阅读说明：本技术 一种含艾纳香总黄酮提取物的药物组合物 (A pharmaceutical composition containing total flavonoids of herba Blumeae Balsamiferae ) 是由 冯贻东 宝艳儒 王丽丽 汪琛 曾伟珍 于 2020-12-07 设计创作，主要内容包括：本发明公开了一种含艾纳香总黄酮提取物的药物组合物。所述的药物组合物中,艾纳香总黄酮提取物与冰片的重量比为1:9～9:1,优选重量比为3:7～5:5。可以根据该组分比例视制剂和使用的需要确定单位剂型,包括但不限于每支、每片、每粒、每瓶、每毫升、每十毫升、每掀等中的活性成分化合物的含量。本发明还公开了以艾纳香总黄酮提取物的药物组合物为药效成分,添加药学上可以接受的药用辅料,或添加其他医学上必须的辅助类有效成分(中药、草药、化学药物、生物药等),并通过本领域的常规方法制备的组合物及其在制备治疗阿尔兹海默病药物中的用途。(The invention discloses a pharmaceutical composition containing a blumea balsamifera total flavone extract. In the pharmaceutical composition, the weight ratio of the blumea balsamifera total flavone extract to the borneol is 1: 9-9: 1, and the preferable weight ratio is 3: 7-5: 5. The unit dosage form may be determined according to the ratio of the components as desired for the formulation and use, including but not limited to the amount of active ingredient compound per tube, tablet, granule, bottle, milliliter, ten milliliters, liter, or the like. The invention also discloses a pharmaceutical composition which takes the total flavonoids extract of the blumea balsamifera as the active ingredient, and is added with pharmaceutically acceptable pharmaceutical excipients or other medically necessary auxiliary active ingredients (traditional Chinese medicines, herbal medicines, chemical medicines, biological medicines and the like), and the composition prepared by the conventional method in the field and the application thereof in preparing the medicine for treating the Alzheimer disease.)

1. A pharmaceutical composition containing blumea balsamifera total flavone extract is characterized in that the weight ratio of the blumea balsamifera total flavone extract to borneol is as follows: 1: 9-9: 1.

2. The pharmaceutical composition containing blumea balsamifera total flavone extract as claimed in claim 1, wherein the weight ratio of blumea balsamifera total flavone extract to borneol is as follows: 3: 7-5: 5.

3. The use of the pharmaceutical composition containing total flavonoid extract of blumea balsamifera according to claim 1 or 2 for the preparation of a medicament for treating alzheimer's disease.

4. A pharmaceutical composition, which is characterized by comprising the pharmaceutical composition containing the blumea balsamifera total flavone extract of claim 1 or 2 and pharmaceutically acceptable auxiliary materials.

5. A pharmaceutical composition comprising the total flavonoid extract of blumea balsamifera according to claim 1 or 2 and other pharmaceutically necessary auxiliary active ingredients.

6. The use of the pharmaceutical composition containing total flavonoid extract of blumea balsamifera according to claim 4 for preparing a medicament for treating alzheimer's disease.

7. The use of the pharmaceutical composition containing total flavonoid extract of blumea balsamifera according to claim 5 for preparing a medicament for treating alzheimer's disease.

Technical Field

The invention relates to a medicinal composition of a blumea balsamifera total flavone extract and borneol and application thereof in preparing a medicament for treating Alzheimer disease.

Background

Senile dementia, also known as Alzheimer's Disease (AD), is a nervous system degenerative disease which is centered on acquired cognitive function impairment and leads to significant decline of patients' daily life, social interaction and working ability. Cognitive dysfunction is a major feature of senile dementia. According to the statistics of the World Health Organization (WHO), 4750 thousands of dementia patients exist in 2016 world, and the total number of dementia patients reaches 7560 thousands in 2030 and reaches 1.355 billion in 2050. The social cost is almost equal to the sum of the social costs of 3 diseases such as cancer, heart disease and cerebral apoplexy. Senile dementia not only seriously affects the life quality of patients, but also brings heavy burden to caregivers and society. At present, no effective therapeutic drug [ introduced from agricultural Fangqing, Chen Guoing, Xixing, Liushu instrument, Li pioneer, Pandayan, Alzheimer's disease non-drug treatment research progress [ J ]. nursing research, 2020,34(20):3669 one-step 3673 ]

Although the exact pathogenesis of senile dementia is not completely studied, the currently accepted etiology hypothesis can be broadly divided into the following, i.e., excessive deposition of beta amyloid protein (a β) due to dysregulation of BACE1 metabolic pathway, abnormal phosphorylation of tau protein, inflammatory response, neuronal apoptosis and oxidative stress. Aiming at the above causes, the chemical drugs for clinically treating senile dementia are mainly divided into cholinesterase inhibitors, NMDA receptor antagonists, antioxidant drugs, neurotrophic drugs, immunotherapy drugs and the like. The traditional Chinese medicine has unique cognition on senile dementia and a large amount of medicines are applied to clinic, wherein the medicines are introduced from Pingyang, Liying Peng, Zhuting, Guan\33534g, Rubia, Lv Shao Wa and Li Yongji. However, despite various treatment modes, the therapeutic effect of the medicine for treating senile dementia still has a great space for improvement, and research on the medicine for treating senile dementia is one of the hot research and development areas of the medicine for a long time.

Borneol is a rare Chinese traditional medicine in China, is mainly divided into natural borneol and synthetic borneol, is considered by traditional Chinese medicine to have the effects of refreshing, restoring consciousness, inducing resuscitation with aromatics and the like, and is mostly applied to prevention and treatment of cardiovascular and cerebrovascular diseases. Borneolum has protective effect on central nervous system. Modern pharmacological studies show that [10] borneol can prolong the sleep time of mice under the action of phenobarbital sodium and can also shorten the sleep time of mice under the action of pentobarbital sodium, so that borneol can regulate excitation and inhibition of central nerves and is helpful for maintaining normal CNS. [ Yinyangshangkun, Lijing, Changmei, Sun Yunlong, Biyingying, Zhang Xin, borneol chemical composition and pharmacological action research [ J ] Jilin traditional Chinese medicine, 2018,38(01):93-95 ]

Chinese patent application No.: CN02134927.4, entitled "blumea balsamifera total flavone extract and extraction method and pharmaceutical application" shows that the blumea balsamifera total flavone extract has the function of improving myocardial ischemia.

The research aiming at the combined use of the blumea balsamifera total flavone extract and borneol for treating the Alzheimer disease is not reported.

Disclosure of Invention

The invention aims to provide a pharmaceutical composition of a blumea balsamifera total flavone extract and borneol.

The invention also provides application of the pharmaceutical composition of the blumea balsamifera total flavone extract and borneol in preparing a medicament for treating alzheimer disease.

The third objective of the present invention is to provide a pharmaceutical composition prepared by using a pharmaceutical composition of total flavonoids of blumea balsamifera and borneol as a pharmaceutical ingredient, adding pharmaceutically acceptable pharmaceutical excipients, or adding other medically necessary auxiliary active ingredients (traditional Chinese medicines, herbal medicines, chemical medicines, biological medicines, etc.), and by using a conventional method in the field, and a use thereof in preparing a medicament for treating alzheimer disease.

In the pharmaceutical composition of the blumea balsamifera total flavone extract and the borneol, the weight ratio of the blumea balsamifera total flavone extract to the borneol is 1: 9-9: 1, and the preferable weight ratio is 3: 7-5: 5. The amount of active ingredient compound in a unit dosage form (including, but not limited to, per tube, tablet, granule, bottle, milliliter, liter, etc.) can be determined by one skilled in the art depending on the formulation and application requirements based on the ratio.

When the pharmaceutical composition of the blumea balsamifera total flavone extract and borneol is prepared into a pharmaceutical preparation, the dosage form of the pharmaceutical preparation is a preparation for injection administration or oral administration or inhalation administration (including but not limited to injection water injection, injection freeze-dried powder, injection emulsion, injection suspension, liposome injection, microsphere injection, nanoparticle injection, depot controlled release injection, gel injection and the like; in the aspects of injection devices and packaging, single-dose/multi-dose needle-free injection, powder injector, pre-filled injection, powder/liquid pre-mixed injection, hypodermic injection and the like; including but not limited to tablets, oral liquid, powder, granules, pills, sustained release oral dosage forms and the like; and inhalation preparations including but not limited to sprays, powder aerosols, atomized therapeutic dosage forms, dry powder for inhalation and the like).

The medicinal auxiliary materials used for preparing the medicinal preparation comprise an aqueous solvent, a non-aqueous solvent and an additive used for the preparation, an additive for increasing the solubility of the main medicament, an additive for assisting the suspension or emulsification of the main medicament, an additive for preventing the oxidation of the main medicament, an additive for adjusting the pH value, an additive for inhibiting the propagation of microorganisms, an additive for relieving pain and the like.

The invention has simple components, high safety, convenient use and strong clinical implementation feasibility, and has strong social significance and economic benefit.

Example 1 shows that the synergistic effect result of the combined use of the blumea balsamifera total flavone extract and borneol in the treatment of Alzheimer's disease shows that the blumea balsamifera extract or borneol used alone does not show obvious anti-Alzheimer's disease treatment effect, but the anti-Alzheimer's disease effect is obviously increased after the combined use of the blumea balsamifera extract and borneol.

Example 2 shows that the treatment effect on Alzheimer's disease under different weight ratios and different dosages of the total flavonoids extract of blumea balsamifera and borneol is respectively examined, and the optimal combination ratio is found. The result shows that when the weight ratio of the extract to the borneol is 3: 7-5: 5, the treatment effect of the composition on the Alzheimer disease is optimal, an ideal treatment effect can be achieved when the dosage of the composition is 25mg/kg, and the effect is not remarkably improved when the dosage is increased to 50 mg/kg.

Example 3 shows that differences in therapeutic effects of natural borneol and synthetic borneol in the pharmaceutical compositions are examined respectively. The results show that the difference of the biological effects of the natural borneol and the synthetic borneol used in the pharmaceutical composition is not obvious, and the results suggest that the more easily obtained synthetic borneol can be used for replacing the valuable natural borneol in the future clinical medication and batch production.

The research shows that the pharmaceutical composition of the total flavonoids extract of blumea balsamifera and borneol has significant clinical treatment potential for treating Alzheimer's disease and has beneficial clinical application value in the preparation of the medicine.

The invention will be explained in more detail below with reference to the drawings and examples.

Drawings

FIG. 1 is a graph showing the synergistic effect of the total flavonoids of blumea balsamifera and borneol.

FIG. 2 is a graph showing the therapeutic effect of total flavonoids of blumea balsamifera and borneol in different weight ratios and different dosages.

FIG. 3 is a graph showing the therapeutic effects of the composition containing natural borneol and synthetic borneol.

Detailed Description

The technical solution of the present invention will be further described with reference to some examples, which should not be construed as limiting the invention in any way.

The total flavonoids from blumea balsamifera used in the following examples were prepared according to the chinese patent application No.: CN02134927.4, entitled "blumea balsamifera total flavone extract and extraction method and pharmaceutical application" method.

The materials and reagents used in the following examples are as follows:

experimental animals: male Kunming mice, weighing 18-22 g, were purchased from Beijing Wittiulihua laboratory animals technologies, Inc.

Drugs and reagents: blumea balsamifera medicinal materials purchased from a medicinal material business network; natural borneol, batch No.: CHB160406, chengdu cloma biotechnology limited; synthetic borneol, batch No.: CHB150916, gendar crama biotechnology limited. Scopolamine, batch K26208347912, Merck.

The preparation method of the medicine comprises the following steps: mixing the total flavone extract of herba Blumeae Balsamiferae and Borneolum Syntheticum, grinding with 10% CMC-Na solution, suspending, mixing, and administering.

And (4) counting results: results are expressed as Mean ± SD, and data analysis between groups was performed using one-way ANOVA and comparison between groups.

Example 1

The purpose is as follows:

this example examines the synergistic effect of the total flavonoids of blumea balsamifera extract in combination with borneol.

The method comprises the following steps:

the method is adopted to carry out the sand promotion and qualified training of animals by using the method in [ Li bin, Shexing shui ling, Pengli swallow, Wangfei, Yang Kun, Wuwen Bin ] 3 dementia-simulating animal models for learning the difference of memory behavior in Morris water maze behavioural test [ J ]. medical research student's report, 2014,27(07):683-685 ] and [ Li Xiaoyu, Qianxiu, Sunjing-Xionggui decoction effective component for resisting the hypomnesis of the scopolamine-induced dementia model-learning memory-effect relationship research [ J ]. the pharmacology and clinic of traditional Chinese medicines, 2015,31(06):124-128 ]. After the qualified animals are dosed, models of senile dementia are made by the method of scopolamine in the above reference, and the dosing effect is tested by examining the retention time of the effective area by the water maze method. The specific administration mode and the administration time are as follows:

note: the normal control group and the model control group are given blank solvent (10% sodium carboxymethyl cellulose solution) without medicine with the same volume; the medicament is administered by adopting natural borneol.

The results are shown in FIG. 1:

the experimental results show that the retention time of the model control group in the effective region is obviously reduced after the scopolamine is used for intraperitoneal injection, and meanwhile, the retention time of the animal using the extract or borneol alone is slightly improved, but the difference is not statistically significant compared with the model control group.

The dosages of the extract and the borneol are kept unchanged, but after the extract and the borneol are mixed and administered simultaneously, the retention time of the animals after the scopolamine administration is obviously improved compared with that of a model control group, although a certain difference is still formed between the animals and a normal control group, the difference from the animal and the model group has statistical significance, and the increase range is large.

Compared with the single extract or borneol group, the combined medicine group has obvious treatment advantages.

Example 2

The purpose is as follows:

this example examines the therapeutic effect of the total flavonoids of blumea balsamifera extract and borneol in different weight ratios and different dosages.

The method comprises the following steps:

the total flavonoids of blumea balsamifera and natural borneol are mixed according to different weight proportions, and are administrated by different dosages, and the administration mode, administration frequency and administration duration and the test and evaluation method in the example 1 are considered. The specific dosage and the proportion are as follows:

the medicines with different proportions are continuously administrated by intragastric administration for 28 days, and the water maze is utilized to measure the treatment effect of the medicines. The results are shown in FIG. 2:

the results show that when the proportion of extract or borneol is too low, the residence time of the animals in the active area is not very different compared to the model group in example 1. When the weight ratio of the extract to the borneol is 3: 7-5: 5, the therapeutic effect of the composition on the Alzheimer disease is optimal, an ideal therapeutic effect can be achieved when the dosage of the composition is 25mg/kg, and the effect is not remarkably improved when the dosage is increased to 50 mg/kg.

Example 3

The purpose is as follows:

this example examines the difference in therapeutic effect between the use of natural borneol and synthetic borneol in the composition.

The method comprises the following steps:

the extract and borneol are mixed according to the weight ratio of 3:7, and the total dose after mixing is 25mg/kg, and the effective area residence time is measured according to the measuring methods of the administration mode, the administration frequency, the administration time and the data effect of the embodiment 1 and the embodiment 2.

The results are shown in FIG. 3:

the results show that the influence of natural borneol and synthetic borneol on the residence time of rats in the effective area in the composition is not significantly different.

Therefore, in the future clinical application, the synthetic borneol with relatively low cost can be selected according to the control of the cost or the protection of natural medicinal materials, and the treatment effect on AD cannot be reduced.