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WO2018192000A1 - Comprimé de type pompe osmotique de périndopril et de sel correspondant et son procédé de préparation - Google Patents

Comprimé de type pompe osmotique de périndopril et de sel correspondant et son procédé de préparation Download PDF

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Publication number
WO2018192000A1
WO2018192000A1 PCT/CN2017/082099 CN2017082099W WO2018192000A1 WO 2018192000 A1 WO2018192000 A1 WO 2018192000A1 CN 2017082099 W CN2017082099 W CN 2017082099W WO 2018192000 A1 WO2018192000 A1 WO 2018192000A1
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WO
WIPO (PCT)
Prior art keywords
perindopril
osmotic pump
controlled release
pump type
type controlled
Prior art date
Application number
PCT/CN2017/082099
Other languages
English (en)
Chinese (zh)
Inventor
张耀华
陈丽
徐伟
周敏
钱十银
Original Assignee
上药东英（江苏）药业有限公司
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
Application filed by 上药东英（江苏）药业有限公司 filed Critical 上药东英（江苏）药业有限公司
Publication of WO2018192000A1 publication Critical patent/WO2018192000A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention belongs to the technical field of medicine, and relates to a perindopril osmotic pump type controlled release tablet and a preparation method thereof. Background technique
  • the osmotic pump type controlled release preparation is based on osmotic pressure and has zero release kinetics as a release characteristic, and can release the drug at a constant speed within a certain time range.
  • the release of drugs is largely independent of physiological parameters such as pH value, gastric emptying time, peristalsis, etc., and the correlation between the body and the outside is good, and the drug can be adjusted.
  • the release characteristics optimize the pharmacodynamic effect of the system; the phenomenon that the blood drug concentration caused by the common oral preparation fluctuates greatly, the adverse reaction is alleviated, and the safety and effectiveness of the drug are greatly improved.
  • osmotic pump controlled release preparations such as nifedipine controlled release tablets, prazosin controlled release tablets, glipizide controlled release tablets, etc., which have been marketed abroad, have achieved good therapeutic and commercial effects. .
  • Osmotic pump type controlled release preparations mainly include oral osmotic pumps, microporous osmotic pumps, and implantable osmotic pumps.
  • oral osmotic pump preparation is an oral osmotic pump, which generally consists of a core and a coating film.
  • Oral osmotic pumps include single chamber osmotic pumps, multi-chamber osmotic pumps and liquid osmotic pumps.
  • the single-chamber osmotic pump has the simplest structure and preparation process, and uses a conventional tablet preparation process to compress the drug and a suitable osmotic active substance into a tablet core, and then uses a water-insoluble polymer material such as cellulose acetate to the core.
  • the coating is carried out to prepare a semi-permeable coating film, and then a small hole having a suitable pore diameter is formed by laser or mechanical means on the film.
  • the moisture in the environmental medium can penetrate into the core through the semipermeable membrane to dissolve the osmotic active substance and the drug in the core, thereby forming a saturated solution of high osmotic pressure in the membrane.
  • the drug is released from the drug release hole and absorbed by the gastrointestinal tract.
  • the drug concentration in the membrane is The osmotic pressure is maintained constant to ensure a constant release rate during this period.
  • Angiotesion Converting Enzyme Inhibitors is a new and widely used antihypertensive and anti-congestive heart failure drug developed in the 1980s.
  • Perindopril is the third generation of potent, long-acting angiotensin-converting enzyme inhibitor (ACEI) that was developed in the early 1980s.
  • ACEI angiotensin-converting enzyme inhibitor
  • Perindopril hydrolyzes in vivo and acts as an active metabolite, perindopril. Its antihypertensive mechanism is to block the conversion of angiotensin I into an active blood vessel.
  • perindopril has a significant antihypertensive effect and is well tolerated. It not only effectively lowers blood pressure, but also reverses vascular abnormalities associated with hypertension and reduces cardiovascular morbidity and mortality. Therefore, perindopril plays an important role in the treatment of hypertension and the prevention and treatment of cardiovascular diseases. However, the production of perindopril is affected by diet, and the food changes the bioavailability of its active metabolite, perindopril.
  • Perindopril tablets must be taken before meals.
  • the commercially available preparation is an ordinary matrix-type sustained-release preparation, which is administered once a day to reduce the frequency of drug administration and improve patient compliance.
  • the drug release of the matrix-type sustained-release tablet is easily affected by the gastrointestinal environment such as gastrointestinal motility and pH, especially in the case of gastrointestinal motility, the matrix is destroyed and loses the sustained release effect, and the sustained and stable drug concentration cannot be maintained. Not conducive to the treatment of the disease. Therefore, there is still a need for a controlled release formulation of perindopril which is simple in process, ideal in release, and effective in efficacy.
  • the object of the present invention is to overcome the deficiencies of the currently used clinically used perindopril tablets.
  • the osmotic pump type controlled release tablets were prepared with perindopril as the main drug.
  • the advantage of the preparation is that the zero-order release kinetics is the release characteristic, and the drug can be released slowly and at a constant speed for a certain period of time, which is beneficial to maintaining the long-term and high-efficiency blood concentration in the body and improving the therapeutic effect of the drug.
  • the drug release rate is controlled by the prescription design, and the release rate is generally not Affected by gastrointestinal physiological factors such as peristalsis, pH, gastric emptying time and other variables, the correlation between internal and external is good.
  • the present invention provides an osmotic pump controlled release tablet of perindopril and a pharmaceutically acceptable salt thereof as a single chamber osmotic pump controlled release formulation comprising a single layer core, a semipermeable film coating and a drug delivery orifice.
  • a single chamber osmotic pump controlled release formulation comprising a single layer core, a semipermeable film coating and a drug delivery orifice.
  • the core of the osmotic pump type controlled release preparation of the invention comprises 1.0-4.0 mg of the drug, 20-50 mg of the filler, 20-60 mg of the osmotic active substance, 10-30 mg of the binder, 10 ⁇ 32 mg of the solubilizing agent and the lubricant. 3 to 6 mg.
  • the semipermeable coating film coating material is 10-30 mg, the plasticizer is 2-10 mg, and an appropriate amount of solvent.
  • the perindopril osmotic pump type controlled release tablet according to the present invention is selected from the group consisting of gum arabic, tragacanth, peach gum, carboxymethyl cellulose, dextrin, starch or a mixture thereof.
  • the perindopril osmotic pump type controlled release tablet of the present invention the osmotic active substance used is selected from the group consisting of mannitol, glucose, lactose, sucrose, sodium chloride or a mixture thereof.
  • the perindopril osmotic pump type controlled release tablet of the present invention is selected from the group consisting of starch syrup, hypromellose, povidone, sodium carboxymethylcellulose or a mixture thereof.
  • the perindopril osmotic pump type controlled release tablet of the present invention uses a release rate adjusting agent selected from the group consisting of polyethylene glycol, propylene glycol, glycerin, dibutyl phthalate or a mixture thereof.
  • the perindopril osmotic pump type controlled release tablet according to the present invention is selected from the group consisting of magnesium stearate, calcium stearate, talc, micronized silica gel, sodium lauryl sulfate, and polyoxyethylene single hard. Glyceryl glycerides, waxes or mixtures thereof.
  • the perindopril osmotic pump type controlled release tablet of the present invention is used as a solubilizing agent, pluronic acid, sodium stearate, polyethylene glycol 4000 or a mixture thereof.
  • the perindopril osmotic pump type controlled release tablet according to the invention, the semipermeable film coating material is selected from the cellulose acetate fiber Wort or hypromellose phthalate, the plasticizer is selected from dibutyl sebacate or PEG 200, and the solvent is selected from acetone or ethanol.
  • a laser puncher can be used to punch 0.1-0.5 mm holes on the semi-permeable film coating layer.
  • Figure 1 is a graph showing the release profiles of Perindopril osmotic pump type controlled release tablets of Examples 1 to 4 in phosphate buffer pH 7.4. As can be seen from the figure, the release of the drug exhibits a significant zero-order release characteristic, indicating that the osmotic pump-controlled release tablets prepared by perindopril can release the drug at a constant rate, thereby maintaining a stable blood concentration and efficiently exerting the drug. Therapeutic effect.
  • Preparation process Perindopril and solubilizer were mixed uniformly for 15 min, mixed with filler and osmotic active substance in a mixer for 15 min, made of soft material with 1% binder aqueous solution, granulated by 20 mesh sieve, 40 ° C Dry for 6h, pass through 16 mesh sieve, and mix and evenly compress.
  • the coating material and other excipients in the coating layer were dissolved in acetone, coated with a coating pan, and cured at 40 ° C for 6 h after the coating was completed. After the coating is cured, a 0.5 mm hole can be punched on the coating layer with a laser puncher.
  • Perindopril and solubilizer were mixed uniformly for 15 min, mixed with filler and osmotic active substance in a mixer for 15 min, made of soft material with 1% binder aqueous solution, and sieved through 20 mesh sieve, 50 ° C Dry for 7h, pass through 16 mesh sieve, and mix and evenly compress.
  • the coating material and other excipients in the coating layer were dissolved in acetone, coated in a coating pan, and cured at 50 ° C for 7 h after the coating was completed. After the coating is cured, a 0.4 mm hole can be punched on the coating layer with a laser puncher.
  • Preparation process Perindopril and solubilizer were mixed uniformly for 15 min, mixed with filler and osmotic active substance in a mixer for 20 min, made of soft material with 2% binder aqueous solution, and sieved by 20 mesh sieve, 40 ° C Dry for 8 h, sieve through 16 mesh sieves, mix and evenly compress.
  • the coating material and other excipients in the coating layer were dissolved in ethanol, coated in a coating pan, and cured at 40 ° C for 8 h after the coating was completed. After the coating is cured, the laser puncher is used. Apply 0.2mm holes to the coating layer.
  • Preparation process Perindopril and solubilizer were mixed uniformly for 20 min, mixed with filler and osmotic active substance in a mixer for 15 min, made of soft material with 2% binder aqueous solution, granulated by 20 mesh sieve, 50 ° C Dry for 6h, pass through 16 mesh sieve, and mix and evenly compress.
  • the coating material and other excipients in the coating layer were dissolved in acetone, coated with a coating pan, and cured at 50 ° C for 8 h after the coating was completed. After the coating is cured, a 0.1 mm hole can be punched on the coating layer with a laser puncher.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un comprimé de périndopril à libération contrôlée de type pompe osmotique, comprenant un noyau de comprimé contenant le médicament et un enrobage de membrane semi-perméable. Il existe un orifice d'administration de médicament sur la couche d'enrobage de membrane semi-perméable. Le noyau de comprimé contient de 1,0 à 4,0 mg de périndopril ou d'un sel pharmaceutiquement acceptable correspondant, de 20 à 50 mg d'une charge, de 20 à 60 mg d'une substance osmotiquement active, de 10 à 30 mg d'un liant, de 10 à 32 mg d'un solubilisant, et de 3 à 6 mg d'un lubrifiant.
PCT/CN2017/082099 2017-04-20 2017-04-27 Comprimé de type pompe osmotique de périndopril et de sel correspondant et son procédé de préparation WO2018192000A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710260148.2A CN107050419A (zh) 2017-04-20 2017-04-20 一种培哚普利及其盐的渗透泵片及其制备方法
CN201710260148.2 2017-04-20

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WO2018192000A1 true WO2018192000A1 (fr) 2018-10-25

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Publication number Priority date Publication date Assignee Title
US20190099377A1 (en) * 2017-10-02 2019-04-04 Powder Pharma Coating Inc. Method for dry powder coating osmotic drug delivery system
CN108902163B (zh) * 2018-08-08 2021-02-19 河北威远生物化工有限公司 一种甲氨基阿维菌素b2苯甲酸盐渗透泵片及其制备方法

Citations (4)

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WO1994001093A1 (fr) * 1992-07-09 1994-01-20 Merck & Co., Inc. Pompe osmotique pour la liberation d'enalapril a porosite regulee
CN101836963A (zh) * 2009-03-16 2010-09-22 鲁南制药集团股份有限公司 一种治疗高血压的药物应用制剂
CN102871982A (zh) * 2012-10-16 2013-01-16 中国科学院上海药物研究所 一种药物渗透泵制剂
CN104473898A (zh) * 2014-12-01 2015-04-01 郑洁 一种甲苯磺酸索拉非尼渗透泵片及其制备方法

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KR100548925B1 (ko) * 2002-10-23 2006-02-02 한미약품 주식회사 약물의 경구투여용 서방성 조성물
CN1552323A (zh) * 2003-12-19 2004-12-08 沈阳药科大学 尼索地平单层渗透泵控释片
CN101342153B (zh) * 2007-07-11 2011-04-20 中国人民解放军军事医学科学院毒物药物研究所 利培酮渗透泵控释片及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
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WO1994001093A1 (fr) * 1992-07-09 1994-01-20 Merck & Co., Inc. Pompe osmotique pour la liberation d'enalapril a porosite regulee
CN101836963A (zh) * 2009-03-16 2010-09-22 鲁南制药集团股份有限公司 一种治疗高血压的药物应用制剂
CN102871982A (zh) * 2012-10-16 2013-01-16 中国科学院上海药物研究所 一种药物渗透泵制剂
CN104473898A (zh) * 2014-12-01 2015-04-01 郑洁 一种甲苯磺酸索拉非尼渗透泵片及其制备方法

Non-Patent Citations (1)

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Title
XU, LU ET AL.: "Investigation on the Preparation and Drug Release in vitro of the Captopril Osmotic Pump-Controlled Release Tablets", JOURNAL OF SHENYANG PHARMACEUTICAL, vol. 20, no. 6, 30 November 2003 (2003-11-30), pages 395 - 398, 408 *

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