阅读说明：本技术 一种药物及其在制备抗颈椎病合并糖尿病药物中的应用 (Medicine and application thereof in preparation of medicine for resisting cervical spondylosis and diabetes mellitus ) 是由 高超 刘杰 崔阳 江玉娟 房建宝 王芳 王艳梅 陆蓉蓉 于 2021-01-29 设计创作，主要内容包括：本发明具体涉及一种药物及其在制备抗颈椎病合并糖尿病药物中的应用。颈椎病和糖尿病具有密切的联系,现有研究表明,颈椎病对于交感神经的刺激会促进胰岛功能的亢进,而糖尿病伴随的血糖升高及代谢异常还会加重颈椎病。针对该现状,本发明提供一种适用于颈椎病合并糖尿病的治疗药物,采用明仁颈痛系列产品与盐酸二甲双胍联合使用,研究结果表明,上述两种药物联合使用能够同时实现降血糖及改善颈椎不适的效果；并且还能够改善盐酸二甲双胍带来的胃肠刺激作用。将其联合应用于颈椎病合并糖尿病治疗药物的开发,具有重要的临床意义。(The invention particularly relates to a medicament and application thereof in preparing a medicament for resisting cervical spondylosis and diabetes mellitus. The cervical spondylosis and the diabetes are closely related, and the existing research shows that the stimulation of the cervical spondylosis to sympathetic nerves can promote the hyperfunction of the pancreatic islet, and the blood sugar rise and the metabolic abnormality accompanied by the diabetes can also aggravate the cervical spondylosis. Aiming at the current situation, the invention provides a therapeutic drug suitable for treating cervical spondylosis with diabetes, and the research result shows that the combined use of the two drugs can simultaneously realize the effects of reducing blood sugar and improving cervical vertebra discomfort by adopting the combination of the Mingren neck pain series products and metformin hydrochloride; and can also improve the gastrointestinal stimulation effect brought by the metformin hydrochloride. The combination of the two drugs is applied to the development of the drugs for treating the cervical spondylosis and the diabetes, and has important clinical significance.)

1. A medicine is characterized in that the medicine comprises metformin and a traditional Chinese medicine extract; the metformin includes metformin and metformin pharmaceutical forms; the traditional Chinese medicine extract is prepared by extracting the following medicinal materials in parts by weight: 1-15 parts of pseudo-ginseng, 3-20 parts of ligusticum wallichii, 2-15 parts of corydalis tuber, 3-20 parts of radix paeoniae alba, 4-25 parts of radix clematidis, 3-20 parts of radix puerariae and 4-25 parts of notopterygium root.

2. The medicament of claim 1, wherein the pharmaceutically acceptable form further comprises a pharmaceutically acceptable salt form of metformin; further, the pharmaceutically acceptable salt form is metformin hydrochloride.

3. The medicament of claim 1, wherein the herbal extract is in the form of aqueous extracts, alcoholic extracts, powders, essential oils, or combinations thereof of the herbs.

4. The medicament of claim 3, wherein the preparation method of the traditional Chinese medicine extract comprises the following steps:

(1) pulverizing Notoginseng radix into 100-120 mesh fine powder;

(2) extracting volatile oil from Notopterygii rhizoma and radix Clematidis, collecting the distilled water solution in another container, decocting the residue with water for 1 hr, and filtering to obtain filtrate;

(3) decocting radix Puerariae and radix Paeoniae alba with water twice (2 hr for the first time and 1 hr for the second time), mixing the filtrate with the above two water solutions, concentrating, precipitating with ethanol, recovering ethanol, and concentrating to obtain fluid extract with relative density of 1.25-1.30 at 50 deg.C;

(4) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with ethanol, removing residue, recovering ethanol from the extractive solution, and concentrating to obtain fluid extract with relative density of 1.25-1.30 at 50 deg.C;

(5) mixing the above two fluid extracts, adding Notoginseng radix powder, mixing, drying, pulverizing into fine powder, adding appropriate amount of rhizoma Peucedani, mixing, and spraying the volatile oil of Notopterygii rhizoma and radix Clematidis.

5. The medicine of claim 1, wherein the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 10 parts of pseudo-ginseng, 15 parts of ligusticum chuanxiong hort, 7 parts of corydalis tuber, 15 parts of white paeony root, 20 parts of clematis root, 18 parts of kudzu-vine root and 22 parts of notopterygium root;

or the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 2.3 parts of pseudo-ginseng, 7.6 parts of ligusticum wallichii, 5.4 parts of corydalis tuber, 7.6 parts of white paeony root, 10.5 parts of clematis root, 7.6 parts of kudzu root and 10.5 parts of notopterygium root;

or the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 15 parts of pseudo-ginseng, 20 parts of ligusticum wallichii, 15 parts of corydalis tuber, 20 parts of white paeony root, 25 parts of clematis root, 20 parts of kudzu root and 25 parts of notopterygium root.

6. Use of the medicament of any one of claims 1 to 5 for the preparation of a product for the treatment of cervical spondylosis and diabetes.

7. A medicinal preparation for resisting cervical spondylosis and/or diabetes is characterized by comprising metformin hydrochloride, a traditional Chinese medicine extract and pharmaceutically necessary auxiliary materials.

8. The pharmaceutical preparation according to claim 7, wherein the metformin hydrochloride and the herbal extract are mixed with excipients to form a uniform product.

9. The pharmaceutical preparation according to claim 7, wherein the metformin hydrochloride and the herbal extract are mixed with excipients to form a separate product.

10. The anti-cervical-spondylosis and/or diabetes pharmaceutical formulation according to claim 7, wherein the excipients include but are not limited to one or more of diluents, fillers, disintegrants, lubricants, binders, flowing agents, complex forming agents, plasticizers, colorants, sweeteners, viscosity enhancers, preservatives, or antioxidants.

Technical Field

The invention belongs to the technical field of medicines for treating cervical spondylosis with diabetes, and particularly relates to a turntable of a winding machine.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

Cervical spondylosis and diabetes have certain relation, 56% of patients with diabetes can have the cervical spondylosis, the cervical spondylosis can stimulate the sympathetic ganglia behind the neck, insulin secretion of islet cells is intensified, nerve roots of the neck are pressed to cause insufficient cell supply nutrition, pancreas secretion function is reduced, and after the cervical spondylosis is cured, treatment and control of the diabetes can be influenced. According to researches, 56% of diabetics have cervical spondylosis and cause sympathetic excitation syndrome similar to hypoglycemia, and if the diabetics are not conscious, the diabetics can relapse due to blind addition or reduction of blood sugar reducing medicines, and the diabetics need to make corresponding examinations in life, particularly under the condition of good cervical vertebra blood sugar. Cervical spondylosis can stimulate sympathetic ganglion behind the neck, so that islet cells secrete insulin hyperfunction, a patient feels fatigue, beta cell insulin secretion is reduced or atrophied, the nerve root of the neck is compressed to cause meridian obstruction, qi and blood disharmony of the whole body and microcirculation obstacle, the conveying of nutrient substances can be influenced, cells cannot be repaired in time, and the pancreatic secretion function is reduced. Patients with diabetes mellitus have common blood sugar rise or viscosity increase, and also can cause unsmooth blood flow, angiosclerosis and abnormal protein and fat metabolism, so that the appearance of cervical spondylosis is aggravated, and the cervical spondylosis is in certain relation with the diabetes mellitus.

Disclosure of Invention

Aiming at the research background, the invention aims to provide a treatment medicine suitable for patients with cervical spondylosis and diabetes, and solves the problems that the existing medicine has unobvious treatment effect on the cervical spondylotic radiculopathy and the diabetes, the patients are difficult to persist, and the recurrent rate is high. The invention provides a new method for treating cervical spondylosis and diabetes by combining traditional Chinese medicine and western medicine. The traditional Chinese medicine and the western medicine are supplemented with each other, and the characteristics of the patients are combined for local treatment, so that the cure rate of the cervical spondylosis is greatly improved.

Based on the technical effects, the invention provides the following technical scheme:

in a first aspect of the present invention, a medicament is provided, which comprises metformin and a herbal extract; the metformin includes metformin and metformin pharmaceutical forms; the traditional Chinese medicine extract is prepared by extracting the following medicinal materials in parts by weight: 1-15 parts of pseudo-ginseng, 3-20 parts of ligusticum wallichii, 2-15 parts of corydalis tuber, 3-20 parts of radix paeoniae alba, 4-25 parts of radix clematidis, 3-20 parts of radix puerariae and 4-25 parts of notopterygium root.

In a second aspect of the invention, the application of the medicament of the first aspect in preparing a product for resisting cervical spondylosis and diabetes is provided.

In a third aspect of the invention, a pharmaceutical preparation for resisting cervical spondylosis and/or diabetes is provided, wherein the pharmaceutical preparation comprises metformin hydrochloride, a traditional Chinese medicine extract and pharmaceutically necessary auxiliary materials.

The beneficial effects of one or more technical schemes are as follows:

1. diabetes mellitus and cervical spondylosis have a close and inseparable relationship, and researches show that about 56 percent of diabetic patients can simultaneously suffer from the cervical spondylosis, and improvement of sympathetic nerve conditions by treating the cervical spondylosis is also of great significance for treatment of the diabetes mellitus. The medicine provided by the invention can simultaneously improve the symptoms of insufficient islet function and cervical vertebra discomfort of a diabetic patient, the existing Mingren neck pain product and metformin hydrochloride are combined for application, the Mingren neck pain product and metformin hydrochloride show synergistic interaction, and compared with the combined application mode of the Mingren neck pain product and other hypoglycemic medicines, the medicine has a better treatment effect.

2. Metformin is used as a first-choice drug for type II diabetes, has the advantages of high curative effect and low cost, and can only reduce hyperglycemia of diabetic patients, has no influence on physiological blood sugar, cannot cause hypoglycemia when used alone, and can also improve cardiovascular function. However, metformin has the defect of obvious gastrointestinal stimulation, and the invention finds that the original gastrointestinal discomfort phenomenon can be effectively improved after the metformin is combined with a cervicodynia product. The original side effect of the metformin is reduced while the blood sugar reducing effect is improved.

Detailed Description

It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.

As introduced in the background technology, diabetes and cervical spondylosis have close correlation, and the invention provides a medicine for providing corresponding treatment medicines for patients with cervical spondylosis complicated with diabetes, and in order to solve the technical problem, the invention provides a medicine which combines the Mingren neck pain product and metformin for use. Proved by verification, the drug combination use mode has good synergistic effect, and can effectively improve the gastrointestinal irritation of the metformin while improving the treatment effect.

In a first aspect of the present invention, a medicament is provided, which comprises metformin and a herbal extract; the metformin includes metformin and metformin pharmaceutical forms; the traditional Chinese medicine extract is prepared by extracting the following medicinal materials in parts by weight: 1-15 parts of pseudo-ginseng, 3-20 parts of ligusticum wallichii, 2-15 parts of corydalis tuber, 3-20 parts of radix paeoniae alba, 4-25 parts of radix clematidis, 3-20 parts of radix puerariae and 4-25 parts of notopterygium root.

Preferably, the pharmaceutical forms further include a pharmaceutically acceptable salt form of the metformin; further, the pharmaceutically acceptable salt form is metformin hydrochloride.

The traditional Chinese medicine extract is in the form of water extract, alcohol extract, medicine grinding powder, volatile oil contained in the medicine or a combination thereof, the preparation method is designed according to the conventional medicine using thought in the field, and the main pharmacodynamic active site in the traditional Chinese medicine extract is reserved.

Preferably, the invention provides a preparation method of a specific traditional Chinese medicine extract, which comprises the following steps:

(1) pulverizing Notoginseng radix into 100-120 mesh fine powder;

(2) extracting volatile oil from Notopterygii rhizoma and radix Clematidis, collecting the distilled water solution in another container, decocting the residue with water for 1 hr, and filtering to obtain filtrate;

(3) decocting radix Puerariae and radix Paeoniae alba with water twice (2 hr for the first time and 1 hr for the second time), mixing the filtrate with the above two water solutions, concentrating, precipitating with ethanol, recovering ethanol, and concentrating to obtain fluid extract with relative density of 1.25-1.30 at 50 deg.C;

(4) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with ethanol, removing residue, recovering ethanol from the extractive solution, and concentrating to obtain fluid extract with relative density of 1.25-1.30 at 50 deg.C;

(5) mixing the above two fluid extracts, adding Notoginseng radix powder, mixing, drying, pulverizing into fine powder, adding appropriate amount of rhizoma Peucedani, mixing, and spraying the volatile oil of Notopterygii rhizoma and radix Clematidis.

In some embodiments with better effects of the above technical scheme, the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 10 parts of pseudo-ginseng, 15 parts of ligusticum chuanxiong hort, 7 parts of corydalis tuber, 15 parts of white paeony root, 20 parts of clematis root, 18 parts of kudzu-vine root and 22 parts of notopterygium root.

In some other embodiments, the Chinese medicinal extract comprises the following raw materials in parts by weight: 2.3 parts of pseudo-ginseng, 7.6 parts of ligusticum wallichii, 5.4 parts of corydalis tuber, 7.6 parts of white paeony root, 10.5 parts of clematis root, 7.6 parts of kudzu root and 10.5 parts of notopterygium root.

In still other embodiments, the Chinese medicinal extract comprises the following raw materials in parts by weight: 15 parts of pseudo-ginseng, 20 parts of ligusticum wallichii, 15 parts of corydalis tuber, 20 parts of white paeony root, 25 parts of clematis root, 20 parts of kudzu root and 25 parts of notopterygium root.

In a second aspect of the invention, the application of the medicament of the first aspect in preparing a product for resisting cervical spondylosis and diabetes is provided.

In a third aspect of the invention, a pharmaceutical preparation for resisting cervical spondylosis and/or diabetes is provided, wherein the pharmaceutical preparation comprises metformin hydrochloride, a traditional Chinese medicine extract and pharmaceutically necessary auxiliary materials.

Preferably, in the pharmaceutical preparation, the metformin hydrochloride and the traditional Chinese medicine extract are mixed and then are mixed with auxiliary materials to form a uniform product.

Preferably, in the pharmaceutical preparation, the metformin hydrochloride and the traditional Chinese medicine extract are respectively mixed with auxiliary materials to form independent products.

In a specific technical scheme, a person skilled in the art can directly combine the metformin hydrochloride tablets with the Ming ren Jing Tong series products, and the Ming ren Jing Tong series products are preferably Ming ren Jing Tong tablets or Ming ren Jing Tong granules.

Preferably, the adjuvant is one or more selected from the group consisting of, but not limited to, diluents, fillers, disintegrants, lubricants, binders, flow agents, complex formers, plasticizers, colorants, sweeteners, viscosity enhancers, preservatives, and antioxidants.

In the above pharmaceutical product, the selection of the pharmaceutical dosage form can be set according to the dosage of the drug, the product research and development requirements, and the like, preferably, in the technical scheme, the metformin hydrochloride adopts a sustained release dosage form, and the traditional Chinese medicine extract is a conventional oral dosage form including but not limited to a liquid dosage form, a granule, a tablet, a capsule, and the like.

In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific examples and test examples. Metformin hydrochloride (CAS:1115-70-4) is a commercially available product, purchased from Drosophila civilian pharmacia.

Example 1

In this embodiment, a drug is provided, the drug includes metformin hydrochloride and a traditional Chinese medicine extract, and the preparation method of the traditional Chinese medicine extract is as follows:

the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 10 parts of pseudo-ginseng, 15 parts of ligusticum chuanxiong hort, 7 parts of corydalis tuber, 15 parts of white paeony root, 20 parts of clematis root, 18 parts of kudzu-vine root and 22 parts of notopterygium root; the preparation method of the medicine comprises the following steps:

(1) firstly, the pseudo-ginseng is crushed into 100-mesh and 120-mesh fine powder;

(2) extracting volatile oil from Notopterygii rhizoma and radix Clematidis, collecting the distilled water solution in another container, decocting the residue with water for 1 hr, and filtering to obtain filtrate;

(3) decocting radix Puerariae and radix Paeoniae alba with water twice, the first time for 2 hr, the second time for 1 hr,

mixing the filtrate with the above two aqueous solutions, concentrating, precipitating with ethanol, recovering ethanol, and concentrating to obtain fluid extract with relative density of 1.25-1.30(50 deg.C);

(4) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with ethanol, removing residue, recovering ethanol from the extractive solution, and concentrating to obtain fluid extract with relative density of 1.25-1.30(50 deg.C);

(5) mixing the two fluid extracts, adding pseudo-ginseng powder, uniformly mixing, drying, crushing into fine powder, and mixing with metformin hydrochloride according to a mass ratio of 10: 1, adding a proper amount of the rhizoma picrorhizae, uniformly mixing, and spraying the extracted notopterygium root and clematis root volatile oil to obtain the medicine in the form of granules.

Example 2

In this embodiment, a drug is provided, the drug includes metformin hydrochloride and a traditional Chinese medicine extract, and the preparation method of the traditional Chinese medicine extract is as follows:

the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 2.3 parts of pseudo-ginseng, 7.6 parts of ligusticum wallichii, 5.4 parts of corydalis tuber, 7.6 parts of white paeony root, 10.5 parts of clematis root, 7.6 parts of kudzu root and 10.5 parts of notopterygium root; the preparation method of the medicine comprises the following steps:

(1) firstly, the pseudo-ginseng is crushed into 100-mesh and 120-mesh fine powder;

(2) extracting volatile oil from Notopterygii rhizoma and radix Clematidis, collecting the distilled water solution in another container, decocting the residue with water for 1 hr, and filtering to obtain filtrate;

(3) decocting radix Puerariae and radix Paeoniae alba with water twice (1.5 hr for the first time and 1 hr for the second time), mixing the filtrate with the above two water solutions, concentrating, precipitating with ethanol, recovering ethanol, and concentrating to obtain fluid extract with relative density of 1.25-1.30(50 deg.C);

(4) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with ethanol, removing residue, recovering ethanol from the extractive solution, and concentrating to obtain fluid extract with relative density of 1.25-1.30(50 deg.C);

(5) mixing the above two fluid extracts, adding Notoginseng radix powder, mixing, drying, pulverizing into fine powder, adding appropriate amount of rhizoma corydalis, mixing, and spraying the volatile oil of Notopterygii rhizoma and radix Clematidis to obtain the Chinese medicinal extract.

Mixing the traditional Chinese medicine extract and metformin hydrochloride according to the mass ratio of 12: 1 mixing and tabletting to obtain the tablet medicament.

Example 3

In this embodiment, a drug is provided, the drug includes metformin hydrochloride and a traditional Chinese medicine extract, and the preparation method of the traditional Chinese medicine extract is as follows:

the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 15 parts of pseudo-ginseng, 20 parts of ligusticum wallichii, 15 parts of corydalis tuber, 20 parts of radix paeoniae alba, 25 parts of radix clematidis, 20 parts of radix puerariae and 25 parts of notopterygium root; the preparation method of the medicine comprises the following steps:

(1) firstly, the pseudo-ginseng is crushed into 100-mesh and 120-mesh fine powder;

(2) extracting volatile oil from Notopterygii rhizoma and radix Clematidis, collecting the distilled water solution in another container, decocting the residue with water for 1 hr, and filtering to obtain filtrate;

(3) decocting radix Puerariae and radix Paeoniae alba with water twice (2.5 hr for the first time and 1.5 hr for the second time), mixing the filtrate with the above two water solutions, concentrating, precipitating with ethanol, recovering ethanol, and concentrating to obtain fluid extract with relative density of 1.25-1.30(50 deg.C);

(4) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with ethanol, removing residue, recovering ethanol from the extractive solution, and concentrating to obtain fluid extract with relative density of 1.25-1.30(50 deg.C);

(5) mixing the above two fluid extracts, adding Notoginseng radix powder, mixing, drying, pulverizing into fine powder, adding appropriate amount of rhizoma corydalis, mixing, spraying above volatile oil of Notopterygii rhizoma and radix Clematidis, and tabletting to obtain tablet. The traditional Chinese medicine extract tablet and the metformin hydrochloride sustained release tablet are used together, the dosage of the traditional Chinese medicine extract tablet is 3 times per day, 4 tablets are taken each time, and the dosage of the metformin hydrochloride sustained release tablet is 1 tablet per day.

Test examples

In the invention, the safety and the effectiveness of the medicine are verified as follows:

first, safety verification

20 SD rats with the body weight of 180-220 g are selected, administration is carried out according to the administration dosage upper limit of 5g/kg per 24h, 1 tablet of Mingren Jingtong tablet and 1 tablet of metformin hydrochloride sustained release tablet are ground and dissolved in 8mL of 0.5% CMC-Na solution, intragastric administration is completed for four times within 12h, and administration is continuously carried out for 10 days according to the mode.

The diet and behavior of rats are observed during administration, and 1-2 rats have symptoms of abdominal pain and diarrhea and have a phenomenon of slow weight growth rate. After the administration, the rats are sacrificed and examined by gross anatomy and pathological histology, and organ abnormality is not found, which proves that the combination of the medicaments has no adverse effect on animal organisms.

Second, analysis of therapeutic effects

80 patients with cervical spondylosis and diabetes are recruited, all the patients are subjected to X-ray radiography, CT scanning or MRI scanning, and are confirmed to be the cervical spondylosis by a clinician, the diagnosis of the diabetes meets the diagnosis standard provided by the international general WHO diabetes expert committee, and the diagnosis history of the type 2 diabetes is provided.

In the experiment, acarbose was selected as a control drug, and the metformin and acarbose were used in the initial doses, i.e. the daily dose of the active ingredient was 500mg for metformin and 50mg for acarbose. The traditional Chinese medicine extract is directly taken by a commercially available minren cervicodynia tablet product, the daily dosage is 3 times/day, 4 tablets are taken each time, the dosage of the cervicodynia tablet is reduced to 9 tablets/day, the setting mode of the experimental group is shown in the following table 1:

TABLE 1 daily dose for each experimental group

The 80 patients were divided into 5 groups and no statistically significant differences were observed in cervical spine function scores and blood glucose levels before treatment initiation and in five groups of patients evaluated separately. After one month of treatment and one week of interval, cervical vertebra function scoring and blood sugar level detection are carried out again, and the detection results are shown in the following table 2:

TABLE 2 comparison of cervical function with blood glucose levels before and after treatment

As can be seen by comparing the results of the control group I and the experimental group in the table 2, compared with the blood sugar reducing effect of the metformin hydrochloride, the combined use of the Mingren neckpain tablet and the metformin hydrochloride has better blood sugar reducing effect, and the probability of gastrointestinal discomfort phenomena such as abdominal pain, diarrhea, nausea and the like of patients of the combined use of the Mingren neckpain tablet and the metformin hydrochloride is lower. Compared with the effects of the control group IV and the experimental group, the combination of the Mingren Jingtong tablets and metformin hydrochloride has more obvious improvement effect on blood sugar reduction and cervical discomfort compared with the combination of acarbose.

The invention also considers the combined effect of the oral drugs for the type II diabetes, including glimepiride, gliclazide, rosiglitazone, repaglinide and the like, and the combined effect is not as good as the combined effect of the metformin hydrochloride and the Mingren Jingtong tablets.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.