CN105434383B - Levamlodipine besylate tablet and preparation method thereof - Google Patents
Levamlodipine besylate tablet and preparation method thereof Download PDFInfo
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- CN105434383B CN105434383B CN201511028812.8A CN201511028812A CN105434383B CN 105434383 B CN105434383 B CN 105434383B CN 201511028812 A CN201511028812 A CN 201511028812A CN 105434383 B CN105434383 B CN 105434383B
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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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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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
- A61K9/2072—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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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Abstract
The invention discloses a levamlodipine besylate tablet, which is prepared by preparing microcrystalline cellulose, menthol and levamlodipine besylate into pellets, adding the pellets into ethanol, stirring, adding the pellets into a benzoic acid solution, reacting the levamlodipine besylate with an alkali liquor to form levamlodipine besylate, filtering and drying to obtain the levamlodipine besylate-containing microcrystalline cellulose pellets. Then mixing with pharmaceutically acceptable auxiliary materials, and tabletting. Compared with the prior art, the invention has good drug stability and simple process.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a levamlodipine besylate tablet.
Background
The amlodipine besylate has two isomers of levorotation and dextrorotation, and the calcium ion antagonistic activity of the levorotation is 1000 times that of the dextrorotation and is twice that of a racemate. The levamlodipine besylate is a levorotatory form of amlodipine besylate, is a 1, 4-dihydropyridine calcium ion antagonist or a slow channel blocker, and is a common medicament for treating hypertension at present. The benzene sulfonic acid levamlodipine is white or white-like powder, is easy to dissolve in methanol and ethanol and is slightly soluble in water; the English name is Levamlodipine Besylate, the chemical name is (S) - (-) 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorphenyl) -1, 4-dihydro-6-methyl-3, 5-pyridine dicarboxylic ester benzene sulfonate, the molecular formula is C20H25N2O5Cl·C6H6O3S, molecular weight 567.05. The clinically applied levamlodipine besylate tablets mainly have two functions: one effect is the treatment of hypertension, for mild and moderate hypertensive patients (alone or in combination with other drugs). Another effect is the treatment of angina pectoris, especially idiopathic angina pectoris (used alone or in combination with other drugs). The levamlodipine besylate has a plurality of unique properties and is different from other calcium antagonists, and the levamlodipine besylate has long-acting and slow absorption and gradually generates a vasodilation effect. The antihypertensive and antianginal tablets have long action time, and can be taken once a day, and the action time can be maintained for nearly 24 hours. The side effect is slight, and the patient can generally tolerate the side effect, so the side effect is more and more widely applied to clinic.
The levamlodipine besylate selectively inhibits calcium ions from entering smooth muscle cells and myocardial cells through a membrane, and the effect on the smooth muscle is larger than that of the myocardial. Its interaction with calcium channels is determined by the progressive rate of its binding to and dissociation from receptor sites, and thus pharmacological effects are gradually developed. Levamlodipine besylate is a peripheral artery dilating agent, directly acts on vascular smooth muscle, reduces peripheral vascular resistance and accordingly reduces blood pressure. The accurate mechanism of levamlodipine besylate for relieving angina is not clear, but the levamlodipine besylate reduces the product of cardiac work and rate blood pressure by reducing peripheral resistance (afterload) and reduces myocardial aerobic treatment labor type angina probably during exercise; the spontaneous angina pectoris is treated by recovering blood supply in ischemic area by inhibiting the contraction of coronary artery and arteriole caused by calcium ion, adrenalin, 5-hydroxytryptamine and thromboxane A2.
CN105106161A, preparing a levamlodipine besylate solid dispersion, wherein the dispersion contains levamlodipine besylate, polyvinylpyrrolidone, beta-cyclodextrin and soybean phospholipids.
CN104257619A, adding a diluent and a disintegrating agent into a binder, and then mixing and granulating by a wet method; drying and granulating; then spraying the levoamlodipine besylate ethanol solution into the granules, adding an additional auxiliary material, mixing, and drying at normal temperature; and (6) tabletting.
CN102697743B, microcrystalline cellulose, calcium sulfate, hydroxypropyl cellulose and magnesium stearate. The preparation does not contain lactose, has simple preparation process and few related substances, and can still maintain higher dissolution performance and higher stability.
However, none of the above patents fundamentally solves the problem that levamlodipine besylate is easily decomposed by light.
Disclosure of Invention
In the prior art, in order to ensure the stability of the medicine to light, only an opacifier is added and the package is protected from light, so that the problem of unstable light in the production process is not thoroughly solved. Aiming at the defects of the prior art, the inventor plans to provide a levamlodipine besylate tablet with good stability.
The inventor considers that the levamlodipine besylate has poor light stability, and can be degraded in the production process of the tablet no matter what auxiliary materials are added, unless the medicament has good light stability, so the inventor plans to improve the light stability of the levamlodipine besylate raw material by a process technology.
In the prior art, the stability of the medicine is ensured by adding an opacifier or keeping the medicine away from light as much as possible in the production process, and the problems are difficult to completely solve.
The inventor tries to add a stabilizer, and after a large number of experiments, the improvement cannot be realized well. Surprisingly, the inventors considered that photodegradation of levamlodipine besylate is related to its surface area, and if the surface area is reduced, the stability should be improved, and the results prove the inventors' guess, but degradation still remains.
Further, the inventor creatively considers that after microcrystalline cellulose, menthol and amlodipine base are prepared into pellets, the pellets are added into ethanol, the menthol is dissolved in the ethanol to form a cavity, then benzenesulfonic acid is added into the system, acid liquor enters the interior of the pellets through the cavity, the levoamlodipine base reacts with the acid liquor to form the levamlodipine besylate, and the levamlodipine besylate is filtered and dried to obtain the microcrystalline cellulose pellets containing the levamlodipine besylate, which is equivalent to the fact that the levamlodipine besylate is wrapped in the microcrystalline cellulose cavity. The pellet prepared by the technology has good light stability because the levamlodipine besylate raw material is wrapped in the microcrystalline cellulose pellet.
Specifically, the invention is realized by the following technologies:
the invention provides a levamlodipine besylate tablet, which is prepared by preparing microcrystalline cellulose, menthol and levamlodipine alkali into pellets, and then adding the pellets into ethanol or ethanol solution for soaking; then filtering out the pellets, adding the pellets into a benzenesulfonic acid aqueous solution, stirring, filtering and drying to obtain microcrystalline cellulose pellets containing the benzenesulfonic acid levamlodipine; then mixing with pharmaceutically acceptable auxiliary materials, and tabletting.
The weight ratio of the levamlodipine alkali to the microcrystalline cellulose is 1: 5-30.
The weight ratio of the levamlodipine alkali to the microcrystalline cellulose is 1: 15.
The weight ratio of the menthol to the microcrystalline cellulose is 1: 5-12.
The weight ratio of the menthol to the microcrystalline cellulose is 1: 8.
The weight ratio of the levamlodipine base to the benzenesulfonic acid is preferably 100: 38-200.
The pharmaceutically acceptable auxiliary materials comprise a filling agent, a disintegrating agent and a lubricating agent.
The filler is one or more of lactose, mannitol, starch and dextrin.
The disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose.
The lubricant is one or more of magnesium stearate, sodium fumarate stearate, talcum powder and silicon dioxide.
Compared with the prior art, the invention has the following advantages:
1) the drug is encapsulated in the microcrystalline cellulose cavity, so that the stability is greatly improved;
2) the preparation process is simple and suitable for industrial production.
Detailed Description
The following examples further illustrate the benefits of the present invention, and the examples are for illustrative purposes only and do not limit the scope of the present invention, and variations and modifications apparent to those of ordinary skill in the art in light of the present disclosure are intended to be included within the scope of the present invention.
Example 1
The preparation process comprises the following steps:
preparing microcrystalline cellulose, menthol and levamlodipine base into micro-pills according to the prescription amount, adding the micro-pills into ethanol for soaking for 1 hour, filtering out the micro-pills, adding the micro-pills into benzenesulfonic acid aqueous solution (dissolving benzenesulfonic acid of the prescription amount into water of the prescription amount), stirring for half an hour, filtering and drying to obtain the microcrystalline cellulose micro-pills containing the levamlodipine besylate; mixing with sodium carboxymethyl starch, lactose and magnesium stearate, and tabletting.
Example 2
The preparation process comprises the following steps:
preparing microcrystalline cellulose, menthol and levamlodipine base into micro-pills according to the prescription amount, adding the micro-pills into ethanol for soaking for half an hour, filtering out the micro-pills, adding the micro-pills into benzenesulfonic acid aqueous solution (dissolving benzenesulfonic acid of the prescription amount into water of the prescription amount), stirring for half an hour, filtering and drying to obtain the microcrystalline cellulose micro-pills containing the levamlodipine besylate; drying at 40 ℃ to obtain the microcrystalline cellulose pellet containing the benzene sulfonic acid levamlodipine. Then mixing with crospovidone, lactose and magnesium stearate, and tabletting.
Example 3
The preparation process comprises the following steps:
preparing microcrystalline cellulose, menthol and levamlodipine base into micro-pills according to the prescription amount, adding the micro-pills into ethanol for soaking for 1 hour, filtering out the micro-pills, adding the micro-pills into benzenesulfonic acid aqueous solution (dissolving benzenesulfonic acid of the prescription amount into water of the prescription amount), stirring for 1 hour, filtering, and drying to obtain the microcrystalline cellulose micro-pills containing the levamlodipine besylate; drying at 40 ℃ to obtain the microcrystalline cellulose pellet containing the benzene sulfonic acid levamlodipine. Mixing with sodium carboxymethyl starch, lactose and magnesium stearate, and tabletting.
Comparative example 1
The preparation process comprises the following steps:
the tablet is prepared by weighing microcrystalline cellulose, levamlodipine besylate, crospovidone, microcrystalline cellulose and magnesium stearate, mixing and tabletting.
Comparative example 2
The preparation process comprises the following steps:
(1) weighing the above substances according to the prescription amount, wherein the prescription amount refers to the substances and the content in the formula;
(2) respectively sieving microcrystalline cellulose, calcium sulfate and hydroxypropyl cellulose with 60 mesh sieve, and mixing;
(3) screening the levamlodipine besylate through a 80-mesh sieve, dispersing the levamlodipine besylate into the mixture obtained in the step (2) in a grading manner, putting the mixture into a wet mixing granulator, and stirring for 10-20 minutes;
(4) adding appropriate amount of 15% alcohol, stirring for 5-10 minutes, and making into soft material;
(5) sieving with 18 mesh sieve twice to obtain wet granule;
(6) drying in an oven at 60-70 deg.C for 2.5 + -0.5 hr, and granulating with a dry granule swing granulator of 16 meshes;
(7) sieving magnesium stearate with a 80-mesh sieve, adding the magnesium stearate in the formula amount into the dried granules, and mixing for 20 minutes by using a V-shaped mixer;
(8) the water content of the granules is controlled to be 2-5 percent, and the content is controlled to be 2.85-3.15 percent;
(9) tabletting, and controlling the hardness to be 2-5 kg;
comparative example 3
The preparation process comprises the following steps:
and (3) granulating auxiliary materials: mixing mannitol and crospovidone, adding into hydroxypropyl cellulose as binder, and granulating; drying the prepared granules at 80 deg.C, collecting when the water content of the granules reaches 1-3%, and grading with a rapid granulating machine;
dissolving levamlodipine besylate in absolute ethanol to prepare an ethanol solution of levamlodipine besylate, spraying the ethanol solution of levamlodipine besylate into the dry granules, adding an additional auxiliary material (silicon dioxide), mixing, and drying at normal temperature;
and (3) measuring the content of the levamlodipine besylate in the mixed granules, and tabletting the mixed granules with qualified content to prepare the levamlodipine besylate tablets.
Verification of the examples:
1. the optical purity is operated in the dark. Measured according to high performance liquid chromatography (appendix V D of the second part of the 2010 edition of Chinese pharmacopoeia).
Chromatographic conditions and system applicability tests show that acetonitrile-0.02 mol/L sodium dihydrogen phosphate aqueous solution (pH7.0) aqueous solution (20: 80) is used as a mobile phase, the detection wavelength is 360nm, and the separation degree of levamlodipine and dextroamlodipine meets the requirement.
The determination method comprises collecting fine powder 0.16g, weighing, adding 50% acetonitrile solution to obtain solution containing 0.2mg of L-amlodipine per 1ml, shaking, filtering, and collecting filtrate as sample solution. And (3) injecting 20 mu l of the mixture into a liquid chromatograph, recording a chromatogram, and calculating according to an area normalization method (a benzenesulfonic acid solvent peak is not counted), wherein the area of the levamlodipine peak is not less than 98.5%.
In the chromatogram recorded under the content determination item of the related substance, the sum of the areas of impurity peaks (the peaks of the solvent are not counted) should be not more than 1.0 percent of the total area.
2. Results of measurement in each example
Results of the cis isomer assay of each example
As can be seen from the table, the stability of the products obtained in examples 1, 2 and 3 of the present invention was better than that of comparative examples 1, 2 and 3.
Claims (7)
1. The levamlodipine besylate tablet is characterized in that microcrystalline cellulose, menthol and levamlodipine alkali are prepared into pellets, and then the pellets are added into ethanol or ethanol solution for soaking; then filtering out the pellets, adding the pellets into a benzenesulfonic acid aqueous solution, stirring, filtering and drying to obtain microcrystalline cellulose pellets containing the benzenesulfonic acid levamlodipine; then mixing with pharmaceutically acceptable auxiliary materials, and tabletting; wherein the weight ratio of the levamlodipine alkali to the microcrystalline cellulose is 1:5-30, wherein the weight ratio of the menthol to the microcrystalline cellulose is 1:5-12, wherein the weight ratio of the levoamlodipine alkali to the benzenesulfonic acid is 100: 38-200.
2. The levamlodipine besylate tablet according to claim 1, wherein the weight ratio of the levamlodipine besylate base to the microcrystalline cellulose is 1: 15.
3. The levamlodipine besylate tablet according to claim 1, wherein the weight ratio of menthol to microcrystalline cellulose in the levamlodipine besylate tablet is 1: 8.
4. Levamlodipine besylate tablets according to any of claims 1 to 3, wherein the pharmaceutically acceptable excipients are fillers, disintegrants, lubricants.
5. Levamlodipine besylate tablets according to claim 4, wherein said filler is one or more of microcrystalline cellulose, lactose, mannitol, starch, dextrin.
6. Levamlodipine besylate tablets according to claim 4, wherein said disintegrant is one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose.
7. Levamlodipine besylate tablets according to claim 4, wherein said lubricant is one or more of magnesium stearate, sodium fumarate stearate, talc and silica.
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| CN105434383B true CN105434383B (en) | 2021-08-03 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006072832A1 (en) * | 2005-01-07 | 2006-07-13 | Pfizer Products Inc. | Fast-disintegrating dosage forms of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene |
| CN103127018A (en) * | 2013-03-06 | 2013-06-05 | 浙江昂利康制药有限公司 | Levamlodipine besylate tablet and preparation method thereof |
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| CN103191073B (en) * | 2013-04-18 | 2015-01-07 | 广东彼迪药业有限公司 | Amlodipine benzenesulfonate tablet and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006072832A1 (en) * | 2005-01-07 | 2006-07-13 | Pfizer Products Inc. | Fast-disintegrating dosage forms of 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]-hexadeca-2(11),3,5,7,9-pentaene |
| CN103127018A (en) * | 2013-03-06 | 2013-06-05 | 浙江昂利康制药有限公司 | Levamlodipine besylate tablet and preparation method thereof |
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