DESC:Field of Invention:
The present invention relates to a topical composition used for the treatment of hair loss related to androgenic alopecia in men and women more preferably men more particularly to topical solution comprising Clascoterone, minoxidil in combination with prostaglandin analog.
Background of the invention:
Androgenetic alopecia also known as androgenic alopecia is a male or female- pattern baldness. In male, hair loss occurs either a receding front hairline, loss of hair on the crown (vertex) of the scalp, or a combination of both wherein in female’s hair loss occurs as diffuse thinning of the hair across the entire scalp. FPHL is characterized as a non-scarring diffuse alopecia that evolves from the progressive miniaturization of hair follicles and subsequent reduction in the number of hairs, especially in the central, frontal, and parietal scalp regions [Olsen E.A. Female pattern hair loss. J Am Acad Dermatol. 2002; 45:S70–S80].
Male androgenetic alopecia (MAA, male pattern baldness) is very common type of hair loss affecting men worldwide. Although MAA is not a major dermatological concern but it affects self-confidence and can cause anxiety and depression in some men. FDA have approved topical minoxidil (Rogaine) which can be used by men and women, oral finasteride (Propecia) which is only prescribed for men and Low Level Laser Light therapy (LLLT) for both men and women. There are other variety of options available for treating AGA like nutraceuticals, Platelet-rich plasma, micro-needling and other several invasive techniques such as transplantation.
Dihydrotestosterone (DHT) and androgen receptor (AR) levels are increased in men suffering from Androgenic alopecia. The enzyme 5-alpha reductase regulates the conversion of testosterone to DHT. Increased levels of DHT, or increased sensitivity to the effects of DHT, leads to miniaturization of the hair follicle, a shortened anagen phase of the hair cycle, and eventual hair loss. Finasteride is USFDA approved drug which is used for the treatment of alopecia and is a competitive inhibitor of types II and III 5-alpha-reductase isoenzyme, resulting in inhibition of testosterone conversion to dihydrotestosterone (DHT). However, it is reported that Finasteride causes sexual side effects in men such as impotence, decreased libido, and ejaculation disorder. Therefore, there is a need of alternate drug which can help in managing the hair loss and does not causes any systemic side effects.
Clascoterone is a novel androgen receptor inhibitor, which was initially approved for acne. It was observed that Clascoterone have similar properties as that of finasteride and the clinical trials of Clascoterone have shown promising results in promoting hair growth. Although the exact mechanism of Clascoterone is not known it is believed that the drug antagonizes dihydrotestosterone (DHT) through competitive binding with cytoplasmic androgen receptors and may be efficacious in treating androgen-mediated hair loss.
Clascoterone has been combined with other agents for treating alopecia for examples patent no. CN114404424 disclosed pharmaceutical composition comprising Clascoterone and minoxidil for treating androgenetic alopecia. Minoxidil is converted to its metabolite minoxidil sulftate and enzyme which is responsible for this conversion is sulfotransferase, which is located in hair follicles and prolong the anagen phase of hair follicle therefore promote hair growth. However, it has been reported that sulfotransferase enzyme varies from human to human and is controlled genetically, therefore patient with higher enzyme activity respond better than patient with lower enzyme activity. [Buhl, AE; Baker, CA Dietz; AJ.; Minoxidil sulfotransferase activity influences the efficacy of Rogaine topical solution (TS): enzyme studies using scalp and platelets, J Invest Dermatol, 1994; 102:534]. Therefore, there is a need of additional agent which provide alternative and complementary mechanism to overcome the variable efficacy of minoxidil in patients and provide a synergistic effect by acting on different targets with fewer side-effects.
The innovators of the present study have found that combining Clascoterone with Minoxidil and Latanoprost provide synergistic effects as compared with Clascoterone and Minoxidil.
Minoxidil was first prescribed for hypertension and it was reported that oral Minoxidil have a side effect of hypertrichosis (hair growth stimulant) causing increased hair growth eventually leading to preparation of topical solution for the treatment of hair loss. Minoxidil is available as topical solution 2% and 5% marketed as ROGAINE® for hair loss and hair regrowth and thinning of hair.
Minoxidil is converted to its metabolite minoxidil sulfate and enzyme which is responsible for this conversion of sulfotransferase, which is located in hair follicles and prolong the anagen phase of hair follicle therefore promote hair growth. It also affects the potassium channels present in vascular smooth muscles and hair follicles which induce stimulation of the microcirculation around the hair follicles; induce vascular endothelial growth factor expression which ultimately prompt hair growth.
Latanoprost is a prodrug analog of prostaglandin F2 alpha that is used to treat elevated intraocular pressure (IOP). It was initially approved by the FDA in 1998. However, it has been found that Latanoprost plays an important role in the hair growth cycle. Ulrike Blume-Peytav et. al., studied the effect of Latanoprost on hair growth and pigmentation in healthy male volunteers with androgenetic alopecia. The volunteers were topically treated with 0.1% latanoprost it was found that latanoprost significantly increased overall hair density and the number of vellus and terminal hairs compared with baseline and the placebo-treated area after 8 weeks of topical treatment. This suggests that latanoprost could be useful for treating androgenetic alopecia.
Thus, the present invention provides a fixed dose combination (FDCs) of Clascoterone with Minoxidil and Latanoprost in a single-dose form. FDC formulations have unique advantages such as complementary mechanism of action, synergistic effects, better tolerability, elongated product life-cycle management, and cost savings. Use of FDCs is a rational approach for achieving optimal therapeutic benefits while minimizing pill-burden. Greater convenience with decreased pill-burden leads to improved adherence, resulting in superior clinical outcomes and greater cost-effectiveness.
The FDC of the present invention provides synergistic effects by:
1. antagonizing dihydrotestosterone (DHT) through competitive binding with cytoplasmic androgen receptors and;
2. converting sulfotransferase, which is located in hair follicles prolonging the anagen phase of hair follicle therefore promote hair growth and simultaneously stimulate microcirculation and induces vascular endothelial growth factor expression
3. Increasing overall hair density and the number of vellus and terminal hairs.
Combining multiple drugs in a single formulation can benefit patients through the potential synergistic or additive increases in efficacy, improved tolerability using lower doses and convenience in terms of administration and increased patient compliance, as well as reducing direct medical costs.
Summary:
The inventors of the present study had formulated a fixed dose combination of triple active agents for the treatment of hair loss related to androgenic alopecia in men and women more preferably men. The active agents belong to different category of pharmacological class with different mechanism of action which provides synergistic effects as compared to single active agent.
The present invention provides synergistic combinations of androgen receptor inhibitors which act by antagonizing dihydrotestosterone (DHT) through competitive binding with cytoplasmic androgen receptors; a vasodilator which is responsible for converting sulfotransferase, which is located in hair follicles and prolong the anagen phase of hair follicle; a prostaglandin analog which increases the overall hair density and number of vellus and terminal hairs.
The composition of the present invention provides a topical formulation which penetrates effectively into the hair without the side effects associated with use of Finasteride in men and can be used easily.
In one aspect the topical formulation is a gel or solution comprising about .5% Clascosterone, 5% Minoxidil and 0.03% Latanoprost including pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide a method for producing said topical pharmaceutical formulation.
Detailed Description of invention:
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
The term “excipients” or “carrier” or “vehicles” as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic and does not interact with other components of the composition in a deleterious matter.
The terms "effective amount" or a "therapeutically effective amount" of a pharmacologically active agent is meant a non-toxic but sufficient amount of the drug or agent to provide the desired effect.
The terms "active agent" or "active pharmaceutical ingredient" or "drug" are used interchangeably herein to refer to a chemical material or compound that induces a desired pharmacological, physiological effect, and include agents that are therapeutically effective, prophylactically effective, or cosmeceutically effective.
The terms "topical" conventionally mean delivery of a drug or pharmacologically active agent to the skin (including hair and scalp) or mucosa.
The present invention provides a fixed dose combination of triple active agents which is an androgen receptor inhibitor, a vasodilator and a prostaglandin analog for the treatment or management of hair loss associated with androgenic alopecia in men and women more preferably men.
In an embodiment androgen receptor inhibitor are selected from Cyproterone, Megestrol, Chlormadinone, Spironolactone, Oxendolone, Osaterone, Clascoterone, Flutamide, Bicalutamide, Nilutamide, Topilutamide, Enzalutamide, and Apalutamide or combinations thereof.
In a preferred embodiment androgen receptor inhibitor is Clascoterone or pharmaceutically acceptable salts, esters, or derivatives thereof wherein Clasocterone act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production such as dihydrotestosterone (DHT) and testosterone and therefore can be beneficial in treating androgen-mediated hair loss.
In another embodiment the vasodilator is selected form but not limited to hydralazine, minoxidil, nitrates, nitroprusside or combinations thereof.
In a preferred embodiment the vasodilator is minoxidil or pharmaceutically acceptable salts, esters, or derivatives thereof. Minoxidil was developed as a potent peripheral vasodilator agent for treating severe refractory hypertension and it was observed that oral use of minoxidil has a side effects of hair growth in patient who was taking Minoxidil, this discovery leads to use of minoxidil for hair growth. Minoxidil is converted to its metabolite minoxidil sulftate and enzyme which is responsible for this conversion of sulfotransferase, which is located in hair follicles and prolong the anagen phase of hair follicle therefore promote hair growth. It also affects the potassium channels present in vascular smooth muscles and hair follicles which induce stimulation of the microcirculation around the hair follicles; induce vascular endothelial growth factor expression which ultimately prompt hair growth.
In another embodiment prostaglandin analog is selected from group consisting of Latanoprost, Travoprost, Bimatoprost, Alprostadil, Misoprostol or combinations thereof.
In a preferred embodiment prostaglandin analog is Latanoprost or pharmaceutically acceptable salts, esters, or derivatives thereof wherein Latanoprost increases overall hair density and number of vellus and terminal hairs.
In a preferred embodiment the pharmaceutical composition comprises effective amount of Clascoterone, Minoxidil and Latanoprost or pharmaceutically acceptable salts, esters, or derivatives thereof wherein composition is a Topical formulation.
In another embodiment the present invention provides a topical formulation comprising a therapeutically effective amount of Clascoterone, Minoxidil and Latanoprost or pharmaceutically acceptable salts, esters, or derivatives thereof and a topical pharmaceutically acceptable excipient or carrier.
In another embodiment the excipients or carriers comprises a surfactant, a co-surfactant, a penetration enhancer, an antioxidant, a buffering agent, a preservative, a viscosity modifying agent, a chelating or complexing agent, a coloring agent, a perfume, a polymer, a gelling agent, an alcohol, a liquid or semi-solid oily component, or any combination thereof.
In some embodiment the topical composition is in the form of foam, cream, paste, gel, aerosol, powder, oil, serum, or solution. In another preferred embodiment of the present invention, a process is provided for preparing the topical pharmaceutical formulation according to the present invention.
In a preferred embodiment the topical composition is a solution comprising effective amount of Clascoterone, Minoxidil and Latanoprost or pharmaceutically acceptable salts, esters, or derivatives thereof and a topical pharmaceutically acceptable excipient or carrier.
In another embodiment the topical solution comprises:
i. 7.5% w/w of Clascosterone and;
ii. 5.00% w/w of Minoxidil and
iii. 0.03% w/w of Latanoprost
iv. One or more pharmaceutically acceptable excipients selected from solvent, surfactant, preservatives, antioxidants, colorant, buffering agent, fragrance, chelating agent, vehicle and any other acceptable inactive ingredients based on the final formulation can be added based on the list of known inactive ingredients available in the art.
The topical formulation may be in the form of aqueous, alcoholic or aqueous-alcoholic solutions.
In an embodiment the topical solution comprises clascoterone or pharmaceutically acceptable salts in an amount ranging from 5 to 10% w/v
In another embodiment the topical solution comprises Minoxidil or pharmaceutically acceptable salts in an amount ranging from 2 to 10% w/v
In another embodiment the topical solution comprises Latanoprost or pharmaceutically acceptable salts in an amount ranging from 0.005 to 0.5% w/v
In a preferred embodiment the topical solution comprises about 7.5% clascosterone, 5% Minoxidil and 0.03% Latanoprost wherein the active agents may be present in base form or in salt form.
In an embodiment the topical formulation is a gel formulation comprises 7.5% clascosterone, 5% Minoxidil and 0.03% Latanoprost including pharmaceutically acceptable salts thereof.
The topical formulations of the present invention may comprise further excipients such as those being suitable for pharmaceutical and/or cosmetic compositions. In particular, the further excipients that may be used according to the invention are known to the skilled person. These include, for example, one or more of a preservative, a pH adjusting agent, a humectant, a permeation enhancer; a skin care compound; an inorganic salt, diluents, wetting agents, dyestuffs, lubricants, surfactants, colorants, thickeners, antioxidants, moisturizing agents, lipids, waxes, polymers or other suitable components of a gel formulation.
In another embodiment the topical gel further comprises one or more antioxidants selected from sodium metabisulfite, vitamin A, tocopherol, ascorbic acid, tartaric acid, retinyl palmitate, sesamol, Butylated Hydroxy Anisole (BHA) and Butylated Hydroxyl Toluene (BHT).
In an embodiment the antioxidant is present in an amount of 0.005 to 1% w/w, humectant in an amount of 0.5 to 20% w/w, penetration enhancer in an amount of 1 to 10% w/w.
In one embodiment the topical gel comprises combination of two antioxidants selected from Butylated Hydroxy Anisole (BHA) and Butylated Hydroxyl Toluene (BHT).
In an embodiment, the humectant is selected from glycerin, glycerol, propylene glycol, butylene glycol, sorbitol, polyethylene glycol, coconut oil, olive oil, jojoba oil, Cyclomethicone, super refined castor oil and combinations thereof.
In a preferred embodiment the humectants are propylene glycol and cyclomethicone.
In another embodiment the topical gel further comprises penetration enhancer selected from sulphoxides such as dimethylsulphoxide, DMSO, azones such as laurocapram, pyrrolidones such as 2-pyrrolidone, alcohols and alkanols such as ethanol, or decanol, glycols such as propylene glycol, diethylene glycol monoethyl ether and combinations thereof.
In a preferred embodiment the penetration enhancer is diethylene glycol monoethyl ether.
In one embodiment the topical gel composition comprises elastomer base.
In one embodiment the topical gel comprises:
v. 7.5% w/w of Clascosterone and;
vi. 5.00% w/w of Minoxidil and
vii. 0.03% w/w of Latanoprost
viii. 0.010 to 0.200% w/w of antioxidants
ix. 2 to 10% w/w of humectants
x. 2% of penetration enhancer
In one embodiment the topical gel comprises:
i. 7.5% w/w of Clascosterone and;
ii. 5.00% w/w of Minoxidil and;
iii. 0.03% w/w of Latanoprost and;
iv. 0.010% w/w of Butylated Hydroxyanisole and;
v. 0.200% w/w of Butylated Hydroxytoluene and;
vi. 2.00% w/w of Propylene glycol and
vii. 10.00% w/w of Cyclomethicone and;
viii. 2.00% w/w of diethylene glycol monoethyl ether
In an embodiment the present invention is used in treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth and helps growth of new and healthy hairs in male and females more preferably the present invention is suitable for male.
The present invention is described in more details by means of the following examples. These examples are not limiting the scope of the present invention and are to be considered under the light of the foregoing detailed disclosure.
EXAMPLES
Example-1: Topical Solution comprising Clascosterone, Minoxidil and Latanoprost
S.NO Ingredients % amount
1. Clascosterone 7.5%
2. Minoxidil 5%
3. Latanoprost 0.03%
4. Excipients q.s.

Example 2: Topical Gel comprising Clascosterone, Minoxidil and Latanoprost
Sr. No. Material Name Rationale % w/w
1. Clascoterone API 7.50
2. Minoxidil API 5.00
3. Latanoprost API 0.03
4. Propylene Glycol Humectant 2.000
5. Citric Acid Monohydrate Acidifier 0.010
6. diethylene glycol monoethyl ether (Transcutol) Penetration enhancer 2.000
7. Titanium Dioxide Opacifier 0.250
8. Cyclomethicone-N5 Humectant 10.00
9. Butylated Hydroxyanisole Anti-Oxidant 0.010
10. Butylated Hydroxytoluene Anti-Oxidant 0.200
11. Elastomer-10 (Csilcare CPDCL) Base QS

,CLAIMS:1. A topical composition comprising a therapeutically effective amount of Clascoterone, Minoxidil and Latanoprost or pharmaceutically acceptable salts thereof.
2. The topical composition as claimed in claim 1 wherein the composition comprises:
i. 5 to 10% w/w of Clascosterone and;
ii. 2 to 10% w/w of Minoxidil and
iii. 0.005 to 0.5% w/w of Latanoprost
3. The topical composition as claimed in claim 1 is a topical gel or solution.
4. The topical composition as claimed in claim 1-3 is a topical gel or solution comprises:
i. 7.5% w/w of Clascosterone and;
ii. 5.00% w/w of Minoxidil and
iii. 0.03% w/w of Latanoprost
5. The topical composition as claimed in claim 3 is a topical gel wherein topical gel comprises one or more pharmaceutically acceptable excipients.
6. The topical gel as claimed in claim 5, wherein excipients are:
i. 0.005 to 1% w/w of antioxidants
ii. 0.5 to 20% w/w of humectants
iii. 1 to 10% w/w of penetration enhancer
7. The topical gel as claimed in claim 4-6, wherein the gel comprises
i. 7.5% w/w of Clascosterone and;
ii. 5.00% w/w of Minoxidil and
iii. 0.03% w/w of Latanoprost
iv. 0.010 to 0.200% w/w of antioxidants
v. 2 to 10% w/w of humectants
vi. 2% of penetration enhancer
8. The topical gel as claimed in claim 7 further comprises:
i. 7.5% w/w of Clascosterone and;
ii. 5.00% w/w of Minoxidil and;
iii. 0.03% w/w of Latanoprost and;
iv. 0.010% w/w of Butylated Hydroxyanisole and;
v. 0.200% w/w of Butylated Hydroxytoluene and;
vi. 2.00% w/w of Propylene glycol and
vii. 10.00% w/w of Cyclomethicone and;
viii. 2.00% w/w of diethylene glycol monoethyl ether
9. The topical gel as claimed in 8 wherein the gel comprises elastomer as base.
10. The topical composition as claimed in claim 3, is topical solution comprises:
i. 7.5% w/w of Clascosterone and;
ii. 5.00% w/w of Minoxidil and
iii. 0.03% w/w of Latanoprost
iv. One or more pharmaceutically acceptable excipients selected from solvent, surfactant, preservatives, antioxidants, colorant, buffering agent, fragrance, chelating agent, vehicle