A traditional Chinese medicine composition for treating diabetic gastroparesis and its preparation method

Abstract

This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a traditional Chinese medicine composition for treating diabetic gastroparesis. The composition is prepared through the following steps: silkworm excrement is added to water and extracted in a water bath at 35℃-55℃ to form a mixture; the mixture is centrifuged, and the supernatant is concentrated, or filtered, and the filtrate is concentrated; the concentrated solution is used to prepare orally disintegrating tablets. The traditional Chinese medicine composition of this invention is used to treat symptoms such as vomiting, nausea, early satiety, upper abdominal distension, and reduced food intake caused by diabetic gastroparesis. The traditional Chinese medicine composition of this invention has good efficacy in treating diabetic gastroparesis, with no toxic side effects and is safe and reliable; furthermore, the silkworm excrement extract is made into orally disintegrating tablets, which are convenient to carry and take.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, and in particular relates to a traditional Chinese medicine composition and preparation method for treating diabetic gastroparesis. Background Technology

[0002] Diabetic gastroparesis is a condition caused by abnormal gastric emptying due to diabetes, leading to symptoms such as vomiting, nausea, early satiety, upper abdominal distension, and reduced food intake. It is very common clinically, affecting 40%-75% of diabetic patients, with 10% experiencing significant symptoms. Clinical treatment outcomes are often unsatisfactory, severely reducing the quality of life for diabetic patients. Currently, Western medicine treatments often utilize prokinetic drugs such as metoclopramide, domperidone, erythromycin, cisapride, and mosapride, which have shown some clinical efficacy. Traditional Chinese medicine (TCM) treatments, primarily through syndrome differentiation and oral herbal remedies, have achieved good results in treating diabetic gastroparesis. Some practitioners have also utilized non-pharmacological treatments such as endoscopy, gastric electrical stimulation, and acupuncture, which have also yielded some clinical efficacy.

[0003] However, treatment with both traditional Chinese and Western medicine has drawbacks, including the risk of drug resistance with long-term use, drug toxicity and side effects, poor patient tolerance, and high economic costs. Furthermore, the diverse classifications and treatment methods for diabetic gastroparesis make it difficult to establish a unified treatment plan and efficacy standards. While non-pharmacological treatments such as endoscopic therapy, gastric electrical stimulation, and acupuncture have shown some clinical efficacy, these methods are technically challenging, invasive, and difficult for patients to accept, and are also expensive, thus limiting their widespread clinical application. Summary of the Invention

[0004] In view of this, the present invention provides a method for preparing a traditional Chinese medicine composition for treating diabetic gastroparesis, the preparation method comprising the following steps:

[0005] Weigh out the late silkworm excrement, add water, and extract it in a water bath at 35℃-55℃ to form a mixture;

[0006] Centrifuge the mixture and concentrate the supernatant; or filter the mixture and concentrate the filtrate.

[0007] Alternatively, the concentration method may be evaporation concentration, dialysis concentration, or ultrafiltration concentration to obtain a concentrated solution with a concentration of 15%-25%.

[0008] Further optionally, the preparation method further includes the following steps: injecting the concentrated liquid into an aluminum trough, wherein the concentrated liquid may or may not contain excipients for preparing orally disintegrating tablets, pre-freezing the concentrated liquid, and freeze-drying to form orally disintegrating tablets.

[0009] Further, optionally, the preparation method includes the following steps:

[0010] Take late-maturing silkworm excrement, dry it in an oven, and grind it into powder using a pulverizer;

[0011] Weigh out late silkworm excrement powder, add water, and extract in a water bath at 35℃-55℃ to form a mixture;

[0012] Centrifuge the mixture and collect the supernatant to obtain a concentrated solution by evaporation.

[0013] The concentrated solution was injected into an aluminum trough, pre-frozen, and freeze-dried to form orally disintegrating tablets.

[0014] Further, optionally, the preparation method includes the following steps:

[0015] Take late-stage silkworm excrement, dry it in an oven at 50℃-70℃, and then grind it into powder using a high-speed pulverizer;

[0016] Weigh out the late-stage silkworm excrement powder, add 2-3 times the amount of distilled water per kg / L, and extract in a water bath at 35℃-55℃.

[0017] Forming a mixture;

[0018] The mixture was centrifuged, and the supernatant was concentrated using a vacuum rotary evaporator to obtain a concentrated solution.

[0019] The concentrated solution was injected into an aluminum trough, pre-frozen, and freeze-dried to form orally disintegrating tablets.

[0020] Further, optionally, the preparation method includes the following steps:

[0021] Take late-stage silkworm excrement, dry it in a 60℃ oven, and grind it into powder using a high-speed pulverizer;

[0022] Weigh out late silkworm excrement powder, add 2.5 times the amount of distilled water, and extract in a water bath at 45°C to form a mixture; centrifuge the mixture at 10000 r / min, and concentrate the supernatant by vacuum rotary evaporator to obtain a concentrated solution;

[0023] The concentrated solution was injected into an aluminum trough, pre-frozen at -60℃, and freeze-dried to form orally disintegrating tablets.

[0024] This invention provides a traditional Chinese medicine composition prepared by the above-described method.

[0025] This invention provides the application of the above-mentioned traditional Chinese medicine composition in the preparation of a drug for treating diabetic gastroparesis.

[0026] Further optionally, the symptoms of diabetic gastroparesis include vomiting, nausea, early satiety, upper abdominal distension, and reduced food intake, and the Chinese medicine composition is administered sublingually.

[0027] The medicinal material used in this invention, late-maturing silkworm excrement, also known as raw silkworm excrement, is a general term for the solid feces excreted by silkworm larvae, leftover mulberry leaves, disinfectant for silkworm bodies, and bedding material in the silkworm rearing process. Late-maturing silkworm excrement has a long history of medicinal use, first recorded in the *Mingyi Bielu* (Records of Famous Physicians), and is the dried excrement of the larvae of the silkworm moth (Bombyx mori L.). It is collected in summer during the second to third molting stages, impurities are removed, and it is dried. Jiangsu and Zhejiang provinces have the highest production of this material.

[0028] Silkworm excrement is a typical fecal-based traditional Chinese medicine containing a large number of microorganisms. Although most of these microorganisms are killed after processing, their metabolic products still remain, which can have positive or negative effects on the growth and reproduction of intestinal microorganisms. Existing research shows that the occurrence and development of diabetic gastroparesis is related to the gut microbiota. Gut microbiota imbalance leads to the release of bacterial endotoxins, causing the body to be in a state of chronic inflammation. Chronic inflammation can cause insulin resistance, eventually leading to diabetes and its complication, diabetic gastroparesis. Therefore, regulating the gut microbiota is beneficial for improving patients' blood lipids, blood sugar, and insulin resistance. Improving the gut microecological environment and adjusting the level of inflammatory factors is a new research direction for the prevention and treatment of diabetic gastroparesis. Existing studies have shown that taking silkworm excrement can balance the gut microbiota in rats, regulate the gut microecology, and improve the pathological state of "dampness obstructing the middle jiao". Late-maturing silkworm excrement is a multi-component substance rich in crude protein and carbohydrates. Dried late-maturing silkworm excrement contains 15.4% crude protein, 3.88% crude fat, 36.2% nitrogen-free extract, 19.6% crude fiber, 0.58% calcium, 0.82% phosphorus, as well as trace elements such as copper, iron, and zinc, and chemical substances such as chlorophyll, carotenoids, pectin, and leaf protein. In addition, it also contains triacontanol, vitamins, sitosterol, amino acids, and plant growth hormones. The rich crude protein and carbohydrates in late-maturing silkworm excrement provide a material basis for regulating the balance of intestinal flora. The dominant bacterial groups in late-stage silkworm excrement include Actinobacteria, Proteobacteria, Klebsiella, Bacillus-like bacteria, and Bacillus. Studies have shown that Actinobacteria produce abundant bioactive substances with antibacterial, antitumor, and antiviral effects. Proteus vulgaris and Klebsiella under the Proteobacteria phylum can both produce indole. Appropriate amounts of indole can effectively alleviate inflammatory responses and enrich the composition of the intestinal flora, meaning that indole has the effect of resisting the invasion of exogenous pathogens. Bacillus has broad-spectrum antibacterial activity and can produce a variety of volatile antibacterial substances, mainly alcohols, aldehydes, acids, esters, and ketones, thereby competing with pathogens for living space and nutrients, i.e., inhibiting the growth of pathogens.

[0029] Traditional Chinese medicine believes that diabetic gastroparesis belongs to the categories of "vomiting", "epigastric fullness", "stomach distension", etc. The basic pathogenesis is that prolonged diabetes damages the transportation and transformation functions of the spleen and stomach and the liver's function of dredging and dispersing, resulting in food retention, qi stagnation, phlegm turbidity, blood stasis, etc., blocking the middle jiao of the spleen and stomach, causing qi stagnation in the middle jiao, and abnormal transportation and transformation functions of the spleen and stomach in ascending and descending. And the excrement of silkworm is warm in nature, sweet and pungent in taste, and belongs to the liver, spleen and stomach meridians. It has the effects of expelling wind and removing dampness, regulating the stomach and resolving turbidity, and promoting blood circulation and dredging meridians. It is mainly used for rheumatic arthralgia, limb paralysis, rubella itching, vomiting and diarrhea with cramps, amenorrhea, metrorrhagia and metrostaxis, and is used in combination for rheumatic arthralgia, limb paralysis, damp turbidity blocking the spleen and stomach, vomiting and diarrhea with cramps, etc. Applying the excrement of silkworm to treat patients with diabetic gastroparesis can adjust the transportation and transformation of the spleen and stomach of patients, improve the pathological states of food retention, qi stagnation, phlegm turbidity, blood stasis, etc. in patients, restore the transportation and transformation functions of the spleen and stomach in ascending and descending, and achieve the effect of relieving symptoms such as vomiting, nausea, early satiety, upper abdominal distension, and reduced food intake in patients with diabetic gastroparesis.

[0030] In this invention, through water bath extraction of the Chinese medicinal material excrement of silkworm, the active ingredients of the excrement of silkworm are obtained. After orally taking the extract, it can treat diabetic gastroparesis. The implementation method for this invention to treat diabetic gastroparesis is to obtain a concentrated solution after water bath extraction of the excrement of silkworm, and then take the concentrated solution and freeze-dry it to form orally disintegrating tablets. And sublingual administration of the orally disintegrating tablets can avoid the first-pass effect of the liver and enhance the drug effect. For example, take the orally disintegrating tablets formed from the concentrated solution of the excrement of silkworm of this invention, sublingual administration, twice a day, 1-2 tablets each time, and continuously use for 3 weeks.

[0031] Compared with the prior art, the beneficial effects of this invention are as follows:

[0032] (1) The traditional Chinese medicine composition of this invention has good curative effects on treating diabetic gastroparesis, has no toxic and side effects, and is safe and reliable;

[0033] (2) Compared with the traditional Chinese medicine decoction of the excrement of silkworm, in this invention, the excrement of silkworm is subjected to water bath extraction, and the effective ingredients are made into an orally disintegrating dosage form, which is convenient to carry and more convenient to take. And there is no high-temperature heating in the process of making the extract, which can better retain the effective ingredients in the excrement of silkworm, improve the curative effect, and play a role in balancing the intestinal flora, regulating the intestinal microecology, and improving the pathological state of "dampness blocking the middle jiao" by having positive or negative effects on the growth and reproduction of intestinal microorganisms.

[0034] (3) The traditional Chinese medicine composition of this invention avoids the first-pass effect of the liver through sublingual administration, and the curative effect is more excellent. Detailed implementation mode

[0035] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0036] The terminology used in the embodiments of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The singular forms “a,” “the,” and “the” used in the embodiments of this invention and the appended claims are also intended to include the plural forms, unless the context clearly indicates otherwise. “Multiple” generally includes at least two, but does not exclude the inclusion of at least one.

[0037] Examples 1-4

[0038] Each traditional Chinese medicine composition was prepared according to the preparation method shown in Table 1.

[0039] Table 1: Preparation methods of each traditional Chinese medicine composition in Examples 1-4

[0040]

[0041] Example 1 involves preparing orally disintegrating tablets from late-maturing silkworm excrement. The preparation method includes the following steps:

[0042] Collect late-maturing silkworm excrement, remove impurities, and filter out surface dust with clean water. Dry in a 60℃ oven for 24 hours, then grind into powder using a high-speed pulverizer. Weigh 200g of the powdered late-maturing silkworm excrement into a 1.5L round-bottom flask, add 500ml of distilled water, and extract in a 45℃ water bath for 12 hours, shaking the flask for 5 minutes every hour to ensure thorough extraction and form a mixture. Centrifuge the mixture at 10000r / min for 15 minutes, collect the supernatant, concentrate using a vacuum rotary evaporator, and bring to a final volume. At 20℃, the relative density of the solution is 1.05-1.08. Pour into aluminum foil, pre-freeze at -60℃ for 6 hours, and freeze-dry to form disintegrating tablets.

[0043] Test case

[0044] This experimental example is a clinical study of the use of the late-blooming silkworm excrement orally disintegrating tablets prepared in Example 1 in the treatment of diabetic gastroparesis.

[0045] Diagnostic criteria:

[0046] Western medicine diagnostic criteria: Referring to the diagnostic criteria for diabetic gastroparesis in the 2020 edition of the "Guidelines for the Diagnosis and Treatment of Type 2 Diabetes in my country" issued by the Chinese Medical Association, the following four criteria are sufficient for a definitive diagnosis: ① History of diabetes; ② Color Doppler ultrasound examination showing delayed gastric emptying; ③ Clinical symptoms of delayed gastric emptying in diabetic gastroparesis, such as vomiting and nausea; ④ Exclusion of organic lesions such as pyloric obstruction.

[0047] Traditional Chinese Medicine (TCM) Diagnostic Criteria: The TCM diagnostic criteria for phlegm-dampness obstruction syndrome are formulated with reference to the "TCM Prevention and Treatment Standards for Diabetes". Primary symptoms: Abdominal distension / suppression, nausea and vomiting, poor appetite and belching, fatigue and weakness, loose / unstable stools; Secondary symptoms: Heaviness and fatigue in the body and limbs, loss of appetite, enlarged tongue, thick and greasy white tongue coating, and a soft or slippery pulse.

[0048] Inclusion criteria:

[0049] (1) Meets the Western medical diagnostic criteria for diabetic gastroparesis;

[0050] (2) Meets the diagnostic criteria for diabetic gastroparesis according to traditional Chinese medicine syndrome differentiation;

[0051] (3) Comorbid diseases such as hypertension and diabetes require blood pressure and blood sugar to be controlled to a generally normal level;

[0052] (4) Age 40-65 years old;

[0053] (5) The subject or their family members agree and sign the informed consent form.

[0054] Exclusion criteria:

[0055] (1) Having severe complications of diabetes;

[0056] (2) Suspected or confirmed history of alcohol or drug abuse;

[0057] (3) Those who have experienced diarrhea within the past month;

[0058] (4) Those who have taken intestinal probiotics in the past month;

[0059] (5) Those who have taken antibiotics in the past month;

[0060] (6) Individuals with a history of allergy to the relevant drugs used in this study or a history of severe food allergy;

[0061] (7) Individuals with organic lesions of the digestive system, or those with serious primary diseases of other organs or systems.

[0062] Treatment plan:

[0063] The treatment group was given two tablets of silkworm excrement orally disintegrating tablets, taken sublingually twice a day for three consecutive weeks; the control group was given one tablet of mosapride citrate orally three times a day for three consecutive weeks.

[0064] Key observation indicators:

[0065] (1) Gastroparesis Major Symptom Index Score

[0066] Before and after treatment, patients were observed to have their Gastroparesis Major Symptom Index (GCS I) scores. The symptoms of gastroparesis (postprandial fullness / early satiety, nausea and vomiting, abdominal distension) were divided into 6 levels: none, very mild, mild, moderate, severe, and very severe, with scores of 0, 1, 2, 3, 4, and 5 respectively. The higher the score, the more severe the symptoms.

[0067] (2) Traditional Chinese Medicine Symptom Scoring

[0068] Before and after treatment, a quantitative grading scale for TCM symptoms of diabetic gastroparesis was developed based on the "Standards for Diagnosis and Efficacy of TCM Diseases" and clinical practice. The main symptoms (abdominal distension / suppression, nausea and vomiting) and secondary symptoms (poor appetite, belching, fatigue, constipation / loose stools) were scored. The main symptoms were scored as 0, 2, 4, and 6 points respectively, and the secondary symptoms were scored as 0, 1, 2, and 3 points respectively. The sum of the scores of each symptom was the total TCM symptom score.

[0069] (3) Gastric emptying rate

[0070] Gastric emptying rate was examined by color Doppler ultrasound before and after treatment. Patients fasted for 12 hours and ate a contrast-enhancing meal the next morning. The gastric antrum was marked on the surface of the patient immediately after the meal (Dm) and 60 minutes after the meal (Dt60). Gastric emptying rate (%) = (Dm - Dt60) ÷ Dm × 100%.

[0071] Criteria for determining the efficacy of the primary observation indicators:

[0072] The efficacy criteria were formulated with reference to the "Standards for Diagnosis and Efficacy Evaluation of Diseases and Syndromes in Traditional Chinese Medicine" and the GCS I score. The efficacy evaluation index divides the efficacy into four levels: clinical control, significant effect, effective, and ineffective. The total effective rate is calculated by combining the number of cases with clinical control, significant effect, and effective. The efficacy index is determined according to the nimodipine method: Efficacy Index (n) = [(Pre-treatment score - Post-treatment score) ÷ Pre-treatment score] × 100%.

[0073] Clinical control: Clinical symptoms have disappeared or basically disappeared, n≥95%;

[0074] Significant effect: Improvement of clinical symptoms, 70% ≤ n < 95%;

[0075] Effective: Clinical symptoms improve, 30% ≤ n < 70%;

[0076] Ineffective: Clinical symptoms do not improve or worsen, n < 30%.

[0077] Experimental results

[0078] Table 2 Comparison of main symptom scores of gastroparesis before and after treatment in the two groups of patients ( point)

[0079]

[0080] Note: Compared with the pre-treatment level in this group. * P < 0.05; compared with the control group at the same time point, # P < 0.05

[0081] Based on the data in Table 2, the following conclusions can be drawn: By comparing the scores of postprandial fullness / early satiety, nausea and vomiting, abdominal distension, and the total score of the main symptoms of gastroparesis between the two groups, it can be found that the treatment group was better after treatment than before treatment, and the treatment group was more effective than the control group, with statistically significant differences.

[0082] Table 3 Comparison of TCM symptom scores before and after treatment in the two groups of patients ( point)

[0083]

[0084]

[0085] Note: Compared with the pre-treatment level in this group. * P < 0.05; compared with the control group at the same time point, # P < 0.05

[0086] Based on the data in Table 3, the following conclusions can be drawn: By comparing the TCM symptom scores of the two groups, it can be found that the treatment group was better after treatment than before treatment, and the treatment group had better efficacy than the control group, with statistically significant differences.

[0087] Table 4 Comparison of gastric emptying rates before and after treatment in the two groups of patients ( %)

[0088]

[0089] Note: Compared with the pre-treatment level in this group. * P < 0.05; compared with the control group at the same time point, # P < 0.05

[0090] Based on the data in Table 4, the following conclusions can be drawn: By comparing the gastric emptying rates of the two groups, it can be found that the treatment group was better after treatment than before treatment, and the treatment group was more effective than the control group, with statistically significant differences.

[0091] Example of a medical record

[0092] The patient, a 53-year-old male, had a 5-year history of diabetes. For the past 3 years, he had experienced symptoms such as abdominal distension / suppression, nausea and vomiting, poor appetite and belching, fatigue and weakness, and loose / uncomfortable bowel movements. He also experienced heaviness and fatigue in the limbs, loss of appetite, a large, swollen tongue with a thick, greasy white coating, and a soft or slippery pulse. After ruling out organic gastric motility abnormalities, the diagnosis was considered to be diabetic gastroparesis caused by prolonged diabetes. Traditional Chinese medicine diagnosis was phlegm-dampness obstruction syndrome. Treatment involved sublingual administration of two tablets of a traditional Chinese medicine formula twice daily. After two weeks of treatment, the symptoms improved, and the treatment was continued. After three weeks of treatment, the aforementioned symptoms disappeared.

[0093] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The application of a traditional Chinese medicine composition in the preparation of a drug for treating diabetic gastroparesis, characterized in that, The preparation method of the traditional Chinese medicine composition comprises the following steps: The dried silkworm excrement is weighed and added with water, and then immersed in a water bath at 35-55 DEG C to form a mixture; The mixture is centrifuged, and the supernatant is concentrated; or the mixture is filtered, and the filtrate is concentrated.

2. Use according to claim 1, characterized in that, The concentration method is evaporation concentration, dialysis concentration or ultrafiltration concentration to obtain a concentrated solution, and the concentration of the concentrated solution is 15-25%.

3. Use according to claim 2, characterized in that, The preparation method further comprises the following steps: the concentrated solution is injected into an aluminum cavity, and the concentrated solution is optionally added with or without excipients for preparing oral disintegrating tablets, the concentrated solution is pre-frozen, and freeze-drying is performed to form the oral disintegrating tablets.

4. Use according to claim 3, characterized in that, The preparation method comprises the following steps: The dried silkworm excrement is weighed and added with water, and then immersed in a water bath at 35-55 DEG C to form a mixture; The mixture is centrifuged, and the supernatant is concentrated; or the mixture is filtered, and the filtrate is concentrated. The concentration method is evaporation concentration, dialysis concentration or ultrafiltration concentration to obtain a concentrated solution, and the concentration of the concentrated solution is 15-25%. The preparation method comprises the following steps:

5. Use according to claim 4, characterized in that, The dried silkworm excrement is weighed and added with water, and then immersed in a water bath at 35-55 DEG C to form a mixture; The mixture is centrifuged, and the supernatant is concentrated; or the mixture is filtered, and the filtrate is concentrated. The concentration method is evaporation concentration, dialysis concentration or ultrafiltration concentration to obtain a concentrated solution, and the concentration of the concentrated solution is 15-25%. The preparation method comprises the following steps: The dried silkworm excrement is weighed and added with water, and then immersed in a water bath at 35-55 DEG C to form a mixture; 6. Use according to claim 5, characterized in that, The mixture is centrifuged, and the supernatant is concentrated; or the mixture is filtered, and the filtrate is concentrated. The concentration method is evaporation concentration, dialysis concentration or ultrafiltration concentration to obtain a concentrated solution, and the concentration of the concentrated solution is 15-25%. The preparation method comprises the following steps: The dried silkworm excrement is weighed and added with water, and then immersed in a water bath at 35-55 DEG C to form a mixture; The mixture is centrifuged, and the supernatant is concentrated; or the mixture is filtered, and the filtrate is concentrated.

7. Use according to claim 6, characterized in that, The concentration method is evaporation concentration, dialysis concentration or ultrafiltration concentration to obtain a concentrated solution, and the concentration of the concentrated solution is 15-25%. The symptoms of the diabetic gastroparesis are vomiting, nausea, early satiety, upper abdominal fullness, and reduced food intake, and the administration mode of the traditional Chinese medicine composition is sublingual administration.

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