.
22. A pharmaceutical composition according to claim 17 wherein the thickening agent is selected from silicon dioxide.
23. A pharmaceutical composition according to claim 17 wherein the sweetener is selected from sugars such as fructose, sucrose, glucose, maltose, or lactose; non caloric sweeteners such as aspartame, saccharin, acesulfame, thaumatin, chalcone, cyclamate, and stevioside and the like.
24. A pharmaceutical composition according to claim 17 wherein the preservative is selected from sodium benzoate, sodium citrate and benzalkonium chloride.
25. A pharmaceutical composition according to claim 17 wherein the bulking agent is selected from lactose, manitol, isomalts, polydextrose, starch, microcrystalline cellulose, sorbitol, calcium sulphate, calcium phosphate, and acacia.
26. A pharmaceutical composition according to claim 17 wherein the flavouring agent is selected from artificial, natural or synthetic fruit flavours such as lemon, orange, banana, grape, lime, apricot and grapefruit oils and fruit essences including apple, strawberry, cherry, orange, pineapple and so forth; bean and nut derived flavours such as coffee, cocoa, cola, peanut, almond root derived flavours such as licorice.
27. A pharmaceutical composition according to claim 14 is in the form of a tablet, an injection, a lotion, a cream or gel.
28. A pharmaceutical composition according to anyone of claims 14 and 27 which is administered orally.
29. A pharmaceutical composition according to anyone of claims 14 and 27 which is administered topically.
30. A pharmaceutical composition according to claim 27 wherein the concentration of peptides of formula (I) is from about 0.01% to about 10 % by weight.
31. A pharmaceutical composition according to claim 27 wherein concentration of peptides of formula (1) is from about 0.5% to about 2 % by weight.
32. A method of promotion and stimulation of hair growth in a mammal comprising administration of an effective amount of pharmaceutical composition of claim
14.
33. A method of promotion and stimulation of hair growth according to claim 32 wherein the mammal is a human.
34. A method of treating alopecia in a mammal comprising of administration of an effective amount of pharmaceutical composition of claim 14.
35. A method according to claim 34 wherein the mammal is a human.
36. A method of promotion and stimulation of hair growth according to claim 32 wherein the mammal is treated with a chemotherapeutic agent.
37. A method of promotion and stimulation of hair growth according to claim 36 wherein the mammal is a human.
38. A method of treating alopecia according to claim 34 wherein the mammal is treated with a chemotherapeutic agent.
39. A method of treating alopecia according to claim 38 wherein the mammal is a human.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN898DE2005 | 2005-04-07 | ||
IN898/DEL/2005 | 2005-04-07 |
Publications (1)
Publication Number | Publication Date |
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WO2006106528A1 true WO2006106528A1 (en) | 2006-10-12 |
Family
ID=36676433
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2005/000453 WO2006106528A1 (en) | 2005-04-07 | 2005-12-30 | Novel peptides useful for treatment of alopecia |
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Country | Link |
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WO (1) | WO2006106528A1 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5252559A (en) * | 1991-08-20 | 1993-10-12 | The Procter & Gamble Company | His-Gly-Gly peptide and derivatives thereof for hair growth |
US5739111A (en) * | 1995-04-28 | 1998-04-14 | Societe L'oreal S.A. | Modulating body/cranial hair growth with derivatives of the α-type melanocyte-stimulating hormone |
WO1999039728A2 (en) * | 1998-02-04 | 1999-08-12 | Trustees Of Boston University | Methods of inducing hair growth and coloration |
US6017888A (en) * | 1994-06-17 | 2000-01-25 | Procyte Corporation | Stimulation of hair growth by peptide copper complexes |
US6489297B1 (en) * | 2000-02-18 | 2002-12-03 | Dabur Research Foundation | Vasoactive intestinal peptide analogs |
-
2005
- 2005-12-30 WO PCT/IN2005/000453 patent/WO2006106528A1/en not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5252559A (en) * | 1991-08-20 | 1993-10-12 | The Procter & Gamble Company | His-Gly-Gly peptide and derivatives thereof for hair growth |
US6017888A (en) * | 1994-06-17 | 2000-01-25 | Procyte Corporation | Stimulation of hair growth by peptide copper complexes |
US5739111A (en) * | 1995-04-28 | 1998-04-14 | Societe L'oreal S.A. | Modulating body/cranial hair growth with derivatives of the α-type melanocyte-stimulating hormone |
WO1999039728A2 (en) * | 1998-02-04 | 1999-08-12 | Trustees Of Boston University | Methods of inducing hair growth and coloration |
US6489297B1 (en) * | 2000-02-18 | 2002-12-03 | Dabur Research Foundation | Vasoactive intestinal peptide analogs |
Non-Patent Citations (1)
Title |
---|
NIETO M; PERKINS H R: "Modifications of the acyl-D-alanyl-D-alanine terminus affecting complex-formation with vancomycin", THE BIOCHEMICAL JOURNAL, vol. 123, August 1971 (1971-08-01), pages 789 - 803, XP002391676 * |
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