CN104997778A - Olmesartan medoxomil and amlodipine medicinal composition - Google Patents
Olmesartan medoxomil and amlodipine medicinal composition Download PDFInfo
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- CN104997778A CN104997778A CN201510398967.4A CN201510398967A CN104997778A CN 104997778 A CN104997778 A CN 104997778A CN 201510398967 A CN201510398967 A CN 201510398967A CN 104997778 A CN104997778 A CN 104997778A
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Abstract
The invention provides an olmesartan medoxomil and amlodipine medicinal composition and a preparation method thereof. The olmesartan medoxomil and amlodipine medicinal composition comprises olmesartan medoxomil, amlodipine, amlodipine besylate, mannitol, calcium hydrogen phosphate and at least one pharmaceutically acceptable excipient. The obtained olmesartan medoxomil and amlodipine medicinal composition has obviously improved stability and medicine dissolution, can effectively guarantee safety and effectiveness of clinic medication, and provides a good choice for preparation of effective preparations with stable quality.
Description
Technical field
The invention belongs to medical art, or rather, relate to olmesartan medoxomil amlodipine and preparation method thereof.
Background technology
Olmesartan medoxomil is Angiotensin Ⅱ receptor antagonist (ARB) class medicine, it is a kind of prodrug, after entering gastrointestinal tract can rapidly, complete hydrolysis is activated metabolite Olmesartan, and it absorbs the impact of unable to take food thing, the interaction of this medicine is few, and the half-life reaches 13h, can 1 time/d administration.
Amlodipine Besylate Tablet oral absorption is good, and hypotensive effect is rapid, steady and evident in efficacy, generally within 1-2 week, occurs obvious antihypertensive effect, 6-8 week effect reaches maximum, and the long 35-50h of its plasma half-life, miss once in a while and once also do not affect antihypertensive effect, the fluctuation of blood pressure can not be caused.Amlodipine Besylate Tablet can treat angina pectoris simultaneously, and is suitable for the patient of the various diseases such as complication with diabetes, asthma, hyperlipemia, heart failure and gout.
Research both domestic and external all shows, olmesartan medoxomil and amlodipine coupling, and antihypertensive effect is good, is applicable to being prepared into compound preparation.
According to FDA description and patent WO2008032107, can learn that former technique of grinding is compress tablet coating after dry granulation, the method is with pregelatinized Starch, silicified microcrystalline cellulose and cross-linking sodium carboxymethyl cellulose etc. for adjuvant carries out dry granulation, but prepared tablet exists the incomplete problem of stripping of amlodipine.
The compound preparation of a kind of amido chloro diping dispersion tablet and olmesartan medoxomil is disclosed in CN201310007759.8, this method solve two kinds of medicine problems that release profiles is inconsistent in vivo, decrease the side reaction of medicine, but this preparation technology needs to prepare dispersion separately, complicated process of preparation, production cost is too high, is not suitable for industrialized great production.
A kind of dry granulation process is disclosed in CN201210258340.5, with the prescription that microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose are adjuvant, this preparation method technique is simple, but reckon without the strong-hydrophobicity of olmesartan medoxomil, cause moisture penetration slow to the speed in tablet, final disintegration time is slightly long, thus affects the stripping of amlodipine.
The complex tablet of olmesartan medoxomil, Amlodipine Besylate Tablet and hydrochlorothiazide three kinds of active substances is disclosed in CN201210101809, and disclose employing mannitol as diluent, but do not adopt the mode of two kinds of disintegrating agent couplings in its prescription, cause olmesartan medoxomil stripping in final products incomplete.
Therefore, according to existing adjuvant and working condition, under guarantee has the prerequisite of lower production cost and simple preparation technology, be necessary to work out a kind of suitable prescription composition and preparation technology, make olmesartan medoxomil amlodipine have good bioavailability and stability of drug products.
Summary of the invention
The invention discloses a kind of pharmaceutical composition of olmesartan medoxomil amlodipine, with mannitol and calcium hydrogen phosphate mixture for stabilizing agent, the mode of two kinds of disintegrating agent couplings is chosen in disintegrating agent aspect, when adopting single disintegrating agent, we find easily to cause the prominent of olmesartan medoxomil to release, and the stripping of amlodipine is incomplete, upon to many attempts, find when employing two kinds of disintegrating agent couplings, not only the burst effect of olmesartan medoxomil disappears, and the stripping of amlodipine also meets corresponding requirement.
Above-mentioned prescription not only solves the problem of the easy moisture absorption of amlodipine, and has ensured the stripping of amlodipine under the prerequisite not causing olmesartan medoxomil to dash forward to release.
Its concrete prescription, and each prescription percentage is as follows:
Wherein said stabilizing agent is the mixture of calcium hydrogen phosphate and mannitol; Amlodipine Besylate Tablet shared prescription percentage by weight in prescription is 3.465%.
Disintegrating agent is selected from the mixture of in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose two kinds, wherein the mixture of preferred carboxymethyl starch sodium and polyvinylpolypyrrolidone;
Filler is selected from one or both the mixture in microcrystalline Cellulose, dextrin, starch, calcium sulfate, maltodextrin, pregelatinized Starch, wherein preferably microcrystalline cellulose
Lubricant is selected from the mixture of a kind of in magnesium stearate, Pulvis Talci, micropowder silica gel or two kinds, wherein preferred magnesium stearate.
The ratio of wherein said calcium hydrogen phosphate and mannitol mixture is 1:1 ~ 3, wherein preferred 1:2 and 1:1.5.
The present invention also discloses the preparation method of described olmesartan medoxomil amlodipine compositions, and its concrete steps are as follows:
1) mannitol mixes with calcium hydrogen phosphate, crosses 40 mesh sieves, for subsequent use;
2) the mixture equal increments of the Amlodipine Besylate Tablet of recipe quantity with vertical compression mannitol and calcium hydrogen phosphate is mixed, and then add remaining vertical compression mannitol and fully mix with calcium hydrogen phosphate mixture, olmesartan medoxomil, filler, disintegrating agent, finally add lubricant and always mix;
3) vertical compression;
4) prepare coating solution, carry out coating
Wherein, step 3) described in vertical compression technique adopt 20N/mm
2or higher pressure, preferred 40-600N/mm
2, more preferably 60-400N/mm
2.
Wherein, step 4) described coating solution joins coating powder by alcohol and forms, and alcohol content is 70-80%, and coating powder is Opadry.
The olmesartan medoxomil amlodipine tool adopting the method to prepare has the following advantages:
1) adopt vertical compression technique, preparation method is simple;
2) coating powder adopting alcohol to join carries out coating, sheet good looking appearance, and the label moisture absorption reduces, and stability improves;
3) by rational stabilizing agent proportioning, and the selection of rational disintegrating agent kind and quantity, optimize the problem of drug-eluting and medicine stability, improve drug quality.
Specific embodiment
Below by way of part most preferred embodiment, foregoing of the present invention is described in further detail again, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Prepare the component prescription (specification is respectively 20mg/5mg, 40mg/5mg) of 1000:
Preparation: the vertical compression mannitol of recipe quantity is mixed with calcium hydrogen phosphate, sieve, then the Amlodipine Besylate Tablet of recipe quantity is mixed with vertical compression mannitol and calcium hydrogen phosphate mixture equal increments, and then add remaining vertical compression mannitol and calcium hydrogen phosphate mixture, olmesartan medoxomil, microcrystalline Cellulose, carboxymethyl starch sodium and polyvinylpolypyrrolidone fully mix, finally add magnesium stearate and always mix.Mixing terminates laggard row direct compression, film-making pressure 28N/mm
2(punching: the plane hole of 9.5mm diameter).Preparation coating solution, adds in agitator by purified water and ethanol, opens stirring paddle, is slowly added in agitator by the Opadry of recipe quantity, fully stirs and within 2 hours, makes it dispersion, then coating.
Embodiment 2
Prepare the component prescription (specification is respectively 20mg/5mg, 40mg/5mg) of 1000:
Preparation: the vertical compression mannitol of recipe quantity is mixed with calcium hydrogen phosphate, sieve, then the Amlodipine Besylate Tablet of recipe quantity is mixed with vertical compression mannitol and calcium hydrogen phosphate mixture equal increments, and then add remaining vertical compression mannitol and calcium hydrogen phosphate mixture, olmesartan medoxomil, microcrystalline Cellulose, carboxymethyl starch sodium and cross-linking sodium carboxymethyl cellulose fully mix, finally add magnesium stearate and always mix.Mixing terminates laggard row direct compression, film-making pressure 85N/mm
2(punching: the plane hole of 9.5mm diameter).Preparation coating solution, adds in agitator by purified water and ethanol, opens stirring paddle, is slowly added in agitator by the Opadry of recipe quantity, fully stirs and within 2 hours, makes it dispersion, then coating.
Embodiment 3
Prepare the component prescription (specification is respectively 20mg/5mg, 40mg/5mg) of 1000:
Preparation: the vertical compression mannitol of recipe quantity is mixed with calcium hydrogen phosphate, sieve, then the Amlodipine Besylate Tablet of recipe quantity is mixed with vertical compression mannitol and calcium hydrogen phosphate mixture equal increments, and then add remaining vertical compression mannitol and calcium hydrogen phosphate mixture, olmesartan medoxomil, microcrystalline Cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose fully mix, finally add magnesium stearate and always mix.Mixing terminates laggard row direct compression, film-making pressure 141N/mm
2(punching: the plane hole of 9.5mm diameter).Preparation coating solution, adds in agitator by purified water and ethanol, opens stirring paddle, is slowly added in agitator by the Opadry of recipe quantity, fully stirs and within 2 hours, makes it dispersion, then coating.
Embodiment 4 comparative example 1---be prepared according to prescription disclosed in CN201210258340.5
The formula making 1000 is composed as follows:
Preparation method, its step comprises:
1) supplementary material prepares and process: olmesartan medoxomil, Amlodipine Besylate Tablet are crossed respectively 100 mesh sieves for subsequent use;
2) by supplementary material 100 DEG C of dryings 3 hours, for subsequent use;
3) by supplementary material mix homogeneously, dry granulation process is adopted to prepare granule;
4) measure intermediates content, calculate sheet weight;
5) tabletting: according to the actual sheet weight of result of calculation gained, tabletting;
Embodiment 5 comparative example 2---adopt single disintegrating agent to prepare
The composition prescription preparing 1000 is as follows:
Preparation: the vertical compression mannitol of recipe quantity is mixed with calcium hydrogen phosphate, sieve, then the Amlodipine Besylate Tablet of recipe quantity is mixed with vertical compression mannitol and calcium hydrogen phosphate mixture equal increments, and then add remaining vertical compression mannitol and calcium hydrogen phosphate mixture, olmesartan medoxomil, microcrystalline Cellulose, polyvinylpolypyrrolidone fully mix, finally add magnesium stearate and always mix.Mixing terminates laggard row direct compression.Preparation coating solution, carries out coating.
Embodiment 6 comparative example 3---be prepared according to prescription disclosed in CN201210101809
Every sheet prescription proportioning is as follows:
Preparation method: with mixer mixing olmesartan medoxomil, Amlodipine Besylate Tablet and hydrochlorothiazide, silicified microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium.Powder was mixed 1.9mm sieve.The powder mixer that will sieve mixes again.Add magnesium stearate and be again mixed and made into final blending constituent.With scrobicula mould tabletting after mixing, select suitable pressure and sheet weight.Thin film coating material selects Opadry II to be dissolved in purified water, selects coating equipment in sugar production line to carry out spray coating.
Embodiment 7 is former grinds technique---be prepared according to the prescription that grinds former disclosed in WO2008032107
Prepare the component prescription of 1000:
Preparation: the pregelatinized Starch of recipe quantity, olmesartan medoxomil, Amlodipine Besylate Tablet, silicified microcrystalline cellulose, cross-linking sodium carboxymethyl cellulose are fully mixed, then dry granulation is carried out, with the screen cloth of 1.9mm, finally add magnesium stearate and particulate matter always mixes.Mixing terminates laggard row tabletting.Preparation coating solution, carries out coating.
Embodiment 8 dissolution determination
Leaching condition: according to dissolution method (China's coastal port two annex XC second methods), with the phosphate buffer 900ml of pH6.8 for dissolution medium, rotating speed is 50 turns per minute, operates in accordance with the law, sampling and measuring dissolution, its result compares following table.
Table 1 embodiment 1-6 stripping and disintegration time contrast
From upper table data, the disintegration time of embodiment 4---comparative example 1 is long, and amlodipine stripping is incomplete.
Embodiment 5---only use a kind of olmesartan medoxomil of comparative example 2 of disintegrating agent to have and prominent release phenomenon, and the same stripping of final amlodipine is incomplete, and all there are not the problems referred to above in embodiment 1-3, not only solve the prominent of olmesartan medoxomil by the coupling of two kinds of disintegrating agents and release problem, and amlodipine stripping is complete.
Three kinds of prescription couplings in embodiment 6---comparative example 3, owing to only having used single disintegrating agent, olmesartan medoxomil has only had the stripping of 82%, and stripping is incomplete, and its disintegration time is long.
And the disintegration time of embodiment 1-3 and stripping well can grind the matching of product phase with former, be even better than formerly grinding technique.
Embodiment 9 study on the stability
Embodiment 1-5,7 long-term stable experiment, the result of the test of accelerated test, refers to following table
Table 2 embodiment 1-5,7 accelerated test results (40 DEG C ± 2 DEG C, 75%RH ± 5%)
Table 3: embodiment 1-5,7 long-term test results (25 DEG C ± 2 DEG C, 60%RH ± 5%)
From upper table data, embodiment 1-3 is steady quality under long-term conditions and acceleration environment, and is better than the stability of embodiment 4-5 comparative example and former stability of grinding tablet.
To sum up, the pharmaceutical composition stripping of olmesartan medoxomil amlodipine disclosed by the invention can with former matching of grinding high similarity, and stability is better than formerly grinding product.
Claims (10)
1. an olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition, is characterized in that, comprises the pharmaceutically acceptable excipient of olmesartan medoxomil, Amlodipine Besylate Tablet, mannitol, calcium hydrogen phosphate and at least one.
2. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 1, is characterized in that, described pharmaceutically acceptable excipient comprises filler, disintegrating agent, lubricant.
3. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 2, is characterized in that, described disintegrating agent is selected from the mixture of in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose two kinds.
4. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 1, is characterized in that, concrete prescription, and the percentage by weight of each prescription is as follows:
Disintegrating agent is selected from the mixture of in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose two kinds; Filler is selected from one or both the mixture in microcrystalline Cellulose, dextrin, starch, calcium sulfate, maltodextrin, pregelatinized Starch, and lubricant is selected from the mixture of a kind of in magnesium stearate, Pulvis Talci, micropowder silica gel or two kinds.
5. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 4, is characterized in that, described disintegrating agent is the mixture of carboxymethyl starch sodium and polyvinylpolypyrrolidone, and described filler is microcrystalline Cellulose, and described lubricant is magnesium stearate.
6. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 1 or 4, is characterized in that, the weight ratio of described calcium hydrogen phosphate and mannitol mixture is 1:1 ~ 3,
7. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 6, is characterized in that, the weight ratio of described calcium hydrogen phosphate and mannitol mixture is 1:2 or 1:1.5.
8. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 1, is characterized in that, its preparation method concrete steps are as follows:
(1) mannitol mixes with calcium hydrogen phosphate, crosses 40 mesh sieves, for subsequent use;
(2) the mixture equal increments of the Amlodipine Besylate Tablet of recipe quantity with vertical compression mannitol and calcium hydrogen phosphate is mixed, and then add remaining vertical compression mannitol and fully mix with calcium hydrogen phosphate mixture, olmesartan medoxomil, filler, disintegrating agent, finally add lubricant and always mix;
(3) vertical compression;
(4) prepare coating solution, carry out coating.
9. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 8, is characterized in that, step 3) described in vertical compression technique adopt pressure be more than or equal to 20N/mm
2, step 4) and described coating solution joins coating powder by alcohol and forms, and alcohol content is 70-80%, and coating powder is Opadry.
10. a kind of olmesartan medoxomil/amlodipinepharmaceutical pharmaceutical composition according to claim 9, is characterized in that, described step 3) described in vertical compression technique take 40-600N/mm
2pressure, be more preferably 60-400N/mm
2.
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| CN201510398967.4A CN104997778A (en) | 2015-07-08 | 2015-07-08 | Olmesartan medoxomil and amlodipine medicinal composition |
| CN201910328107.1A CN109875972B (en) | 2015-07-08 | 2015-07-08 | Olmesartan medoxomil and amlodipine pharmaceutical composition |
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| CN105902510A (en) * | 2015-12-24 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of olmesartan medoxomil-amlodipine compound preparation |
| CN107929287A (en) * | 2016-10-12 | 2018-04-20 | 武昌理工学院 | A kind of compound medicament composition and preparation method comprising Amlodipine |
| CN110237073A (en) * | 2019-07-10 | 2019-09-17 | 安庆回音必制药股份有限公司 | A kind of olmesartan medoxomil amlodipine and preparation method thereof |
| CN112691084A (en) * | 2019-10-23 | 2021-04-23 | 南京正大天晴制药有限公司 | Pharmaceutical composition and preparation method thereof |
| CN113811294A (en) * | 2019-02-26 | 2021-12-17 | 株式会社大熊制药 | Single-dosage pharmaceutical composition for treating or preventing hypertension and hyperlipidemia |
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| CN109875972B (en) | 2021-08-03 |
| CN109875972A (en) | 2019-06-14 |
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