CN103110929A - Pharmaceutical composition of mildronate and lisinopril and preparation method thereof - Google Patents
Pharmaceutical composition of mildronate and lisinopril and preparation method thereof Download PDFInfo
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- CN103110929A CN103110929A CN2012105243000A CN201210524300A CN103110929A CN 103110929 A CN103110929 A CN 103110929A CN 2012105243000 A CN2012105243000 A CN 2012105243000A CN 201210524300 A CN201210524300 A CN 201210524300A CN 103110929 A CN103110929 A CN 103110929A
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- lisinopril
- meldonium
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Abstract
The invention discloses a prescription and a preparation method of an oral preparation of a pharmaceutical composition of mildronate and lisinopril. Each preparation unit of the pharmaceutical composition comprises the following main components: 50-1000 mg of mildronate, and 2.5-80 mg of lisinopril. The pharmaceutical composition disclosed by the invention and pharmaceutically acceptable auxiliary materials can be prepared into the oral preparation beneficial to being taken by patients through the methods of tabletting or pelletizing and the like according to a certain proportion. The pharmaceutical composition disclosed by the invention is applied to greatly increasing applicability of patients and providing more convenient clinical selection for patients suffering from cardiovascular diseases.
Description
Technical field
The present invention relates to the stable pharmaceutical composition of a kind of active component content.Specifically, relate to the preparation of the pharmaceutical composition of Meldonium and lisinopril, comprise the preparation method of conventional tablet, effervescent tablet, capsule, granule and oral solution in solid preparation, belong to field of pharmaceutical preparations.
Background technology
Meldonium (claims again THP; MET-88 and mildronate) be a kind of novel heart protecting medicine; developed by the LV Latvia organic synthesis; 1989 by Grindeks company first in former Soviet Union's list marketing; it is the analog of carnitine; chemistry 3-(2 by name, 2,2-trimethyl hydrazine) propionate dihydrate.After in succession in more than 20 national registration listing such as Russia, Turkey, India, Romania.The Meldonium site of action improves energy metabolism of myocardial at mitochondrion at cellular level.In view of the obvious difference of this type of medicine and other myocardial ischemic antagonist, also be referred to as cell ischemia resisting medicine.JSC Grinderks listing product comprises injection (500mg/5ml), capsule (250mg, 500mg) and syrup (250ml, 50mg/ml), China has applied for import injection (500mg/5ml) and capsule (500mg), and commodity are called Milderonate.
Lisinopril is angiotensin-convertion enzyme inhibitor of new generation.It can suppress Angiotensin-Converting (ACE), but latter's catalysis angiotensin i-converting is vasoconstrictor peptide, i.e. Angiotensin II.Angiotensin II can stimulate adrenal cortex secretion aldosterone.Thereby suppressing ACE can make the reduction of Angiotensin II concentration that boosting and Aldosterone Secretion are descended.The latter's reduction causes the rising of serum potassium.Lisinopril mainly reduces blood pressure by suppressing renin angiotensin aldosterone system, and lisinopril also has hypotensive effect to low renin hypertension simultaneously.Many Lisinopril Tablets in Chinese Volunteers of country's Bureau of Drugs Supervision's approved, capsule manufacture.
Two kinds of medicine effects are obvious, be the cardio-cerebralvascular diseases medication, and both have been reported by drug combination, Meldonium (M) 1000mg+ lisinopril (L) 20mg and Meldonium (M) 1000mg+ lisinopril (L) 5mg show in by the I of NYHA classification～III level IV phase randomized, double-blind research in chronic heart failure due to coronary heart disease can improve dyspnea, myocardial reserve significantly increases, and the bradycardia of patient's carotid artery baroreflex and hypotension amplitude increase.(referring to Mildronate improves carotid baroreceptor reflex function in patients with chronic heart failure. Seminars in Cardiology, 2005, Vol.11, No.2).
The single preparations of ephedrine of these two kinds of medicines all goes on the market, evident in efficacy, safety is better, but also there is no so far the compound preparation listing of Meldonium lisinopril, so the present invention aims to provide so new pharmaceutical combination, and with the preparations shaping mode that has comparative maturity now, prepare the pharmaceutical preparation that facilitates the patient to take.The compound preparation that contains specifically the pharmaceutical composition of Meldonium and lisinopril comprises that the prescription of conventional tablet, fuse, effervescent tablet, capsule, granule and oral solution in solid preparation forms and preparation method.Both drug combinations can heighten the effect of a treatment, and reduce take medicine kind and quantity, facilitate the patient, improve compliance.
Summary of the invention
The present invention aims to provide prescription and the preparation method of oral solid formulation and the oral liquid of a kind of Meldonium and lisinopril pharmaceutical composition.
The combining form of medicine: (wherein the Meldonium specification is 50mg～1000mg, preferred 500mg and 1000mg for Meldonium and lisinopril; The specification 2.5mg of lisinopril～80mg, preferred 10mg and 20mg).
Described dosage form comprises tablet, capsule, granule and oral solution.
Described Tablet and Capsula agent adjuvant used is acceptable adjuvant pharmaceutically, comprising: the wherein combinations of one or more such as starch, microcrystalline Cellulose, hyprolose, carboxymethylstach sodium, cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, hypromellose, polyvidone, magnesium stearate, calcium stearate, sodium stearyl fumarate, micropowder silica gel.
Described fuse, effervescent tablet, granule and oral solution adjuvant used is acceptable adjuvant pharmaceutically, comprise: lactose, sucrose, mannitol, sorbitol, Aspartane, stevioside, acesulfame potassium, the wherein combinations of one or more such as carmethose, arabic gum, xanthan gum, sodium bicarbonate, citric acid, tartaric acid, fumaric acid, malic acid, sorbic acid, glycerol, propylene glycol, parabens.
Described preparation method comprises: dry powder vertical compression or fill (be about to supplementary material and press the recipe quantity mixing, directly carry out tabletting and capsule fill); Non-slurry pelletizing (be about to the supplementary material mix homogeneously, use dry granulating machine to carry out carrying out tabletting, fill or granulate after pelletize); Wet granulation (comprise add after supplementary material mixes binding agent granulate, dry, outer mixed; Can be also to measure little material dissolution in binding agent, carry out said process or a step granulating and forming).
The specific embodiment
The below sets forth the present invention with example:
1. the implementation case is capsule
| Meldonium | 500g |
| Lisinopril | 5g |
| Hyprolose | 30g |
| Cross-linked carboxymethyl cellulose sodium | 6g |
| Magnesium stearate | 4g |
| Make | 1000 (approximately 545mg/ grain) |
Preparation process: above-mentioned each supplementary material 80 orders sieve rear by the recipe quantity weighing, get lisinopril, hyprolose, cross-linked carboxymethyl cellulose sodium, the abundant mixing of magnesium stearate, add again the abundant mixing of Meldonium, carry out non-slurry pelletizing, collect 40 orders～60 order granules (﹥ 60 order fine powder amount account for total particle quantity≤10% and get final product), through intermediate assay, fill hard capsule.
2. the implementation case is conventional tablet
| Meldonium | 500g |
| Lisinopril | 10g |
| Microcrystalline Cellulose | 100g |
| Carboxymethylstach sodium | 50g |
| Polyvidone | 2.4g |
| 50% ethanol | 80ml |
| Differential silica gel | 3g |
| Sodium stearyl fumarate | 2.5g |
| Make | 1000 (approximately 670mg/ sheet) |
Preparation process one: take the recipe quantity polyvidone and add 80ml50% ethanol, use after the dissolving fully.Above-mentioned all the other each supplementary material 80 orders are sieved rear by the recipe quantity weighing, get the abundant mixing of lisinopril and carboxymethylstach sodium, add the abundant mixing of microcrystalline Cellulose, equivalent increases progressively and adds the abundant mixing of Meldonium, adds above-mentioned 3% polyvidone for preparing (50% ethanol) solution soft material processed again, 20 orders are granulated, 40 ℃ of dryings, 16 order granulate add differential silica gel and sodium stearyl fumarate mixing, through intermediate assay, tabletting.
Unit type and the production capacity of considering different manufacturers are different, also can adopt following preparation process.
Preparation process two: take the recipe quantity lisinopril and add 40ml water to make it dissolving, adding 40ml ethanol to be mixed with the 80ml50% alcoholic solution, take polyvidone and add, use after the dissolving fully.Above-mentioned all the other each supplementary material 80 orders are sieved rear by the recipe quantity weighing, get the abundant mixing of carboxymethylstach sodium and microcrystalline Cellulose, equivalent increases progressively and adds the abundant mixing of Meldonium again, add above-mentioned 3% polyvidone for preparing (50% ethanol) solution soft material processed, 20 orders are granulated, 40 ℃ of dryings, 16 order granulate, add differential silica gel and sodium stearyl fumarate mixing, through intermediate assay, tabletting.
3. the implementation case is effervescent tablet
| Meldonium | 1000g |
| Lisinopril | 20g |
| Microcrystalline Cellulose | 100g |
| Sodium bicarbonate | 150g |
| Malic acid | 200g |
| Stevioside | 2g |
| Essence (solid) | 1g |
| Hypromellose | 3g |
| Ethanol | 150ml |
| Magnesium stearate | 5g |
| Make | 1000 (approximately 1.5g/ sheet) |
Preparation process: take the recipe quantity hypromellose and add 150ml ethanol, use after the dissolving fully.The Meldonium raw material is crossed 40 mesh sieves, all the other each supplementary material 80 orders sieve rear by the recipe quantity weighing, get the abundant mixing of lisinopril, microcrystalline Cellulose, sodium bicarbonate, malic acid, stevioside and essence, add the above-mentioned 2% hypromellose alcoholic solution soft material processed for preparing, 24 orders are granulated, 40 ℃ of dryings, 20 order granulate, add Meldonium and magnesium stearate mixing, through intermediate assay, tabletting.
4. the implementation case is granule
| Meldonium | 1000g |
| Lisinopril | 20g |
| Mannitol | 500g |
| Aspartane | 6g |
| Hypromellose | 2.4g |
| Essence | 1g |
| 60% ethanol | 120ml |
| Make | 1000 bags (approximately 1.53g/ bag) |
Preparation process: take the recipe quantity lisinopril and add 72ml water to make it dissolving, adding 48ml ethanol to be mixed with 120ml 60% alcoholic solution, take hypromellose and add, use after the dissolving fully.Above-mentioned all the other each supplementary material 80 orders are sieved rear by the recipe quantity weighing, get the abundant mixing of Aspartane, essence and mannitol, add again the abundant mixing of Meldonium, add above-mentioned 2% hypromellose for preparing (60% ethanol) solution soft material processed, 18 orders are granulated, 40 ℃ of dryings, 18 order granulate, through gradation and intermediate assay, fill.
Experimental result:
With reference to above-mentioned each dosage form formulation and technology, the preparation sample, carry out study on the stability (with reference to existing procucts character, the easy moisture absorption of this product powder, so acceleration environment is decided to be 30 ± 2 ℃/60 ± 5%RH, long-term condition is decided to be 25 ± 2 ℃/40 ± 5%RH; The Meldonium raw material is dihydrate, molecular weight 182.26, and water of crystallization content 19.75%, following moisture data have all been deducted moisture in raw material), result is as follows:
Case one: capsule (the self-control lot number: 091101,091102,091103, aluminium-plastic bubble plate packing)
Case two: tablet (the self-control lot number: 091201,091202,091203, aluminium-plastic bubble plate packing)
Case three: effervescent tablet (the self-control lot number: 091204,091205,091206, two aluminum packings)
Case four: the granule agent (the self-control lot number: 100101,100102,100103, aluminum-plastic packaged)
Claims (6)
1. prescription and the preparation method of the oral formulations of a Meldonium and lisinopril pharmaceutical composition.
2. the oral formulations of Meldonium and Lenno Puli's pharmaceutical composition comprises oral solid formulation and oral solution as described in claim 1.
3. oral solid formulation comprises tablet as described in claim 2, capsule, granule, powder, drop pill, dry suspension, powder spray.
4. the prescription of the oral formulations of Meldonium and lisinopril pharmaceutical composition as described in claim 1, it is characterized in that: the Meldonium specification is 50mg～1000mg, the specification 2.5mg of lisinopril～80mg.
5. the prescription of the oral formulations of Meldonium and lisinopril pharmaceutical composition as described in claim 4, it is characterized in that: the preferred specification of Meldonium is 500mg, the preferred specification of lisinopril is 10mg and 20mg.
6. the prescription of the oral formulations of Meldonium and lisinopril pharmaceutical composition as described in claim 1, it is characterized in that: the adjuvant that uses in prescription is starch, microcrystalline Cellulose, hyprolose, carboxymethylstach sodium, cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, hypromellose, polyvidone, magnesium stearate, calcium stearate, sodium stearyl fumarate, differential silica gel, lactose, sucrose, mannitol, sorbitol, Aspartane, stevioside, acesulfame potassium, carmethose, arabic gum, xanthan gum, sodium bicarbonate, citric acid, tartaric acid, fumaric acid, malic acid, sorbic acid, glycerol, propylene glycol, one or more in Nipagin ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105243000A CN103110929A (en) | 2012-12-10 | 2012-12-10 | Pharmaceutical composition of mildronate and lisinopril and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012105243000A CN103110929A (en) | 2012-12-10 | 2012-12-10 | Pharmaceutical composition of mildronate and lisinopril and preparation method thereof |
Publications (1)
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| CN103110929A true CN103110929A (en) | 2013-05-22 |
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| CN2012105243000A Pending CN103110929A (en) | 2012-12-10 | 2012-12-10 | Pharmaceutical composition of mildronate and lisinopril and preparation method thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1966519A (en) * | 2002-11-18 | 2007-05-23 | 希普拉有限公司 | Hydrated perindopril salt, preparation method thereof and composition containing the same |
| CN101780266A (en) * | 2010-03-24 | 2010-07-21 | 天津生机集团股份有限公司 | Compound preparation for preventing and treating respiratory disease of livestock and poultry |
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2012
- 2012-12-10 CN CN2012105243000A patent/CN103110929A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1966519A (en) * | 2002-11-18 | 2007-05-23 | 希普拉有限公司 | Hydrated perindopril salt, preparation method thereof and composition containing the same |
| CN101780266A (en) * | 2010-03-24 | 2010-07-21 | 天津生机集团股份有限公司 | Compound preparation for preventing and treating respiratory disease of livestock and poultry |
Non-Patent Citations (1)
| Title |
|---|
| ANDRIS VITOLS ET AL: "Midronate improves carotid baroreceptor reflex function in patients with chronic heart failure", 《 SEMINARS IN CARDIOVASCULAR MEDICINE》, 31 December 2008 (2008-12-31) * |
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Application publication date: 20130522 |