Field of invention

The present invention relates to the preparation of pharmaceutical compositions comprising minoxidil; and also relevant excipients, useful for the topical treatment (regrowth) of androgenic alopecia in males and females and stabilisation of hair loss in patients with androgenic alopecia.

Background of the invention

Androgenetic alopecia is a common form of hair loss in both men and women. Alopecia, or hair loss, in its various forms is an ongoing problem effects humankind. Men, women and children can all suffer from disease of alopecia, The reasons can be of one, or a combination of different factors including genetic factors, hormonal factors, surgery, trauma, chemotherapy, aging, certain drug side effects and stress.

Minoxidil is one of topical active ingredient used for alopecia treatment. It is a medication used for the treatment of male-pattern hair loss and also high blood pressure. It is effective in helping promote hair growth in people with androgenic alopecia regardless of sex.

Minoxidil is available as a generic medication by prescription in oral tablet form and over the counter as a topical gel, liquid or foam.

Minoxidil, has a chemical name as 2-Imino-6-(l-piperidinyl)-l,2-dihydro-4-pyrimidinamine 3 -oxide and its chemical structure is shown in the Figure I. Minoxidil has molecular weight of 209.248 g/mol, is a white or almost white crystalline powder.

Figure 1: Minoxidil One of the existing drug comprising minoxidil in topical product is Regaine marketed by Johnson & Johnson. This product is available in the form of foam and solution for men and also women. It is used to treat baldness or Androgenetic alopecia’s long-term, hair loss prevention and hair growth. Regaine includes butane, butylated hydroxytoluene, cetyl alcohol, citric acid mono hydrate, glycerin, isobutane, lactic acid, polysorbate 60, propane, stearyl alcohol and water.

Summary of the invention

Present invention relates to a topical pharmaceutical composition comprising; a) 0,1 to 5,0 % by weight of minoxidil, b) a gelling agent, c) one or more pharmaceutically acceptable excipients.

Present invention relates to a topical pharmaceutical composition comprising; a) 5,0 % by weight of minoxidil, b) a gelling agent, c) one or more pharmaceutically acceptable excipients.

Present invention relates to a topical pharmaceutical composition comprising; a) 5,0 % by weight of minoxidil, b) Hydroxyethyl Acrylate / Sodium Dimethyl Acryloyl Taurate Copolymer as a gelling agent, c) one or more pharmaceutically acceptable excipients.

The present invention also relates to a process for preparing a topical pharmaceutical gel composition and uses of the composition.

Detailed description of the invention

Minoxidil particularly has many advantages for the treatment of hair loss or baldness. Active ingredient of minoxidil has been used to treat of alopecia for many years.

Minoxidil is a wellknown pharmaceutical active ingredient for treatment of androgenic alopecia and it is proven with many clinical studies.

Genetic and environmental factors play a major role in causing androgenetic alopecia. Although researchers are studying risk factors that may contribute to this condition, most of these factors still remain unknown.

Investigations continue to understand the connection between androgenetic alopecia and other medical diseases, such as coronary heart disease and prostate cancer in men and polycystic ovary syndrome in women. The hair loss may be related to alopecia disease for men and/or women. Related indications may include weakening of hair strength, loss of hair colour and the like.

Minoxidil is a pharmaceutically active ingredient having several indications including use as a hair growth stimulant.

The composition of the present invention is also useful for preventing hair loss and thinning hair.

Minoxidil is externally applied then it shows excellent hair-fostering and hair growing effects. Minoxidil’s property of hair restorer is accepted prevalently.

In the market, there are many minoxidil pharmaceutical products including OTC with different dosage forms such as foam, solution or gel.

Minoxidil has poor solubility in water and ethanol and pharmaceutical preparations currently marketed only contain with a percentage of minoxidil that is, below 5%.

In one embodiment, the invention provides a topical composition containing the composition that is suitable for administering to mammalian skin, such as human skin.

In one embodiment, such topical composition contains an effective amount of (i) the composition, and (ii) a pharmaceutically acceptable carrier.

The dosage form of the minoxidil containing composition for external use is not particularly limited. The dosage form is preferably a gel, a lotion, or a liquid.

The present inventions provide pharmaceutical compositions comprising minoxidil and relevant excipients, characterized by i) to control / program the release of the active ingredient according to desired therapeutical needs such as hair loss or baldness, ii) a simple and competitive manufacturing process to achieve effect of hair restorer in medically.

Present invention relates to a specific topical pharmaceutical gel composition comprises a) 0,1 to 5,0 % by weight of minoxidil, b) a gelling agent, c) one or more pharmaceutically acceptable excipients.

Present invention relates to a specific topical pharmaceutical gel composition comprises a) 5,0 % by weight of minoxidil, b) a gelling agent, c) one or more pharmaceutically acceptable excipients.

In one embodiment of the invention, the weight ratio of minoxidil is between 0,1 to 5,0 % (w/w) in topical gel composition. In one embodiment of the invention, the weight ratio of minoxidil is 2,0 % (w/w) in topical gel composition.

In one embodiment of the invention, the weight ratio of minoxidil is 5,0 % (w/w) in topical gel composition.

Gelling agents are commonly used for topical gel compositions. Gelling agents has selfgelling and thickening properties and also the ability to emulsify oily phases, which make it easy to use in the formulation of gels and o/w emulsion gels.

In one embodiment, gelling agents can be selected from polymers or copolymers. Some copolymers are used as a gelling agent for topical pharmaceutical or cosmetic products. Because of their structure and characteristics, it is very useful for topical products.

Sepineo Derm is a brand of Seppic that is used as a gelling agent and in copolymer structure. Structure of Sepineo Derm is a copolymer of hydroxyethyl acrylate and sodium acryloyl dimethyl taurate.

According to Seppic - manufacturer of Sepineo Derm, it is a ready-to-use polymer in powder form with thickening, stabilizing and texturizing properties.

Using Sepineo Derm has some advantages in manufacturing process. Firstly, it is preneutralised powder and therefore does not require a neutralisation step before use. Also, it is dispersible in aqueous or fatty phases and can be mixed equally well in a hot or cold process. Additionally, it is UV resistant, allowing the use of transparent or clear packaging without compromising the formula’s stability.

The compositions according to the invention may also comprise gelling agents ranging from 0.1 to 3% by weight relative to the total weight of the composition.

Preferably the compositions of the invention preferentially contain from 0.1 to 3%, and preferably from 0.8 to 1.4%, of gelling agent, more preferably 1.1 %.

In one embodiment, present invention relates to a specific topical pharmaceutical gel composition comprises a) 5,0 % by weight of minoxidil, b) 1,1 % by weight of gelling agent, c) one or more pharmaceutically acceptable excipients.

In one embodiment, present invention relates to a specific topical pharmaceutical gel composition comprises a) 5,0 % by weight of minoxidil, b) 1,1 % by weight of copolymer of hydroxy ethyl acrylate and sodium acryloyl dimethyl taurate, c) one or more pharmaceutically acceptable excipients. The invention also relates to a process for preparing a topical pharmaceutical gel compositions as described above, comprising the steps of: a) Adding: Ethanol, distilled water and propylene glycole b) Mixing: Minoxidil c) Mixing: Gelling agent d) Mixing: Menthol and ethanol e) Made up volume with ethanol e) Filling f) Packaging.

It is found that when present invention of minoxidil gel composition, is prepared with a gelling agent such as Hydroxy ethyl Acrylate / Sodium Dimethyl Acryloyl Taurate Copolymer, Franz diffusion results were satisfy. (Table 1)

Advantages

The present invention provides pharmaceutical composition comprising minoxidil characterized by a) Simple and also competitive manufacturing process, b) Enhanced patient compliance and convenience, c) The product is administered easily and quickly, d) A dose can be removed with out contamination of materials, e) Eower dose of drug can be used and hence minimize adverse and side effects, f) Medication can be delivered directly to the affected area in a desired form, g) Irritation produced by the mechanical application of topical medication is reduced or eliminated.

The present invention shows well physical properties depends on its solubility characteristics in appropriate excipients for topical compositions. It shows good properties to provide basic physical stability.

The success of a dermotological drug depends on the ability of the drug to penetrate through skin in sufficient quantities to achieve the desired therapeutic effect. The present invention provides to increase the rate of percutaneous penetration, thereby shortening the time period in which the active agents can show their effect.

In one aspect, the components of the pharmaceutical composition according to the present invention are brought together into a gel for topical administration according to standard practice and procedures well known to one of ordinary skill in the art using conventional composition and manufacturing techniques.

Another object is to provide improved manufacturing processes which is simple, cost- effective and time saving for preparing the topical compositions of minoxidil. The present invention relates a composition comprising minoxidil as an active ingredient for external use, and also relates to a minoxidil composition, which is clear and viscous, is inhibited from dripping, and has a good comfort of use.

In an embodiment, the invention provides pharmaceutical composition comprising minoxidil as an active agent, process of preparation thereof and method of using the same.

In an embodiment, the invention provides a topical pharmaceutical composition comprising effective amount of minoxidil as an active agent and process of preparation thereof.

In an embodiment, the invention provides method to treating one or more dermatological conditions such as androgenic alopecia, baldness or hair loss and the like, by applying topical pharmaceutical composition of minoxidil onto the the affected skin area of a subject in need of such treatment.

The composition of the invention can be packed into suitable containers such as bottle, tube, pouch, or suitable container.

The topical gel composition of minoxidil comprises one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, gelling agents, polymers, aromas, emollients, solvents, pH adjusting agents, preservatives, fragrances, stabilizers, penetration enhancers, moisturizers, and mixtures thereof.

Gelling agents can be selected from the group, but are not limited to, carbomer, Carbopol 981, Carbopol ETD 2020, Carbopol 980, Carbopol Ultrez 10 NF and Pemulen TRI, Hydroxyethyl Aery late/S odium Dimethyl Acryloyl Taurate Copolymer (such as Sepineo Derm) or the family of modified starches or mixtures thereof. The preferred gelling agent is Hydroxyethyl Aery late/S odium Dimethyl Acryloyl Taurate Copolymer.

Solvents/cosolvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvents are ethanol, propylene glycol and distilled water.

Aromas can be selected from the group, but are not limited to, natural aroma oil (e.g. peppermint oil, partridge currant oil, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil, etc.), menthol, mentane, anethole, methyl salicylate, eucalyptol, cinnamon, 1- methyl acetate, salvia, eugenol, oxanone, alpha-ionone, marjoram, lemon, orange, propenyl guaethol acetyl, sinnamon, vanilla, thymol, linaolol, cinnamaldehyde glycerol acetal, N- substituted p-menthane-3-carboxyamide, 3,1- methoxy propane 1,2-diol.and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred aroma is menthol.

As used herein, the term "treating" or "treatment" means the alleviation or elimination of symptoms, cure, prevention, or inhibition of a disease or medical condition, or improvement of tissue growth/healing or cosmetic conditions. The topical composition may be any form suitable for application to the skin or an animal or human. The forms may include gels, solutions, lotions, ointments, mousses, foams, sprays, aerosols, shampoos, creams, pastes or other topical composition forms known in the art.

The topical compositions may be made into a wide variety of products that include but are not limited to leave-on products (such as lotions, creams, gels, sticks, sprays, and ointments), hair products (such as shampoos, conditioners, sprays, and mousses) and the like. These product types may contain any of several pharmaceutically acceptable carrier forms including, but not limited to solutions, suspensions, emulsions such as microemulsions and nanoemulsions, gels, and solids carrier forms. Other product forms can be formulated by those of ordinary skill in the art.

The term “pharmaceutically acceptable” means molecular entities and compositions that are of sufficient purity and quality for use in the formulation of a composition or medicament of the present invention.

“Pharmaceutically acceptable excipients” are components that are added to the pharmaceutical formula tion other than the active ingredient ivermectin. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance skin penetration, enhance patient acceptability etc. Pharmaceutically acceptable excipients includes, but not limited to, one or more filler, gelling agent, surfactant, humectant, pH modifier, chelating agent, acidifying agent, viscosity enhance, solvent, vehicle, oily vehicle, color, preservative, suspending agent, dispersing agent, and any other excipient known to the art for making pharmaceutical formulation.

The term “reference product” means Regaine product comprising minoxidil 5% from Johnson & Johnson Limited, UK with an expiry date 07/2021.

The term “competitor product” means Tugain Gel product comprising minoxidil 5% from CiplaMed, India with an expiry date 04/2021.

The term “test product” means Minoxidil Gel product comprising minoxidil 5% from Pharmactive, Turkey with an expiry date 08/2021.

Example for gel composition comprising minoxidil is below.

Example: Minoxidil Gel Composition

Figure 1: Manufacturing flowchart for pharmaceutical composition comprising minoxidil topical gel. Franz diffusion study

A Franz diffusion cell system is used as an apparatus for transdermal permeation test, which used a dialyses membrane has receptor media (20/80 Ethanole/water) with 0,45 pm PTFE filter. Samples were collected from the receptor compartment at scheduled time points of 0,5 hour, 1 hour, 2 hours, 3 hours, 4 hours and 5 hours. 1 mL of the sample was collected and analyzed to determine a 5 hour cumulative permeation amount (pg/cm2) for the percutaneous absorption preparation containing minoxidil. The results are presented in Table 1.

Table 1: Franz diffusion study results of test product, reference product (Regaine) and competitor product (Tugain Gel)

Time (h)

As can be seen from Table 1, the percutaneous absorption preparations using test product shows a skin permeation equivalent to or higher than the competitor product (Tugain Gel).

Viscosity results of test product and competitor product (Tugain Gel) are shown in Table 2.

Table 2: Analysis results of viscosity for test product and competitor (Tugain Gel)

Table 3: Initial pH results of present invention for test product, reference product (Regaine) and competitor product (Tugain Gel)

„ „ Competitor

Reference Initial results . _ . . product Test product product (Regaine) (Tugain Gel) pH 8,37 7,51 8,60

There is no significient changes were observed for initial pH values of the test product, reference product (Regaine) and competitor product (Tugain Gel). (Table 3)

Table 4: Impurity results of present invention for test product, reference product (Regaine) and competitor product (Tugain Gel) (Initial)

Competitor

Related Substances , Test product product > (Impurities) (Minoxidil gel) (Tugain Gel) ^s ’

Impurity A 051 04

Impurity B Not detected Not detected

Impurity E 0,03 Not detected

The Biggest Unidentified Impurity Not detected 0,02

Total Impurity 0,54 0,05

According to table 4, test product has advantages for impurities comparing to competitor product.