DESC:TOPICAL COMPOSITION FOR HAIR GROWTH PROMOTING AGENTS
FIELD OF THE INVENTION
[001] The present application relates to a topical composition comprising one or more hair growth promoting agents for treating alopecia or androgenic alopecia. The application also relates to preparing stable, non-irritant, and easily penetrable topical composition, with improved aesthetic properties and patient compliance.

BACKGROUND
[002] Hair loss is a common condition among healthy adult males, and also occurs frequently in adult females. In fact, some degree of alopecia on the vertex from puberty onwards is thought to be a universal phenomenon in both men and women. It is common that, as people age, hair growth slows down. However, the phenomenon of hair loss can be due to many other causes also. Some of them are pathological or external or diet related, with effects on hair growth that vary depending on the evolution of the related disease or external event.
[003] Alopecia (hair loss) can be classified as being one of two types: non-scarring alopecia and scarring alopecia. Non-scarring alopecia has been attributed to: Genetics and advanced age (i.e. androgenetic alopecia, female pattern hair loss) high fevers, severe infections, thyroid disease, childbirth, taking birth control pills, inadequate proteins or iron in diet, patients on drugs like blood thinners, treatments for gout, arthritis, depression, hypertension, chemotherapy, alopecia areata, physical or emotional stress, topical use of chemical treatments, such as hair dyes, permanent wave solutions, etc. diseases, such as leprosy or syphilis Allergy.
[004] Scarring alopecia may be a consequence of burns (accidental or post-surgical from cryosurgery or laser surgery) or trauma, which often causes destruction of hair follicles.
[005] The most common cause of baldness or hair loss (95%) is androgenetic alopecia, that is the well-known tendency to baldness or thinning, developing in the twenty, thirty or forty aged persons.
[006] Androgenic alopecia (AGA) is characterized by hereditary thinning of the hair induced by androgens in genetically susceptible men and women. This condition is also known as male pattern hair loss or common baldness in men and as female pattern hair loss in women.
[007] Drug therapies specifically approved for treating AGA are limited to minoxidil and finasteride as major category products. Several other drugs are also used off label and a plethora of treatments with unsubstantiated hair growth claims can be obtained. However, looking at the number of treatment options currently available to patients with AGA, the clinical data supporting their use is often very limited. Some of other therapies known in the literature include adenosine, androgenic hormones and natural extracts.
[008] Minoxidil (i.e., 2,4-diamino-6-piperidinylpyrimidine-3 -oxide) is the active ingredient of the brand ROGAINE® (in USA and Canada) and REGAINE® (in Europe and Asia Pacific) as a treatment and prevention for androgenic alopecia (male and female pattern baldness) available as 5% minoxidil solution designed for men and 2% solutions designed for women.
[009] Minoxidil is poorly soluble in water. The preparation of minoxidil is described in U.S. Pat. No. 3,461,461. U.S. Pat. Nos. 4,139,619 and 4,596,812 describes topical preparations for minoxidil and methods to treat male and female pattern baldness.
[0010] Adenosine is a purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule ribofuranose moiety via a ß-N9-glycosidic bond. Adenosine has been shown to promote thickening of hair on people with thinning hair.
[0011] Pharmaceutical compositions for topical application to hair/scalp, may take a variety of forms including, for example, solutions, gels, suspensions, and the like. Most of the marketed hair growth compositions contain alcohol based vehicles for administering the active ingredient. In general, minoxidil dissolves poorly in both water and water immiscible organic solvents. Generally topical formulations of minoxidil contain high percentages of lower alcohol (e.g. ethanol) and propylene glycol, which are reported to contribute to various allergic reactions including dryness of scalp resulting in itching, pruritus, erythema, scaling, flakes, dandruff, light sensitivity and inflammation. For example, ROGAINE® extra strength (5% minoxidil) contains 30% ethanol and 50% propylene glycol. Alcohols like ethanol may make the hair brittle and leave a very cold feeling on the skin. Alcohols may also cause skin irritation. The ethanol-based vehicle, such as ethanol/propylene glycol/water, evaporates shortly after spreading over the bald skin; whereas, the greasy propylene glycol/water mixture stays on the applied area. Further, it has also been reported that after application of the topical products comprising either high percentages of solvents such as propylene glycol or ethanol, tend to undergo recrystallization or precipitation of the drug/active ingredient on the scalp thereby, leading to poor patient compliance.
[0012] In a composition for topical administration, a wide variety of components are employed, which are in many cases specifically adapted to the particular active ingredients used. Many of the active compounds used in the pharmaceutical or cosmetic industries require some degree of dissolution in order to carry out the function for which they are intended. Solubility plays an essential role as a part of formulation development since inadequate drug solubility in a formulation will impede the formulation development as the target dose cannot be achieved. The solubility of a particular drug may necessitate the selection of suitable components such as proper solvents, solubilizers or pH modifiers. Further said components needs to be optimized in appropriate amounts suitable for various active agents and dosage forms. For example, it is challenging to formulate a highly lipophilic or an insoluble drug into an aqueous formulation.
[0013] The selection of the solvents is based on the active agents and dosage forms of choice. Some of the approaches used to dissolve drugs for topical formulation development include the use of co-solvents also called as ‘mixed-solvency’ approach, pH adjustment, complexation, micronization, nanoization use of surfactants, developing micellar or liposomal systems and forming microemulsions or nanoemulsions. Of these approaches, mixed-solvency approach is probably the most practical and commonly used approach to solubilize poorly soluble drugs or to increase drug solubility in aqueous systems. A variety of solvents can be used and it is important that the selection of mixture of solvents is based on the miscibility of each solvent to avoid phase separation. The mixed-solvency approach has been accepted widely in pharmaceutical field to develop various formulations of poorly water-soluble drugs by combining various water-soluble excipients in safe concentrations.
[0014] It is important that solvents which are qualitatively and quantitatively suitable for the solubilization of the active agents should not evaporate rapidly upon the administration which decreases the drug penetration into the skin, causes the deposition of drug crystals and skin irritation. Most of the times, solvents employed for achieving this purpose have varying viscosities and oily nature, which have a negative impact on the aesthetic properties of the composition such as greasiness, odor, color and texture, which reduces patient compliance.
[0015] The pH of the composition plays an important role in solubilizing the drug and also in stabilizing the composition. Use of acidifying agents and basifying agents for adjusting the pH of the composition is one of the most common approaches. However, pH suitable for the complete solubilization for drug may not be suitable for topical application, and can cause itching, irritation, leading to discomfort to the patient. Proper selection of components in appropriate amounts which impart sufficient pH which aids in solubilization, stability and also safer for topical application is challenging and may vary for different active agents and dosage forms.
[0016] It is also commonly seen on the usage of penetration/ permeation enhancers in topical compositions, to provide enough permeation of the therapeutic agent across the skin into the target site. These penetration enhancers can also exhibit a wide range of excipient effects in addition to their primary function of skin permeabilization.
[0017] It is challenging to obtain a topical composition for any hair growth promoting agent, which is stable, non-irritant, easily penetrable, and with aesthetic properties.
[0018] The international patent application WO 1995/25500 discloses formulations containing minoxidil and cyclodextrins in the presence of alcohol (ethanol).
[0019] US patent nos. 5,030,442 and US 4,828,837 disclose solubility enhanced minoxidil compositions by inclusion of amphipathic excipients with a pKa less than 5.
[0020] The international patent application WO 2014/122436 discloses topical solution of minoxidil which was nanosized to less than or equal to about 1000 nm.
[0021] US patent no. US 8,444,960 describes a topical minoxidil composition comprising a carrier including water, glycerin and polysorbate, with high amounts of ethanol.
[0022] The US patent application no. US 2011/0112125 discloses a topical minoxidil composition comprising polymers such as carbomer, polyvinyl alcohol, polyacrylic acids, natural cyclodextrins etc.
[0023] The Japanese patent application JP 2001/288048 discloses a scalp hair composition comprising minoxidil and adenosine compounds, wherein the compositions contain more than 50% of alcohol.
[0024] In view of aforementioned problems, there is a need for a topical composition for hair growth promoting agents which are stable, non-irritant, easily penetrable, and with aesthetic properties such as less oiliness/greasiness, odor, texture etc., and with improved patient compliance.

BRIEF DESCRIPTION OF THE DRAWING

[0025] FIG. 1 shows comparison of systemic absorption of topical minoxidil test compositions (Example 3 and Example 2) composition vs. commercial product (MINTOP FORTE® 5%, from Dr. Reddy’s Laboratories, India); the test compositions show lesser concentrations of minoxidil in receptor fluid compared to commercial product.
[0026] FIG. 2 shows comparison of skin penetration of topical minoxidil test compositions (Example 3 and Example 2) composition vs. commercial product (MINTOP FORTE® 5% from Dr. Reddy’s Laboratories, India); the test compositions show higher skin penetration compared to commercial product.
[0027] FIG. 3 shows dermal irritation study of topical minoxidil test compositions (Example 5 and Example 7) in Rabbits; the composition of Example 5 which is devoid of oleic acid does not show any signs of dermal irritation after 22 days, while composition of Example 7 shows signs of irritation including erythema, edema and skin flaking, and the treatment was discontinued after 7 days.
[0028] FIG. 4 shows microscopic pictures for comparison of recrystallization of topical minoxidil test composition (Example 3) Vs. commercial product (MINTOP FORTE® 5%), studied under 20X magnification scale; it is observed that the test composition of Example 3 remain clear even after 8 hours of time, while the commercial product is seen recrystallized considerably after 4 hours of time.

DETAILED DESCRIPTION OF THE APPLICATION

[0029] The present application relates to a topical composition comprising one or more hair growth promoting agents useful for treating hair loss due to alopecia or androgenic alopecia. The application also relates to a topical composition comprising one or more hair growth promoting agents which is non-greasy, non-irritating, and stable in nature.
[0030] The details of one or more embodiments of the present application are set forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom.
[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
[0032] Definitions: The terms as used herein have the following meanings:
[0033] The term "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. These terms are not in the exclusive sense of "consisting only of." All ranges recited herein include the endpoints, including those that recite a range "between" two values.
[0034] The terms "a" and "the" as used herein are understood to encompass the plural as well as the singular or otherwise clearly mentioned wherever needed. For example, reference to “an excipient” includes reference to one or more of such excipients, and reference to "the carrier" includes reference to one or more of such carriers.
[0035] The terms such as “about”, “up to”, “generally” and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skilled in the art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given experiment, technique or an instrument used to measure a value. The term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. As used herein, the term "about" means a slight variation of the value specified, within 10 percent of the value specified. Nevertheless, the term "about" can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present invention.
[0036] The terms “effective amount” or “therapeutically effective amount” or “therapeutically effective concentration” as used herein refer to a non-toxic, but sufficient amount of the drug in the skin tissue, to achieve therapeutic results in treating a condition for which the drug is known to be effective, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The effective amount of the active agent or a pharmaceutically acceptable salt will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, and the duration of the treatment, the nature of concurrent therapy, and like factors within the knowledge and expertise of the attending physician.
[0037] As used herein, the term “at least” refers to presence of recited substance in the composition in recited least amount.
[0038] The terms “topical” or “topically” as used herein refer to the application of the composition onto skin or head or scalp or hair, wherein said composition is absorbed into skin layers without providing any systemic absorption of the active ingredient.
[0039] The terms “applying”, “applied”, “administering”, “administered” or “administration”, as used herein, refer to topical application of composition to affected and adjoining areas of skin by spreading or gentle rubbing or massaging.
[0040] The terms “topical composition” or “composition” as used herein refer to a topically administrable composition of present application.
[0041] The term “carrier system” as used herein refers to a set of components including, but not limited to, solvents or mixture of solvents, organic or inorganic ingredients, natural or synthetic, with which an active ingredient is combined to facilitate application of a composition. Further said components are used in suitable amounts and proportions such that the active ingredient does not show any signs of recrystallization or precipitation during storage, do not cause irritation and provides patient compliance.
[0042] The term “aqueous based” as used herein refers to the composition which is substantially free of lower alcohol(s), and comprises aforementioned carrier system.
[0043] The term “hair growth promoting agents” as used herein refers to the agents useful for treating hair/scalp, or promoting hair growth or treating hair loss or such associated conditions. This term is also associated with stimulating the hair or hair follicles, maintaining or increasing the growth of a hair, an increase in the number of active hair follicles, an increase in the length or diameter of the hair shaft, an increase in the total quantity of hair, an increase in the thickness of hair, an increase in the number of terminal hairs, an increase in the length of one or more hair shafts, elongation of hair, an increase in the rate of hair shaft elongation, or an increase in the diameter of one or more hair shafts, on a given area of skin. In the present application, this term is interchangeably used with “active”, “active substance” “active agent” or “active ingredient” or “drug”.
[0044] The term “non-irritating” as used herein refers to the absence of development of any signs of irritation or inflammation on the skin or scalp, including, but not limited to, erythema, reddening of the skin, edema, ulcers, swelling, itching, cracking, peeling, blistering and/or an allergic reaction, for at least up to two weeks after the topical administration of the composition of the present application.
[0045] The term “non-greasy” as used herein refers to improved oil control, non-stickiness, pleasant odor, and improved skin feel composition.
[0046] The term “acidifying agent” as used herein refers to substances which are able to create an acidic pH environment within and around the dosage form and therefore increase the solubility and dissolution of the active ingredients which are soluble in acidic pH. The composition of the present application has a pH value in a range of 2 to 7.
[0047] The terms “impurities” or “related substances” as used herein refer to one or more degradation substances arising in the composition during its preparation or its shelf life; or intermediates or by-products occurring in the manufacturing process of the active agents.
[0048] The terms “excipient” or “topically acceptable excipient” or “pharmaceutically acceptable excipient” or “dermatologically acceptable excipient” are used interchangeably to mention any pharmaceutically acceptable material or a component of the topical composition, that is not having any pharmacological effect, which is acceptable for using in topical compositions and does not provide any therapeutic effect, and may contribute to aesthetic properties or any relevant nontherapeutic function of the topical composition. The excipients that are useful in preparing a topical/pharmaceutical composition are generally safe, non-toxic, do not interact with other components of a composition in a deleterious manner, and are acceptable for human or veterinary use. The term "excipient" or a “topically acceptable excipient" as used in the specification includes both one and more than one such excipients.
[0049] The terms “agent”, “excipient”, “ingredient”, “substance” and “compound”, encompass both the singular and plural forms to indicate one or more such agents, excipients, ingredients, substances, or compounds.
[0050] The term “substantially free” as used herein indicates that the specified substance referred to is present in amounts not more than 5% by weight of the total composition or in amounts not more than about 4% by weight of the total composition, or in amounts not more than about 3% by weight of the total composition, or in amounts not more than about 2% by weight of the total composition, or in amounts not more than about 1% by weight of the total composition, or in an amount of about 0.5% by weight of the total composition or completely free of specified substance (i.e.) 0%.
[0051] The terms "reference product" or “commercial composition” or “commercial product” are used interchangeably and refer to an approved topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof. In an aspect, these terms refer to an approved topical composition of minoxidil marketed under the brand name MINTOP FORTE® at 5% strength by Dr. Reddy’s Laboratories, India or any of its later approved pharmaceutical equivalents or its therapeutic equivalents or its bioequivalents.
[0052] The term "minoxidil" as used herein refers to its free base, pharmaceutically acceptable salts such as sulfate, sulfonate, phosphate, phosphonate free acid, etc., all polymorphic forms (amorphous or crystalline), hydrates, anhydrous forms, enantiomers, prodrugs of minoxidil, and/or mixtures thereof.
[0053] The term "adenosine" as used herein refers to its free base, pharmaceutically acceptable salts such as sulfate, phosphate, monophosphate, diphosphate, triphosphate, phophosulfate, etc., acid addition salts, all polymorphic forms (amorphous or crystalline), hydrates, anhydrous forms, enantiomers, prodrugs of adenosine, and/or mixtures thereof.
[0054] The term "pharmaceutically acceptable salt” includes derivatives of the disclosed compounds which are, within the scope of sound medical judgment, suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art. The salt can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by the reaction of the pharmaceutically active substance, having a freebase function, with a suitable organic acid or inorganic acid. Further the term refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salt.
[0055] The term “alopecia” as used herein is meant to comprise the loss of hair, and is intended to mean all the forms of alopecia, namely, androgenic alopecia, acute alopecia or alopecia areata. This term encompasses both male pattern alopecia, also called as “baldness”, and female pattern hair loss. The term alopecia also encompasses various types of alopecia such as alopecia androgenetica, alopecia areata diffusa, alopecia areata, ophiasis, alopecia barbae, alopecia cicatricial, alopecia marginalis, alopecia mucinosa, alopecia partialis, alopecia totalis, alopecia universalis, congenial alopecia, reticular alopecia areata, sisaipho alopecia areata, syphilitic alopecia, and traction alopecia. Androgenic alopecia is characterized by the progressive, diffuse, symmetrical loss of hair from the scalp, typically starts at the frontal end of the scalp and gradually spreads to the vertex.
[0056] The term "androgenic alopecia" refers to an autosomal disorder which begins in puberty in genetically disposed individuals. Androgenic alopecia is also known as hereditary baldness, male pattern baldness, and seborrheic alopecia. Androgenic alopecia may occur in males and females. This term encompasses both male pattern alopecia also called as “baldness”, and female pattern hair loss.
[0057] The term "substantially free of propellant(s)" or "propellant-free" or "free of propellant(s)" as used herein indicates that the compositions are not delivered and/or not prepared using any of the commonly used aerosol propellants, such as fluorochloro hydrocarbons, hydrocarbons, compressed gases, and the like.
[0058] The term "lower alcohol" as used herein refers to an alcohol with 10 carbon atoms or less. In an aspect, this term refers to alcohols with 3 carbon atoms or less. In another aspect, it refers to monohydric lower alcohols with 3 carbon atoms or less. In another aspect, it refers to aliphatic monohydric lower alcohols with 3 carbon atoms or less such as methanol, ethanol, propanol, isopropanol and the like.
[0059] The term “stability” or “stable” as used herein, includes both chemical stability and physical/polymorphic stability of the topical composition of the present application, wherein said composition remains within the established specifications to maintain its identity, strength, quality and purity throughout the storage, retest or expiry period and do not change or decompose due to internal reaction, or due to the effects of oxygen, heat, light, moisture or pressure; and wherein the drug is present in an amount of at least about 95% to about 100% of the originally specified amount and total impurity of not more than about 2.0% for at least about 3 months upon storage at 25°C / 60% relative humidity (RH), 30°C / 65% RH or at 40°C / 75% RH.
[0060] In an embodiment, the present application relates to an aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent.
[0061] In an aspect of the above embodiment, said agents are present in a ratio of about 1:0.2 to about 1:2.
[0062] In another embodiment, the present application relates to an aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent, wherein said agents are present in a ratio of about 1:0.2 to about 1:2, preferably in a ratio of about 1:0.3 to about 1:1.5.
[0063] In an aspect of the above embodiments, said composition is substantially free of lower alcohol(s).
[0064] In another embodiment, the present application relates to an aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent, wherein said composition is substantially free of lower alcohol(s).
[0065] In another embodiment, the present application relates to a topical composition comprising one or more hair growth promoting agents and at least one acidifying agent, wherein said agents are present in a ratio of about 1:0.2 to about 1:2, preferably in a ratio of about 1:0.3 to about 1:1.5 and said composition is substantially free of lower alcohol(s).
[0066] In an aspect of the above embodiments, said hair growth promoting agents are selected from minoxidil, adenosine, finasteride, dutasteride, ketoconazole, spironolactone, alfatradiol or flutamide, and their pharmaceutically acceptable salts, esters, hydrates, and other derivatives thereof.
[0067] Hair growth promoting agents may also include one or more vitamins (water soluble or fat soluble or both) eg. Biotin, D-panthenol, niacinamide; herbal extracts and dietary supplements, and their pharmaceutically acceptable salts, esters, hydrates, and other derivatives thereof.
[0068] In an embodiment, the present application relates to an aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent, wherein said hair growth promoting agents are selected from minoxidil, adenosine, finasteride, dutasteride, ketoconazole, spironolactone, alfatradiol or flutamide, and their pharmaceutically acceptable salts, esters, hydrates, and other derivatives thereof.
[0069] In an aspect of the above embodiments, said hair growth promoting agents comprise minoxidil or a pharmaceutically acceptable salt thereof.
[0070] In an embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent.
[0071] In an aspect of the above embodiment, said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[0072] In an embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2, preferably in a ratio of about 1:0.3 to about 1:1.5.
[0073] In an aspect of the above embodiment, said composition is substantially free of lower alcohol(s).
[0074] In an embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said composition is substantially free of lower alcohol(s).
[0075] In an aspect of the above embodiments, said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2, preferably in a ratio of about 1:0.3 to about 1:1.5 and said composition is substantially free of lower alcohol(s).
[0076] In another embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2, and wherein said composition is substantially free of lower alcohol(s).
[0077] In an aspect of the above embodiments, said composition further comprises adenosine or a pharmaceutically acceptable salt thereof.
[0078] In an embodiment, the present application relates to an aqueous based non-irritating and non-greasy topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said composition further comprises adenosine or a pharmaceutically acceptable salt thereof.
[0079] In an aspect of the above embodiment, said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[0080] In another embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2, preferably in a ratio of about 1:0.3 to about 1:1.5.
[0081] In an aspect of the above embodiments, said composition is substantially free of lower alcohol(s).
[0082] In an embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said composition is substantially free of lower alcohol(s).
[0083] In another embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2, preferably in a ratio of about 1:0.3 to about 1:1.5 and wherein said composition is substantially free of lower alcohol(s).
[0084] In an embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[0085] In another embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said composition is substantially free of lower alcohol(s).
[0086] In yet another embodiment, the present application relates to an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2, and wherein said composition is substantially free of lower alcohol(s).
[0087] In certain aspects of the above embodiments, said minoxidil is present in an amount from about 0.5% to about 20%, based on the total volume of the composition.
[0088] In another aspect of the above embodiments, said minoxidil is present in an amount from about 1% to about 10%, based on the total volume of the composition.
[0089] In another aspect of the above embodiments, said minoxidil is present in an amount from about 2% to about 10%, based on the total volume of the composition.
[0090] In another aspect of the above embodiments, said minoxidil is present in an amount from about 5% to about 10%, based on the total volume of the composition.
[0091] In an embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent.
[0092] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[0093] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said composition is substantially free of lower alcohol(s).
[0094] In yet another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2, and wherein said composition is substantially free of lower alcohol(s).
[0095] In one aspect of the above embodiments, said minoxidil is present in an amount of about 0.5%, 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about 15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, or about 20%.
[0096] In some aspects of the above embodiments, said composition further comprises from about 0.01% to about 10% adenosine or a pharmaceutically acceptable salt thereof.
[0097] In certain aspects of the above embodiments, said adenosine is present in an amount from about 0.01% to about 10%, based on the total volume of the composition.
[0098] In another aspect of the above embodiments, said adenosine is present in an amount from about 0.05% to about 5%, based on the total volume of the composition.
[0099] In another aspect of the above embodiments, said adenosine is present in an amount from about 0.1% to about 5%, based on the total volume of the composition.
[00100] In another aspect of the above embodiments, said adenosine is present in an amount from about 0.5% to about 5%, based on the total volume of the composition.
[00101] In another aspect of the above embodiments, said adenosine is present in an amount from about 1% to about 5%, based on the total volume of the composition.
[00102] In an embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, from about 0.01% to about 10% adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent.
[00103] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, from about 0.01% to about 10% adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[00104] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, from about 0.01% to about 10% adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said composition is substantially free of lower alcohol(s).
[00105] In one aspect of the above embodiments, said adenosine is present in an amount of about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10%.
[00106] In certain aspects, said acidifying agent is present in an amount from about 0.5% to about 20%, based on the total volume of the composition.
[00107] In another aspect of the above embodiments, said acidifying agent is present in an amount from about 1% to about 20%, based on the total volume of the composition.
[00108] In another aspect, the amount of said acidifying agent is not less than about 2%, based on the total volume of the composition, wherein said composition comprises at least about 2% of minoxidil or a pharmaceutically acceptable salt thereof.
[00109] In another aspect, the amount of said acidifying agent is not less than about 5%, based on the total volume of the composition, wherein said composition comprises at least about 5% of minoxidil or a pharmaceutically acceptable salt thereof.
[00110] In another aspect, the amount of said acidifying agent is not less than about 10%, based on the total volume of the composition, wherein said composition comprises at least about 10% of minoxidil or a pharmaceutically acceptable salt thereof.
[00111] Suitable examples of acidifying agent that may be used in the present application include, but are not limited to, citric acid, citric acid anhydrous, citric acid monohydrate, DL-lactic acid, DL-malic acid, DL-tartaric acid, fumaric acid, L-malic acid, L-tartaric acid, salicylic acid, glycol acid, potassium acid tartrate, potassium citrate, potassium DL-bitartarate, potassium gluconate, sodium lactate, sodium L-tartrate, sodium citrate, ascorbic acid, sorbic acid, methane sulfonic acid, or any combinations thereof.
[00112] In an embodiment, the present application relates to an aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent, wherein said acidifying agent is present in an amount from about 0.5% to about 20%, based on the total volume of the composition.
[00113] In some aspects of the above embodiments, said acidifying agent is citric acid.
[00114] In some aspects of the above embodiments, said acidifying agent is lactic acid.
[00115] In some aspects of the above embodiments, said acidifying agent is malic acid.
[00116] In some aspects of the above embodiments, said acidifying agent is tartaric acid.
[00117] In some aspects of the above embodiments, said acidifying agent is fumaric acid.
[00118] In some aspects of the above embodiments, said acidifying agent is methane sulfonic acid.
[00119] In some aspects of the above embodiments, said acidifying agent is sorbic acid.
[00120] In some aspects of the above embodiments, the pH of the said composition ranges from about 2 to about 7.
[00121] In some aspects of the above embodiments, the pH of the said composition ranges from about 2.5 to about 6.5.
[00122] In some aspects of the above embodiments, the pH of the said composition ranges from about 3 to about 6.
[00123] In some aspects of the above embodiments, the pH of the said composition ranges from about 3 to about 5.
[00124] In some aspects of the above embodiments, the pH of the said composition ranges from about 3 to about 4.5.
[00125] In some aspects of the above embodiments, the pH of the said composition ranges from about 3 to about 4.
[00126] In some aspects of the above embodiments, the pH of the said composition ranges from about 3.5 to about 6.5.
[00127] In some aspects of the above embodiments, the pH of the said composition ranges from about 3.5 to about 5.5.
[00128] In some aspects of the above embodiments, the pH of the said composition ranges from about 3.5 to about 4.5.
[00129] In one embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof and from about 0.5% to about 20% of an acidifying agent.
[00130] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, and from about 0.5% to about 20% of acidifying agent, based on the total volume of the composition, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[00131] In some aspects of the above embodiments, said composition further comprises from about 0.01% to about 10% adenosine or a pharmaceutically acceptable salt thereof.
[00132] In some embodiments, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, from about 0.01% to about 10% adenosine or a pharmaceutically acceptable salt thereof, and from about 0.5% to about 20% of an acidifying agent, based on the total volume of the composition, wherein said minoxidil and the acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[00133] In certain aspects of the above embodiments, said composition is substantially free of lower alcohol(s).

[00134] In one aspect of the above embodiments, the topical composition of the present application comprises a carrier system comprising:
i. at least one aprotic solvent and
ii. at least one protic solvent.

[00135] In another aspect of the above embodiments, the topical composition of the present application comprises a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer.
[00136] In an embodiment, the present application relates to an aqueous based topical composition comprising one or more hair growth promoting agents, at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer.

[00137] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent and
ii. at least one protic solvent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.3 to about 1:1.5 and said composition is substantially free of lower alcohol.

[00138] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.

[00139] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, from about 0.01% to about 10% of adenosine or a pharmaceutically acceptable salt thereof, at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent and
ii. at least one protic solvent wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.3 to about 1:1.5 and said composition is substantially free of lower alcohol.

[00140] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, from about 0.01% to about 10% of adenosine or a pharmaceutically acceptable salt thereof, at least one acidifying agent, and a carrier system comprising:
iii. at least one aprotic solvent,
iv. at least one protic solvent,
v. at least one solvent having an alkane diol group and
vi. at least one solubilizer, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.

[00141] Suitable examples of aprotic solvent that may be used in the present application include, but are not limited to, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), dimethyl acetamide (DMAC), dimethyl isosorbide (DMI), N-methyl-2-pyrrolidone (NMP), hexamethyl phosphoramide (HMPA) or any combinations thereof.
[00142] In another aspect, said aprotic solvent is present in an amount from about 5% to about 60%, based on the total volume of the composition.
[00143] In an aspect of the above embodiments said aprotic solvent is dimethyl sulfoxide (DMSO).
[00144] In an aspect of the above embodiments said aprotic solvent is dimethyl formamide (DMF).
[00145] Suitable examples of protic solvent that may be used in the present application include, but are not limited to, water, glycerol, higher chain alcohols or glycols such as hexylene glycol, polyethylene glycol, polyols, polymers and derivatives (e.g. esters, alkyl esters, ethers) such as diethylene glycol monoethylether and ethyl acetate), acids such as acetic acid and formic acid, bases such as ammonia, ketones such as methyl isobutyl ketone and acetone, or nitriles such as acetonitrile, or any combinations thereof.
[00146] In another aspect, said protic solvent is present in an amount not more than about 40%, based on the total volume of the composition.
[00147] In an aspect of the above embodiments said protic solvent is water.
[00148] In another aspect of the above embodiments said protic solvent is glycerol.
[00149] In another aspect of the above embodiments said protic solvent is hexylene glycol.
[00150] In another aspect of the above embodiments said protic solvent is a polyethylene glycol.
[00151] Suitable examples of solvent having an alkane diol group containing 4 or more carbon atoms that may be used in the present application include, but are not limited to, 1,3-butanediol (butylene glycol), 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2-pentanediol (pentylene glycol), 1,5-pentanediol, 2-methyl-2,4-pentanediol (hexylene glycol), hexanediol, 1,6-hexanediol, 1,2-hexanediol, , 2-ethyl-1,3-hexanediol (ethyl hexanediol), 1,2-octanediol (caprylyl glycol), octanediol, 1,2-decanediol (decylene glycol), 1,10-decanediol, methylpropanediol, butyl ethyl propanediol, isopentyldiol, or any suitable combinations thereof.
[00152] In another aspect, said solvent having an alkane diol group is present in an amount from about 5% to about 15%, based on the total volume of the composition.
[00153] In an aspect of the above embodiments, said solvent having an alkane diol group is butylene glycol.
[00154] In an aspect of the above embodiments, said solvent having an alkane diol group is pentylene glycol.
[00155] In an aspect of the above embodiments, said solvent having an alkane diol group is hexylene glycol.
[00156] Suitable examples of solubilizer that may be used in the present application include, but are not limited to, polyethylene glycols (PEG) of various grades such as PEG 200, PEG 300, PEG 400, PEG, 600, PEG 1000, PEG 1500, and PEG 4000, aliphatic alcohols/ aromatic alcohols containing 4 or more carbon atoms, one or more of glycerols, polyoxyl castor oil, polyoxyl hydrogenated castor oil, or any suitable combinations thereof.
[00157] In another aspect, said solubilizer is present in an amount from about 10% to about 35%, based on the total volume of the composition.
[00158] In an aspect of the above embodiments, said solubilizer is PEG 400.
[00159] In another aspect of the above embodiments, said solubilizer is PEG 300.
[00160] In another aspect of the above embodiments, said solubilizer is PEG 400.
[00161] In another aspect of the above embodiments, said solubilizer is PEG 600.
[00162] In another aspect of the above embodiments, said solubilizer is PEG 1000.
[00163] In another aspect of the above embodiments, said solubilizer is PEG 1500.
[00164] In another aspect of the above embodiments, said solubilizer is PEG 4000.
[00165] In one aspect of the above embodiments, the topical composition of the present application may further comprise at least one penetration enhancing agent.
[00166] A “penetration enhancing agent” or “permeation enhancing agent” or “permeation enhancer” is a compound used to enhance the penetration rate of drugs through the skin membrane, such as by temporarily diminishing the impermeability of the skin or membrane.
[00167] Suitable examples of penetration enhancing agent that may be used in the present application include, but are not limited to, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether; dialkyl ethers and dialkyl ether esters such as ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, and ethylene glycol methyl ether acetate, ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether acetate, oleic acid, oleyl alcohol, limonene, or any suitable combinations thereof.
[00168] In another aspect, said penetration enhancing agent is present in an amount from about 5% to about 20%, based on the total volume of the composition.
[00169] In an aspect of the above embodiments, said penetration enhancing agent is diethylene glycol monoethyl ether.
[00170] In an aspect of the above embodiments, said penetration enhancing agent is diethylene glycol monomethyl ether.
[00171] In an aspect of the above embodiments, said penetration enhancing agent is ethylene glycol monomethyl ether.
[00172] In an aspect of the above embodiments, said penetration enhancing agent is ethylene glycol monoethyl ether.
[00173] In an aspect of the above embodiments, said penetration enhancing agent is ethylene glycol methyl ether acetate.
[00174] In an aspect of the above embodiments, said penetration enhancing agent is ethylene glycol monoethyl ether acetate.
[00175] In certain embodiments, the present application relates to an aqueous based topical composition comprising one or more hair growth promoting agents, at least one acidifying agent, at least one penetration enhancing agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer.
[00176] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5 % to about 20% minoxidil or a pharmaceutically acceptable salt thereof, at least one acidifying agent, at least one penetration enhancing agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer.
[00177] In another embodiment, the present application relates to an aqueous based topical composition comprising from about 0.5 % to about 20% minoxidil or a pharmaceutically acceptable salt thereof, at least one acidifying agent, at least one penetration enhancing agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[00178] In some embodiments, the present application relates to an aqueous based topical composition comprising from about 0.5 % to about 20% minoxidil or a pharmaceutically acceptable salt thereof, from about 0.01% to about 10% of adenosine or a pharmaceutically acceptable salt thereof, at least one acidifying agent, at least one penetration enhancing agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2
[00179] In an aspect of the above embodiments, the said composition is substantially free of lower alcohol(s).
[00180] The composition of the present application can be formulated in any suitable topical dosage form including, but not limited to, solutions, lotions, suspensions, dispersions, emulsions, gels, foams, sprays, aerosols, ointments, creams, droppers, mousse, and the like.
[00181] In an aspect of the above embodiments, said composition is a topical solution.
[00182] In an aspect of the above embodiments, said composition is a topical lotion.
[00183] In an aspect of the above embodiments, said composition is a topical suspension.
[00184] In an aspect of the above embodiments, said composition is a topical dispersion.
[00185] In an aspect of the above embodiments, said composition is a topical emulsion.
[00186] In an aspect of the above embodiments, said composition is a topical gel.
[00187] In an aspect of the above embodiments, said composition is a topical spray.
[00188] In an aspect of the above embodiments, said composition is a topical foam.
[00189] In an aspect of the above embodiments, said composition is a topical aerosol.
[00190] In an aspect of the above embodiments, said composition is a topical dropper.
[00191] In certain aspects, the composition of the present application is substantially free of propellant(s).
[00192] In another aspect, the composition of the present application may further comprise one or more topically acceptable pharmaceutical excipients.
[00193] The topically acceptable excipients that may be used in the present application include, but not limited to, preservatives, humectants, moisturizers, anti-oxidants, de-tackifying agents, surfactants/wetting agents, conditioning agents, proteins, fragrances or combinations thereof.
[00194] Suitable examples of preservatives, that may be used in the present application include, but are not limited to, aliphatic or aromatic alcohols; glycols; parahydroxybenzoic acid derivatives (e.g. parabens); Vitamin E or its derivatives, ethyl alcohol, benzyl alcohol, propylene glycol, glycerin, benzoic acid/sodium benzoate, sorbic acid, methylparaben, propylparaben, benzalkonium chloride or combinations thereof.
[00195] Suitable examples of de-tackifying agents that may be used in the present application include, but are not limited to, silanes; methicones; alkyl/aryl lactates or combinations thereof.
[00196] Surfactants/wetting agents may be of anionic, cationic, nonionic, zwitterionic, amphoteric or ampholytic types.
[00197] Suitable non-limiting examples of surfactants that may be used in the present application include, but are not limited to, polyethoxylated fatty acids, fatty acid diesters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters/ polysorbates; polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene- polyoxypropylene block copolymers, sorbitan fatty acid esters and lower alcohol fatty acid esters; polyoxyethylene fatty acid esters, such as Myrj®; polyoxyethylene alkylyl ethers, such as poly oxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, sodium dodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide, docusate sodium, cetyl trimethyl ammonium bromide; octoxynol; N,N-dimethyldodecylamine-N-oxide; hexadecyltrimethylammonium bromide; polyoxyl 10 lauryl ether; bile salts (sodium deoxycholate, sodium cholate); methicones; polyoxyl castor oil; nonylphenol ethoxylated cyclodextrins; lecithins; methylbenzethonium chloride; glycol esters of fatty acids, carboxylic amides, monoalkanolamine condensates, polyoxyethylene fatty acid amides, quaternary ammonium salts, polyoxyethylene alkyl and alicyclic amines or combinations thereof.
[00198] In one aspect, said one or more surfactants/wetting agents is present in an amount from about 0.1% w/v to about 10% w/v.
[00199] In another aspect, the topical composition of present application as described in above embodiments is stable for at least about 3 months, and has not more than about 2% of the total impurities, when subjected to stability study conditions of 40°C/75% RH.
[00200] In another aspect, the topical composition of present application as described in above embodiments is stable for at least about 3 months, and has not more than about 2% of the total impurities, when subjected to stability study conditions of 30°C/65% RH.
[00201] In another aspect, the topical composition of present application as described in above embodiments is stable for at least about 3 months, and has not more than about 2% of the total impurities, when subjected to stability study conditions of 30°C/75% RH.
[00202] In another aspect, the topical composition of present application as described in above embodiments is stable for at least about 3 months, and has not more than about 2% of the total impurities, when subjected to stability study conditions of 25°C/60% RH.
[00203] In another aspect, the topical composition of present application as described in above embodiments is stable for at least about 3 months, and having no signs of recrystallization or precipitation, when subjected to freezing conditions of about 2°C to about 8°C.
[00204] In an embodiment, the present application relates to a method of treating alopecia or androgenic alopecia comprising topically administering the composition of present application as described in any of the above embodiments.
[00205] In another embodiment, the present application relates to a method of treating alopecia or androgenic alopecia, said method comprising topically administering an aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent.
[00206] In another embodiment, the present application relates to a method of treating alopecia or androgenic alopecia, said method comprising topically administering an aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent, wherein said agents are present in a ratio of about 1:0.2 to about 1:2.
[00207] In another embodiment, the present application relates to a method of treating alopecia or androgenic alopecia, said method comprising topically administering an aqueous based topical composition comprising one or more hair growth promoting agents, at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group, and
iv. at least one solubilizer.
[00208] In another embodiment, the present application relates to a method of treating alopecia or androgenic alopecia, said method comprising topically administering an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group, and
iv. at least one solubilizer, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[00209] In another embodiment, the present application relates to a method of treating alopecia or androgenic alopecia, said method comprising topically administering an aqueous based topical composition comprising from about 0.5% to about 20% minoxidil or a pharmaceutically acceptable salt thereof, from about 0.01% to about 10% of adenosine or a pharmaceutically acceptable salt thereof, at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group, and
iv. at least one solubilizer, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[00210] In an aspect of the above embodiments, the topical composition of the present application may further comprise at least one penetration enhancing agent.
[00211] In certain aspects of the above embodiments, the topical composition of the present application may have enhanced skin penetration of the active agent(s) with minimal systemic absorption.
[00212] In another aspect of the above embodiments, the topical composition of the present application have at least about 30% lesser systemic absorption compared to the commercially available product.
[00213] In yet another aspect of the above embodiments, the topical composition of the present application upon topical administration, does not show significant plasma concentration compared to the commercially available product.
[00214] In one aspect of the above embodiments, the topical pharmaceutical composition of the present application can be used in combination with any other agents for the treatment of alopecia or androgenic alopecia.
[00215] In yet another aspect of the above embodiments, the topical composition of the present application is substantially non-irritant to skin.
[00216] In yet another aspect of the above embodiments, the topical composition of the present application is substantially non-greasy in nature.
[00217] The topical composition of the present application may be prepared in any conventional known methods or otherwise effective techniques, suitable for making the desired composition.
[00218] In an embodiment, the present application relates to a process of preparing an aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent.
[00219] In an aspect of the above embodiment, said agents are present in a ratio of about 1:0.2 to about 1:2.
[00220] In another embodiment, the present application relates to a process of preparing an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent.
[00221] In another embodiment, the present application relates to a process of preparing an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said agents are present in a ratio of about 1:0.2 to about 1:2.
[00222] In another embodiment, the present application relates to a process of preparing an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer,
wherein said agents are present in a ratio of about 1:0.2 to about 1:2.
[00223] In an aspect of the above embodiments, the present application relates to a process of preparing an aqueous based topical composition comprising one or more hair growth promoting agents, wherein said process comprises steps of:
a) dissolving acidifying agent in aqueous solvent,
b) adding one or more excipients to the solution of step a,
c) adding one or more hair growth promoting agents to the solution of step b,
d) the mixture of step c, is mixed well and dispensed in suitable container.
[00224] In an aspect of the above embodiments, the present application relates to a process of preparing an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, wherein said process comprises steps of:
a) dissolving acidifying agent in aqueous solvent,
b) adding one or more excipients to the solution of step a,
c) adding minoxidil or a pharmaceutically acceptable salt thereof to the solution of step b,
d) the mixture of step c, is mixed well and dispensed in suitable container.
[00225] In another embodiment, the present application relates to a process of preparing an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent.
[00226] In another embodiment, the present application relates to a process of preparing an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[00227] In another embodiment, the present application relates to a process of preparing an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, and at least one acidifying agent, and a carrier system comprising:
i. at least one aprotic solvent,
ii. at least one protic solvent,
iii. at least one solvent having an alkane diol group and
iv. at least one solubilizer,
wherein said minoxidil and acidifying agent are present in a ratio of about 1:0.2 to about 1:2.
[00228] In an aspect of the above embodiments, the present application relates to a process of preparing an aqueous based topical composition comprising minoxidil or a pharmaceutically acceptable salt thereof, adenosine or a pharmaceutically acceptable salt thereof, wherein said process comprises steps of:
a) dissolving adenosine in suitable solvent,
b) dissolving acidifying agent in aqueous solvent,
c) mixing the solution of step a and step b,
d) adding one or more excipients to the solution of step c,
e) adding minoxidil or a pharmaceutically acceptable salt thereof to the solution of step d,
f) the mixture of step e, is mixed well and dispensed in a suitable container.
[00229] The topical compositions of the present application can be part of a kit or device and may be filled into laminated tubes, jars, bottles, pumps, aerosol containers, and any other forms of packaging that facilitate application topically. The compositions are meant to be applied topically, either manually or by using a convenient applicator, for patient compliance and ease of application. The dose, number, and frequency of applications can be determined by a person skilled in the art of treating conditions, such as a physician, a dermatologist, and the like.
[00230] Laminated tubes may be used for packaging. The features and advantages of laminated tubes include ability to retain smoothness, flexibility and softness, increase in product shelf life, excellent barrier properties, excellent seal ability, resistance to print bleeding, tamper evident closures with nozzle seals available, and hot foil stamping. HDPE tubes may also be used for packaging. Examples are pre-printed monolayer plastic tubes made of LDPE/LLDPE blends by extrusion processes and fitted with snap-on flip caps made up of polypropylene.
[00231] The present application is further illustrated by the examples which are provided merely to be exemplary of the pharmaceutical composition described above and do not limit the scope of the application. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.
[00232] The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the present invention, and not to be construed as limiting the application. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the present invention.

EXAMPLES
[00233] Examples 1-8:
[00234] The topical composition comprising minoxidil and/or adenosine or a pharmaceutically acceptable salt thereof, was prepared as given in Table 1.
Table 1
S. No. Ingredients % w/v
Ex:
1 Ex: 2 Ex: 3 Ex: 4 Ex: 5 Ex: 6 Ex: 7 Ex: 8 Mintop Forte®
1 Minoxidil 2 5 5 5 5 2 5 10 5
2 Adenosine 1 1 - - - - - -
3 PEG 400 21.5 10 10 QS to 100 ml QS to 100 ml 21.5 17 QS to 100 ml -
4 Benzyl alcohol 2 2 2 2 2 2 2 2 -
6 Citric acid monohydrate 2 5 5 5 5 2 5 5 -
7 Hexylene glycol 6 12 12 10 10 6 10 12 -
8 Transcutol-P 10 10 10 10 10 10 10 -
9 DMSO 45 45 45 40 40 45 40 40 -
11 Alcohol - - - - - - 42
12 Propylene glycol - - - - - - - - 41.5
13 Fragrance 1 1 1 0.5 0.5 1 0.5 0.5 0.5
Oleic acid - - - - - - 5
14 Methyl Paraben - - - - - - - 0.15
15 Propyl Paraben - - - - - - - 0.05
16 Di-sodium EDTA - - - - - - - 0.0175
17 Methane Sulfonic acid - 2
18 Sorbic acid - - - - - - - -
19 Purified Water QS to 100 ml QS to 100 ml QS to 100 ml 5.5 5.5 QS to 100 ml 5.5 5.5 QS to 100 ml

Transcutol-P* - diethylene glycol monoethylether
[00235] Procedure:
a. Citric acid monohydrate was solubilized in water,
b. other liquid excipients including PEG 400, benzyl alcohol, transcutol-P, DMSO and hexylene glycol were added to the solution of step a and mixed.,
c. minoxidil was added to the solution mixture of step b,
d. fragrance was added to the solution of step c, and
e. the mixture of step d was stirred to obtain clear transparent solution
In adenosine-included compositions, adenosine was solubilized in DMSO followed by the addition of citric acid solution, the addition of other liquid excipients, which was further followed by the addition of minoxidil and fragrance and stirred until clear transparent solution was obtained.

[00236] Example 9:
[00237] The dermal tolerability of the topical minoxidil compositions of Example 5 and Example 7 was assessed in New Zealand White Rabbits.
[00238] There was no mortality or any clinical signs of toxicity during the treatment period. The composition of Example 5 did not cause any signs of dermal irritation upon repeated topical application for 22 days, while the composition of Example 7 had shown significant signs of irritation including erythema, edema and skin flaking, and the treatment was discontinued after 7 days. The study results can be seen in Fig 3.

[00239] Example 10:
[00240] The topical test compositions comprising minoxidil (Example 3) and, combination of minoxidil and adenosine (Example 2), were subjected to skin penetration studies in comparison with the commercial product MINTOP FORTE® (from Dr. Reddy’s Laboratories, India) using ‘Franz Diffusion Cells’ invitro diffusion study apparatus. The skin penetration of the drug from the test compositions of Examples 3 and 2, was found to be increased by at least about 50% and about 80% respectively, when compared to the commercial product. The average percentages of drugs escaped into the receptor fluid (RF) from the test compositions were found to be reduced by at least about 40% and about 58% for Examples 3 and 2 respectively, when compared to commercial product. This suggests that the systemic migration of the test compositions is considerably less than the commercial product. Fig. 1 and Fig. 2 respectively represent comparative RF concentrations and skin penetration of the drug from test compositions and the commercial product.

[00241] Example 11:
[00242] The topical minoxidil test compositions of Examples 11A, 11B and 11C as shown in Table 2, were studied for the impact of varying concentrations of acidifying agent on solubilization or recrystallization of the active agent. No crystal formation was observed after 4 days, in compositions comprising = 3% acidifying agent.
Table 2
S. No. Ingredients % w/v
Example 11A Example 11B Example 11C
1 Minoxidil 5 5 5
2 PEG 400 11 12 13
3 Benzyl alcohol 2 2 2
4 Citric acid monohydrate 4 3 2
5 Hexylene glycol 12 12 12
6 Transcutol-P 10 10 10
7 DMSO 45 45 45
9 Fragrance Everest 1 1 1
10 Purified water 19 19 19
Initial Observation Minoxidil Solubilized Minoxidil Solubilized Minoxidil Not soluble
Observation after 4 Days No Crystals No crystals -
Transcutol-P* - diethylene glycol monoethylether
[00243] Example 12:
[00244] The topical minoxidil compositions comprising minoxidil was prepared according to Examples 2, 3 and 6 were subjected to accelerated stability evaluation for a period of 3 months under storage conditions at 40°C /75% RH and 30°C/65%RH. At the end of 3 months, the compositions were tested for various parameters and the results are shown in Table 3. It was observed that the total impurities did not exceed 1% and the drug content and other parameters were found to be maintained well within the limits.
Table 3
Storage Condition
Example 2 Example 3 Example 6
Assay of Minoxidil Related Substances pH Assay Related Substances pH Assay Related Substances pH
Assay of Adenosine Total Impurities Minoxidil Total Impurities Adenosine Single Major Unknown impurity Total Impurities Single Major Unknown impurity Total Impurities
Acceptance criteria 90.0-
110.0% 90.0-
110.0% NMT 0.2% NMT 2% 2.5-7.0 90.0-
110.0% NMT 0.2% NMT 2% 2.5-7.0 90.0-
110.0% NMT 0.2% NMT 2% 2.5-7.0
Initial 99.7 97.2 0 0 3.81 100.41 0 0 3.69 101 0 0 3.72
1 M 40°C/75%RH 100.1 98.1 0.0 0.30 3.97 99.9 0.04 0.04 3.7 101.3 0.13 0.13 3.73
2 M 40°C/75%RH 98.5 96.8 0.0 0.40 3.79 96.97 0.03 0.03 3.74 96.17 0.03 0.03 3.76
3 M 40°C/75%RH 98.9 98.0 0.0 0.46 3.89 98.26 0.04 0.04 3.74 96.54 0.04 0.04 3.73
3 M 30°C/65%RH 100.6 98.5 0.0 0.25 3.81 97.95 ND 0 3.74 97.97 ND 0 3.76

[00245] While several particular forms of the application have been illustrated and described, it will be apparent that various modifications and combinations of the application detailed in the text can be made without departing from the spirit and scope of the application.
,CLAIMS:We Claim:

1. An aqueous based topical composition comprising one or more hair growth promoting agents and at least one acidifying agent, wherein said agents are present in a ratio of about 1:0.3 to about 1:1.5 and said composition is substantially free of lower alcohol.
2. The composition of claim 1, wherein said hair growth promoting agents are selected from minoxidil, adenosine, finasteride, dutasteride, ketoconazole, spironolactone, alfatradiol or flutamide, and their pharmaceutically acceptable salts, esters, hydrates, and any suitable combinations thereof.
3. The composition of claim 2, wherein said hair growth promoting agents comprise minoxidil or pharmaceutically acceptable salts thereof.
4. The composition of claim 3, wherein said minoxidil is present in an amount ranging from about 0.5% to about 20% by weight, based on the total volume of the composition.
5. The composition of claim 2, wherein said hair growth promoting agents comprise adenosine or pharmaceutically acceptable salts thereof.
6. The composition of claim 5, wherein said adenosine is present in an amount ranging from about 0.01% to about 10% by weight, based on the total volume of the composition.
7. The composition of claim 1, wherein said one or more hair growth promoting agents are minoxidil and adenosine, or their pharmaceutically acceptable salts, esters, hydrates thereof.
8. The composition of claim 1, wherein said acidifying agent is selected from citric acid, citric acid anhydrous, citric acid monohydrate, DL-lactic acid, DL-malic acid, DL-tartaric acid, fumaric acid, L-malic acid, L-tartaric acid, salicylic acid, glycol acid, potassium acid tartrate, potassium citrate, potassium DL-bitartarate, potassium gluconate, sodium lactate, sodium L-tartrate, sodium citrate, ascorbic acid, or any combinations thereof.

9. The composition of claim 1, wherein said acidifying agents is present in an amount ranging from about 0.5% to about 20% by weight, based on the total volume of the composition.
10. The composition of claim 1, wherein said composition comprises a carrier system comprising:
i. at least one aprotic solvent and
ii. at least one protic solvent.
11. The composition of claim 10, wherein said aprotic solvent is selected from dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), dimethyl acetamide (DMAC), dimethyl isosorbide (DMI), N-methyl-2-pyrrolidone (NMP), hexamethyl phosphoramide (HMPA) or any combinations thereof.
12. The composition of claim 11, wherein said aprotic solvent is present in an amount ranging from about 15% to about 60% by weight, based on the total volume of the composition.
13. The composition of claim 10, wherein said protic solvent is selected from water, glycerol, hexylene glycol, polyethylene glycol, diethylene glycol monoethylether and ethyl acetate, higher chain alcohols, polyols, polymers and derivatives, acetic acid, formic acid, ammonia, ketones, methyl isobutyl ketone and acetone, or nitriles such as acetonitrile, or any combinations thereof.
14. The composition of claim 13, wherein said aprotic solvent is present in an amount not more than about 40% by weight, based on the total volume of the composition.
15. The composition of claim 10, wherein the said carrier system further comprising at least one solvent having an alkane diol group and at least one solubilizer.
16. The composition of claim 15, wherein said solvent having an alkane diol group containing 4 or more carbon atoms is selected from 1,3-butanediol (butylene glycol), 1,2-butanediol, 2,3-butanediol, 1,4-butanediol, 1,2-pentanediol (pentylene glycol), 1,5-pentanediol, 2-methyl-2,4-pentanediol (hexylene glycol), hexanediol, 1,6-hexanediol, 1,2-hexanediol, , 2-ethyl-1,3-hexanediol (ethyl hexanediol), 1,2-octanediol (caprylyl glycol), octanediol, 1,2-decanediol (decylene glycol), 1,10-decanediol, methylpropanediol, butyl ethyl propanediol, isopentyldiol, or any combinations thereof.
17. The composition of claim 15, wherein said solubilizer is selected from polyethylene glycols (PEG) of various grades, aliphatic alcohols or aromatic alcohols containing 4 or more carbon atoms, one or more of glycerols, polyoxyl castor oil, polyoxyl hydrogenated castor oil, or any combinations thereof.
18. The composition of claim 10, wherein said carrier system further comprises at least one penetration enhancing agent.
19. The composition of claim 1, wherein said composition is dispensed in the form of solutions, lotions, suspensions, dispersions, emulsions, gels, foams, sprays, aerosols, ointments, creams, droppers, mousse, and the like.