阅读说明：本技术 一种用于神经根颈椎病的组合物及治疗上肢麻木的应用 (Composition for treating nerve root cervical spondylosis and application of composition for treating upper limb numbness ) 是由 贾庆文 石丽娟 王振 李君霞 刘杰 龙玉波 刘迎雪 任雯 于 2021-09-01 设计创作，主要内容包括：本发明涉及一种用于神经根颈椎病的组合物及治疗上肢麻木的应用。现有治疗药物能够较快的改善疼痛症状,但对于肢体麻木等症状的改善速度较慢。甲钴胺作为一种修复神经活性的成分也可用于神经根颈椎病的治疗,但是甲钴胺代谢速度较快,在肌肉和神经组织中的分布效果不理想。本发明提供了一种明仁颈痛产品与甲钴胺的联合用药方式,将羌活、威灵仙中的挥发油作为甲钴胺的脂质载药基质,改善甲钴胺代谢性能。经验证,本发明提供的药物联用方式能够有效的改善疼痛、麻木症状,用药期间无不良反应,具有理想的临床治疗效果。(The invention relates to a composition for treating nerve root cervical spondylosis and application of the composition for treating numbness of upper limbs. The existing treatment medicine can improve pain symptoms quickly, but has slow improvement speed on symptoms such as numbness of limbs and the like. Mecobalamin as a component for repairing nerve activity can also be used for treating cervical spondylotic radiculopathy, but the metabolic rate of mecobalamin is higher, and the distribution effect in muscle and nerve tissues is not ideal. The invention provides a combined medication mode of a Mingren neck pain product and mecobalamin, volatile oil in notopterygium root and clematis root is used as a lipid drug-carrying matrix of the mecobalamin, and the metabolic performance of the mecobalamin is improved. Proved by verification, the drug combination mode provided by the invention can effectively improve pain and numbness symptoms, has no adverse reaction during the administration period, and has ideal clinical treatment effect.)

1. A pharmaceutical composition is characterized in that the pharmaceutical composition comprises a traditional Chinese medicine extract and also comprises B vitamins;

the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 1-15 parts of pseudo-ginseng, 3-20 parts of ligusticum chuanxiong hort, 2-15 parts of rhizoma corydalis, 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;

the B vitamins include, but are not limited to, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, and derivatives of the above vitamins.

2. The pharmaceutical composition of claim 1, wherein said vitamin in group B is mecobalamin.

3. The use of the pharmaceutical composition according to claim 1 or 2 for the preparation of a medicament for the treatment of cervical spondylosis.

4. The use of the pharmaceutical composition of claim 3 in the preparation of a medicament for treating cervical spondylotic radiculopathy, wherein in the preparation method of the pharmaceutical composition, the volatile oil in the Chinese medicinal extract partially comprises mecobalamin.

5. The use of the pharmaceutical composition of claim 4 in the preparation of a medicament for treating cervical spondylotic radiculopathy, wherein said inclusion further comprises the inclusion of an oligosaccharide compound to encapsulate the volatile oil portion and mecobalamin.

6. The use of the pharmaceutical composition of claim 5 for preparing a medicament for treating cervical spondylotic radiculopathy, wherein the pharmaceutical composition is prepared by the following steps:

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

(2) extracting volatile oil parts of notopterygium roots and radix clematidis, collecting distilled water solution in another container, adding water into dregs for decocting for 1-3 hours, and filtering for later use;

(3) respectively taking beta-cyclodextrin with the volume 8-10 times that of the volatile oil of the notopterygium root and the clematis root prepared in the step (2), adding a minimum amount of water, heating to completely dissolve the beta-cyclodextrin into an aqueous solution, continuously adding mecobalamin, uniformly mixing, cooling, respectively adding the volatile oil of the notopterygium root and the clematis root, stirring, refrigerating overnight, and performing suction filtration to obtain clathrate compound powder; if the agglomeration phenomenon of the solid after suction filtration is serious, drying at 35-40 ℃ and then grinding;

(4) decocting radix Puerariae and radix Paeoniae alba with water, mixing the decoction and the filtrate obtained in step (1), concentrating, precipitating with ethanol, removing ethanol in the ethanol precipitation part, and concentrating the rest medicinal liquid to obtain fluid extract;

(5) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with ethanol solution, recovering ethanol from the extractive solution, and concentrating under reduced pressure to obtain fluid extract;

(6) and (5) mixing the clear paste obtained in the step (4) and the clear paste obtained in the step (5), crushing the mixture into fine powder, adding the pseudo-ginseng powder and the inclusion powder, and uniformly mixing the mixture to obtain the pharmaceutical composition.

7. The use of the pharmaceutical composition according to claim 6 for preparing a medicament for treating cervical spondylotic radiculopathy, wherein in step (3), the β -cyclodextrin is dissolved in water by heating at 50-60 ℃;

or, in the step (3), the notopterygium root and clematis root volatile oil is added into the beta-cyclodextrin solution and then stirred for 150-250 r/min, wherein the stirring time is 1-3 h;

or in the step (5), the concentration of the ethanol solution is 75-85%;

or, in the step (4) or (5), the relative density of the clear paste is 1.25-1.30.

8. A therapeutic agent for radicular cervical spondylosis, comprising the pharmaceutical composition of claim 1 or 2; the treatment medicine is an oral preparation, and further is an oral solid preparation or a liquid preparation; the oral solid preparation includes but is not limited to tablets, capsules, granules, pills, paste and powder; the oral liquid preparation includes but is not limited to suspension, syrup, mixture, tincture and emulsion.

9. An agent for improving upper limb numbness in radiculocervical spondylosis, comprising the composition of claim 1 or 2 or the remedy for radiculocervical spondylosis of claim 7 or 8.

10. A medicament for improving vision disorder of radiculocervical spondylosis, comprising the composition according to claim 1 or 2 or the therapeutic agent for radiculocervical spondylosis according to claim 7 or 8.

Technical Field

The invention belongs to the technical field of medicines for treating radicular cervical spondylosis, and particularly relates to a medicinal composition combining a Mingren neck pain product and mecobalamin and application of the medicinal composition in the fields of treating radicular cervical spondylosis, improving upper limb numbness and the like.

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 spondylopathy is a disease caused by cervical degeneration, nerve root compression and other factors, and the innervation area of the cervical spondylopathy has certain pain, numbness, sensory loss and reflex change. The degenerative change of cervical vertebrae and other factors may cause damage to the neck tissue, and oppress nerve root, causing typical nerve root symptoms such as numbness and pain of upper limbs, and its range is consistent with the range dominated by cervical spine nerves. The main clinical manifestations are soreness of the neck and shoulder, radiating down the nerve root to the forearm and fingers, causing pain in the arm and fingers, and motor and sensory disturbances in certain areas.

The cervical spondylotic radiculopathy accounts for about 60-70% of the onset of the cervical spondylopathy, the radicular symptom characterized by stiff neck and shoulder with pain and numbness of one or two sides of upper limbs is the most main symptom of the cervical spondylotic radiculopathy and also the most painful and main factor for the patient to see a doctor, the severity of the disease is the main index for judging the severity of the disease, the remission degree is the main index for judging the curative effect, and the disease is the most main observation index in the cervical spondylopathy curative effect evaluation systems at home and abroad. At present, the mechanism of radicular neuropathic pain and numbness caused by cervical spondylotic radiculopathy and the difference between the two are not completely clear, and it is generally considered that demyelination of nerve root fibers caused by ischemia and hypoxia injury of spinal nerve root is the main cause of numbness of upper limbs. Clinical treatment conditions show that the pain of the upper limbs of the cervical spondylotic radiculopathy can be quickly relieved after treatment, but the upper limbs are numb, even if the upper limbs have amyotrophy, the curative effect is not ideal, and the treatment period is longer.

The existing treatment means comprises the treatments of traditional Chinese medicine acupoint injection, physical therapy, traction, traditional Chinese medicine fumigation, massage, nerve block and the like, and the treatment means has the characteristics of simplicity, convenience, safety and rapidness, and patients can feel comfortable immediately after treatment, so the treatment means is accepted by the patients clinically. It is generally recognized in the art that the mechanism of tuina manipulations for cervical spondylotic radiculopathy can be summarized as relieving muscle spasm, promoting local circulation and absorption of inflammatory mediators, loosening nerve and soft tissue adhesions, etc., and still cannot fundamentally improve spinal nerve injury. Therefore, the medicine can effectively treat the cervical spondylotic radiculopathy and relieve the numbness symptom of the upper limb distal end, effectively shorten the treatment period of the cervical spondylotic radiculopathy and relieve the pain of patients.

Mikebao, the main ingredient of which is mecobalamin, is a metabolite of naturally occurring vitamin B12, and contains methyl (CH) by artificial synthesis₃-B12) also known as methylvitamin B12. Because the medicine can effectively accelerate the nucleic acid of nerve cells andprotein synthesis, myelination promotion, axon regeneration and axon conduction improvement, so that the medicine has good curative effects on relieving subjective symptoms of patients and improving nerve conduction, and is commonly used for treating radiculocervical spondylosis. The clinical medication mode comprises oral administration and local injection treatment, or treatment by combining other Chinese patent medicines and chemical medicines and combining acupuncture and moxibustion and other means.

Disclosure of Invention

As described in the background art, nerve root cervical spondylosis is often accompanied by numbness of limbs, and the existing treatment method can quickly improve pain symptoms, but the speed of alleviating symptoms such as visual disturbance, dizziness or numbness of limbs caused by nerve injury is slow. Mecobalamin has nerve repairing effect, and can be used for treating cervical spondylopathy of nerve root. Aiming at the defects that the metabolism speed of mecobalamin in vivo is too high and the distribution amount of mecobalamin in nerve and muscle tissues is low, the invention provides an optimized combination mode, and the volatile oil component in the minren cervicodynia product is used as a lipid drug-loaded matrix to carry out inclusion on mecobalamin, so that the metabolism speed of mecobalamin is reduced. The combined medicine can effectively relieve nerve injury of nerve root cervical spondylosis, improve the phenomena of numbness of limbs, visual disturbance and the like, and obtain better clinical treatment effect.

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

in a first aspect of the present invention, a pharmaceutical composition is provided, wherein the pharmaceutical composition comprises a traditional Chinese medicine extract, and further comprises B vitamins;

the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 1-15 parts of pseudo-ginseng, 3-20 parts of ligusticum chuanxiong hort, 2-15 parts of rhizoma corydalis, 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;

the B vitamins include, but are not limited to, vitamin B1 (ammonium sulfate), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid), vitamin B12 (cobalamin), and derivatives of the above vitamins.

The main functions of the B vitamins include regulating the metabolism of substances such as sugar, fat, protein and the like, and the B vitamins are used as coenzymes in the energy metabolism process and have important effects on the nervous system, the cardiovascular system, the hematopoietic function, the reproductive system and the vision, relieving pressure, improving hair quality and skin and the like.

It should be understood that the derivatives of vitamins described in the above technical schemes include derivatives without modification with functional groups, and the derivatives commonly used in the art include cyanocobalamin, hydroxycobalamin, cobamamide or mecobalamin. In one embodiment of the present invention, which is particularly effective, the vitamin in group B is mecobalamin.

Mecobalamin, english name: compared with other vitamin B12, Mecobalamin has good transferability into nerve tissue, and can repair damaged nerve tissue. Can be used for treating peripheral neuropathy and megaloblastic anemia caused by vitamin B12 deficiency. Mecobalamin is also used for treating cervical spondylotic radiculopathy, and adverse reactions are reported, and inappetence, nausea, vomiting and diarrhea are common side effects of mecobalamin.

In the existing preparation method of the Mingren Jingtong product, volatile oil components are directly sprayed on the surface of a medicine extract. Since the volatile oil usually has pungent and pungent odor and strong volatility, the direct spraying on the surface of the extract has the following two defects: (1) may cause a part of the active ingredients to be volatilized together with the volatile oil; (2) the pungent taste of the volatile oil can affect the taste of the medicine, and reduce patient compliance. In addition, the mecobalamin has a high metabolism speed in the organism, reaches the peak value of blood concentration 3 hours after oral administration, and can be metabolized from the organism after about 8 hours. The existing research shows that the mecobalamin can be detected from blood, kidney, adrenal gland, pancreas, liver and stomach tissues of an organism after being orally taken by an animal model, and the concentration is higher, while the concentration of drugs in muscles and central nerves is lower. This distribution of mecobalamin is detrimental to its full potential for repair of the nervous system.

Based on the defects, the invention conjectures that the volatile oil is adopted as the medicine carrying matrix of the mecobalamin, and the medicine retention in muscles and the like is increased by increasing the fat solubility of the medicine so as to enhance the repair effect on the nervous system. The verification proves that the optimized medicine mecobalamin has a more gradual release effect, effectively prolongs the metabolism time of the mecobalamin in vivo, and is expected to increase the distribution of the medicine in muscles and nerves. In addition, clinical curative effects prove that the medicine provided by the invention can effectively improve limb numbness symptoms accompanied by nerve root cervical spondylosis, and realizes the technical effect that the product or the product for treating the kernel neck pain cannot be realized by single use.

Therefore, the second aspect of the present invention also provides the application of the above pharmaceutical composition in the preparation of drugs for resisting cervical spondylotic radiculopathy. In a preferred scheme, in the preparation process of the pharmaceutical composition, the volatile oil part in the traditional Chinese medicine extract comprises mecobalamin.

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 described in the background section, the nerve root cervical spondylosis accompanied by numbness of limbs and the like has a slow speed of alleviating symptoms, and causes serious influence on the daily life of the patient. In order to solve the technical problems, the invention provides a combined pharmaceutical composition form of mecobalamin and a mindedrum neck pain product.

In a first aspect of the present invention, a pharmaceutical composition is provided, wherein the pharmaceutical composition comprises a traditional Chinese medicine extract, and further comprises B vitamins;

the traditional Chinese medicine extract comprises the following raw materials in parts by weight: 1-15 parts of pseudo-ginseng, 3-20 parts of ligusticum chuanxiong hort, 2-15 parts of rhizoma corydalis, 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;

the B vitamins include, but are not limited to, vitamin B1 (ammonium sulfate), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), vitamin B7 (biotin), vitamin B9 (folic acid), vitamin B12 (cobalamin), and derivatives of the above vitamins.

In one embodiment of the present invention, which is particularly effective, the vitamin in group B is mecobalamin.

In a second aspect of the present invention, an application of the pharmaceutical composition described in the first aspect in preparing a drug for resisting cervical spondylotic radiculopathy is provided.

Preferably, in the preparation method of the pharmaceutical composition, the volatile oil part in the traditional Chinese medicine extract comprises mecobalamin.

Furthermore, the inclusion also adopts oligosaccharide compound to wrap the volatile oil part and mecobalamin.

In a specific embodiment of the present invention, the preparation method of the pharmaceutical composition is as follows:

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

(2) extracting volatile oil parts of notopterygium roots and radix clematidis, collecting distilled water solution in another container, adding water into dregs for decocting for 1-3 hours, and filtering for later use;

(3) respectively taking beta-cyclodextrin with the volume 8-10 times that of the volatile oil of the notopterygium root and the clematis root prepared in the step (2), adding a minimum amount of water, heating to completely dissolve the beta-cyclodextrin into an aqueous solution, continuously adding mecobalamin, uniformly mixing, cooling, respectively adding the volatile oil of the notopterygium root and the clematis root, stirring, refrigerating overnight, and performing suction filtration to obtain clathrate compound powder; if the agglomeration phenomenon of the solid after suction filtration is serious, drying at 35-40 ℃ and then grinding;

(4) decocting radix Puerariae and radix Paeoniae alba with water, mixing the decoction and the filtrate obtained in step (1), concentrating, precipitating with ethanol, removing ethanol in the ethanol precipitation part, and concentrating the rest medicinal liquid to obtain fluid extract;

(5) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with ethanol solution, recovering ethanol from the extractive solution, and concentrating under reduced pressure to obtain fluid extract;

(6) and (5) mixing the clear paste obtained in the step (4) and the clear paste obtained in the step (5), crushing the mixture into fine powder, adding the pseudo-ginseng powder and the inclusion powder, and uniformly mixing the mixture to obtain the pharmaceutical composition.

In a preferable scheme, in the step (3), the beta-cyclodextrin is dissolved by heating at 50-60 ℃ after being added with water.

In a preferred scheme, in the step (3), the notopterygium root and clematis root volatile oil is added into the beta-cyclodextrin solution and then stirred for 150-250 r/min, wherein the stirring time is 1-3 h.

In a preferable embodiment, in the step (5), the concentration of the ethanol solution is 75-85%.

In a preferable scheme, in the step (4) or (5), the relative density of the clear paste is 1.25-1.30.

In a third aspect of the invention, a therapeutic drug for radicular cervical spondylosis is provided, which comprises the pharmaceutical composition of the first aspect.

Preferably, the therapeutic drug is an oral preparation, further, an oral solid preparation or a liquid preparation; the oral solid preparation includes but is not limited to tablets, capsules, granules, pills, paste and powder; the oral liquid preparation includes but is not limited to suspension, syrup, mixture, tincture and emulsion.

In a fourth aspect of the present invention, there is provided a medicament for improving numbness of upper limbs caused by radicular cervical spondylosis, the medicament comprising the composition of the first aspect or a therapeutic agent for radicular cervical spondylosis of the third aspect.

In a fifth aspect of the present invention, there is provided a medicament for improving vision disorders of radicular cervical spondylosis, wherein the medicament comprises the composition of the first aspect or a therapeutic agent for radicular cervical spondylosis of the third aspect.

In order to make the technical solution of the present invention more clearly understood by those skilled in the art, the technical solution of the present invention will be described in detail below with reference to specific examples and comparative examples.

Example 1

In this embodiment, a medicine for treating cervical spondylotic radiculopathy is provided, and the preparation method of the medicine includes the following steps:

the medicine comprises the following raw materials in parts by weight: 15 parts of pseudo-ginseng, 20 parts of ligusticum chuanxiong hort, 15 parts of corydalis tuber, 20 parts of white paeony root, 25 parts of clematis root, 20 parts of kudzuvine root, 25 parts of notopterygium root and 0.05 part of mecobalamin (purchased from Sigma).

The preparation method of the medicine comprises the following steps:

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

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

(3) and (3) respectively taking beta-cyclodextrin with the volume 8 times that of the volatile oil of the notopterygium root and the clematis root prepared in the step (2), adding a minimum volume of water, heating to 55 ℃ to completely dissolve the volatile oil of the notopterygium root and the clematis root into an aqueous solution, continuously adding mecobalamin, uniformly mixing, cooling, respectively adding the volatile oil of the notopterygium root and the clematis root, stirring for 2 hours at 200r/min, refrigerating overnight, and performing suction filtration to obtain clathrate powder. If the agglomeration phenomenon of the solid after suction filtration is serious, the solid can be dried at 35-40 ℃ and then ground.

(4) Adding 3 times of water into the kudzu root and the white paeony root, decocting for 2 hours for the first time and 1 hour for the second time, combining the water solution decocted for the two times and the filtrate obtained in the step (1), concentrating, precipitating with ethanol, removing ethanol in the ethanol precipitation part, and concentrating the residual liquid medicine into clear paste with the relative density of 1.25-1.30 at 50 ℃;

(5) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with 80% ethanol, recovering ethanol from the extractive solution, and concentrating under reduced pressure to obtain fluid extract with relative density of 1.25-1.30 at 50 deg.C;

(6) mixing the fluid extracts obtained in the steps (4) and (5), pulverizing into fine powder, adding Notoginseng radix powder and the clathrate powder, mixing to obtain active medicinal powder, adding magnesium stearate and starch into the active medicinal powder, and tabletting to obtain tablet.

Example 2

In this embodiment, a medicine for treating cervical spondylotic radiculopathy is provided, and the preparation method of the medicine includes the following steps:

the medicine comprises the following raw materials in parts by weight: 12 parts of pseudo-ginseng, 18 parts of ligusticum chuanxiong hort, 13 parts of corydalis tuber, 18 parts of white paeony root, 22 parts of clematis root, 18 parts of kudzuvine root, 22 parts of notopterygium root and 0.053 part of mecobalamin (purchased from Sigma).

The preparation method of the medicine comprises the following steps:

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

(2) extracting volatile oil from Notopterygii rhizoma and radix Clematidis by steam extraction, collecting the distilled water solution in another container, decocting the residue in water for 1.5 hr, and filtering to obtain filtrate;

(3) and (3) respectively taking beta-cyclodextrin with the volume of 10 times of the volatile oil of the notopterygium root and the clematis root prepared in the step (2), adding a minimum volume of water, heating to 60 ℃ to completely dissolve the volatile oil of the notopterygium root and the clematis root into a solution state, continuously adding mecobalamin, uniformly mixing, cooling to room temperature, respectively adding the volatile oil of the notopterygium root and the clematis root, stirring for 3 hours at a speed of 150r/min, refrigerating overnight, and performing suction filtration to obtain clathrate compound powder. If the agglomeration phenomenon of the solid after suction filtration is serious, the solid can be dried at 35-40 ℃ and then ground.

(4) Adding 2 times of water into the kudzu root and the white paeony root, decocting for 1.5 hours for the first time and 1 hour for the second time, combining the water solution decocted for the two times and the filtrate obtained in the step (1), concentrating, precipitating with ethanol, removing the ethanol in the ethanol precipitation part, and concentrating the residual liquid medicine into clear paste with the relative density of 1.25-1.30 at 55 ℃;

(5) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with 75% ethanol, recovering ethanol from the extractive solution, and concentrating under reduced pressure to obtain fluid extract with relative density of 1.25-1.30 at 55 deg.C;

(6) mixing the fluid extracts obtained in the steps (4) and (5), pulverizing into fine powder, adding Notoginseng radix powder and inclusion powder, mixing to obtain active medicinal powder, adding magnesium stearate, starch or microcrystalline cellulose into the active medicinal powder, and making into granule.

Example 3

In this embodiment, a medicine for treating cervical spondylotic radiculopathy is provided, and the preparation method of the medicine includes the following steps:

the medicine comprises the following raw materials in parts by weight: 17 parts of pseudo-ginseng, 23 parts of ligusticum chuanxiong hort, 17 parts of corydalis tuber, 23 parts of white paeony root, 28 parts of clematis root, 22 parts of kudzuvine root, 27 parts of notopterygium root and 0.07 part of mecobalamin (purchased from Sigma).

The preparation method of the medicine comprises the following steps:

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

(2) extracting volatile oil from Notopterygii rhizoma and radix Clematidis by steam distillation, collecting distilled water solution in another container, decocting the residue in water for 1.5 hr, and filtering to obtain filtrate;

(3) and (3) respectively taking beta-cyclodextrin with the volume of 10 times of that of the volatile oil of the notopterygium root and the clematis root prepared in the step (2), adding a minimum volume of water, heating to 50 ℃ to completely dissolve the volatile oil of the notopterygium root and the clematis root into a water solution, continuously adding mecobalamin, uniformly mixing, cooling, respectively adding the volatile oil of the notopterygium root and the clematis root, stirring for 2 hours at 200r/min, refrigerating overnight, and performing suction filtration to obtain clathrate compound powder. If the agglomeration phenomenon of the solid after suction filtration is serious, the solid can be dried at 35-40 ℃ and then ground.

(4) Adding 3 times of water into the kudzu root and the white paeony root, decocting for 2 hours for the first time and 1 hour for the second time, combining the water solution decocted for the two times and the filtrate obtained in the step (1), concentrating, precipitating with ethanol, removing ethanol in the ethanol precipitation part, and concentrating the residual liquid medicine into clear paste with the relative density of 1.25-1.30 at 50 ℃;

(5) extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with 85% ethanol under reflux, recovering ethanol from the extractive solution, and concentrating under reduced pressure to obtain fluid extract with relative density of 1.25-1.30 at 45 deg.C;

(6) mixing the fluid extracts obtained in the steps (4) and (5), pulverizing into fine powder, adding Notoginseng radix powder and the clathrate powder, mixing to obtain active medicinal powder, adding magnesium stearate and starch into the active medicinal powder, and tabletting to obtain tablet.

Comparative example 1

In the research process of the invention, the invention also provides a medicine for directly mixing mecobalamin with the active component of the kernel of angelica keiskei koidz, and the difference of the preparation method of the medicine from the example 1 is as follows:

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

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

(3) adding 2 times of water into the kudzu root and the white paeony root, decocting for 2 hours for the first time and 1 hour for the second time, combining the water solution decocted twice and the filtrate obtained in the step (2), concentrating, precipitating with ethanol, removing ethanol in the ethanol precipitation part, and concentrating the residual liquid medicine into clear paste with the relative density of 1.25-1.30 at 50 ℃;

(4) reflux-extracting rhizoma Ligustici Chuanxiong and rhizoma corydalis with 75% ethanol, removing residue, recovering ethanol from the extractive solution, and concentrating under reduced pressure to obtain fluid extract with relative density of 1.25-1.30 at 50 deg.C;

(5) mixing the fluid extracts obtained in the steps (3) and (4), adding Notoginseng radix powder and mecobalamin, mixing, pulverizing into fine powder, and spraying volatile oil of Notopterygii rhizoma and radix Clematidis onto the surface of the powder.

Validity verification

1. Drug release effect verification

Preparing a mecobalamin reference substance into 0.1g/L standard working solution by adopting 0.1mol/L normal saline, diluting the standard working solution into a series of concentrations, and establishing a standard curve of the concentration-absorbance of the mecobalamin.

The active drug powders of examples 1-3 and comparative example 1 were sieved through a five-mesh sieve. Taking 20mg of undersize powder, using methanol as a dissolving medium to prepare a solution with the concentration of 10 mu g/mL, detecting the content of mecobalamin in the medicine powder by using a high performance liquid phase (acetonitrile-phosphate buffer solution (20: 80) is used as a mobile phase), and calculating the actual medicine loading amount of the mecobalamin in the medicine powder.

Taking 20mg of the undersize powder, tabletting, placing in phosphate buffer solution with pH of 6.8, rotating at 50r/min, sampling 1ml (complementing after sampling) for 1, 2, 3, 4, 5, 6, 8 and 12 hours, filtering through a microporous filter membrane, detecting the accumulated release amount of mecobalamin, and calculating the release rate of the medicine; the drug release rate is the cumulative release amount of the drug/the actual drug-loading amount of mecobalamin in the drug powder x 100%.

The results of the mecobalamin release rates in examples 1-3 and comparative example 1 are shown in table 1 below:

TABLE 1 mecobalamin Release Rate (%) of drug powder

In the in vitro release test of the above drugs, it can be seen that the half-release time of mecobalamin drug in examples 1-3 is about 6h, while the half-release time of mecobalamin in comparative example 1 is about 3h, which is similar to the half-life data of mecobalamin, and this may indicate that the direct mixing of mecobalamin powder and herbal extract has no significant effect on the metabolic properties of mecobalamin. In addition, from the results of the release rate of the drug, the mecobalamin in the comparative example achieves the maximum release effect of the drug already in about 8 hours, the final release rate of the drug is about 85%, the mecobalamin in the examples 1 to 3 achieves the maximum release effect of the drug in about 12 hours, and the final release amount reaches over 90%.

The above research results show that the combined use mode of mecobalamin described in examples 1-3 can effectively prolong the retention time of mecobalamin in vivo and optimize the release effect of mecobalamin. By prolonging the retention time of mecobalamin in vivo and adopting the lipid matrix to coat the mecobalamin, the distribution of the mecobalamin in tissues such as muscles, nerves and the like can be increased.

2. Drug safety verification

(1) Acute toxicity test:

the 6mL suspension was administered by gavage three times (approximately 60 times the clinical therapeutic dose) in 12h at intervals of 4h, taking a rat weighing 200gSD at a concentration of 500mg drug powder/mL, calculated as 2.2g drug powder/day for the clinical dose (2.2 g for the 70kg adult daily dose). The administration was continued for one week, during which the rats were observed for changes in eating behavior and abnormal changes in fur, diet, body weight, feces, etc., and for the presence or absence of toxic symptoms and death. Animals are weighed and sacrificed after one week for anatomical and histopathological examination, and the heart, the lung, the liver, the kidney, the spleen, the stomach, the intestine, the bladder, the adrenal gland, the thymus, the pancreas, the thyroid gland, the lymph node, the uterus, the ovary, the testis, the prostate, the brain and the like are taken for histological observation, and no abnormal pathological change is found, thereby prompting that the clinical application dose of the traditional Chinese medicine composition is safe.

(2) Long-term toxicity test:

SD rats are randomly divided into three dose groups of high (300mg drug powder/mL), medium (100mg drug powder/mL) and low (25mg drug powder/mL), each group of males and females is half-and-half, and the administration of 2mL by intragastric administration is carried out at 8 am and 4 pm every day, and the administration is carried out for two months continuously. During the administration period, rats were observed for feeding, body weight, appearance and behavioral activity, and after two months, rats were sacrificed and subjected to a hematological and biochemical related index determination in parallel with systematic dissection and histopathological examination. The examination result shows that the rat has good condition, and the visceral organs and blood indexes have no obvious change, which shows that the dispersion has good safety performance.

3. Validity verification

In this example, the distribution content of mecobalamin in rat muscle tissue was determined by pharmacokinetic experiments, and SD rats were randomly divided into mecobalamin groups (0.2mg/mL, twice the dose of mecobalamin in example 1 and comparative example 1), example 1 group (100mg drug powder/mL), comparative example 1 group (100mg drug powder/mL), and each group was administered by gavage for 2mL at 8 am and 4 pm every day for one week. One week later, the rats were sacrificed by heart perfusion, and 1.0g of neck muscle was taken, homogenized with two times the volume of Tris buffer and tested by HPLC. The results are shown in table 2 below:

TABLE 2

Group of	Mecobalamin dosage (μ g/g)
		Mecobalamin group	0.42±0.01
Example 1	0.95±0.06
		Comparative example 1	0.55±0.03

As can be seen from the above data, although the administration dose of the mecobalamin group was significantly higher than that of the comparative examples and examples, the amount of the drug actually accumulated in the muscle was not high. In comparative example 1, mecobalamin powder was mixed directly with the mingren cervicodynia product, and the drug accumulation amount of mecobalamin in the neck muscle was higher than that of the mecobalamin administration group, which shows that the combination of mingren cervicodynia and mecobalamin can promote the distribution of mecobalamin components to muscle tissues. Example 1 optimizes the coating form of mecobalamin, further improves the accumulation amount of mecobalamin in muscles, and promotes the medicine to act on nerve tissues more fully, which means that the medicine combination preparation provided by the invention is helpful for the mecobalamin to play a role in nerve repair better.

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.