CN109316455B - Trimetazidine hydrochloride sustained release tablet - Google Patents

Trimetazidine hydrochloride sustained release tablet Download PDF

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Publication number
CN109316455B
CN109316455B CN201710637560.1A CN201710637560A CN109316455B CN 109316455 B CN109316455 B CN 109316455B CN 201710637560 A CN201710637560 A CN 201710637560A CN 109316455 B CN109316455 B CN 109316455B
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release
sustained
release tablet
trimetazidine
mixture
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CN109316455A (en
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黄玉锋
张英杰
杨文涛
彭小玲
杨西邈
耿玉先
产运霞
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Beijing Fuyuan Pharmaceutical Co ltd
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    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin

Abstract

The invention relates to a trimetazidine hydrochloride sustained release tablet, which specifically comprises trimetazidine hydrochloride, a framework material, a diluent and an adhesive, wherein the framework material is a mixture of hydroxypropyl methylcellulose and zein. In the trimetazidine dihydrochloride sustained release tablet, hydroxypropyl methylcellulose and zein are used as framework materials, so that the early burst release phenomenon of trimetazidine dihydrochloride can be avoided; in addition, the in vitro release of the obtained sustained release tablet is not influenced by pH environment, the release degree in 8 hours is more than 80 percent, and the sustained release tablet is consistent with the release curve of a commercially available product and is suitable for industrial large-scale production.

Description

Trimetazidine hydrochloride sustained release tablet
Technical Field
The invention relates to a sustained-release preparation for treating angina pectoris, in particular to a trimetazidine dihydrochloride sustained-release tablet and a preparation method thereof.
Background
Angina pectoris is a common cardiovascular disease, is caused by coronary atherosclerosis and stenosis, resulting in insufficient blood supply to coronary arteries, transient myocardial ischemia and hypoxia, and a group of syndromes with precordial pain as the main clinical manifestation, is one of the coronary heart diseases with the highest incidence rate, and seriously threatens the health and life of human beings. It is mainly classified into stable angina pectoris and unstable angina pectoris. Angina pectoris can be onset at any time 24 hours, but with early morning to late afternoon, angina pectoris of variability is more episodic at night. Thus, it is desirable that therapeutic agents maintain an effective therapeutic concentration for 24 hours to ensure efficacy, safety and stability of treatment.
The trimetazidine hydrochloride is different from traditional therapeutic drugs such as nitrates, beta-receptor blockers, calcium ion antagonists and the like in chemical structure and pharmacological action, does not depend on the rate of the heart or the reduction of blood pressure, has the functions of resisting adrenaline, noradrenaline and vasopressin, can reduce vascular resistance, increase coronary blood flow and peripheral circulation blood flow, and promote myocardial metabolism and myocardial energy generation. Meanwhile, the workload of the heart can be reduced, the oxygen consumption of the cardiac muscle and the energy consumption of the cardiac muscle are reduced, and the supply and demand balance of the cardiac muscle oxygen is improved. Trimetazidine hydrochloride is used as a representative of a new class of metabolic drugs for preventing and treating angina pectoris, has been widely applied in Europe and multiple countries, has proved to have good curative effect in treating angina pectoris, enters China in 2000, and is listed in the national basic drug catalogue.
Currently, trimetazidine hydrochloride preparations on the market comprise a quick-release preparation and a sustained-release preparation, and the half-life period of the trimetazidine hydrochloride is less than 6 hours because the trimetazidine hydrochloride is quickly absorbed and eliminated by a human body. In order to ensure adequate blood levels in immediate release dosage forms, it must be administered 2-3 times a day, with the most frequently required dosage regimen being 3 times a day, 1 tablet each, during the treatment period. The patient has poor compliance of taking the medicine and the phenomenon of missing the medicine is often caused. In addition, due to the fast absorption and the half-life period of about 6 hours, the quick-release preparation can reach high blood drug peak concentration in a short time after being taken, and the blood drug concentration in the next time of taking the preparation is very low, however, the treatment of angina pectoris diseases is important to maintain effective myocardial protection in the whole 24 hours, especially in the early morning, the ischemia of the body is the most serious, so the quick-release preparation can not safely and effectively treat the angina pectoris. The trimetazidine dihydrochloride sustained-release preparation can provide uniform and constant blood concentration, improve the safety and the effectiveness of medication and the compliance of patients, control the plasma drug level and reduce the administration frequency.
The chemical name of the trimetazidine dihydrochloride is 1- (2, 3, 4-trimethylphenyl) piperazine dihydrochloride, the structural formula is shown as follows, the trimetazidine dihydrochloride is very easy to dissolve in water, and the solubility is more than 1000mg/ml, so that the control of the burst release of a high-solubility medicament is the key of the research of a sustained-release preparation. Burst release refers to the phenomenon of release of a large amount of drug in a sustained or controlled release preparation at the initial stage of release.
Figure 645929DEST_PATH_IMAGE001
。
Patent CN1166408A discloses a matrix tablet capable of releasing trimetazidine for a long time after oral administration, specifically discloses that the release of trimetazidine for a long time is controlled by using cellulose derivative polymer (hydroxypropyl methyl cellulose). The single dose of 35mg is taken twice a day, after each dose, the tablet can obtain the blood concentration which is more than 70 mu g/L in a human body, and can ensure that the blood concentration is more than or equal to 40 mu g/L until the next dose is taken, but the matrix tablet is basically completely released within 4 hours, and the release speed is too fast for a sustained release dosage form.
Patent CN1124140A describes a membrane-controlled sustained release formulation using ethylcellulose or polymethacrylic acid polymers. Although the composition has long release time, the drug is released about 75% in 16 hours, and the release is incomplete.
Patent CN1994280A describes that trimetazidine dihydrochloride pellets are prepared by a centrifugal granulation or extrusion spheronization method, and the sustained release effect is achieved after fluidized bed coating, and the preparation process steps are complicated and not beneficial to industrial production.
Therefore, further research on trimetazidine hydrochloride sustained release formulations is needed to obtain a trimetazidine hydrochloride sustained release formulation with stable dissolution and release and long-term storage stability.
Disclosure of Invention
The invention provides a trimetazidine hydrochloride sustained release tablet, which has stable dissolution release property, does not generate the phenomenon of early sudden release of trimetazidine hydrochloride, the in vitro release of the sustained release tablet is not influenced by pH environment, the release degree in 8 hours is more than 80 percent, and the sustained release tablet is consistent with the release curve of a commercially available medicine; meanwhile, the trimetazidine dihydrochloride sustained release tablet disclosed by the invention has the advantages of better quality stability, simple preparation process and low production cost, and is suitable for industrial large-scale production.
Sustained release preparations can be divided into three categories from the prescription and preparation process, namely, membrane-controlled type, osmotic pump type and skeleton type. The membrane-controlled slow-release preparation is mainly characterized by that the medicine-containing core is made into uniform coating membrane by adopting a certain coating liquor to attain the goal of slow-release. The osmotic pump type sustained release preparation is composed of a medicament, a semipermeable membrane material, an osmotic pressure active substance, a propellant and the like, and the production process of the type has complicated steps and unstable quality and is not beneficial to industrial production. The skeleton type slow release preparation is prepared by uniformly dispersing the medicine in various carrier materials to achieve the slow release effect, has simple production process and low cost, is the main production process of the existing slow release preparation, and can be used as a skeleton material in various types at present.
The trimetazidine dihydrochloride sustained-release tablet disclosed by the invention comprises trimetazidine dihydrochloride, a framework material, a diluent and an adhesive, wherein the framework material is a mixture of hydroxypropyl methylcellulose and zein.
The inventor researches the physical properties of trimetazidine dihydrochloride, and discovers through a large number of experiments that the problem of burst release of a sustained-release tablet caused by high solubility of trimetazidine dihydrochloride can be well solved by adopting a mixture of hydroxypropyl methylcellulose and zein as a framework material; meanwhile, the in vitro release of the sustained release tablet obtained by the invention is not influenced by pH environment, the 8-hour release degree is more than 80 percent, and the sustained release tablet is consistent with the release curve of the commercially available medicine.
Further research on the dosage of hydroxypropyl methylcellulose and zein of the framework material shows that when the dosage ratio of hydroxypropyl methylcellulose to zein is 0.5-3:1, the burst release problem of the release rate of the sustained-release tablet can be well controlled, and more preferably, the dosage ratio of hydroxypropyl methylcellulose to zein is 1.5-2.5: 1.
The sustained-release tablet diluent does not contain lactose, and the inventor finds that trimetazidine hydrochloride is unstable, when lactose is added into the prescription, the content of impurity C is increased, and the impurity C is a hydrolysis impurity, and the structure is as follows. Therefore, in order to control the content of the impurity C in the sustained-release tablet, the trimetazidine dihydrochloride sustained-release tablet does not contain lactose in the prescription.
Figure 938108DEST_PATH_IMAGE002
。
The diluent in the sustained release tablet is one or more of calcium hydrogen phosphate, microcrystalline cellulose, mannitol, pregelatinized starch, sucrose, dextrin and sorbitol.
The binder is one or more of hydroxypropyl cellulose, sodium carboxymethylcellulose and polyvidone.
The dosage ratio of the components is 10-30% of trimetazidine hydrochloride, 20-60% of framework material, 20-60% of diluent and 2-7% of adhesive.
The sustained release tablet also comprises a lubricant, wherein the lubricant is one or more of talcum powder, magnesium stearate, silicon dioxide and sodium stearyl fumarate.
The invention also provides a preparation method of the trimetazidine dihydrochloride sustained release tablet, which comprises the following steps:
a. uniformly mixing trimetazidine hydrochloride, a diluent and an adhesive to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above medicinal granules with the matrix material, and tabletting.
When the trimetazidine dihydrochloride sustained-release tablet contains the lubricant, the step c of the method also comprises the step of adding the lubricant.
Detailed Description
Example 1
Figure 980014DEST_PATH_IMAGE003
The preparation method comprises the following steps:
a. uniformly mixing trimetazidine hydrochloride, calcium hydrophosphate and povidone to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above medicinal granules with hydroxypropyl methylcellulose and zein, and tabletting.
Example 2
Figure 277134DEST_PATH_IMAGE004
The preparation method comprises the following steps:
a. uniformly mixing trimetazidine hydrochloride, microcrystalline cellulose, dextrin and sodium carboxymethylcellulose to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above medicinal granules with hydroxypropyl methylcellulose and zein, and tabletting.
Example 3
Figure 719529DEST_PATH_IMAGE005
The preparation method comprises the following steps:
a. uniformly mixing trimetazidine hydrochloride, pregelatinized starch and povidone to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above granules with hydroxypropyl methylcellulose, zein, magnesium stearate and silicon dioxide, and tabletting.
Example 4
Figure 468DEST_PATH_IMAGE006
The preparation method comprises the following steps:
a. uniformly mixing trimetazidine hydrochloride, calcium hydrophosphate, sucrose and hydroxypropyl cellulose to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above granules with hydroxypropyl methylcellulose, zein, magnesium stearate and pulvis Talci, and tabletting.
Example 5
Figure 111644DEST_PATH_IMAGE007
The preparation method comprises the following steps:
a. uniformly mixing trimetazidine hydrochloride, mannitol, microcrystalline cellulose, povidone and sodium carboxymethylcellulose to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above medicinal granules with hydroxypropyl methylcellulose, zein, silicon dioxide and sodium stearyl fumarate, and tabletting.
Example 6
Figure 761806DEST_PATH_IMAGE008
The preparation method comprises the following steps:
a. uniformly mixing trimetazidine hydrochloride, calcium hydrophosphate, sorbitol and povidone to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above granules with hydroxypropyl methylcellulose, zein and magnesium stearate, and tabletting.
Comparative examples
Figure 136286DEST_PATH_IMAGE009
The preparation method is the same as example 1.
COMPARATIVE EXAMPLE 4 (formula F4 with CN 1166408A)
Figure 638943DEST_PATH_IMAGE010
The preparation method comprises the following steps:
a. mixing trimetazidine hydrochloride, polyvinylpyrrolidone and calcium hydrogen phosphate dihydrate, wetting the mixture with purified water, granulating, and drying the granules;
b. mixing the above granules with hydroxypropyl methylcellulose;
c. lubricating the mixture obtained in step b with magnesium stearate and colloidal silicon dioxide;
d. compressing the mixture obtained in step c to obtain tablets with a hardness of about 40-160N.
Dissolution test
The samples prepared in examples 1-6 and comparative examples 1-4 and the products sold on the market of Wanli are respectively tested for release in 4 dissolution media, namely, phosphate buffer solution with pH of 6.8, acetate solution with pH of 4.5, hydrochloric acid solution with 0.1mol/L and water according to the dissolution rate second method of Chinese pharmacopoeia, and the test results are as follows:
Figure 255607DEST_PATH_IMAGE011
Figure 58478DEST_PATH_IMAGE012
Figure 603860DEST_PATH_IMAGE013
Figure 357927DEST_PATH_IMAGE014
from the experimental data, the release curve of the sample prepared by using hydroxypropyl methylcellulose and zein as framework materials is stable, the burst release phenomenon cannot occur in 4 dissolution media of pH6.8 phosphate buffer solution, pH4.5 acetate solution, 0.1mol/L hydrochloric acid solution and water, the release degree in 8 hours is more than 80%, and the release curve is consistent with that of a commercial product. The samples prepared by the comparative examples 1, 2 and 4 without hydroxypropyl methylcellulose and zein as framework materials have burst release phenomenon, the release is fast, and the release degree reaches over 80 percent in 4 hours.
Stability test
The samples obtained in examples 1 to 6 and comparative examples 1 to 4 and the commercial products of Wanli were placed in an incubator at a Relative Humidity (RH) of 75% and a temperature of 40 ℃ for 6 months, and the maximum impurity content (%) was measured, as follows:
Figure 951850DEST_PATH_IMAGE015
from the above data, it can be seen that the samples and commercial products prepared in examples 1-6 of the present invention and comparative examples 1, 2, and 4 all contained no lactose and had a slow increase in the maximum impurity content measured at 6 months; while comparative example 3, which contains lactose as an adjuvant, showed a significant increase in the maximum impurity level at 6 months.

Claims (8)

1. The trimetazidine hydrochloride sustained release tablet is characterized by comprising trimetazidine hydrochloride, a framework material, a diluent and an adhesive, wherein the framework material is a mixture of hydroxypropyl methylcellulose and zein; wherein the dosage ratio of each component is 10-30% of trimetazidine hydrochloride, 20-60% of framework material, 20-60% of diluent and 2-7% of adhesive; the dosage ratio of the hydroxypropyl methylcellulose to the zein is 0.5-3:1, and the diluent does not contain lactose.
2. The sustained-release tablet of claim 1, wherein the diluent is one or more of calcium hydrogen phosphate, microcrystalline cellulose, mannitol, pregelatinized starch, sucrose, dextrin, and sorbitol.
3. The sustained-release tablet according to claim 1, wherein the binder is one or more of hydroxypropyl cellulose, sodium carboxymethyl cellulose, and povidone.
4. The sustained-release tablet of claim 1, wherein the dosage ratio of hydroxypropyl methylcellulose to zein is 1.5-2.5: 1.
5. The extended release tablet of claim 1, further comprising a lubricant.
6. The sustained-release tablet according to claim 5, wherein the lubricant is one or more of talc, magnesium stearate, silicon dioxide and sodium stearyl fumarate.
7. A method for preparing trimetazidine dihydrochloride sustained release tablets according to claim 1, which is characterized by comprising the following steps:
a. uniformly mixing trimetazidine hydrochloride, a diluent and an adhesive to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above medicinal granules with the matrix material, and tabletting.
8. A method for preparing trimetazidine dihydrochloride sustained release tablets according to claim 5, which is characterized by comprising the following steps:
a. uniformly mixing trimetazidine hydrochloride, a diluent and an adhesive to obtain a mixture;
b. wet granulating the mixture, and grading to obtain medicinal granules;
c. mixing the above medicinal granules with skeleton material and lubricant, and tabletting.
CN201710637560.1A 2017-07-31 2017-07-31 Trimetazidine hydrochloride sustained release tablet Active CN109316455B (en)

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Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2802424B1 (en) * 1999-12-17 2002-02-15 Adir MATRIX TABLET FOR THE EXTENDED RELEASE OF TRIMETAZIDINE AFTER ORAL ADMINISTRATION
EP1195160B1 (en) * 2000-10-05 2009-09-16 USV Ltd. Sustained release trimetazidine pharmaceutical compositions and a method of their preparation
FR2986431B1 (en) * 2012-02-03 2017-03-17 Servier Lab PROLONGED RELEASE OF TRIMETAZIDINE PHARMACEUTICAL COMPOSITION, PROCESS FOR THE PRODUCTION THEREOF AND USE IN THERAPEUTIC TREATMENTS
CN103385861A (en) * 2013-08-06 2013-11-13 山东大学 Trimetazidine hydrochloride sustained release tablet and preparation method thereof

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