WO2013035997A2

WO2013035997A2 - Pharmaceutical composition for preventing or treating alopecia comprising tianeptine or its salt

Info

Publication number: WO2013035997A2
Application number: PCT/KR2012/006698
Authority: WO
Inventors: So-Ra Park; Sung-Ki Seo; Mase LEE
Original assignee: Kuhnil Pharm. Co., Ltd.
Priority date: 2011-09-06
Filing date: 2012-08-23
Publication date: 2013-03-14
Also published as: WO2013035997A9; WO2013035997A3; KR101136976B1

Abstract

The present invention provides a pharmaceutical composition for preventing or treating alopecia comprising tianeptine or its pharmaceutically acceptable salt as an active ingredient.

Description

PHARMACEUTICAL COMPOSITION FOR PREVENTING OR TREATING ALOPECIA COMPRISING TIANEPTINE OR ITS SALT

The present invention relates to a novel pharmaceutical use of tianeptine or its pharmaceutically acceptable salt. Specifically, the present invention relates to a pharmaceutical composition for preventing or treating alopecia comprising tianeptine or its pharmaceutically acceptable salt as an active ingredient.

Tianeptine or its salt (for example, sodium salt) is one of the selective serotonin reuptake enhancers (SSRE) and the chemical name thereof is 7-(3-chloro-6-methyl-6,11-dihydrodibenzo[c,f][1,2]tiazepin-11-ylamino)heptanoic acid S,S-dioxide. Tianeptine has the following chemical structure of Formula 1.

< Formula 1>

Tianeptine or its salt is useful for treating various depressions, for example endogenous depressions; neuroreactive depressions; anxiety-related depressions accompanied by physical or psychotic symptoms such as gastrointestinal disorders; depressions related to various alcoholisms and alcohol withdrawal, etc. (e.g., US3,758,528).

In addition to anti-depressant activity, tianeptine or its salt shows activities for treating neurodegenerative disorders (WO 2000/059511); and suppressing asthmatic symptoms in children (Lechin F et al., October 1998, Journal of Clinical Pharmacology 38 (10): 918-925). And also, it has been reported that tianeptine or its salt has a therapeutic efficacy for patients suffering from depression and erectile dysfunction (El-Shafey H, et al., September 2006, The Journal of Sexual Medicine 3 (5): 910-917); an anticonvulsant and analgesic efficacy (Uzbay TI, May 2008, Progress in Neuro-psychopharmacology & Biological Psychiatry 32 (4): 915-924); and a therapeutic efficacy against Parkinson's disease (Levin OS, May 2007, Neuroscience and Behavioral Physiology 37 (4): 419-424).

Alopecia is classified to alopecia areata, alopecia totalis, and alopecia universalis, etc. In alopecia areata, one or more circular or egg-shaped bald spots are suddenly seen, usually on the scalp. In addition to the scalp, the bald spots may be seen on mustache, eyebrows, eyelashes, and any other hair-bearing part of the body. Although there is no peculiar pathological symptom, alopecia areata is often progressed and fused each other, thereby resulting in magnification of the bald spots. Spontaneous recovery may be expected, but recurrence also occurs frequently. The loss of all head hairs is referred to as alopecia totalis and the loss of all hairs in the body is referred to as alopecia universalis (Journal of the Korean Medical Association, Vol. 42, No. 7, pp. 682).

The etiologic mechanism of alopecia such as alopecia areata remains unknown, although various mechanisms thereof were proposed in the literatures. For treating alopecia, there have been performed a topical application with steroids, a steroid injection to the hair loss sites, and/or a systemic therapy with steroids or immunosuppressive agents. In addition, a topical immunotherapy (using dinitrochlorobenzene, diphenylcyclopropenone (DPCP), etc.), a medication such as minoxidil, and/or a light therapy are used for treating alopecia (Korean Journal of Dermatology, Vol. 46, No. 4, 2008). However, the efficacies thereof are not yet satisfactory. For example, the known therapies are accompanied by severe pains and side effects, thereby resulting in abandonment thereof. In cases of steroid injection to the hair loss sites, topical immunotherapy, and light therapy, there is inconvenience that the patients should come to clinics periodically. And also, in case of the steroid injection to the hair loss sites, there have been reported various side effects, such as atrophy of the surrounding tissues, discoloration, sterile abscess formation, menstrual irregularity, adrenal gland suppression. And also, in case of the systemic therapy with steroids, there have been reported various side effects, such as purpura, edema, acne-like rash, pigmentation, peptic ulcer, osteomalacia. The immunosuppressive agents such as cyclosporine are very expensive and also have side effects in various organs including kidney (Journal of the Korean Medical Association, Vol. 42, No. 7, pp. 686-687).

The present inventors performed various researches in order to search for compounds capable of preventing or treating alopecia. Surprisingly, the present inventors found that tianeptine or its salt known as an antidepressant can improve hair growth and hair thickness and inhibit apoptosis in hair follicles, thereby being useful for preventing or treating alopecia.

Therefore, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating alopecia comprising tianeptine or its salt as an active ingredient.

In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating alopecia comprising tianeptine or its pharmaceutically acceptable salt as an active ingredient.

In an embodiment of the present invention, the alopecia may be alopecia areata. In another embodiment of the present invention, the composition may be for oral administration, for example formulated into an oral solid dosage form in the form of tablet or capsule. And also, the oral solid dosage form may comprise tianeptine or its pharmaceutically acceptable salt in an amount suitable for administering in a dose ranging from 20 to 75 mg/day.

It is newly found by the present invention that tianeptine or its salt known as an antidepressant can improve hair growth and hair thickness and inhibit apoptosis in hair follicles. Therefore, the pharmaceutical composition is useful for preventing or treating alopecia, such as alopecia areata.

FIG. 1a and 1b show the results obtained by evaluating the effects of tianeptine on hair growth in the mice of each group with naked eyes, using a folliscope (FIG. 1a) and a dermoscope (FIG. 1b), respectively.

FIG. 2 shows the results obtained by measuring the hair follicle cycles in the mice of each group, through hematoxylin and eosin staining.

FIG. 3 shows the results obtained by measuring the apoptosis in hair follicles in the mice of each group, through TUNEL staining.

The present invention provides a pharmaceutical composition for preventing or treating alopecia comprising a compound of the following formula 1 or its pharmaceutically acceptable salt as an active ingredient:

The alopecia includes any form of alopecia, such as alopecia areata, alopecia totalis, and alopecia universalis, etc. In an embodiment of the present invention, the alopecia may be alopecia areata.

It is newly found by the present invention that tianeptine or its salt known as an antidepressant can improve hair growth and hair thickness and inhibit apoptosis in hair follicles. The pharmaceutically acceptable salt of tianeptine may be in any nontoxic salt form, such as a sodium salt form, a potassium salt form, a calcium salt form, a magnesium salt form, a lithium salt form, a strontium salt form; preferably in a sodium salt form, i.e., tianeptine sodium.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier, in addition to a compound of the following formula 1 or its pharmaceutically acceptable salt as an active ingredient. The pharmaceutical composition of the present invention may be formulated into a dosage form for oral administration, external use, suppository, or sterile injection. Preferably, the pharmaceutical composition of the present invention may be formulated into a dosage form for oral administration, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, or aerosols; more preferably an oral solid dosage form in the form of tablet or capsule. For example, the pharmaceutical composition of the present invention may be a commercially available tablet comprising tianeptine sodium (e.g., Stablon^TM Tablet, Jeil Pharmaceutical Co., Ltd.).

The pharmaceutically acceptable carrier includes lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose 2910, polyethylene glycol 6000, polyvinylpyrrolidone, methyl hydroxybenzoate, propyl hydroxybenzoate, titanium dioxide, talc, magnesium stearate, or mineral oil, but not limited thereto. And also, the pharmaceutically acceptable carrier includes a filler, a bulking agent, a binder, a wetting agent, a disintegrating agent, a surfactant, a diluent, and/or an additive. And also, the solid oral formulation including powders, granules, tablets, capsules, or pills may include at least one excipient selected from, for example, starch, calcium carbonate, sucrose, lactose, and gelatin. In addition, such solid formulations may further include a lubricant, such as magnesium stearate or talc. Specifically, the pharmaceutical composition of the present invention is a tablet form comprising tianeptine or its salt as an active ingredient; and mannitol, corn starch, magnesium stearate, ethyl cellulose, glycerol oleate, polyvidone, sodium carboxymethyl cellulose, silica, talc, titanium dioxide, sodium bicarbonate, wax, sucrose, polysorbate, etc. as a carrier. The table form may further comprise a conventional coating agent. A liquid oral formulation including suspensions, solutions, emulsions, or syrups may include a dilluent such as water, physiological saline, liquid paraffin; a humectant; a sweetening agent; an odorant; or a preservative. A parenteral formulation including sterile solutions, non-aqueous solutions, suspensions, emulsions, freeze-drying formulations, or suppositories, may include water, non-aqueous solvent, propylene glycol, polyethylene glycol, vegetable oil (e.g., olive oil), injectable esters (e.g., ethyl oleate). The suppository base includes Witepsol, Macrogol, Tween 61, cacao butter, laurin fat, and/or glycerogelatin.

In the pharmaceutical composition according to the present invention, a dose of tianeptine or its salt may vary depending on patient's state or body weight, seriousness of disease, dosage forms, administration routes, and the period of administration, and can be appropriately determined by a person having ordinary skill in the art. For example, tianeptine or its salt may be orally administered in a dose of 10 to 150 mg/kg per day, preferably 20 to 75 mg/kg per day. Therefore, the pharmaceutical composition according to the present invention, preferably in a oral solid dosage form, may comprise tianeptine or its pharmaceutically acceptable salt in an amount suitable for administering in a dose ranging from 10 to 155 mg/day, preferably from 20 to 75 mg/day. The unit dosage form may be formulated into a form suitable for once-a-day administration; or a form for two or more administrations per day (e.g., a table form containing 12.5 mg of tianeptine or its salt for administering twice or thrice per day)

The present invention will be described in further detail with reference to the following example. This example is for illustrative purposes only and is not intended to limit the scope of the present invention.

Example: Evaluation of the preventing and treating efficacies of tianeptine against alopecia, according to oral administration

The preventing and treating efficacies of tianeptine against alopecia were evaluated using a mouse model of alopecia known in the art, i.e., WS Park, et al, Journal of Applied Micromagnetic Energy, 2004, Vol. 2, No. 1, pp 1-6.

(1) Administration

C57BL/6 J mice (6~8 weeks old) having the telogen hair follicle phase were used as test animals. The mice were divided into 4 groups in total, each group having 8 mice. Two groups (Group 1 and Group 2) were allotted to control groups and another two groups (Group 3 and Group 4) were allotted to test groups. The mice of Group 1 (Control group 1) were orally administered with a physiological saline for 22 days, except that the mice were subject to ultrasonic treatment at the 15th day for one day. The mice of Group 2 (Control group 2) were orally administered with a physiological saline for 22 days without ultrasonic treatment. The mice of Group 3 (Test group 1) were orally administered with tianeptine sodium for 14 days; subject to ultrasonic treatment at the 15th day for one day; and then orally administered with tianeptine sodium for additional 7 days. The mice of Group 4 (Test group 2) were orally administered with a physiological saline for 14 days; subject to ultrasonic treatment at the 15th day for one day; and then orally administered with tianeptine sodium for additional 7 days. The ultrasonic treatment was performed by applying an ultrasound having 300Hz of frequency intermittently (i.e., every other 10 seconds) for 24 hours, with an ultrasonic bug eradicator. The tianeptine sodium was dissolved in a physiological saline and then orally administered in a dose of 5mg/kg twice a day (i.e., every morning / every evening).

(2) Effects of tianeptine on the hair growth

After the 22 days, the hair growths were observed using a folliscope and a dermoscope and the results thereof were shown in FIG. 1a and FIG. 1b, respectively. As shown in FIG. 1a and FIG. 1b, the hair thicknesses and the hair growth rates were Control group 2 > Test group 1 > Test group 2 > Control group 1. The mice of Control group 2 and Test group 1 showed normal hair thicknesses. The mice of Test group 2 showed some bald spots having about 1X1 cm of size, but the vellus hairs were being re-grown. The mice of Control group 1 showed the largest size of bald spots and the number thereof also highest. And also, in the mice of Control group 1, the vellus hairs were observed in only less than 50% of bald spots.

(2) Hair follicle cycle Identification of tissues: Hematoxylin & Eosin staining

At the 21st day, the back skin samples were subject to Hematoxylin & Eosin staining, which was performed with an AccuMax^TM array kit (ISU ABXIS CO., Ltd), according to the manufacturer's H&E protocol. The results were shown in FIG. 2. As shown in FIG. 2, the normal anagen hair follicles and hair elongation processes were observed in Test group 1 and Control group 2. However, Test group 2 and Control group 1 showed a small number of hair follicles and a large number of telogen hair follicle. Perifollicular lymphocytic infiltration was also observed in Control group 1. For growing up to thick hairs, the hair follicles should be located in from the deep dermis layers to the subcutaneous fat layer. However, the hair elongation process was most inhibited in Control group 1.

(3) Identification of apoptosis in hair follicles: TUNEL staining

TUNEL assay detects DNA fragmentation by labeling the terminal end of nucleic acids. Apoptosis level was assessed in hair follicles. The TUNEL assay was carried out using in situ cell death detection kit (Roche Applied Science) according to manufacturer's instructions. Tissue sections were deparaffinized using xylene and then rehydrated with ethanol. The tissue section was performed for proteinase digestion with proteinase K at room temperature. And then, TUNEL labeling was performed using TUNEL cocktail solution. As a final step, we performed counterstaining with DAPI. TUNEL signal was observed by fluorescence microscopy. FIG. 3 is the results obtained by visualizing with fluorescence microscopy. As shown in FIG. 3, the apoptosis was significantly reduced in Test group 1 and Test group 2, while Control group 1 showed lots of apoptosis. And also, the apoptosis was much more reduced in Test group 1 than in Test group 2.

(4) Conclusion

It is found through the folliscope and dermoscope evaluations that the test groups administered with tianeptine showed improvements in the hair growth rate and the hair thickness. And also, it is confirmed through the H&E and TUNEL staining assays that the telogen hair follicles and the apoptosis in the hair follicles are inhibited in the test groups administered with tianeptine. Therefore, although the specific pharmacological mechanism thereof remains under investigation, tianeptine is expected to apply to the prevention or treatment of alopecia.

Claims

A pharmaceutical composition for preventing or treating alopecia comprising a compound of the following formula 1 or its pharmaceutically acceptable salt as an active ingredient:

<Formula 1>
The pharmaceutical composition according to claim 1, wherein the alopecia is alopecia areata.
The pharmaceutical composition according to claim 1, wherein the composition is for oral administration.
The pharmaceutical composition according to claim 3, wherein the composition has an oral solid dosage form in the form of tablet or capsule.
The pharmaceutical composition according to claim 4, wherein the oral solid dosage form comprises the compound of the formula 1 or its pharmaceutically acceptable salt in an amount suitable for administering in a dose ranging from 20 to 75 mg/day.