CN101053563A - Zofenopril oral medicinal composition - Google Patents
Zofenopril oral medicinal composition Download PDFInfo
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- CN101053563A CN101053563A CN 200610073073 CN200610073073A CN101053563A CN 101053563 A CN101053563 A CN 101053563A CN 200610073073 CN200610073073 CN 200610073073 CN 200610073073 A CN200610073073 A CN 200610073073A CN 101053563 A CN101053563 A CN 101053563A
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- zofenopril
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Abstract
The invention relates to a medical composition comprising zofenopril which is of simple processing and good dissolve-out. Said composition can be further used to prepare various oral-taken solid agents, such as common tablet, granule agent, dispersive tablet and capsule for treating high blood pressure.
Description
Technical field
The present invention relates to the Pharmaceutical composition that contains zofenopril that a kind of preparation technology is simple, stripping is good, said composition can be further used for being prepared into various oral solid formulations, as ordinary tablet, granule, dispersible tablet, capsule etc., is used for hypertensive treatment.
Background technology
Zofenopril (zofenopril), chemical name [1 (R
*), 2 α, 4 α]-1-[3-(benzoyl sulfydryl)-2 methyl isophthalic acids-oxopropyl]-4-(thiophenyl)-L-proline.This product is used for the treatment of mild to moderate essential hypertension, and is used for acute myocardial infarction and has or patient asymptomatic, that hemodynamic stability is not accepted thromboembolism treatment in 24 hours.This product is the first long-acting ACE inhibitor that contains sulfydryl, because this product contains sulfydryl, therefore makes it to have lipotropy and anti-oxidation characteristics, and this product hydrolyzable is the active matter zofenoprilat.
Zofenopril is an insoluble drug, and is water-soluble hardly, so adopt necessary method to increase the stripping of medicine when it is prepared into oral formulations, improving bioavailability is a major issue that must solve on the pharmaceutics.Yet in the pharmaceutics field, mainly be to reach the effect that increases the medicine stripping by means such as beta-cyclodextrin inclusion compound, solid dispersion technologies.Yet when adopting beta-cyclodextrin inclusion compound and solid dispersion technology to come solubilising, condition is wayward, and final products must verify that as X-diffraction, differential thermal analysis (DSC) etc., process is numerous and diverse through any special measures.The method of adding surfactant such as sodium lauryl sulphate, tween, cholate, phospholipid etc. in compositions, in pharmaceutical preparation, add these surfactants, though can reach the purpose that improves the medicine stripping, they also can cause certain stimulation in vivo and be unfavorable for using clinically or the mensuration of principal agent produced and disturb or instability itself causes degraded in the put procedure; Yet some other technology such as self emulsifying technology and solid nano grain technology still are in conceptual phase, shortcoming such as technical difficulty is bigger, and process is wayward.
A kind of insoluble drug tablet and preparation method thereof has been proposed among the Chinese patent CN03113470, adopting the hydrophilicity condiment lactose in the invention is diluent, microcrystalline Cellulose and carboxymethyl starch sodium are the disintegrating agent diluent of holding concurrently, add lactose when preparation technology pulverizes for insoluble drug earlier and mix pulverizing, cross the 60-100 mesh sieve.This research tries to adopt the method for being mentioned in this patent to add lactose and the blend of raw material zofenopril is sieved, microcrystalline Cellulose and carboxymethyl starch sodium are the disintegrating agent diluent of holding concurrently, with PVP solution is that binding agent is granulated, but finds that prepared mobility of particle is poor, and the tablet stripping of being suppressed is bad.Method that adopts document and the preparation that technology is not suitable for insoluble drug zofenopril in this research are described.Therefore, need to obtain a kind of stripping that can effectively improve the zofenopril active substance, and the product that can improve preparation stability and bioavailability is necessary.
Summary of the invention
The purpose of this invention is to provide the Pharmaceutical composition that contains zofenopril that a kind of preparation technology is simple, stripping is good, said composition can be further used for being prepared into various oral solid formulations, as ordinary tablet, granule, dispersible tablet, capsule etc., be used for hypertensive treatment.
Pharmaceutical composition of the present invention contains the hydrophilic pharmaceutic adjuvant that is selected from a kind of or its mixture in lactose, sucrose, mannitol, starch, polyvinylpyrrolidone, the Polyethylene Glycol, and has good dissolution and bioavailability.
Pharmaceutical composition of the present invention, as the hydrophilic pharmaceutic adjuvant, its content is 10-90 weight % with lactose, preferred 20-80 weight %, most preferably 48.6%.
Pharmaceutical composition of the present invention also contains pharmaceutic adjuvants such as diluent commonly used, disintegrating agent, adhesive, lubricant and fluidizer.Preferred pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium and the crospolyvinylpyrrolidone etc. of adding.Its consumption is 2-70 weight % in solid composite medicament, preferred 5-50 weight %.
Pharmaceutical composition of the present invention contains 2～10% zofenoprils, most preferably is 6.1%; 10～50% starch most preferably are 32.4%; 5～15% pregelatinized Starch most preferably are 12.1%; 0.5～1% magnesium stearate most preferably is 0.8%.
Be to implement the present invention, can water or ethanol make wetting agent, preferred water is as moistening, obtains to have the pharmaceutical composition of the particle form of good fluidity.
Pharmaceutical composition of the present invention, for single dose form as oral pharmaceutical forms such as capsule, tablet and granules.
Pharmaceutical composition of the present invention, unexpected have superior stability, dissolving out capability and a good bioavailability.
Description of drawings
Fig. 1 zofenopril blood drug level-time graph
The specific embodiment
Specifying the present invention in conjunction with the embodiments, but be not limited to following embodiment.Wherein " % " is meant " weight % ".
Pharmaceutical composition of the present invention can prepare by the following method: zofenopril and water soluble adjuvant are total to crushing screening compositions and other adjuvant mix homogeneously, granulate drying by a common wet granulation technology or a step prilling.Dried particles adding mix lubricant is even, gets final product.
Embodiment 1
| Component | Percentage ratio (%) | The mg/ sheet |
| Zofenopril | 6.1 | 7.5 |
| Lactose | 48.6 | 60 |
| Starch | 32.4 | 40 |
| Pregelatinized Starch | 12.1 | 15 |
| Magnesium stearate | 0.8 | 1 |
| Water | / | In right amount |
Preparation technology:
Zofenopril and lactose are pulverized altogether, cross 100 mesh sieves, starch, pregelatinized Starch and cross 80 mesh sieves respectively, and magnesium stearate is crossed 60 mesh sieves, and is standby.Take by weighing zofenopril, lactose, starch, the pregelatinized Starch of recipe quantity, by the equivalent principle of progressively increasing, mix homogeneously, solid mixture.With the solid mixture water-wet, the system soft material is crossed 24 mesh sieves and is granulated, and wet granular is 40～50 ℃ of dryings 2～4 hours, with 24 mesh sieve granulate.Add the magnesium stearate of recipe quantity, mixing.Measure drug content in the granule, determine that sheet is heavy.With the stamping of 7mm scrobicula.
Embodiment 2
| Component | Percentage ratio (%) | The mg/ sheet |
| Zofenopril | 6.1 | 7.5 |
| Lactose | 48.6 | 60 |
| Starch | 32.4 | 40 |
| Pregelatinized Starch | 12.1 | 15 |
| Magnesium stearate | 0.8 | 1 |
| Ethanol | / | In right amount |
Preparation technology:
Zofenopril and lactose are pulverized altogether, cross 100 mesh sieves, and 80 mesh sieves are crossed in starch, pregelatinized Starch respectively, and magnesium stearate is crossed 60 mesh sieves, and is standby.Take by weighing zofenopril, lactose, starch, the pregelatinized Starch of recipe quantity, by the equivalent principle of progressively increasing, mix homogeneously, solid mixture.With solid mixture ethanol moistening, the system soft material is crossed 24 mesh sieves and is granulated, and wet granular is 40～50 ℃ of dryings 2～4 hours, with 24 mesh sieve granulate.Add the magnesium stearate of recipe quantity, mixing.Measure drug content in the granule, determine that sheet is heavy.With the stamping of 7mm scrobicula.
Embodiment 3
| Component | Percentage ratio (%) | The mg/ sheet |
| Zofenopril | 6.1 | 7.5 |
| Sorbitol | 48.6 | 60 |
| Starch | 32.4 | 40 |
| Pregelatinized Starch | 12.1 | 15 |
| Magnesium stearate | 0.8 | 1 |
| Water | / | In right amount |
Preparation technology:
Zofenopril and sorbitol are pulverized altogether, cross 100 mesh sieves, and 80 mesh sieves are crossed in starch, pregelatinized Starch respectively, and magnesium stearate is crossed 60 mesh sieves, and is standby.Take by weighing zofenopril, lactose, starch, the pregelatinized Starch of recipe quantity, by the equivalent principle of progressively increasing, mix homogeneously, solid mixture.With the solid mixture water-wet, the system soft material is crossed 24 mesh sieves and is granulated, and wet granular is 40～50 ℃ of dryings 2～4 hours, with 24 mesh sieve granulate.Add the magnesium stearate of recipe quantity, mixing.Measure drug content in the granule, determine that sheet is heavy.With the stamping of 7mm scrobicula.
Embodiment 4
| Component | Percentage ratio (%) | The mg/ sheet |
| Zofenopril | 6.1 | 7.5 |
| Sucrose | 48.6 | 60 |
| Microcrystalline Cellulose | 32.4 | 40 |
| Pregelatinized Starch | 12.1 | 15 |
| Magnesium stearate | 0.8 | 1 |
| Water | / | In right amount |
Preparation technology:
Zofenopril and sucrose are pulverized altogether, cross 100 mesh sieves, and 80 mesh sieves are crossed in starch, pregelatinized Starch respectively, and magnesium stearate is crossed 60 mesh sieves, and is standby.Take by weighing zofenopril, lactose, microcrystalline Cellulose, the pregelatinized Starch of recipe quantity, by the equivalent principle of progressively increasing, mix homogeneously, solid mixture.With the solid mixture water-wet, the system soft material is crossed 24 mesh sieves and is granulated, and wet granular is 40～50 ℃ of dryings 2～4 hours, with 24 mesh sieve granulate.Add the magnesium stearate of recipe quantity, mixing.Measure drug content in the granule, determine that sheet is heavy.With the stamping of 7mm scrobicula.
Embodiment 5
| Component | Percentage ratio (%) | The mg/ sheet |
| Zofenopril | 6.1 | 7.5 |
| Lactose | 32.4 | 40 |
| Starch | 48.6 | 60 |
| Carboxymethylstach sodium | 12.1 | 15 |
| Magnesium stearate | 0.8 | 1 |
| Water | / | In right amount |
Preparation technology:
Zofenopril and lactose are pulverized altogether, cross 100 mesh sieves, and 80 mesh sieves are crossed in starch, pregelatinized Starch respectively, and magnesium stearate is crossed 60 mesh sieves, and is standby.Take by weighing zofenopril, lactose, starch, the carboxymethylstach sodium of recipe quantity, by the equivalent principle of progressively increasing, mix homogeneously, solid mixture.With the solid mixture water-wet, the system soft material is crossed 24 mesh sieves and is granulated, and wet granular is 40～50 ℃ of dryings 2～4 hours, with 24 mesh sieve granulate.Add the magnesium stearate of recipe quantity, mixing.Measure drug content in the granule, determine that sheet is heavy.With the stamping of 7mm scrobicula.
Embodiment 6
| Component | Percentage ratio (%) | The mg/ sheet |
| Zofenopril | 6.1 | 7.5 |
| Lactose | 48.6 | 60 |
| Microcrystalline Cellulose | 32.4 | 40 |
| Carboxymethylstach sodium | 12.1 | 15 |
| Magnesium stearate | 0.8 | 1 |
| 10%PVP solution | / | In right amount |
Preparation technology:
Zofenopril and lactose are pulverized altogether, cross 100 mesh sieves, and microcrystalline Cellulose, carboxymethylstach sodium are crossed 80 mesh sieves respectively, and magnesium stearate is crossed 60 mesh sieves, and is standby.Take by weighing zofenopril, lactose, starch, the pregelatinized Starch of recipe quantity, by the equivalent principle of progressively increasing, mix homogeneously, solid mixture.With solid mixture 10%PVP solution-wet, the system soft material is crossed 24 mesh sieves and is granulated, and wet granular is 40～50 ℃ of dryings 2～4 hours, with 24 mesh sieve granulate.Add the magnesium stearate of recipe quantity, mixing.Measure drug content in the granule, determine that sheet is heavy.With the stamping of 7mm scrobicula.
The dissolution test
Pressing dissolution method (two appendix XC second methods of Chinese Pharmacopoeia version in 2000), is dissolution medium with water 500ml, and rotating speed is 50 rev/mins.Measure dissolution at 247nm wavelength place according to ultraviolet spectrophotometry (two appendix IVA of Chinese Pharmacopoeia version in 2000).The results are shown in Table 1.
Table 1 zofenopril sheet dissolution result of the test
| Time (branch) | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 |
| 5 | 80.46 | 68.27 | 68.93 | 76.21 | 76.21 | 56.21 |
| 10 | 92.91 | 70.60 | 76.83 | 75.19 | 75.19 | 65.19 |
| 20 | 96.95 | 75.01 | 87.90 | 83.52 | 83.52 | 63.52 |
| 30 | 97.64 | 86.24 | 91.79 | 87.69 | 87.69 | 67.69 |
| 45 | 97.46 | 85.14 | 91.48 | 87.80 | 87.80 | 67.80 |
| 60 | 98.07 | 87.14 | 92.92 | 92.51 | 87.51 | 67.51 |
The foregoing description 1 prepared sample was placed 6 months down in acceleration environment (40 ℃ ± 2 ℃, relative humidity 75% ± 5%), and after long term test condition (25 ℃ ± 2 ℃, relative humidity RH60% ± 10%) is placed 18 months down, detect, every investigation index of sample the results are shown in Table 2:
Table 2 embodiment 1 stability test is investigated the result
| Time | Related substance (%) | Disintegration (second) | Dissolution (%) | Content (%) | |
| Accelerated test 6 | 0 | 0.21 | 180 | 98.88±2.11 | 98.93 |
| 1 | 0.30 | 176 | 98.14±1.37 | 98.67 | |
| 2 | 0.22 | 189 | 98.29±2.88 | 98.59 | |
| 3 | 0.35 | 145 | 98.60±2.82 | 98.68 | |
| 6 | 0.39 | 156 | 98.79±2.62 | 98.54 | |
| Long term test 18 | 0 | 0.30 | 179 | 98.42±2.81 | 98.97 |
| 3 | 0.35 | 145 | 98.41±1.59 | 98.58 | |
| 6 | 0.38 | 138 | 98.82±2.83 | 98.49 | |
| 9 | 0.39 | 156 | 98.26±1.92 | 98.96 | |
| 12 | 0.38 | 146 | 98.01±1.08 | 98.65 | |
| 18 | 0.34 | 179 | 98.75±1.90 | 98.18 |
Can find out that from last table data the sample size, dissolution, disintegration and the related substance check result that prepare according to embodiment 1 prescription have no significant change.
Bioavailability is measured: 5 of male rabbits, fasting 24h.Weigh oral administration, each 1 before every test.Press 20min after the administration, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4.5h, the 5h blood sampling will be got 1 part of blood sample equally and be made blank usefulness before the test.The results are shown in Figure 1.
Claims (7)
1. one kind contains the zofenopril pharmaceutical composition, it is characterized in that containing the hydrophilic pharmaceutic adjuvant, and has good dissolution and bioavailability.
2. pharmaceutical composition as claimed in claim 1 is characterized in that described hydrophilicity condiment is selected from one or more in lactose, sucrose, mannitol, starch, polyvinylpyrrolidone, the Polyethylene Glycol.
3. pharmaceutical composition as claimed in claim 2 is characterized in that described hydrophilicity condiment is a lactose, and its content is 10-90 weight %, preferred 20-80 weight %, most preferably 48.6%.
4. pharmaceutical composition as claimed in claim 3 is characterized in that containing diluent, disintegrating agent, lubricant and binding agent.
5. pharmaceutical composition as claimed in claim 4 is characterized in that containing 10～50% starch, 5～15% pregelatinized Starch and 0.5～1% magnesium stearate.
6. as each described preparation of drug combination method of claim 1-5, it is characterized in that adopting water is that wetting agent is granulated.
7. the composition for oral liquid of single dose form as claimed in claim 6 is characterized in that the form for capsule, tablet and granule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610073073 CN101053563A (en) | 2006-04-12 | 2006-04-12 | Zofenopril oral medicinal composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610073073 CN101053563A (en) | 2006-04-12 | 2006-04-12 | Zofenopril oral medicinal composition |
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| CN101053563A true CN101053563A (en) | 2007-10-17 |
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|---|---|---|---|
| CN 200610073073 Pending CN101053563A (en) | 2006-04-12 | 2006-04-12 | Zofenopril oral medicinal composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102114014A (en) * | 2009-12-30 | 2011-07-06 | 北京德众万全药物技术开发有限公司 | Pharmaceutical composition containing almotriptan |
| WO2013095307A1 (en) | 2011-12-19 | 2013-06-27 | Silverstone Pharma | New crystal salts of zofenopril, process for obtaining them and their use in therapy |
| CN104138359A (en) * | 2013-05-06 | 2014-11-12 | 扬子江药业集团上海海尼药业有限公司 | Preparing method of zofenopril calcium tablet |
-
2006
- 2006-04-12 CN CN 200610073073 patent/CN101053563A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102114014A (en) * | 2009-12-30 | 2011-07-06 | 北京德众万全药物技术开发有限公司 | Pharmaceutical composition containing almotriptan |
| WO2013095307A1 (en) | 2011-12-19 | 2013-06-27 | Silverstone Pharma | New crystal salts of zofenopril, process for obtaining them and their use in therapy |
| CN104138359A (en) * | 2013-05-06 | 2014-11-12 | 扬子江药业集团上海海尼药业有限公司 | Preparing method of zofenopril calcium tablet |
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Open date: 20071017 |