阅读说明：本技术 度他雄胺的局部用组合物 (Topical composition of dutasteride ) 是由 M·拉金达 T·阿加迪希雷马特 S·雷迪 P·希瓦库马尔 于 2018-06-18 设计创作，主要内容包括：本发明涉及用于防止毛发脱落、雄激素性脱发(AA)和刺激毛发生长的局部施用的组合物,该组合物具有度他雄胺。根据本发明的用于防止毛发脱落和刺激毛发生长的局部施用的组合物提供等同或优越的毛发脱落防止和毛发生长刺激效果,同时使用远远小于常规组合物(口服剂型)的剂量,该常规组合物使用非那雄胺和度他雄胺。(The present invention relates to a composition for topical application having dutasteride for preventing hair loss, Androgenic Alopecia (AA) and stimulating hair growth. The topically applied composition for preventing hair loss and stimulating hair growth according to the present invention provides equivalent or superior hair loss prevention and hair growth stimulation effects while using a much smaller dose than conventional compositions (oral dosage forms) using finasteride and dutasteride.)

1. A topically applied composition for preventing hair loss and stimulating hair growth comprising dutasteride or a pharmaceutically acceptable salt thereof, medium chain triglycerides, castor oil, and ethanol, wherein dutasteride contained in the topical application is administered at a daily dose of about 0.1mg to about 0.5 mg.

2. The composition of claim 1, wherein dutasteride contained in the composition is administered at a daily dose of about 0.1mg to about 0.4 mg.

3. The composition of claim 1, wherein dutasteride contained in the composition is administered at a daily dose of about 0.2 mg.

4. The composition of claim 1, wherein dutasteride is present in an amount of about 0.01 wt% to about 0.06 wt% based on the total weight of the composition.

5. The composition of claim 1, wherein medium chain triglycerides are present in an amount of about 25 wt% to about 35 wt%, based on the total weight of the composition.

6. The composition of claim 1, wherein ethanol is present in an amount from about 25 wt% to about 35 wt%, based on the total weight of the composition.

7. The composition of claim 1, wherein castor oil is present in an amount from about 35 wt% to about 45 wt% based on the total weight of the composition.

8. A topically applied composition for preventing hair loss and stimulating hair growth comprising about 0.01 wt% to about 0.06 wt% dutasteride, about 25 wt% to about 35 wt% medium chain triglycerides, about 25 wt% to about 35 wt% ethanol, and about 35 wt% to about 45 wt% castor oil, based on the total weight of the composition, wherein dutasteride contained in the composition is in an amount to provide a daily dose of about 0.1 to about 0.5 mg.

9. The composition of claim 8, wherein dutasteride contained in the composition is in an amount to provide a daily dose of about 0.2 mg.

10. The composition of claim 8, wherein the composition comprises about 0.022 wt% (equivalent to 0.02% w/v) dutasteride, about 30 wt% medium chain triglycerides, about 30 wt% ethanol, and about 40 wt% castor oil, based on the total weight of the composition.

Technical Field

The present invention relates to topically applied compositions for preventing hair loss, androgenic alopecia and stimulating hair growth comprising a 5 α -reductase inhibitor, especially dutasteride.

Background

According to studies conducted so far, it has been found that causes of hair loss include disorders of endocrine system such as hormonal disorders; excessive sebum formation caused by circulatory diseases (such as autoimmune neurological diseases, blood circulation diseases); nutritional deficiencies in hair roots, allergies, bacterial infections, genetic factors psychological stress, environmental factors (such as atmospheric pollution or food) and aging, among others.

Products sold as hair growth stimulants or hair loss preventives for hair include anagen-inducing effects, anagen-extending effects, 5 α -reductase-inhibiting effects, blood circulation-promoting effects, antiseptic effects, anti-dandruff effects, moisturizing effects, antioxidant effects, and the like, but the effects of preventing hair loss and stimulating hair growth of conventional agents are insufficient.

Male pattern alopecia is dependent on male hormones and is therefore directly related to the amount of male hormones DHT is an enzyme responsible for the conversion of testosterone (male hormones) to Dihydrotestosterone (DHT) DHT is an androgenic compound which causes hyperandrogenic disorders, such as the increase of the prostate of men with increasing age, known as "benign prostatic hyperplasia". another consequence of the increase in the level of DHT includes Androgenic Alopecia (AA), which is commonly referred to as "male pattern baldness". the cause of male pattern alopecia is the synthesis of excess DHT through the action of 5 α -reductase and thus, by inhibiting the activity of 5 α -reductase, it is possible to prevent and treat male pattern alopecia fundamentally and effectively.

Currently, the U.S. food and drug administration has approved two therapies for the treatment of Androgenetic Alopecia (AA) in men, topical minoxidil (minoxidil) and oral finasteride (finasteride), although minoxidil (having the chemical name: 6-piperidin-1-ylpyrimidine-2, 4-diamine 3-oxide) is an arterial vasodilator, finasteride is a class II 5 α -reductase inhibitor.

Minoxidil was developed to lower blood pressure in hypertensive patients, but it is most widely used as a hair growth drug because its use is changed due to side effects on hair growth occurring during use. The mechanism of action of minoxidil has not been clearly elucidated. However, the mechanism of action of minoxidil has been explained by two hypotheses: minoxidil increases blood flow to the hair follicle to cause an increase in blood flow, thereby stimulating hair growth; minoxidil acts directly on the hair follicle epithelium to induce hair growth. However, the hair restorer comprising minoxidil should be applied several times per day to maintain the hair growth effect, which is extremely troublesome and easy to forget. Thus, in many cases, the hair growth effect is not sufficiently obtained due to irregular application and arbitrary interruption of treatment.

Finasteride is a drug that inhibits class II 5 α -reductase, which converts testosterone (a species of male hormone) into dht that causes hair loss-oral finasteride 1mg (which is used for male pattern baldness) causes possible sexual side effects even after discontinuation in use-therefore, the USFDA advises medical professionals and patients' attention-as a result of reviewing the safety database of after-market cases and commercial products reported on the FDA Adverse Event Reporting System (AERS), it was found that some sexual function related adverse effects such as hyposexuality, ejaculation disorder, orgasmic disorder, etc. persist even after discontinuation in use.

Yet another compound of the 5 α -reductase inhibitor class is dutasteride, which has the chemical name (5 α,17 β) -N- {2, 5-bis (trifluoromethyl) phenyl } -3-oxo-4-azaandrost-1-ene-17-carboxamide.

Dutasteride is a synthetic 4-azasteroid, a class I and of the steroid 5 α -reductase (5AR)Selective inhibitors of class II isomers (intracellular enzymes that convert testosterone to 5 α -Dihydrotestosterone (DHT)) and are indicated for the treatment of symptomatic Benign Prostatic Hyperplasia (BPH) in men pharmaceutical products comprising dutasteride as an active ingredient may be used

Commercially available from GlaxoSmithKline (GlaxoSmithKline), which is approved by the USFDA in the form of soft gelatin capsules for oral administration and contains 0.5mg of the active ingredient. Oral dutasteride has been approved by the korean food and drug safety department for the treatment of male pattern baldness (androgenic alopecia) at a dose of 0.5mg once a day.

Dutasteride is a highly lipophilic molecule (Log P ═ 6.8). It is insoluble in water and soluble in ethanol, methanol and polyethylene glycol 400. The absolute bioavailability of oral dutasteride is only about 60% (40% -94%). Some known ways to improve the solubility characteristics and bioavailability of pharmaceutical compounds include salt formation, particle size reduction, pH adjustment, use of surfactants, complexes with cyclodextrins, use of oily formulations, use of self-emulsifying drug delivery systems, formation of co-precipitates with hydrophilic polymers, and co-milling with hydrophilic excipients, among others.

Systemic administration of 5 α -reductase inhibitors inhibits the levels of Dihydrotestosterone (DHT) in the blood, thus presenting the potential for sexual side effects.

U.S. patent publication No.20100048598 discloses a topically applied pharmaceutical composition comprising dutasteride or a pharmaceutically acceptable salt, ester, derivative thereof, and a pharmaceutically acceptable carrier, and optionally one or more other pharmaceutically acceptable excipients. In addition, the us' 598 publication discloses a topically applied pharmaceutical composition comprising 0.5 wt% dutasteride.

The present invention has been made to solve the above-mentioned problems of the prior art, and an object of the present invention is to provide a composition of dutasteride for topical application for preventing hair loss and stimulating hair growth, which has the following advantages

1. It provides hair loss prevention and hair growth stimulation effects that are equal to or higher than those of conventional therapeutic agents (oral dutasteride & finasteride), i.e. the amount of dutasteride used is less than half, more preferably less than two fifths, of the amount of conventional therapeutic agents (oral dutasteride and finasteride).

2. There were few systemic side effects of conventional therapeutic agents (oral dutasteride and finasteride).

3. Due to the rapid onset of effect, it is possible to effectively prevent hair loss from the beginning of treatment; and

4. unlike conventional formulas (oral dutasteride and finasteride) which provide about 70% efficiency, they provide nearly 100% efficiency to hair loss patients.

Object of the Invention

It is an object of the present invention to provide a topically applied composition for preventing hair loss and stimulating hair growth comprising dutasteride or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a topically applied composition for preventing hair loss and stimulating hair growth comprising dutasteride, wherein the effect of preventing hair loss and stimulating hair growth is equal to or higher than that of conventional oral therapeutic agents (oral finasteride and oral dutasteride), even though the amount of dutasteride is much less than the amount (less than half, more preferably less than two fifths) of conventional oral therapeutic agents (oral finasteride and oral dutasteride).

It is another object of the present invention to provide a topically applied composition for preventing hair loss and stimulating hair growth, comprising dutasteride, wherein the topical composition uses a small amount of dutasteride, and thus has slight side effects such as having decreased libido, impotence, ejaculatory disorders, etc. additionally, compared to using conventional oral 5 α -reductase inhibitors (oral finasteride and dutasteride), it can effectively prevent hair loss from the beginning of treatment due to the rapid onset of effect, and can provide an effect of improving patient treatment compliance.

Disclosure of Invention

The present invention relates to a topically applied composition for preventing hair loss and stimulating hair growth comprising a 5 α -reductase inhibitor, in particular dutasteride or a pharmaceutically acceptable salt thereof.

In various embodiments of the present invention, the present invention provides pharmaceutical compositions for improved topical delivery of dutasteride, including salts, esters, isomers, solvates, hydrates, and polymorphs thereof.

Topical administration for preventing hair loss and stimulating hair growth comprises dutasteride administered at a daily dose of about 0.1mg to about 0.5mg, preferably about 0.25m, most preferably about 0.2mg, which is preferably less than about half and most preferably less than two-fifths of the dose of oral dutasteride (0.5mg), a currently commercially available 5 α -reductase inhibitor (a commercially available daily dose of 0.5mg and oral finasteride of 1 mg).

The present invention provides a topically applied composition for preventing hair loss and stimulating hair growth comprising dutasteride or a pharmaceutically acceptable salt thereof, medium chain triglycerides, castor oil and ethanol, wherein topical application comprises dutasteride applied at a daily dose of about 0.1 to about 0.5 mg.

In another embodiment, the present invention also provides a topically applied composition for preventing hair loss and stimulating hair growth comprising about 0.01 wt% to about 0.06 wt% dutasteride, about 25 wt% to about 35 wt% medium chain triglycerides, about 25 wt% to about 35 wt% ethanol, and about 35 wt% to about 45 wt% castor oil, based on the total weight of the composition, wherein the dutasteride comprised by the composition is in an amount to provide a daily dose of about 0.1 to about 0.5 mg.

In yet another embodiment, the present invention also provides a topically applied composition for preventing hair loss and stimulating hair growth comprising about 0.022 wt% (equivalent to 0.02% w/v) dutasteride, about 30 wt% medium chain triglycerides, about 30 wt% ethanol, and about 40 wt% castor oil, based on the total weight of the composition.

In another embodiment, the present invention also provides a topically applied composition for preventing hair loss and stimulating hair growth comprising about 0.022 wt% (equivalent to 0.02% w/v) dutasteride, about 30 wt% medium chain triglycerides, about 30 wt% ethanol, and about 40 wt% castor oil, based on the total weight of the composition.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is in the form of a solution, an ointment, a cream, a gel, a lotion, a suspension, a mousse, an aerosol, a spray, a foam, a microsphere, a microemulsion, a nanoemulsion, a nanoparticle, a nanosuspension, a dermal stick, a wound roll, a pump, a patch, a tape, or the like.

In one embodiment, the pharmaceutical compositions of the present invention exhibit excellent physicochemical stability during storage at 40 ℃ and 75% Relative Humidity (RH) for a period of at least 6 months.

In another embodiment, the present invention provides a method of using the pharmaceutical composition described herein for the prevention, amelioration and/or treatment of androgenetic alopecia.

In another embodiment, the pharmaceutical composition of the invention comprises dutasteride as an active agent, and additionally comprises at least one other active agent, which dutasteride can be used for the prevention, amelioration or treatment of androgenetic alopecia.

Detailed Description

In various embodiments, the present invention provides pharmaceutical compositions for improved topical delivery of dutasteride, including salts, esters, isomers, solvates, hydrates, and polymorphs thereof.

Topical administration for preventing hair loss and stimulating hair growth comprises dutasteride administered at a daily dose of about 0.1mg to about 0.5mg, preferably about 0.25m, most preferably about 0.2mg, which is preferably less than about half and most preferably less than two-fifths of the dose of oral dutasteride (0.5mg), a currently commercially available 5 α -reductase inhibitor (a commercially available daily dose of 0.5mg and oral finasteride of 1 mg).

If the daily dose of dutasteride is less than 0.1mg, then the onset of effect is not significant; however, if the daily dose exceeds 0.5mg, side effects such as decreased libido, decreased ejaculation, and the like may occur. The daily dose of topically administered dutasteride is preferably 0.4mg, more preferably 0.25mg, and most preferably 0.2 mg. If the dose of dutasteride is outside this range, the effect is not significant, or side effects may occur.

In various embodiments of the present invention, the present invention relates to a composition for topical administration comprising dutasteride, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipients of the present invention are hydrophilic, hydrophobic, lipophilic or amphiphilic.

In various embodiments of the present invention, pharmaceutically acceptable excipients include, but are not limited to, penetration enhancers, oily carriers, antioxidants, buffers, preservatives, viscosity modifiers, chelating/complexing agents, colorants, fragrances, polymers, gelling agents, surfactants, co-surfactants, alcohols, liquid or semi-solid oily components, and any mixtures thereof.

Dutasteride has side effects such as decreased libido, impotence, ejaculatory disorders, and the like. Therefore, there is a need to reduce these side effects. In various embodiments of the present invention, the present invention relates to a topically applied composition comprising dutasteride, at least one penetration enhancer, and an oily carrier. Topically applying a topical composition comprising dutasteride, at least one penetration enhancer, and an oily carrier to a target; and the inventors of the present invention surprisingly found that dutasteride is efficiently delivered to the target, which provides nearly 100% efficiency for hair-loss patients, and provides very rapid and excellent effects, even though the amount of dutasteride is less than two fifths of that of conventional oral dutasteride (0.5mg, once per day).

A topically applied composition for preventing hair loss and stimulating hair growth may be prepared comprising dutasteride or a pharmaceutically acceptable salt thereof in an amount of from about 0.1mg to about 0.5mg, more preferably 0.15mg to 0.4mg, and most preferably 0.2mg relative to 1ml of topically applied composition. Preferably, the topically applied composition prepared in the above manner is applied in an amount of 1ml comprising 0.2mg of dutasteride once or twice daily, most preferably 1ml once daily.

The present invention relates to topically applied compositions for preventing hair loss and stimulating hair growth comprising dutasteride, at least one penetration enhancer, and an oily carrier.

In various embodiments of the present invention, dutasteride is present in a range of about 0.001 wt% to about 0.5 wt%, preferably in a range of about 0.01 wt% to about 0.1 wt%, more preferably in a range of about 0.01 wt% to about 0.06 wt%, and most preferably 0.022 wt% (equivalent to 0.02% w/v), based on the total weight of the composition.

Suitable penetration enhancers that may be used in the present invention include, but are not limited to: medium chain triglycerides (which may be Labrafac)^TMCommercially available) sulfoxides such as dimethyl sulfoxide (DMSO) and decylmethyl sulfoxide (C10 MSO); ethers, such as diethylene glycol monoethyl ether (Transcutol may be used)^TMCommercially available) and diethylene glycol monomethyl ether; 1-substituted azepan-2-ones, such as 1-n-dodecyl-cycloazacycloheptan-2-one; alcohols such as ethanol, propanol, octanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid, and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; polyol esters, such as butanediol and polyethylene glycol monolaurateCinnamic acid ester; amides and other nitrogen-containing compounds such as urea, N-Dimethylacetamide (DMA), N-Dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes and terpenoids; an alkanone; organic acids such as salicylic acid and salicylates, citric acid and succinic acid, and the like; and any mixtures thereof. Most preferably, the penetration enhancer used is a mixture of medium chain triglycerides and ethanol. The penetration enhancer is preferably used in the range of about 20 wt% to about 80 wt% relative to the total weight of the composition. Preferably, the medium chain triglycerides are used in a range of about 25 wt% to about 35 wt%, most preferably about 30 wt%, based on the total weight of the composition. Preferably, ethanol is used in the range of about 25 wt% to about 35 wt%, most preferably about 30 wt%, based on the total weight of the composition.

Examples of oily carriers include glycerol esters of fatty acids, such as monoglycerides or triglycerides of fatty acids, including polyethylene glycol complexes thereof, polyethylene glycol or propylene glycol esters of fatty acids; vegetable oils, including hydrogenated forms thereof, such as sesame oil, soybean oil, castor oil, corn oil, palm oil, peanut oil, cocoa butter, cottonseed oil, sunflower oil, safflower oil, almond oil or olive oil; fatty acids and fatty alcohols, and esters thereof, such as oleic acid, linolenic acid, linoleic acid, palmitic acid, palmitoleic acid, arachidonic acid, myristic acid, capric acid, caprylic acid, lauric acid, stearic acid, lauryl alcohol, oleyl alcohol, cetyl alcohol, stearyl alcohol, ethyl oleate, oleyl laurate, isopropyl myristate, isopropyl palmitate, 2-octyldodecyl myristate, or cetyl palmitate; and mixtures thereof. The most preferred oily carrier for use in the present compositions is castor oil. Preferably, castor oil is used in the range of about 35 wt% to about 45 wt%, most preferably about 40 wt%, based on the total weight of the composition.

The present invention relates to a topically applied composition for preventing hair loss and stimulating hair growth comprising about 0.01 wt% to about 0.06 wt% dutasteride, about 25 wt% to about 35 wt% medium chain triglycerides, about 25 wt% to about 35 wt% ethanol, and about 35 wt% to about 45 wt% castor oil, based on the total weight of the composition, wherein the composition comprises dutasteride in an amount to provide a daily dose of about 0.1 to about 0.5 mg.

The present invention relates to a topically applied composition for preventing hair loss and stimulating hair growth comprising about 0.022 wt% (equivalent to 0.02% w/v) dutasteride, about 30 wt% medium chain triglycerides, about 30 wt% ethanol and about 40 wt% castor oil, based on the total weight of the composition.

The present invention also relates to a topically applied composition for preventing hair loss and stimulating hair growth comprising about 0.022 wt% (equivalent to 0.02% w/v) dutasteride, about 30 wt% medium chain triglycerides, about 30 wt% ethanol and about 40 wt% castor oil, based on the total weight of the composition.

Antioxidants useful in the present invention include, but are not limited to, tocopherol succinate, ascorbic acid, propyl gallate, vitamin E, butylated hydroxytoluene, butylated hydroxyanisole, including any mixture thereof.

Buffers useful in the present invention include, but are not limited to: basic metal salts such as potassium and sodium carbonates, acetates, borates, phosphates, citrates and hydroxides; weak acids such as acetic acid, boric acid, phosphoric acid, and the like; and mixtures thereof.

Preservatives useful in the present invention include, but are not limited to, methyl, ethyl, propyl, and butyl esters of p-hydroxybenzoic acid (p-hydroxy benzoates), and the like, including any mixtures thereof.

Viscosity modifiers useful in the present invention include, but are not limited to, cetyl alcohol, glycerin, polyethylene glycol (PEG), PEG-stearate, xanthan gum, and the like, including any mixtures thereof.

Chelating or complexing agents useful in the present invention include, but are not limited to, ethylenediaminetetraacetic acid (EDTA) and derivatives thereof, including mixtures thereof.

In one embodiment of the present invention, the pharmaceutical composition of the present invention is in the form of a solution, an ointment, a cream, a gel, a lotion, a suspension, a mousse, an aerosol, a spray, a foam, a microsphere, a microemulsion, a nanoemulsion, a nanoparticle, a nanosuspension, a dermal stick, a wound roll, a pump, a patch, a tape, or the like.

In one embodiment, the pharmaceutical compositions of the present invention exhibit excellent physicochemical stability during storage at 40 ℃ and 75% Relative Humidity (RH) for a period of at least 6 months.

In various embodiments of the present invention, the present invention provides methods of using the pharmaceutical compositions described herein for the prevention, amelioration, and/or treatment of androgenetic alopecia.

In various embodiments of the present invention, the pharmaceutical composition provides for the topical delivery of dutasteride to enhance the availability of the active agent to the hair follicles of the scalp, particularly when applied to the scalp.

In various embodiments, the pharmaceutical compositions of the present invention allow penetration of the drug product through the skin or scalp upon administration, and they block the 5 α -reductase locally on the scalp and without significant systemic DHT levels.

Such other active agents may enhance or potentiate the activity of the 5 α -reductase inhibitor, or may be useful in the management (prevention, amelioration, or treatment) of any associated disease/disorder indicated by the 5 α -reductase inhibitor.

Additional active agents include, but are not limited to: hair loss preventive agents; a hair growth promoter; hair loss preventive agents such as finasteride, FCE 28260 and minoxidil; an anti-infective agent; an antibacterial agent; an antifungal agent; an antihistamine; an immunomodulator; anti-dandruff agents; an antiviral agent; antiandrogens such as fluconazole, ketoconazole and spironolactone; hormones; a steroid; and so on.

In various embodiments of the present invention, the present invention provides methods for preparing the pharmaceutical compositions of the present invention. In one embodiment, the composition of the invention is prepared by combining dutasteride with at least one pharmaceutically acceptable excipient and formulating into a suitable topical dosage form.

In one embodiment, the method of preparing the pharmaceutical composition of the invention comprises

(a) Dissolving dutasteride in ethanol

(b) Adding medium chain triglycerides and castor oil to the contents of step a

(c) The mixture is formed into a solution.

The manufacturing method of the present invention may comprise filling the composition of the present invention into a suitable container. The compositions of the present invention may be packaged, for example, in unit-dose or multi-dose containers.

The following examples also describe certain specific aspects and embodiments, provided for illustrative purposes only, and should not be construed as limiting the scope of the invention in any way.

Example 1: solution composition comprising topically applied dutasteride for preventing hair loss and stimulating hair growth

TABLE 1

Composition (I)	Percent (w/w)
		Dutasteride	0.005-1％
Castor oil	30-50％
		Medium chain triglycerides	25-35％
Ethanol	25-35％

Preparation process

1. Dissolving dutasteride in ethanol

2. Medium chain triglycerides and castor oil were added to the contents of step 1 to form a solution.

3. The above solution was filled into a suitable container.

Example 2 to example 4: composition for topical application of dutasteride

TABLE 2

Equivalent to 0.01% w/v, 0.02% w/v & 0.05% w/v of example 2, example 3& example 4, respectively.

Preparation process

1. Dissolving dutasteride in ethanol

2. Medium chain triglycerides and castor oil were added to the contents of step 1 to form a solution.

3. The above solution was filled into a suitable container.

Example 5 to example 7: composition for topical application of dutasteride

TABLE 3

Equivalent to 0.01% w/v, 0.02% w/v & 0.05% w/v of example 5, example 6& example 7, respectively.

Preparation process

1. Dissolving dutasteride in ethanol

2. Medium chain triglycerides and castor oil were added to the contents of step 1 to form a solution.

3. The above solution was filled into a suitable container.

Example 8 to example 10: composition for topical application of dutasteride

TABLE 4

Equivalent to 0.01% w/v, 0.02% w/v & 0.05% w/v of example 8, example 9& example 10, respectively.

Preparation process

1. Dutasteride was dissolved in ethanol.

2. Medium chain triglycerides and castor oil were added to the contents of step 1 to form a solution.

3. The above solution was filled into a suitable container.

Example 11 to example 13: composition for topical application of dutasteride

TABLE 5

Equivalent to 0.01% w/v, 0.02% w/v & 0.05% w/v of example 11, example 12& example 13, respectively.

Preparation process

1. Dutasteride was dissolved in ethanol.

2. Medium chain triglycerides and castor oil were added to the contents of step 1 to form a solution.

3. The above solution was filled into a suitable container.

Comparative example 1:

in comparative example 1, finasteride active ingredient was dissolved to prepare a composition containing an oral pharmaceutical agent using the following ingredients as shown in table 6.

TABLE 6

The oral finasteride dose administered to rats at 0.1mg/kg corresponds to a 1mg human dose.

Test example 1: preclinical tests for prevention of hair loss and stimulation of hair growth (evaluation of changes in hair growth and thickness).

Hair growth and hair thickness measurements were performed on weisda rats. Wistar (Wistar) rats were divided into groups of 13 animals each. The study was conducted for 21 days on Wisdar rats. On the "0" day of the study, the pelts on and around the flanks of the wisida rats were shaved with an electric trimmer and an area of 2 × 2cm was used for the topical application of the dutasteride compositions of examples 2 to 13 (at a dose of 100 μ l/kg of examples 2 to 13) together with the composition of reference example 1 (finasteride taken orally at a dose of 0.1 mg/kg) for 21 days, once a day (between 10 and 11 pm per day). 100 μ l of 1% testosterone was injected subcutaneously daily for 21 days (9 am each day) and after sacrifice the effect (hair growth and thickness) was assessed on day 22. Normal controls (no testosterone applied) of shaved rats a group of 13 animals was arranged.

The change in hair growth was measured by visual scoring (hair growth score) of 13 animals per group and the mean was calculated. The visual score was calculated based on the following parameters:

fraction 0: no hair growth was observed

Fraction 1: growth of less than 20% was observed

And 2, fraction: growth of 20% to less than 40% was observed

Score 3: growth of 40% to less than 60% was observed

And 4, fraction: growth of 60% to less than 80% was observed

Score 5: 80% to 100% growth

The visual scores of the mean and normal controls for the compositions of examples 2-13, along with a reference oral finasteride-treated group of 13 animals, are shown in table 7.

Hair thickness was measured by a castile hair analysis instrument attached to a microscope at 200X magnification and the results are shown in table 7 with the compositions of examples 2 to 13 along with the hair thickness (μm) of each group of the reference oral finasteride treatment and the normal control.

TABLE 7

The data in table 7 show that the onset of effect of the compositions described above for topical administration of the invention can significantly improve therapeutic compliance in the case of conventional formulations (oral finasteride) is similar to the onset of effect of the smaller dose formulation as disclosed in example 3 and has slight side effects when compared to oral finasteride) when compared to other formulations, in examples 2 to 4 (most preferably the composition of example 3 comprising dutasteride 0.022 wt% (equivalent to 0.02% w/v), castor oil 40 wt%, medium chain triglyceride 30 wt% and ethanol (about 30 wt%): the hair growth fraction and hair thickness significantly increased in wisida rats of moderate to 100 wt% have the highest hair growth fraction and hair thickness.