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WO2008101375A1 - Composition pharmaceutique de rétention gastrique à libération prolongée comprenant de l'irbesartan - Google Patents

Composition pharmaceutique de rétention gastrique à libération prolongée comprenant de l'irbesartan Download PDF

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Publication number
WO2008101375A1
WO2008101375A1 PCT/CN2007/002833 CN2007002833W WO2008101375A1 WO 2008101375 A1 WO2008101375 A1 WO 2008101375A1 CN 2007002833 W CN2007002833 W CN 2007002833W WO 2008101375 A1 WO2008101375 A1 WO 2008101375A1
Authority
WO
WIPO (PCT)
Prior art keywords
irbesartan
composition
group
hypromellose
cetyl alcohol
Prior art date
Application number
PCT/CN2007/002833
Other languages
English (en)
Chinese (zh)
Inventor
Qingsheng Bei
Original Assignee
Guangzhou Pui's Pharmaceutical Factory 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
Application filed by Guangzhou Pui's Pharmaceutical Factory Ltd. filed Critical Guangzhou Pui's Pharmaceutical Factory Ltd.
Publication of WO2008101375A1 publication Critical patent/WO2008101375A1/fr

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to a gastric retention type sustained release pharmaceutical composition, in particular to a gastric retention type sustained release pharmaceutical composition for antihypertensive drug irbesartan and a preparation method thereof.
  • Irbesartan has the chemical name: 2-butyl-3_[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-1,3-diazaspiro- [4. 4] ⁇ -1-en-4-one. It is a novel angiotensin II receptor antagonist that specifically antagonizes angiotensin II (Ang II) receptor ⁇ . For AT, the selectivity of the receptor is 8500 times that of ⁇ 2 , by selectively Antagonizes the binding of Ang II to ⁇ receptor, inhibits vasoconstriction and aldosterone release, and produces antihypertensive effect. Suitable for a variety of levels of essential hypertension.
  • irbesartan is similar or slightly superior to enalapril, amlodipine, atenolol, losartan, and valsartan. With the deepening of the research, it has also been found that irbesartan has the effects of treating left ventricular hypertrophy, congestive heart failure, and diabetic nephropathy.
  • Irbesartan can be rapidly absorbed after oral administration, and the bioavailability is 60-80%, which is not affected by food.
  • the plasma peak time is 1. 5 ⁇ 2 hours, the elimination half-life is 11 ⁇ 15 hours, and the steady state is reached within 3 days.
  • a dose of 50 mg or more can significantly reduce the patient's blood pressure and is dose-related.
  • Irbesartan is mainly metabolized by cytochrome P450 2C9.
  • the plasma protein binding rate is 90%, and the average volume of distribution is 53 ⁇ 93L. It is excreted by the biliary tract and kidneys with the original drug form and metabolites. It is suitable for liver and kidney dysfunction. patient.
  • irbesartan dosage forms sold on the domestic and international markets include ordinary tablets, capsules, dispersible tablets, etc., because of its long biological half-life, it can produce a 24-hour antihypertensive effect once a day.
  • the blood pressure can be controlled 24 hours a day, but the blood pressure is highly volatile. Studies have shown that blood pressure fluctuations on the heart, blood vessels and target organs are more harmful than hypertension itself. Therefore, it can be used to control blood pressure fluctuations and reduce blood pressure by making a slow-release preparation with small fluctuations in blood concentration. The peak-to-valley ratio is achieved, and a 24-hour smooth buck can be achieved.
  • the gastric retention-type sustained release preparation can prolong the residence time of the drug in the gastrointestinal tract (mainly the stomach), increase the drug concentration in the adsorption-absorption site, and promote the site.
  • the driving force of passive absorption of cells thereby increasing the absorption of drugs in the stomach or duodenum, and improving the bioavailability of drugs; slow release of drugs can avoid fluctuations in blood concentration, reduce systemic side effects, and improve drug safety.
  • the drug can be absorbed immediately after it is released, thereby avoiding the possible degradation of the drug in the channel fluid and the decrease in solubility caused by the increase in intestinal pH, improving the effectiveness of the drug and reducing the cost.
  • the surprising discovery of the present invention is that irbesartan is stable under acidic conditions and is readily soluble and absorbable, with reduced solubility in alkaline buffers.
  • the present invention utilizes its unique characteristics to prepare a sustained-release drug for gastric retention, which is mainly absorbed in the stomach and exerts its efficacy, and is further formulated by a sustained-release pharmaceutical composition for irbesartan gastric retention type. Screening, found the appropriate formula composition, so that the obtained irbesartan gastric retention type sustained release tablets obtained a good gastric retention effect and complete drug release, significantly reduced blood drug concentration fluctuations, improved bioavailability Degree and medication safety. Summary of the invention
  • An object of the present invention is to provide an irbesartan gastric retention type sustained release pharmaceutical composition which has a drug release property and a safe and effective drug administration. It has the characteristics of complete absorption, stable and long-lasting effect and high safety.
  • the irbesartan gastric continuous release sustained-release pharmaceutical composition of the present invention comprises irbesartan or a physiologically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient Acceptable excipients are selected from the group consisting of hydrophilic polymeric gel materials, bleaching aids, gas generating agents, surfactants, swelling materials, fillers, lubricants, wetting agents or binders, and packages.
  • a coating agent or the like may be used in combination of one or more of them.
  • the hydrophilic polymer gel material is selected from one or more of hypromellose, alginate, chitosan, and the like having a viscosity of 4000 to 10000 centipoise.
  • the bleaching agent is selected from one or more of a mixture of cetyl alcohol, stearyl alcohol, cetyl alcohol and stearyl alcohol.
  • the gas generating agent is one or more selected from the group consisting of sodium hydrogencarbonate, magnesium carbonate, calcium carbonate and the like.
  • the surfactant is selected from one or more of poloxamer, sodium dodecyl sulfate, magnesium decyl sulfate or Tween 80.
  • the swelling material is selected from one or more of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, cross-linked polyvinylpyrrolidone, and the like.
  • the filler is selected from one or more of microcrystalline cellulose, lactose, starch, mannitol, sorbitol, dextrin, etc., preferably microcrystalline cellulose, lactose.
  • the wetting agent or binder may be one or more selected from the group consisting of water, ethanol, starch slurry, povidone, low viscosity hypromellose or other cellulose solution, and may or may not be needed. selected.
  • the lubricant is selected from one or more of stearic acid, magnesium stearate, talc, micronized silica gel, starch, paraffin, etc., preferably magnesium stearate, talc.
  • the coating agent is preferably gastric-soluble Opadry.
  • the active ingredient and the pharmaceutically acceptable excipient used in the preparation of the irbesartan gastric retention type sustained release pharmaceutical composition of the present invention are composed of the following ratios (weight ratio of the core): irbesartan 1 -90%
  • Hydrophilic polymer gel material 0-50%
  • Intumescent material 0-10%
  • the preferred ratio of the active ingredient and the pharmaceutically acceptable excipient used in the preparation of the irbesartan gastric retention type sustained release pharmaceutical composition of the present invention is composed of: Irbesartan 40-80%
  • Hydrophilic polymer gel material 5-30%
  • the invention also provides a preparation method of the irbesartan gastric retention type sustained release pharmaceutical composition.
  • Method 1 The original amount and the auxiliary material of the prescription amount are separately sieved, fully mixed, and compressed into tablets.
  • Method 2 Mix the prescription raw materials and auxiliary materials separately, mix them thoroughly, add granules by adding wetting agent or binder, add lubricant or flow aid after drying, mix well, and press into tablets.
  • Method 3 The prescription raw materials and auxiliary materials are separately sieved, uniformly mixed, and pressed into a tablet core; a coating liquid is prepared; and the obtained core is coated with a coating liquid according to a conventional process.
  • the configuration of the coating liquid can be as follows:
  • the appropriate amount refers to the amount of addition required to meet the formulation requirements according to conventional techniques of pharmacy, and can be added according to the requirements of the textbook.
  • Particularly preferred formulations of the present invention are listed in the examples of the present invention. These most preferred formulations are screened and have a longer gastric retention time, a stable and complete release, and a stable blood concentration compared to the prior art. Small fluctuations.
  • Example 3 of the present invention In order to investigate the in vitro retention performance and release effect of the present invention, we have determined the irbesartan stomach prepared in Example 3 of the present invention according to the first method of the dissolution test method according to the first method of the Chinese Pharmacopoeia 2005 edition two appendix XD. The floating time of the internal retention type sustained release tablets Continued floating time and in vitro release.
  • the release profile of the irbesartan gastric retention type sustained release tablet prepared according to Example 3 is shown in Fig.-1.
  • irbesartan gastric retention-type sustained-release tablets 6 healthy beagle dogs were divided into two groups, and the eubesartan sustained release sustained-release was prepared by single dose cross-administration method. Tablets and commercially available irbesartan tablets were each 150 mg. The concentration of irbesartan in plasma at different times after administration was determined by high performance liquid chromatography, and the blood concentration-time curve was plotted. The AUC value was calculated using the trapezoidal method based on the plasma concentration-time data. The results are shown in Table -2.
  • Irbesartan sustained-release sustained-release tablets and reference preparations prepared according to Example 3 The plasma concentration-time curve of the besartan tablet is shown in Figure-2. The results showed that the relative bioavailability of the irbesartan sustained-release tablet prepared according to Example 3 was 11.0% compared with the reference preparation of the irbesartan. It can be seen from the blood drug concentration-time graph that the irbesartan gastric retention type sustained release tablet of the present invention has a stable blood concentration and a small fluctuation compared with the ordinary tablet.
  • Example 1 The invention is further described in detail below by way of embodiments, without restricting the invention.
  • Example 1 The invention is further described in detail below by way of embodiments, without restricting the invention.
  • the obtained core is coated with the above coating liquid according to a conventional process.
  • Preparation Weigh the above-mentioned raw materials and excipients except magnesium stearate, mix them thoroughly, mix them thoroughly, add granules of povidone 50% ethanol solution, add magnesium stearate after drying, mix thoroughly, and compress into tablets. That is.
  • Preparation method same as the third embodiment Note:
  • the appropriate amount described in the formulation of the above examples refers to the amount of addition required to meet the formulation requirements according to the conventional pharmacy technique, and may be added according to the requirements of the textbook, generally 0.01% to 30%, preferably 1%, of the total weight. 10% 0

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une composition pharmaceutique de rétention gastrique à libération prolongée comprenant de l'irbesartan et sur des excipients pharmaceutiquement acceptables pour contrôler efficacement le temps de rétention du médicament dans l'estomac afin d'obtenir une concentration sanguine stable après administration et augmenter la sécurité et l'efficacité du médicament. L'invention porte également sur le procédé de préparation de ladite composition.
PCT/CN2007/002833 2007-02-16 2007-09-28 Composition pharmaceutique de rétention gastrique à libération prolongée comprenant de l'irbesartan WO2008101375A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710079878.9 2007-02-16
CN2007100798789A CN101011393B (zh) 2007-02-16 2007-02-16 厄贝沙坦胃内滞留型缓释药物组合物

Publications (1)

Publication Number Publication Date
WO2008101375A1 true WO2008101375A1 (fr) 2008-08-28

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PCT/CN2007/002833 WO2008101375A1 (fr) 2007-02-16 2007-09-28 Composition pharmaceutique de rétention gastrique à libération prolongée comprenant de l'irbesartan

Country Status (2)

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CN (1) CN101011393B (fr)
WO (1) WO2008101375A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113648281A (zh) * 2021-09-24 2021-11-16 宁夏医科大学 一种多晶型厄贝沙坦纳米混悬液及其制备方法和应用
CN115350158A (zh) * 2022-09-28 2022-11-18 南京海纳医药科技股份有限公司 一种富马酸沃诺拉赞的胃内滞留片及其制备方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2651400B2 (fr) * 2010-12-16 2023-01-18 Amgen (Europe) GmbH Formes posologiques pour des médicaments peu solubles administrés par voie orale à libération contrôlée et leurs utilisations
CN104840443B (zh) * 2015-05-27 2018-04-27 齐鲁制药有限公司 含活性成分普瑞巴林的药物组合物
CN115444829B (zh) * 2022-10-25 2023-08-22 南京康川济医药科技有限公司 一种沙库巴曲缬沙坦钠胃滞留缓释片及其制备方法

Citations (4)

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Publication number Priority date Publication date Assignee Title
US20030152622A1 (en) * 2001-10-25 2003-08-14 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral diuretic
US20030198676A1 (en) * 1998-03-04 2003-10-23 Yasutaka Igari Sustained-release preparation for AII antagonist, production and use thereof
CN1520286A (zh) * 2001-07-04 2004-08-11 ̫��ҽҩ��ҵ���޹�˾ 胃滞留控制药物释出系统
WO2005025566A1 (fr) * 2003-09-18 2005-03-24 Nobel Ilac Sanayi Ve Ticaret As Formulations pharmaceutiques a administration par voie orale contenant le principe actif irbesartan

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060003002A1 (en) * 2003-11-03 2006-01-05 Lipocine, Inc. Pharmaceutical compositions with synchronized solubilizer release
CN1895228A (zh) * 2005-07-11 2007-01-17 刘凤鸣 厄贝沙坦滴丸及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030198676A1 (en) * 1998-03-04 2003-10-23 Yasutaka Igari Sustained-release preparation for AII antagonist, production and use thereof
CN1520286A (zh) * 2001-07-04 2004-08-11 ̫��ҽҩ��ҵ���޹�˾ 胃滞留控制药物释出系统
US20030152622A1 (en) * 2001-10-25 2003-08-14 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral diuretic
WO2005025566A1 (fr) * 2003-09-18 2005-03-24 Nobel Ilac Sanayi Ve Ticaret As Formulations pharmaceutiques a administration par voie orale contenant le principe actif irbesartan

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113648281A (zh) * 2021-09-24 2021-11-16 宁夏医科大学 一种多晶型厄贝沙坦纳米混悬液及其制备方法和应用
CN115350158A (zh) * 2022-09-28 2022-11-18 南京海纳医药科技股份有限公司 一种富马酸沃诺拉赞的胃内滞留片及其制备方法
CN115350158B (zh) * 2022-09-28 2023-07-25 南京海纳医药科技股份有限公司 一种富马酸沃诺拉赞的胃内滞留片及其制备方法

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CN101011393B (zh) 2010-10-06
CN101011393A (zh) 2007-08-08

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