JPH02501570A - Use of nicorandil to treat alopecia - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Background of the use of nicorandil to treat alopecia The present invention relates to N-[2-troxy)ethyl rho-3-pyridinecarboxamide. topical application of corandil (nicorandil) and its pharmaceutically acceptable salts. Male pattern baldness (androgenic baldness) including use in conjunction with a pharmaceutical carrier compatible with Methods and systems for treating human alopecia, including alopecia areata) and alopecia areata Concerning compositions and solutions.

Dermatologists recognize many different types of hair loss, and by far the most common As human males grow older, they begin to lose hair on the temples and the top of the brain. androgenic alopecia.” This type of hair loss is mostly limited to men. Therefore, the most common name is "male pattern baldness," but it is not known among women. That's not to say it hasn't. Effective treatments for these and related disorders have long been sought. It's here.

There are two types of hair: terminal hair and soft hair. It is a coarse, colored, long hair whose root ball is located deep in the dermis. on the other hand , vellus hair is a delicate, fine, non-pigmented, short hair whose root bulb is located in the superficial layer of the dermis. . As alopecia progresses, a transition occurs near the bald area, where the hair grows naturally. The body changes from a hard hair type to a soft hair type.

Another factor contributing to the final result is changes in the hair growth cycle.

In both humans and animals, all hair has three phases: (1) growth initiator; It goes through a life cycle that includes (2) a regressive founder and (3) a dormant founder. growth development The period of active hair growth is the period of active hair growth, and as far as scalp hair is concerned, this generally lasts for 3 to 5 years. Continue. Regressive founder is a short transition phase between growth founder and regressive founder, and in the case of hair, It only lasts 1-2 weeks. The last phase is the dormant founder, which is actually , all growth stops and finally the hair grows before the overgrowth can grow new hair. It can be called ``body stop phase,'' which causes hair to fall out. The hair of the dormant founder is also relatively Short-lived, lasting about 3-4 months before hair falls out and new hair begins to grow .

Under normal hair growth conditions on the scalp, approximately 88% of the hair is in the anagen phase and 1% of the hair is in the anagen phase. Only one is in the regressive founder, and the rest is in the dormant founder. Gradual increase with the onset of male pattern baldness A large proportion of hair is in the dormant origin, with a correspondingly active growth origin. becomes less.

The remaining result regarding alopecia is a severe reduction in epidermis. On average, bald human patients It is about 306 pieces per square centimeter in the same age group (30-9 0 year olds) who are not bald still have an average of 460 hairs per square centimeter. have This is a 1/3 decrease in the upper position, and the increase rate of the upper position of the fur and Add in the increased number of telogen superpositions and it is significant and noteworthy. in the eyes of the hair It is said that approximately 50% of the hair must fall out for the hair to become visibly thinner.

Thus, ``baldness'' is caused by these factors: (1) the change in hair from terminal hair to soft hair; transition, (2) an increase in the number of telogen hairs, some of which fall out, and overgrowth. (degeneration in the description of settel).

Although so much is unknown about the consequences of male pattern baldness, the causes are unknown. is little known. In most cases, the cause is genetic. It is thought that it has a hormonal origin, and we will soon find out. However, attempts to control it through hormonal regulation are strange. I have also failed.

At present, one known treatment for androgenetic alopecia is hair transplantation. hair A small piece of skin containing hair is transplanted from the area of the scalp where hair grows to the bald area. However, the method is time consuming and has considerable This is a painful and expensive method. Furthermore, if the solution is not economical In any case, it replaces all but the smallest portion of hair that exists on a head of normal, healthy hair. is inappropriate because it is actually impossible.

As far as other non-drug related studies on the problem are concerned, they have been therapy, psychotherapy, and physical exercise therapy. However, these None of these are generally accepted as valid. Vascular transplant surgery and Even something like acupuncture offers little, if any, promise.

Traditionally, the most common research into the problem of finding a cure for male pattern baldness has focused on drugs. It's a drug treatment. Many types of drugs ranging from vitamins to hormones has been attempted with only moderate success recently. For example, male hormones is necessary for the development of male-pattern baldness, so systemic or local administration of anti-androgenic hormones may be effective against baldness. has long been thought to provide the necessary inhibitory effect to prevent hair loss. . Although this theory offers hope, the results have generally been disappointing.

The male hormone testosterone, for example, when applied topically to the deltoid area. It is known to stimulate hair growth when injected into the beard and pubic areas. Ivy. Even oral administration.

It was found to cause increased hair growth in the beard area and on the trunk and limbs. It was done. Topical application on the arms causes an increase in hair growth, but on the scalp there is no effect. It may even become somewhat thinner. High doses of testosterone are harmful to men It is known to cause sexual pattern baldness.

Topical application of minocindil is currently the most effective drug therapy for the treatment of alopecia. Mino Xydil is a well-known pharmaceutical compound. That's high blood pressure. Treatment F! 4゜yu5- 2 (LONITEN■) in tablet. Active ingredients and 7 Upjohn It is commercially available by. It is also useful in topical compositions for the treatment of baldness . The structure and uses of this compound are described in U.S. Pat. Nos. 4,139,619 and 4,596. It is described in No. 812. This compound depends on the patient, the degree of baldness, and the topical composition. Depending on the dose and nature, they have varying degrees of effect on hair growth purposes.

The present invention is novel and non-obvious regarding human baldness, such as pattern baldness. It provides effective treatment.

Disclosure of information U.S. Patent No. 4,200,640 has coronary vasodilatory effect, antihypertensive effect, antiarrhythmia effect, As an anticoagulant and peripheral vasodilator, it is thus useful in the treatment of bivascular heart disease. and its pharmaceutically acceptable nicorandil and its pharmaceutically acceptable compounds for treating cardiovascular diseases. Salt as antihypertensive, anticoagulant, antiarrhythmic, and cerebral vasodilator Discloses their use as peripheral vasodilators, including agents and renal vasodilators.

Wier et al., Pritish Journal of 7 Full Macology (Br, J, PharmaXl 986), 88.12 1-128, electrical and The effect of nicorandil on mechanical activity is described.

U.S. Pat. No. 4,596,812 describes minoxidil, 6-amino-112-dihydro- Do not treat alopecia with 1-hydroxy-2-imino-4-piperidinopyrimidine. and its use as a therapeutic agent for preventing and reversing male pattern baldness. ing. U.S. Pat. No. 4,139,619 describes minoxidil and related 6-amino- 4-(Substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidine (a) increasing the rate of growth of terminal hair; and (b) growing villous hair as terminal hair. discloses its use as a means of converting

Retinoids alone or in combination with minoxidil and analogously substituted pyrimidines Its use for increasing the rate of hair growth is disclosed in PCT Application No. LJS8510. No. 4577, PCT US83102558 and PCT US821028 It is disclosed in No. 33.

Minoxidil sulfate (2,6-diamy2-4-(l-piperidinyl)-1-(sulphate) pyrimidinium hydroxide (inner salt)) that stimulates the rate of hair growth. PCT application US published July 31, 1986 for use as a therapeutic agent for It is disclosed in No. 86100073. In addition, treatment with minoxidil sulfate The induction of relaxation of the heron superior mesenteric artery smooth muscle and its dependence on potassium permeability have been reported. It is.

K. D. Meisheri et al. "Mechanism of the vascular smooth muscle relaxing effect of minoxidil sulfate": Smooth muscle function symposium Newsletter: International Union of Physiological Sciences (the International Union or Physiolo The 30th International Conference of the GicalS Sciences), Pant Center (Ba nff Center), Pants (Banff), Canada, 1986. 114 pages , see Abstract W4-P5.

The dawn of invention In particular, the present invention (1) Effectiveness of a pharmaceutical composition containing the compound of formula 1 or a pharmaceutically acceptable salt thereof A method of treating a human for alopecia comprising topically applying an amount to the scalp; and (2) a compound of formula I or a pharmaceutically acceptable salt thereof and a drug compatible with topical application; A topical pharmaceutical composition for treating alopecia comprising a drug carrier is provided.

The invention thus provides a pharmaceutical product containing at least one compound of formula I as its active ingredient. An androgenic drug characterized by regular topical application of a pharmaceutical composition to affected areas of human skin. Treating humans for alopecia including Mon's alopecia (male pattern baldness) Regarding how to. It also shows that compounds of formula I can inhibit androgenetic alopecia. It also includes use as a therapeutic agent for reversing the disease.

Including N-[2-trooxin)ethylcou-3-pyridinecarboxamide A compound of formula ■ and a pharmaceutically acceptable salt thereof, as well as a process for producing the same, are patented in the United States. No. 4,200,640.

Methods that can be used to formulate compounds of Formula I are described in U.S. Patent No. 413,961. It is stated in No. 9. U.S. Patent Nos. 4,200,640 and 4,139,619 These methods are listed here for reference.

Pharmaceutical compositions contemplated by the present invention include pharmaceutical compositions adapted for topical application to the human scalp. include. The usual pharmaceutical forms for this purpose are ointments, lotions, pastes, and gels. This includes liquids, gels, mousses, sprays, foams, aerosols, etc. "ointment" The term refers to oleaginous, absorbent, water-soluble and emulsion-type bases, e.g. Contains phosphorus, lanolin, polyethylene glycol, and their combinations ( (including creams) formulations. The compound may also be used in liposomal preparations or lipids. It can be formulated into emulsions, or acetonitrile, dimethylformamide ( D　MF　), dimethylacetamide (DM, A), alcohol, propatu It can also be dissolved in water, etc.

The weight percent of the compound of formula I used herein is typically about 0.1% or less of the pharmaceutical preparation. to about 1050%, preferably from about 1% to about 5%; In the formulation, the carrier for topical application constitutes the major amount of the formulation.

The pharmaceutical preparation of the present invention, encapsulated or otherwise, is sufficient to achieve hair growth. Period, applied based on the official herbal medicine. Seal the preparation with a bandage or plastic This can be achieved by conventional means such as plastic covers, shower caps, swimming caps. will be accomplished. To achieve the desired result, add a portion of the active ingredient (formula ■) as necessary. It is possible, or desirable, to vary the application rate as well as the frequency of application.

Description of preferred specific examples The invention will be more fully understood by the following examples.

blaming Nasal hair follicles from neonatal mice were collected in Dulbecco's minimal essential oil containing 20% fetal bovine serum. Medium (modified Eagle medium, Difco Company) (manufactured by Y). by recording the increase in hair shaft length during culture, and Measuring hair growth by measuring the uptake of S6S cysteine into the hair shaft did. The administration of nicorandil 0.1 mg/m (to this medium) was carried out at the end point of stimulated hair growth as measured by

Example 2 Propylene glycol USP 51kg 800g (specific gravity -1,036) Nicorandil (5kg) 5kg030g Alcohol USP, appropriate amount up to 25012, nicorandil pharmaceutical nilegant Prepare 250 liters of a 2% topical solution.

Add polyethylene glycol and 150 liters of alcohol to the mixing tank; Add nicorandil and dissolve in the propylene glycol/alcohol mixture. Add alcohol to make 250 liters. The resulting nicorandil topical solution into a suitable medication bottle with a metered dropper, starting from the center of the affected area and dispensing a total of 1xQ. Apply 1 dose to the scalp after washing in advance. Treatment of early and ongoing male short selling It takes 2 to 7 months or longer before hair growth stimulation is expected. It is necessary to apply twice a day for a period of time. Does the onset and extent of hair growth stimulation vary between individuals? It can be expected that there will be a difference.

In place of the 5,0 kg used in preparing the 2% solution in Example 2, nicorandil According to the above method by using 0.25 kg and 2,5 kg respectively. 0.1% and 1% nicorandil topical solutions are prepared similarly.

The formula I range for nicorandil was prepared by the methods of Examples 1 and 2 above, inclusively. The compositions are similarly prepared by substituting an equimolar amount of another compound within the range.

By the methods of Examples 1 and 2 above, various pharmaceutically acceptable compounds of nicorandil were prepared. The compositions are similarly prepared by substituting equimolar amounts of the salts.

Thus, modifications and variations of the invention heretofore disclosed or suggested are beyond the scope of the prior art. is considered to be encompassed by the appended claims except to the extent limited by .

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Claims (8)

[Claims] 1. Formula I: ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ Compound (I) or its pharmaceutically acceptable characterized by the topical application of an effective amount of a pharmaceutical composition containing a salt to the human scalp. Methods of treating humans for alopecia. 2. The compound is a nitrate ester of N-(2-hydroxyethyl)-nicotinamide. and pharmaceutically acceptable salts thereof. How to put it on. 3. The compound is an acid addition salt: hydrochloride, nitrate, oxalate, p-toluenesulfone. N-(2-hydroxyethyl) selected from the group consisting of acid salts and maleate salts. )--A pharmaceutical acid addition salt of nicotinamide. 4. The compound is N-(2-hydroxyethyl)nicotinamide nitrate. The method according to claim 2, which is a hydrochloride. 5. Formula I: ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ Compound (I) or its pharmaceutically acceptable A topical agent for the treatment of alopecia, characterized in that it consists of a salt and a pharmaceutical carrier compatible with topical application. Pharmaceutical composition. 6. The compound is N-(2-hydroxyethyl)nicotinamide and its medical and a pharmaceutical carrier compatible with topical application. A topical pharmaceutical composition according to claim 5. 7. The pharmaceutically acceptable salts include hydrochloride, nitrate, oxalate, p-toluenesulfonate. The topical agent according to claim 6, which is selected from the group consisting of phosphate salts and maleic acid. Pharmaceutical composition. 8. The pharmaceutically acceptable compound is N-(2-hydroxyethyl)nicotinic acid amide. 8. The topical pharmaceutical composition according to claim 7, which is a hydrochloride salt.