WO2016161683A1 - Composition pharmaceutique de statine, et formulation de capsule et son procédé de préparation - Google Patents

Composition pharmaceutique de statine, et formulation de capsule et son procédé de préparation Download PDF

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Publication number
WO2016161683A1
WO2016161683A1 PCT/CN2015/078263 CN2015078263W WO2016161683A1 WO 2016161683 A1 WO2016161683 A1 WO 2016161683A1 CN 2015078263 W CN2015078263 W CN 2015078263W WO 2016161683 A1 WO2016161683 A1 WO 2016161683A1
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WO
WIPO (PCT)
Prior art keywords
polyethylene glycol
colchicine
statin
vitamin
succinate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2015/078263
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English (en)
Chinese (zh)
Inventor
李小羿
戴向荣
叶文锐
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ZHAOKE PHARMACEUTICAL (GUANGZHOU) Co Ltd
Original Assignee
ZHAOKE PHARMACEUTICAL (GUANGZHOU) Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2016161683A1 publication Critical patent/WO2016161683A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/366—Lactones having six-membered rings, e.g. delta-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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a statin pharmaceutical composition and a capsule preparation, and a preparation method thereof.
  • Cardiovascular diseases generally refer to ischemic or hemorrhagic diseases of the heart and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, and hypertension. It is a common disease that seriously threatens the health of human beings, especially middle-aged and older people over the age of 50. The number of people who die of cardiovascular and cerebrovascular diseases every year in the world is as high as 15 million, ranking first in all causes of death.
  • Statins are commonly used drugs for the treatment of cardiovascular diseases, but existing statins do not specifically address the occurrence and development of cardiovascular disease inflammation. Atherosclerotic plaques are prone to damage, making neutrophils easy to infiltrate, which in turn causes an aggressive inflammatory response, leading to plaque instability, increasing the risk of plaque enlargement and rupture, thus increasing clinical cardiovascular disease. risk. Therefore, targeted inhibition of neutrophil function in plaque can increase the stability of plaque, thereby reducing the incidence of cardiovascular disease.
  • Colchicine is widely used in the treatment of gout, and it has a unique anti-inflammatory effect, including inhibition of neutrophil function by inhibiting tubulin.
  • colchicine Although the combination of colchicine and statin can enhance the effect of treating stable coronary heart disease, the therapeutic index of colchicine is narrower, and the effective concentration (0.3-4 ng/mL) is lower than the toxicity concentration (>5 ng/mL). Small, and, colchicine itself is a substrate for P-glycoprotein, which can significantly increase its blood in combination with P-glycoprotein inhibitors (including erythromycin, cyclosporine A, verapamil, etc.). The concentration in the medium reaches a toxic concentration, which induces serious adverse reactions, and even certain foods (such as grapefruit juice) also have this effect.
  • P-glycoprotein inhibitors including erythromycin, cyclosporine A, verapamil, etc.
  • the object of the present invention is to provide a statin composition and a capsule preparation, and a preparation method thereof, and the statin composition provided by the invention has low toxicity.
  • the present invention provides a statin composition comprising the following mass fractions of components:
  • statin 0.01 to 5% colchicine and 85 to 98% polyethylene glycol 1000 vitamin E succinate.
  • the statin comprises one or more of simvastatin, atorvastatin calcium, pravastatin calcium and rosuvastatin calcium.
  • the statin comprises one or more of simvastatin, atorvastatin calcium and rosuvastatin calcium;
  • the mass fraction of the statin is from 1 to 8%.
  • the colchicine has a mass fraction of 0.02 to 3%.
  • the polyethylene glycol 1000 vitamin E succinate has a mass fraction of 90 to 97%.
  • the present invention provides a capsule formulation comprising a content comprising the above-described statin composition and adjuvant.
  • the excipient comprises lauric acid polyethylene glycol glyceride, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, ethanol, propylene glycol and caprylic acid phthalic acid polyethylene One or more of the alcohol glycerides;
  • the mass fraction of the excipient in the content is 5 to 19%.
  • the auxiliary material comprises one or more of polyethylene glycol 200, propylene glycol and polyglycol phthalate of caprylic acid;
  • the mass fraction of the excipient in the content is 8 to 15%.
  • the invention provides a preparation method of a capsule preparation, comprising the following steps:
  • step B) mixing 0.1 to 10% of the statin, 0.01 to 5% of colchicine, and the mixed adjuvant obtained in the step A) by mass fraction to obtain a content;
  • step B) The contents obtained in the step B) are filled into capsules to obtain a capsule preparation.
  • the temperature of the mixing in the step A) is 38 to 80 ° C;
  • the temperature of mixing in the step B) is 38 to 80 °C.
  • the present invention provides a statin composition
  • a statin composition comprising the following components in mass fraction: 0.1 to 10% statin, 0.01 to 5% colchicine, and 85 to 98% polyethylene glycol 1000 vitamin E Succinate.
  • the polyethylene glycol 1000 vitamin E succinate can inhibit the P-glycoprotein in advance, and can prevent the statin from interacting with the colchicine by affecting the P-glycoprotein, thereby Reduces gastrointestinal toxicity and other toxicity of colchicine.
  • polyethylene glycol 1000 vitamin E succinate increased the bioavailability of colchicine, reduced the therapeutic effective dose of colchicine, and further reduced the toxicity of colchicine.
  • the present invention provides a statin composition
  • a statin composition comprising the following components in mass fraction: 0.1 to 10% statin, 0.01 to 5% colchicine, and 85 to 98% polyethylene glycol 1000 vitamin E Succinate.
  • the polyethylene glycol 1000 vitamin E succinate in the statin composition provided by the invention can prevent the statin from interacting with colchicine by affecting the P-glycoprotein, thereby reducing the gastrointestinal of the colchicine Toxicity and other toxicities.
  • the statin composition provided by the present invention comprises a statin, and the statin preferably comprises one or more of simvastatin, atorvastatin calcium, pravastatin calcium and rosuvastatin calcium, and more Preferably, one or more of simvastatin, atorvastatin calcium and rosuvastatin calcium are included, most preferably including simvastatin and/or atorvastatin calcium; said statin is in said statin
  • the mass fraction in the pharmaceutical composition is from 0.1 to 10%, preferably from 1 to 8%, more preferably from 2 to 6%.
  • the statin composition provided by the present invention comprises colchicine, and the colchicine has a mass fraction of 0.01 to 5%, preferably 0.02 to 3%, more preferably 0.03 to 1 in the statin composition. %.
  • the statin composition provided by the present invention comprises polyethylene glycol 1000 vitamin E succinate, and the mass fraction of the polyethylene glycol 1000 vitamin E succinate in the statin composition is 85 to 98%. It is preferably 90 to 97%, more preferably 93 to 96%.
  • the polyethylene glycol 1000 vitamin E succinate can be converted into a vitamin after being absorbed into the body. E, supplementation with a certain amount of vitamin E is beneficial for patients with stable coronary heart disease.
  • the present invention also provides a capsule preparation comprising a content prepared from the statin composition and the adjuvant described in the above technical solution, wherein the statin composition is a statin as described in the above technical solution.
  • the pharmaceutical composition will not be described here.
  • the excipients include glycerol laurate, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, ethanol, propylene glycol, and caprylic acid phthalic acid.
  • ethylene glycol glycerides preferably one or more of polyethylene glycol 200, propylene glycol, and polyglycolic acid decanoic acid glyceride, more preferably polyethylene glycol 200 and / Or propylene glycol; the mass fraction of the adjuvant in the content is preferably from 5 to 19%, more preferably from 8 to 15%, most preferably from 9 to 13%.
  • the invention adopts the above-mentioned ratio of excipients combined with polyethylene glycol 1000 vitamin E succinate to obtain a temperature-sensitive capsule preparation, so that the capsule contents are presented in a solid form at room temperature, in the human gastrointestinal tract,
  • the conversion of the contents of the capsule into a liquid state facilitates the stability and uniformity of the contents of the capsule and also facilitates the preparation of the capsule.
  • capsule preparations are safer and more effective in treating stable coronary heart disease.
  • the capsule preparation provided by the present invention further comprises a capsule coated with a content
  • the capsule may be a hard capsule or a soft capsule, preferably a hard capsule, and the capsule is preferably of the type 000, 00 or 0.
  • the invention also provides a preparation method of a capsule preparation, comprising the following steps:
  • A) 80 to 90% of polyethylene glycol 1000 vitamin E succinate and 5 to 19% of auxiliary materials are mixed in a mass fraction to obtain a mixed auxiliary.
  • the excipients include glycerol laurate, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, ethanol, propylene glycol, and polyglycolic acid decanoic acid glyceride One or several of them;
  • step B) mixing 0.1 to 10% of the statin, 0.01 to 5% of colchicine, and the mixed adjuvant obtained in the step A) by mass fraction to obtain a content;
  • step B) The contents obtained in the step B) are filled into capsules to obtain a capsule preparation.
  • the polyethylene glycol 1000 vitamin E succinate and 5 to 19% of an auxiliary material are mixed to obtain a mixed auxiliary material, and the polyethylene glycol 1000 vitamin E amber is preferably used in the present invention.
  • the acid ester is heated to a liquid state, and then the liquid polyethylene glycol 1000 vitamin E
  • the succinate is mixed with the auxiliary material to obtain a mixed auxiliary.
  • the invention combines polyethylene glycol 1000 vitamin E succinate and auxiliary materials in a certain ratio to prepare a temperature sensitive capsule preparation, so that the capsule contents are presented in solid form at room temperature, in the human stomach. In the channel, the contents of the capsule are converted into a liquid state; it is advantageous for the stability and uniformity of the contents of the capsule, and is also convenient for the preparation of the capsule.
  • the source of the polyethylene glycol 1000 vitamin E succinate is consistent with the source of the polyethylene glycol 1000 vitamin E succinate in the above technical solution, and will not be described herein; the type of the auxiliary material and The source is the same as the adjuvant in the capsule preparation described in the above technical scheme, and will not be described herein.
  • the polyethylene glycol 1000 vitamin E succinate has a mass fraction of 80 to 90%, preferably 82 to 88%, more preferably 83 to 86%; and the mass fraction of the auxiliary material is 5 to 19%, preferably 8 to 15%, more preferably 9 to 13%.
  • the heating temperature of the polyethylene glycol 1000 vitamin E succinate is preferably 38 to 80 ° C, more preferably 40 to 70 ° C, and most preferably 50 to 60 ° C;
  • the heating time of the diol 1000 vitamin E succinate is not particularly limited, and it can be melted to a liquid state;
  • the temperature at which the polyethylene glycol 1000 vitamin E succinate is mixed with the auxiliary material is preferably 38 to 80 ° C, It is preferably 40 to 70 ° C, and most preferably 50 to 60 ° C.
  • the time for mixing the polyethylene glycol 1000 vitamin E succinate and the auxiliary material in the present invention is not particularly limited, and the two can be uniformly mixed.
  • the present invention mixes 0.1 to 10% of the statin and 0.01 to 5% of the colchicine with the mixed adjuvant obtained in the step A) in terms of mass fraction to obtain a content, and the present invention preferably The statin and the colchicine are separately pulverized, and then mixed with the obtained mixed auxiliary material to obtain a content.
  • the types and sources of the statins and colchicine are the same as those of the statins and colchicines in the above technical solutions, and will not be described herein.
  • the mass fraction of the statin is 0.1 to 10%, preferably 1 to 9%, more preferably 2 to 6%; and the mass fraction of the colchicine is 0.01 to 5%, preferably 0.02 to 1%, more preferably 0.03 to 0.2%.
  • the method and the particle size of the statin and colchicine pulverization of the present invention are not particularly limited, and a pulverization method commonly used by those skilled in the art may be employed.
  • the temperature at which the statin, the colchicine, and the mixed auxiliary are mixed Preferably, it is 38 to 80 ° C, more preferably 40 to 70 ° C, and most preferably 50 to 60 ° C; the present invention has no particular limitation on the time of mixing the statin, colchicine and the mixed adjuvant, and can The above materials can be mixed evenly.
  • the present invention fills the content into a capsule to obtain a capsule preparation.
  • the type and model of the capsule are the same as those of the above-mentioned technical solution, and will not be described herein.
  • the obtained content is preferably filled in a capsule, and then cooled to room temperature to obtain a capsule preparation.
  • the capsule preparation provided by the invention has a solid content in the capsule under the condition of room temperature (25 ° C), but under the condition of human body temperature (37 ° C), the content is in a liquid state, which is favorable for the stability and uniformity of the contents of the capsule. It is also convenient for the preparation of capsules.
  • the present invention provides a statin composition
  • a statin composition comprising the following components in mass fraction: 0.1 to 10% statin, 0.01 to 5% colchicine, and 85 to 98% polyethylene glycol 1000 vitamin E Succinate.
  • the polyethylene glycol 1000 vitamin E succinate can inhibit the P-glycoprotein in advance, and can prevent the statin from interacting with the colchicine by affecting the P-glycoprotein, thereby Reduces gastrointestinal toxicity and other toxicity of colchicine.
  • polyethylene glycol 1000 vitamin E succinate increased the bioavailability of colchicine, reduced the therapeutic effective dose of colchicine, and further reduced the toxicity of colchicine.
  • statin and the colchicine which are active ingredients for treating coronary heart disease
  • the statin composition provided by the present invention reduces the colchicine. At the same time of toxicity, it maintains a good therapeutic effect on coronary heart disease.
  • the invention also provides a preparation method of a capsule preparation and a capsule preparation, wherein the polyethylene glycol 1000 vitamin E succinate and the auxiliary material are combined in a certain ratio to prepare a temperature sensitive capsule preparation, thereby making The contents of the capsule are presented in solid form at room temperature.
  • the contents of the capsule are converted into a liquid state; the stability and uniformity of the contents of the capsule are facilitated, and the preparation of the capsule is also facilitated.
  • the capsule preparation provided by the invention can also increase the compliance and tolerance of the medication, and ultimately safe and effective treatment for patients with stable coronary heart disease.
  • statin pharmaceutical composition and a capsule preparation provided by the present invention and a preparation method thereof are described in detail below with reference to examples, but it should not be construed as The scope of protection of the present invention is limited.
  • Table 1 is the ratio of the raw materials and the amount of the drug in the first embodiment of the present invention.
  • the experimental animals were female rats (180 g to 200 g), with 6 rats in each group.
  • 0.3 ml blood samples were collected at the time points of 15 min, 30 min, 45 min, 1 h, 1.5 h, 3 h, 4 h, 6 h and 24 h after administration of the test solution.
  • Anticoagulation the concentration of colchicine in plasma was determined by HPLC, and the pharmacokinetic parameters were calculated.
  • Table 2 shows the results of the pharmacokinetic experiments of Example 1 of the present invention, and the data shown in Table 2 is the mean value ⁇ standard deviation of each set of experimental data.
  • the experimental animals were 350 g to 400 g male rats, 5 rats in each group, and the bile duct cannulation and carotid artery cannulation were performed under anesthesia (the anesthesia state was maintained during the experiment), and the four groups of drugs as shown in Table 3 were used respectively. Injection into the tail vein.
  • the specific administration method is as follows: firstly, administration of polyethylene glycol 1000 vitamin E succinate (using physiological saline containing 50% concentration of propylene glycol as a solvent), and then giving colchicine after 30 minutes (using a physiological saline containing 50% concentration of propylene glycol) For the solvent).
  • Table 4 is a pharmacokinetic parameter of colchicine in rat bile and plasma according to Example 2 of the present invention.
  • the results shown in Table 4 indicate that polyethylene glycol 1000 vitamin E succinate significantly reduced the secretion of colchicine in bile in a dose-dependent manner with a maximum reduction of approximately 75%.
  • Group Test article dose 1 Colchicine 10mg/kg 2 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 10mg/kg+2mg/kg 3 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 10mg/kg+10mg/kg 4 Colchicine + Polyethylene Glycol 1000 Vitamin E Succinate 10mg/kg+50mg/kg
  • the experimental animals were 300 g to 350 g male rats, 5 in each group, and administered according to the dosing schedule in Table 5.
  • Table 5 shows the administration formula and the administration amount of Example 3 of the present invention.
  • the specific administration method is as follows: first injection of polyethylene glycol 1000 vitamin E succinate (using physiological saline containing 50% concentration of propylene glycol as a solvent), and then administering colchicine (containing 50%) after 10 minutes.
  • the physiological saline of the concentration of propylene glycol is a solvent).
  • the fecal shape of the rats was recorded and scored before administration and the day after administration, and the evaluation criteria for diarrhea were evaluated. For: 0 (normal stool); 1 (mild, wet stool); 2 (moderate, unformed liquid feces with small stool particles); 3 points (severe, unformed liquid feces, not seen Small stool particles, perianal stained with stool color).
  • Table 6 is the diarrhea score of the rat in Example 3 of the present invention.
  • Table 6 the results showed that the diarrhea score of the polyethylene glycol 1000 vitamin E succinate-administered group was dose-dependently reduced compared with colchicine alone, with a maximum reduction of about 50%. , from severe to light to moderate.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique de statine comprenant des constituants des fractions en masse suivantes : 0,1-10 % de statines, 0,01-5 % de colchicine et 85-98 % de succinate de polyéthylène glycol 1000 et de vitamine E. Dans la composition pharmaceutique de statine, le succinate de polyéthylène glycol 1000 et de vitamine E peut inhiber des glycoprotéines P à l'avance, et peut empêcher des statines d'interagir avec la colchicine en affectant les glycoprotéines P, permettant ainsi de réduire la toxicité gastro-intestinale de la colchicine et d'autres toxicités. En même temps, le succinate de polyéthylène glycol 1000 et de vitamine E améliore la biodisponibilité de la colchicine, réduit la dose thérapeutiquement efficace de colchicine, et réduit davantage la toxicité de la colchicine.
PCT/CN2015/078263 2015-04-09 2015-05-05 Composition pharmaceutique de statine, et formulation de capsule et son procédé de préparation Ceased WO2016161683A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510167319.8 2015-04-09
CN201510167319.8A CN104739855A (zh) 2015-04-09 2015-04-09 一种他汀类药物组合物及胶囊制剂、其制备方法

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WO2016161683A1 true WO2016161683A1 (fr) 2016-10-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022129002A1 (fr) * 2020-12-15 2022-06-23 Dsm Ip Assets B.V. Dispersion grossière comprenant de la statine et de l'huile de vitamine e

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118717741A (zh) * 2024-01-15 2024-10-01 华中科技大学同济医学院附属协和医院 秋水仙碱在制备用于增加冠状动脉斑块纤维帽厚度药物中的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HUANG, CONGWU ET AL.: "Synergistic effects of colchicine combined with atorvastatin in rats with hyperlipidemia", LIPIDS IN HEALTH AND DISEASE, vol. 13, no. 67, 31 December 2014 (2014-12-31), pages 1 - 6, XP021184842 *
LI, YI ET AL.: "Application of colchicine on angiocardiopathy", CHINESE CIRCULATION JOURNAL, vol. 28, no. 7, 30 November 2013 (2013-11-30), pages 558 - 559 *
YU , YONGXIN ET AL.: "Development on application of Polyethylene 1000 Vitamin E and Succinate", SHENYANG PHARMACEUTICAL UNIVERSITY JOURNAL, vol. 23, no. 6, 30 June 2006 (2006-06-30), pages 407 - 412 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022129002A1 (fr) * 2020-12-15 2022-06-23 Dsm Ip Assets B.V. Dispersion grossière comprenant de la statine et de l'huile de vitamine e

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