阅读说明：本技术 A型肉毒毒素在制备用于治疗脱发的方法中的药物的用途 (Use of botulinum toxin type A in the preparation of a medicament for use in a method of treating alopecia ) 是由 罗蔚锋 陈仪婷 李娇 曹佳倩 刘晶 李凯 季江 刘春风 于 2020-04-28 设计创作，主要内容包括：本发明公开了一种A型肉毒毒素在制备用于治疗脱发的方法中的药物的用途。所述药物包括作为活性成分的A型肉毒毒素以及佐剂,所述佐剂包括蔗糖、右旋糖苷及明胶,所述的方法包括：将所述药物以生理盐水稀释后,并选定头部肌肉组织的20-40个区域作为注射位点进行注射。本发明将A型肉毒毒素通过局部头皮注射有效改善了患处头发生长,简单易行,避免了重复用药及口服药物的副作用大等问题,相对于化学合成的药物而言,本发明的技术方案的效果稳定,副作用少,且单次注射即可,维持时间长,且本发明技术简洁,操作步骤较少,适合规模生产及临床应用。(The invention discloses an application of botulinum toxin type A in preparing a medicament for a method for treating alopecia. The medicament comprises botulinum toxin type A as an active ingredient and an adjuvant, wherein the adjuvant comprises sucrose, dextran and gelatin, and the method comprises the following steps: the drug was diluted with physiological saline and injected by selecting 20-40 regions of the head muscle tissue as injection sites. According to the invention, the botulinum toxin A is injected into the scalp locally to effectively improve the hair growth of an affected part, the method is simple and feasible, and the problems of large side effect and the like of repeated medication and oral medication are avoided.)

1. Use of a botulinum toxin type A in the manufacture of a medicament for use in a method of treating hair loss, the medicament comprising as active ingredients botulinum toxin type A and an adjuvant comprising sucrose, dextran and gelatin, the method comprising: the drug was diluted with physiological saline and injected by selecting 20-40 regions of the head muscle tissue as injection sites.

2. Use of a botulinum toxin type A according to claim 1 in the manufacture of a medicament for use in a method of treating alopecia, wherein: the injection site is selected from at least any one of frontalis, temporalis, occipitalis, and periauricular muscles.

3. Use of a botulinum toxin type A according to claim 1 in the manufacture of a medicament for use in a method of treating alopecia, wherein: the concentration of botulinum toxin type A in the saline-diluted pharmaceutical composition is 2.5-5.0U/0.1 ml.

4. Use of a botulinum toxin type A according to claim 1 in the manufacture of a medicament for use in a method of treating alopecia, wherein: the saline diluted pharmaceutical composition is prepared for use within 4 h.

5. Use of a botulinum toxin type A according to claim 1 in the manufacture of a medicament for use in a method of treating alopecia, wherein: the injection unit of each site of the botulinum toxin type A is 2.5-5U.

6. Use of a botulinum toxin type A according to claim 1 in the manufacture of a medicament for use in a method of treating alopecia, wherein: the brine was normal brine with a sodium chloride concentration of 0.9 wt%.

7. Use of a botulinum toxin type A according to claim 1 in the manufacture of a medicament for use in a method of treating alopecia, wherein: the botulinum toxin type A is used to increase prostaglandin E2 receptor expression.

8. Use of a botulinum toxin type A according to claim 1 in the manufacture of a medicament for use in a method of treating alopecia, wherein: the botulinum toxin type A is used for improving the expression of vascular endothelial growth factors.

9. Use of a botulinum toxin type A according to claim 1 in the manufacture of a medicament for use in a method of treating alopecia, wherein: the botulinum toxin type A is used to inhibit the release of acetylcholine from nerve endings.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to application of botulinum toxin type A in preparation of a medicine for treating alopecia.

Background

Botulinum toxin type A is a white loose body which is a clear, transparent or pale yellow solution when dissolved in physiological saline. Botulinum toxin type A has been approved clinically by the U.S. FDA since 1989 and, due to its potent nerve blocking effect, has been used in multidisciplinary, multi-disease treatments as an effective method of addressing local symptoms of dystonia, spasticity, tic movement, pain, and the like.

The botulinum toxin has a relative molecular mass of 150000 and consists of a heavy chain (molecular mass 100000) and a light chain (molecular mass 50000). Heavy chains recognize and bind to specific receptors on the presynaptic membrane of the nerve terminal; the light chain serving as a zinc-titanium endopeptidase hydrolyzes an N-ethylmaleimide-sensitive factor attachment protein receptor complex, so that the fusion of synaptic vesicles and presynaptic membranes is influenced, the release of neurotransmitters such as acetylcholine and the like is blocked, and the chemical denervation effects such as muscle relaxation, glandular secretion disorder and the like are caused. Antigenically, it is known that botulinum toxin is present in 8 serotypes (A-H), of which botulinum toxin type A acts on synaptosome associated protein 25 (SNAP-25). The botulinum toxin type A takes effect 3-14 days after injection, the effect usually lasts for 3-6 months, the transmitter transmission function is recovered along with the nerve bud growth at the nerve terminal, and the nerve blocking effect of the botulinum toxin is gradually disappeared.

Alopecia refers to the phenomenon of hair loss. The normal hair loss is the hair in the catagen and telogen phases, and the normal amount of hair can be maintained because the hair entering the catagen phase and the hair newly entering the anagen phase are constantly in dynamic balance. Pathological hair loss refers to abnormal or excessive loss of hair for a number of reasons. The problem of hair loss is receiving increasing attention due to the unaesthetic nature of hair loss, which has a series of malignant effects on social interactions with humans. Although a series of medicines and lotion are continuously applied and developed, the problem of alopecia is still not fundamentally solved, and the life of people suffering from alopecia is seriously troubled.

Alopecia can be classified into cicatricial alopecia and non-cicatricial alopecia depending on the integrity of hair follicles. The hair follicle of the non-cicatricial alopecia is completely preserved, and comprises stationary phase alopecia, androgenetic alopecia, alopecia areata and the like. Androgenetic alopecia is characterized by shortened hair growth period and miniaturization of hair follicles, and the hair may not grow sufficiently and become thin and soft, or may not pass through the scalp. Androgenetic alopecia is the most common type of alopecia, affecting about 40% of the population, and genetic and androgenic hormones are currently known as major causative factors. The treatment mode of androgenetic alopecia is mainly drug therapy, and the only drugs approved by the FDA to be marketed are Finasteride (Finasteride) and Minoxidil (Minoxidil). Finasteride is a drug for treating prostatosis in the beginning, has high risk of causing congenital malformation of embryo for women, and has side effects of hyposexuality, impotence, ejaculation disorder and the like for men. In addition, it is necessary to take the medicine for life in order to maintain the effect of preventing hair loss, or the disease will recur immediately after stopping taking the medicine. Even after withdrawal, some adverse effects of sexual function may persist. Based on the fact that the drug treatment has large side effect and poor patient matching degree, the treatment effect aiming at the androgenetic alopecia is not satisfactory, and a new drug for treating the alopecia is urgently needed to be found at present. The current applications of botulinum toxin type A have expanded from dyskinesia to areas of limb spasm, pain, autonomic dysfunction, and the like, and have attempted to be used in depression, Raynaud's syndrome, and the like. In the field of alopecia, related reports are still few.

Disclosure of Invention

The main object of the present invention is to provide the use of a botulinum toxin for the preparation of a medicament for a method for the treatment of alopecia, overcoming the drawbacks of the prior art.

In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:

the embodiment of the invention provides an application of botulinum toxin in preparing a medicament for a method for treating alopecia, wherein the medicament comprises botulinum toxin A serving as an active ingredient and an adjuvant, the adjuvant comprises sucrose, dextran and gelatin, and the method comprises the following steps: the drug was diluted with physiological saline and injected by selecting 20-40 regions of the head muscle tissue as injection sites.

In the invention, the injection site is concentrated on the obvious alopecia part of a patient, and can obviously improve the microenvironment of the scalp, enhance the percutaneous oxygen flow and reduce the greasy feeling of the scalp by adjusting according to the state of illness.

Compared with the prior art, the invention has the beneficial effects that: the botulinum toxin A is used for treating androgenetic alopecia, the hair growth of an affected part is effectively improved through local scalp injection, the method is simple and easy to implement, the problems of large side effect and the like of repeated medication and oral medication are solved, and compared with a chemically synthesized medicament, the botulinum toxin A has the advantages of stable effect, less side effect, single injection and long maintenance time, and the botulinum toxin A is simple in technology, less in operation steps and suitable for mass production and clinical application.

Drawings

In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings needed to be used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments described in the present application, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 is an injection site diagram in one embodiment of the present invention;

FIG. 2 is a schematic diagram of the mechanism of botulinum toxin type A to treat alopecia in accordance with the present invention;

FIG. 3 is a Norwood Hamilton rating scale for one embodiment of the present invention;

FIG. 4 is a dot diagram of the injection sites of botulinum toxin type A according to example 1 of the present invention;

FIGS. 5a-5b are comparative images of this example 1 before and after treatment with botulinum toxin type A;

FIG. 6 is a dot diagram of the injection sites of botulinum toxin type A in example 2 of the present invention;

FIGS. 7a-7b are comparative images of this example 2 before and after treatment with botulinum toxin type A;

FIGS. 8a-8b are schematic illustrations of the percutaneous pO of the scalp of patient 3 after injection of botulinum toxin type A, 1u₂The values were measured before and after.

Detailed Description

In view of the defects of the prior art, the inventor of the present invention has long studied and largely practiced to propose the technical solution of the present invention, which will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

An aspect of an embodiment of the present invention provides a use of botulinum toxin type a in the manufacture of a medicament for use in a method of treating alopecia, the medicament comprising botulinum toxin type a as an active ingredient and an adjuvant, the adjuvant comprising sucrose, dextran and gelatin, the method comprising: the drug was diluted with physiological saline and injected by selecting 20-40 regions of the head muscle tissue as injection sites.

Further, the number of injection sites is 20 to 40.

In the invention, the injection site is concentrated on the obvious alopecia part of a patient, can be adjusted according to the state of illness, obviously improves the scalp microenvironment and reduces the greasy feeling of the scalp. Further, the injection site is selected from at least any one of frontalis, temporalis, occipitalis, and periauricular muscles. The injection site is shown in fig. 1, hair loss occurs well in the frontal lobe, the supratrochlear and supraorbital arteries of the frontal and parietal lobes are small branches of the internal carotid artery, which covers the aponeurosis, and there are relatively few vessels of the aponeurosis as compared to the temporal occipital area covering the muscles. Several muscles near the parietal lobe were selected as injection sites.

Further, the concentration of botulinum toxin type A in the saline-diluted pharmaceutical composition is 2.5 to 5.0U/0.1 ml. The effect is better when the concentration is relatively higher.

Further, the concentration of the adjuvant in the saline-diluted pharmaceutical composition is 12.5 to 50 μ g/0.1 ml.

Furthermore, the ratio of the sucrose to the dextran to the gelatin is 1: 2-5.

Further, the saline-diluted pharmaceutical composition is prepared for use within 4 h.

Further, the injection unit of each site of the botulinum toxin is 2.5-5U.

Further, the brine is normal brine, wherein the concentration of sodium chloride is 0.9 wt%.

Further, the botulinum toxin type A is used to increase prostaglandin E2 receptor expression.

Further, the botulinum toxin type A is used for improving the expression of vascular endothelial growth factor.

Further, the botulinum toxin type A is used for inhibiting the release of acetylcholine from nerve terminals.

In the existing research, alopecia can be divided into cicatricial alopecia and non-cicatricial alopecia according to the integrity of hair follicles. The hair follicle of the non-cicatricial alopecia is completely preserved, and comprises stationary phase alopecia, androgenetic alopecia, alopecia areata and the like. Androgenetic alopecia is characterized by shortened hair growth period and miniaturization of hair follicles, and the hair may not grow sufficiently and become thin and soft, or may not pass through the scalp. Androgenetic alopecia is the most common type of alopecia, affects about 40% of the population, and genetic and androgenic hormones are currently known main pathogenic factors, but the specific pathogenesis is not clear, and may also be related to factors such as inflammatory response, cytokines and the like.

In the present invention, androgenetic alopecia may be associated with androgen receptor gene, WNT10A gene, beta-catenin gene, etc. Botulinum toxin type A of the present invention promotes hair growth by activating a major anagen-related induction signaling pathway. It is possible that the Wnt/β -catenin signaling pathway may be maintained/activated by local injection of botulinum toxin and modulated by phosphorylated GSK3 β levels, and upstream PKA/PKB may mediate this change as well. Meanwhile, the prostaglandin E2 receptor (PGE2) and vascular endothelial growth factor (VGEF) are expressed and increased, so that the slow relaxation effect on arterioles is achieved, the local blood supply can be increased, the growth of hair follicles is promoted, the growth period of hairs is prolonged, and the transition of the hair follicles in the resting stage to the growth period is accelerated.

In addition, botulinum toxin inhibits acetylcholine release from nerve endings, while follicular keratinocyte movement is inhibited by stimulation of large doses of nicotinic acetylcholine receptors. Through parasympathetic effect, acetylcholine release is inhibited, keratinocyte migration is indirectly increased, hair follicle obstruction can be reduced, sweat gland secretion is inhibited, greasy feeling of scalp is reduced, and hair growth is promoted. Abnormal androgen levels in bald people can also increase the amount of acetylcholine on the keratinocytes of the pilosebaceous glands, and by inhibiting acetylcholine release, botulinum toxin can reduce acetylcholine stimulation and increase keratinocyte motility. The hair follicle blockage and the increase of scalp blood flow are reduced, the scalp oxygen flow is improved, the high-oxygen environment can obviously inhibit the conversion of testosterone to Dihydrotestosterone (DHT), the DHT/estradiol imbalance is improved, the hair follicle miniaturization is inhibited, and the hair loss problem is improved. Among them, the mechanism of botulinum toxin type A for treating alopecia is shown in FIG. 2.

In the present invention, the injection of botulinum toxin relaxes the muscles, reducing the pressure of the muscles and the perforated blood vessels, thereby potentially increasing blood supply and transdermal pO2, while adjuvants (sucrose, dextran, and gelatin) can act as nutrients to promote the development and growth of hair follicles.

In the present invention, the preparation of the local injection medicine comprises:

(1) dissolving 100u of botulinum toxin A into 2-4 mL of 0.9% sodium chloride solution;

(2) the botulinum toxin type A is injected into the serious area of the frontal lobe alopecia with 2.5-5U of each site and 20-40 injection sites according to the alopecia condition of the patient, and the corresponding adjustment is made according to the different disease conditions of the patient.

In the invention, the criteria for judging the curative effect of the patient are as follows: the healing is that all new hairs or terminal hairs grow on the skin injury, the distribution is dense, the hairs are thick and thin, and the color is black and similar to that of normal hairs; the effect is that the coverage area of the terminal hair is larger than 1/2 bald hair areas, and more vellus hairs become terminal hairs, and the terminal hairs are sparse and become melanin; effective is more than 10% of new hair growth, including fine, short, pale vellus hair, but slow, incompletely recovered, dark or light brown in color; failure was no significant improvement from pre-treatment.

In the present invention, the admission criteria for patients enrolled in the study include:

(1) a male patient;

(2) the diagnosis of androgenetic alopecia is clear according to clinical manifestations and hair examination;

(3) norwood Hamilton grades 2-4 (as shown in FIG. 3);

(4) no treatment was performed in approximately 6 months;

(5) the compliance of patients is high, and the patients are matched with regular follow-up visits and photographing.

In the present invention, patients enrolled in the study are excluded from patients with any one of the following:

(1) complications exist at the injection part, such as infection, alopecia areata and the like;

(2) recently, drugs that interact with botulinum toxin, such as aminoglycoside antibiotics, clindamycin, polymyxin, magnesium sulfate, quinidine, and the like, have been used;

(3) patients are complicated with peripheral neuropathy, such as Eaton-Lambert syndrome, amyotrophic lateral sclerosis, myasthenia gravis, etc.;

(4) patients with a malignant tumor that has not been treated;

(5) the patient compliance is poor and follow-up cannot be matched.

The technical solutions of the present invention are further described in detail below with reference to several preferred embodiments and the accompanying drawings, which are implemented on the premise of the technical solutions of the present invention, and a detailed implementation manner and a specific operation process are provided, but the scope of the present invention is not limited to the following embodiments.

The following example selects 7 androgenetic alopecia patients between 48 and 65 years of age, grade 2-4 on the Norwood Hamilton scale, excluding congenital baldness and hair follicle atrophy without growth function, and untreated within approximately 6 months, and is given a local injection of botulinum toxin type A. Avoiding water collision 24 hours after injection, and paying attention to cleanness and sanitation.

After 3 months of treatment, 6 patients complain of strong and obvious improvement of greasy feeling of the scalp. Wherein, 1 is cured, 3 are effective, 2 are effective and 1 is ineffective.

All treated patients have no obvious adverse reaction after treatment, and the botulinum toxin type A is one of effective choices for treating alopecia.

Example 1

Patient 1, male, aged 61 years, was treated with a drug (of which botulinum toxin type A100 u) dissolved in 0.9% sodium chloride solution to 4mL and injected at 20 sites (injection sites are shown in FIG. 4) at the site of frontal lobe alopecia, and the pre-and post-treatment pictures of patient l 3 months after drug injection are shown in FIGS. 5a-5 b. It can be seen that after the treatment, the patients' complaints about the greasy feeling of the scalp are obviously improved, and the hair volume is also obviously increased.

Example 2

Patient 2, male, aged 48 years, was treated with a drug (of which botulinum toxin type A100 u) dissolved in 0.9% sodium chloride solution to 4mL and injected at 30 sites (injection sites are shown in FIG. 6) at the site of frontal lobe alopecia, and the pre-and post-treatment pictures of patient 2 after 3 months of drug injection are shown in FIGS. 7a-7 b. It can be seen that after the treatment, the patients' complaints about the greasy feeling of the scalp are obviously improved, and the hair volume is also obviously increased.

Example 3

Patient 3, male, aged 65 years, had a change in transdermal DO2 of patient 3 after dilution injection of the drug (botulinum toxin type A1 u therein) in 0.9% sodium chloride solution, which was increased by one percentage point (as shown in FIGS. 8a-8 b).

In addition, the inventors of the present invention have also made experiments with other materials, process operations, and process conditions described in the present specification with reference to the above examples, and have obtained preferable results.

The aspects, embodiments, features and examples of the present invention should be considered as illustrative in all respects and not intended to be limiting of the invention, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.

The use of headings and chapters in this disclosure is not meant to limit the disclosure; each section may apply to any aspect, embodiment, or feature of the disclosure.

Throughout this specification, where a composition is described as having, containing, or comprising specific components or where a process is described as having, containing, or comprising specific process steps, it is contemplated that the composition of the present teachings also consist essentially of, or consist of, the recited components, and the process of the present teachings also consist essentially of, or consist of, the recited process steps.

It should be understood that the order of steps or the order in which particular actions are performed is not critical, so long as the teachings of the invention remain operable. Further, two or more steps or actions may be performed simultaneously.

While the invention has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated any use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.