Pharmaceutical composition containing herba epimedii and poria cocos granulation-promoting granules and simeglutide

Abstract

The invention provides a pharmaceutical composition containing herba epimedii and poria cocos granulation promoting granules and simeglutide, and particularly provides a pharmaceutical composition containing the herba epimedii and poria cocos granulation promoting granules and the simeglutide, and application of the pharmaceutical composition in preparation of the pharmaceutical composition for losing weight and reducing muscle loss at the same time.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine pharmacy, and particularly relates to a pharmaceutical composition containing Huoling Shengji Granules and semaglutide, and its use in preparing a pharmaceutical composition for weight loss while reducing muscle loss. Background Art

[0002] Obesity has become a major public health problem globally, and its incidence is continuously rising with the improvement of people's living standards and the change of lifestyle. Obesity not only affects an individual's quality of life and mental health, but also increases the risk of various chronic diseases, such as type 2 diabetes, cardiovascular diseases, non-alcoholic fatty liver disease, etc. At present, weight loss treatment methods mainly include diet adjustment, exercise, drug treatment, and surgical treatment. However, these methods have their own limitations, and some patients are difficult to adhere to in the long term, resulting in poor weight loss effects or weight rebound. Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, which regulates multiple metabolic processes by mimicking the physiological function of GLP-1, thereby achieving the effects of weight loss and improving blood glucose control. Semaglutide may be accompanied by adverse reactions such as muscle loss during the weight loss process, which may further lead to muscle loss, and in severe cases, it may affect health during the weight loss process.

[0003] In summary, there is an urgent need in this field to provide a safer and more effective weight loss treatment plan for obese patients. Summary of the Invention

[0004] The purpose of the present invention is to provide a pharmaceutical composition for the combined use of Huoling Shengji Granules and semaglutide.

[0005] Another purpose of the present invention is to protect the application of the combined use plan of Huoling Shengji Granules and semaglutide in treating muscle loss caused by semaglutide.

[0006] In the first aspect of the present invention, a pharmaceutical combination is provided, and the pharmaceutical combination includes: (1) Huoling Shengji traditional Chinese medicine composition; the Huoling Shengji traditional Chinese medicine composition is made from the following raw materials in parts by weight: 2 - 5 parts of Epimedium brevicornum, 1 - 3 parts of stir-fried Atractylodes macrocephala with bran, 1 - 3 parts of Poria cocos, 2 - 6 parts of Astragalus membranaceus, 1 - 4 parts of Cornus officinalis processed with wine, 2 - 4 parts of Rehmannia glutinosa. (2) Semaglutide.

[0007] In another preferred embodiment, the Huoling Shengji traditional Chinese medicine composition is a granule.

[0008] In another preferred embodiment, in the pharmaceutical combination, the Huoling Shengji traditional Chinese medicine composition and / or the semaglutide are each independently a pharmaceutical dosage form selected from the following group: tablets, capsules, injections, ointments, injectable powders, powder inhalants, sprays, granules, or a combination thereof.

[0009] In another preferred embodiment, the Huoling herbal composition is an oral preparation.

[0010] In another preferred embodiment, the semaglutide is an injectable preparation.

[0011] In another preferred embodiment, the semaglutide is a subcutaneous injection.

[0012] In another preferred embodiment, the herbal composition containing *Huo Ling Sheng Ji* and smegglutinin is prepared as a single dosage form, or the herbal composition containing *Huo Ling Sheng Ji* and smegglutinin are prepared as different dosage forms.

[0013] In another preferred embodiment, the Huoling herbal composition and the Smeglucopyranoside are prepared into different dosage forms.

[0014] In another preferred embodiment, the drug combination comprises the Huoling Shengji Traditional Chinese Medicine Composition and the Smeglucopyranoside, used simultaneously or sequentially.

[0015] In another preferred embodiment, the dosage of the Huoling Shengji Traditional Chinese Medicine Composition in the drug combination is 3-8 g / kg body weight; and / or In the pharmaceutical composition described above, the dosage of smegglutide is 0.1-0.15 mg / kg body weight.

[0016] In another preferred embodiment, the treatment or improvement includes improving the appetite of the recipient.

[0017] In another preferred embodiment, the treatment or improvement may further include: increasing the weight of the subject or slowing down weight loss caused by tumor cachexia.

[0018] In another preferred embodiment, the mass ratio of the Huoling Shengji Traditional Chinese Medicine Composition and Smeglucopyranoside in the drug combination is 30,000-40,000:0.8-1.2.

[0019] In another preferred embodiment, the medicinal composition is prepared in the form of 28g-35g of the herbal composition for oral administration each time; more preferably, the medicinal composition is prepared for oral administration twice a day.

[0020] In another preferred embodiment, the pharmaceutical composition is prepared by the following method: (1) Mix Epimedium, stir-fried Atractylodes macrocephala, Poria cocos, Astragalus membranaceus, Cornus officinalis, and Rehmannia glutinosa, add water and decoct, filter, and dry the filtrate to obtain dry extract powder; (2) The dry extract powder obtained in step 1 is mixed with magnesium stearate, sucralose and dextrin and granulated to obtain granules.

[0021] In another preferred embodiment, in step (1), the raw materials consist of the following parts by weight: 2-5 parts of Epimedium, 1-3 parts of stir-fried Atractylodes macrocephala, 1-3 parts of Poria cocos, 2-6 parts of Astragalus membranaceus, 1-4 parts of Cornus officinalis, and 2-4 parts of Rehmannia glutinosa.

[0022] In another preferred embodiment, in step (1), during the first water addition and decoction process, the weight of water added is 8-12 times that of the raw materials.

[0023] In another preferred embodiment, in step (1), during the second boiling process, the weight of water added is 6-10 times that of the raw materials.

[0024] In another preferred embodiment, in step (1), the temperature of the first boiling with water is 50-70°C.

[0025] In another preferred embodiment, in step (1), the temperature of the second boiling with water is 50-70°C.

[0026] In another preferred embodiment, in step (1), the first boiling time is 80-100 minutes.

[0027] In another preferred embodiment, in step (1), the second boiling time is 50-70 minutes.

[0028] In another preferred embodiment, in step (2), the vacuum degree during the reduced pressure concentration process is -90 to -120 kPa.

[0029] In another preferred embodiment, in step (2), the vacuum drying temperature is ≤75°C.

[0030] In another preferred embodiment, in step (2), the vacuum drying time is 10-24 hours.

[0031] In another preferred embodiment, in step (3), the mass ratio of magnesium stearate to raw material is 1:(20-150).

[0032] In another preferred embodiment, in step (3), the mass ratio of sucralose to raw materials is 1:(120-380).

[0033] In another preferred embodiment, in step (3), the mass ratio of dextrin to raw materials is 1:(1-5).

[0034] In a second aspect of the invention, a pharmaceutical composition is provided comprising the pharmaceutical composition as described in the first aspect of the invention, and a pharmaceutically acceptable carrier.

[0035] In another preferred embodiment, the pharmaceutical composition is a dosage form selected from the group consisting of tablets, capsules, injections, ointments, powders for injection, powder inhalers, sprays, granules, or combinations thereof.

[0036] In another preferred embodiment, the pharmaceutical composition is an oral formulation.

[0037] In a third aspect of the invention, the use of a pharmaceutical composition as described in the first aspect of the invention, or a pharmaceutical composition as described in the second aspect of the invention, is provided for the preparation of a pharmaceutical composition for weight loss.

[0038] In another preferred embodiment, the pharmaceutical composition is also used to improve muscle loss caused by the use of smegglutinin during weight loss.

[0039] In another preferred embodiment, the pharmaceutical composition is also used to improve the user's body fat percentage.

[0040] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0041] Figure 1 Body fat percentage data of mice in different groups on day 13; Note: Data are expressed as mean ± SEM. n = 6. **: P < 0.01; ***: P < 0.001; ****, p < 0.0001 Vs G1 by one-way ANOVA.

[0042] Figure 2 Body fat percentage data of D27 mice in different groups; Note: Data are expressed as mean ± SEM. n = 6. **: P < 0.01; ****, p < 0.0001 Vs G1 by one-way ANOVA.

[0043] Figure 3 The changes in body fat and muscle mass in mice of different groups during the drug's effective period are shown; Note: Data are expressed as mean ± SEM. n = 6.

[0044] Figure 4 The endpoint tissue weights of mice in different groups are shown; Note: Data are expressed as mean ± SEM. n = 6. ***: P < 0.001; ****, p < 0.0001 Vs G1 by one-way ANOVA.

[0045] Figure 5The changes in gastrocnemius muscle in mice from different groups are shown; Note: Data are expressed as mean ± SEM. n = 6. ***: P < 0.001; ****: p < 0.0001 Vs G1 by one-way ANOVA. Detailed Implementation

[0046] Through long-term and in-depth research, the inventors have discovered a new use for an existing traditional Chinese medicine compound preparation in the preparation of an oral drug to improve muscle loss during weight loss. The oral drug can effectively reduce muscle loss caused by semaglutide while maintaining the weight loss effect of semaglutide, and ultimately achieves statistical significance and a clear dose-response relationship.

[0047] Drug compositions that reduce muscle loss Smegglutide has good effects on lowering blood sugar and reducing weight. However, during the weight loss process of using Smegglutide, fat and muscle are metabolized simultaneously, leading to muscle loss in users.

[0048] To address this issue, the inventors combined Huoling Shengji Granules with Smegglutinin. Huoling Shengji Granules is a traditional Chinese medicine preparation whose main ingredients include Epimedium, Astragalus, Cornus officinalis, Atractylodes macrocephala (stir-fried with wheat bran), Poria cocos, and Rehmannia glutinosa. It has the effects of strengthening the spleen and replenishing qi, removing dampness and resolving phlegm. The applicant discovered that the combined use of Huoling Shengji Granules and Smegglutinin can effectively improve the muscle loss problem commonly encountered when using Smegglutinin.

[0049] The Composition of Poria Cocos for Muscle Regeneration and Its Uses This invention provides a traditional Chinese medicine composition of *Huo Ling Sheng Ji* for use in the preparation of an oral medication for treating tumor cachexia. The composition is characterized by being made from the following raw materials in parts by weight: 2-5 parts of *Epimedium*, 1-3 parts of stir-fried *Atractylodes macrocephala*, 1-3 parts of *Poria cocos*, 2-6 parts of *Astragalus membranaceus*, 1-4 parts of *Cornus officinalis*, and 2-4 parts of *Rehmannia glutinosa*.

[0050] The dosage form of the Huoling Shengji Traditional Chinese Medicine Composition is granules; In a preferred embodiment, the preparation method of the traditional Chinese medicine composition includes the following steps: (1) Mix the raw materials, add water and boil for the first time, then filter. Add water to the dregs for the second time, boil and filter, and combine the filtrates. (2) The filtrate obtained in step 1 is concentrated under reduced pressure and dried under vacuum to obtain dry extract powder; (3) Mix the dry extract powder obtained in step 2 with magnesium stearate, sucralose and dextrin to granulate and obtain granules.

[0051] In Step 1 described above, the raw materials consist of the following raw materials in parts by weight: 2 - 5 parts of Epimedium brevicornum, 1 - 3 parts of stir-fried Atractylodes macrocephala with bran, 1 - 3 parts of Poria cocos, 2 - 6 parts of Astragalus membranaceus, 1 - 4 parts of Cornus officinalis processed with wine, and 2 - 4 parts of Rehmannia glutinosa; In another preferred example, in Step 1 described above, during the first water decoction process, the weight of the added water is 8 - 12 times that of the raw materials; In Step 1 described above, during the second water decoction process, the weight of the added water is 6 - 10 times that of the raw materials; In Step 1 described above, the temperature of the first water decoction is 50 - 70°C;​​​​​​​​​​​​​​​​​​​​​​​​​​​​​The existing literature (Qinming Zhou, et al. Sci Rep, 2018, 8(1): 1668), published data, and normal rat studies have not found any efficacy in promoting appetite or increasing weight, nor have they revealed any therapeutic or ameliorative effect on tumor cachexia. However, the experimental data in this invention show that in a mouse model of tumor cachexia induced by C26 colon cancer cells, it can continuously increase appetite reduced by the tumor and ultimately significantly increase weight. Therefore, the pharmaceutical composition of this invention can effectively improve problems such as reduced appetite and weight loss caused by tumor cachexia, and this mechanism is related to the occurrence of tumor cachexia, while this effect is not present in normal rat models.

[0056] (2) Security advantages Medroxyprogesterone acetate, clinically used to treat tumor cachexia, can cause serious and life-threatening thrombotic events and significantly promote tumor growth—increasing tumor volume by more than 100% in preclinical pharmacodynamic studies (Beck SA, Tisdale MJ.Br.J.Cancer, 1990, 62:420-424.). However, the drug of this invention (named Huoling Shengji Granules in clinical trials) has completed a Phase II clinical trial for ALS (Amyotrophic Lateral Sclerosis), and no drug-related thrombotic events or other serious adverse reactions were observed during the trial. Secondly, the drug components of this invention are all traditional Chinese medicinal herbs with a long history of human use, demonstrating excellent safety. Thirdly, in the embodiments of this invention, only diarrhea was observed with Huoling Shengji Extract Powder (the extract powder of this invention), and no significant acceleration of tumor growth was observed. Therefore, the drug of this invention has a significant safety advantage.

[0057] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0058] Unless otherwise stated, the Chinese herbal raw materials and other reagents used in the embodiments of this invention are obtained commercially available.

[0059] Example 1: Preparation of Poria cocos extract powder for promoting tissue regeneration It is made from the following raw materials in parts by weight: Epimedium 2-5 parts (2.5 parts), stir-fried Atractylodes macrocephala 1-3 parts (1.5 parts), Poria cocos 1-3 parts (1.5 parts), Astragalus membranaceus 2-6 parts (3 parts), Cornus officinalis 1-4 parts (2 parts), Rehmannia glutinosa 2-4 parts (2.5 parts).

[0060] A preferred traditional Chinese medicine composition is made from the following raw materials in parts by weight: Epimedium 5 parts (150g), Astragalus 6 parts (180g), Cornus officinalis 4 parts (120g), Rehmannia glutinosa 5 parts (150g), Atractylodes macrocephala stir-fried with wheat bran 3 parts (90g), and Poria cocos 3 parts (90g).

[0061] Prepare according to the following steps: Weigh the raw material according to the stated weight proportions, add 8-12 times the amount of water and decoct, simmering for 60-90 minutes, then filter. Add 6-10 times the amount of water to the residue and simmer for 45-60 minutes, then filter. Combine the two decoctions, concentrate under reduced pressure at 60 degrees Celsius and a vacuum of -90 to -120 kPa until the relative density is 1.25 to 1.30. After removal, vacuum dry for 10-24 hours at a drying temperature ≤75 degrees Celsius, maintaining a vacuum of -90 to -120 kPa to obtain the extract powder.

[0062] A preferred preparation method is as follows: Take the above-mentioned raw medicinal materials (commercially available), add 7800ml of water and decoct for 90 minutes at a gentle boil, then filter. Add 4680ml of water to the dregs and decoct for 60 minutes at a gentle boil, then filter. Combine the two decoctions, concentrate under reduced pressure at 60 degrees Celsius and a vacuum of -90 to -120 kPa until the relative density is 1.25 to 1.30. After removal, vacuum dry for 10-24 hours at a drying temperature ≤75 degrees Celsius and a vacuum of -90 to -120 kPa. Add 5.0g of magnesium stearate, 1.5g of sucralose, and 700g of dextrin to the obtained dry extract powder, mix evenly, granulate, and prepare 1000g of traditional Chinese medicine granules.

[0063] The following experimental examples further illustrate the beneficial effects of the present invention: Example 1: This experiment evaluated the efficacy of the test product in a high-fat diet-induced obesity model in DIO mice (C57BL6J). Model construction: Mouse information: C57BL6 mice, age: 23-29 weeks (fed on a high-fat diet for 18-24 weeks, with an average weight of 48-50g).

[0064] Grouping: All mice were acclimatized for 3 days or more, and their body fat percentage was measured. Based on body fat percentage and body weight as the main indicators, the mice were divided into 3 groups of 6 mice each. The day of grouping was defined as Day 0. Among them, the Huoling Shengji Traditional Chinese Medicine Composition was the traditional Chinese medicine granule prepared in Example 2. 1.1 Changes in body fat ratio in mice during the drug efficacy period Mice in different groups were tested for body fat percentage on days 13 and 27 after drug administration. The results are as follows: Figures 1-3As shown in the figure. The body fat percentage results on days 13 and 27 showed that the lean meat mass, fat mass, water mass, and body fat percentage of mice in the G2 Semaglutide (0.12 mg / kg) positive control group and the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined administration group were significantly lower than those in the G1 control group. Compared with the G2 Semaglutide (0.12 mg / kg) positive control group, the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined administration group had higher fat mass and lean meat mass, indicating that HLSJ (4500 mg / kg) reduced the fat-reducing effect of semaglutide to some extent and improved the muscle loss induced by semaglutide.

[0065] Compared with the body fat data of mice before grouping on day 3, the results of fat-to-body weight ratio and lean-to-body weight ratio, as well as changes in fat and lean meat during the drug-effect period are as follows: Figure 3 As shown.

[0066] The results showed that both the G2 Semaglutide (0.12 mg / kg) positive control group and the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined administration group exhibited significant decreases in fat and lean meat levels after 13 days of treatment. The reduction in fat and lean meat levels in the G3 combined administration group was less than that in the positive control group. After changing the Semaglutide dose to 10 nmol / kg, the reduction in fat levels in the G3 combined administration group remained lower than that in the G2 positive control group. After reducing the Semaglutide dose, the lean meat levels in the G2 group showed a rebound trend compared to before the dose adjustment, and at the endpoint, they were close to those in the G3 combined administration group.

[0067] 1.2 Endpoint tissue weight At the endpoint, perirenal fat, epididymal fat, brown fat, and gastrocnemius muscle samples were collected from mice in different groups and weighed. The results are as follows: Figure 4As shown in the figure. Compared with the G1 control group, the perirenal fat, brown fat, and gastrocnemius muscle of mice in the G2 Semaglutide (0.12 mg / kg) positive control group and the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined administration group were significantly lower than those in the G1 control group. Compared with the G2 Semaglutide (0.12 mg / kg) positive control group, the weight of various types of fat and gastrocnemius muscle of mice in the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined administration group were higher.

[0068] The results of gastrocnemius muscle changes in different groups of mice are as follows: Figure 5 As shown in the figure. The results showed that, compared with the G1 control group, the gastrocnemius muscle mass levels were significantly reduced in the G2 Semaglutide (0.12 mg / kg) positive control group and the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined administration group. Compared with the G2 Semaglutide (0.12 mg / kg) positive control group, the proportion of gastrocnemius muscle weight reduction in mice in the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined administration group was lower, indicating that the test products improved the muscle loss induced by semaglutide to a certain extent.

[0069] in conclusion Results of changes in body fat percentage in mice during the drug efficacy period showed that both the G2 Semaglutide (0.12 mg / kg) positive control group and the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combination therapy group experienced significant decreases in fat and lean meat levels after 13 days of administration. However, the decrease in fat and lean meat levels in the G3 combination therapy group was less pronounced than that in the positive control group. After reducing the Semaglutide dose, the decrease in fat and lean meat levels in the G3 combination therapy group remained lower than that in the G2 positive control group. The decrease in lean meat levels in the G2 group after reducing the Semaglutide dose showed a rebound trend, eventually approaching the lean meat levels of the G3 combination therapy group at the endpoint.

[0070] The endpoint tissue weight results showed that, compared with the G1 control group, the perirenal fat, brown fat, and gastrocnemius muscle of mice in the G2 Semaglutide (0.12 mg / kg) positive drug group and the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined drug group were significantly lower than those in the G1 control group. Compared with the G2 Semaglutide (0.12 mg / kg) positive drug group, the proportion of gastrocnemius muscle weight reduction in mice in the G3 Semaglutide (0.12 mg / kg) + HLSJ (4500 mg / kg) combined drug group was lower, indicating that the test products improved the muscle loss induced by semaglutide to a certain extent.

[0071] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A drug combination, characterized in that, The drug combination includes: (1) A traditional Chinese medicine composition for promoting tissue regeneration; the traditional Chinese medicine composition for promoting tissue regeneration is made from the following raw materials in parts by weight: Epimedium 2-5 parts, stir-fried Atractylodes macrocephala 1-3 parts, Poria cocos 1-3 parts, Astragalus membranaceus 2-6 parts, Cornus officinalis 1-4 parts, Rehmannia glutinosa 2-4 parts; (2) Smegglutinin.

2. The pharmaceutical composition according to claim 1, characterized in that, In the aforementioned drug combination, the Huoling Shengji Traditional Chinese Medicine Composition and / or the Smeglucopyriole are each independently selected from the following dosage forms: tablets, capsules, injections, ointments, powders for injection, powder inhalers, sprays, granules, or combinations thereof.

3. The drug combination as described in claim 1, characterized in that, In the aforementioned drug combination, the Huoling Shengji Traditional Chinese Medicine Composition and Smeglucopyriole are prepared as a single dosage form, or the Huoling Shengji Traditional Chinese Medicine Composition and Smeglucopyriole are prepared as different dosage forms respectively.

4. The pharmaceutical combination as described in claim 1, characterized in that, In the aforementioned drug combination, the Huoling Shengji Traditional Chinese Medicine Composition and the aforementioned Smeglucopyranoside are used simultaneously or sequentially.

5. The pharmaceutical combination as described in claim 1, characterized in that, In the aforementioned drug combination, the dosage of the Huoling Shengji traditional Chinese medicine composition is 3-8 g / kg body weight; and / or In the pharmaceutical composition described above, the dosage of smegglutide is 0.1-0.15 mg / kg body weight.

6. The pharmaceutical combination as described in claim 1, characterized in that, In the aforementioned drug combination, the mass ratio of the Huoling Shengji Traditional Chinese Medicine Composition and Smeglucopyranoside is 30,000-40,000:0.8-1.

2.

7. A pharmaceutical composition comprising the pharmaceutical combination as described in any one of claims 1-6, and a pharmaceutically acceptable carrier.

8. The use of the pharmaceutical combination as described in any one of claims 1-6, or the use of the pharmaceutical composition as described in claim 7, characterized in that, Used to prepare pharmaceutical compositions for weight loss.

9. The use as described in claim 8, characterized in that, The pharmaceutical composition is also used to improve muscle loss caused by the use of smegglutinin during weight loss.

10. The use as described in claim 8, characterized in that, The pharmaceutical composition is also used to improve the user's body fat percentage.

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