WO2006051287A1

WO2006051287A1 - Composition and method for treatment of alopecia areata

Info

Publication number: WO2006051287A1
Application number: PCT/GB2005/004318
Authority: WO
Inventors: Brian Bert
Original assignee: Arrow International Limited; Tabatznik, Anthony, S.
Priority date: 2004-11-10
Filing date: 2005-11-09
Publication date: 2006-05-18

Abstract

A Alopecia areata treatment comprises administration of a combination of immunosuppressant stereoid and hair growth stimulant wherein one preferred combination is betamethasone and minoxidil in a carrier containing water and alcohol, forming a solution that can be sprayed onto the scalp. An alternative formulation also contains a mast cell stabilizer and can have reduced stereoid concentration.

Description

Composition and method for treatment of Alopecia areata

The present invention relates to a composition for treatment of Alopecia areata, to methods of preparing the composition and to methods and uses employing the composition.

Alopecia areata is a non-scarring, inflammatory, hair loss disease that can affect men, women and children. There are currently believed to be approximately 15 million or more sufferers worldwide, many of whom suffer also from psychological side-effects such as depression and nervous conditions. It is distinct from Alopecia androgenetica (male pattern baldness).

The causative factors of the onset of Alopecia areata and the mechanisms of its development are not fully understood. The disease varies in degree from a few bare patches to the whole scalp (referred to as Alopecia Totalis) and, in extreme cases, to the whole body (referred to as Alopecia Universalis). Alopecia is in addition a notoriously unpredictable disease, with pronounced peaks and flares.

Currently, treatment has a poor success rate. Alopecia areata of less than one year duration can respond to treatment with a success rate estimated at 75%. However, Alopecia areata of longer duration responds poorly to treatment and often the aim is to have acceptable hah^* growth so as to avoid having to wear a wig or a hat.

Existing treatments can be divided into several groups.

Contact sensitizers (dermatitis inducers) can be used, such as dinitrochlorobenzene (DNCB), diphenylcyclopropenone (DPCP), squaric acid dibutyl ester (SADBE). These, however, are not suitable for children, are painful and produce spotty results. Treatment has to be undertaken by the practitioner on a regular basis and cannot be self applied in the home setting. Non specific immunosuppressants can be used, such as corticosteroids, 8- methoxypsoralen plus ultra violet A light (PUVA) and phototherapy.

Other current drug treatment approaches include the use of regrowth stimulators such as topical minoxidil, finasteride, dithranol (anthralin), corticosteroids, and psoralen plus ultraviolet A irradiation (PUVA) therapy.

Of these, corticosteroids are probably the most popular form of treatment, but as with other therapies are inefficient, temporary hi effect and have other problems. For example, side effects of topical steroids include folliculitis (that can be persistent, but not irreversible), acne outbreaks, local atrophy where cream is applied and very occasionally hypertrichosis. If doses of topical steroids are too high there is a small risk of systemic absorption and the potential associated side effects.

A specific known treatment is a two-step application of a corticosteroid and minoxidil. First a small volume of the minoxidil lotion is sprayed onto the scalp and then spread over the scalp. Half an hour later, several drops of steroid are applied and again spread onto the scalp using fingers. However, there is the same problem that the treatment is effective only at a low rate and often uneven when large areas are involved and further that patient compliance is low - i.e. few patients complete the prescribed treatment.

Corticosteroids can be injected, but side effects can include pain from the injections and atrophy of the skin around the injection site.

It is also known to give systemic corticosteroids for Alopecia areata, but this treatment is usually only a treatment of last resort because of the potential for serious side effects. Systemic corticosteroid use is generally limited to just a few weeks of use before it must be stopped. Side effects include weight gain, acne outbreaks, menstrual problems, mood swings, migraines, cataracts and other eye complications, stunted growth in children, osteoporosis, high blood pressure, and/or diabetes.

Other background to Alopecia areata is described in:- Freyschmidt-Paul P, Hoffmann R₅ Levine E, Sundberg JP, Happle R, McElwee KJ. Current and potential agents for the treatment of Alopecia areata. Curr Phaπn Des 2001 Feb;7(3):213-30; and

Meidan VM, Touitou E. Treatments for androgenetic Alopecia and Alopecia areata: current options and future prospects. Drugs 2001;61(l):53-69.

Hence there currently exists a need for alternative and preferably improved treatments for this disease.

An object of the present invention is to provide an alternative composition and its use in treating Alopecia areata. An object of specific embodiments of the invention is to provide an improved such composition and use.

Accordingly, the present invention provides a composition, comprising (i) a hair growth stimulant, and (ii) an immunosuppressor. We have advantageously found that with this combination of active agents rapid and effective treatment of this disease can be achieved.

Compositions of the invention are for treatment of Alopecia areata, especially of the Totalis and Universalis types and typically comprise a hair growth stimulant, an immunosuppressant, and a pharmaceutically acceptable carrier. The hair growth stimulant can be selected from a wide range of such agents, but is especially a vasodilator, and a preferred example is Minoxidil. Another is Finasteride. Further, preferred compositions contain Minoxidil at a concentration of from 0.5% to 2% by weight, preferably 0.5% to 1.5%, more preferably from 0.7% to 1.3%, most preferably to about 1%. Lower concentrations are more suitable for children and others who might be more sensitive to this agent; higher concentrations are more suitable for adults and those who do not respond to the lower concentrations. Generally a concentration in the range of from about 0.4 up to 2% is suitable, with increased dosage occasionally useful for men or stubborn cases. The relatively low doses of this agent in the formulations mean that prolonged use for treatment of Alopecia areata is possible without or with reduced side effects of prolonged or high-dose Minoxidil administration, these side effects including excessive hair growth on other parts of the body such as on the arms or face, the latter being more unacceptable for women and children being treated. The immunosuppressant used in the invention typically comprises a steroid, and is hence present in an amount, giving an effective dose, sufficient to have an immunosuppressant effect in the region the composition is applied - i.e. most commonly the scalp. Formulations of the invention thus differ from prior art formulations which occasionally contained very high doses of hair growth stimulant (say 15% by weight) but also very low doses of steroid, the steroid included specifically to avoid or reduce scalp irritation caused by the high dose of hair growth stimulant but not included so as to have a therapeutic effect in autoimmune conditions. The compositions of the invention contain sufficient steroid, having regard to the anticipated relatively high volume of composition to be used in a treatment regime, to achieve a satisfactory immunosuppressant effect. For example, with a weight % of betamethasone of 0.025% w/w and a dose of 2ml, this is an effective dose of at least 0.05mg betamethasone.

An advantage of the formulations is that both active agents are in a single formulation and are applied at the same time to the same place and in a single application. This has been found to result in efficient treatment. Patient compliance may also be increased. Treatment using formulations according to the invention is particularly effective in treating totalis and universalis types of Alopecia areata.

Formulations of particular embodiments of the invention are formulated so as to be of relatively high volume and can be liberally applied to the scalp, thoroughly wetting the scalp. The user can feel which parts of the scalp have been covered so that application to the whole scalp can be easily checked, and again good patient compliance can be achieved. These high volume formulations are of relatively low concentration so there is not the risk of side effects associated e.g. with high steroid dose. The formulations can evaporate quickly, making them easy to use without disrupting daily activities - this again can assist in raising patient compliance.

In a further aspect the present invention provides a composition, comprising (i) a hair growth stimulant, (ii) an immunosuppressant, and (iii) a mast cell stabilizer. In particular embodiments of the invention the composition includes a mast cell stabilizer, typically selected from one of the topically used mast cell stabilizers such as cromolyn sodium, nedocromil sodium, lodoxamide tromethamine, pemirolast, olopatadine hydrochloride, ketotifen fumarate, azelastine hydrochloride, emadastine difumaraet, levocabastine hydrochloride and an antMstamine with mast cell stabilizing activity, such as ebastine, by way of one example. Preferably sodium cromoglycate is used, and is preferred at concentrations of from 0.1% w/w to 5% w/w, more preferably to l%w/w. In a specific example about 0.5% w/w has been used.

An advantage of including a mast cell stabilizer is that the flaring aspect of Alopecia areata is reduced, offering improved treatment. A further advantage is that when a steroid and a mast cell stabilizer are both used there is reduction in immune activity caused by both components and there is treatment of additional aspects of the disease, hence a synergy is seen in the combination.

Use of a mast cell stabilizer in specific embodiments of the invention reduces the concentration of immunosuppressant steroid required to give effective treatment. Steroid use has a number of side effects that generally contraindicate continued use over a long time period. Those compositions with reduced steroid concentration may be effectively used ab initio or as maintenance compositions in the treatment of Alopecia areata.

Generally, formulations of the invention that use corticosteroids can have the following components:

Most steroids are suitable, for example betamethasone, betamethasone dipropionate, betamethasone valerate, dexamethasone sodium phosphate, clobetasol propionate, diflorasone diacetate, halobetasol dipropionate, amcinodide, fucinodide, halcinonide, fluocinolone acetonide, mometasone furoate, flumethasone, triamcinolone acetonide, flurandrenolide, hydrocortisone valerate, hydrocortisone butyrate and aclometasone dipropionate and mixtures thereof.

In an embodiment of the invention set out in detail in an example, good results have been achieved using betamethasone, which can be used as free base or as a pharmaceutically acceptable salt or other derivative. Compositions of the invention preferably contain from 0.02 to 0.5%, more preferably from 0.025 to 0.3%, most preferably 0.025% by weight betamethasone base or an equivalent amount of a pharmaceutically acceptable salt or other derivative of betamethasone. The results using this formulation have shown high efficacy in treating the disease.

Corticosteroids are suitable as suppressors of the immune system, preferably by suppressing T cell infiltration which is associated with hair loss in diseased patients. Betamethasone is particularly suitable as base or pharmaceutically acceptable salt e.g. dipropionate or valerate.

Particular compositions of the invention based on a combination of minoxidil, sodium cromoglycate and betamethasone can have components in the ranges;-

More particularly, the composition can have the components in the ranges:-

Compositions of the invention contain a sufficiently high amount of corticosteroid to provide an immunosuppressant effect, and it is preferred that the ratio of the weight percent of hair growth stimulant (as Minoxidil or Minoxidil equivalent): steroid (as betamethasone or betamethasone equivalent) is maintained within the range of from 2:1 to 150:1, more preferably from 4:1 to 100:1, further preferably from 5:1 to 40:1 and most preferably 4: 1 to 20: 1.

Selected embodiments of the invention are designed for ease of application. Hence, in preferred formulations of the Alopecia treatment composition the carrier comprises water or an alcohol or water and an alcohol so that the composition can be applied as a spray. Thus, application to the whole of the scalp (especially significant in Alopecia totalis and universalis) is facilitated. Achieving good patient compliance with any treatment is important and we have found that the adaptation of the formulation so that it can be sprayed has the result of improving compliance with the recommended treatment regime as well as making is easier for the whole scalp to be wetted by the composition.

The alcohol content is preferably from 25 to 95% alcohol by weight, more preferably from 50 to 92% alcohol by weight, most preferably from 60 to 90%, more preferably from 60 to 85% alcohol by weight. Lower alcohols are preferred, and the formulations typically comprise a straight or branched C₂-C₆ alcohol or a mixture of such alcohols. Ethyl alcohol and isopropyl alcohol and mixtures thereof are used in specific examples described below.

A further advantage of using water and/or alcohol as described is that the resulting formulation is relatively quick drying, hi use, a patient is recommended to apply the spray in the morning on waking and in the evening. The specific formulations dry quickly and are not a nuisance for the patient, i.e. they do not remain wet on the scalp for long periods, do not force the patient to wait too long before going to sleep or do not mean the patient goes to sleep with a wet head. These factors are again important in increasing patient compliance with the treatment. Generally the spray formulations dry on the scalp within 30 minutes, preferably within 25 minutes, more preferably within 20 minutes, at average room temperature (25C).

In a specific embodiment of the invention the composition is provided as a spray formulation. This is a solution which can be sprayed through a nozzle to form a spray for easy application e.g. to the scalp. Also provided is a container comprising (i) a reservoir containing the spray formulation, and (ii) a spray nozzle. Typical containers carry from 80 to 120ml of solution. Typical spray nozzles deliver 2ml of solution, as a spray, in from 10 to 20 actuations. The nozzle used in the example below delivered approximately 2ml in 14 actuations or sprays.

The invention additionally provides a method of treatment of Alopecia areata, comprising applying a composition of the invention to the scalp of an affected individual, and allowing the composition to dry.

The method preferably comprises applying the composition twice daily, more preferably by spraying. The duration of treatment will vary from patient to patient, but generally treatment over 3 months and up until acceptable hair growth and/or regression _t of autoimmune activity is recommended. The method of the invention enables the formulation to be sprayed in a one step action, allowing the patient to cover the whole affected area thoroughly without the need for subsequent spreading or massaging, another factor in improving patient compliance. Treatment can comprise application of an initial formulation and then a reduced steroid maintenance formulation.

In one particularly preferred method the patient is treated with a formulation having a mast cell stabilizer and reduced steroid concentration after completing treatment for around a month with a formulation according to the invention not having a mast cell stabiliser and higher steroid concentration. This treatment regime reduces side effects attributable to ongoing steroid use and can also reduce itching of the scalp.

In a particular method, used in an example below, the treatment comprises spraying the composition onto the scalp twice daily, once in the evening and once shortly after waking up (usually in the morning). The relatively quick-drying nature of the formulation means that the patient can go to bed within 30 minutes of spraying on the composition.

Also provided by the invention is the use of a combination of a vasodilator, optionally a mast cell stabilizer, and an immunosuppressant steroid in manufacture of a spray formulation for treatment of Alopecia areata, and more specifically the use of a combination of minoxidil, optionally sodium cromoglycate, and betamethasone in manufacture of a spray formulation for treatment of Alopecia areata. The spray formulation is preferably for twice daily administration to a patient. The formulations are as described in the embodiments and preferred embodiments above and in the specific examples below.

The invention is now illustrated in specific examples.

Examples

Example 1 - Alopecia areata spray

A spray formulation was prepared having the formula:-

This was prepared by adding the propylene glycol, PVP and BPA to the water and mixing well. (Solution A) hi a separate container (Solution B) the minoxidil first and the Betamethasone thereafter, were added to the ethyl alcohol and mixed well. Solution A was added to Solution B slowly and mixed well. The pH was found to be about 4.5 - 5. This can if needed be adjusted using sodium hydroxide, to pH from about 4 to about 6.

Treatment of Alopecia areata

A formulation prepared according to the example above was prepared and a volume of approximately 100ml transferred to a polyethylene bottle with a spray nozzle. Testing of the volume per spray showed that 14 sprays (actuations of the spray nozzle) corresponded to 2ml of solution.

A patient with Alopecia Areata Totalis was provided with the bottled solution and instructed to apply 14 sprays (i.e. 2ml of solution) to her scalp, twice daily, once in the evening and once immediately upon awakening. The patient followed this regime and after 15 days presented with new but patchy regrowth of hair. After 30 days there was an even coverage of the scalp, with short but stable (difficult to pull out) hair and by 90 days full scalp coverage with hair averaging l-2cm in length. At this stage the patient felt comfortable enough to move about in public without the need for a hat or wig.

This patient suffered from a very aggressive autoimmune disease and had to continue treatment for 24 months, at which stage the hair was thick and covering the whole scalp. Blood tests were performed on a monthly basis and no unacceptable side effects were observed that might have required a lessening or stoppage of treatment.

Hence effective treatment was seen after 30 - 90 days using the formulation described. The patient reported ease of application of the formulation to the whole scalp (one step action) and as such easy compliance, also commenting that the formulation did not produce any scalp irritation and dried quickly. Most importantly, due to the efficacy of the invention, when the hair growth became widespread and thick, the patient could still get enough of the spray to the scalp to maintain activity, due to the high volume of the application.

Example 2 - Alternative Alopecia areata spray

A spray formulation was prepared having the formula: -

This was prepared by adding the sodium cromoglycate to the water and mixing. Then the propylene glycol, PVP and IPA were added to this solution and mixed in well. (Solution A) hi a separate container (Solution B) the minoxidil first and the Betamethasone thereafter, were added to the ethyl alcohol and mixed well. Solution A was added to Solution B slowly and mixed well. The pH was found to be about 4.5 - 5. This can if needed be adjusted using sodium hydroxide, to pH from about 4 to about 6.

Example 3 - Low steroid Alopecia areata spray with MCS

A spray formulation was prepared having the formula:-

The formulation was prepared according to the method used in the preparation of example 2 (above).

The formulation of example 3 was used for treatment after 2mL of the formulation of example 1 was applied twice a day for a month. Use of the formulation of example '3 was found to significantly reduce itching of the scalp of the patient, leading to greater patient compliance and comfort. The formulation of example 3 was used as a maintenance composition over an extended period of time without concern for patient exposure to high levels of steroid and the consequent side-effects.

The invention thus provides a composition and method for treatment of Alopecia areata, and in specific embodiments provides a formulation that can be applied as a spray in a one step treatment in a sufficiently high volume to deliver the optimum dose and cover the whole affected area at the same time, which is particularly critical to Alopecia totalis and universalis cases, thus affording a high level of patient compliance.

Claims

1. A composition, for treatment of Alopecia areata, comprising:- - a hair growth stimulant,

- an immunosuppressant, and

- a pharmaceutically acceptable carrier.

2. A composition according to claim 1, wherein the hair growth stimulant comprises a vasodilator.

3. A composition according to claim 1 or 2, wherein the hair growth stimulator comprises Minoxidil.

4. A composition according to claim 3, comprising Minoxidil at a concentration of from 0.5 to 2% by weight.

5. A composition according to claim 3, comprising Minoxidil at a concentration of up to 1.5%.

6. A composition according to claim 3, comprising Minoxidil at a concentration of around 1%.

7. A composition according to any previous claim, wherein the immunosuppressant comprises a steroid.

8. A composition according to claim 7, wherein the steroid is selected from betamethasone, betamethasone dipropionate, betamethasone valerate, dexamethasone sodium phosphate, clobetasol propionate, diflorasone diacetate, halobetasol dipropionate, amcinodide, fucinodide, halcinonide, fluocinolone acetonide, mometasone furoate, flumethasone, triamcinolone acetonide, flurandrenolide, hydrocortisone valerate, hydrocortisone butyrate and aclometasone dipropionate.

9. A composition according to claim 8, comprising from 0.02 to 0.5% by weight betamethasone base or an equivalent amount of a pharmaceutically acceptable salt or other derivative of betamethasone.

10. A composition according to any previous claim, comprising Minoxidil (or Minoxidil equivalent) and betamethasone (or betamethasone equivalent) in a weight per cent ratio of from 2:1 to 150:1.

11. A composition according to any previous claim, comprising Minoxidil (or Minoxidil equivalent) and betamethasone (or betamethasone equivalent) in a weight per cent ratio of from 4:1 to 100:1.

12. A composition according to any previous claim, wherein the carrier comprises water and from 25 to 95% alcohol so that the composition can be applied as a spray.

13. A composition according to any previous claim, wherein the carrier comprises from 50 to 92% alcohol by weight.

14. A composition according to any previous claim, wherein the carrier comprises from 60 to 90% alcohol by weight.

15. A composition according to any previous claim, wherein the carrier comprises from 60 to 85% alcohol by weight.

16. A composition according to any of claims 12 to 15, wherein the alcohol comprises a straight or branched C₂-C₆ alcohol or a mixture of such alcohols.

17. A composition according to any previous claim, further comprising a mast cell stabilizer.

18. A composition, for treatment of Alopecia areata, comprising:-

- a hair growth stimulant,

- an immunosuppressant, - a mast cell stabilizer, and

- a pharmaceutically acceptable carrier.

19. A composition according to claim 17 or claim 18, wherein the mast cell stabilizer is an antihistamine.

20. A composition according to claim 17 or claim 18, wherein the mast cell stabilizer is selected from cromolyn sodium, nedocromil sodium, lodoxamide tromethamine, pemirolast, olopatadine hydrochloride, ketotifen fumarate, azelastine hydrochloride, emadastine difumaraet, and levocabastine hydrochloride.

21. A spray formulation of a composition according to any of the preceding claims.

22. A container comprising (i) a reservoir containing an aerosol formulation according to claim 21 and (ii) a spray nozzle.

23. A method of treatment of Alopecia areata, comprising applying a composition according to any of claims 1 to 21 to the scalp of an affected individual, and allowing the composition to dry.

24. A method according to claim 23, comprising applying the composition twice daily.

25. A method according to claim 23 or 24, comprising spraying the composition onto the scalp.

26. A method according to claim 25, comprising spraying the composition onto the scalp twice daily, once shortly before going to sleep in the evening and once shortly after waking up in the morning.

27. A method of treatment of Alopecia areata, comprising applying a composition according to any of claims 1 to 16 to the scalp of an affected individual for a period of time followed by treatment with a composition according to any one of claims 17 to 20.

28. A method according to claim 27 wherein the period of time is around a month.

29. Use of a combination of a vasodilator and a steroid in manufacture of a spray formulation for treatment of Alopecia areata.

30. Use of a combination of a vasodilator, a steroid and a mast cell stabilizer in manufacture of a spray formulation for treatment of Alopecia areata.

31. Use of a combination of minoxidil and betamethasone in manufacture of a spray formulation for treatment of Alopecia areata.

32. Use of a combination of minoxidil, betamethasone and sodium cromoglycate in manufacture of a spray formulation for treatment of Alopecia areata.

33. Use according to claim 29 to 32, wherein the spray formulation is for twice daily administration to a patient.

34. An aqueous composition, for treatment of Alopecia areata, comprising, by weight-

- from 0.5 to 2% hair growth stimulant - from 0.025 to 0.5% steroid

- from 50 to 92% alcohol

35. A composition, for treatment of Alopecia areata, comprising, by weight:-

- from 0.5 to 2% minoxidil - from 0.025 to 0.5% steroid

- from 50 to 92% alcohol

36. A composition according to claim 34 or claim 35 further comprising a mast cell stabilizer.

37. A composition according to any one of claims 34 to 36, comprising from 0.5 to 1.5% minoxidil.

38. A composition according to any one of claims 34 to 37, comprising from 0.03 to 0.3% steroid.

39. A composition according to any of claims 34 to 38, comprising from 60 to 90% alcohol.

40. A composition according to any of claims 34 to 39, comprising from 60 to 85% alcohol.

41. A composition according to any of claims 34 to 40, comprising betamethasone or a pharmaceutically acceptable salt or other derivative thereof.

42. A composition substantially as hereinbefore described and claimed.

43. A method substantially as hereinbefore described and claimed.

44. Use substantially as hereinbefore described and claimed.