WO2014184173A1 - Hair care formulations - Google Patents

Hair care formulations Download PDF

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Publication number
WO2014184173A1
WO2014184173A1 PCT/EP2014/059722 EP2014059722W WO2014184173A1 WO 2014184173 A1 WO2014184173 A1 WO 2014184173A1 EP 2014059722 W EP2014059722 W EP 2014059722W WO 2014184173 A1 WO2014184173 A1 WO 2014184173A1
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WO
WIPO (PCT)
Prior art keywords
topical pharmaceutical
pharmaceutical formulation
peg
formulation according
minoxidil
Prior art date
Application number
PCT/EP2014/059722
Other languages
French (fr)
Inventor
Ümit Cifter
Ali TÜRKYILMAZ
Gülay Yelken
Merve ZAN
Original Assignee
Montero Gida Sanayi Ve Ticaret A.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Montero Gida Sanayi Ve Ticaret A.S. filed Critical Montero Gida Sanayi Ve Ticaret A.S.
Publication of WO2014184173A1 publication Critical patent/WO2014184173A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers

Definitions

  • the present invention relates to a topical formulation comprising minoxidil and at least one penetration enhancer, as well as to a method for producing the same.
  • the present invention further relates to the use of said pharmaceutical formulation in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth in mammalians.
  • Androgenetic alopecia also known as the male-type hair loss, is the most-frequently encountered hair loss condition in both genders. It constitutes 95% of all kinds of hair loss conditions. Approximately 50% of all individuals suffer from male-type hair loss. This results from the negative influence of the testosterone hormone, one type of male hormones (androgen), on the hair follicles in genetically-susceptible individuals. In this regard, androgenetic alopecia is known as the hair loss problem which is caused by the androgen hormone based on the genetics of the hair follicles.
  • the cause of androgenetic alopecia is based on the influence of the male hormones on genetically-susceptible individuals. As a result of this influence of the male hormones on the genetically-susceptible hair follicles, the follicles become damaged, thereby leading to hair loss. More specifically, the most important reason of androgenetic alopecia is the conversion of the testosterone hormone to the dihydrotestosterone hormone (DHT), which is more potent than the former. Testosterone circulating in the blood stream reaches the hair follicles via blood vessels and interacts with the 5-a-reductase enzymes naturally present in the hair follicles, thereby converting to the more potent dihydrotestosterone hormone.
  • DHT dihydrotestosterone hormone
  • the resulting DHT molecules are captured by the androgen receptors (AR) in the hair follicles.
  • AR androgen receptors
  • the resulting AR-DHT complex prevents the biochemical polymerization required for hair growth in the hair follicle cells and the hair follicle cells enter into the telogen phase.
  • vascularisation is prevented as a result of the reduction in the vascular endothelial growth factor (VEGF) in the hair follicles and the capillary vessels move away from the hair follicle cells.
  • VEGF vascular endothelial growth factor
  • Minoxidil 6-amino-1 ,2-dihydro-1 -hydroxy-2-imino-4- piperidinopyrimidine. Minoxidil was first released to the market for regulating the blood pressure. When a substantial hair development was observed on the body of those individuals using this drug, it was thought that this side effect could have a positive influence on hair loss. Minoxidil is the first drug approved by FDA for the prevention of hair loss.
  • minoxidil Although the effect mechanism of minoxidil is not exactly known, it is thought to prolong the anagen phase (i.e. the growth phase) of the hairs and therefore to increase the thickness and length of the hairs. It is widely used in the treatment of many types of baldness, AGA being in the first place.
  • minoxidil is a drug which further has a vasodilator effect besides hair growing effect
  • the oral administration of this drug in the treatment of AGA may lead to undesired side effects and therefore to an interruption or cessation of the treatment.
  • the aforesaid drawbacks of the oral administration of those drugs comprising minoxidil may particularly problematic in patients which have to permanently take drugs for a chronic disease.
  • a novel topical pharmaceutical formulation of minoxidil for dermal administration may be developed for use in the treatment of AGA to minimize or eliminate the likelihood of encountering systemic side effects.
  • the efficiency of the topical pharmaceutical formulations comprising minoxidil was seen to increase in a dose- dependent manner.
  • topical pharmaceutical formulations comprising minoxidil through the skin bears great importance in terms of increasing the drug efficiency. This may be explained in that the amount of drug penetrating through the skin without becoming metabolized increases as the drug's penetration rate increases, and therefore, the efficiency of the drug will increase accordingly. For this reason, the efficiency of an active agent comprised by a topical pharmaceutical formulation is substantially associated with the penetration rate of the formulation through the skin.
  • patient compliance is an important factor for sustaining the treatment.
  • EP1307181 B1 discloses a single-phase gel composition comprising greater than 3% minoxidil.
  • W09953923A1 discloses a topical pharmaceutical composition comprising minoxidil as well as a solvent and co-solvent.
  • WO0007627A2 discloses a topical composition comprising minoxidil as well as a polyol and a solvent.
  • topical formulations comprising minoxidil.
  • the topical formulations according to the prior art are not specifically formulated to increase the dermal penetration rate of minoxidil and to enhance the patient compliance. For this reason, a novel topical formulation is required which could improve the dermal administration of topical formulations comprising minoxidil. Accordingly, an object of the present invention is to provide a novel topical pharmaceutical formulation comprising minoxidil for dermal use ensuring the aforesaid effect.
  • the present invention relates to an easily-administrable topical pharmaceutical formulation comprising minoxidil, overcoming the aforesaid problems and providing additional advantages. Accordingly, the basic object of the present invention is to provide a topical pharmaceutical formulation by which the dermal penetration rate is increased and accordingly the efficiency of the active agent is enhanced.
  • Another object of the present invention is to provide a topical pharmaceutical formulation contributing to a successful progress of the treatment by increasing the patient compliance as well as increasing the dermal penetration rate.
  • Another object of the present invention is to provide a method for producing said topical pharmaceutical formulation. Accordingly, a topical pharmaceutical formulation is developed in order to achieve all of the objects stated above.
  • the present invention provides a topical pharmaceutical formulation comprising at least one penetration enhancer and minoxidil.
  • the penetration enhancer is selected from the group consisting of polyethylene glycol (PEG), PEG-75, PEG-75 shea butter glycerides and a mixture thereof, PEG-75 shea butter glycerides is the most preferred penetration enhancer.
  • the topical pharmaceutical formulation comprises 0.01 % (w/v) to 10% (w/v) of PEG-75 shea butter glycerides based on the total volume of the formulation.
  • the ratio of the total weight of minoxidil to the total weight of penetration enhancer comprised in the topical pharmaceutical formulation is between 75:1 and 1 :10, and preferably between 60:1 and 1 :5.
  • the topical pharmaceutical formulation comprises aminexil besides minoxidil and PEG-75 shea butter glycerides.
  • the ratio of the total weight of aminexil to the total weight of the penetration enhancer comprised in the topical pharmaceutical formulation is between 50:1 and 1 :50, and preferably between 30:1 and 1 :20.
  • the topical pharmaceutical formulation may further comprise at least one more active agent besides minoxidil and aminexil.
  • the topical pharmaceutical formulation comprises at least one pharmaceutically acceptable excipient selected from the group comprising viscosity enhancers, gelling agents, preservatives, antioxidants, surface active agents, solvents, silicon oils, chelating agents, emulsifying agents, buffering agents or a mixture thereof.
  • the topical pharmaceutical formulation is in the form of a gel, ointment, foam, cream, spray, tonic, serum, paste, or lotion, preferably in the form of spray, tonic or serum.
  • a process is provided for preparing the topical pharmaceutical formulation according to the present invention.
  • the topical pharmaceutical formulation is for use in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth in mammalians.
  • a novel topical pharmaceutical formulation is provided with the present invention, which prevents hair loss and stimulates hair growth, is absorbed in a surprisingly rapid manner and ensures a good patient compliance.
  • active agent means any agent, which is therapeutically active in the prevention of hair loss and stimulation of hair growth and is suitable for use in pharmaceutical formulations.
  • pharmaceutically acceptable excipient means any agent which, based on the therapeutically inactive and nontoxic properties thereof, is suitable for use as an auxiliary agent in the preparation of pharmaceutical formulations for humans and animals.
  • All herbal extracts comprised by the formulation according to the present invention can be obtained from the shells, leaves, flowers, roots, or seeds of the respective plants.
  • Herbal extracts may either be in a dry form, or in a dissolved form, e.g. in an alcohol or aqueous solution.
  • the present invention provides a topical pharmaceutical formulation which comprises minoxidil and at least one penetration enhancer and is effective in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth in mammalians.
  • the at least one penetration enhancer comprised by the topical pharmaceutical formulation according to the present invention is selected from the group consisting of 1 ,3-didocyl urea, 1 ,3-difenyl urea, 1 ,8-cineole, 3-caren, 7-oxabicyclo 2,2-heptan, ascaridol, dimetyl isosorbide, dimetyl formamide (DMF), d-limonen, isopropyl myristat, carveol, carvon, menton, N-metyl-2- pyrolidon, NN-dimetyl toluamide, oleic acid, pinen oxide, cyclohexan oxide, cyclopenten oxide, PEG, PEG-75, PEG-75 shea butter glycerides, sodium lauryl sulfate, terpinen-4-ol, urea, a-pinene, a-terpinol, or a mixture thereof; preferably selected from
  • PEG-75 shea butter glycerides helps in increasing the penetration rate of the formulation according to the present invention through the skin by interacting with the lipids present in the skin's membrane structure and creating some gaps in the structure as a result of getting therein. Additionally, the PEG-75 shea butter glycerides provides an easy penetration of minoxidil and other agents comprised in the formulation according to the present invention through the skin without damaging the lipids present in the membrane structure of the skin. These properties of PEG-75 shea butter glycerides were surprisingly found to be synergistically effective in improving the dermal penetration of the topical pharmaceutical formulation comprising minoxidil.
  • the shea butter comprised in the PEG-75 shea butter glycerides it is also effective in reducing the irritation that would result in the skin due to other ingredients of the formulation. Beside these features, by virtue of the softening and moisturizing influence of PEG-75 shea butter glycerides, the formulation according to the present invention can be easily applied (i.e. spread) to an affected site and leave a natural feeling on the skin after it is spread. Accordingly, PEG-75 shea butter glycerides is used as an penetration enhancer, a carrier for the topical administration of pharmaceuticals, as an irritation reducer, a moisturizer and a skin softener.
  • the PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulations according to the present invention increases both the dermal penetration rate of said formulation and the patient compliance to the therapy.
  • the PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulations according to the present invention is suitable for use in water-based formulations and can be used together with other penetration enhancers.
  • At least 30% by weight of the PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulations according to the present invention is PEG-75 and the remainder is shea butter glycerides; and more preferably 50% by weight of said formulation is PEG-75 and the 50% by weight thereof is shea butter glycerides.
  • the topical pharmaceutical formulations according to the present invention comprise 0.01 % (w/v) to 10% (w/v) of PEG-75 shea butter glycerides, preferably 0.05% (w/v) to 7.5% (w/v) of PEG-75 shea butter glycerides, and more preferably 0.1 % (w/v) to 5% (w/v) of PEG-75 shea butter glycerides based on the total volume of the formulation.
  • the topical pharmaceutical formulations according to the present invention comprise preferably aminexil besides minoxidil and PEG-75 shea butter glycerides.
  • the topical pharmaceutical formulations according to the present invention comprise 0.01 % (w/v) to 15% (w/v) of minoxidil, preferably 0.1 % (w/v) to 10% (w/v) of minoxidil, more preferably 0.5% (w/v) to 7.5% (w/v) of minoxidil; as well as 0.01 % (w/v) to 25% (w/v) of aminexil, preferably 0.05% (w/v) to 15% (w/v) of aminexil, more preferably 0.1 % (w/v) to 5% (w/v) of aminexil based on the total volume of the topical pharmaceutical formulation.
  • the ratio of the total weight of minoxidil to the total weight of PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulation according to the present invention is between 75:1 and 1 :10, preferably between 60:1 and 1 :5, and more preferably between 45:1 and 1 :1 .
  • the ratio of the total weight of aminexil to the total weight of PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulation according to the present invention is between 50:1 and 1 :50, preferably between 30:1 and 1 :20, and more preferably between 20:1 and 1 :10.
  • the topical pharmaceutical formulations according to the present invention may also comprise one or more pharmaceutically acceptable excipient(s).
  • excipients may be selected from the group comprising viscosity enhancers, gelling agents, preservatives, antioxidants, surface active agents, solvents, chelating agents, silicon oils, buffering agents, emulsifying agents, or the mixtures thereof.
  • Suitable preservatives comprise, but are not limited to methylparaben, propylparaben, sodium and potassium benzoate, imidurea, monothioglycol, potassium sorbate, benzoic acid, sorbic acid, sodium sorbate, cetrimide, benzalkonium chloride, glycerin, benzyl alcohol, butylparaben, ethylparaben, chlorobutanol, chlorhexidine or a mixture thereof.
  • the topical pharmaceutical formulation according to the present invention comprise preferably benzyl alcohol as a preservative besides minoxidil, aminexil, and PEG-75 shea butter glycerides.
  • the percent amount of benzyl alcohol in the formulation is between 0.05% (w/v) and 15% (w/v) and preferably between 0.1 % (w/v) and 10% (w/v) based on the total volume of the formulation.
  • Benzyl alcohol has an antimicrobial effect and when used in the topical pharmaceutical formulations according to the present invention in the stated amounts, it increases the stability of the formulation and contributes to maintaining the stability of the formulation throughout its shelf life.
  • the topical pharmaceutical formulations according to the present invention further comprise a hydrate of zinc sulfate, preferably zinc sulfate heptahydrate as an antifungal agent besides minoxidil, aminexil, PEG-75 shea butter glycerides, and benzyl alcohol.
  • the percent amount of zinc sulfate heptahydrate in the topical pharmaceutical formulation is between 0.001 % (w/v) and 20% (w/v), preferably between 0.05% (w/v) and 10% (w/v) based on the total volume of the formulation.
  • Zinc sulfate heptahydrate was selected for use in the formulation since other hydrate forms of zinc sulfate are generally unstable. Additionally, since the water absorption capability of zinc sulfate heptahydrate is higher than those of the other hydrate forms, zinc sulfate heptahydrate further contributes to maintaining the stability of the formulation according to the present invention throughout the shelf life thereof.
  • Suitable solvents comprise, but are not limited to ethyl alcohol, methyl alcohol, polyethylene glycol, glycerin, isopropyl alcohol, butylene glycol, propylene glycol, tetrahydrofuran, ether, liquid vaseline, benzene, toluene, pentane, hexane, heptane, acetone, methyl ethyl ketone, chloroform, methylene chloride, ethylene dichloride, ethyl acetate, mineral oils, and water or a mixture thereof.
  • the topical pharmaceutical formulations according to the present invention further comprise preferably a mixture of propylene glycol, ethyl alcohol, and water as a solvent besides minoxidil, aminexil, PEG-75 shea butter glycerides, benzyl alcohol, and zinc sulfate heptahydrate. It was observed that the formulation according to the present invention left a natural feeling on the skin following administration when the percent amount of propylene glycol used as a solvent was between 0.5% (w/v) and 80% (w/v), preferably between 0.75% (w/v) and 60% (w/v), and more preferably between 1 % (w/v) and 50% (w/v) based on the total volume of the topical formulation.
  • Suitable surface active agents comprise, but are not limited to polysorbate (e.g. polysorbate 60), glyceryl monostearate, polyethylene glycol succinate, oleic acid, diethanolamine, sodium lauryl sulfate, polyoxyl 25 cetostearyl ether, propylene glycol or a mixture thereof.
  • Suitable gelling agents comprise, but are not limited to hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethyl cellulose, carbomer, carbomer copolymers, poloximer, polyacrylamide, polyvinyl alcohol, gelatin, aluminum monostearate, sodium alginate, pectin, carrageenan, xanthane, or a mixture thereof.
  • the gelling agent is preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose and/or carbomer.
  • Suitable viscosity enhancers comprise, but are not limited to glycerin, gelatin, modified starches, synthetic or semisynthetic gums, pulluan, dextran, cellulose and the derivatives thereof, chitosan, carbomer, or a mixture thereof.
  • Suitable chelating agents comprise, but are not limited to ethylenediaminetetraacetic acid (EDTA), disodium edetate and EDTA derivatives and the like, and a mixture thereof.
  • Suitable buffering agents comprise, but are not limited to sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like, and a mixture thereof.
  • Suitable antioxidants comprise, but are not limited to butylated hydroxytoluene (BHT), butyl hydroxyanisole (BHA), ascorbic acid, hydroxy methyl butylphenol, tert-butylhydroquinone, sodium meta bisulfate, sodium sulfate, potassium meta bisulfate, or a mixture thereof.
  • BHT butylated hydroxytoluene
  • BHA butyl hydroxyanisole
  • ascorbic acid hydroxy methyl butylphenol
  • tert-butylhydroquinone sodium meta bisulfate, sodium sulfate, potassium meta bisulfate, or a mixture thereof.
  • Suitable emulsifying agents comprise, but are not limited to glycerin fatty acid esters, organic acid monoglycerides, polyglycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, lecithine, or a mixture thereof.
  • Suitable silicon oils may be volatile or nonvolatile and comprise, but are not limited to dimethicone, cyclomethicone, polyalkyl siloxanes, polyether siloxane copolymers, polyalkylaryl siloxanes, polydimethyl siloxanes, polydimethyl cyclosiloxane, disiloxane, trisiloxane, amodietion, stearyl dimethicone, cyclopentasiloxane, trimethylsiloxysilicate, and a mixture thereof.
  • an emulsifying agent more preferably cetyl alcohol is used for increasing the foaming capacity and the foam stability.
  • the pH range of the formulation is kept between 4 and 7 and preferably between 5 and 5.5.
  • Triethanolamine and citric acid can be used to regulate the pH of the gel formulations and foam formulations, respectively, according to the present invention.
  • the topical pharmaceutical formulations according to the present invention further comprise at least one active agent which is used for the prevention and/or treatment of alopecia, comprising finasteride, pinacidil, nicorandil, chromakalim, flupirtine, turosteride, epristeride, oxycanthin, catechin, epicatechin, epicatechin-3-gallate, linoleic acid, gamma linoleic acid, retinol, epigallocatechin-3-gallate, vitamin B (vitamin B 2 , B 6 , Bi 2 , etc.), vitamin C, vitamin E, oligomeric proanthocyanidin or proanthenols, procyanidin (particularly procyanidin extracted from apple), silymarin, echinacoside, carotenoid, aminobenzoic acid, ascorbic acid, benzoic acid, estradiol and other topical hormones, lanolin, nucleic acids, pantothenol,
  • active agent which is
  • the topical pharmaceutical formulation further comprise at least one active agent selected from the group consisting of finasteride, vitamin B 6 , panthenol, azelaic acid, zinc sulfate heptahydrate, grape seed extract, biotin, L-arginine, taurine, panax ginseng extract, saw palmetto ⁇ Serenoa repens) extract, caffeine, jojoba oil, retinol and procyanidin (particularly procyanidin extracted from apple).
  • active agent selected from the group consisting of finasteride, vitamin B 6 , panthenol, azelaic acid, zinc sulfate heptahydrate, grape seed extract, biotin, L-arginine, taurine, panax ginseng extract, saw palmetto ⁇ Serenoa repens
  • the topical pharmaceutical formulation is in the form of a gel, ointment, cream, foam, spray, tonic, serum, paste, or lotion, more preferably in the form of spray, tonic or serum.
  • the spray formulation and the tonic formulation are formulated using the same unit formula. The difference of the spray formulations to the tonic formulations is that the spray formulations are administered by spraying to an affected site using a device.
  • the present invention is further used in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth and helps growth of new and healthy hairs in mammalians. Beside the use of the present invention stated above, it may further be used in the treatment of alopecia areata, alopecia totalis, alopecia universalis, and other types of alopecia.
  • the formulations according to the present invention is suitable for use both in the females and the males, whereas the formulations according to the present invention comprising finasteride is preferably used by the males.
  • the methods according to the prior art were used for obtaining all extracts used within the scope of the present invention.
  • a topical pharmaceutical formulation used in the treatment of a disease such as AGA which relates to the physical appearance of the respective patient has to ensure the continuation of the therapy without negatively effecting the life quality and psychology of the patient.
  • AGA a disease which relates to the physical appearance of the respective patient
  • One of the problems frequently encountered in pharmaceutical or cosmetic hair care products is that these products have an unpleasant odor which disturbs the user and his/her surrounding due to the substances comprised and that the users face difficulties in the daily use thereof due to the lack of features suitable for topical use.
  • the topical pharmaceutical formulation according to the present invention is formulated so as to be easily applicable and leave a natural feeling on the skin following application, as well as to have an odor and appearance which would not disturb the respective user and his/her surrounding.
  • these topical pharmaceutical formulations formulated according to the present invention does not cause irritation and itching on the skin. Therefore, the compliance of the patients to the therapy is enhanced and it is made possible to use the topical pharmaceutical formulation according to the present invention regularly and comfortably throughout the alopecia therapy.
  • the topical pharmaceutical formulation according to the present invention preferably comprises the followings: a. 0.01 % (w/v) to 15% (w/v) of minoxidil,
  • the topical pharmaceutical formulation preferably comprises the followings: a. 0.01 % (w/v) to 15% (w/v) of minoxidil,
  • the topical pharmaceutical formulation according to the present invention more preferably comprises the followings: a. 0.5% (w/v) to 7.5% (w/v) of minoxidil,
  • formulations disclosed above are preferably in the form of spray, tonic or serum.
  • the percent amount of a substance comprised by the topical pharmaceutical formulation according to the present invention represents the gram-based amount of that substance in a 100 ml formulation, and is expressed as weight/volume (w/v).
  • a method for preparing a topical pharmaceutical formulation in order to achieve another object of the present invention is preferably composed of the following steps: a. alcohol, propylene glycol and water are weighed in the amounts stated and are mixed for a while at room temperature (mixture A),
  • mixture B b. minoxidil and preferably aminexil are added to mixture A and the resulting mixture is stirred for around 30 minutes until a homogeneous solution is obtained (mixture B), c. other ingredients of the formulation are added one by one to mixture B and the resulting mixture is stirred for at least 30 minutes at room temperature until a homogeneous solution is obtained (mixture C),
  • the mixture C is left settling for at least two hours and then subjected to filtration, e. the product obtained at the end of the settling period is subjected to a filling and packaging process.
  • Formulation 1 Amount % (weight/volume)
  • Vitamin B 6 0.05% to 30%
  • Zinc sulfate heptahydrate 0.001 % to 20%
  • Grape seed extract 0.05% to 20% Biotin 0.001 % to 10%
  • Jojoba oil 1 % to 80%
  • Formulation 6 Amount % (weight/volume)
  • Formulation 8 Amount % (weight/volume)
  • Alcohol, propylene glycol, and water are weighed in the amounts stated in the following formulation, minoxidil is introduced after the resulting mixture is stirred for some period at room temperature, and then stirred for around 30 minutes until a homogeneous solution is obtained. Then, other ingredients of the formulation are added one by one and the resulting mixture is stirred for at least 30 minutes at room temperature to give a homogeneous solution. The mixture is left settling for at least 2 hours and is then subjected to filtration. At the end of the settling period, a filling and packaging process is carried out.
  • the production method described above can be adapted to all spray/tonic formulation examples given below.
  • formulation examples comprise aminexil or finasteride
  • aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
  • the spray and tonic formulations are formulated so as to comprise the same unit formula.
  • the difference of the spray formulations to the tonic formulations is that the spray formulations are administered to an affected site in the form of a spray by means of a device.
  • Formulation 1 Amount % (weight/volume)
  • Vitamin B 6 0.05% to 30%
  • Zinc sulfate heptahydrate 0.001 % to 20%
  • Formulation 5 Amount % (weight/volume)
  • Formulation 6 Amount % (weight/volume)
  • Formulation 7 Amount % (weight/volume)
  • Formulation 8 Amount % (weight/volume)
  • Formulation 9 Amount % (weight/volume)
  • Ethyl alcohol, propylene glycol, and water are weighed in the amounts stated in the following formulation, minoxidil is introduced after the resulting mixture is stirred for some period at room temperature, and then stirred for around 30 minutes until a homogeneous solution is obtained.
  • the pH value of the formulation is adjusted using triethanolamine. Then carbomer is added and is thoroughly mixed to give a gel formulation.
  • the production method described above can be adapted to all gel formulation examples given below.
  • formulation examples comprise aminexil or finasteride
  • aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
  • Formulation 5 Amount % (weight/volume)
  • Formulation 7 Amount % (weight/volume)
  • Formulation 8 Amount % (weight/volume)
  • Formulation 11 Amount % (weight/volume)
  • Minoxidil is dissolved in an aqueous solution of Cremophor A 25. Some portion of the resulting solution is filled into suitable packages together with a mixture of propane and butane.
  • the production method described above can be adapted to the foam formulation examples given below.
  • formulation examples comprise aminexil or finasteride
  • aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
  • Formulation 9 Amount % (weight/volume)
  • Minoxidil is dissolved in an aqueous solution of Polysorbate 60.
  • the resulting solution is mixed with PEG-75 shea butter glycerides, BHT, glycerin, citric acid, cetyl alcohol, ethyl alcohol, and water. Some portion of the resulting solution is filled into suitable packages together with a mixture of propane and butane.
  • the production method described above can be adapted to the foam formulation examples given below.
  • formulation examples comprise aminexil or finasteride
  • aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
  • Formulation 1 Amount % (weight/volume)
  • Polysorbate 60 Polyoxyethylene
  • Polysorbate 60 Polyoxyethylene
  • Polysorbate 60 Polyoxyethylene
  • Polysorbate 60 Polyoxyethylene
  • Polysorbate 60 Polyoxyethylene
  • Formulation 6 Amount % (weight/volume)
  • Polysorbate 60 Polyoxyethylene
  • Formulation 7 Amount % (weight/volume)
  • Polysorbate 60 Polyoxyethylene
  • Polysorbate 60 Polyoxyethylene
  • Formulation 9 Amount % (weight/volume)
  • Polysorbate 60 Polyoxyethylene

Abstract

The present invention relates to a topical formulation comprising minoxidil and at least one penetration enhancer, as well as to a method for producing the same. The present invention further relates to the use of said pharmaceutical formulation in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth in mammalians.

Description

Description HAIR CARE FORMULATIONS
Field of Invention The present invention relates to a topical formulation comprising minoxidil and at least one penetration enhancer, as well as to a method for producing the same. The present invention further relates to the use of said pharmaceutical formulation in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth in mammalians.
Background of Invention
Androgenetic alopecia (AGA), also known as the male-type hair loss, is the most-frequently encountered hair loss condition in both genders. It constitutes 95% of all kinds of hair loss conditions. Approximately 50% of all individuals suffer from male-type hair loss. This results from the negative influence of the testosterone hormone, one type of male hormones (androgen), on the hair follicles in genetically-susceptible individuals. In this regard, androgenetic alopecia is known as the hair loss problem which is caused by the androgen hormone based on the genetics of the hair follicles.
As stated above, the cause of androgenetic alopecia is based on the influence of the male hormones on genetically-susceptible individuals. As a result of this influence of the male hormones on the genetically-susceptible hair follicles, the follicles become damaged, thereby leading to hair loss. More specifically, the most important reason of androgenetic alopecia is the conversion of the testosterone hormone to the dihydrotestosterone hormone (DHT), which is more potent than the former. Testosterone circulating in the blood stream reaches the hair follicles via blood vessels and interacts with the 5-a-reductase enzymes naturally present in the hair follicles, thereby converting to the more potent dihydrotestosterone hormone. The resulting DHT molecules are captured by the androgen receptors (AR) in the hair follicles. The resulting AR-DHT complex prevents the biochemical polymerization required for hair growth in the hair follicle cells and the hair follicle cells enter into the telogen phase. In parallel, vascularisation is prevented as a result of the reduction in the vascular endothelial growth factor (VEGF) in the hair follicles and the capillary vessels move away from the hair follicle cells. Thus, the vascular nutrition of the hair follicle cells is stopped. Accordingly, the new hair growth ability of the hair follicle cells ceases, thereby giving place to baldness.
When androgenetic alopecia appears, large and active hair follicles at certain sites become smaller and are replaced by smaller and less active hair follicles in each anagen phase, and in result, hairs begin to grow in a thinner and transparent form and afterwards hair growth completely ceases.
There are two main targets of an androgenetic alopecia therapy. These are stopping hair loss and stimulating new hair growth. There are two treatment modalities approved by the Food and Drug Administration (FDA) in the US for the treatment of androgenetic alopecia in the males. These are minoxidil for topical administration and finasteride for oral administration. Minoxidil can be used both by the females and the males, whereas the administration of finasteride to women is absolutely not recommended.
The chemical designation of minoxidil is 6-amino-1 ,2-dihydro-1 -hydroxy-2-imino-4- piperidinopyrimidine. Minoxidil was first released to the market for regulating the blood pressure. When a substantial hair development was observed on the body of those individuals using this drug, it was thought that this side effect could have a positive influence on hair loss. Minoxidil is the first drug approved by FDA for the prevention of hair loss.
Although the effect mechanism of minoxidil is not exactly known, it is thought to prolong the anagen phase (i.e. the growth phase) of the hairs and therefore to increase the thickness and length of the hairs. It is widely used in the treatment of many types of baldness, AGA being in the first place.
Since minoxidil is a drug which further has a vasodilator effect besides hair growing effect, the oral administration of this drug in the treatment of AGA may lead to undesired side effects and therefore to an interruption or cessation of the treatment. The aforesaid drawbacks of the oral administration of those drugs comprising minoxidil may particularly problematic in patients which have to permanently take drugs for a chronic disease. For this reason, a novel topical pharmaceutical formulation of minoxidil for dermal administration may be developed for use in the treatment of AGA to minimize or eliminate the likelihood of encountering systemic side effects. In a performed study in the prior art relating to the efficiency of minoxidil, the efficiency of the topical pharmaceutical formulations comprising minoxidil was seen to increase in a dose- dependent manner. For this reason, a more potent penetration of topical pharmaceutical formulations comprising minoxidil through the skin bears great importance in terms of increasing the drug efficiency. This may be explained in that the amount of drug penetrating through the skin without becoming metabolized increases as the drug's penetration rate increases, and therefore, the efficiency of the drug will increase accordingly. For this reason, the efficiency of an active agent comprised by a topical pharmaceutical formulation is substantially associated with the penetration rate of the formulation through the skin. In addition to those described above, since topical pharmaceutical formulations require a suitable administration to an affected site on the body by the respective patient for a long treatment period, patient compliance is an important factor for sustaining the treatment. Particularly for those individuals with a disease such as AGA having negative effects on their life quality and psychology, an easy and rapid adaptation to the treatment has a great contribution to the progress of the treatment. For this reason, a regular administration of the topical formulation to the affected site by the patient can be achieved by a satisfactory patient compliance.
Many topical formulations comprising minoxidil have been disclosed in the prior art.
EP1307181 B1 discloses a single-phase gel composition comprising greater than 3% minoxidil.
W09953923A1 discloses a topical pharmaceutical composition comprising minoxidil as well as a solvent and co-solvent.
WO0007627A2 discloses a topical composition comprising minoxidil as well as a polyol and a solvent. There are further examples of topical formulations comprising minoxidil. The topical formulations according to the prior art, however, are not specifically formulated to increase the dermal penetration rate of minoxidil and to enhance the patient compliance. For this reason, a novel topical formulation is required which could improve the dermal administration of topical formulations comprising minoxidil. Accordingly, an object of the present invention is to provide a novel topical pharmaceutical formulation comprising minoxidil for dermal use ensuring the aforesaid effect.
Description of Invention
The present invention relates to an easily-administrable topical pharmaceutical formulation comprising minoxidil, overcoming the aforesaid problems and providing additional advantages. Accordingly, the basic object of the present invention is to provide a topical pharmaceutical formulation by which the dermal penetration rate is increased and accordingly the efficiency of the active agent is enhanced.
Another object of the present invention is to provide a topical pharmaceutical formulation contributing to a successful progress of the treatment by increasing the patient compliance as well as increasing the dermal penetration rate.
Another object of the present invention is to provide a topical pharmaceutical formulation, which has improved stability and physical properties, is safely administrable to the skin, and can be used easily. Another object of the present invention is to provide a topical pharmaceutical formulation which leaves a natural feeling on the skin following administration, does not have an unpleasant odor for the user and his/her surrounding, and can be easily applied to the skin.
Another object of the present invention is to provide a method for producing said topical pharmaceutical formulation. Accordingly, a topical pharmaceutical formulation is developed in order to achieve all of the objects stated above.
According to one embodiment, the present invention provides a topical pharmaceutical formulation comprising at least one penetration enhancer and minoxidil.
According to a preferred embodiment of the present invention, the penetration enhancer is selected from the group consisting of polyethylene glycol (PEG), PEG-75, PEG-75 shea butter glycerides and a mixture thereof, PEG-75 shea butter glycerides is the most preferred penetration enhancer.
According to another preferred embodiment of the present invention, the topical pharmaceutical formulation comprises 0.01 % (w/v) to 10% (w/v) of PEG-75 shea butter glycerides based on the total volume of the formulation.
According to a further preferred embodiment of the present invention, the ratio of the total weight of minoxidil to the total weight of penetration enhancer comprised in the topical pharmaceutical formulation is between 75:1 and 1 :10, and preferably between 60:1 and 1 :5.
According to a further preferred embodiment of the present invention, the topical pharmaceutical formulation comprises aminexil besides minoxidil and PEG-75 shea butter glycerides. According to another preferred embodiment of the present invention, the ratio of the total weight of aminexil to the total weight of the penetration enhancer comprised in the topical pharmaceutical formulation is between 50:1 and 1 :50, and preferably between 30:1 and 1 :20.
According to a further preferred embodiment of the present invention, the topical pharmaceutical formulation may further comprise at least one more active agent besides minoxidil and aminexil.
According to another preferred embodiment of the present invention, the topical pharmaceutical formulation comprises at least one pharmaceutically acceptable excipient selected from the group comprising viscosity enhancers, gelling agents, preservatives, antioxidants, surface active agents, solvents, silicon oils, chelating agents, emulsifying agents, buffering agents or a mixture thereof.
According to a preferred embodiment of the present invention, the topical pharmaceutical formulation is in the form of a gel, ointment, foam, cream, spray, tonic, serum, paste, or lotion, preferably in the form of spray, tonic or serum. In another preferred embodiment of the present invention, a process is provided for preparing the topical pharmaceutical formulation according to the present invention.
In a further preferred embodiment of the present invention, the topical pharmaceutical formulation is for use in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth in mammalians.
Other advantages and embodiments of the present invention will be clarified in the following detailed description.
Detailed Description of Invention A novel topical pharmaceutical formulation is provided with the present invention, which prevents hair loss and stimulates hair growth, is absorbed in a surprisingly rapid manner and ensures a good patient compliance.
Within the context of the present invention, the term "active agent" means any agent, which is therapeutically active in the prevention of hair loss and stimulation of hair growth and is suitable for use in pharmaceutical formulations. The term "pharmaceutically acceptable excipient", in turn, means any agent which, based on the therapeutically inactive and nontoxic properties thereof, is suitable for use as an auxiliary agent in the preparation of pharmaceutical formulations for humans and animals.
All herbal extracts comprised by the formulation according to the present invention can be obtained from the shells, leaves, flowers, roots, or seeds of the respective plants. Herbal extracts may either be in a dry form, or in a dissolved form, e.g. in an alcohol or aqueous solution.
As stated above, the present invention provides a topical pharmaceutical formulation which comprises minoxidil and at least one penetration enhancer and is effective in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth in mammalians.
The at least one penetration enhancer comprised by the topical pharmaceutical formulation according to the present invention is selected from the group consisting of 1 ,3-didocyl urea, 1 ,3-difenyl urea, 1 ,8-cineole, 3-caren, 7-oxabicyclo 2,2-heptan, ascaridol, dimetyl isosorbide, dimetyl formamide (DMF), d-limonen, isopropyl myristat, carveol, carvon, menton, N-metyl-2- pyrolidon, NN-dimetyl toluamide, oleic acid, pinen oxide, cyclohexan oxide, cyclopenten oxide, PEG, PEG-75, PEG-75 shea butter glycerides, sodium lauryl sulfate, terpinen-4-ol, urea, a-pinene, a-terpinol, or a mixture thereof; preferably selected from the group consisting of PEG, PEG-75, PEG-75 shea butter glycerides, or a mixture thereof; and it is the most preferably PEG-75 shea butter glycerides. PEG-75 shea butter glycerides helps in increasing the penetration rate of the formulation according to the present invention through the skin by interacting with the lipids present in the skin's membrane structure and creating some gaps in the structure as a result of getting therein. Additionally, the PEG-75 shea butter glycerides provides an easy penetration of minoxidil and other agents comprised in the formulation according to the present invention through the skin without damaging the lipids present in the membrane structure of the skin. These properties of PEG-75 shea butter glycerides were surprisingly found to be synergistically effective in improving the dermal penetration of the topical pharmaceutical formulation comprising minoxidil.
Additionally, by virtue of the shea butter comprised in the PEG-75 shea butter glycerides, it is also effective in reducing the irritation that would result in the skin due to other ingredients of the formulation. Beside these features, by virtue of the softening and moisturizing influence of PEG-75 shea butter glycerides, the formulation according to the present invention can be easily applied (i.e. spread) to an affected site and leave a natural feeling on the skin after it is spread. Accordingly, PEG-75 shea butter glycerides is used as an penetration enhancer, a carrier for the topical administration of pharmaceuticals, as an irritation reducer, a moisturizer and a skin softener. Based on said features, the PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulations according to the present invention increases both the dermal penetration rate of said formulation and the patient compliance to the therapy. Based on its chemical structures, the PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulations according to the present invention is suitable for use in water-based formulations and can be used together with other penetration enhancers.
Preferably at least 30% by weight of the PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulations according to the present invention is PEG-75 and the remainder is shea butter glycerides; and more preferably 50% by weight of said formulation is PEG-75 and the 50% by weight thereof is shea butter glycerides.
The topical pharmaceutical formulations according to the present invention comprise 0.01 % (w/v) to 10% (w/v) of PEG-75 shea butter glycerides, preferably 0.05% (w/v) to 7.5% (w/v) of PEG-75 shea butter glycerides, and more preferably 0.1 % (w/v) to 5% (w/v) of PEG-75 shea butter glycerides based on the total volume of the formulation.
The topical pharmaceutical formulations according to the present invention comprise preferably aminexil besides minoxidil and PEG-75 shea butter glycerides.
The topical pharmaceutical formulations according to the present invention comprise 0.01 % (w/v) to 15% (w/v) of minoxidil, preferably 0.1 % (w/v) to 10% (w/v) of minoxidil, more preferably 0.5% (w/v) to 7.5% (w/v) of minoxidil; as well as 0.01 % (w/v) to 25% (w/v) of aminexil, preferably 0.05% (w/v) to 15% (w/v) of aminexil, more preferably 0.1 % (w/v) to 5% (w/v) of aminexil based on the total volume of the topical pharmaceutical formulation.
The ratio of the total weight of minoxidil to the total weight of PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulation according to the present invention is between 75:1 and 1 :10, preferably between 60:1 and 1 :5, and more preferably between 45:1 and 1 :1 .
The ratio of the total weight of aminexil to the total weight of PEG-75 shea butter glycerides comprised by the topical pharmaceutical formulation according to the present invention is between 50:1 and 1 :50, preferably between 30:1 and 1 :20, and more preferably between 20:1 and 1 :10.
The topical pharmaceutical formulations according to the present invention may also comprise one or more pharmaceutically acceptable excipient(s). These excipients may be selected from the group comprising viscosity enhancers, gelling agents, preservatives, antioxidants, surface active agents, solvents, chelating agents, silicon oils, buffering agents, emulsifying agents, or the mixtures thereof.
Suitable preservatives comprise, but are not limited to methylparaben, propylparaben, sodium and potassium benzoate, imidurea, monothioglycol, potassium sorbate, benzoic acid, sorbic acid, sodium sorbate, cetrimide, benzalkonium chloride, glycerin, benzyl alcohol, butylparaben, ethylparaben, chlorobutanol, chlorhexidine or a mixture thereof. The topical pharmaceutical formulation according to the present invention comprise preferably benzyl alcohol as a preservative besides minoxidil, aminexil, and PEG-75 shea butter glycerides. The percent amount of benzyl alcohol in the formulation is between 0.05% (w/v) and 15% (w/v) and preferably between 0.1 % (w/v) and 10% (w/v) based on the total volume of the formulation. Benzyl alcohol has an antimicrobial effect and when used in the topical pharmaceutical formulations according to the present invention in the stated amounts, it increases the stability of the formulation and contributes to maintaining the stability of the formulation throughout its shelf life. The topical pharmaceutical formulations according to the present invention further comprise a hydrate of zinc sulfate, preferably zinc sulfate heptahydrate as an antifungal agent besides minoxidil, aminexil, PEG-75 shea butter glycerides, and benzyl alcohol. The percent amount of zinc sulfate heptahydrate in the topical pharmaceutical formulation is between 0.001 % (w/v) and 20% (w/v), preferably between 0.05% (w/v) and 10% (w/v) based on the total volume of the formulation. Zinc sulfate heptahydrate was selected for use in the formulation since other hydrate forms of zinc sulfate are generally unstable. Additionally, since the water absorption capability of zinc sulfate heptahydrate is higher than those of the other hydrate forms, zinc sulfate heptahydrate further contributes to maintaining the stability of the formulation according to the present invention throughout the shelf life thereof. Suitable solvents comprise, but are not limited to ethyl alcohol, methyl alcohol, polyethylene glycol, glycerin, isopropyl alcohol, butylene glycol, propylene glycol, tetrahydrofuran, ether, liquid vaseline, benzene, toluene, pentane, hexane, heptane, acetone, methyl ethyl ketone, chloroform, methylene chloride, ethylene dichloride, ethyl acetate, mineral oils, and water or a mixture thereof. The topical pharmaceutical formulations according to the present invention further comprise preferably a mixture of propylene glycol, ethyl alcohol, and water as a solvent besides minoxidil, aminexil, PEG-75 shea butter glycerides, benzyl alcohol, and zinc sulfate heptahydrate. It was observed that the formulation according to the present invention left a natural feeling on the skin following administration when the percent amount of propylene glycol used as a solvent was between 0.5% (w/v) and 80% (w/v), preferably between 0.75% (w/v) and 60% (w/v), and more preferably between 1 % (w/v) and 50% (w/v) based on the total volume of the topical formulation.
Suitable surface active agents comprise, but are not limited to polysorbate (e.g. polysorbate 60), glyceryl monostearate, polyethylene glycol succinate, oleic acid, diethanolamine, sodium lauryl sulfate, polyoxyl 25 cetostearyl ether, propylene glycol or a mixture thereof.
Suitable gelling agents comprise, but are not limited to hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, carboxymethyl cellulose, carbomer, carbomer copolymers, poloximer, polyacrylamide, polyvinyl alcohol, gelatin, aluminum monostearate, sodium alginate, pectin, carrageenan, xanthane, or a mixture thereof. The gelling agent is preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose and/or carbomer.
Suitable viscosity enhancers comprise, but are not limited to glycerin, gelatin, modified starches, synthetic or semisynthetic gums, pulluan, dextran, cellulose and the derivatives thereof, chitosan, carbomer, or a mixture thereof. Suitable chelating agents comprise, but are not limited to ethylenediaminetetraacetic acid (EDTA), disodium edetate and EDTA derivatives and the like, and a mixture thereof.
Suitable buffering agents comprise, but are not limited to sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like, and a mixture thereof.
Suitable antioxidants comprise, but are not limited to butylated hydroxytoluene (BHT), butyl hydroxyanisole (BHA), ascorbic acid, hydroxy methyl butylphenol, tert-butylhydroquinone, sodium meta bisulfate, sodium sulfate, potassium meta bisulfate, or a mixture thereof.
Suitable emulsifying agents comprise, but are not limited to glycerin fatty acid esters, organic acid monoglycerides, polyglycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, lecithine, or a mixture thereof. Suitable silicon oils may be volatile or nonvolatile and comprise, but are not limited to dimethicone, cyclomethicone, polyalkyl siloxanes, polyether siloxane copolymers, polyalkylaryl siloxanes, polydimethyl siloxanes, polydimethyl cyclosiloxane, disiloxane, trisiloxane, amodietion, stearyl dimethicone, cyclopentasiloxane, trimethylsiloxysilicate, and a mixture thereof. If the topical pharmaceutical formulations according to the present invention are formulated in a foam form, preferably an emulsifying agent, more preferably cetyl alcohol is used for increasing the foaming capacity and the foam stability. Since the pharmaceutical formulation according to the present invention is administered to human skin topically, the pH range of the formulation is kept between 4 and 7 and preferably between 5 and 5.5. Triethanolamine and citric acid can be used to regulate the pH of the gel formulations and foam formulations, respectively, according to the present invention. Beside minoxidil, the topical pharmaceutical formulations according to the present invention further comprise at least one active agent which is used for the prevention and/or treatment of alopecia, comprising finasteride, pinacidil, nicorandil, chromakalim, flupirtine, turosteride, epristeride, oxycanthin, catechin, epicatechin, epicatechin-3-gallate, linoleic acid, gamma linoleic acid, retinol, epigallocatechin-3-gallate, vitamin B (vitamin B2, B6, Bi2, etc.), vitamin C, vitamin E, oligomeric proanthocyanidin or proanthenols, procyanidin (particularly procyanidin extracted from apple), silymarin, echinacoside, carotenoid, aminobenzoic acid, ascorbic acid, benzoic acid, estradiol and other topical hormones, lanolin, nucleic acids, pantothenol, sulfanilamide, ginkgo biloba, green tea polyphenols, lutein, lycopene, progesterone, cyproterone acetate, azelaic acid and the derivatives thereof, panthenol, biotin, caffeine, taurine, L-arginine, panax ginseng extract, saw palmetto (Serenoa repens) extract, grape seed extract, jojoba oil, argan oil, and a mixture thereof. Preferably the topical pharmaceutical formulation further comprise at least one active agent selected from the group consisting of finasteride, vitamin B6, panthenol, azelaic acid, zinc sulfate heptahydrate, grape seed extract, biotin, L-arginine, taurine, panax ginseng extract, saw palmetto {Serenoa repens) extract, caffeine, jojoba oil, retinol and procyanidin (particularly procyanidin extracted from apple).
According to a preferred embodiment of the present invention, the topical pharmaceutical formulation is in the form of a gel, ointment, cream, foam, spray, tonic, serum, paste, or lotion, more preferably in the form of spray, tonic or serum. According to the present invention, the spray formulation and the tonic formulation are formulated using the same unit formula. The difference of the spray formulations to the tonic formulations is that the spray formulations are administered by spraying to an affected site using a device.
The present invention is further used in the long-term treatment of alopecia, particularly androgenetic alopecia, in the prevention or retardation of hair loss, and in the stimulation of hair growth and helps growth of new and healthy hairs in mammalians. Beside the use of the present invention stated above, it may further be used in the treatment of alopecia areata, alopecia totalis, alopecia universalis, and other types of alopecia.
Except those which comprise finasteride, the formulations according to the present invention is suitable for use both in the females and the males, whereas the formulations according to the present invention comprising finasteride is preferably used by the males. The methods according to the prior art were used for obtaining all extracts used within the scope of the present invention.
A topical pharmaceutical formulation used in the treatment of a disease such as AGA which relates to the physical appearance of the respective patient has to ensure the continuation of the therapy without negatively effecting the life quality and psychology of the patient. One of the problems frequently encountered in pharmaceutical or cosmetic hair care products is that these products have an unpleasant odor which disturbs the user and his/her surrounding due to the substances comprised and that the users face difficulties in the daily use thereof due to the lack of features suitable for topical use. For this reason, the topical pharmaceutical formulation according to the present invention is formulated so as to be easily applicable and leave a natural feeling on the skin following application, as well as to have an odor and appearance which would not disturb the respective user and his/her surrounding. Having said that, these topical pharmaceutical formulations formulated according to the present invention does not cause irritation and itching on the skin. Therefore, the compliance of the patients to the therapy is enhanced and it is made possible to use the topical pharmaceutical formulation according to the present invention regularly and comfortably throughout the alopecia therapy.
The topical pharmaceutical formulation according to the present invention preferably comprises the followings: a. 0.01 % (w/v) to 15% (w/v) of minoxidil,
b. 0.05% (w/v) to 30% (w/v) of vitamin B6,
c. 0.01 % (w/v) to 20% (w/v) of panthenol,
d. 0.001 % (w/v) to 20% (w/v) of zinc sulfate heptahydrate,
e. 0.001 % (w/v) to 10% (w/v) of biotin,
f. 0.1 % (w/v) to 30% (w/v) of L-Arginine,
g. 0.005% (w/v) to 10% (w/v) of taurine,
h. 0.01 % (w/v) to 35% (w/v) of caffeine,
i. 0.05% (w/v) to 15% (w/v) of benzyl alcohol,
j. 0.01 % (w/v) to 10% (w/v) of PEG-75 shea butter glycerides,
k. 0.5% (w/v) to 80% (w/v) of propylene glycol,
I. 0.5% (w/v) to 80% (w/v) of ethyl alcohol,
m. 0.5% (w/v) to 80% (w/v) of water.
Another embodiment of the present invention, the topical pharmaceutical formulation preferably comprises the followings: a. 0.01 % (w/v) to 15% (w/v) of minoxidil,
b. 0.01 % (w/v) to 25% (w/v) of aminexil,
c. 0.05% (w/v) to 30% (w/v) of vitamin B6,
d. 0.01 % (w/v) to 20% (w/v) of panthenol,
e. 0.001 % (w/v) to 20% (w/v) of zinc sulfate heptahydrate,
f . 0.001 % (w/v) to 10% (w/v) of biotin,
g. 0.1 % (w/v) to 30% (w/v) of L-Arginine,
h. 0.005% (w/v) to 10% (w/v) of taurine,
i. 0.01 % (w/v) to 35% (w/v) of caffeine,
j. 0.05% (w/v) to 15% (w/v) of benzyl alcohol,
k. 0.01 % (w/v) to 10% (w/v) of PEG-75 shea butter glycerides,
I. 0.5% (w/v) to 80% (w/v) of propylene glycol,
m. 0.5% (w/v) to 80% (w/v) of ethyl alcohol,
n. 0.5% (w/v) to 80% (w/v) of water.
The topical pharmaceutical formulation according to the present invention more preferably comprises the followings: a. 0.5% (w/v) to 7.5% (w/v) of minoxidil,
b. 0.1 % (w/v) to 5% (w/v) of aminexil,
c. 0.05% (w/v) to 30% (w/v) of vitamin B6,
d. 0.01 % (w/v) to 20% (w/v) of panthenol,
e. 0.05% (w/v) to 10% (w/v) of zinc sulfate heptahydrate,
f. 0.001 % (w/v) to 10% (w/v) of biotin,
g. 0.1 % (w/v) to 30% (w/v) of L-Arginine,
h. 0.005% (w/v) to 10% (w/v) of taurine,
i. 0.01 % (w/v) to 35% (w/v) of caffeine,
j. 0.1 % (w/v) to 10% (w/v) of benzyl alcohol,
k. 0.1 % (w/v) to 5% (w/v) of PEG-75 shea butter glycerides,
I. 1 % (w/v) to 50% (w/v) of propylene glycol,
m. 0.5% (w/v) to 80% (w/v) of ethyl alcohol,
n. 0.5% (w/v) to 80% (w/v) of water.
The formulations disclosed above are preferably in the form of spray, tonic or serum.
The percent amount of a substance comprised by the topical pharmaceutical formulation according to the present invention represents the gram-based amount of that substance in a 100 ml formulation, and is expressed as weight/volume (w/v). A method for preparing a topical pharmaceutical formulation in order to achieve another object of the present invention is preferably composed of the following steps: a. alcohol, propylene glycol and water are weighed in the amounts stated and are mixed for a while at room temperature (mixture A),
b. minoxidil and preferably aminexil are added to mixture A and the resulting mixture is stirred for around 30 minutes until a homogeneous solution is obtained (mixture B), c. other ingredients of the formulation are added one by one to mixture B and the resulting mixture is stirred for at least 30 minutes at room temperature until a homogeneous solution is obtained (mixture C),
d. the mixture C is left settling for at least two hours and then subjected to filtration, e. the product obtained at the end of the settling period is subjected to a filling and packaging process.
The present invention is described in more details by means of the following examples. These examples are not limiting the scope of the present invention and are to be considered under the light of the foregoing detailed disclosure.
Examples:
Serum Formulations
Alcohol, propylene glycol, and water are weighed in the amounts stated in the following formulation, minoxidil is introduced after the resulting mixture is stirred for some period at room temperature, and is then stirred for around 30 minutes until a homogeneous solution is obtained. Then, other ingredients of the formulation are added one by one and the resulting mixture is stirred for at least 30 minutes at room temperature to give a homogeneous solution. The mixture is left settling for at least 2 hours and is then subjected to filtration. At the end of the settling period, a filling and packaging process is carried out. The production method described above can be adapted to all serum formulation examples given below. When the following formulation examples comprise aminexil or finasteride, aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
Formulation 1 Amount % (weight/volume)
Minoxidil 0.01 % to 15%
Vitamin B6 0.05% to 30%
Panthenol 0.01 % to 20%
Azelaic acid 0.5% to 30%
Zinc sulfate heptahydrate 0.001 % to 20%
Grape seed extract 0.05% to 20% Biotin 0.001 % to 10%
L-Arginine 0.1 % to 30%
Taurine 0.005% to 10%
Caffeine 0.01 % to 35%
Jojoba oil 1 % to 80%
Benzyl alcohol 0.05% to 15%
Retinol 0.01 % to 5%
Procyanidin 0.1 % to 10%
PEG-75 shea butter glycerides 0.01 % to 10%
Propylene glycol 0.5% to 80%
Ethyl alcohol 0.5% to 80%
Water 0.5% to 80%
Formulation 2 Amount % (weight/volume)
Minoxidil %0.1 to %10
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Azelaic acid %0.5 to %30
Zinc sulfate heptahydrate %0.001 to %20
Grape seed extract %0.05 to %20
Biotin %0.001 to %10
L-Arginine %0.1 to %30
Taurine %0.005 to %10
Caffeine %0.01 to %35
Jojoba oil %1 to %80
Benzyl alcohol %0.05 to %15
Retinol %0.01 to %5
Procyanidin %0.1 to %10
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 3 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Azelaic acid %0.5 to %30
Zinc sulfate heptahydrate %0.05 to %10
Grape seed extract %0.05 to %20
Biotin %0.001 to %10
L-Arginine %0.1 to %30
Taurine %0.005 to %10
Caffeine %0.01 to %35
Jojoba oil %1 to %80
Benzyl alcohol %0.1 to %10
Retinol %0.01 to %5
Procyanidin %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 4 Amount % (weight/volume)
Minoxidil %0.01 to %15
Aminexil %0.01 to %25
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Azelaic acid %0.5 to %30
Zinc sulfate heptahydrate %0.001 to %20
Grape seed extract %0.05 to %20
Biotin %0.001 to %10
L-Arginine %0.1 to %30
Taurine %0.005 to %10
Caffeine %0.01 to %35
Benzyl alcohol %0.05 to %15
Retinol %0.01 to %5
Procyanidin %0.1 to %10
PEG-75 shea butter glycerides %0.01 to %10
Propylene glycol %0.5 to %80
Ethyl alcohol %0.5 to %80
Water %0.5 to %80 Formulation 5 Amount % (weight/volume)
Minoxidil %0.1 to %10
Aminexil %0.05 to %15
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Azelaic acid %0.5 to %30
Zinc sulfate heptahydrate %0.001 to %20
Grape seed extract %0.05 to %20
Biotin %0.001 to %10
L-Arginine %0.1 to %30
Taurine %0.005 to %10
Caffeine %0.01 to %35
Benzyl alcohol %0.05 to %15
Retinol %0.01 to %5
Procyanidin %0.1 to %10
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 6 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Aminexil %0.1 to %5
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Azelaic acid %0.5 to %30
Zinc sulfate heptahydrate %0.05 to %10
Grape seed extract %0.05 to %20
Biotin %0.001 to %10
L-Arginine %0.1 to %30
Caffeine %0.01 to %35
Taurine %0.005 to %10
Benzyl alcohol %0.1 to %10
Retinol %0.01 to %5
Procyanidin %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Water %0.5 to %80 Formulation 7 Amount % (weight/volume)
Minoxidil %0.01 to %15
Finasteride %0.01 to %25
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Azelaic acid %0.5 to %30
Zinc sulfate heptahydrate %0.001 to %20
Grape seed extract %0.05 to %20
Saw palmetto extract %0.005 to %10
Biotin %0.001 to %10
L-Arginine %0.1 to %30
Taurine %0.005 to %10
Caffeine %0.01 to %35
Benzyl alcohol %0.05 to %15
Retinol %0.01 to %5
Procyanidin %0.1 to %10
PEG-75 shea butter glycerides %0.01 to %10
Propylene glycol %0.5 to %80
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 8 Amount % (weight/volume)
Minoxidil %0.1 to %10
Finasteride %0.05 to %15
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Azelaic acid %0.5 to %30
Zinc sulfate heptahydrate %0.001 to %20
Grape seed extract %0.05 to %20
Saw palmetto extract %0.005 to %10
Biotin %0.001 to %10
L-Arginine %0.1 to %30
Taurine %0.005 to %10
Caffeine %0.01 to %35
Benzyl alcohol %0.05 to %15
Retinol %0.01 to %5
Procyanidin %0.1 to %10
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Water %0.5 to %80 Formulation 9 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Finasteride %0.1 to %10
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Azelaic acid %0.5 to %30
Zinc sulfate heptahydrate %0.05 to %10
Grape seed extract %0.05 to %20
Saw palmetto extract %0.005 to %10
Biotin %0.001 to %10
L-Arginine %0.1 to %30
Taurine %0.005 to %10
Caffeine %0.01 to %35
Benzyl alcohol %0.1 to %10
Retinol %0.01 to %5
Procyanidin %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Spray/Tonic Formulations
Alcohol, propylene glycol, and water are weighed in the amounts stated in the following formulation, minoxidil is introduced after the resulting mixture is stirred for some period at room temperature, and then stirred for around 30 minutes until a homogeneous solution is obtained. Then, other ingredients of the formulation are added one by one and the resulting mixture is stirred for at least 30 minutes at room temperature to give a homogeneous solution. The mixture is left settling for at least 2 hours and is then subjected to filtration. At the end of the settling period, a filling and packaging process is carried out.
The production method described above can be adapted to all spray/tonic formulation examples given below. When the following formulation examples comprise aminexil or finasteride, aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
According to the present invention, the spray and tonic formulations are formulated so as to comprise the same unit formula. The difference of the spray formulations to the tonic formulations is that the spray formulations are administered to an affected site in the form of a spray by means of a device.
Formulation 1 Amount % (weight/volume)
Minoxidil 0.01 % to 15%
Vitamin B6 0.05% to 30%
Panthenol 0.01 % to 20%
Zinc sulfate heptahydrate 0.001 % to 20%
Biotin 0.001 % to 10%
Caffeine 0.01 % to 35%
Taurine 0.005% to 10%
L-Arginine 0.1 % to 30%
Benzyl alcohol 0.05% to 15%
PEG-75 shea butter glycerides 0.01 % to 10%
Propylene glycol 0.5% to 80%
Ethyl alcohol 0.5% to 80%
Water 0.5% to 80% Formulation 2 Amount % (weight/volume)
Minoxidil %0.1 to %10
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Zinc sulfate heptahydrate %0.001 to %20
Biotin %0.001 to %10
Caffeine %0.01 to %35
Taurine %0.005 to %10
L-Arginine %0.1 to %30
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 3 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Zinc sulfate heptahydrate %0.05 to %10
Biotin %0.001 to %10
Caffeine %0.01 to %35
Taurine %0.005 to %10
L-Arginine %0.1 to %30
Benzyl alcohol %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 4 Amount % (weight/volume)
Minoxidil %0.01 to %15
Aminexil %0.01 to %25
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Zinc sulfate heptahydrate %0.001 to %20
Biotin %0.001 to %10
Caffeine %0.01 to %35
Taurine %0.005 to %10
L-Arginine %0.1 to %30
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.01 to %10
Propylene glycol %0.5 to %80
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 5 Amount % (weight/volume)
Minoxidil %0.1 to %10
Aminexil %0.05 to %15
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Zinc sulfate heptahydrate %0.001 to %20
Biotin %0.001 to %10
Caffeine %0.01 to %35
Taurine %0.005 to %10
L-Arginine %0.1 to %30
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 6 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Aminexil %0.1 to %5
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Zinc sulfate heptahydrate %0.05 to %10
Biotin %0.001 to %10
Caffeine %0.01 to %35
Taurine %0.005 to %10
L-Arginine %0.1 to %30
Benzyl alcohol %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 7 Amount % (weight/volume)
Minoxidil %0.01 to %15
Finasteride %0.01 to %25
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Zinc sulfate heptahydrate %0.001 to %20
Saw palmetto extract %0.005 to %10
Biotin %0.001 to %10
Caffeine %0.01 to %35
Taurine %0.005 to %10
L-Arginine %0.1 to %30
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.01 to %10
Propylene glycol %0.5 to %80
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 8 Amount % (weight/volume)
Minoxidil %0.1 to %10
Finasteride %0.05 to %15
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Zinc sulfate heptahydrate %0.001 to %20
Saw palmetto extract %0.005 to %10
Biotin %0.001 to %10
Caffeine %0.01 to %35
Taurine %0.005 to %10
L-Arginine %0.1 to %30
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Water %0.5 to %80
Formulation 9 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Finasteride %0.1 to %10
Vitamin B6 %0.05 to %30
Panthenol %0.01 to %20
Zinc sulfate heptahydrate %0.05 to %10
Saw palmetto extract %0.005 to %10
Biotin %0.001 to %10
Caffeine %0.01 to %35
Taurine %0.005 to %10
L-Arginine %0.1 to %30
Benzyl alcohol %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Water %0.5 to %80 Gel Formulations
Ethyl alcohol, propylene glycol, and water are weighed in the amounts stated in the following formulation, minoxidil is introduced after the resulting mixture is stirred for some period at room temperature, and then stirred for around 30 minutes until a homogeneous solution is obtained. The pH value of the formulation is adjusted using triethanolamine. Then carbomer is added and is thoroughly mixed to give a gel formulation.
The production method described above can be adapted to all gel formulation examples given below. When the following formulation examples comprise aminexil or finasteride, aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
Figure imgf000025_0001
q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1. Formulation 3 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Carbomer %0.5 to %25
Zinc sulfate heptahydrate %0.05 to %10
Benzyl alcohol %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1.
Formulation 4 Amount % (weight/volume)
Minoxidil %0.01 to %15
Aminexil %0.01 to %25
Carbomer %0.1 to % 40
Zinc sulfate heptahydrate %0.001 to %20
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.01 to %10
Propylene glycol %0.5 to %80
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1.
Formulation 5 Amount % (weight/volume)
Minoxidil %0.1 to %10
Aminexil %0.05 to %15
Carbomer %0.2 to %30
Zinc sulfate heptahydrate %0.001 to %20
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1. Formulation 6 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Aminexil %0.1 to %5
Carbomer %0.5 to %25
Zinc sulfate heptahydrate %0.05 to %10
Benzyl alcohol %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1.
Formulation 7 Amount % (weight/volume)
Minoxidil %0.01 to %15
Aminexil %0.01 to %25
HPMC %0.01 to %40
HPC %0.5 to %40
Zinc sulfate heptahydrate %0.001 to %20
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.01 to %10
Propylene glycol %0.5 to %80
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1.
Formulation 8 Amount % (weight/volume)
Minoxidil %0.1 to %10
Aminexil %0.05 to %15
HPMC %0.1 to %30
HPC %1 .0 to %35
Zinc sulfate heptahydrate %0.001 to %20
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1. Formulation 9 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Aminexil %0.1 to %5
HPMC %0.1 to %25
HPC %1 .0 to %30
Zinc sulfate heptahydrate %0.05 to %10
Benzyl alcohol %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1.
Formulation 10 Amount % (weight/volume)
Minoxidil %0.01 to %15
Finasteride %0.01 to %25
HPMC %0.01 to %40
HPC %0.5 to %40
Zinc sulfate heptahydrate %0.001 to %20
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.01 to %10
Propylene glycol %0.5 to %80
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1.
Formulation 11 Amount % (weight/volume)
Minoxidil %0.1 to %10
Finasteride %0.05 to %15
HPMC %0.1 to %30
HPC %1 .0 to %35
Zinc sulfate heptahydrate %0.001 to %20
Benzyl alcohol %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
Propylene glycol %0.75 to %60
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80 q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1. Formulation 12 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Finasteride %0.1 to %10
HPMC %0.1 to %25
HPC %1 .0 to %30
Zinc sulfate heptahydrate %0.05 to %10
Benzyl alcohol %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Propylene glycol %1 to %50
Ethyl alcohol %0.5 to %80
Triethanolamine q.s.
Water %0.5 to %80
q.s.: Amount which is sufficient to set the pH of the formulation to 5.3±0.1.
Foam Formulations
Minoxidil is dissolved in an aqueous solution of Cremophor A 25. Some portion of the resulting solution is filled into suitable packages together with a mixture of propane and butane.
The production method described above can be adapted to the foam formulation examples given below. When the following formulation examples comprise aminexil or finasteride, aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
Figure imgf000029_0001
q.s.: Amount which is sufficient to bring the total volume of the formulation to 100 ml.
Figure imgf000029_0002
q.s.: Amount which is sufficient to bring the total volume of the formulation to 100 ml. Formulation 3 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
PEG-75 shea butter glycerides %0.1 to %5
Cremophor A 25 (Polyoxyl 25
%0.005 to %10
cetostearyl ether)
Water q.s.
q.s.: Amount which is sufficient to bring the total volume of the formulation to 100 ml.
Figure imgf000030_0001
q.s.: Amount which is sufficient to bring the total volume of the formulation to 100 ml.
Figure imgf000030_0002
q.s.: Amount which is sufficient to bring the total volume of the formulation to 100 ml.
100 ml.
Figure imgf000030_0003
q.s.: Amount which is sufficient to bring the total volume of the formulation to 100 ml. Formulation 8 Amount % (weight/volume)
Minoxidil %0.1 to %10
Finasteride %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
Cremophor A 25 (Polyoxyl 25
%0.005 to %10
cetostearyl ether)
Water q.s.
q.s.: Amount which is sufficient to bring the total volume of the formulation to
Formulation 9 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Finasteride %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
Cremophor A 25 (Polyoxyl 25
%0.005 to %10
cetostearyl ether)
Water q.s.
q.s.: Amount which is sufficient to bring the total volume of the formulation to 100 ml.
Minoxidil is dissolved in an aqueous solution of Polysorbate 60. The resulting solution is mixed with PEG-75 shea butter glycerides, BHT, glycerin, citric acid, cetyl alcohol, ethyl alcohol, and water. Some portion of the resulting solution is filled into suitable packages together with a mixture of propane and butane.
The production method described above can be adapted to the foam formulation examples given below. When the following formulation examples comprise aminexil or finasteride, aminexil or finasteride is also added in the step of adding minoxidil in the production method described above.
Formulation 1 Amount % (weight/volume)
Minoxidil 0.01 % to 15%
PEG-75 shea butter glycerides 0.01 % to 10%
BHT 0.5% to 1 .0%
Glycerin 0.5% to 80%
Citric acid 0.1 % to 2.0%
Cetyl alcohol 2.0% to 10.0%
Polysorbate 60 (Polyoxyethylene
0.1 % to 15%
Sorbitan Fatty Acid Esters)
Ethyl alcohol 0.5% to 50%
Water 0.5% to 80% Formulation 2 Amount % (weight/volume)
Minoxidil %0.1 to %10
PEG-75 shea butter glycerides %0.05 to %7.5
BHT %0.5 to %1 .0
Glycerin %0.5 to %80
Citric acid %0.1 to %2.0
Cetyl alcohol %2.0 to %10.0
Polysorbate 60 (Polyoxyethylene
%0.1 to %15 Sorbitan Fatty Acid Esters)
Ethyl alcohol %0.5 to %50
Water %0.5 to %80
Formulation 3 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
PEG-75 shea butter glycerides %0.1 to %5
BHT %0.5 to %1 .0
Glycerin %0.5 to %80
Citric acid %0.1 to %2.0
Cetyl alcohol %2.0 to %10.0
Polysorbate 60 (Polyoxyethylene
%0.1 to %15 Sorbitan Fatty Acid Esters)
Ethyl alcohol %0.5 to %50
Water %0.5 to %80
Formulation 4 Amount % (weight/volume)
Minoxidil %0.01 to %15
Aminexil %0.01 to %25
PEG-75 shea butter glycerides %0.01 to %10
BHT %0.5 to %1 .0
Glycerin %0.5 to %80
Citric acid %0.1 to %2.0
Cetyl alcohol %2.0 to %10.0
Polysorbate 60 (Polyoxyethylene
%0.1 to %15 Sorbitan Fatty Acid Esters)
Ethyl alcohol %0.5 to %50
Water %0.5 to %80 Formulation 5 Amount % (weight/volume)
Minoxidil %0.1 to %10
Aminexil %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
BHT %0.5 to %1 .0
Glycerin %0.5 to %80
Citric acid %0.1 to %2.0
Cetyl alcohol %2.0 to %10.0
Polysorbate 60 (Polyoxyethylene
%0.1 to %15 Sorbitan Fatty Acid Esters)
Ethyl alcohol %0.5 to %50
Water %0.5 to %80
Formulation 6 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Aminexil %0.1 to %5
PEG-75 shea butter glycerides %0.1 to %5
BHT %0.5 to %1 .0
Glycerin %0.5 to %80
Citric acid %0.1 to %2.0
Cetyl alcohol %2.0 to %10.0
Polysorbate 60 (Polyoxyethylene
%0.1 to %15 Sorbitan Fatty Acid Esters)
Ethyl alcohol %0.5 to %50
Water %0.5 to %80
Formulation 7 Amount % (weight/volume)
Minoxidil %0.01 to %15
Finasteride %0.01 to %25
PEG-75 shea butter glycerides %0.01 to %10
BHT %0.5 to %1 .0
Glycerin %0.5 to %80
Citric acid %0.1 to %2.0
Cetyl alcohol %2.0 to %10.0
Polysorbate 60 (Polyoxyethylene
%0.1 to %15 Sorbitan Fatty Acid Esters)
Ethyl alcohol %0.5 to %50
Water %0.5 to %80 Formulation 8 Amount % (weight/volume)
Minoxidil %0.1 to %10
Finasteride %0.05 to %15
PEG-75 shea butter glycerides %0.05 to %7.5
BHT %0.5 to %1 .0
Glycerin %0.5 to %80
Citric acid %0.1 to %2.0
Cetyl alcohol %2.0 to %10.0
Polysorbate 60 (Polyoxyethylene
%0.1 to %15 Sorbitan Fatty Acid Esters)
Ethyl alcohol %0.5 to %50
Water %0.5 to %80
Formulation 9 Amount % (weight/volume)
Minoxidil %0.5 to %7.5
Finasteride %0.1 to %10
PEG-75 shea butter glycerides %0.1 to %5
BHT %0.5 to %1 .0
Glycerin %0.5 to %80
Citric acid %0.1 to %2.0
Cetyl alcohol %2.0 to %10.0
Polysorbate 60 (Polyoxyethylene
%0.1 to %15 Sorbitan Fatty Acid Esters)
Ethyl alcohol %0.5 to %50
Water %0.5 to %80

Claims

1 . A topical pharmaceutical formulation comprising minoxidil and at least one penetration enhancer.
2. The topical pharmaceutical formulation according to Claim 1 , wherein said at least one penetration enhancer is selected from the group consisting of 1 ,3-didocyl urea, 1 ,3-difenyl urea, 1 ,8-cineole, 3-caren, 7-oxabicyclo 2,2-heptan, ascaridol, dimetyl isosorbide, dimetyl formamide (DMF), d-limonen, isopropyl myristat, carveol, carvon, menton, N-metyl-2-pyrolidon, NN-dimetyl toluamide, oleic acid, pinen oxide, cyclohexan oxide, cyclopenten oxide, PEG, PEG-75, PEG-75 shea butter glycerides, sodium lauryl sulfate, terpinen-4-ol, urea, a-pinene, a-terpinol, or the mixtures thereof.
3. The topical pharmaceutical formulation according to Claim 2, wherein said penetration enhancer is selected from the group consisting of PEG, PEG-75, PEG-75 shea butter glycerides, or the mixtures thereof.
4. The topical pharmaceutical formulation according to Claim 3, wherein said penetration enhancer is PEG-75 shea butter glycerides.
5. The topical pharmaceutical formulation according to Claim 4, wherein the percent amount of PEG-75 shea butter glycerides is between 0.01 % (w/v) and 10% (w/v), preferably between 0.05% (w/v) and 7.5% (w/v) based on the total volume of the formulation.
6. The topical pharmaceutical formulation according to any of the preceding claims, wherein the percent amount of minoxidil is between 0.01 % (w/v) and 15% (w/v), preferably between 0.1 % (w/v) and 10% (w/v) based on the total volume of the formulation.
7. The topical pharmaceutical formulation according to any of the preceding claims, wherein said formulation further comprising aminexil.
8. The topical pharmaceutical formulation according to Claim 7, wherein the percent amount of aminexil is between 0.01 % (w/v) and 25% (w/v), preferably between 0.05% (w/v) and 15% (w/v) based on the total volume of the formulation.
9. The topical pharmaceutical formulation according to any of the preceding claims, further comprising one or more pharmaceutically acceptable excipient selected from the group comprising viscosity enhancers, preservatives, gelling agents, antioxidants, surface active agents, solvents, chelating agents, silicon oils, buffering agents, emulsifying agents, or the mixtures thereof.
10. The topical pharmaceutical formulation according to Claim 9, wherein the preservative is selected from the group comprising methylparaben, propylparaben, sodium and potassium benzoate, imidurea, monothioglycol, potassium sorbate, benzoic acid, sorbic acid, sodium sorbate, cetrimide, benzalkonium chloride, glycerin, benzyl alcohol, butylparaben, ethylparaben, chlorobutanol, chlorhexidine, or the mixtures thereof, the preferred preservative is benzyl alcohol.
1 1 . The topical pharmaceutical formulation according to Claim 10, wherein the percent amount of benzyl alcohol is between 0.05% (w/v) and 15% (w/v), preferably between 0.1 % (w/v) and 10% (w/v) based on the total volume of the formulation.
12. The topical pharmaceutical formulation according to any of the preceding claims, further comprising an antifungal agent.
13. The topical pharmaceutical formulation according to Claim 12, wherein the antifungal agent is zinc sulfate heptahydrate.
14. The topical pharmaceutical formulation according to Claim 13, wherein the percent amount of zinc sulfate heptahydrate is between 0.001 % (w/v) and 20% (w/v), preferably between 0.05% (w/v) and 10% (w/v) based on the total volume of the formulation.
15. The topical pharmaceutical formulation according to Claim 9, wherein the solvent is selected from the group comprising ethyl alcohol, methyl alcohol, polyethylene glycol, glycerin, isopropyl alcohol, butylene glycol, propylene glycol, tetrahydrofuran, ether, liquid vaseline, benzene, toluene, pentane, hexane, heptane, acetone, methyl ethyl ketone, chloroform, methylene chloride, ethylene dichloride, ethyl acetate, mineral oils and water, or the mixtures thereof, the preferred solvent is the mixture of propylene glycol, ethyl alcohol, and water.
16. The topical pharmaceutical formulation according to Claim 15, wherein the percent amount of propylene glycol is between 0.5% (w/v) and 80% (w/v), preferably between 0.75% (w/v) and 60% (w/v) based on the total volume of the formulation.
17. The topical pharmaceutical formulation according to any of the preceding claims, wherein said formulation further comprising at least one active agent selected from the group comprising finasteride, pinacidil, nicorandil, chromakalim, flupirtine, turosteride, epristeride, oxycanthin, catechin, epicatechin, epicatechin-3-gallate, linoleic acid, gamma linoleic acid, retinol, epigallocatechin-3-gallate, vitamin B, vitamin C, vitamin E, oligomeric proanthocyanidin or proanthenol, procyanidin, silymarin, echinacoside, carotenoid, aminobenzoic acid, ascorbic acid, benzoic acid, estradiol and other topical hormones, lanolin, nucleic acids, pantothenol, sulfanilamide, ginkgo biloba, green tea polyphenols, lutein, lycopene, progesterone, cyproterone acetate, azelaic acid and the derivatives thereof, panthenol, biotin, caffeine, taurine, L-arginine, panax ginseng extract, saw palmetto (Serenoa repens) extract, grape seed extract, jojoba oil, argan oil, and the mixtures thereof.
18. The topical pharmaceutical formulation according to Claim 17, wherein said formulation further comprising at least one active agent selected from the group consisting of finasteride, vitamin B6, panthenol, azelaic acid, zinc sulfate heptahydrate, grape seed extract, biotin, L-arginine, taurine, panax ginseng extract, saw palmetto (Serenoa repens) extract, caffeine, jojoba oil, retinol and procyanidin.
19. The topical pharmaceutical formulation according to any of the preceding claims, wherein said formulation is in the form of a gel, ointment, cream, foam, spray, tonic, serum, paste, or lotion, preferably in the form of spray, tonic or serum.
20. The topical pharmaceutical formulation according to any of the preceding claims, comprising the followings: a. 0.01 % (w/v) to 15% (w/v) of minoxidil,
b. 0.05% (w/v) to 30% (w/v) of vitamin B6,
c. 0.01 % (w/v) to 20% (w/v) of panthenol,
d. 0.001 % (w/v) to 20% (w/v) of zinc sulfate heptahydrate,
e. 0.001 % (w/v) to 10% (w/v) of biotin,
f. 0.1 % (w/v) to 30% (w/v) of L-Arginine,
g. 0.005% (w/v) to 10% (w/v) of taurine,
h. 0.01 % (w/v) to 35% (w/v) of caffeine,
i. 0.05% (w/v) to 15% (w/v) of benzyl alcohol,
j. 0.01 % (w/v) to 10% (w/v) of PEG-75 shea butter glycerides,
k. 0.5% (w/v) to 80% (w/v) of propylene glycol,
I. 0.5% (w/v) to 80% (w/v) of ethyl alcohol,
m. 0.5% (w/v) to 80% (w/v) of water.
21 . The topical pharmaceutical formulation according to any of the preceding claims, comprising the followings: a. 0.01 % (w/v) to 15% (w/v) of minoxidil, b. 0.01 % (w/v) to 25% (w/v) of aminexil,
c. 0.05% (w/v) to 30% (w/v) of vitamin B6,
d. 0.01 % (w/v) to 20% (w/v) of panthenol,
e. 0.001 % (w/v) to 20% (w/v) of zinc sulfate heptahydrate,
f. 0.001 % (w/v) to 10% (w/v) of biotin,
g. 0.1 % (w/v) to 30% (w/v) of L-Arginine,
h. 0.005% (w/v) to 10% (w/v) of taurine,
i. 0.01 % (w/v) to 35% (w/v) of caffeine,
j. 0.05% (w/v) to 15% (w/v) of benzyl alcohol,
k. 0.01 % (w/v) to 10% (w/v) of PEG-75 shea butter glycerides,
I. 0.5% (w/v) to 80% (w/v) of propylene glycol,
m. 0.5% (w/v) to 80% (w/v) of ethyl alcohol,
n. 0.5% (w/v) to 80% (w/v) of water.
22. The topical pharmaceutical formulation according to Claim 21 , comprising the followings: a. 0.5% (w/v) to 7.5% (w/v) of minoxidil,
b. 0.1 % (w/v) to 5% (w/v) of aminexil,
c. 0.05% (w/v) to 30% (w/v) of vitamin B6,
d. 0.01 % (w/v) to 20% (w/v) of panthenol,
e. 0.05% (w/v) to 10% (w/v) of zinc sulfate heptahydrate,
f. 0.001 % (w/v) to 10% (w/v) of biotin,
g. 0.1 % (w/v) to 30% (w/v) of L-Arginine,
h. 0.005% (w/v) to 10% (w/v) of taurine,
i. 0.01 % (w/v) to 35% (w/v) of caffeine,
j. 0.1 % (w/v) to 10% (w/v) of benzyl alcohol,
k. 0.1 % (w/v) to 5% (w/v) of PEG-75 shea butter glycerides,
I. 1 % (w/v) to 50% (w/v) of propylene glycol,
m. 0.5% (w/v) to 80% (w/v) of ethyl alcohol,
n. 0.5% (w/v) to 80% (w/v) of water.
23. A method for preparing the topical pharmaceutical formulation according to any of the preceding claims, comprising the following steps: a. weighing alcohol, propylene glycol, and water in the amounts stated and mixing the resulting mixture for a while at room temperature (mixture A), b. adding minoxidil and preferably aminexil to mixture A and stirring the resulting mixture for around 30 minutes until a homogeneous solution is obtained (mixture B),
c. adding other ingredients of the formulation one by one to mixture B and stirring the resulting mixture for at least 30 minutes at room temperature until a homogeneous solution is obtained (mixture C),
d. leaving mixture C for settling for at least two hours and then subjecting the mixture to filtration,
e. subjecting the product obtained at the end of the settling period to a filling and packaging process.
PCT/EP2014/059722 2013-05-14 2014-05-13 Hair care formulations WO2014184173A1 (en)

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WO2018015973A1 (en) * 2016-07-21 2018-01-25 Khorakiwala Habil F Topical pharmaceutical composition for promoting hair growth and/or reducing hair loss
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EP3840725A4 (en) * 2018-08-26 2022-06-08 Hair Plus Health LLC Methods and compositions to increase hair growth and/or prevent hair loss
CN115475111A (en) * 2022-09-23 2022-12-16 上海纳米技术及应用国家工程研究中心有限公司 Hair growth stock solution matched with microneedle for use, and preparation method and application thereof
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EP3840725A4 (en) * 2018-08-26 2022-06-08 Hair Plus Health LLC Methods and compositions to increase hair growth and/or prevent hair loss
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CN115475111A (en) * 2022-09-23 2022-12-16 上海纳米技术及应用国家工程研究中心有限公司 Hair growth stock solution matched with microneedle for use, and preparation method and application thereof

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