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WO2021097651A1 - Composition pharmaceutique comprenant de l'orlistat et un inhibiteur de lipase d'origine végétale - Google Patents

Composition pharmaceutique comprenant de l'orlistat et un inhibiteur de lipase d'origine végétale Download PDF

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Publication number
WO2021097651A1
WO2021097651A1 PCT/CN2019/119382 CN2019119382W WO2021097651A1 WO 2021097651 A1 WO2021097651 A1 WO 2021097651A1 CN 2019119382 W CN2019119382 W CN 2019119382W WO 2021097651 A1 WO2021097651 A1 WO 2021097651A1
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WO
WIPO (PCT)
Prior art keywords
orlistat
lipase inhibitor
lipase
molar ratio
polyphenol
Prior art date
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Ceased
Application number
PCT/CN2019/119382
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English (en)
Chinese (zh)
Inventor
向飞
杜志博
彭韪
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Zhongshan Wanhan Pharmaceutical Co Ltd
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Zhongshan Wanhan Pharmaceutical Co Ltd
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Priority to PCT/CN2019/119382 priority Critical patent/WO2021097651A1/fr
Publication of WO2021097651A1 publication Critical patent/WO2021097651A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to the technical field of medicine, in particular to a pharmaceutical composition containing orlistat and a plant-derived lipase inhibitor.
  • Orlistat is a lipase inhibitor weight-loss drug developed by Roche Pharmaceuticals under the trade name Xenical. It was the first to be marketed in Europe and the United States in the late 1990s. It was listed in China in 2001 and was approved by China Food in 2005. The Drug Administration approved the conversion to over-the-counter drugs.
  • Its chemical name is N-formyl-L-leucine(s)-1[(2s,3s)3-hexyl-4oxy-2-epoxypropylmethyl]dodecyl ester, also known as tetrahydro Lipostatin (Tetrahydrolipstatin, THL) is a semi-synthetic lipostatin derivative, and its chemical structure is shown in the following formula:
  • Orlistat forms a covalent bond with the serine residue of gastric pancreatic lipase, which inactivates the enzyme, and cannot hydrolyze triglycerides in food into absorbable fatty acids, thereby reducing the amount of fat absorbed.
  • Orlistat is the only chemical weight loss drug that does not affect appetite and does not act on the central nervous system at home and abroad. It has superior safety characteristics.
  • An article published by Bray GA in The Lancet is called Management of Obesity's article described orlistat as the "safest" weight loss drug.
  • orlistat can only inhibit 30% of fat absorption after oral administration. Bray GA et al.
  • lipase inhibitors that have been approved for marketing at home and abroad are orlistat and cetilistat.
  • the former can be obtained by total synthesis or semi-synthesis, and the latter can only be obtained by total synthesis.
  • plants also contain a wealth of lipase inhibitors, and their structure types include polyphenols, saponins, terpenes, flavonoids, alkaloids, etc.
  • the lipase inhibitor extracted from tea not only has the advantages of wide sources, diverse structures, high specificity, low toxicity, etc., but also because it acts on different active sites of lipase, it may produce synergistic weight loss with orlistat effect.
  • the purpose of the present invention is to provide a pharmaceutical composition containing orlistat and polyphenol lipase inhibitors extracted from tea, the active ingredients in the pharmaceutical composition It can produce a synergistic lipase inhibitory effect, and has a good weight loss effect, and can be used to treat and prevent obesity.
  • the present invention provides a pharmaceutical composition for the treatment and prevention of obesity.
  • the pharmaceutical composition comprises orlistat and a plant-derived lipase inhibitor.
  • the plant-derived lipase inhibitor is from tea Polyphenolic lipase inhibitor extracted from it.
  • the lipase inhibitor extracted from the tea leaves is selected from at least one compound whose structural formula is shown in the following formula.
  • the in vitro test results show that the molar ratio (ratio of the amount of substance) of orlistat in the pharmaceutical composition for the treatment and prevention of obesity provided by the present invention and the polyphenol lipase inhibitor extracted from tea is 1: In the range of 10-10:1, the interaction index of inhibiting lipase activity is lower than 1, indicating that the two have a synergistic lipase inhibitory effect.
  • the polyphenol lipase inhibitor is a compound represented by formula I (compound 1)
  • the molar ratio of compound 1 to orlistat is 1:9 to 1:6. More preferably, the molar ratio of compound 1 to orlistat is 1:7.75.
  • the polyphenol lipase inhibitor is a compound represented by formula II (compound 2)
  • the molar ratio of compound 2 to orlistat is 1:4 to 1:2. More preferably, the molar ratio of compound 2 to orlistat is 1:3.
  • the polyphenol lipase inhibitor is a compound represented by formula III (compound 3)
  • the molar ratio of compound 3 to orlistat is 1:2 to 2:1. More preferably, the molar ratio of compound 3 to orlistat is 1.25:1.
  • the polyphenol lipase inhibitor is a compound represented by formula VI (compound 4)
  • the molar ratio of compound 4 to orlistat is 1:4 to 1:1. More preferably, the molar ratio of compound 4 to orlistat is 1:2.5.
  • animal test results show that orlistat and polyphenol lipase inhibitors extracted from tea in the pharmaceutical composition for the treatment and prevention of obesity provided by the present invention are the most preferred according to in vitro tests.
  • the molar ratio of the combination, calculated by mole ratio, the total dose is the same, and the doses of orlistat and polyphenol lipase inhibitor in the composition are both lower than the two separate administration groups under the premise that the composition has an effect on nutrition
  • the weight control effect of obese rats is better than that of the orlistat group and the polyphenol lipase inhibitor alone administration group, further verifying the synergy.
  • the present inventors were surprised to find that when orlistat was used in combination with polyphenol lipase inhibitors, the number of animals with grease distribution in rat hair in the test group was significantly reduced, suggesting the drug combination provided by the present invention
  • the compound can reduce the probability of the appearance of grease in rat hair, and the polyphenol lipase inhibitor can reduce the unpleasant gastrointestinal side effects of orlistat, and alleviate adverse reactions such as oil spots, fat/oily stools and the like.
  • the pharmaceutical composition for the treatment and prevention of obesity provided by the present invention can be used directly, or one or more pharmaceutical excipients can be added and an oral preparation, such as a powder, can be prepared by a preparation method well known to those skilled in the art. , Granules, capsules, tablets, pills, etc.
  • the preparation methods well-known to those skilled in the art can refer to but not limited to the editor-in-chief Cui Fude, "Pharmaceuticals” (7th edition) (published by People's Medical Publishing House), which is incorporated herein by reference.
  • the polyphenol lipase inhibitor extracted from the tea can be mixed with at least one pharmaceutically acceptable excipient, such as citric acid or dicalcium phosphate , Or: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as cellulose derivatives, starch, alginate, gelatin, Polyvinylpyrrolidone, sucrose and acacia gum; (c) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicate and sodium carbonate; d) Solution retarders, such as paraffin; (e) absorption enhancers, such as quaternary ammonium compounds; (f) wetting agents, such as cetyl alcohol and glyceryl monostearate, magnesium stearate, etc.; (g ) Adsorbents, such as kaolin and
  • the pharmaceutical composition provided by the present invention is made into a capsule by adding an appropriate amount of pharmaceutical excipients.
  • the present invention discloses for the first time that the composition of orlistat and polyphenol lipase inhibitors (compounds represented by formula I-VI) extracted from tea has a synergistic lipase inhibitory effect, and it is applied to the treatment or prevention of obesity
  • the disease has a good synergistic gain effect, and the weight control effect on the nutritionally obese rats is significantly better than the orlistat group and the polyphenol lipase inhibitor alone administration group.
  • the polyphenols Lipase inhibitors can also reduce the unpleasant gastrointestinal side effects of orlistat, relieve oily spots, fat/oily stools and other adverse reactions, achieving unexpected results.
  • Figure 1 is a graph showing the relationship between the interaction index (Y) of compound 1 and orlistat and the molar ratio of the two (molar ratio range 1:10-10:1).
  • Figure 2 is a graph showing the relationship between the interaction index (Y) and the molar ratio of the compound 1 and orlistat (preferred molar ratio range).
  • Figure 3 is a diagram showing the relationship between the interaction index (Y) of compound 2 and orlistat and the molar ratio of the two (molar ratio range 1:10-10:1).
  • Figure 4 is a graph showing the relationship between the interaction index (Y) and the molar ratio of the compound 2 and orlistat (preferred molar ratio range).
  • Figure 5 is a diagram showing the relationship between the interaction index (Y) of compound 3 and orlistat and the molar ratio of the two (molar ratio range 1:10-10:1).
  • Fig. 6 is a graph showing the relationship between the molar ratio of the interaction index (Y) of compound 3 and orlistat (preferred range of molar ratio).
  • Figure 7 is a diagram showing the relationship between the molar ratio of the interaction index (Y) of compound 4 and orlistat (molar ratio range 1:10-10:1).
  • Figure 8 is a graph showing the relationship between the molar ratio of the interaction index (Y) of compound 4 and orlistat (preferred range of molar ratio).
  • test methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used, unless otherwise specified, are commercially available reagents and materials.
  • Zhongshan Wanyuan New Drug Research and Development Co., Ltd.
  • Zhongshan Wanyuan New Drug Research and Development Co., Ltd.
  • the present invention adopts the lipase inhibitory activity assay method disclosed by Nakai M et al. (Journal of Agricultural and Food Chemistry, 2005, 53(11):4593 ⁇ 4598), and uses the interaction index (Y) as an indicator to investigate The synergistic inhibitory effect of orlistat and a single polyphenol lipase inhibitor combined with a molar ratio of 1:10 to 10:1 on lipase activity, and the optimal molar ratio was screened. The results are shown in Figure 1 -8 shown.
  • the calculation method of the interaction index (Y) is shown in the following formula.
  • IC50(A) and IC50(B) respectively represent the IC50 value of lipase when orlistat is treated with one of the corresponding compounds 1-4 separately
  • IC50(mixA) and IC50(mixB) respectively represent mixed The concentration of orlistat and the corresponding polyphenol lipase inhibitor when the system produces half inhibition of lipase.
  • Test Example 1 The weight loss effect of the combination of orlistat and polyphenol lipase inhibitors on nutritionally obese rats
  • Test group D 15 rats in each group.
  • the definitions and treatment methods of the blank control group, model group and orlistat group are consistent with those disclosed by Liu Jingru et al.; the experimental group A1-4 was fed with nutrient feed while the rats were fed with compounds 1-4 respectively.
  • the pretreatment method before gavage is the same as the orlistat group, and the dosage is the same as that of the orlistat group, which is 0.121mmol/kg/d.
  • the test group B1-4 while feeding the rats with nutritious feed, the compound 1-4 and orlistat were combined according to the most preferred substance ratio measured in the in vitro test, and then gavage the rats before gavage.
  • the pretreatment method is the same as that of the orlistat group, and the total dose of the two active ingredients in the combination is the same as that of the orlistat group, which is 0.121mmol/kg/d.
  • experimental group C while feeding the rats with nutritive feed, they were given epigallocatechin gallate (EGCG, purchased from Shaanxi Sovere Natural Products Co., Ltd.) by gavage.
  • EGCG epigallocatechin gallate
  • the pretreatment method before gavage was the same as that of Orly In the stat group, the dose is the same as the orlistat group in terms of the amount of substance, that is, 0.121mmol/kg/d.
  • mice while feeding the rats with nutritious feed, they were given a combination of epigallocatechin gallate and orlistat at a ratio of 1:1 and then gavage.
  • the pretreatment method before gavage was the same
  • the orlistat group the total dose of the two active ingredients in the combination is the same as the orlistat group, which is 0.121mmol/kg/d.
  • the weight changes of the animals in each group were observed, and the number of animals with fat distribution in the hair of nutritionally obese rats was counted, and the probability of fat was calculated. The results are shown in Tables 1 and 2 below.
  • the present invention confirms that the combined application of EGCG and orlistat has a slightly better effect on inhibiting weight gain in rats than the EGCG group alone or the orlistat group alone, but there is no significant difference, indicating that EGCG and orlistat His combination did not produce a synergistic effect.
  • the above results indicate that only when a specific polyphenol lipase inhibitor is combined with orlistat can a synergistic weight loss effect be obtained.
  • the mixed powder is slowly added to a 50% ethanol solution containing 10% povidone K30 to make soft material, 20 mesh squeezed through a sieve to make granules, and the wet granules are dried in a blast drying oven at 30°C for 6 hours, and the 20 mesh sieve is taken out Take the whole capsule and put it into No. 0 capsule to get it.
  • microcrystalline cellulose as filler, croscarmellose sodium and polyvinylpyrrolidone as disintegrants, and 5% PVP 60% ethanol solution as binder.
  • Micronized silica gel is a glidant, which is granulated in a fluidized bed in one step, and then compressed into tablets.
  • Preparation process According to the preparation process of the sustained-release tablet, it can be prepared into a sustained-release tablet.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Child & Adolescent Psychology (AREA)
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  • Diabetes (AREA)
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  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention divulguée concerne une composition pharmaceutique comprenant de l'orlistat et un inhibiteur de lipase d'origine végétale. L'inhibiteur de lipase d'origine végétale est un inhibiteur de lipase polyphénol extrait du thé. Les résultats de tests in vitro montrent que lorsque le rapport molaire de l'orlistat et de l'inhibiteur de lipase polyphénol se situe dans la plage de 1:10 à 10 :1, l'indice d'interaction d'inhibition de l'activité lipase est inférieur à 1, indiquant que les deux ont un effet inhibiteur de lipase synergique. Les résultats de test sur animaux montrent que l'effet de la composition comprenant de l'orlistat et l'inhibiteur de lipase polyphénol sur la régulation du poids de rats présentant une obésité nutritionnelle est meilleur que celui du groupe comprenant l'administration indépendante d'un groupe orlistat et de l'inhibiteur de lipase polyphénol, vérification supplémentaire de la production d'un effet synergique. De plus, l'inhibiteur de lipase polyphénol peut réduire les effets secondaires gastro-intestinaux désagréables de l'orlistat, et atténuer les boutons de gras, les selles grasses/huileuses et d'autres réactions indésirables.
PCT/CN2019/119382 2019-11-19 2019-11-19 Composition pharmaceutique comprenant de l'orlistat et un inhibiteur de lipase d'origine végétale Ceased WO2021097651A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115490740A (zh) * 2022-07-14 2022-12-20 广西壮族自治区中国科学院广西植物研究所 具有脂肪酶抑制活性的酚类成分及其制备方法、盐、脂化衍生物、药物和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108542903A (zh) * 2018-04-11 2018-09-18 中山万汉制药有限公司 一种含有奥利司他与植物来源脂肪酶抑制剂的药物组合物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108542903A (zh) * 2018-04-11 2018-09-18 中山万汉制药有限公司 一种含有奥利司他与植物来源脂肪酶抑制剂的药物组合物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115490740A (zh) * 2022-07-14 2022-12-20 广西壮族自治区中国科学院广西植物研究所 具有脂肪酶抑制活性的酚类成分及其制备方法、盐、脂化衍生物、药物和应用

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