USE OF NICORANDIL TO TREAT ALOPECIA BACKGROUND The present invention relates to methods, compositions and solu¬ tions for treating human alopecia, including male pattern alopecia (androgenic alopecia) and alopecia areata, involving the use of N-[2-(nitrooxy)ethyl]-3-pyridine carboxamide(nicorandil) and pharma¬ ceutically acceptable salts thereof in association with a pharma¬ ceutical carrier adapted for topical application.

Dermatologists recognize many different types of hair loss, the most common by far being "androgenic alopecia" wherein human males begin losing scalp hair at the temples and on the crown of the head as they get older. While this type of hair loss is largely confined to males, hence its common name "male pattern baldness", it is not unknown in women. An effective treatment for these and related conditions has long been sought.

There are two types of hair, namely "terminal hairs" and "vellus hairs". Terminal hairs are coarse, pigmented, long hairs in which the bulb of the hair follicle is seated deep in the dermis. Vellus hairs, on the other hand, are fine, thin, non-pigmented short hairs in which the hair bulb is located superficially in the dermis. As alopecia progresses, a transition takes place in the area of ap¬ proaching baldness wherein the hairs themselves are changing from the terminal to the vellus type.

Another factor that contributes to the end result is a change in the cycle of hair growth. All hair, both human and animal, passes through a life cycle that includes three phases, namely, (1) the anagen phase (2) the catagen phase and (3) the telogen phase. The anagen phase is the period of active hair growth and, insofar as scalp hair is concerned, this generally lasts from 3-5 years. The catagen phase is a short transitional phase between the anagen and telogen phases which, in the case of scalp hair, lasts only 1-2 weeks. The final phase is the telogen phase which, for all practical purposes, can be denominated by a "resting phase" where all growth ceases and the hair eventually is shed preparatory to the follicle commencing to grow a new one. Scalp hair in the telogen phase is also relatively short-lived, some three to four months elapsing before the hair is shed and a new one begins to grow.

Under normal hair growth conditions on the scalp, approxi-

mately 88% of the hairs are in the anagen phase, only 1% in catagen and the remainder in telogen. With the onset of male pattern baldness, a successively greater proportion of the hairs are in the telogen phase with correspondingly fewer in the active growth anagen phase.

The remaining result associated with alopecia is the severe diminution of hair follicles. A. bald human subject will average only about 306 follicles per square centimeter, whereas, a non-bald one in the same age group (30-90 years) will still have an average of 460 follicles per square centimeter. This amounts to a one-third reduction in hair follicles which, when added to the increased proportion of vellus hair follicles and the increase number of hair follicles in telogen, is both significant and noticeable. It is written that approximately 50% of the hairs must be shed to produce visible thinning of scalp hair. It is thus a combination of these factors: (1) transition of hairs from terminal to vellus, (2) increased number of telogen hairs - some of which have been shed, and (3) loss of hair follicles (atrophy in Settel's description) that produces "baldness". While a good deal is known about the results of male pattern baldness, very little is known about its cause. About all that can be said is that the cause is felt to be genetic and hormonal in origin although as will be seen presently, the known prior art attempts to control it through hormone adjustment have been singu- larly unsuccessful.

At the present time, one known treatment for male pattern alopecia is hair transplantation. Plugs of skin containing hair are transplanted from areas of the scalp where hair is growing to bald areas with reasonable success; however, the procedure is a costly one in addition to being time-consuming and quite painful. Furthermore, the solution is inadequate from the standpoint that it becomes a practical, if not an economic, impossibility to replace but a tiny fraction of the hair present in a normal healthy head of hair.

As far as the other non-drug related approaches to the problem are concerned, they include such things as ultra-violet radiation, massage, psychiatric treatment and exercise therapy. None of these, however, has been generally accepted as being effective. Even such things as revascularization surgery and acupuncture have shown

little, if any, promise.

By far, the most common approach to the problem of discovering a remedy for male pattern alopecia has been one of drug therapy. Many types of drugs ranging from vitamins to hormones have been tried and only recently has there been any indication whatsoever of even moderate success. For instance, it was felt for a long time that since an androgenic hormone was necessary for the development of male pattern baldness, that either systemic or topical application of an antiandrogenic hormone would provide the necessary inhibiting action to keep the baldness from occurring. The theory was promising but the results were uniformly disappointing.

The androgenic hormone testosterone was known, for example, to stimulate hair growth when applied topically to the deltoid area as well as when injected into the beard and pubic regions. Even oral administration was found to result in an increased hair growth in the beard and pubic areas as well as upon the trunk and extremities. While topical application to the arm causes increased hair growth, it is ineffective on the scalp and some thinning may even result. Heavy doses of testosterone have been even been known to cause male pattern alopecia.

The topical application of minoxidil is currently the most effective drug therapy for the treatment of alopecia. Minoxidil is a well-known pharmaceutical compound. It is marketed by the Upjohn Company as the active ingredient in LONITEN® Tablets for the treat- ment of hypertension. It is also useful in topical compositions for the treatment of baldness. The structure and use of this compound is described in U.S. Patents 4,139,619 and 4,596,812. This compound has varying degrees of efficacy for hair growth purposes, depending on the patient, the degree of baldness, the dose and the nature of the topical composition.

The present invention provides a novel, non-obvious and ef¬ fective treatment for human baldness, such as pattern baldness.

INFORMATION DISCLOSURE U.S. Patent 4,200,640 discloses the use of nicorandil and its pharmaceutically acceptable salts for treating circulatory disease, such as coronary vasodilating action, antihypertensive action, antiarrhythmic action, anticoagulative action and peripheral vaso¬ dilating action and, thus, it is useful for treating ischemic heart

disease, as an antihypertensive drug, anticoagulative drug, anti- arrhythmic drug, and as a peripheral vasodilator Including cerebral vasodilator and renal vasodilator.

WIer et al, Br. J. Pharme (1986), 88, pp. 121-128 describe the effects of nicorandil on electrical and mechanical activity on ⁸⁶ Rb efflux in rat blood vessels.

U.S. Patent 4,596,812 discloses the use of minoxidil, 6-amino- l,2-dihydro-l-hydroxy-2-Imino-4-piperidinopyrimidine, as a thera¬ peutic agent to treat alopecia and arrest and reverse male pattern alopecia. U.S. Patent 4,139,619 discloses the use of minoxidil and related 6-amino-4-(substituted amino)-l,2-dihydro-l-hydroxy-2-imino- pyrimidines as a means for (a) Increasing the rate of growth of terminal hair, and (b) converting vellus hair to growth as terminal hair. The use of retinoids alone or in combination with minoxidil and related substituted pyrimidines to increase the rate of hair growth is disclosed in PCT publication numbers US85/04577, PCT US83/02558 and PCT US82/02833.

The use of minoxidil sulfate (2,6,-diamino-4-(l-piperidinyl)-1- (sulfooxy)-pyrimidinium hydroxide, inner salt) as a therapeutic agent to stimulate the rate of hair growth is disclosed in PCT Application US86/00073 published 31 July 1986. In addition, the induced relax¬ ation of rabbit superior mesenteric artery smooth muscle by minoxidil sulfate and dependence on potassium permeability has been reported. See K.D. Meisheri, et al, "The Mechanisms of Vascular Smooth Muscle Relaxing Effects of Minoxidil Sulfate"; Smooth Muscle Function Symposium Proceedings: Official Satellite Symposium of the XXX Internation Congress of the International Union of Physiological Sciences, Banff Center, Banff, Canada, 1986, page 114, abstract W4- P5.

SUMMARY OF THE INVENTION The present invention particularly provides:

(1) a method of treating humans for alopecia which comprises topically applying to the human scalp an effective amount of a pharmaceutical composition containing a compound of Formula I or a pharmaceutically acceptable salt thereof; and

(2) a topical pharmaceutical composition for the treatment of alopecia consisting of a compound of Formula I or a pharmaceutically

acceptable salt thereof and a pharmaceutical carrier adapted for topical application.

Thus, this invention relates to the method for treating humans for alopecia, Including androgenic alopecia (male pattern baldness; male pattern alopecia) and alopecia areata, which comprises regular topical application to the affected areas of the human skin a pharmaceutical composition containing as at least one of its active ingredients a compound of Formula I. It also encompasses the use of a compound of Formula I as a therapeutic agent to arrest and reverse androgenic alopecia.

The compounds of Formula I including N- [2-(nitrooxy)ethyl] -3- pyridine carboxamide and pharmaceutically acceptable salts thereof and methods for their preparation are disclosed in U.S. Patent No. 4,200,640. Methods that can be used for formulating the compounds of Formula I are described in U.S. Patent No. 4,139,619. These methods from U.S. Patent 4,200,640 and 4,139,619 are hereby incorporated by reference.

The pharmaceutical compositions contemplated by this invention include pharmaceutical compositions adapted for topical application to the human scalp. Conventional pharmaceutical forms for this purpose include ointments, lotions, pastes, jellies, gels, mousses, sprays, foams, aerosols, and the like. The term "ointment" embraces formulations (including creams) having oleaginous, absorption, water- soluble and emulsion-type bases, e.g., petrolatum, lanolin, poly- ethylene glycols, as well as mixtures of these. The compounds may also be formulated into lipsomal preparations or lipid emulsions or dissolved in conventional solvents such as acetonitrile, dimethyl- formamide (DMF) , dimethylacetamide (DMA), alcohol, propanol, and the like. The percentage by weight of the compound of the Formula I herein utilized typically ranges from about 0.1% to about 10.0% of the pharmaceutical preparation, preferably from about 1% to about 5% and in these preparations the aforesaid pharmaceutical carrier for topical application constitutes a major amount of the said prepar- ation.

The pharmaceutical preparations of the subject invention are applied on a regular basis, with or without occlusion, for a period of time sufficient to effect hair growth. Occlusion of the prepar-

ation may be obtained by any conventional means such as bandages, plastic coverings, shower caps swimming caps, etc. The percentage of active ingredient (Formula I) as well as frequency of application may be varied as necessary or desirable to achieve the desired results. DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention is seen more by fully the examples given below. Example 1

Vibrissae follicles from neonatal mice were cultured in Del- beco's-minimum essential medium (Modified Eagles Medium - manu¬ factured by DIfco Company) with 20% fetal calf serum. Hair growth was measured by recording increases in hair shaft length during culture and by determining incorporation of -"S cysteine in hair shafts. The administration of 0.1 mg/ml of nicorandil to this medium stimulated hair growth as measured by both of these endpoints. Example 2

Two hundred and fifty liters of a pharmaceutically elegant 2% topical solution of Nicorandil is prepared from:

Propylene Glycol USP 51 kg 800 g (Sp.Gr. - 1.036)

Nicorandil (5 kg)

5 kg 030 g Alcohol USP q.s. ad 250 L

The propylene glycol and 150 liters of alcohol are added to a mixing tank, the Nicorandil is added and dissolved in the propylene glycol/- alcohol mixture and additional alcohol added to make 250 liters. The resulting Nicorandil topical solution is packaged in suitable dispensing bottles, accompanied by a metered dropper, and applied to the prewashed scalp as a total dose of 1 ml. , beginning in the center of the affected area. Twice daily application for 2 to 7 months or longer may be required before evidence of hair growth stimulation can be expected in the treatment of early, progressive male pattern baldness. Onset and degree of hair growth stimulation can be expected to vary considerably among patients. 0.1% and 1% Nicorandil topical solutions are similarly prepared in accordance with the foregoing procedure by utilizing 0.25 kg. and 2.5 kg., respectively of Nicorandil for the 5.0 kg. utilized In the preparation of the 2% solution of Example 2.

Following the procedure of the preceding Examples 1 and 2, inclusive, compositions are similarly prepared substituting an equimolar amount of another compound within the scope of Formula I for Nicorandil. Following the procedure of the preceding Examples 1 and 2, inclusive, compositions are similarly prepared substituting an equimolar amount of the various pharmaceutically acceptable salts of nicorandil.

Thus, it is intended that modifications and variations of the present invention, which have been hereinbefore disclosed or sug¬ gested, be included within the scope of the appended claims except insofar as limited by the prior art.

FORMUIA

(I)