WO2006084312A1

WO2006084312A1 - Method of promoting hair growth

Info

Publication number: WO2006084312A1
Application number: PCT/AU2006/000155
Authority: WO
Inventors: Andrew Jonathan Humberstone; Karen Lee Gard'ner
Original assignee: Acrux Dds Pty Ltd
Priority date: 2005-02-09
Filing date: 2006-02-09
Publication date: 2006-08-17

Abstract

This invention relates to method of promoting hair growth comprising topically applying to the area of skin in which loss is to be treated or prevented a composition comprising an androgen selected from the group consisting of testosterone and pharmaceutically acceptable esters thereof and a carrier comprising a volatile solvent. The invention also relates to a topical composition for promoting hair growth.

Description

METHOD OF PROMOTING HAIR GROWTH

The present invention relates to a method of promoting hair growth and to composition for promotion of hair growth. The invention also relates to the use of certain agents in the preparation of a composition for the treatment or prevention of hair loss. The invention is useful in the treatment or prevention of hair loss and also in promotion of new hair growth.

Background

Alopecia (hair loss) is understood to result from the conversion of systemic testosterone to dihydrotestosterone (DHT) in the hair root ball and stem cell regions of the skin. The formation of DHT from testosterone results in a shorter hair growth cycle, finer hair and hair loss.

The most common type of hair loss is alopecia endogenetica (hereditary hair loss) which is commonly called male pattern baldness. Male pattern baldness represents an androgen-mediated miniaturisation of terminal hair follicles without actual loss of the follicles. The progression of male pattern baldness is associated with a local accumulation of DHT from testosterone.

DHT is also associated with female pattern hair loss. Before menopause various forms of estrogen block testosterone resulting in low levels of DHT in the skin. After menopause however, estrogen levels decline and more testosterone is bioavailable to be converted to DHT resulting in finer hair in a proportion of women. Minoxidil in a 2% concentration has been found to help their growth in about 20% of women.

5-Alpha reductase inhibitors such as finasteride are currently prescribed for treatment of hair loss in men and women. Much of the prior art concerned with preventing or treating hair loss therefore focused on blocking the pathway which controls the capacity of the skin to convert testosterone to dihydrotestosterone in individuals at risk. This path is regulated by 5-alpha reductase. US Patent 6,420352 adopts a strategy of blocking the binding of testosterone or DHT to the cell surface. Their use is said to provide the key shortfall that efficacy is compromised by blocking of androgen feedback inhibition of gonadotrophin secretion which in turn increases secretion of testosterone. A high level of systemic testosterone is said to overcome the action of the anti- androgen.

Summary

As a result of their studies of transdermal testosterone administration in hypoandrogenic women the present inventors have found as an unexpected side effect that topically applied testosterone may be used to promote hair growth in localised areas.

Accordingly we provide in a first aspect a method of promoting hair growth (or reducing hair loss) comprising topically applying to the area of skin in which hair growth is to be promoted a composition comprising an androgen selected from the group consisting of testosterone and pharmaceutically acceptable esters thereof and a carrier comprising a volatile solvent.

We also believe that the use of at least one androgen selected from testosterone or pharmaceutically acceptable esters thereof in combination with a 5-alpha reductase inhibitor could provide a further significant enhancement of activity in treatment or prevention of hair loss.

The composition will preferably further comprise a volatile solvent such as selected from the group consisting of lower alkanols such as ethanol, isopropanol and glycol. The composition of the invention is preferably in the form of a topical spray composition.

In a further embodiment the invention provides the use of testosterone or an ester of testosterone in preparation of a transdermal composition for promotion of hair growth. In another aspect the invention provides a composition for promoting hair growth comprising at least one androgen selected from the group consisting of testosterone and esters thereof and at least one 5-alpha reductase inhibitor. The composition will generally comprise a carrier which preferably includes a volatile solvent and penetration enhancer.

Detailed Description

The composition used in the present invention for promoting hair growth contains at least one androgen selected from testosterone and esters of testosterone. It was surprising to find that testosterone was effective in prevention or treatment of hair loss as it was previously believed that the blocking of conversion of testosterone to dihydrotestosterone was important to understanding the activity of previously used 5-alph reductase inhibitors. We have found that locally applied testosterone, which may have been expected to increase the formation of DHT and exacerbate the problem of hair loss actually promotes hair growth thereby treating or preventing hair loss. Suitable esters of testosterone include lower alkyl esters of testosterone such as the isopropyl ester.

We believe that 5-alpha reductase inhibitors in combination with testosterone and its esters provide significantly enhanced activity. The 5-alpha reductase inhibitors used in the process of the invention may inhibit the activity of type one or type two 5-alpha reductase. The preferred 5-alpha reductase inhibitors include finasteride, gamma linolenic acid, alpha linolenic acid, linolenic acid, azelaic acid, vitamin B6, zinc sulfate, permixon, flutamide and beta sitosterol.

Compositions of the invention may additionally comprise other hair growth promoters such as potassium channel openers. Examples of potassium channel openers include minoxidil, chromicalyn, pinacidil and the compounds selected from the classes of s-triazine, thiane-1 -oxide, benzo pyran and pyhdino pyran derivatives or pharmaceutically acceptable salts thereof. The ratio of the androgen component selected from testosterone and esters thereof to the 5-alpha reductase inhibitors in the present invention is preferably in the range of from 5:1 to 100:1 and preferably from 10:1 to 50:1. The androgen components selected from testosterone and esters thereof may be present in the composition in a range of concentrations depending on the mode and dose of composition to be applied. Typically the composition will comprise in the range of from 0.1 - 10 percent by weight of the total androgen component.

The composition of the invention will typically include a volatile solvent. The preferred volatile solvents are selected from the group consisting of ethanol, isopropanol, ethylene glycol and propylene glycol. Typically the volatile solvent will constitute from 50 to 99.9 percent by weight of the total composition.

The composition of the invention will preferably include a penetration enhancer. We have found that the presence of a penetration enhancer, particularly in combination with the androgen provides good activity at the site of application.

A range of penetration enhancers may be used including one or more selected from the group consisting of fatty acids, fatty acid esters, fatty alcohols, glycols and glycol esters, 1 ,3-dioxolanes and 1 ,3-dioxanes, macrocyclic ketones containing at least 12 carbon atoms, oxazolidinones and oxazolidinone derivatives, alkyl-2-(N,N-disubstituted amino)-alkanoate esters, (N, N- disubstituted amino)-alkanol alkanoates, sunscreen esters and mixtures thereof. More preferably the dermal penetration enhancer is selected from the list including oleic acid, oleyl alcohol, cyclopentadecanone (CPE-128™), sorbitan monooleate, glycerol monooleate, propylene glycol monolaurate, polyethylene glycol monolaurate, 2-n-nonyl 1 ,3-dioxolane (SEPA™), dodecyl 2-(N, N- dimethylamino)-propionate (DDAIP) or its salt derivatives, 2-ethylhexyl 2- ethylhexanoate, isopropyl myhstate, dimethyl isosorbide, 4-decyloxazolidinon-2- one (SR-38™, TCPI, Inc.), 3-methyl-4-dycyloxazolidinon-2-one, octyl dimethyl- para-aminobenzoate, octyl para-methoxycinnamate, octyl salicylate and mixtures thereof. One preferred group of penetration enhancers are fatty acid esters including esters formed between C₆ to Ci₈ fatty acids and alcohols such as Ci to C₆ alcohols and C₂ to C₆ polyols. The esters may be mono esters, diesters of polyols such as the caprylic acid diesters of diols such as propylene glycol. The most preferred penetration enhancers are sunscreen esters such as the compounds disclosed in our US Patent No. 6,229,900 the contents of which are herein incorporated by reference. These preferred sunscreen esters are generally compounds of Formula I:

(I) wherein

R¹ is hydrogen, lower alcohol, lower alkoxy, halide, hydroxy or NR³R⁴;

R² is a C₈ to Ci8 alkyl,

R³ and R⁴ are each independently hydrogen, lower alkyl or R³ and R⁴ together with the nitrogen atom to which they are attached form a 5- or 6- membered heterocyclic ring; n is 0 or 1 , q is 1 or 2, and preferably when n is 0 and R1 is NR³R⁴, the NR³N⁴ is para- substitued.

Particularly preferred penetration enhancers are octyl dimethyl-para- aminobenzoate, octyl para-methoxycinnamate, octyl salicylate and mixtures thereof

The compositions of the invention may be applied to the region of skin in which hair loss is to be prevented or treated in a range of forms. For example, suitable forms include lotions, gels, pastes, aerosols and the like. The composition may be applied in an occlusive or non-occlusive manner. Methods of occlusive application include application using a patch which may be used to cover over a topically applied composition or within which the composition is present as a reservoir contained within the patch. It is preferred however that the composition is applied in a non-occlusive manner and in the most preferred embodiment the composition is applied as a spray.

In the most preferred embodiment of the invention the composition is applied as a spray which is preferably formulated to dry on the skin within three minutes of application. In this way we have found that the composition is driven into the skin and the testosterone (and preferably also 5-alpha reductase inhibitor) form a reservoir in the skin which we have found is particularly active in enhancing the growth of hair. Drying time may be determined by in vitro or in vivo tests. A suitable in vitro test involves placing a 10 μl_ sample on a clean glass slide at room temperature (approx 20 °C) and using a four decimal place analytical balance to measure the time take for the vehicle to stop evaporating. The resulting drying times from three repetitions of the test may be averaged. For in vivo drying time measurement 10 μL is applied to volar fore arms (32 °C) of three subjects and the drying time measured by touch and visual verification (no visible surface vehicle or shine).

The drug system used in the composition of the invention may further comprise a pharmaceutical compounding agent, co-solvent, surfactant, emulsifier, antioxidant, preservative, stabiliser, diluent or a mixture of two or more thereof. These additional components will preferably be compatible with the ability of the composition to become touch-dry within three minutes after application.

The drug delivery system of the present invention may be applied to the skin by means of a spray which may for example be delivered from a pressurised aerosol container or pump-pack, brush, swab, or other applicator. Preferably, the applicator provides either a fixed or variable metered dose application such as a metered dose aerosol, a stored-energy metered dose pump or a manual metered dose pump. The application is most preferably performed by means of a topical metered dose aerosol or spray pack combined with an actuator nozzle shroud which together accurately control the amount and/or uniformity of the dose applied.

One function of the shroud is to keep the nozzle at a pre-determined height above, and perpendicular to, the skin or membrane to which the drug delivery system is being applied. This function may also be achieved by means of a spacer-bar or the like. Another function of the shroud is to enclose the area above the skin or membrane in order to prevent or limit bounce-back and/or loss of the drug delivery system to the surrounding environment. Preferably the area of application defined by the shroud is substantially circular in shape.

The composition of the invention may be propelled to form a spray by either pump pack or by the use of propellants such as hydrocarbons, hydro fluorocarbons, nitrogen, nitrous oxide, carbon dioxide or ethers, preferably dimethyl ether. Hydrocarbon propellants and hydroflurocarbons such as HFC134a are particularly preferred. The non-occlusive, drug delivery system is preferably in a single phase system as this allows less complicated manufacture and ease of dose uniformity where used as propellant may be in an amount of from 1 to 10% and preferably 1 to 5% by weight of the total composition. It may also be necessary to apply a number of dosages on untreated skin to obtain the desired result.

Male pattern baldness represents an androgen-mediated miniaturisation of terminal hair follicles without actual loss of the follicles. It is possible that the "super-loading" of testosterone at the site of application may account for the increase in hair growth.

A list of the conditions which can be treated using the method of the invention and the compositions of the invention include male pattern baldness, female- pattern baldness, alopecia areata, alopecia totalis.

Contributing factors to hair loss include poor diet, poor circulation, acute illness, radiation, chemotherapy, high stress, thyroid imbalance, certain drugs, diabetes, high doses of vitamin A (more than 100,000 IU), sudden weight loss, high fever, iron deficiency, ringworm, some fungal infections, chemicals and hair dyes, vitamin deficiencies, and lack of proper nutrition. Hair loss as a result of these factors may also be treated using the method of the current invention.

The term "hair growth" where used herein in the specification and claims refers generally to any growth in number, thickness and/or length of both new and existing hairs.

The invention will now be described with reference to the following examples. It is to be understood that the examples are provided by way of illustration of the invention and that they are in no way limiting to the scope of the invention.

Examples

Example 1

Study Design: Multi-centre, randomised, parallel, double blind, and placebo-controlled trial.

Study Population: A total of 261 female patients (35-45 years old) were enrolled into the study.

Administration Route: Daily application of transdermal spray(s) applied to the abdomen.

Treatments: A: Testosterone MDTS^® (2 x 90 μl_ sprays) containing

5.0% w/v testosterone and 8.0% w/v octyl salicylate in 95% ethanol applied to the same sites daily. B: Testosterone MDTS^® (1 x 90 μl_ spray) containing 5.0% w/v testosterone and 8.0% w/v octyl salicylate in

95% ethanol applied to the same site daily. C: Testosterone MDTS^® (1 x 56 μl_ spray) containing 5.0% w/v testosterone and 8.0% w/v octyl salicylate in 95% ethanol applied to the same site daily. D: Placebo MDTS^® (1 or 2 x 90 or 56 μl_ sprays) containing 8.0% w/v octyl salicylate in 95% ethanol to the same site(s) daily.

Study Duration: 16 weeks (plus a 4-8 week selection period and 4-week follow up period).

Study Results: An increase in fine, dark coloured hair was noted at the site of application approximately 2 months after concurrent use of the spray.

Example 2

Combined topical spray composition

Component Amount (%w/v)

Testosterone 5.0

Finasteride 0.2

Octyl salicylate 5.0

Ethanol 95% to volume

Example 3

Combined topical spray composition

Component Amount (%w/v)

Testosterone 5.0

Flutamide 0.2

Octyl salicylate 5.0

Ethanol 95% to volume

Example 4

Compositions such as described in Examples 2 and 3 above may be applied as a spray from a pump-pack or may be delivered from an aerosol container in the presence of a propellant such as P134a or butane (in an amount of about 1 to

5% by weight) which forms an additional component of the volatile solvent carrier. In manufacture of an aerosol product a plastic-coated glass aerosol container of suitable fill volume such as 1 to 100 ml and preferably about 10 ml fill volume may be fitted with a pharmaceutical grade metered-dose valve of a nominated discharge volume such as 10 to 1000 μl for the testosterone aerosol. A stainless steel O-ring may lock the valve in place on the aerosol container.

The aerosol container may be charged with testerone, non-volatile, dermal penetration enhancer when used, volatile liquid carrier and optionally any other actives such as the 5-alpha reuctase inhibitor, surfactants or additives followed by the propellant according to any suitable process.

A pharmaceutical grade spray nozzle and an aerosol shroud may fitted to keep the spray nozzle perpendicular to the skin at a height of about 20 to 100mm and preferably about 50 mm.

The aerosol may be used as follows:

1. Hold the device upright in the palm of your preferred hand with your thumb resting gently on the actuator button. 2. Rest the shroud opening on the skin and depress the actuator button once and release the button. Remove the device from the skin. 3. Repeat steps 1 and 2 on a new area of skin until the correct number of doses have been given and the appropriate area for promoting hair growth is treated. 4. The applied composition will preferably be formulated to dry on the skin within 3 minutes and more preferably 1 minute.

During application of the spray, the nozzle shroud envelopes the spray, providing an effective closed system which deposits the active agent into the skin, and such that when the spray hits the surface of the skin it does not undergo any appreciable bounce-back into the atmosphere. A defined dose of active agent and penetration enhancer is forced through a uniform spray nozzle at a constant pressure form a defined height to give a uniform dose per cm².

Claims

1. A method of promoting hair growth comprising topically applying to the area of skin in which loss is to be treated or prevented a composition comprising an androgen selected from the group consisting of testosterone and pharmaceutically acceptable esters thereof and a carrier comprising a volatile solvent.

2. A method according to claim 1 wherein the composition comprises the penetration enhancer.

3. A method according to claim 1 wherein the composition further comprises a 5-alpha reductase inhibitor.

4. A method according to any one of the previous claims wherein the carrier provides a drying time of no more than three minutes.

5. A method according to claim 4 wherein the volatile solvent comprises at least one compound selected from the group consisting of ethanol, isopropanol and glycol.

6. A method according to claim 1 wherein the esters of testosterone are selected from the group consisting of lower alkyl esters of testosterone.

7. A method according to any one of the previous claims wherein the composition comprises a 5-alpha reductase inhibitor which inhibits the activity of type one or type two 5-alpha reductase.

8. A method according to any one of the previous claims wherein the composition comprises at least one 5-alpha reductase inhibitor selected from the group consisting of finasteride, gamma linolenic acid, alpha linolenic acid, linolenic acid, azelaic acid, vitamin B6, zinc sulfate, permixon, flutamide and beta sitosterol.

9. A method according to any one of the previous claims wherein the composition further comprises at least one potassium channel opener.

10. A method according to claim 9 wherein the at least one potassium channel opener is selected from the group consisting of minoxidil, chromicalyn, pinacidil and the compounds selected from the classes of s-thazine, thiane-1 -oxide, benzo pyran, pyridino pyran derivatives and pharmaceutically acceptable salts thereof.

11. A method according to any one of the previous claims wherein the composition comprises a ratio of the androgen component selected from testosterone and esters thereof to a 5-alpha reductase inhibitor in the range of from 10:1 to 50:1.

12. A method according to any one of the previous claims wherein the total androgen content is in the range of from 0.1 - 10 percent by weight of the total composition.

13. A method according to any one of the previous claims wherein the composition is applied to an area of skin in a non-occlusive manner and in the most preferred embodiment the composition is applied as a spray.

14. A method according to any one of the previous claims wherein the composition is applied as a spray which is formulated to dry on the skin within three minutes of application.

15. A method according to any one of the previous claims wherein the composition is applied to an area of skin to treat a disease selected from the group consisting of male pattern baldness, female-pattern baldness, alopecia areata and alopecia totalis.

16. A method according to any one of the previous claims wherein the composition comprises a volatile solvent component comprising at least one solvent selected from the group consisting of ethanol, isopropanol, ethylene glycol and propylene glycol present in an amount of from 50 to 99.9 percent by weight of the total composition.

17. A method according to any one of the previous claims wherein the the composition comprises a penetration enhancer comprising at least one selected from the group consisting of fatty acids, fatty acid esters, fatty alcohols, glycols and glycol esters, 1 ,3-dioxolanes and 1 ,3-dioxanes, macrocyclic ketones containing at least 12 carbon atoms, oxazolidinones and oxazolidinone derivatives, alkyl-2-(N,N-disubstituted amino)-alkanoate esters, (N, N- disubstituted amino)-alkanol alkanoates, sunscreen esters and mixtures thereof. More preferably the dermal penetration enhancer is selected from the list including oleic acid, oleyl alcohol, cyclopentadecanone (CPE-128™), sorbitan monooleate, glycerol monooleate, propylene glycol monolaurate, polyethylene glycol monolaurate, 2-n-nonyl 1 ,3-dioxolane (SEPA™), dodecyl 2-(N, N- dimethylamino)-propionate (DDAIP) or its salt derivatives, 2-ethylhexyl 2- ethylhexanoate, isopropyl myhstate, dimethyl isosorbide, 4-decyloxazolidinon-2- one (SR-38™, TCPI, Inc.), 3-methyl-4-dycyloxazolidinon-2-one, octyl dimethyl- para-aminobenzoate, octyl para-methoxycinnamate, octyl salicylate and mixtures thereof.

18. A method according to any one of the previous claims wherein the composition comprises at least one penetration enhancer which is a sunscreen ester.

19. A topical spray composition for promoting hair growth comprising at least one androgen selected from the group consisting of testosterone and esters thereof and at least one 5-alpha reductase inhibitor and a carrier comprising a volatile solvent and penetration enhancer.

20. A composition according to claim 19 wherein the esters of testosterone are lower alkyl esters of testosterone.

21. A composition according to claim 19 or 20 wherein the 5-alpha reductase inhibitors is of the type which inhibits the activity of type one or type two 5-alpha reductase.

22. A composition according to claim 19 wherein the composition comprises at least one 5-alpha reductase inhibitor selected from the group consisting of finasteride, gamma linolenic acid, alpha linolenic acid, linolenic acid, azelaic acid, vitamin B6, zinc sulfate, permixon, flutamide and beta sitosterol.

23. A composition according to claim 19 wherein the composition comprises at least one potassium channel opener.

24. A composition according to claim 17 wherein the at least one potassium channel opener is selected from the group consisting of minoxidil, chromicalyn, pinacidil and the compounds selected from the classes of s-triazine, thiane-1 - oxide, benzo pyran, pyridino pyran derivatives and pharmaceutically acceptable salts thereof.

25. A composition according to any one of claims 19 to 24 wherein the weight ratio of the androgen component selected from testosterone and esters thereof to the 5-alpha reductase inhibitors is in the range of from 10:1 to 50:1.

26. A composition according to any one of claims 19 to 25 wherein the androgen component selected from testosterone and esters thereof is present in the composition in the range of from 0.1 % - 10% androgen by weight of the total composition.

27. A composition according to any one of claims 19 to 26 wherein the volatile solvents is selected from the group consisting of ethanol, isopropanol, ethylene glycol and propylene glycol present in an amount of from 50 to 99.9 percent by weight of the total composition.

28. A composition according to any one of claims 19 to 27 wherein the penetration enhancer comprises at least one selected from the group consisting of fatty acids, fatty acid esters, fatty alcohols, glycols and glycol esters, 1 ,3- dioxolanes and 1 ,3-dioxanes, macrocyclic ketones containing at least 12 carbon atoms, oxazolidinones and oxazolidinone derivatives, alkyl-2-(N,N-disubstituted amino)-alkanoate esters, (N,N-disubstituted amino)-alkanol alkanoates, sunscreen esters and mixtures thereof. More preferably the dermal penetration enhancer is selected from the list including oleic acid, oleyl alcohol, cyclopentadecanone (CPE-128™), sorbitan monooleate, glycerol monooleate, propylene glycol monolaurate, polyethylene glycol monolaurate, 2-n-nonyl 1 ,3- dioxolane (SEPA™), dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) or its salt derivatives, 2-ethylhexyl 2-ethylhexanoate, isopropyl myristate, dimethyl isosorbide, 4-decyloxazolidinon-2-one (SR-38™, TCPI, Inc.), 3-methyl-4- dycyloxazolidinon-2-one, octyl dimethyl-para-aminobenzoate, octyl para- methoxycinnamate, octyl salicylate and mixtures thereof.

29. A composition according to any one of claims 19 to 28 wherein the composition comprises at least one penetration enhancer which is a sunscreen ester.

30. A composition according to any one of claims 19 to 29 wherein the composition dries within three minutes of application.