WO2019070142A2

WO2019070142A2 - Topical lotion for hair loss treatment (biohair®)

Info

Publication number: WO2019070142A2
Application number: PCT/QA2018/000002
Authority: WO
Inventors: Ahmad Mohd H H AL-SULAITI
Original assignee: Qatar Pharma For Pharmaceuticals Industries
Priority date: 2017-10-08
Filing date: 2018-04-09
Publication date: 2019-04-11
Also published as: WO2019070142A3

Abstract

Increase in the rate of hair growth, stimulation of hair follicles to produce new hair growth, prolongation of the anagen phase of the hair cycle, conversion of vellus hair to growth as terminal hair, and treatment of alopecia due to organic dysfunction of the hair follicles in the scalp is attained by topical application of The combination has been administered or applied with minoxidil, retinoids, Clobetasol propionate, AC.NET and Phytantriol

Description

TOPICAL LOTION FOR HAIR LOSS TREATMENT (BIOHAIR®)

L ABSTRACT

Increase in the rate of hair growth, stimulation of hair follicles to produce new hair growth, prolongation of the anagen phase of the hair cycle, conversion of vellus hair to growth as terminal hair, and treatment of alopecia due to organic dysfunction of the hair follicles in the scalp is attained by topical application of The combination has been administered or applied with minoxidil, retinoids, Clobetasol propionate, AC.NET and Phytantrio.1 . BACKGROUND OF THE INVENTION 2J . Description of the Prior Art

MINOXIDIL is an antihypertensive vasodilator medication and is used to treat hair loss. It is available as a generic medication and over the counter for the treatment of androgenic alopecia, stop hair loss and even new hair growth in men and women. MINOXIDIL is a medication that has had long term testing in the treatment for hair loss. The drug was originally developed to treat high blood pressure and a side effect of causing hair growth was discovered. It is still not exactly how MINOXIDIL works to cause hair growth, but we do know that in a small percentage of men and women terminal hair will re-grow .The fact that the rate of hair loss slows down. In fact the latest research shows that there is an 80% possibility of slowing down or even stopping the process of hair loss in men and women. In general, 5% (extra strength) is recommended for men, while 2% (regular strength) is suggested for women.

Figure (1), (2), (3), (4)

2,2» Field of the Invention

The invention relates to the use of (retinoic acid) , (clobetasol propionate), (AC.NET™) and (Phytantriol ) in combination with minoxidil (2 , 4,-diamino-6- piperidino- pyrimidirie-3-oxide) in order to increase the rate of growth of human scalp hair and to treat certain types of alopecias.

THE INVENTION is a unique and innovative formulation developed to be an effective role of providing the appropriate conditions for stem cells for hair regrowth in baldness, hair loss and low hair density through the daily use of THE INVENTION that the impressive results of hair growth are usually visible after use of the product within 1 to 2 months and Hair growth improves with continuous use of THE INVENTION.

THE INVENTION is an integrated formulation; combination of Retinoic acid (Vitamin A) with Minoxidil enhances the penetration of THE INVENTION into the scalp and increases its effectiveness by stimulating hair follicles

• Hair growth from its origin. •Increase the number of hair significantly.

• Increase hair density.

• Hair texture becomes more boosted.

Stem cells have a key role in the hair building up process and regeneration of new hair. Hair follicles naturally contain stem cells that have an unprecedented effect on the renewed growth of hair. Increasing of blood flow to scalp will allow stem cells to be supplied by nutrients and oxygen needed to stimulate hair follicles to produce new and healthy hair. However, if stem cells environment deteriorated, it can reduce their activities and effectiveness, resulting in weak hair follicles and reduced hair density.

THE INVENTION treats the oily scalp, reducing hyper seborrhea and inflammation and thus reducing proliferation of bacteria. And treat inflammation arid itching of the skin caused by any cases such as allergies and eczema. THE INVENTION makes hair to be soft and keep it in a healthy appearance.

The synergistic combination of Retinoids and Minoxidil (2, 4,-diamino-6- piperidino- pyrimidine-3-oxide) with topical steroid (clobetasol propionate) and an association of oleanolic acid and nordihydroguaiaretic acid(AC.NET™) and Phytantriol to Increase the Rate of Growth of Human Scalp Hair to prolong the anagen phase of the hair cycle, to convert vellus hair to grow as terminal hair, and to treat certain Types of Alopecias.

Alopecia results when the pilar cycle is disturbed, resulting in excessive hair loss. The most frequent phenomenon is a shortening of the hair growth phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out. This shortening of the growth or anagen phase of the pilar cycle may have different origins, among which are very diverse pathological origins such as febrile conditions, mental stresses, hormonal problems (such as androgeneiic alopecia due to male hormones) and secondary effects of drugs. Alopecia may also be due to age and to a slowing down of mitotic activity. This dysfunction of the biological mechanism of hair growth leading to alopecia may be regarded as a disease. While there are other causes of alopecia such as greasy or oily scalp due to seborrhea and the dandruff accompanying it, the present invention is not directed to treating these extraneous causes of alopecia, but rather to treating the organic dysfunction of the hair follicle. Figure (6), (7).

This invention concerns the use of certain retinoids, including all-trans retinoic acid (Tretinoin) in combination with minoxidil in order to increase the rate of hair growth and to treat various alopecias. All Trans' retinoic acid can also be shown to increase the turnover time of epidermal cells in cell culture experiments as well as in vivo experiments with human subjects. The present inventor has discovered that the cells of the hair follicle including the papillae can be stimulated by retinoids including all-trans retinoic acid. When tested experimentally, the retinoids caused the cells of the dermal papillae and the cells of the root sheath to incorporate more tritiated thymidine into DNA and to reproduce at a more rapid rate than untreated cells from other hair follicles. This stimulation by the retinoid compounds ultimately causes the entire hair follicle to become more activated. Therefore, the individual scalp hairs can be shown to grow at an increased rate and the anagen phase is prolonged. Figure (8).

A major problem in influencing alopecia is to revascularize the area of alopecia and initiate the primary new hair growth. All-trans retinoic acid has been shown to give excellent percutaneous absorption and to be very active on the keratinizing cells of the skin, including the hair follicle, however, it is difficult for retinoids alone to revascularize the area of the pilosebaceous apparatus.

Studies have shown that minoxidil, a potent antihypertensive medication and peripheral vasodilator can increase the rate of hair growth on the body when taken systemically, particularly in areas of the limbs and facial areas, primarily due to vasodilatory properties. Further studies have suggested that minoxidil may be effective in initiating and promoting veil us hair growth on the scalp in individuals with alopecia, however, minoxidil is not able to sustain the growth of terminal hairs from vellus hairs on the scalp; and in the majority of subjects w⁷ith alopecia even pronounced vellus hair growth on the scalp is not initiated or sustained by the topical application of minoxidil nor by the systemic administration. The mechanism by which minoxidil exerts its effect is believed to be revascularization and by its vasodilatory properties, however, vasodilation alone is not sufficient stimulus for hair growth, particularly in an area affected by alopecia.

The synergistic combination of Retinoids and Minoxidil can increase the rate of hair growth in both males and females and can prolong the anagen phase of the hair cycle thereby converting vellus to terminal follicles. The mechanism of action of the retinoid compounds is believed to be through the initiation and activation of increased cell differentiation, i.e., compounds which of themselves can initiate the differentiation of cells of the pilosebaceous apparatus which eventually form the hair follicle and become terminal hairs.

Because of the advanced state of scalp thinning and atrophy of the pilary portion of the pilosebaceous apparatus, it is difficult to initiate hair growth from areas of advanced male pattern alopecia. Certain of the retinoid compounds sustain and promote hair growth in areas where some hair is present to some extent.

The present application is for the use of all-trans retinoic acid (Tretinoin) with minoxidil. The stimulatory actions of both compounds can promote each other's effectively, i.e., synergism, retinoid can initiate cell growth and differentiation (not initiated by minoxidil) and minoxidil can promote the vasodilator action not readily obtained with the retinoid. While neither compound alone can have profound effects on advanced alopecia, in combination the compounds are very effective as promoters of new hair, growth in areas of alopecia.

The net result of application of minoxidil and retinoids is initiating and production of new hair growth, and conversion of vellus to terminal hair growth, i.e., the increase in size from a vellus to a terminal hair and the continued and more prolonged maintenance of the hair in the anagen phase.

As rioted previously, this effect is obtained not only as the addition of two compounds but as synergism, i.e., the combination of these substances in the present invention produces an effect which cannot be produced by either compound separately under conditions of its use and, therefore, represents a major advance in the treatment of alopecia.

The pharmaceutical or cosmetic preparation of the present invention can be prepared by the conventional techniques for the preparation of lotions, creams, conditioners or shampoos for the scalp. In addition to the active retinoid and minoxidil of this invention, the various preparations can contain any conventional pharmaceutically acceptable or cosmetically acceptable inert or pharmacodynamically active additives like (retmoic acid), (Clobetasol propionate), (AC.NET™) and (Phytanfriol)

Clobetasol propionate 0.015%, the objective of treatment is to applying low concentration of topical corticosteroids directly to the scalp for treatment the inflammation and itching caused by skin conditions such as allergic reactions, eczema.

AC.net 3% Fights "break-out" by reducing hyperseborrhoea, hyperkeratosis, inflammation and bacterial proliferation

Phytantriol 0.2% Hair conditioning agent.

Propylene glycol, 25 % Humectants (hydrating) (moisturizer)

The topical lotion will be with from 0.001 to 2% weight of all-trans retinoic acid as the preferred dosages in the described compositions and with dosages from 2% to 5% minoxidil in suitable vehicles for percutaneous adsorption.

Retinoic acid is a member of the over 4,000-strong family of RETINOIDS, which are compounds deri ved from retinol or vitamin A, or compounds structurally similar to it. Vitamin A itself is derived only from food, and cannot be made in the body of any animal. It is esterified and stored in the liver, the richest source of vitamin A apart from supplements.

Retinoic acid is synthesized from retinol via two enzymatic reactions, involving first reversible oxidation of retinol to retinal, and then a second oxidation, this time irreversibly, to retinoic acid. It is a light-sensitive compound, like other RETINOIDS, because of the alternating double bonds between the carbon atoms in its hydrophobic tail, which is attached to a 6-carbon ring. The low molecular weight of the compound also makes it highly fat-soluble, which means it easily diffuses across cell membranes.

RETINOIDS are thus important biological molecules, which act in cell growth, epithelial cell growth and maturation, apoptosis and immunologic function, and are vital in embryonic life for organ development. It is also Key for visual function. RETINOIDS like retinoic acid help to transform cell types from the proliferative profile to the maturation profile, by inducing differentiation.

Retinoic acid pathway is required for the repression of sox2 and p27kip in supporting cells and initiation of cell proliferation after hair cell damage. Figure (5).

Retinoic acid is bound in the cell by cellular retinoic acid binding protein (CRABP) and inside the nucleus by two types of receptors, the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). There are various biologically active forms of retinoic acid, and they isomerize under physiological conditions. The different isomers act on different receptors.

All RETINOIDS have a variety of uses in visual and skin conditions, and in cancer therapeutics, A low vitamin A intake is associated with a higher cancer risk.. Abnormal RA receptors are also linked to cancer development. Animal studies show that RETINOIDS suppress cancerous changes. Human studies confirm that retinoid administration suppresses cancers of the breast, lung and liver; reverses premalignant changes and induces differentiation of the myeloid cell series in blood.

All-trans RA, or TRETINOIN, is the most abundant natural isoform, and has been found to be an active agent against a wide range of cancers of the lung, brain, kidney, blood cells, lymphatic tissue, uterine cervix and skin. Another form of retinoic acid, called 9~cis RETINOIN, or isotretinoin, is also used in the treatment of skin lesions of Kaposi's sarcoma, as well as for cancers of the breast and prostate.

Vitamin A is found in all dark green, yellow and red vegetables as well as red or yellow non-citrus fruits. It is also richly found in fish like sardines and cod, and in liver and fish oils. Retinoic acid has been extensively used to prevent and treat photo aged skin and to treat psoriasis. Both ETRETINOIN and isotretinoin, two synthetic forms of vitamin A, are highly teratogenic. ETRETINOIN is not available for medical use, while isotretinoin is strictly controlled. CLOBETASOL topical is a (glucocorticoid) prescription drug that is only available as a generic drug. It's also available as a topical lotion, shampoo, topical spray, topical solution, topical foam, topical cream, topical ointment, and topical gel. The solution are used for scalp problems, the foam is used for mild to moderate plaque psoriasis, the cream, lotion, and spray are used for moderate to severe plaque psoriasis, and the foam and shampoo are used for moderate to severe scalp psoriasis. This medicine is a corticosteroid (cortisone-like medicine or steroid).

This drug is used to treat inflammation and itching from various skin conditions. The emollient cream is also used to treat moderate to severe plaque psoriasis. This drug may be used as part of a combination therapy .Is indicated for the treatment of moderate to severe scalp psoriasis. Used to treat skin irritation & skin rashes CLOBETASOL Work s by decreasing body's response to Inflammation. It also reduces the activity of immune system. This prevents inflammation and itching

AC.NET is an association of oleanolic acid and nordihydroguaiaretic acid in an osmotic gel. Cosmetically, it is used in toners, emulsions, gels, masks, foundations for oily and acne-prone skin. This product fights "break-out" by reducing hyper seborrhea, hyperkeratosis, inflammation and bacterial proliferation. AC.NET provides a global treatment for oily and acne-prone skin. The osmotic gel helps to control bacterial growth.

100 % bacterial inactivation with 3% ac.net

PHYTANTRIOL is an alcohol found in beauty products and cosmetics for a variety of uses, including as an anti-caking agent, hair conditioning agent, skin-conditioning agent and humectants (Source). It is primarily in hair care products because of its ability to reduce the breakage of hair. When used in the formulation of hair-care products, PHYTANTRIOL enhances the appearance and feel of hair by increasing body, suppleness or sheen, or by improving the texture of hair that has been damaged physically or by chemical treatment. PHYTANTRIOL enhances the appearance of dry or damaged skin by reducing flaking and restoring suppleness. It is also used as a processing aid that prevents powdered or granular substances from forming clumps.

PHYTANTRIOL is a long-chained polyhydroxyl alcohol (polyol). Polyols are compounds which contain three or more hydroxyl groups per molecule. The most important members of this class are glycerin and sorbitol, which are used as humectants in skin preparations and oral-care products, and as cosolvents in these and other cosmetic products.

Safety Information: The safety of PHYTANTRIOL has been assessed by the Cosmetic Ingredient Review (CIR) Expert Panel. The CIR Expert Panel evaluated the scientific data and concluded that PHYTANTRIOL was safe as a cosmetic ingredient. Some studies suggested that allergic reactions were possible at concentrations less than or equal to 3%; however, all of the irritation and sensitization data, when considered as a whole, suggested to the CIR Expert Panel that cosmetic products could be formulated at concentrations as high as 3% without significant irritation or sensitization. PHYTANTRIOL may be marketed for use as a cosmetic ingredient within the European Union according to the general provisions of the Cosmetics Regulation.

PHYTANTRIOL low to moderate hazard depending on usage, and it warns of allergic reactions that can include itching, burning, scaling, hives, and blistering of skin.

CLAMIS

3.1. Topical lotion for treatment hair loss formulated in a unique combination of

3.1.1. Active Ingredients :

Minoxidil, Tretinoin, Phytantriol, AC.net, Clobetasol propionate and Propylene glycol.

3.1.2. Inactive Ingredients:

Purified water, Alcohol. Topical lotion for hair loss treatment, the active ingredient Minoxidil concentration will be from 2% up to 5%.

Topical lotion for hair loss treatment, the active ingredient Tretinoin concentration will be 0.01 %.

Topical lotion for hair loss treatment, the active ingredient Phytantriol concentration will be 0.2%.

Topical lotion for hair loss treatment, the active ingredient AC.net concentration will be 3%.

Topical lotion for hair loss treatment, the active ingredient Clobetasol propionate concentration will be 0.015%.

Topical lotion for hair loss treatment, the active ingredient Propylene glycol propionate concentration will be 25 %.

Topical lotion for hair loss treatment, the inactive ingredient Purified water concentration will be 15 %.

Topical lotion for hair loss treatment, the inactive ingredient Alcohol concentration will be Q.S. up to the required volume size.

Topical lotion for hair loss treatment assigned to be formulated and available as 2 ml ampoule for topical use only.

Topical lotion for hair loss treatment assigned to be formulated and available as 15 ml dropper for topical use only.

Topical lotion for hair loss treatment assigned to be formulated and available as 120 ml bottle for topical use only.

Topical lotion for hair loss treatment containers manufactured from:

3.1. Polyethylene in dosage forms of 2ml ampoule.

3.2. Polyethylene in dosage forms of 15ml dropper.

3.3. Polyethylene in dosage forms of 120ml bottle.

Topical lotion for hair loss treatment Method of preparation:

4.1. Prepare a solution from alcohol (concentration 96 %) and propylene glycol.

4.2. Dissolve the minoxidil in the solution previously prepared using a magnetic stirrer regulated at high speed and heating up to 50°C. Until complete dissolution of minoxidil to obtain clear solution.

4.3. Keep the solution to be cool at room temperature (25°C).

4.4. After cooling to room temperature, add Clobetasol propionate, Tretinoin, Phytantriol and AC.net. 14.5. Stirring until complete dissolution of all ingredients, the dissolution of the Tretinoin is somewhat slow.

14.6. Add the water in small portions with stirring until the perfect incorporation.

14.7. A yellowish, clear and transparent solution is obtained. MMARY OF THE INVENTION

, Method of prepa ration

The effectiveness of the active ingredients for increasing and stimulating the rate of hair growth will be illustrated by the following preparation:

4.3.1. Prepare a solution from alcohol (concentration 96 %) and propylene glycol.

4.3.2. Dissolve the minoxidil in the solution previously prepared using a magnetic stirrer regulated at high speed and heating up to 50°C. Until complete dissolution of minoxidil to obtain clear solution.

4.3.3. Keep the solution to be cool at room temperature (25°C).

4.3.4. After cooling to room temperature, add Clobetasol propionate, Tretinoin, Phytantriol and AC.net.

4.3.5. Stirring until complete dissolution of all ingredients, the dissolution of the Tretinoin is somewhat slow. 4.3.6 Add the water in small portions with stirring until the perfect incorporation.

4.3.7 A yellowish, clear and transparent solution is obtained. 4.4. Directions

4.4.1. Wash the scalp with mild shampoo 2-3 times a week.

4.4.2. Dry hair and scalp before applying THE INVENTION.

4.4.3. Use 1-2 ml (20-40 drops) on hair loss area once a day.

4.4.4. Using fingers to gently massage the scalp, helps absorb and distribute the product well on the affected surface.

4.4.5. Wash your hands after finishing and in case of product contact with eye, wash with water. Important information for use

4.4.6. Using more than the recommended dose will not lead to better and faster results.

4.4.7. Do not wet or rinse the scalp for at least four hours after using THE INVENTION.

4.4.8. Do not use a hair dryer on your head to dry the product.

4.4.9. Do not worry if you forget a dose or two doses, just use the following dose on time as determined for the regular dose schedule, and do not use two doses of the product at one time.

4.4.10. THE INVENTION can be used safely in the long term.

•15, Packing and storage

THE INVENTION is available in a container of (120 ml), ampoules for topical use (2 ml) and (15ml) dropper .Store at room temperature, not above (25 °C) in a tightly sealed container.

Store away from heat and light.

Keep out of reach and sight of children. , FINISHED FSODUCT (The invention* 5%) METHOD OF ANALYSIS 5.1, FlwsIeaJ Parameters

5X1_* Colour;

Using identical tubes of colorless, transparent, neutral glass of 12 mm external diameter compare 10 ml of the liquid to be examined with 10 ml of water. Compare the colors in diffused daylight, viewing horizontally against a white background. The solution must be slightly yellow in color.

SXL Volume

Select 1 container if the nominal volume is lOmL or more, 3 containers if the nominal volume is more than 3 ml and less than 10 mL or 5 containers if the nominal volume is 3 mL or less. Measure the volume transferred.

5X Chemical Parameters

5,2. L Minoxidil Content;

Pipette 3 ml of the sample in to 250 mL conical flask and evaporate till dryness. And add 50 mL of glacial acetic acid to the residue and stir the residue completely dissolved. Add few drops of crystal violet indicator and titrate against 0.1 N perchloric acid to until green color end point is obtained. Carryout a blank titration.

Calculation:

Amount of minoxidil content as g/lOOmL =

.2.2, C!otieiaso! Propionate Content:

Mobile Phase: Prepared a filtered and degassed mixture of acetonitrile, 0.05 M Monobasic Sodium Phosphate (Adjusted with 85% phosphoric acid to a pH of 2.5), and methanol (95:85:20).

Standard Preparation:

Dissolve an accurately weighed to quantity of Clobetasol Propionate Working standard about 4 mg in 100 mL of methanol.

Sample Preparation:

Dissolve 3 ml of sample in to 10 ml volumetric flask and dilute the sample with methanol.

Chromatographic System :

Mode LC

Detector 240 nm

Column 4.6 mm x 15 cm column that contains packing

Flow rate : 1 mL per minute.

Injection size: 10 μL_.

Calculation:

g per 100 mL =

(Sample area xSTD weight in mg/mLxpurity of WSxlOO)/ (STD Area xDilution factor for sample preparation xlOO xlOOO) »23, Retimae add coiitmi:

Mobile Phase: Prepare 85% HPLC grade methanol and 15% 0.01 M Sodium Acetate buffer, pH at 5.2.

Standard Preparation:

Dissolve an accurately weighed to quantity of retinoic acid working standard about 3.5 mg per 100 mL of methanol.

Sample Preparation:

g per 100 mL =

(Sample area xstd weight in mg/mLxpurity of WSxl00)/(Std Area xDilution factor for sample preparation xlOO xlOOO)

Active vitamin - hormone receptors and synthesis of vitamin - hormones in human skin cells. RAR = retinoic acid receptors; RXR = retinoid X receptors; RXR = retinoid X receptor type, VDR = vitamin D receptors; atRA = all-trans retinoic acid

IS

21

Figure (4)

Figure (5)

Figure (6)

Figure (8)

Claims

TOPICAL LOTION FOR HAIR LOSS TREATMENT

(B IOHAIR®)

3. CLAIMS

3.1.1. Active Ingredients :

3.1.2. Inactive Ingredients:

Purified water, Alcohol.

3.2. Topical lotion for hair loss treatment, the active ingredient Minoxidil concentration will be from 2% up to 5%.

3.3. Topical lotion for hair loss treatment, the active ingredient Tretinoin concentration will be 0.01 %.

3.4. Topical lotion for hair loss treatment, the active ingredient Phytantriol concentration will be 0.2%.

3.5. Topical lotion for hair loss treatment, the active ingredient AC.net concentration will be 3%.

3.6. Topical lotion for hair loss treatment, the active ingredient Clobetasol propionate concentration will be 0.015%.

3.7. Topical lotion for hair loss treatment, the active ingredient Propylene glycol propionate concentration will be 25 %.

3.8. Topical lotion for hair loss treatment, the inactive ingredient Purified water concentration will be 15 %.

3.9. Topical lotion for hair loss treatment, the inactive ingredient Alcohol concentration will be Q.S. up to the required volume size.

3.10. Topical lotion for hair loss treatment assigned to be formulated and available as 2 ml ampoule for topical use only.

3.11. Topical lotion for hair loss treatment assigned to be formulated and available as 15 ml dropper for topical use only.

3.12. Topical lotion for hair loss treatment assigned to be formulated and available as 120 ml bottle for topical use only.

3.13. Topical lotion for hair loss treatment containers manufactured from:

3.13.1. Polyethylene in dosage forms of 2ml ampoule.

3.13.2. Polyethylene in dosage forms of 15ml dropper.

3.13.3. Polyethylene in dosage forms of 120ml bottle.

3.14. Topical lotion for hair loss treatment Method of preparation:

3.14.1. Prepare a solution from alcohol (concentration 96 %) and propylene glycol.

3.14.

2 Dissolve the minoxidil in the solution previously prepared using a magnetic stirrer regulated at high speed and heating up to 50°C. Until complete dissolution of minoxidil to obtain clear solution.

3.14.3 Keep the solution to be cool at room temperature (25°C). 3.14.4 After cooling to room temperature, add Clobetasol propionate, Tretinoin, Phytantriol and AC.net. 3.14.5 Stirring until complete dissolution of all ingredients, the dissolution of the Tretinoin is somewhat slow. 3.14.6 Add the water in small portions with stirring until the perfect incorporation.

3.14.7 A yellowish, clear and transparent solution is obtained.