KR20220020637A - Oral administration pharmaceutical composition for prevention of hair loss and improvement of hair growth comprising salt of meta-arsenite - Google Patents

Abstract

The present invention contains a (meta)arsenite salt as an active ingredient, and thus provides excellent hair loss prevention or hair growth promotion effects on: patients with common alopecia caused by overactivity of androgenic hormones, hypersecretion of sebum, poor blood circulation, scalp dysfunction due to peroxides or bacteria, genetic factors, aging, stress and the like; and alopecia in cancer patients in which hair loss is caused by chemotherapy or radiotherapy for cancer treatment. The described composition according to the present invention enables cancer to be overcome with only a single effect and, when co-administered as an adjuvant in other cancer therapies, can prevent hair loss during cancer treatment while improving cancer treatment effects, and thus can increase overall anti-cancer treatment effects and prevent cancer patients from becoming stressed by hair loss caused by anti-cancer treatment.

Description

A pharmaceutical composition for oral administration containing a salt of metaarsenite that prevents hair loss and promotes hair growth for alopecia patients, including alopecia of cancer patients due to chemotherapy or radiation therapy {Oral administration pharmaceutical composition for prevention of hair loss and improvement of hair growth comprising salt of meta-arsenite}

The present invention relates to a pharmaceutical composition for oral administration for preventing hair loss or promoting hair growth, and more particularly, preventing hair loss in general alopecia patients and promoting hair growth as well as preventing hair loss in cancer patients due to chemotherapy or radiation therapy. and to a pharmaceutical composition for oral administration that can promote hair growth.

The causes of hair loss include the theory that excessive male hormone action, excessive sebum secretion, poor blood circulation, peroxide, and decreased scalp function caused by bacteria, genetic factors, aging, and stress are being discussed. In addition, the population with hair loss is gradually increasing due to the increase in social stress, westernized eating habits such as environmental pollution and instant food, and frequent perms and dyeing. The hair cycle consists of the anagen phase when hair grows, the catagen phase when growth ends and the hair bulb shrinks, the talogen phase when the dermal papilla stops and the hair stays on the scalp, and the dermal papilla is active It can be divided into the developmental period, which is the period when old hair is depilated by starting or generating new hair.

Anagen Stage (2-7 years) is the period of hair growth, and it is divided into the hair generation stage, when the hair goes out from the hair follicle to the follicle, and the stage where hard keratin is made in the hair follicle. Hair continues to grow on its own until the catagen stage.

Catagen Stage (2~3 weeks) is the period when the growth phase ends and the metabolic process slows down while maintaining the shape of the hair. In this stage, keratin is not produced. The catagen stage accounts for 1% of all hair. At this time, the hair bulb is contracted and divided into dermal papilla, surrounded by hair follicles and ascending upwards, and cell division is in a stationary state.

In the telogen stage (3 months), the dermal papilla atrophy, the hair follicles gradually shrink, and the hair roots are pushed upwards and fall out. As the period of hair loss, the lifespan until the next growth phase begins is 3 to 4 months.

A normal person has a lot of hair in the growth phase, whereas a person with alopecia has a lot of hair in the telogen phase, which causes visible hair loss. As hair loss progresses, the growth period becomes shorter and the hair becomes smaller and smaller.

Therefore, for the treatment of hair loss, it is important to allow the hair follicles in the resting state to quickly go to the growth phase and to extend the shortened growth phase.

Androgenetic alopecia is a phenomenon that is caused by a male hormone called testosterone. When testosterone is converted into a more powerful hormone, dihydrotestosterone (DHT) by an enzyme called α-reductase, this Hormones act on the hair follicles to induce hair follicles from the growth phase to the degeneration phase, causing hair loss.

Therefore, in order to treat androgenetic alopecia, a method of inhibiting the production of DHT by 5-alpha-reductase is mainly used. It was developed as a treatment for benign prostatic hyperplasia as a substance that inhibits the growth of hair, but as it is known to promote hair growth, it is used as a hair growth agent (Kaufman KD, Dawber RP., Expert Opin Investig Drugs 8:403-15, 1999).

However, gynecomastia can occur even when taking finasteride, and as such cases have been reported recently, there is a trend to consider gynecomastia as a side effect of low-dose finasteride (Ferrando et al., 2002; Wade et al., 2000). .

Gynecomastia is mainly caused by a decrease in the amount of estrogen after menopause. As a treatment for female pattern alopecia, minoxidil and tricosaccharide (trichosaccharide or estrogen) are mainly used.

Alopecia areata is caused by autoimmune diseases, mental stress, or genetic predisposition. This alopecia areata has a fundamentally different cause from androgenetic alopecia, and the treatment is also different, so a method of treating adrenocortical hormones, applying minoxidil to the affected area, or artificially stimulating the affected area is used.

However, in the case of formulations such as minoxidil and tricosaccharide, which have been known to prevent hair loss and have effects on hair growth and hair growth, lack of clear efficacy and side effects such as human stability and skin irritation are emerging. Therefore, there is an urgent need to develop a composition that has secured safety and efficacy.

Also, until now, there are mainly three types of treatment methods for treating cancer, which is a malignant tumor, namely, surgical operation, radiation therapy, and chemotherapy, and cancer is treated through one or a combination of these. Among them, hair loss occurs due to radiation therapy and chemotherapy.

Radiation therapy is used as a treatment for various diseases, and is generally used effectively for malignant tumors composed of rapidly dividing cells. Disadvantages of such radiation therapy are that there is a risk of weakening or loss of normal tissue function depending on the radiation treatment, skin diseases of the treated area after treatment, and delay in intellectual development or impaired bone growth in children whose organs are developing. In particular, it can cause serious side effects such as hair loss. Hair loss is limited to the area irradiated with radiation. However, there is a difference in the degree of hair loss depending on the area and amount of radiation.

Chemotherapy is widely used to treat breast, lung, and testis cancer by disrupting the replication or metabolism of cancer cells, and the biggest drawback of this method is the side effects induced by the chemotherapy used for cancer treatment. The side effects caused by chemotherapy have a significant impact on the patient's life and may increase the patient's anxiety about treatment. In addition, side effects associated with chemotherapeutic agents are generally dose limiting toxicity (DLT), which should be taken into account when administering these drugs.

In this regard, as a result of a toxicity test for metaarsenite salt's anticancer drug development, it was confirmed that there was no side effect at the dose-limited toxic dose (refer to Patent Registration No. 10-0456831).

Anticancer drugs that cause hair loss cause hair loss all over the body, and when receiving radiation treatment, hair loss appears only in the area irradiated with radiation. These side effects are emerging as an important problem in the treatment of cancer patients. Among the side effects, it is expected that there will be many patients who refuse treatment because of the problem of hair loss.

1. Republic of Korea Patent Registration No. 10-1343857 2. Korean Patent Registration No. 10-1208736

Therefore, the problem to be solved by the present invention is a theory of excess male hormone action, excess sebum secretion, poor blood circulation, hypothalamus of scalp function due to peroxide, bacteria, etc., and general alopecia caused by genetic factors, aging, stress, etc. An object of the present invention is to provide a pharmaceutical composition for oral administration having excellent hair loss prevention or hair growth promoting effect for alopecia of cancer patients who suffer from hair loss due to chemotherapy or radiation therapy for cancer treatment as well as patients.

In order to achieve the above object, the present invention

Provided is a pharmaceutical composition for oral administration that contains metaarsenite salt as an active ingredient to prevent hair loss and promote hair growth.

In the pharmaceutical composition for oral administration according to the present invention, the hair loss may be due to chemotherapy or radiation therapy to treat cancer.

In the pharmaceutical composition for oral administration according to the present invention, the hair loss is common due to excessive male hormone action, excessive sebum secretion, poor blood circulation, hypothesized scalp function due to bacteria, genetic factors, aging, and stress. It could be hair loss.

In the pharmaceutical composition for oral administration according to the present invention, the metaarsenite salt may be an alkali metal salt or an alkaline earth metal salt, and the alkali metal salt is preferably a potassium salt or a sodium salt.

The composition according to the present invention is not only suitable for patients with general alopecia caused by excessive male hormone action, excessive sebum secretion, poor blood circulation, decreased scalp function due to peroxide, bacteria, etc., genetic factors, aging, stress, etc. It provides an excellent effect of preventing hair loss or promoting hair growth even for alopecia in cancer patients who have hair loss due to chemotherapy or radiation therapy for treating cancer.

In addition, although there is a method that can overcome cancer only with the single effect of the composition according to the present invention, when the composition according to the present invention is administered in combination with other cancer therapy as an adjuvant, the cancer treatment effect is improved while preventing hair loss in the cancer treatment process It can increase the overall effect of chemotherapy and provides an effect that can prevent the stress of cancer patients due to hair loss during chemotherapy.

Ultimately, the present invention can be applied to general hair loss patients and will become the most innovative composition in alopecia that can be applied to hair loss in cancer patients and greatly contribute to improving the quality of life.

1 is a view showing the growth image of hair follicles treated with sodium metaarsenite at 0.03 and 0.3 μg/ml and cultured for 0, 5, 7, 9, 12 days.
Figure 2 is a diagram of the results for the hair growth effect using a 6-week-old hair loss model Balb / c mouse mouse.
3 is a graph showing the results of anticancer and hair growth effects using 6-week-old C57BL/6 mice with tumors.

Hereinafter, a detailed description for carrying out the present invention will be described.

The present invention treats cancer as well as patients with general alopecia caused by factors such as excessive male hormone action, excessive sebum secretion, poor blood circulation, decreased scalp function due to peroxide, bacteria, etc., genetic factors, aging, stress, etc. In order to provide a composition having an excellent hair loss prevention or hair growth promoting effect for alopecia of cancer patients who have hair loss due to chemotherapy or radiation therapy for The composition is disclosed.

In the pharmaceutical composition for oral administration according to the present invention, the metaarsenite salt may be an alkali metal salt or an alkaline earth metal salt, and the alkali metal salt is preferably a potassium salt or a sodium salt.

The pharmaceutical composition for oral administration in the present invention refers to all formulations administered orally, such as syrups, tablets, soft capsules, and hard capsules, and all formulation techniques known for making such formulations are included in the present invention. .

In general, the use of anticancer drugs is expected to have an effect of suppressing cancer, but various side effects cannot be ignored.

Among the side effects, there are many patients who refuse chemotherapy because of concerns about hair loss. Although the purpose of developing an anticancer drug is treatment, it will be a truly revolutionary anticancer drug if we consider the part that can compensate for other side effects without focusing only on the treatment.

In such a part, a composition containing metaarsenite salt as an active ingredient can be a perfect anticancer-related oral pharmaceutical composition that not only has anticancer effects but also compensates for hair loss, which is a side effect.

The appropriate administration dose of the metaarsenite salt containing the active ingredient in the composition of the present invention is easy by those of ordinary skill in the art to which the present invention pertains, depending on the patient's condition, whether administered in combination with an anticancer agent, etc. Considering that cytotoxicity and side effects are very low, administration is possible in a wide range, and the range can be scheduled to be about 1 ng to 10 mg per 1 kg of mammal per day, and is not limited thereto. is clear

Hereinafter, the present invention will be described in more detail through the following examples. However, the following examples only illustrate the present invention, the content of the present invention is not limited to the following examples, and various modifications that can be made by those skilled in the art within the technical spirit of the present invention It is clear that all of the

Example One

Testing Institution : Bioalternatives, Inc. (France)

Test purpose : In this study, hair follicles were cultured using a human ex vivo model, and sodium metaarsenite containing metaarsenite ions was treated at an optimal concentration for hair follicle cell proliferation, thereby affecting hair growth and survival. was verified. In this study, the co-culture model for culturing hair follicle cells was conducted by establishing the most stable culture conditions for hair growth and survival as the environmental conditions most similar to human hair follicle cells.

Test method and results

Hair follicle cell model and culture conditions

A 37-year-old male (n°E1758) underwent face lift and a small amount of hair follicle cells was obtained from the skin fragment.

Hair follicle cells were cultured in William's medium E containing penicillin 50U/ml, streptomycin 50㎍/ml, L-glutamine 2mM, insulin 10㎍/ml, hydrocortisone 4ng/ml at 37°C in the presence of 5% carbon dioxide. .

Sodium Metaarsenite of condition

Sodium metaarsenite used in the test (CAS Number:7784-45-5, Batch n° SLBW7984, Ref. S7400 Sigma, Purity:100%, AD180303-1(R00838) was purchased in powder form from Sigma and stored at room temperature. It was used, and it was prepared at 1 mg/ml in William's medium E, which is a culture medium.

For the hair follicle proliferation experiment, sodium metaarsenite was used at concentrations of 0.03 μg/ml and 0.3 μg/ml, respectively.

Image analysis for hair growth experiments

NIKON DS-Fi1 camera and image J software were used as equipment to check the image, and the image recorded in the report provided by Bioalternatives, Inc. was checked.

Hair growth experiment using hair follicle cells

Hair follicles were obtained from a 24-well plate (1 follicle/well) containing a culture medium.

The length of the hair follicle from day 0 to day 12 is the growth date of 0 days (D0), 2 days (D2), 5 days (D5), 7 days (D7), 9 days (D9), and 12 days (D12). was measured, and proliferation and survival were confirmed through morphological analysis of the hair follicles. The following percentage of viability was calculated using the following formula.

viability (%) = (OD _sample /OD _control )ｘ100

As shown in Table 1, Table 2, and attached Figure 1, the control group was 1369 μm at 5 days (D5), 1725 μm at 7 days (D7), 1996 μm at 9 days (D9), and at 12 days (D12). It grew to 2290 μm.

In comparison, in the group treated with sodium metaarsenite at a concentration of 0.03 μg/ml, 1542 μm (113% (viability%)) at 5 days (D5), and 1981 μm (115% (115%) at 7 days (D7) viability%)), 9 days (D9) to 2369 μm (119% (viability%)), and 12 days (D12) to 2890 μm (126% (viability%)) to confirm significant growth compared to the control group. .

In addition, in the group treated with sodium metaarsenite at 0.3 μg/ml, at 5 days (D5) 1539 μm (112% (viability%)), at 7 days (D7) at 1972 μm (114% (viability%)) ), 2345 μm (117% (viability%)) at 9 days (D9), and 2793 μm (122% (viability%)) at 12 days (D12), confirming significant growth compared to the control group.

When sodium metaarsenite was compared with 0.03㎍/ml and 0.3㎍/ml, it showed an excellent effect at 0.03㎍/ml, although it was found that it was not necessarily a good effect at a high dose.

Example 2.

Using a 6-week-old hair loss model Balb/c mouse mouse, the experiment was divided into a control group (physiologic saline) and an experimental group (sodium metaarsenite 0.1mg per 1 kg of body weight), and the sodium metaarsenite used for the test was (CAS Number: 7784-45-5, Batch n° SLBW7984, Ref. S7400 Sigma, Purity: 100%, AD180303-1(R00838) were purchased from Sigma in powder form and used. The result of oral administration once daily is shown in Fig. .

In the case of FIG. 2 , there was no change in the control group, and it was confirmed that the test group showed a very good effect to the extent that the hair was almost covered in the hair loss area after about 15 days.

Example 3. Tumor beraring Establishment and treatment of mouse model

It is difficult to produce a hair loss mouse by chemotherapy, so the present inventors have sought a method. Based on the references, it was referred to a hair growth test after perfect hair removal using a cosmetic depilatory agent (Journal of Biomedical Research 11(2): 103-116 (2010)). Meanwhile, in order to confirm the hair growth effect, an experiment was performed using C57BL/6 mice.

After transplanting 4T1 (2~5x10 ⁴ ) mouse breast cancer cell lines into the right thigh of 6-week-old C57BL/6 mice (sc injection), approximately 7 days later, when the tumor size reached 100 mm ³ , Hair removal was performed perfectly over one time.

And sodium metaarsenite used in the test (CAS Number: 7784-45-5, Batch n° SLBW7984, Ref. S7400 Sigma, Purity: 100%, AD180303-1(R00838) was purchased from Sigma in powder form and used. and sodium metaarsenite (1mg/kg BW) was orally administered daily, and only physiological saline was administered in the control group, and the results are shown in FIG. 3 .

Referring to FIG. 3, hairs started to appear in the group fed with sodium metaarsenite from the 15th day, but no reaction was observed in the control group fed only with physiological saline. Moreover, on the 30th day, the control group administered with physiological saline died, but the sodium metaarsenite group did not die, but showed activity like normal mice, confirming the antitumor effect, and it was confirmed that the hair grew evenly throughout.

Through these results, oral administration of sodium metaarsenite can not only solve the problem of hair loss due to various common causes, but also prevent hair loss from tumor treatment.

Claims (4)

A pharmaceutical composition for oral administration that contains metaarsenite salt as an active ingredient to prevent hair loss and promote hair growth.
The pharmaceutical composition for oral administration according to claim 1, wherein the hair loss is caused by chemotherapy or radiation therapy to treat cancer.
The pharmaceutical composition for oral administration according to any one of claims 1 to 2, wherein the metaarsenite salt is an alkali metal salt or an alkaline earth metal salt.
The pharmaceutical composition for oral administration according to claim 3, wherein the alkali metal salt is a potassium salt or a sodium salt.

Images