CN105434383A - Levamlodipine besylate tablets and preparation method thereof - Google Patents
Levamlodipine besylate tablets and preparation method thereof Download PDFInfo
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- CN105434383A CN105434383A CN201511028812.8A CN201511028812A CN105434383A CN 105434383 A CN105434383 A CN 105434383A CN 201511028812 A CN201511028812 A CN 201511028812A CN 105434383 A CN105434383 A CN 105434383A
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- levamlodipine
- microcrystalline cellulose
- beaylate tablets
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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 levamlodipine besylate tablets. According to a preparation method, pellets are prepared from microcrystalline cellulose, menthol and levamlodipine base, added to ethyl alcohol and stirred, then a product is added to a benzoic acid solution, the levamlodipine base and alkali liquor react to form levamlodipine besylate, the levamlodipine besylate is filtered and dried, and microcrystalline cellulose pellets containing the levamlodipine besylate are obtained, are mixed with pharmaceutically acceptable auxiliaries and are subjected to tablet compressing. Compared with the prior art, the levamlodipine besylate tablets and the preparation method have the advantages of good drug stability and simple process.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of Levamlodipine beaylate tablets agent.
Background technology
Amlodipine Besylate Tablet has left-handed and dextrorotation two kinds of isomers, and levo form calcium antagonist is 1000 times of d-isomer, is the twice of raceme.Levamlodipine besylate is the levo form of Amlodipine Besylate Tablet, is Isosorbide-5-Nitrae-dihydropyridine calcium ion antagonist or slow channel blocking agent, is current Hypertension common drug.Levamlodipine besylate is white or off-white powder, easily molten in methanol, ethanol, slightly soluble in water; Its English name is LevamlodipineBesylate, chemical name is (S)-(-) 3-ethyl-5-methyl-2-(the amino ethoxymethyl of 2-)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate, molecular formula is C
20h
25n
2o
5clC
6h
6o
3s, molecular weight is 567.05.Clinical practice Levamlodipine beaylate tablets mainly has two kinds of effects: a kind of effect is Hypertension, for hyperpietic's (independent or merge with other drug use) of slight and moderate.Another kind of effect is treatment angina pectoris, especially spontaneous angina pectoris (separately or merge with other drug use).Levamlodipine besylate has many peculiar properties and different with other calcium antagonist, show as long-acting, slowly absorb, produce hemangiectasis effect gradually.Blood pressure lowering and the Antianginal effect time long, daily once, nearly 24 hours can be maintained action time.Side effect is smaller, and patient generally can tolerate, and is thus applied to clinical more and more widely.
Levamlodipine besylate Selective depression calcium ion cross-film enters smooth muscle cell and myocardial cell, is greater than cardiac muscle to the effect of smooth muscle.Itself and the interaction of calcium channel are decided by the gradual speed that it and acceptor site are combined and dissociate, and therefore pharmacological action produces gradually.Levamlodipine besylate is peripheral arterial expander, directly acts on vascular smooth muscle, reduces peripheral vascular resistance, thus reduces blood pressure.The precise mechanism of Levamlodipine besylate allevating angina pectoris is still not clear, but may when moving, Levamlodipine besylate reduces heart acting and speed pressure product by reducing Peripheral resistance (afterload), reduces myocardium aerobic treatment exertional angina pectoris; The coronary artery caused by suppressing calcium ion, epinephrine, 5-hydroxy tryptamine and thromboxane A2 and small artery shrink, and recover ischemic region blood supply treatment spontaneous angina pectoris.
CN105106161A, prepares Levamlodipine besylate solid dispersion, and dispersion contains Levamlodipine besylate, polyvinylpyrrolidone, beta-schardinger dextrin-, soybean phospholipid.
CN104257619A, after diluent and disintegrating agent are added binding agent, adopts wet-mixed to granulate; Dry, granulate; Then Levamlodipine besylate alcoholic solution sprayed into above-mentioned granule and add additional adjuvant, mixing, dry under room temperature; Tabletting.
CN102697743B, microcrystalline Cellulose, calcium sulfate, hyprolose, magnesium stearate.Not containing lactose, preparation process is simple, and related substance is few, still can keep higher dissolving out capability and higher stability.
But above patent, does not all fundamentally solve Levamlodipine besylate and sees the labile problem of light.
Summary of the invention
In prior art, for ensureing that medicine is to the stability of light, only add opacifier and on the packaging outside lucifuge, the problem thoroughly to photo-labile in solution production process.For the defect of prior art, inventor intends the Levamlodipine beaylate tablets agent providing a kind of good stability.
Inventor considers, Levamlodipine besylate photostability is poor, no matter add which kind of adjuvant, in tablet manufacturing process, all may degrade, except the photostability of non-drug own is good, therefore, inventor plans by Technology, to improve the stability of Levamlodipine besylate raw material to light.
In prior art, being all the stability ensureing medicine by adding in opacifier or production process lucifuge of trying one's best, being difficult to thoroughly solve the problem.
Inventor attempts adding a kind of stabilizing agent, through great many of experiments, all can not well improve.Unexpectedly, inventor considers that the light degradation of Levamlodipine besylate is relevant with its surface area, if reduce its surface area, then should be able to improve stability, result demonstrates the guess of inventor, but still has degraded.
Further, after inventor's creativeness is considered and microcrystalline Cellulose, Mentholum and amlodipine base is prepared into micropill, join in ethanol, Mentholum is dissolved in ethanol and forms cavity, then in this system, benzenesulfonic acid is added, acid solution enters micropill inside by cavity, Levamlodipine alkali and acid liquid reaction form Levamlodipine besylate, filter, dry, obtain the microcrystalline cellulose pellets containing Levamlodipine besylate, be equivalent to Levamlodipine besylate and be wrapped in microcrystalline Cellulose cavity.The micropill prepared of this technology is wrapped in microcrystalline cellulose pellets due to Levamlodipine besylate raw material, and light stability is good.
Specifically, the present invention is realized by following technology:
The invention provides a kind of Levamlodipine beaylate tablets agent, be specially after microcrystalline Cellulose, Mentholum and Levamlodipine alkali are prepared into micropill, join in ethanol or alcoholic solution and soak; Leach micropill afterwards, join in benzenesulfonic acid aqueous solution, stir, filter, dry, obtain the microcrystalline cellulose pellets containing Levamlodipine besylate; Then mix with pharmaceutically acceptable adjuvant, tabletting forms.
Described Levamlodipine alkali and the weight ratio of microcrystalline Cellulose are 1:5-30.
Described Levamlodipine alkali and the weight ratio of microcrystalline Cellulose are 1:15.
Described Mentholum and the weight ratio of microcrystalline Cellulose are 1:5-12.
Described Mentholum and the weight ratio of microcrystalline Cellulose are 1:8.
Described Levamlodipine alkali and the weight ratio of benzenesulfonic acid are preferably 100:38-200.
Described pharmaceutically acceptable adjuvant is filler, disintegrating agent, lubricant.
Described filler is one or more in lactose, mannitol, starch, dextrin.
Described disintegrating agent is one or more in carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose.
Described lubricant is one or more in magnesium stearate, sodium stearyl fumarate, Pulvis Talci, silicon dioxide.
Compared with prior art, the present invention has following advantage:
1) medicine is encapsulated in microcrystalline Cellulose cavity, and stability improves greatly;
2) preparation technology is simple, is suitable for suitability for industrialized production.
Detailed description of the invention
Following examples further describe beneficial effect of the present invention, embodiment is only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
Embodiment 1
Preparation technology:
By recipe quantity, after microcrystalline Cellulose, Mentholum and Levamlodipine alkali are prepared into micropill, join in ethanol and soak 1 hour, leach micropill afterwards, join in benzenesulfonic acid aqueous solution (benzenesulfonic acid of recipe quantity being dissolved in the water of recipe quantity), stir half an hour, filter, drying, obtains the microcrystalline cellulose pellets containing Levamlodipine besylate; Then with carboxymethyl starch sodium, lactose, magnesium stearate mixing, tabletting forms.
Embodiment 2
Preparation technology:
By recipe quantity, after microcrystalline Cellulose, Mentholum and Levamlodipine alkali are prepared into micropill, join in ethanol and soak half an hour, leach micropill afterwards, join in benzenesulfonic acid aqueous solution (benzenesulfonic acid of recipe quantity being dissolved in the water of recipe quantity), stir half an hour, filter, drying, obtains the microcrystalline cellulose pellets containing Levamlodipine besylate; 40 degrees Celsius of dryings, obtain the microcrystalline cellulose pellets containing Levamlodipine besylate.Then with polyvinylpolypyrrolidone, lactose, magnesium stearate mixing, tabletting forms.
Embodiment 3
Preparation technology:
By recipe quantity, after microcrystalline Cellulose, Mentholum and Levamlodipine alkali are prepared into micropill, join in ethanol and soak 1 hour, leach micropill afterwards, join in benzenesulfonic acid aqueous solution (benzenesulfonic acid of recipe quantity being dissolved in the water of recipe quantity), stir 1 hour, filter, drying, obtains the microcrystalline cellulose pellets containing Levamlodipine besylate; 40 degrees Celsius of dryings, obtain the microcrystalline cellulose pellets containing Levamlodipine besylate.Then with carboxymethyl starch sodium, lactose, magnesium stearate mixing, tabletting forms.
Comparative example 1
Preparation technology:
Recipe quantity takes microcrystalline Cellulose and mixes with Levamlodipine besylate, polyvinylpolypyrrolidone, microcrystalline Cellulose, magnesium stearate, and tabletting forms.
Comparative example 2
Preparation technology:
(1) take above-mentioned substance by recipe quantity, described recipe quantity refers to material and content described in above-mentioned formula;
(2) microcrystalline Cellulose, calcium sulfate and hyprolose are crossed 60 eye mesh screens respectively, mix homogeneously;
(3) Levamlodipine besylate crosses 80 mesh sieves, and classification is diffused in the mixture that step (2) obtains, and drops in wet mixing pelletizer, stirs 10-20 minute;
(4) add 15% ethanol appropriate, stir 5-10 minute, make soft material;
(5) 18 mesh sieve secondaries are crossed with waving granule, obtained wet granular;
(6) in 60-70 DEG C of baking oven dry 2.5 ± 0.5 hours, dry granule oscillating granulator 16 order granulate;
(7) magnesium stearate crosses 80 mesh sieves, and dry granule adds recipe quantity magnesium stearate, and V-Mixer mixes 20 minutes;
(8) granule water content control is at 2%-5%, and content controls at 2.85%-3.15%;
(9) tabletting, Hardness Control is at 2-5kg;
Comparative example 3
Preparation technology:
Adjuvant is granulated: by adding in binding agent hyprolose after mannitol, polyvinylpolypyrrolidone mixing, granulate; By obtained granule in 80 DEG C of dryings, the rewinding when the moisture of granule reaches 1-3%, use Fast granulate machine granulate;
Levamlodipine besylate is dissolved in dehydrated alcohol and makes Levamlodipine besylate alcoholic solution, sprayed into dry granule and add additional adjuvant (silicon dioxide), mixing, dry under room temperature;
Measure the Levamlodipine besylate content in hybrid particles, hybrid particles qualified for content is carried out tabletting, makes Levamlodipine beaylate tablets.
Checking embodiment:
1. optical purity lucifuge operation.Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex V D).
Chromatographic condition and system suitability, acetonitrile-0.02mol/L biphosphate sodium water solution (pH7.0) aqueous solution (20:80) is mobile phase, determined wavelength 360nm, the separating degree of Levamlodipine and R(+)-AMLODIPINE should meet the requirements.
Algoscopy is got this product fine powder and is about 0.16g, accurately weighed, adds 50% acetonitrile solution and makes the solution containing Levamlodipine 0.2mg in every 1ml, shake up, filter, get subsequent filtrate as need testing solution.Get 20 μ l, injection liquid chromatography, record chromatogram, calculate according to area normalization method (benzenesulfonic acid solvent peak is disregarded), Levamlodipine peak area must not be less than 98.5%.
In the chromatogram that related substance records under assay item, impurity peak area summation (solvent peak is disregarded) should be not more than 1.0% of the gross area.
2. each embodiment measurement result
Each embodiment cis-isomer measurement result
As seen from the table, compared with comparative example 1,2,3, having good stability of the embodiment of the present invention 1,2,3 products obtained therefrom.
Claims (10)
1. a Levamlodipine beaylate tablets agent, is characterized in that, is specially after microcrystalline Cellulose, Mentholum and Levamlodipine alkali are prepared into micropill, joins in ethanol or alcoholic solution and soak; Leach micropill afterwards, join in benzenesulfonic acid aqueous solution, stir, filter, dry, obtain the microcrystalline cellulose pellets containing Levamlodipine besylate; Then mix with pharmaceutically acceptable adjuvant, tabletting forms.
2. Levamlodipine beaylate tablets agent according to claim 1, is characterized in that, described Levamlodipine beaylate tablets agent, and the weight ratio of Levamlodipine alkali and microcrystalline Cellulose is 1:5-30.
3. Levamlodipine beaylate tablets agent according to claim 2, is characterized in that, described Levamlodipine beaylate tablets agent, and the weight ratio of Levamlodipine alkali and microcrystalline Cellulose is 1:15.
4. Levamlodipine beaylate tablets agent according to claim 1, is characterized in that, described Levamlodipine beaylate tablets agent, and the weight ratio of Mentholum and microcrystalline Cellulose is 1:5-12.
5. Levamlodipine beaylate tablets agent according to claim 4, is characterized in that, described Levamlodipine beaylate tablets agent, and the weight ratio of Mentholum and microcrystalline Cellulose is 1:8.
6. Levamlodipine beaylate tablets agent according to claim 1, is characterized in that, described Levamlodipine alkali and the weight ratio of benzenesulfonic acid are 100:38-200.
7. the Levamlodipine beaylate tablets agent according to the arbitrary claim of claim 1-6, is characterized in that, pharmaceutically acceptable adjuvant is filler, disintegrating agent, lubricant.
8. Levamlodipine beaylate tablets agent according to claim 7, is characterized in that, described filler is one or more in microcrystalline Cellulose, lactose, mannitol, starch, dextrin.
9. Levamlodipine beaylate tablets agent according to claim 7, is characterized in that, described disintegrating agent is one or more in carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose.
10. Levamlodipine beaylate tablets agent according to claim 7, is characterized in that, described lubricant is one or more in magnesium stearate, sodium stearyl fumarate, Pulvis Talci, silicon dioxide.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201511028812.8A CN105434383B (en) | 2015-12-31 | 2015-12-31 | Levamlodipine besylate tablet and preparation method thereof |
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| CN201511028812.8A CN105434383B (en) | 2015-12-31 | 2015-12-31 | Levamlodipine besylate tablet and preparation method thereof |
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| CN105434383A true CN105434383A (en) | 2016-03-30 |
| CN105434383B CN105434383B (en) | 2021-08-03 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4023221A4 (en) * | 2019-11-08 | 2023-09-27 | Shihuida Pharmaceuticals Group (Jilin) Ltd. | Composition containing legoamodipine besylate hydrate and preparation method therefor |
Citations (3)
| 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 |
| CN103191073A (en) * | 2013-04-18 | 2013-07-10 | 广东彼迪药业有限公司 | Amlodipine benzenesulfonate tablet and preparation method thereof |
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2015
- 2015-12-31 CN CN201511028812.8A patent/CN105434383B/en active Active
Patent Citations (3)
| 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 |
| CN103191073A (en) * | 2013-04-18 | 2013-07-10 | 广东彼迪药业有限公司 | Amlodipine benzenesulfonate tablet and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4023221A4 (en) * | 2019-11-08 | 2023-09-27 | Shihuida Pharmaceuticals Group (Jilin) Ltd. | Composition containing legoamodipine besylate hydrate and preparation method therefor |
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