CN114948976B - Weight-losing composition and preparation method and application thereof - Google Patents
Weight-losing composition and preparation method and application thereof Download PDFInfo
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- CN114948976B CN114948976B CN202210694607.9A CN202210694607A CN114948976B CN 114948976 B CN114948976 B CN 114948976B CN 202210694607 A CN202210694607 A CN 202210694607A CN 114948976 B CN114948976 B CN 114948976B
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- orlistat
- weight
- gastrointestinal
- aesculin
- saponin
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- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- AXNVHPCVMSNXNP-GKTCLTPXSA-N Aescin Natural products O=C(O[C@H]1[C@@H](OC(=O)C)[C@]2(CO)[C@@H](O)C[C@@]3(C)[C@@]4(C)[C@@H]([C@]5(C)[C@H]([C@](CO)(C)[C@@H](O[C@@H]6[C@@H](O[C@H]7[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O7)[C@@H](O)[C@H](O[C@H]7[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O7)[C@@H](C(=O)O)O6)CC5)CC4)CC=C3[C@@H]2CC1(C)C)/C(=C/C)/C AXNVHPCVMSNXNP-GKTCLTPXSA-N 0.000 description 1
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- AHLBNYSZXLDEJQ-UHFFFAOYSA-N N-formyl-L-leucylester Natural products CCCCCCCCCCCC(OC(=O)C(CC(C)C)NC=O)CC1OC(=O)C1CCCCCC AHLBNYSZXLDEJQ-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 description 1
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- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
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- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
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- 239000002329 esterase inhibitor Substances 0.000 description 1
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- 210000003608 fece Anatomy 0.000 description 1
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- 108010091264 gastric triacylglycerol lipase Proteins 0.000 description 1
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- 235000019322 gelatine Nutrition 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- OQMAKWGYQLJJIA-CUOOPAIESA-N lipstatin Chemical class CCCCCC[C@H]1[C@H](C[C@H](C\C=C/C\C=C/CCCCC)OC(=O)[C@H](CC(C)C)NC=O)OC1=O OQMAKWGYQLJJIA-CUOOPAIESA-N 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
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- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940016667 resveratrol Drugs 0.000 description 1
- 235000021283 resveratrol Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 229940124024 weight reducing agent Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Child & Adolescent Psychology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to a weight-losing composition containing orlistat, which comprises orlistat and horse chestnut saponin. The present invention provides a body-beneficial, orlistat-containing weight loss pharmaceutical composition that exhibits a surprising weight loss effect, while no significant adverse gastrointestinal reactions and liver function impairment are observed in patients, and no such effects are observed in other flavonoids in combination with orlistat.
Description
Technical Field
The invention belongs to the technical field of biological medicine. More particularly, relates to a weight-losing composition, a preparation method and application thereof.
Background
Orlistat (tetrahydrolipstatin, THL) is a semisynthetic lipstatin derivative having the chemical structural formula shown below:
orlistat is a powerful and high-selectivity gastric lipase and pancreatic esterase inhibitor, can inhibit the hydrolysis of triglyceride in the gastrointestinal tract on the ingested diet, reduce the absorption of hydrolysis products of monoglyceride and free fatty acid, promote the energy negative balance to achieve the weight reduction purpose, is the only OTC weight-reducing medicament approved by the national drug administration, and can reduce Body Mass Index (BMI) and inhibit weight rebound after weight reduction by combining with dietary intervention.
However, adverse gastrointestinal reactions caused by the administration of orlistat are common, in addition, liver enzyme elevation is also a potential adverse reaction of orlistat, but the occurrence mechanism of the liver injury related to the orlistat and the extremely rare fulminant liver failure observed in the administration process of the orlistat is not clear, and the adverse reaction may be related to hypersensitivity, and the content of liver injury possibly caused by the orlistat is increased in the notification about revising the preparation instructions of the orlistat issued by the food and drug administration of the state of China in 2010.
Currently, gastrointestinal adverse reactions caused by orlistat are generally regarded as important, for example, CN111228238A discloses that the incidence of oil leakage adverse reactions caused by orlistat is reduced by adopting oligosaccharide and orlistat for compounding; CN108542903a discloses that the combination of a polyphenol-containing lipase inhibitor derived from tea and orlistat can reduce unpleasant gastrointestinal side effects of orlistat and relieve adverse reactions such as oil spots, fat, oil feces and the like; CN106924270a discloses a slimming drug containing orlistat, resveratrol and oligosaccharide, which has a significantly better slimming effect than orlistat and a significantly lower incidence of gastrointestinal reactions than conventional doses of orlistat. None of the above studies, however, disclose how the potential liver function damage of orlistat can be reduced.
The aesculin, also called aescine, is a main active ingredient of aesculus, has high medicinal value, and can be used for treating cerebral hemorrhage, cerebral edema, respiratory diseases and the like, but has no application in weight reduction.
Reference is made to patent literature:
(1) CN111228238A, a pharmaceutical composition containing orlistat and an oligosaccharide;
(2) CN108542903a, a pharmaceutical composition comprising orlistat and a plant derived lipase inhibitor;
(3) CN106924270a, a pharmaceutical composition containing orlistat with weight-reducing function.
Disclosure of Invention
Aiming at solving the problems of gastrointestinal tract reaction and potential liver function injury risk existing in single-dose orlistat, the invention provides a weight-losing composition containing orlistat and horse chestnut saponin.
The above object of the present invention is achieved by the following technical scheme: a weight-reducing composition comprising orlistat and horse chestnut saponin.
In the slimming composition of the present invention, the orlistat and the horse chestnut saponin are present in an amount sufficient to produce a synergistic inhibition of lipase activity; in some cases, the weight ratio of the two is 1:0.1 to 0.8, preferably 1: any value between 0.3 and 0.8. More preferably, the weight ratio of orlistat to horse chestnut saponin is 1:0.5, 1:0.3 or 1:0.6. only when the amounts of orlistat and escin are within this weight range, a strong synergistic effect is exhibited.
In some cases, the aesculin of the present invention is aesculin form α. Only when the configuration of the aesculin is alpha-form in cis configuration, the aesculin shows the strongest effect of inhibiting lipase activity, reducing gastrointestinal reaction and stronger potential liver function injury risk. When the aesculin is beta-type, the combination also exhibits a strong synergistic effect of inhibiting lipase activity and an effect of inhibiting gastrointestinal reaction, but no effect of reducing liver function impairment is observed. This also occurs when another flavonoid compound is substituted for escin, but some flavonoid compounds in combination with orlistat show neither synergistic weight loss nor effects of reducing the gastrointestinal response of orlistat and liver function damage. Of these flavonoids, therefore, the alpha-form of aesculin is particular, at least an irreplaceable interaction with orlistat occurs, which interaction shows a surprising effect.
Another object of the invention is to provide the use of the slimming composition for the preparation of a slimming drug.
In particular, the weight-losing medicament significantly reduces the weight, the body mass index and the body fat percentage of overweight and obese patients;
specifically, the weight-losing medicament does not cause liver damage to the patient, and after the patient takes the medicament, the liver function index of the patient is not obviously different from that before taking the medicament. In contrast, after administration of other flavonoids in combination with orlistat, the liver function index of the patient was significantly different from that before administration. The liver function indexes include: alanine aminotransferase ALT, total bilirubin Tbil and aspartate aminotransferase AST, which are functional indicators that are directly indicative of changes in liver function.
In particular, the weight-reducing agent reduces gastrointestinal reactions caused by orlistat, including steatosis, steatorrhea, abdominal pain, increased gastrointestinal discharge, etc.
Another object of the present invention is to provide a weight-reducing medicament containing orlistat, comprising the weight-reducing composition. The weight loss composition may be present in the medicament as the primary or sole functional ingredient.
In some cases, the medicament is formulated in the form of a capsule or granule, preferably a capsule. When the drug is formulated into a capsule, it may be formulated into a hard capsule, a soft capsule, a sustained-release capsule, a controlled-release capsule or an enteric capsule. Preferably made into hard capsule, and when made into hard capsule, the capsule wall material can be gelatin; in order to increase toughness and plasticity, plasticizers such as glycerol, sorbitol, CMC-Na, HPC, etc. may be included; thickeners may also be included to reduce flowability, and agar may be used as a thickener; in addition, coloring agent, antiseptic, etc. can be added. For the preparation process of the capsule, the capsule can be prepared by adopting a conventional preparation process.
The invention has the following beneficial effects:
the present invention provides a body-beneficial, orlistat-containing weight-loss pharmaceutical composition that exhibits a surprising weight-loss effect, while no significant adverse gastrointestinal reactions and liver function impairment are observed in patients, and no such effect is observed in flavonoids in combination with orlistat.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof.
Example one preparation of capsules containing orlistat (1000 granules, g)
Note that: escin is aesculin, and among them, the other prescriptions (1) to (3) and (6) and (9)) are all alpha-type aesculin except beta-type aesculin for prescription (4).
Clinical trial
1 data and method
1.1 general data
270 patients with primary obesity are selected, randomly divided into 9 groups, 30 groups each, and ages 26-60, average age 42.36+ -8.12, average BMI (30.25+ -3.02) kg/m 2 . General data for gender, age, BMI, etc. of each group of patients were compared without statistical differences (P > 0.05).
1.2 diagnostic criteria for obesity
Reference is made to dialectical standards in the national expert consensus for prevention and treatment of adult obesity: (1) Obesity = [ (measured body mass-standard body mass)/standard body mass]X 100%; adult standard body mass (kg) = [ height (cm) -100]X 0.9, obesity is defined as obesity with obesity degree > 20%; (2) Body Mass Index (BMI) =body mass (kg)/height 2 (m 2 ) With BMI not less than 24kg/m 2 Is overweight, and the BMI is more than or equal to 28kg/m 2 Is obese; (3) Percent body fat (F%) =fat content/body mass x 100%, with men > 25% obese and women > 30% obese.
1.3 inclusion criteria
(1) Meets the national expert consensus for preventing and treating adult obesity [5 ]]Is based on the syndrome differentiation criteria; (2) Over standard body weight > 20%, or BMI over 24kg/m 2 The method comprises the steps of carrying out a first treatment on the surface of the (3) age 25-70 years; (4) Patients and family members sign informed consent, and the study meets the requirements of the world medical society, helsinki statement revised in 2013.
1.4 exclusion criteria
(1) Secondary obesity; (2) those with diabetes, hyperlipidemia or heart disease; (3) Combining liver and kidney insufficiency, mental diseases and systemic infectious diseases; (4) allergic constitution; (5) females in gestation or lactation.
1.5 methods of treatment
Each group of patients is correspondingly given the corresponding medicine, and the medicine is taken for 1 hour after meal or 1 hour after meal for one dose/time, 3 times/d, and the treatment is continued for 12 weeks.
1.6 observations index
1.6.1 weight, BMI and percent body fat changes
1.6.2 adverse reactions
1.6.2.1 observations of gastrointestinal side reactions: the adverse gastrointestinal reaction conditions, such as fatty stool, diarrhea, abdominal pain, and increased gastrointestinal exhaust, were counted during the administration of each group of patients. Adverse reactions were counted in the form of questionnaires, which were timely and accurate filled out by each group of patients daily from the first day of the test, and gastrointestinal conditions were recorded.
1.6.2.2 liver function observation: the fasting venous blood of the patient is extracted for 10mL before treatment and after 12 weeks of treatment, and after serum is separated, liver function indexes are detected.
2. Statistical method
Processing test data using SPSS, metering data usingThe representation uses t-test and the count data comparison uses x 2 The difference is statistically significant when P < 0.05 is detected.
2 results
2.1 weight, BMI and percent body fat changes
Before administration, the weight, BMI and body fat percentage of each group of patients are not obviously different, and after administration, the weight, BMI and body fat percentage of each group of patients are obviously reduced (P is less than 0.05); wherein, a synergistic weight loss effect is observed in the combination of the two configurations of aesculin or ergot saponin and orlistat, and experimental data show that the simultaneous administration of aesculin or ergot saponin has significant differences in weight, BMI and body fat percentages (P < 0.01) in patients with orlistat as compared to patients with orlistat alone; the weight and fat reducing effects of mangiferin and orlistat are not as good as those of horse chestnut saponin or ergot saponin and orlistat, and the effects are equivalent to those of orlistat alone, as shown in Table 1.
TABLE 1 weight, BMI and percent body fat changes
Note that: compared with the preparation before the medicine is taken, * P＜0.05， ** p is less than 0.01; in contrast to the group (5), # P＜0.05， ## P＜0.01。
2.2 adverse reaction observations
The phenomenon of fatty stool, fat writing, abdominal pain or increased gastrointestinal exhaustion can be observed in part of patients after 12 weeks of orlistat administration alone (a plurality of adverse gastrointestinal reactions exist in most patients simultaneously); compared with the single administration of orlistat, the simultaneous administration of the alpha-horse chestnut saponin and the orlistat can obviously relieve gastrointestinal adverse reactions caused by the orlistat. The phenomenon of relieving adverse gastrointestinal reaction is also observed when mangiferin and orlistat are simultaneously administered, but the effect is not as good as when alpha-type horse chestnut saponin and orlistat are administered; and when the aesculin is beta-form, no effect of significantly reducing the gastrointestinal reaction of orlistat is observed. This also occurs when ergot saponin replaces horse chestnut saponin, see table 2.
TABLE 2 observations of gastrointestinal side effects (n)
| Prescription of prescription | n | Fatty stool | Diarrhea with fat | Abdominal pain | Increased gastrointestinal bleed |
| ① | 30 | 0 | 0 | 0 | 0 |
| ② | 30 | 0 | 0 | 0 | 0 |
| ③ | 30 | 0 | 0 | 0 | 0 |
| ④ | 30 | 8 | 12 | 8 | 15 |
| ⑤ | 30 | 12 | 16 | 10 | 20 |
| ⑥ | 30 | 0 | 0 | 0 | 1 |
| ⑦ | 30 | 10 | 12 | 5 | 22 |
| ⑧ | 30 | 8 | 10 | 6 | 14 |
| ⑨ | 30 | 3 | 2 | 3 | 5 |
The content of alanine aminotransferase ALT, total bilirubin Tbil and aspartic acid aminotransferase AST in serum of patients after 12 weeks of single orlistat administration is still in a normal range, but each function index is obviously increased (P < 0.01) compared with that before treatment, which indicates that the liver injury trend possibly exists; the alpha-aesculin and the orlistat are not obviously different from ALT, tbil and AST before and after treatment, so that the safety is high; however, when the aesculin is beta-type, a significant increase in ALT, tbil and AST levels was also observed, which also occurs when ergot saponin or mangiferin is substituted for aesculin, see table 3.
TABLE 3 liver function observations
Note that: in contrast to the pre-treatment period, * P＜0.05， ** P＜0.01。
overall, the administration of alpha-escin in combination with orlistat showed surprising efficacy, in particular a weight loss effect significantly better than orlistat alone, and significantly reduced gastrointestinal adverse effects and liver function damage caused by orlistat alone, and it was not surprising that this effect was not observed in other pharmaceutical combinations.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (7)
1. A weight-reducing composition comprising orlistat, characterized in that it comprises orlistat and horse chestnut saponin; the weight ratio of the orlistat to the horse chestnut saponin is 1:0.3 to 0.8; the aesculin is alpha-type aesculin.
2. The weight loss composition according to claim 1, wherein the weight ratio of orlistat to horse chestnut saponin is 1:0.5.
3. the weight loss composition according to claim 1, wherein the weight ratio of orlistat to horse chestnut saponin is 1:0.3.
4. the weight loss composition according to claim 1, wherein the weight ratio of orlistat to horse chestnut saponin is 1:0.6.
5. use of the slimming composition according to any one of claims 1 to 4 for the preparation of a slimming drug.
6. A weight-reducing medicament containing orlistat, comprising the weight-reducing composition according to any one of claims 1 to 4.
7. The weight loss medication of claim 6, wherein the medication is formulated in the form of a capsule or granule.
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