CN108403817B - Application of thoroughfare bitter orange, thoroughfare bitter orange extract and pharmaceutical composition containing thoroughfare bitter orange extract in maintaining pancreatic islet cell function - Google Patents
Application of thoroughfare bitter orange, thoroughfare bitter orange extract and pharmaceutical composition containing thoroughfare bitter orange extract in maintaining pancreatic islet cell function Download PDFInfo
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Abstract
The invention relates to the field of islet cell function treatment, in particular to the application of thoroughfare bitter orange, thoroughfare bitter orange extract and a pharmaceutical composition containing thoroughfare bitter orange or thoroughfare bitter orange extract in preparing medicaments for protecting islet cells, recovering the function of the islet cells, promoting the secretion of insulin or increasing the number of the islet cells. The invention develops new medical application of thoroughfare bitter orange creatively and develops a new application field. The thoroughfare bitter orange of the invention has the functions of protecting islet cells, promoting insulin secretion, recovering exhausted islet cells and increasing the number of islet cells, and has strong pharmacological action, safety and no toxicity. The product of the invention has rich raw material sources, low price, safety, no toxic or side effect, simple preparation process route and low production cost, can be prepared into conventional dosage forms such as oral dosage forms, tablets and the like, is convenient to use, and is an islet cell protective agent with very promising prospect and development value.
Description
Technical Field
The invention relates to the field of islet cell function treatment, in particular to the application of thoroughfare bitter orange, thoroughfare bitter orange extract and a pharmaceutical composition containing thoroughfare bitter orange or thoroughfare bitter orange extract in preparing medicaments for protecting islet cells, recovering the function of the islet cells, promoting the secretion of insulin or increasing the number of the islet cells.
Background
Diabetes Mellitus (DM) is a chronic endocrine and metabolic disease caused by genetic and environmental factors and is characterized by an increase in blood sugar level, and mainly includes three types, i.e., insulin-dependent Type1Diabetes Mellitus (T1 DM), non-insulin-dependent Type2Diabetes Mellitus (T2 Diabetes mellitis, T2DM) and Gestational Diabetes Mellitus (GDM). Wherein the incidence of T2DM accounts for more than 90% of the population with diabetes. It has been found that although insulin resistance is considered to be the most important factor in the progression of T2DM, the disease progresses more severely than the impairment of islet cell function.
The existing oral hypoglycemic agents mainly comprise sulfonylureas, glinides insulin secretagogues, glucosidase inhibitors, biguanides, thiazolidinediones insulin sensitizers and the like. The medicines capable of promoting insulin secretion are sulfonylurea medicines and glinide medicines, but the medicines have various adverse reactions, such as hypoglycemia, gastrointestinal tract reactions, cardiovascular risks and the like, and have poor curative effect on patients with complete damage of late islet cell functions.
At present, the literature report and the patent application of the mature grapefruit peel extract as a medicinal substance for treating diabetes and hyperlipidemia exist, but the curative effect is not good.
Therefore, the search for safe, effective and economical high-efficiency hypoglycemic drugs is urgent and needed.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provides the application of thoroughfare bitter orange, thoroughfare bitter orange extract and a pharmaceutical composition containing thoroughfare bitter orange or thoroughfare bitter orange extract in preparing medicaments for protecting islet cells, recovering the function of the islet cells, promoting the secretion of insulin or increasing the number of the islet cells. The invention uses thoroughfare bitter orange as an active ingredient and is used for treating pancreatic islet cell failure with remarkable curative effect.
In order to achieve the above objects, the present invention provides, in one aspect, an application of thoroughfare bitter orange and/or thoroughfare bitter orange extract in the preparation of a medicament for protecting islet cells, restoring islet cell function, promoting insulin secretion, or increasing the number of islet cells.
Preferably, the thoroughfare bitter orange extract is thoroughfare bitter orange alcohol extract prepared by heating reflux extraction.
Preferably, the thoroughfare bitter orange crushed product is soaked in an alcohol solvent for 0.5 to 2 hours before reflux extraction.
The second aspect of the present invention provides a pharmaceutical composition comprising thoroughfare bitter orange or thoroughfare bitter orange extract and a pharmaceutically acceptable carrier.
A third aspect of the present invention provides the use of a pharmaceutical composition as described above for the manufacture of a medicament for protecting islet cells, restoring islet cell function, promoting insulin secretion, or increasing the number of islet cells.
The invention develops new medical application of thoroughfare bitter orange creatively and develops a new application field. The thoroughfare bitter orange of the invention has the functions of protecting islet cells, promoting insulin secretion, recovering exhausted islet cells and increasing the number of islet cells, and has strong pharmacological action, safety and no toxicity. The product of the invention has rich raw material sources, low price, safety, no toxic or side effect, simple preparation process route and low production cost, can be prepared into conventional dosage forms such as oral dosage forms, tablets and the like, is convenient to use, and is an islet cell protective agent with very promising prospect and development value.
Drawings
FIG. 1 shows islet cell morphology (HE staining and immunohistochemistry) of db/db mice in the control, model, A1 low dose, and A1 high dose groups.
FIG. 2 shows the number of islet cells in db/db mice from the control, model, A1 low dose and A1 high dose groups.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
According to the first aspect of the present invention, there is provided the use of thoroughfare bitter orange and/or thoroughfare bitter orange extract in the manufacture of a medicament for protecting pancreatic islet cells, restoring pancreatic islet cell function, promoting insulin secretion or increasing the number of pancreatic islet cells.
Thoroughfare fructus aurantii, i.e. Hu shaddock slices, is dried immature fruit of Citrus changshan-huyou Y.B.Chang, which is a Rutaceae plant, is harvested when 7 months of pericarp is green, cut into two halves from the middle, and dried in the sun or at low temperature. Bitter, pungent and sour, slightly cold in nature, entering spleen and stomach meridians, with the effects of regulating qi, relieving epigastric distention, activating stagnancy and relieving flatulence, and can be used for treating qi stagnation in chest and hypochondrium, fullness and pain, indigestion, phlegm and fluid retention, gastroptosis, proctoptosis, and uterine prolapse. It was recorded in 2015 edition Zhejiang province Standard for processing Chinese herbs in 2016 (8 months). Wherein, the immature fruit of the grapefruit dichroa febrifuga is greatly different from the mature fruit and the component composition and content of the pericarp, thus leading to the difference of the effects.
It is known in the art that in type2diabetes, insulin resistance is expressed at the initial stage of onset, but as the onset progresses, the function of islet cells is depleted, resulting in insufficient insulin secretion. Therefore, the technical scheme of the invention is particularly suitable for treating type2diabetes, and can be used for restoring the functions of islet cells and increasing the secretion of insulin by repairing damaged islet cells and increasing the number of islet cells. However, it should be noted that the technical solution of the present invention is not only applicable to the treatment of type2diabetes, but also applicable to any related diseases and complications caused by damaged islet cells, functional failure, decreased insulin secretion amount and islet cell number.
According to the present invention, when the islet cell protective agent is prepared by directly taking thoroughfare bitter orange, thoroughfare bitter orange can be directly ground into thoroughfare bitter orange powder for taking, and the granularity of thoroughfare bitter orange powder is not particularly limited as long as the thoroughfare bitter orange powder can be easily taken by a patient. In addition, the thoroughfare bitter orange powder can also be taken together with other food materials or medicinal materials.
According to the present invention, when the islet cell protective agent is used as a thoroughfare type fructus aurantii extract, preparation of the thoroughfare type fructus aurantii extract can be performed by various methods known in the art, for example, the thoroughfare type fructus aurantii can be prepared by brewing and extracting in a manner of replacing a tea bag, can be prepared by brewing and extracting with wine as a solvent, can be prepared by decocting with water and decocting with water, and can also be prepared by extracting in a manner of heating and refluxing, an ultrasonic extraction manner, a supercritical fluid extraction method, a macroporous resin adsorption method, and the like.
According to the invention, the thoroughfare bitter orange extract can be an alcohol extract of thoroughfare bitter orange and can also be water extract of thoroughfare bitter orange. Among them, the alcohol is preferably ethanol.
According to a preferred embodiment of the present invention, the thoroughfare bitter orange extract is a thoroughfare bitter orange alcohol extract prepared by heating reflux extraction, and the extraction method comprises:
(1) pulverizing thoroughfare fructus Aurantii decoction pieces, and reflux-extracting with alcohol solvent to obtain extractive solution;
(2) carrying out solid-liquid separation on the extracting solution, and recovering an alcohol solvent to obtain a concentrated solution;
(3) drying the concentrated solution to obtain the thoroughfare bitter orange extract.
According to the present invention, in the step (1), the particle size of the thoroughfare bitter orange pulverized product can be selected within a wide range.
Wherein, the dosage of the alcoholic solvent can be selected in a wide range, preferably, the dosage of the alcoholic solvent is 10 to 20 times, more preferably 12 to 18 times, even more preferably 14 to 16 times, and most preferably 15 times relative to each kilogram of thoroughfare bitter orange.
Also, the concentration of the alcohol solvent is not particularly limited, and it is preferable to use a high concentration of the alcohol solvent, for example, 70 to 90% by weight, more preferably 75 to 85% by weight, and most preferably 80% by weight.
The heating reflux condition can be selected in a wide range, preferably, the heating reflux temperature is 50-90 ℃ and the time is 0.5-6 hours, more preferably, the reflux temperature is 60-80 ℃ and the time is 1-3 hours, most preferably, the reflux temperature is 70 ℃ and the time is 2 hours.
According to a preferred embodiment of the present invention, in order to further improve the extraction efficiency and the content of active substances in the extract, the method further comprises immersing the thoroughfare bitter orange crushed product in an alcohol solvent for 0.5 to 2 hours before the heating reflux extraction.
Further preferably, in order to further enhance the extraction efficiency, the heating reflux extraction may be performed in a plurality of times, for example, 2 times, 3 times, 4 times, 5 times, etc., and then the extract liquids extracted each time are combined to be the final extract liquid. The skilled person can select the extraction effect according to the actual extraction effect, as long as the total time of the reflux extraction is controlled within the above range, and each extraction can be performed in equal time.
According to the present invention, in the step (2), the method of subjecting the extract to solid-liquid separation may be various methods conventional in the art, for example, filtration, centrifugation and the like, as long as the solid residue in the extract can be sufficiently removed. The conditions for the solid-liquid separation can be appropriately selected by those skilled in the art according to the desired solid content of the filtrate.
Wherein the solid-liquid separation can be carried out at normal temperature.
According to the present invention, the method for recovering the alcohol solvent from the filtrate in the step (2) may be performed according to various methods known in the art, for example, a freezing condensation method, etc.
According to the present invention, in the step (3), the drying method of the concentrated solution may be performed according to various methods known in the art, for example, a freeze-drying method, a spray-drying method, and the like.
In a second aspect of the present invention, a pharmaceutical composition is provided, which comprises a thoroughfare bitter orange or thoroughfare bitter orange extract and a pharmaceutically acceptable carrier.
According to the present invention, the pharmaceutical composition may further comprise an additional drug, which may be a drug for treating diabetes, such as sulfonylurea, glinide insulinotropic agent, glucosidase inhibitor, biguanide drug, thiazolidinedione type islet, etc., and may also be a drug for treating other complications due to diabetes.
In addition, the pharmaceutically acceptable carrier may be a carrier commonly used in the pharmaceutical field for preparing various dosage forms, for example, a pharmaceutically acceptable adjuvant, preservative or stabilizer. The kind and content of adjuvant, preservative or stabilizer are well known to those skilled in the art, and will not be described herein.
According to the present invention, the pharmaceutical composition may be prepared in various dosage forms, for example, may be prepared as, but not limited to, tablets, capsules (including soft and hard capsules), oral liquids, granules, pills or injections.
In a third aspect of the invention, the application of the pharmaceutical composition as described above in preparing a medicament for protecting islet cells, restoring the function of islet cells, promoting insulin secretion or increasing the number of islet cells is also provided.
According to the present invention, when used for protecting islet cells, restoring islet cell function, promoting insulin secretion or increasing the number of islet cells, the thoroughfare bitter orange or thoroughfare bitter orange extract can be administered in a dosage of 0.1-0.3g per kg body weight per day, or can be administered in multiple doses.
The present invention will be described in detail below by way of examples. In the following examples of the present invention,
1. materials and reagents
Thoroughfare bitter orange: provided and identified by traditional Chinese medicine Limited in south pore of Quzhou.
A blood sugar detection kit: purchased from dessely diagnostics system (shanghai) limited.
Insulin ELISA detection kit: purchased from Invitrogen, usa.
Insulin (Insulin) primary antibody: purchased from CST corporation, usa.
Secondary antibody: purchased from CST corporation, usa.
Metformin (glyburide): purchased from Shanghai Shigui pharmaceutical Co., Ltd, of China and America.
2 laboratory animals
Male spontaneous type2diabetes C57BLKS/J db/db mice (db/db mice), Stock No:000642, 7-8 weeks old, body weight 30-40 g; the same genetic background C57BLKS/J db wild type mouse (db/m), 7-8 weeks old, weight 18-22g, the above animals purchased from Nanjing university-Nanjing biomedical research institute, animal production license number: SYXK (threo) 2015-0001. The feed is raised in the animal experiment center of Zhejiang university of traditional Chinese medicine, and free to eat and drink water. The animal experiments were approved by the medical ethics committee of the people's hospital in Quzhou City.
Preparation example
Preparation example 1
The preparation example is used for explaining the preparation of thoroughfare bitter orange alcohol extract
Weighing 1kg of thoroughfare bitter orange medicinal material, cleaning, crushing, adding 15 times of 80% ethanol (15000mL), soaking for 1h, heating and refluxing for 3 times, each time for 2h, combining extracting solutions, cooling and filtering, recovering a solvent from the filtrate, and drying to obtain the thoroughfare bitter orange alcohol extract (A1).
Preparation example 2
The preparation example is used for explaining the preparation of thoroughfare bitter orange water extract
Weighing 1kg of thoroughfare fructus aurantii medicinal material, cleaning, crushing, adding 15 times of water, soaking for 1h, heating and refluxing for extraction for 3 times, 2h each time, combining the extracting solutions, cooling, filtering, concentrating and drying to obtain thoroughfare fructus aurantii water extract (A2).
Comparative example preparation example 1
This comparative preparation example is illustrative of the preparation of alcohol extract of ripe grapefruit
The preparation of alcohol extract of ripe grapefruit (D1) was carried out in accordance with the method of preparation example 1, except that the thoroughfare bitter orange was replaced with an equal amount of ripe grapefruit.
Comparative example preparation example 2
This comparative preparation example is intended to illustrate the preparation of an alcohol extract of ripe citrus grandis peel
Alcohol extraction of mature citrus grandis peel (D2) was carried out in the same manner as in preparation example 1, except that the thoroughfare bitter orange was replaced with an equal amount of mature citrus grandis peel.
Examples
1. Animal grouping and administration
63 spontaneous type2 diabetic mice (db/db mice), 7-8 weeks old, after being acclimatized for one week, were randomly divided into 7 groups of 9 mice each:
a model negative control group, wherein distilled water is used for intragastric administration;
a model positive control group is subjected to intragastric gavage by 150mg/kg/d of metformin;
a1 Low dose group, gavage at 100 mg/kg/d;
a1 high dose group, gavage at 300 mg/kg/d;
a2 high dose group, gavage at 300 mg/kg/d;
d1 high dose group, gavage at 300 mg/kg/D;
d2 high dose group, gavage at 300 mg/kg/D;
another 9 wild-type mice (db/m mice) were used as normal control groups.
All mice were fed water on a normal diet for 6 weeks.
2. Blood sugar and insulin determination
After 1h of the last administration, the mice are anesthetized by pentobarbital sodium, blood is collected from abdominal aorta, serum is separated, the blood glucose level (FBG) of each group of mice is determined by adopting a blood glucose detection kit, and the average value is taken for each group; serum insulin levels (FINS) of mice in each group were measured using an insulin ELISA test kit, and the results are averaged for each group and are shown in table 1.
3. Observation of pancreatic histopathology
Pancreatic tissues were taken, fixed with 10% formalin, sectioned by conventional paraffin embedding, and observed under HE staining at 400-fold microscope, wherein HE staining patterns of the model negative control group, the a1 low dose group, the a1 high dose group, and the normal control group are shown in fig. 1.
4. Immunohistochemical staining of pancreatic tissue
Dewaxing the paraffin-embedded section according to the sequence of xylene, absolute ethyl alcohol, 90% ethyl alcohol, 80% ethyl alcohol and 70% ethyl alcohol; then carrying out antigen retrieval in an ammonium citrate buffer solution for 15min, and washing for 3 times with PBS (phosphate buffer solution), wherein each time is 3 min; inactivating peroxidase in 3% hydrogen peroxide for 10min, and washing with PBS for 3 times, each for 3 min; sealing goat serum for 1h, and adding insulin-primary antibody at 4 deg.C overnight. Washing with PBS for 3 times, 3min each time, incubating with secondary antibody at room temperature for 15min, adding DBA for staining for 3min, staining with hematoxylin, dehydrating, and sealing. The number of islet cells was observed and recorded under microscope, and at least 5 islet cells in 100-fold mirror field were counted, wherein immunohistochemical staining patterns of model negative control group, a1 low dose group, a1 high dose group and normal control group are shown in fig. 2.
5. Data processing
All data were processed using SPSS 17.0 statistical software, data are expressed as mean. + -. standard deviation (x. + -. SD), and differences between groups were examined by ANOVA and pairwise comparisons were made using the least significant difference test, statistically significant when P < 0.05.
6. Results
(1) Effect on blood glucose and serum insulin levels in db/db mice
TABLE 1
| Group of | FBG(mmol/L) | FINS(pmol/L) |
| Normal control group | 9.47 | 99.43 |
| Model negative control group | 32.02 | 74.07 |
| Model positive control group | 25.54 | 75.32 |
| A1 Low dose group | 29.82 | 85.36 |
| A1 high dose group | 28.7 | 86.74 |
| A2 high dose group | 30.01 | 80.29 |
| D1 high dose group | 30.91 | 76.23 |
| D2 high dose group | 30.41 | 77.67 |
As shown in the results in table 1, compared with the normal control group, the blood sugar level of the mice in the model negative control group is obviously increased, and the serum insulin level is obviously reduced; compared with a model negative control group, the thoroughfare bitter orange and the water extract and the alcohol extract thereof can obviously reduce the blood sugar level of db/db mice and increase the insulin level, and have a certain dose dependence relationship, and particularly have obvious effects in an A1 group, particularly an A1 high dose group. In contrast, extracts from the ripe fruit (D1) and pericarp (D2) of grapefruit showed some downward trend in blood glucose levels in db/db mice, but did not show significant effects in increasing insulin levels.
(2) Influence on islet cell morphology and number in db/db mice.
As shown in the results of fig. 1 and fig. 2, the normal control group mice had intact islet structure, approximately circular or elliptical shape, larger size, clear boundary, and larger number of islet cells; the islet cells of the model negative control group are irregular broken bands, are arranged loosely, have unclear boundaries, and have fewer islet cells than the normal control group; compared with the model negative control group, the mouse islet cells of the A1 low-dose group and the A1 high-dose group are large in size, large in quantity, clear in boundary and in a certain circular structure. In contrast, the water extraction of thoroughfare bitter orange (a2 high dose group) also had the same effect, but the effect was worse than that of the a1 high and low dose group (results not shown), while the improvement effect of the D1-D2 high dose group (extract of mature fruit and pericarp of grapefruit) was not significant (results not shown).
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (5)
1. The application of the islet cell protective agent in preparing a medicament for protecting islet cells, recovering the function of the islet cells, promoting the secretion of insulin or increasing the number of the islet cells in the treatment of type2 diabetes; wherein the islet cell protective agent is a thoroughfare bitter orange water extract.
2. The application of the islet cell protective agent in preparing a medicament for protecting islet cells, recovering the function of the islet cells, promoting the secretion of insulin or increasing the number of the islet cells in the treatment of type2 diabetes; wherein the islet cell protective agent is an ethanol extract of thoroughfare bitter orange;
wherein the ethanol extract of thoroughfare fructus aurantii is prepared by heating reflux extraction, and the extraction method comprises the following steps:
(1) pulverizing fructus Aurantii, and extracting with ethanol under reflux to obtain extractive solution;
(2) carrying out solid-liquid separation on the extracting solution, and recovering an ethanol solvent to obtain a concentrated solution;
(3) drying the concentrated solution to obtain the ethanol extract of the thoroughfare bitter orange;
wherein, the dosage of the ethanol solvent is 10 to 20 times of that of per kilogram of thoroughfare bitter orange;
wherein the concentration of the ethanol solvent is 70-90 wt%;
wherein, in the step (1), the thoroughfare bitter orange crushed product is soaked in an ethanol solvent for 0.5 to 2 hours before reflux extraction.
3. A pharmaceutical composition for protecting islet cells, restoring islet cell function, promoting insulin secretion, or increasing the number of islet cells, comprising the ethanol extract of claim 2, and a pharmaceutically acceptable carrier.
4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a tablet, a capsule, an oral liquid, a granule, a pill or an injection.
5. Use of a pharmaceutical composition according to claim 3 or 4 for the preparation of a medicament for protecting islet cells, restoring islet cell function, promoting insulin secretion, or increasing the number of islet cells in the treatment of type2 diabetes.
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Non-Patent Citations (3)
| Title |
|---|
| Hypoglycemic and hypolipidemic effects of neohesperidin derived from Citrus aurantium L. in diabetic KK-Ay mice;Sheng Jia等;《Food & Function》;20151231;第878-886页，尤其是第878页摘要，第879页左栏第3段，第881页图1 * |
| 刘春荣等.常山胡柚小青果乙醇提取物的黄酮类物质含量及抗氧化活性测定.《中国南方果树》.2015,第44卷(第4期),第41-44页，尤其是第41页摘要，第42页左栏第2段、右栏倒数第1段，第43页左栏第1段. * |
| 常山胡柚小青果乙醇提取物的黄酮类物质含量及抗氧化活性测定;刘春荣等;《中国南方果树》;20151231;第44卷(第4期);第41-44页，尤其是第41页摘要，第42页左栏第2段、右栏倒数第1段，第43页左栏第1段 * |
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