CN1709253A - Stable medicinal composition containing pitavastatin - Google Patents
Stable medicinal composition containing pitavastatin Download PDFInfo
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- CN1709253A CN1709253A CN 200510057110 CN200510057110A CN1709253A CN 1709253 A CN1709253 A CN 1709253A CN 200510057110 CN200510057110 CN 200510057110 CN 200510057110 A CN200510057110 A CN 200510057110A CN 1709253 A CN1709253 A CN 1709253A
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Abstract
The present invention relates to a medicine composition containing (E)-3.5-dihydroxy-7-[4'-4'-fluophenly-2'-cyclopropyl-quinoline-3'-group]-6-heptenoic acid or its salt or ester, and the pH value of its aqueous solution or suspension can be kept to make it be less than 7, but greater than 6, so that it can ensure that said medicine composition has good stability.
Description
Technical field:
This patent relates to a kind of stable pharmaceutical composition, in particular to containing (E)-3,5-dihydroxy-7-[4 '-4 "-fluorophenyl-2 '-cyclopropyl-quinoline-3 '-yl]-pharmaceutical composition of 6-heptenoic acid or its salt or ester, the pH value of its aqueous solution or suspension is less than 7 but greater than 6.
Background technology:
Pitavastatin is the HMG-CoA reductase inhibitor, can be used as treatment hypercholesterolemia, familial hypercholesterolemia and atherosclerosis in Japan's listing in 2004.The chemistry of Pitavastatin is called (E)-3,5-dihydroxy-7-[4 '-4 "-fluorophenyl-2 '-cyclopropyl-quinoline-3 '-yl]-6-heptenoic acid (hereinafter referring to) with Pitavastatin, its chemical structural formula is
3 of known 7 replacements, 5-dihydroxy--6-heptenoic acid and calcium salt thereof be less stable in low pH environment, usually needs to adopt some special methods to be made into preparation.CN1091634 discloses a kind of pharmaceutical dosage form that contains β-Qiang Ji-β-Jia Jiwuersuandanxian CoA-reductase inhibitors chemical compound (as Fluvastatin), contain the alkaline matter that specially adds in the said preparation, the aqueous solution of pharmaceutical composition or the pH value of dispersion are remained on more than 8.CN1189098 discloses a kind of pharmaceutical composition, it comprises (E)-3,5-dihydroxy-7-[4 '-4 " fluorophenyl-2 '-cyclopropyl-quinoline-3 '-yl]-6-heptenoic acid or its salt or ester, by adding alkaline matter, making the aqueous solution of this pharmaceutical composition or the pH of suspension is 7 to 8.
Having had researcher will have 3 of 7 replacements, the 5-dihydroxy--it is 8 or higher preparation that the HMG-CoA reductase inhibitor of 6-heptenoic acid general formula is made pH, but people are surprised to find that Pitavastatin Calcium is still unstable in too high pH value scope.The people is also arranged in order to improve the stability of Pitavastatin Calcium, adjust the pH value of pharmaceutical composition with alkaline matter, the pH value that makes compositions is between 7-8.
Summary of the invention
In order to obtain containing the stable pharmaceutical composition of Pitavastatin Calcium, we further investigate the multiple pharmaceutical composition that contains Pitavastatin Calcium, and we are surprised to find that in low relatively pH scope and can obtain stable Pitavastatin calcium medicine compound as a result.On this basis, we have finished the present invention.We find, need not be painstakingly add alkaline matter to the pharmaceutical composition of Pitavastatin Calcium, as long as keep the aqueous solution of this pharmaceutical composition or the pH value of suspension is 6-7 (not comprising 7), the stability of said composition is same good.Owing to need not painstakingly add alkaline pH value regulator, make the prescription of pharmaceutical composition simple and convenient, the industrialization operation is simpler, and saves cost.Simultaneously we find, be not when the pH value of the aqueous solution of pharmaceutical composition or suspension greater than 7 the time with regard to a stability that guarantees compositions surely, as comparative example's table 2 as a result.
The invention provides a kind of pharmaceutical composition that contains Pitavastatin Calcium, the pH value of its aqueous solution or suspension is 6-7 (not comprising 7), and preferred pH value is 6.20-6.99, and more preferably pH value is 6.40-6.99.
The pH value assay method of this paper is as follows: get the solid preparation that contains Pitavastatin or its salt or its ester of unit dose, it is dissolved or dispersed in the pure water of 1-10ml, measure the pH value of obtained aqueous solution or suspension.
The active component of the present composition is the Pitavastatin that above-mentioned chemical structural formula is represented.At this, there is no particular limitation to the configuration of this material.In addition, Pitavastatin also can occur with arbitrary form of its salt and ester, and these salt comprise (for example) sodium salt, potassium salt, magnesium salt and calcium salt, the calcium salt of preferred Pitavastatin.The molecular proportion of its Pitavastatin of the calcium salt here and calcium is 2: 1.
There is no particular limitation for the dosage of above-mentioned Pitavastatin or its calcium salt, and its dosage range can be 0.1-10mg, preferred 0.5-5mg, more preferably 1-2mg.
Pharmaceutical composition alkali-free pH value regulator of the present invention.
Pharmaceutical composition of the present invention can be used to prepare various forms of preparations, but preferred oral solid preparation, for example, said composition can be made into tablet, capsule, granule, powder, lozenge, membrane, pill, suspensoid, and the film-coat of these preparations or sugar-coated preparation, more preferably tablet, capsule.When making film-coat or sugar-coated preparation, used coating material comprises hydroxypropyl level methylcellulose, hydroxypropyl level cellulose, methylcellulose, crylic acid resin, sucrose, starch, ethyl cellulose.In coating solution, can contain or not contain plasticizer, opacifier, antiplastering aid and coloring agent.
When pharmaceutical composition of the present invention is formulated into above-mentioned oral solid formulation, if necessary, can be to wherein adding any one filler (excipient), disintegrating agent, binding agent and lubricant.
Described filler (excipient) comprises lactose, mannitol, xylitol, starch, pregelatinized Starch, corn starch, microcrystalline Cellulose, sorbitol, and they can use separately also can mix use.Aforementioned filler is preferably lactose, mannitol, microcrystalline Cellulose, mannitol more preferably, and its consumption is about the 10%-99.5% of pharmaceutical composition gross weight, is preferably 20%-99%, more preferably 50%-98%.
Described disintegrating agent comprises low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, polyvinylpyrrolidone, starch, microcrystalline Cellulose, sodium carboxymethyl cellulose, and they can use separately also can mix use.Aforementioned disintegrating agent is preferably low-substituted hydroxypropyl cellulose, starch, polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose more preferably, and its consumption is about the 0%-40% of pharmaceutical composition gross weight, is preferably 1%-30%, more preferably 3%-20%.
Described binding agent comprises the alcoholic solution of hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, starch slurry, polyvinyl alcohol, microcrystalline Cellulose, water, various concentration, and they can use separately also can mix use.The aforementioned adhesion agent is preferably the alcoholic solution of microcrystalline Cellulose, hydroxypropyl emthylcellulose, various concentration, the alcoholic solution of microcrystalline Cellulose and various concentration more preferably, its consumption is about the 0-20% of pharmaceutical composition gross weight, is preferably 0%-15%, more preferably 0%-10%.
Described lubricant comprises stearic acid, magnesium stearate, calcium stearate, Palmic acid, aluminium silicate, stearmide, Pulvis Talci, silicon dioxide, and they can use separately also can mix use.Aforementioned lubricants is preferably magnesium stearate, aluminium silicate, magnesium stearate more preferably, and its consumption is about the 0.01%-10% of pharmaceutical composition gross weight, more preferably 0.1%-3%.
If necessary, other adjuvants can also be added, as sweeting agent, coloring agent, odor mask, stabilizing agent in pharmaceutical composition of the present invention.
Can prepare pharmaceutical composition of the present invention according to preparation any conventional method that oral solid formulation adopted, as: wet granule compression tablet, encapsulated after direct powder compression, the granulation.Use conventional coating device, this pharmaceutical composition peplos can be made film coated tablet or sugar coated tablet.Coated substrate comprises cellulose family, crylic acid resin, saccharide, as hydroxypropyl level methylcellulose, Eudragit L, sucrose.Also can add plasticizer, antiplastering aid, opacifier in this coated substrate.
Embodiment
Below be examples of pharmaceutical compositions of the present invention, but and do not mean that the present invention is only in the scope of embodiment.
Embodiment 1:
The tablet formulation and the preparation technology of present embodiment preparation are as follows:
Pitavastatin Calcium 1.0mg
Mannitol 74.2mg
Low substituted hydroxy-propyl methylcellulose 4.0mg
Magnesium stearate 0.8mg
Amount to (a slice) 80.0mg
Pitavastatin Calcium, mannitol, low substituted hydroxy-propyl methylcellulose are crossed 100 orders, mix homogeneously, the soft ability of an amount of system of the ethanol with 50%, 40 mesh sieves are granulated, 50 ℃ of oven for drying, 30 mesh sieve granulate add magnesium stearate, mix tabletting.
Embodiment 2:
With the method preparation identical with embodiment 1, the Pitavastatin Calcium tablet recipe of present embodiment is as follows:
Pitavastatin Calcium 1.0mg
Lactose 74.2mg
Crospolyvinylpyrrolidone 4.0mg
Magnesium stearate 0.8mg
Amount to (a slice) 80.0mg
Embodiment 3:
The Pitavastatin Calcium tablet recipe and the preparation technology of present embodiment are as follows:
Pitavastatin Calcium 1.0mg
Pregelatinized Starch 68.2mg
Low substituted hydroxy-propyl methylcellulose 10.0mg
Magnesium stearate 0.8mg
Amount to (a slice) 80.0mg
Pitavastatin Calcium, pregelatinized Starch, low substituted hydroxy-propyl methylcellulose and magnesium stearate are crossed 100 orders, mix homogeneously, tabletting respectively.
Embodiment 4:
With the method preparation identical with embodiment 1, the Pitavastatin Calcium tablet recipe of present embodiment is as follows:
Pitavastatin Calcium 2.0mg
Mannitol 110.8mg
Low substituted hydroxy-propyl methylcellulose 6.0mg
Magnesium stearate 0.8mg
Amount to (a slice) 120mg
Measure the pH value of 5% suspension (getting in suspension of a slice tablet and the 2.4ml pure water) of arbitrary tablet of embodiment 1-4 preparation.And 40 ℃ store 1 month after, observe each tablet cosmetic variation, that adopts that the HPLC method measures Pitavastatin Calcium in the tablet retains percentage composition and its related substances.This test the results are shown in Table 1:
Table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
| 5% suspension pH value cosmetic variation Pitavastatin Calcium retain the percentage composition its related substances | 6.85 no change 99.20% 0.80% | 6.92 no change 99.41% 0.59% | 6.52 no change 99.15% 0.85% | 6.94 no change 99.37% 0.63% |
Comparative example 1-4
By the method identical with the comparative example, prepare each sheet contrast tablet composed as follows, same 5% suspension of measuring arbitrary tablet (get a slice tablet suspend with the 2.4ml pure water in) pH value, Pitavastatin Calcium retain percentage composition and its related substances, and observe each tablet outward appearance.The results are shown in Table 2.
Table 2
| The comparative example 1 | The comparative example 2 | The comparative example 3 | The comparative example 4 | |
| Pitavastatin Calcium (mg) sweet mellow wine (mg) sodium carboxymethylcellulose (mg) low-substituted hydroxypropyl cellulose (mg) sodium ascorbate (mg) sodium carboxymethyl starch (mg) sodium hydrogen phosphate (mg) ascorbic acid (mg) dolomol (mg) 5% pH of suspension value cosmetic variation Pitavastatin Calcium retain percentage composition | 1.0 72.2 42 0.8 4.8 unchanged 47% | 1.0 63.2 10 5 0.8 5.9 unchanged 69% | 1.0 63.2 10 5 0.8 7.4 unchanged 88% | 2.0 105.8 65 1.2 7.5 unchanged 90% |
| Its related substances | ??53％ | ??31％ | ??12％ | ??10％ |
Shown in the result of table 1 and table 2, when the pH value of pharmaceutical composition suspension is between 6-7,40 ℃ store 1 month after, its Pitavastatin Calcium retain the percentage composition height, its related substances is low; And when the pH value of pharmaceutical composition surpassed the 6-7 scope, the percentage composition that retains of its Pitavastatin Calcium significantly reduced, and its related substances obviously raises.
By above result as can be known, pharmaceutical composition of the present invention has good stable, even preserve long time, its outward appearance and content of effective do not have significant change yet.Therefore, this compositions can successfully be applied to field of medicaments.By the patient being given pharmaceutical composition of the present invention, for suffering from hyperlipemia or atherosclerotic patient has the positive therapeutic effect.
Claims (13)
1. a stable pharmaceutical composition comprises (E)-3,5-dihydroxy-7-[4 '-4 "-fluorophenyl-2 '-cyclopropyl-quinoline-3 '-yl]-6-heptenoic acid or its salt or ester, the pH value that it is characterized in that its aqueous solution or suspension is less than 7 but greater than 6.
2. pharmaceutical composition according to claim 1, wherein said (E)-3,5-dihydroxy-7-[4 '-4 "-fluorophenyl-2 '-cyclopropyl-quinoline-3 '-yl]-salt of 6-heptenoic acid is calcium salt.
3. pharmaceutical composition according to claim 2 does not wherein contain the pH regulator agent of alkalescence.
4. according to the described pharmaceutical composition of any claim of claim 1 to 3, also contain at least a in filler (excipient), disintegrating agent, binding agent and the lubricant.
5. pharmaceutical composition according to claim 4 is oral solid formulation, is preferably tablet, capsule.
6. pharmaceutical composition according to claim 4, wherein said filler comprises lactose, mannitol, xylitol, starch, sorbitol, pregelatinized Starch, corn starch, microcrystalline Cellulose.
7. pharmaceutical composition according to claim 6, wherein said filler is preferably lactose, mannitol, microcrystalline Cellulose, mannitol more preferably, its consumption is about the 10%-99.5% of pharmaceutical composition gross weight.
8. pharmaceutical composition according to claim 4, wherein said disintegrating agent comprises low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, polyvinylpyrrolidone, starch, microcrystalline Cellulose, sodium carboxymethyl cellulose.
9. pharmaceutical composition according to claim 8, wherein said disintegrating agent is preferably low-substituted hydroxypropyl cellulose, starch, polyvinylpyrrolidone, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose more preferably, its consumption is about the 0%-40% of pharmaceutical composition gross weight.
10. pharmaceutical composition according to claim 4, wherein said lubricant comprises magnesium stearate, calcium stearate, Palmic acid, Pulvis Talci, aluminium silicate, stearmide, silicon dioxide.
11. pharmaceutical composition according to claim 10, wherein said lubricant is preferably magnesium stearate, aluminium silicate, magnesium stearate more preferably, and its consumption is about the 0.01%-10% of pharmaceutical composition gross weight.
12. pharmaceutical composition according to claim 4, wherein said binding agent comprises the alcoholic solution of hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, starch slurry, polyvinyl alcohol, microcrystalline Cellulose, water, various concentration.
13. pharmaceutical composition according to claim 12, wherein said binding agent is preferably the alcoholic solution of microcrystalline Cellulose, hydroxypropyl emthylcellulose, various concentration, the alcoholic solution of microcrystalline Cellulose and various concentration more preferably, its consumption is about the 0-20% of pharmaceutical composition gross weight.
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| CN 200510057110 CN1709253A (en) | 2005-06-08 | 2005-06-08 | Stable medicinal composition containing pitavastatin |
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| CN 200510057110 CN1709253A (en) | 2005-06-08 | 2005-06-08 | Stable medicinal composition containing pitavastatin |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101103983B (en) * | 2006-07-14 | 2012-09-26 | 海南盛科生命科学研究院 | Medicinal composition stabilized by base reagent containing pitavastatin calcium and preparation technology thereof |
| CN102861018A (en) * | 2011-07-05 | 2013-01-09 | 南京长澳医药科技有限公司 | Pitavastatin calcium preparation and preparation technology |
| JP2013035798A (en) * | 2011-08-10 | 2013-02-21 | Kyowa Yakuhin Kogyo Kk | Stabilized pharmaceutical composition containing pitavastatin |
| US20130237579A1 (en) * | 2007-07-13 | 2013-09-12 | Timothy Stanley | Stable pharmaceutical compositions comprising one or more hmg-coa reductas inhibitiors |
| CN104644587A (en) * | 2015-03-20 | 2015-05-27 | 王雪雁 | Preparation method of medicine composition for treating cardiovascular disease |
| CN105125545A (en) * | 2015-10-13 | 2015-12-09 | 杨献美 | Medicine composition containing pitavastatin calcium and preparing method thereof |
| CN105213339A (en) * | 2015-10-19 | 2016-01-06 | 迪沙药业集团有限公司 | A kind of Pitavastatin calcium composition |
-
2005
- 2005-06-08 CN CN 200510057110 patent/CN1709253A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101103983B (en) * | 2006-07-14 | 2012-09-26 | 海南盛科生命科学研究院 | Medicinal composition stabilized by base reagent containing pitavastatin calcium and preparation technology thereof |
| US20130237579A1 (en) * | 2007-07-13 | 2013-09-12 | Timothy Stanley | Stable pharmaceutical compositions comprising one or more hmg-coa reductas inhibitiors |
| CN102861018A (en) * | 2011-07-05 | 2013-01-09 | 南京长澳医药科技有限公司 | Pitavastatin calcium preparation and preparation technology |
| JP2013035798A (en) * | 2011-08-10 | 2013-02-21 | Kyowa Yakuhin Kogyo Kk | Stabilized pharmaceutical composition containing pitavastatin |
| CN104644587A (en) * | 2015-03-20 | 2015-05-27 | 王雪雁 | Preparation method of medicine composition for treating cardiovascular disease |
| CN105125545A (en) * | 2015-10-13 | 2015-12-09 | 杨献美 | Medicine composition containing pitavastatin calcium and preparing method thereof |
| CN105213339A (en) * | 2015-10-19 | 2016-01-06 | 迪沙药业集团有限公司 | A kind of Pitavastatin calcium composition |
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