WO2011026312A1 - Nouveau composé à matrice à libération lente contenant du succinate de métoprolol - Google Patents

Nouveau composé à matrice à libération lente contenant du succinate de métoprolol Download PDF

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Publication number
WO2011026312A1
WO2011026312A1 PCT/CN2010/001294 CN2010001294W WO2011026312A1 WO 2011026312 A1 WO2011026312 A1 WO 2011026312A1 CN 2010001294 W CN2010001294 W CN 2010001294W WO 2011026312 A1 WO2011026312 A1 WO 2011026312A1
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Prior art keywords
release
sustained
skeleton
double
layer
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PCT/CN2010/001294
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English (en)
Chinese (zh)
Inventor
赵志全
Original Assignee
鲁南制药集团股份有限公司
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Publication of WO2011026312A1 publication Critical patent/WO2011026312A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 present invention relates to a novel sustained-release tablet comprising metoprolol succinate, in particular to a metoprolol succinate double-layer sustained-release tablet having an auxiliary layer capable of regulating drug release rate. It belongs to the field of pharmaceutical preparations. Background technique
  • Metoprolol chemical name 1-[4-(2-methylethyl)phenoxy]-3-isopropylaminopropanol, is a selective ⁇ -receptor blocker It is mainly used for the treatment of mild to moderate hypertension, stable angina and arrhythmia. Its oral absorption is rapid and complete, the absorption rate is greater than 90%, but the liver metabolic rate is 95%, the first pass effect is 25% ⁇ 60%, so the bioavailability (F) is only 40% ⁇ 75%.
  • the peak time of oral blood plasma concentration is generally 1.5 hours, and the maximum action time is 1 to 2 hours.
  • the half-life (tl/2) of fast metabolizers is 3 to 4 hours; the half-life (tl/2) of slow metabolizers can reach 7.55 hours, and the individual difference in plasma peak concentration can reach 20 times, leading to plasma drug concentration in patients.
  • the fluctuations are large, and adverse reactions such as slow heart rate, lower blood pressure, fatigue and dizziness, depression, nausea, stomach pain, shortness of breath, joint pain, etc. are obvious.
  • the products currently on the market are mainly R, S-Metoprolol tartrate and succinate and S-Metoprolol succinate.
  • AstraZeneca's Metoprolol Tartrate Tablet (trade name: Betaloc) is the first Metoprolol to be marketed. However, because of its short elimination half-life, about 3 ⁇ 4h, it takes 2 ⁇ 4 times a day to take the drug, which causes the patient's plasma drug concentration to fluctuate greatly, which makes the plasma drug concentration unable to maintain an effective therapeutic concentration and brings about more side effects. In order to overcome these shortcomings, several metoprolol controlled release preparations appeared on the market, and AstraZeneca used a multi-microcapsule technology which can be used as an independent constant-speed release unit, and used a relatively small solubility of amber.
  • the acid salt replaces the tartrate, and the metoprolol succinate sustained release tablet (trade name: Betaloc ZOK, Betaloc sustained release tablets) is introduced, which significantly delays the dissolution rate of the drug and overcomes the previous metoprolol.
  • the lack of pharmacokinetics of the tablet not only reduces the side effects of the drug, but also greatly improves the therapeutic efficacy and tolerance of the drug.
  • AstraZeneca's marketed products use pelletizing technology, and its preparation process mainly includes preparation of pellet core, slow release coating, pelleting and film coating.
  • the preparation process has many steps, and each step is more Complex, especially in the pelleting process, because the density and particle size of the pellets are relatively large, it is not easy to mix well with the tableting materials or particles, and the pellet film has a certain pressure resistance, which makes the production process very difficult. control.
  • Guangzhou Tianxin Pharmaceutical Co., Ltd. uses a controlled release film coating technology to prepare metoprolol tartrate controlled release tablets.
  • the sampling time point of the standard release limit is lh, 5h, 10h and 20h instead of the 24h long-acting preparation usually used for lh, 4h, 8h and 20h.
  • the sampling time was measured at lh, 4h, 8h and 20h. The release data showed that the 4h and 8h release exceeded the reasonable release limit, indicating that the technology used in the preparation could not Effectively control drug release.
  • U.S. Patent No. 4,792,452 discloses a controlled release pharmaceutical composition which provides a pH-independent release of a basic drug such as metoprolol.
  • the formulation includes a pH dependent polymer that is an alginate, a pH independent hydrocolloid gelling agent, and a binder.
  • U.S. Patent 5,081,154 relates to an oral pharmaceutical composition of metoprolol succinate coated with an anionic polymer dissolved at a pH above 5.5 and a water-insoluble acrylic polymer.
  • the metoprolol controlled release tablets prepared by the above two patents have a shorter controlled release time and cannot achieve 24-hour release.
  • the drug release mechanism is the combined effect of matrix dissolution and drug diffusion.
  • the pH and rotation speed of the release medium have no significant effect on the release rate, but the amount of HPMC is The viscosity, the amount of retarder, the preparation method, and the tableting pressure have significant effects on the release rate. Therefore, the influencing factors are too many, and it is difficult to operate, and it is difficult to industrialize mass production.
  • the present invention provides a metoprolol succinate double layer skeleton sustained release tablet having an auxiliary layer which can assist in adjusting the release rate.
  • the novel skeleton sustained-release tablet technology of the invention successfully prepares a long-acting sustained-release preparation of metoprolol succinate by adding an auxiliary layer which assists in adjusting the release rate on the basis of the conventional matrix sheet.
  • the release rate of metoprolol succinate sustained-release tablets surprisingly shows good linearity and is fully compliant with the USP30 standard. Compared to AstraZeneca's marketed products, its in vitro release behavior is very close, and preparation The process is simple and the production cost is low.
  • the present invention provides a double-layered skeleton sustained-release tablet containing metoprolol succinate, characterized in that the core has an inclusion A sustained release layer of metoprolol succinate and an auxiliary layer capable of regulating the release rate.
  • the sustained release layer is composed of metoprolol succinate, skeleton sustained release material and other pharmaceutically acceptable excipients;
  • the auxiliary layer is composed of a skeleton sustained release material and other pharmaceutically acceptable excipients.
  • the type and amount of pharmaceutically acceptable excipients in the sustained release layer and the auxiliary layer can be selected according to the requirements of a general skeleton sustained release tablet, and the metoprolol succinate in the sustained release layer is R, S-metoprolol succinate. Or S-metoprolol succinate, preferably S-Metoprolol succinate.
  • the sustained release layer accounts for 51-80% by weight of the entire core, and the auxiliary layer accounts for 20-49% by weight of the entire core.
  • the skeleton sustained-release material may be selected from the group consisting of an insoluble skeleton sustained-release material, a wax skeleton slow-release material, a hydrophilic gel skeleton sustained-release material, and a mixed material skeleton. Sustained release material.
  • insoluble skeleton sustained-release materials are ethyl cellulose, polyethylene, polypropylene, polysiloxane, and polyoxyethylene.
  • electrolytes such as sodium chloride, potassium chloride or sodium sulfate
  • sugars such as lactose, fructose, sucrose or mannitol
  • hydrophilic gels such as hydroxypropyl
  • Methyl cellulose, sodium carboxymethyl cellulose or scutellaria gum, etc. may be added to the prescription.
  • waxy skeleton materials are beeswax, hydrogenated vegetable oil, synthetic wax, butyl stearate, stearic acid, carnauba wax, glyceryl stearate, propylene glycol monostearate and stearyl alcohol, etc.
  • Commonly used backbone porogens for use at the same time are polyvinylpyrrolidone, polyethylene glycol 1500, 1400, a 600 and water soluble surfactants.
  • the hydrophilic gel skeleton sustained-release material can be classified into four types of 1 cellulose derivatives (methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose).
  • non-cellulosic polysaccharides such as glucose, chitin, chitosan and galactomannan
  • natural rubber pectin, sodium alginate, Mixtures such as potassium alginate, agar, horn, etc., locust bean gum, claw gum and gelatin, etc.
  • vinyl polymer or acrylic polymer such as polyvinyl alcohol and polyhydroxyethylene 934, etc.
  • the skeleton sustained-release material sheet is obtained by mixing the above two or more insoluble skeleton sustained-release materials, a wax skeleton slow-release material or a hydrophilic gel skeleton material with each other.
  • the other pharmaceutically acceptable excipients include a binder, a lubricant, a filler, and a porogen.
  • the other auxiliary materials in the sustained release layer include a binder, a lubricant, and a filler; and the porogen may be optionally added as needed.
  • Other pharmaceutical excipients in the auxiliary layer include binders, lubricants, fillers, porogens.
  • the filler may be selected from the group consisting of micronized silica gel, starch, lactose, pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, mannitol, starch lactose mixture, mannitol starch or a combination thereof; when the skeleton sustained release material is a hydrophilic gel In the case of a skeleton material, fine powder silica gel is preferred as a filler.
  • the binder may be selected from one or more of polyvinylpyrrolidone (also known as povidone, PVP), methylcellulose, hydroxypropylmethylcellulose; preferably an aqueous ethanol solution of PVP K30, most preferably 10 % PVP K30 85% ethanol solution, It can simultaneously act as a wetting agent.
  • PVP polyvinylpyrrolidone
  • methylcellulose hydroxypropylmethylcellulose
  • hydroxypropylmethylcellulose preferably an aqueous ethanol solution of PVP K30, most preferably 10 % PVP K30 85% ethanol solution, It can simultaneously act as a wetting agent.
  • the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, PEG, talc, preferably magnesium stearate.
  • the porogen comprises one or more of sucrose, sorbitol, mannitol, glucose, lactose, fructose, sodium chloride, potassium chloride, magnesium sulfate, potassium sulfate, sodium sulfate, preferably lactose.
  • the components of the sustained-release layer account for the weight percentage of the sustained-release layer:
  • the weight percentage of the auxiliary layer component of the auxiliary layer is - skeleton sustained release material 40-80%
  • the skeleton sustained-release material is a mixture of hydroxypropylmethylcellulose and stearic acid of different molecular weights, wherein the sustained-release material of the sustained-release layer is preferably hydroxypropylmethylcellulose K4M.
  • the skeleton sustained-release material of the auxiliary layer is preferably a mixture of hydroxypropyl methylcellulose K4M and K100 and stearic acid;
  • the filler is a micro-silica gel, and at the same time, has a certain retarding effect;
  • the lubricant is magnesium stearate;
  • the binder is an aqueous alcohol solution of PVP K30, such as 10% PVP K30 85% aqueous ethanol solution, which simultaneously acts as a wetting agent;
  • the porogen is lactose.
  • the preparation method of the metoprolol succinate skeleton sustained-release tablet of the invention comprises the following steps -
  • sustained-release layer Put metoprolol succinate and other components of the sustained-release layer (except lubricant) into a wet granulator, mix well, add a prescribed amount of binder, mix well, prepare Soft material, sifted, made into wet granules, dried, whole granules, added with a prescription amount of lubricant, mixed and hooked, and pressed together with the auxiliary layer granules;
  • auxiliary layer Put each component (except lubricant) into a wet granulator and mix it evenly, add a prescribed amount of binder, mix well, prepare soft material, sift, make wet granules, and dry , whole grain, adding a prescribed amount of lubricant, mixing evenly, and pressing together with the prepared sustained release layer particles into a double layer sheet, that is, obtained.
  • the metoprolol succinate double-layer sustained-release tablet of the invention has the advantages of effectively overcoming the defects of the early release of the conventional slow-release tablet and the large residual at the end, and the sustained-release curve is close to the Aspen.
  • the sustained-release curve of metoprolol succinate sustained-release tablets produced by Likang, and the sustained-release tablets of the present invention only require ordinary double-layered tablet technology, and the process only includes conventional
  • the granulation, pressure double-layer sheet and film-coated garment have simpler process, lower production process control difficulty and lower cost, so it is more suitable for industrial large-scale production and can achieve greater economic benefits.
  • S-succinic acid metoprolol core preparation process the core is a two-layer film, one layer is a sustained release layer, and the other layer is an auxiliary layer.
  • the preparation process is as follows - sustained release layer:
  • the two parts of the granules were punched into a double layer with a 10 mm circle; both layers were shallow concave.
  • film coating preparation process Weigh the prescribed amount of ordinary stomach-soluble coating powder, add to the full amount of water, stir and hook, that is.
  • Film coating The pressed core is placed in a coating pan for coating.
  • the spray speed of the coating liquid is l ⁇ 2ml/min, atomization pressure It is 0.7 ⁇ 0.9bar, the pot speed is 6 ⁇ 10rpm, the bed temperature is 32 ⁇ 35°C, and the inlet air temperature is 50 ⁇ 55°C.
  • a small amount of tablets was weighed regularly to calculate the weight gain of the coating. When the weight gain of the tablet reaches about 1 to 3%, the coating is stopped.
  • the drug Compared with the S-Metoprolol succinate monolayer sustained-release tablet prepared by the present inventors, the drug has a smaller cumulative release rate in the early stage, thereby effectively prolonging the maintenance time of the effective concentration of the drug in the body.
  • Example 2 S-Metoprolol succinate double-layer skeleton sustained-release tablets with auxiliary layer
  • the film coating solution is the same as the embodiment 1.
  • the difference is that the auxiliary layer of hydroxypropylmethylcellulose is K4M and / or 100.
  • the preparation process of the double-layer skeleton sustained-release tablet of the same embodiment 1 is that the hydroxypropylmethylcellulose of the core auxiliary room is K4M and 100.
  • the metoprolol succinate described in this example is R, S-metoprolol succinate, and the lh sample release rate is Between 14.8% and 16.2%, the release rate of the sample was between 26.2% and 37.2% for 4 hours, and the release rate of the sample for 8 hours was 50.8°/. Between -58.2, the sample release rate is between 84.0-90.5 for 20h, and the sustained release effect is obvious.
  • Example 2 The stability of the prescriptions 8, 2, 23 (specifications 11.875mg, 23.75m g , 47.7mg) in Example 2 was investigated. The specific results are as follows - I. Influencing factors test
  • Sample source Metoprolol succinate double-layer skeleton sustained-release tablet with auxiliary layer prepared by the invention
  • control solution 20 ⁇ 1 inject it into the liquid chromatograph, adjust the sensitivity of the instrument so that the peak height of the main peak is 10 ⁇ 20% of the full scale; then accurately measure the solution and the pair 20 ⁇ l of each solution was injected into the liquid chromatograph, and the chromatogram was recorded to twice the retention time of the main peak. If the impurity peak is obtained in the chromatogram of the test solution, the blank impurity peak and the succinic acid peak are subtracted, and the maximum impurity peak area shall not be larger than the main peak area of the control solution (0.5%). The sum of the impurity peak areas shall not be greater than the main peak area of the control solution. Times (1.0%).
  • Isomers Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix VD).
  • the chromatographic conditions and system suitability test were carried out using a chiral column (Chiral CD-PH) with a mobile phase of 0.025 mol/L sodium perchlorate-acetonitrile (70:30) at a detection wavelength of 223 nm.
  • a chiral column Chiral CD-PH
  • a mobile phase 0.025 mol/L sodium perchlorate-acetonitrile (70:30) at a detection wavelength of 223 nm.
  • the separation of the tolol peak from the metoprolol R-succinate should be in accordance with the regulations.
  • Test methods and results Take this product and remove the packaging materials that are in direct contact with the drug, respectively, at a light intensity of 4500Lx, The samples were placed at 60 ° C and 40 ° C and relative humidity of 75% and 92.5%, and samples were taken on days 5 and 10, respectively. The results are shown in Tables 12-1, 12-2, and 12-3.
  • Sample source A metoprolol succinate double-layer skeleton sustained-release tablet having an auxiliary layer prepared by the present invention.
  • Investigation items and methods included appearance traits, related substances, and heterogeneity Body, release, content, investigation Method and method of influencing factors

Abstract

La présente invention concerne un comprimé à matrice bicouche à libération lente qui comprend une couche à libération lente contenant du succinate de métoprolol et une couche auxiliaire aidant à la régulation de la vitesse de libération du médicament.
PCT/CN2010/001294 2009-09-04 2010-08-26 Nouveau composé à matrice à libération lente contenant du succinate de métoprolol WO2011026312A1 (fr)

Applications Claiming Priority (2)

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CN200910169819.XA CN102008456B (zh) 2009-09-04 2009-09-04 含有美托洛尔琥珀酸盐的新型骨架缓释片
CN200910169819.X 2009-09-04

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Cited By (1)

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CN108653228A (zh) * 2018-08-15 2018-10-16 重庆市畜牧科学院 骨架型缓释多拉菌素片剂及其制备方法

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CN102357087B (zh) * 2011-10-26 2013-11-06 山东齐都药业有限公司 一种富马酸美托洛尔缓释片及其制备方法
CN104523642A (zh) * 2015-01-21 2015-04-22 田武 美托洛尔缓释片及其制备方法
CN111202716B (zh) * 2018-11-05 2021-10-26 广州白云山光华制药股份有限公司 茶碱缓释片及其制备方法

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US5464633A (en) * 1994-05-24 1995-11-07 Jagotec Ag Pharmaceutical tablets releasing the active substance after a definite period of time
AU2003282375A1 (en) * 2003-02-05 2004-08-30 Ipca Laboratories Limited Pharmaceutical compositions and process of production thereof

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HUANG GUIHUA ET AL.: "The Factors Influencing Metoprolol Succinate Release from HPMC Matrix Tablet", CHINESE JOURNAL OF BIOMEDICAL ENGINEERING, vol. 23, no. 3, 2006, pages 587 - 591 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108653228A (zh) * 2018-08-15 2018-10-16 重庆市畜牧科学院 骨架型缓释多拉菌素片剂及其制备方法
CN108653228B (zh) * 2018-08-15 2021-05-28 重庆市畜牧科学院 骨架型缓释多拉菌素片剂及其制备方法

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