WO1997017953A1

WO1997017953A1 - Method for the treatment, prevention or minimization of hair loss using a source of fatty acids

Info

Publication number: WO1997017953A1
Application number: PCT/US1996/018143
Authority: WO
Inventors: Wen G. Chen; Maria Cifuentes; Stephen J. Galli; George C. Hwang; Alice Lin; Maureen H. Mcaloon; Karen A. Sanborn; Richard J. Sharpe; Zianbo Zhang
Original assignee: Arcturus Pharmaceutical Corporation
Priority date: 1995-11-13
Filing date: 1996-11-13
Publication date: 1997-05-22
Also published as: AU7678796A

Abstract

A composition and method for the treatment, prevention or minimization of hair loss. The compound, which comprises a source of fatty acids as the active agent, is topically administered to patients having various forms of alopecia.

Description

METHOD FOR THE TREATMENT, PREVENTION OR MINIMIZATION OF HAIR LOSS USING A SOURCE OF FATTY ACIDS

FIELD OF THE INVENTION

This invention relates to a method for the treatment of alopecia (hair loss) by the topical administration of a fatty acid source.

BACKGROUND OF THE INVENTION

Description of the Prior Art

Alopecia is generally divided into androgenetic alopecia, telogen effluvium (shed) , anagen effluvium, and alopecia areata. The most common form of alopecia iε androgenetic alopecia. Synonyms for this disorder include common baldness, hereditary baldness, male-pattern baldness, premature baldness, and diffuse alopecia. It is a genetically determined form of gradual hair loss that begins as a receding hair line and/or thinning at the vertex (crest) of the scalp. A gradual decrease in hair shaft length and diameter may eventually result in near total replacement of terminal hair with soft, short vellus hair. A band of hair is usually retained along the peripheral scalp. In men, onset can begin as early as adolescence. In women, the pattern is exhibited as thinning of the parietal and vertex regions, and the age of onset is usually two decades after the onset in men.

A topical solution of the piperidinyl pyrimidine compound, minoxidil, is available for the treatment of androgenetic alopecia. However, the utility of this treatment is modest at best . After four months of treatment, approximately 25%, 7%, and 0.7% of patients achieve minimal, moderate and dense regrowth of hair, respectively. The response appears to be more favorable in women and men under 40, in those who have been bald for less than 10 years, and when the affected area is less than 10 cm in diameter (Price, V.H., Rogaine in "The Management of Male- Pattern Baldness and Alopecia Areata", Proceedings of a Symposium, J. Am. Acad. Dermatol . , 1987, Vol. 16, pp. 749-750) . Patients with severe hair loss are currently instructed that most therapeutic attempts to treat hair loss are ultimately unsuccessful, and physicians must simply help patients make the psychological adjustment to permanent hair loss.

Telogen effluvium is the second most common form of alopecia. It can be induced by such factors as childbirth, surgery, psychological stress, certain drugs, androgen excess, nutritional and metabolic disorders, autoimmune diseases, chronic infections, chronic scalp disease and chronic alopecia areata. Telogen effluvium usually affects less than 20 to 35 percent of the scalp hair, and occurs approximately 6 weeks to 3 months after a triggering event.

Anagen effluvium usually affects more than 80-90 percent of the total body hair, and begins 1 to 2 weeks after a triggering event. Anagen effluvium can be caused by anti-coagulants, anti-metabolites, cytotoxic agents, alkylating agents, and alopecia areata, or by poisoning with lead, arsenic, mercury, thallium, and certain chemotherapeutic agents as well as ionizing radiation.

Alopecia areata, a non-cicatricial (non- scarring) alopecia, is a relatively common disorder of unknown cause or causes. It is characterized by well defined areas of total hair loss, typically affecting the scalp, although it may extend to effect the entire scalp or even hair follicles on the entire body. Alopecia areata occurs in patients with atopy or Down's syndrome, and usually occurs before age 25. The typical lesions usually appear over a 24 hour period as 3-4 cm asymptomatic smooth bald patches, commonly on the scalp. However, the beard, eyebrows, and/or eyelashes may also be affected. The course of the baldness is variable, and some patients experience regrowth of hair within one year. One third of the patients never experience hair regrowth, and many suffer from recurrences of areas of baldness. High potency corticosteroids may be prescribed for topical or intralesional treatment of alopecia areata. Topical therapies are often ineffective and intralesional therapy is impractical. The effectiveness of this approach is questionable, however, and most patients who respond experience a recurrence of hair loss upon discontinuation of therapy. Moreover, any benefits of this therapy usually are outweighed by its side effects.

An alternative therapy is the combination of Psoralen and ultraviolet radiation treatments

(photochemotherapy, PUVA) . This therapy has had some effect in certain severe cases of alopecia areata. However, the inconvenience and long-term toxicity and low rate of response of this treatment make it impractical for most patients. Furthermore, as treatments are successful, hair grows in, preventing effective penetration of light and therefore limiting the effectiveness of subsequent treatments.

The induction of irritant dermatitis or allergic contact dermatitis in areas affected by alopecia areata can sometimes promote hair regrowth. However, the local pain and discomfort associated with this therapy renders it essentially useless.

In addition to the four forms of hair loss already discussed, a wide range of inflammatory disorders can cause hair loss as a result of scarring that produces complete destruction of the pilosebaceous unit. These disorders include discoid lupus erythematosus (DLE) , lichen planopilaris (LPP) , morphea, cicatπcial pemphigoid, and follicular mucinosis Basal cell carcinoma, infections (e.g., herpes zoster, leprosy) , and physical injury (e.g., burns, radiodermatitis) may also result m scarring and hair loss . Radiation and chemotherapy treatments for cancers may also cause alopecia, which may be transient or permanent The loss of hair due to radiation therapy is dose dependent, but usually occurs in the range of 200-800 rads. Follicles in the anagen phase are about 3 times more sensitive to this disruption than are follicles in the telogen phase. Free radicals generated as a result of the cytotoxic mechanisms of action of chemotherapeutic agents and ionizing radiation are thought to have a manor role in the hair loss associated with those modalities of cancer therapy.

Cytotoxic drugs may also produce partial or complete inhibition of mitosis or impairment of metabolic processes in the hair matrix, resulting in a thinned, weakened hair shaft This form of alopecia only affects hairs in the anagen phase of growth, and is therefore classified as a type of anagen effluvium. Hair loss due to chemotherapy is most pronounced in the scalp. Other terminal hairs, such as facial or pubic hairs, are variably affected Hair loss is usually first observed 1-2 weeks after initiation of chemotherapy, but becomes progressively more marked 1- 2 months later.

It has been reported that medically and cosmetically acceptable inhibitors of lipid- peroxidation may have value in reducing hair loss. However, these antioxidants produce numerous side effects when applied to the skin and they are further limited in their ability to penetrate the epidermis. Thiele, F.A.J. British J. of Dermatology, 92:355 (1975) .

Most current treatments for the common or uncommon alopecias are either not effective or have unfavorable side effects that render them unsuitable for the treatment of a cosmetic condition. Several substances are known to be effective when administered systemically, but the increased hair growth is not limited to the target areas and many such agents have unacceptable side effects when administered systemically. Accordingly, an effective topical therapy which could prevent or lessen the extent of the hair loss, or which could promote regrowth of hair, would be valuable in serving the cosmetic and psychological needs of subjects with alopecia, especially in patients undergoing chemotherapy, since a common adverse side effect of chemotherapeutic drugs is hair loss. In addition to providing the primary benefit of preventing hair loss or promoting hair regrowth, an effective topical therapy for alopecia would avoid the introduction of a secondary systemic drug which could interfere, for example, with chemotherapy or lessen the effectiveness of anti¬ cancer agents.

A study has been conducted to determine the effect of fatty acid administration in the treatment of alopecia caused by carboxylase deficiency, a biotin-dependent metabolic disease. Munnich et al . , Lancet, pp. 1080-1081, May 17, 1980 A 12-month old boy who had carboxylase deficiencies of three carboxylases, including propionyl CoA carboxylase, pyruvate carboxylase and methylcrotonyl CoA carboxylase, presented with total alopecia. Munnich et al . used oral administration and cutaneous application of unsaturated fatty acids composed of 11% of C18:l, 71% of C18:2, 8% of C18:3 and 0.3% of C20:4 to treat the boy. After treatment with unsaturated fatty acids, hair started to grow on the whole scalp of the boy.

U.S. Patent No. 5,030,442 discloses a composition containing minoxidil complexed with an amphipathic compound, oleic acid and with pharmaceutically acceptable excipients which is disclosed as being useful for preparing a non- crystalline minoxidil composition. This patent further discloses that the presence of an amphipathic compound in the minoxidil formulation serves to prevent crystallization of minoxidil on the scalp after application due to evaporation of the ethanol solvent and that preferred amphipathic compounds also improved the transdermal penetration of the drug through the skin. This patent also discloses a minoxidil composition in which the minoxidil is complexed with an amphipathic compound which has a pK of less than about 5 and which contains a single lipophilic chain and a polar head group selected from a sulfate, sulfonate, phosphate, or phosphonate free acid.

It is an object of the present invention to provide a method for the treatment of alopecia, which is especially useful in preventing or treating the hair loss that occurs as an adverse side effect of radiation therapy or chemotherapy used in cancer treatments .

It is another object of the present invention to provide a pharmaceutical composition that can readily pass through the skin and, in particular, the stratum corneum, for effective treatment of alopecia .

SUMMARY OF THE INVENTION According to one aspect of the present invention, there is provided a pharmaceutical composition for the topical treatment of alopecia which contains, as the active agent, an effective amount of a source of fatty acid or a pharmaceutically acceptable salt or derivative thereof.

According to another aspect of the present invention, there is provided a method for treating alopecia via the topical administration of a source of fatty acid or a pharmaceutically acceptable salt or derivative thereof, optionally in a pharmaceutically acceptable carrier, to induce regrowth of hair, and/or to prevent further loss of hair.

The delivery of a fatty acid source through the skin, is useful in the treatment, prevention or minimization of all types of alopecia, including androgenetic alopecia, alopecia areata, telogen effluvium, anagen effluvium, and other, non-specific types of hair loss which are caused by oxidative damage .

DETAILED DESCRIPTION OF THE INVENTION

I . Pharmaceutical Compositions of a Source of Fatty Acidε

Humans, equines, canines, bovines and other animals, and in particular, mammals, with alopecia, and in particular, alopecia caused by oxidative stress or free radicals, arising from either external factors, chemicals, ionizing radiation, or endogenous sources, especially the radiation therapy and chemotherapy used in cancer treatments, can be treated by delivery of an effective amount of a pharmaceutically acceptable source of fatty acid, salt or derivative thereof, optionally in a pharmaceutically acceptable carrier or diluent.

As used herein, the term pharmaceutically acceptable salts or complexes refers to salts or complexes that retain the desired biological activity of the source of fatty acids and exhibit minimal undesired toxicological effects. Pharmaceutically acceptable carboxylic acid salts are known to those skilled in the art, including inorganic salts with cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a cation formed with a nitrogenous base such as ammonia, N,N- dibenzylethylene-diamine, D-glucosamine, or ethylenediamin .

Modifications of the active agent can affect its bioavailability and rate of metabolism, thus providing control over the delivery of the agent through the stratum corneum. For example, it is well known in the art that various modifications of the active molecule, such as alteration of charge, can effect water and lipid solubility and thus alter the potential for crossing the stratum corneum. Further, the modifications can affect the bioactivity of the resulting compound, in some cases increasing the activity over the parent compound or increasing the permeability of the parent compound through the stratum corneum. This can easily be assessed by synthesizing the derivative and testing its activity according to the methods described herein, or other methods known to those skilled in the art . The active agent is preferably included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount of the compound for any of the above conditions without causing serious toxic effects in the patient treated. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art. The concentration of active agent in a composition of the invention will depend on absorption, distribution, deactivation, and excretion rates of the drug aε well as other factors known to those skilled in the art. Dosage values will also vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. The concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying time intervals .

As used herein, the expression "source of fatty acid" refers to aliphatic carboxylic acids, salts or derivatives thereof, e.g. esters, having chain lengths containing from 3 to 24 carbon atoms. In a preferred embodiment, the source of fatty acids provides aliphatic carboxylic acids with chain lengths containing from 14 to 22 carbon atoms. Among the foregoing, unsaturated fatty acids are preferred, with oleic acid being particularly preferred. Examples of suitable fatty acids which can be used in this invention include, but are not limited to, linoleic, linolenic, lactic, crotonic, isocrotonic, sorbic, cinnamic, maleic, fumaric, lauric, caproic, caprylic, capric, acrylic, pelargonic, neononaoic, neodecanoic, palmitelaidoic, myristic, palmitic, stearic, arachidic, behenic, lignoceric, heptanoic, nonanoic, undecanoic, tridecanoic, pentadecanoic, heptadecanoic, nonadecanoic, henicosanoic, tricosanoic, arachidonic, docosahexanoic, elaidic, erucic, nervonic, palmitoleic, petroselinic, undecylenic, and other saturated and unsaturated fatty acids.

The active agent or pharmaceutically acceptable salts thereof can, if desired, be mixed with other active materials that do not impair the intended effect, or with materials that supplement the intended effect, such as antioxidants, antibiotics, anti-fungals, anti-inflammatories, disinfectants, or anti-viral compounds. When administered topically, a topical formulation containing an effective amount of a source of fatty acids is administered typically in a compatible solution that can include polymers, suspension agents, ointment, gel or cream vehicle. In certain cases, these vehicles may contain liposomes for creating a reservoir of dissolved agent.

II. Method or Determining the Therapeutic Benefit of the Topical Application of a Source of Fatty Acids in the Treatment and/or Prevention of Alopecia

A number of animal model assays are available to evaluate the effectiveness of a compound in treating alopecia. Any of these assays can be used to determine the effectiveness of the compounds described herein in treating one or more forms of alopecia. Specifically, the ability of a source of fatty acids to enhance regrowth of hair or to minimize hair loss can be evaluated, for example, by one or more of the following methods :

(a) an established rodent (rat) model for chemotherapeutically induced alopecia where regrowth of hair can be measured/observed (see Example 1) ;

(b) an established mouse model which measures hair regrowth after androgenetic alopecia is induced;

(c) an established primate model (stumptail macaque monkey) in which the animals develop baldnesε in a similar pattern to androgenetic alopecia in humans ; and

(d) in humans with alopecia caused by any of the factorε outlined herein. For example, women with ovarian cancer who are to be treated with chemotherapeutic agents could topically apply a source of fatty acid, preferably 100% oleic acid, three days prior to chemotherapy and once daily throughout the prescribed course of chemotherapy to reduce or prevent the hair loss that often results from chemotherapy.

EXAMPLE 1 Effect of Different Concentrations of Oleic Acid in Cytoxan^®-Induced Alopecia

The experiment was carried out according to a block design in which each litter of rat pups was treated as a block. Each block contained seven treatment groups with two pups in each group, except for groups VI and VII which had only one pup per group. The pups were treated with Cytoxan^®, a chemotherapeutic drug, whose side effects include hair loss . The pups were obtained when they were 5 days old. When the pups were 7 days old, the pups in groups II to V were given a topical treatment of acetone or oleic acid solution. Group I was a healthy control group which was not treated with Cytoxan® (CTX) or oleic acid.

Day 1 of the study occurred when the pups were 8 days old. On Day 1 of the study, the each pup in Groups II to VII was given a single intraperitoneal injection of Cytoxan^® at a concentration of 30 mg/kg in USP water for injection. The pups in Groups VI and VII were given their first topical treatment with oleic acid on Day 1 of the study, i.e., the first day that Cytoxan^® was administered. Topical treatment with acetone or oleic acid solution was performed once daily on each pup in Groups II to VII for the next 13 days . The pups were videotaped daily to monitor the results of the study.

The following table indicates the treatment of each group of pups.

Group Formulation or Treatment

I Healthy Control Group: Not treated with Cytoxan^® or acetone or oleic acid.

II CTX + treatment with acetone starting on the day before CTX was administered.

III CTX + treatment with 10.0% oleic acid starting on the day before CTX was administered.

IV CTX + treatment with 6.0% oleic acid starting on the day before CTX was administered. V CTX + treatment with 100% oleic acid brushed into the pups' coat starting on the day before CTX was administered. VI CTX + treatment with 10.0% oleic acid starting on the same day that CTX was administered. VII CTX + treatment with 6.0% oleic acid starting on the same day that CTX waε administered.

Videotaping to monitor the pups' hair was started on the day prior to Day 1 of the study when the pups were 7 days old. Baby hairs continued to grow on the pups between days 1 to 6 of the study regardless of which treatment they had received. After 7 days, the pups' hair began to fall out in varying amounts according to the treatment that they had received. Table 1 sets forth the results of this study in terms of the per cent area of the dorsal area of the pups that is covered with hair.

Table 1

Per Cent of Dorsal Area Covered with Hair at the Age of

Treatment Group Days 1 to 6 Day 7 Day 8 Day 1 1 Day 12 Day 13 Day 14

I Healthy 100 100 100 100 IOO 100 100 Control

II CTX + 100 > 0 -30 <S - 0 - 0 - 0 Acetone (one has (one has (Control) new new hair) hair)

III CTX + 10% 100 > 9₅ > 9₅ - 50 - 40 - 20 - 20 O A

( 1 day)

IV CTX + 6% 1(H) >95 > 95 - 40 - 20 - 10 - 10 O A ( 1 day)

V CTX + 100 100 >98 - 80 - 80 - 70 - 70 100% O A (-1 day)

VI CTX + 10% 100 >95 >95 - 50 - 40 - 40 - 40 O A (0 day)

VII CTX + 6% 100 >95 >90 - 20 - 5 < 5 0 O A (0 day)

The results indicate that treatment with oleic acid m appropriate dosages prevents hair loss in Cytoxan^®-induced alopecia. For example, when the pups were treated with Cytoxan^® and acetone as a control, 0% of their dorsal area was covered with hair after Day 12 of the study. However, when the pups were treated with Cytoxan^® and oleic acid, they retained hair on their dorsal area until the end of the study. The pups in Group III, which were treated with 10% oleic acid, retained approximately 50% of the hair on the dorsal area on Day 11 of the study and retained approximately 20% of the hair on the dorsal area at the end of the study. The pups in Group IV, which were treated with 6% oleic acid, retained approximately 40% of the hair on the dorsal area on Day 11 of the study and retained approximately 10% of the hair on the dorsal area at the end of the study. The pups in Group V, which were treated with 100% oleic acid, retained approximately 80% of the hair on the dorsal area on Day 11 of the study and retained approximately 40% of the hair on the dorsal area at the end of the study. The pups in Group VI, which were treated with 10% oleic acid starting on the same day that the Cytoxan^® was administered, retained approximately 50% of the hair on the dorsal area on Day 11 of the study and retained approximately 40% of the hair on the dorsal area at the end of the study. The pups in Group VII, which were treated with 6% oleic acid starting on the same day that the Cytoxan^® was administered, retained approximately 20% of the hair on the dorsal area on Day 11 of the study and had no hair on the dorsal area at the end of the study.

The results of the study show that topical application of oleic acid is particularly effective in treating Cytoxan^®-induced alopecia especially when 100% oleic acid is used.

Claims

WHAT IS CLAIMED IS:

1. A composition for the treatment of alopecia comprising, as the active agent, a source of fatty acid, or a pharmaceutically acceptable salt or derivative thereof, in an amount effective to prevent or reduce hair loss, and a pharmaceutically acceptable carrier.

2. A composition as claimed in claim 1, wherein said source of fatty acid comprises at least one carboxylic acid having a chain length of 14- 22 carbon atoms.

3. A composition as claimed in claim 1, wherein said source of fatty acid is selected from the group consisting of oleic, linoleic, linolenic, myristic, palmitic, stearic, arachidic, behenic, pentadecanoic, heptadecanoic, nonadecanoic, henicosanoic, tricosanoic, arachidonic, elaidic, erucic, petroselenic and palmitoleic acid, or a mixture of said acids.

4. A composition as claimed in claim

1, wherein said source of fatty acid is oleic acid.

5. A composition as claimed in claim 1, which further comprises a supplement selected from the group consisting of an antioxidant, antibiotic, anti-fungal, anti-inflammatory, disinfectant or anti¬ viral compound.

6. A method of treating alopecia in a patient requiring said treatment by administering a source of fatty acid in an amount effective to prevent or reduce hair loss in said patient.

7. A method of treating alopecia, aε claimed in claim 6, wherein said source of fatty acid is topically administered to said patient.

8. A method as claimed in claim 6, wherein said patient is a cancer patient and said alopecia is induced by radiation therapy.

9. A method as claimed in claim 6, wherein said patient is a cancer patient and said alopecia is induced by chemotherapy.

10. A method as claimed in claim 6, wherein said source of fatty acid comprises at least one carboxylic acid having a chain length of 14-22 carbon atoms .

11. A method as claimed in claim 6, wherein said source of fatty acid is selected from the group consisting of oleic, linoleic, linolenic, myristic, palmitic, stearic, arachidic, behenic, pentadecanoic, heptadecanoic, nonadecanoic, henicosanoic, tricosanoic, arachidonic, elaidic, erucic, petroselenic and palmitoleic acid, or a mixture of said acids .

12. A method as claimed in claim 6, wherein said source of fatty acid is oleic acid.

13. A method as claimed in claim 6, wherein said fatty acid is co-administered with a supplement selected from the group consisting of an antioxidant, antibiotic, anti-fungal, anti¬ inflammatory, disinfectant or anti-viral compound.