CN101574324A - Felodipine sustained-release tablet and method for controlling sustained-release of Felodipine sustained-release tablet - Google Patents
Felodipine sustained-release tablet and method for controlling sustained-release of Felodipine sustained-release tablet Download PDFInfo
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- CN101574324A CN101574324A CNA2009101478700A CN200910147870A CN101574324A CN 101574324 A CN101574324 A CN 101574324A CN A2009101478700 A CNA2009101478700 A CN A2009101478700A CN 200910147870 A CN200910147870 A CN 200910147870A CN 101574324 A CN101574324 A CN 101574324A
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Abstract
The invention discloses a Felodipine sustained-release tablet and a method for controlling the sustained-release of the Felodipine sustained-release tablet. The Felodipine sustained-release tablet comprises Felodipine and HPMC high polymer material, the Felodipine accounts for 2.0-7.0% of the total sum of the granules or the powder, wherein, the viscosity range of the granules or the powder of the prepared Felodipine sustained-release tablet is respectively 2000-2400 centipoise and 6840-7240centipoise. The Felodipine sustained-release tablet has quality conforming to the standard and similar release property with the preparation of the same type sold in markets, and the quality control is carried out before production, thus reducing re-doing, saving production cost, reducing energy consumption and improving productivity.
Description
Technical field
The present invention relates to the method that a kind of felodipine sustained-release tablets and control felodipine sustained-release tablets thereof discharge.
Background technology
Hypertension is modal cardiovascular diseases, is the great public health problem in the global range.Along with the raising of China's living standards of the people, and the improvement of level of medical and health, cardiovascular and cerebrovascular disease has replaced the No.1 killer that infectious disease becomes harm humans health.And hypertension is the arch-criminal of cardiovascular and cerebrovascular disease.Show according to national statistics: the existing hyperpietic of China has reached 1.2 hundred million, and annual newly-increased more than 3,000,000, wherein about 60% patient's blood pressure is in the scope of 140-160/90-95mmHg.The whole nation is annual because of hypertension and complication death toll thereof surpass 1,000,000, and therefore, effectively treatment and prophylaxis of hypertension seem and be important.
Felodipine is dihydropyridine calcium channel antagonist (calcium channel blocker), its effect is a reversibility competition dihydropyridine binding site, the voltage-dependent Ca2+ electric current of the Cor Leporis room cell of blocking-up vascular smooth muscle and artificial culture, and the inductive Mus portal vein of blocking-up K+ contracture.In vitro study shows that this product is better than the cardiac muscle effect the vascular smooth muscle selective inhibitory; Detect negative inotropic action external, but in whole animal, do not observe this effect.This product can make peripheral vascular resistance descend and the hyperamization pressure drop is low, and this pharmacological action is relevant with dosage, and follows the increase of reflexive heart rate.In animal and human's body, observe this product to the reduction effect of peripheral vascular resistance and cause slight diuresis.The hypotensive effect of this product is dose dependent, is proportionate with blood drug level.When first all medications, can have the reflexive heart rate to increase, but this effect reduce in time.The long term administration heart rate may increase by 5～10 times/minute, and the b-blocker can resist this effect.This product single with or do not influence Electrocardiographic P-R interval when share with the b-blocker.Clinical research and electrophysiologic study show, this product single with or share with the b-blocker cardiac conduction (P-R, P-Q and H-V interval) had no significant effect.In clinical trial, do not find clear and definite negative inotropic action to the hyperpietic that do not have left ventricular insufficiency.This product can lower renal vascular resistance and not influence glomerular filtration.Visible slight diuresis, natriuresis and kaliuresis effect when first all medications, short-term and long-term treatment do not influence electrolyte.Find that in to hyperpietic's clinical trial this product can increase the plasma norepinephrine level.
At present, only rest on the preparation method, do not see relevant controlling felodipine sustained-release preparation and discharge patent about the patent of felodipine sustained-release preparation.
Summary of the invention
One of purpose of the present invention provides a kind of felodipine sustained-release tablets.
Two of purpose of the present invention provides a kind of method that felodipine sustained-release tablets discharges of controlling, and reaches the release of controlling felodipine sustained-release tablets by the granule of control felodipine sustained-release tablets or the viscosity of powder.
These and other purpose of the present invention will further embody and set forth by following detailed description and explanation.
The invention provides the method that a kind of viscosity by control granule of felodipine sustained-release tablets or powder reaches sustained release; according to checking a release requirement down among felodipine sustained-release tablets drug standard WS1-(X-152)-2005Z; make this product should be respectively below 20% of labelled amount 1 hour, 4 hours, 7 hours burst size, more than 40%～70% and 80%; and carry out release relatively with 8 sample points of felodipine sustained-release tablets (specification 5mg) of list marketing, utilize the release profiles similarity factor (f
2) method estimates, and judges whether the felodipine sustained-release tablets of preparation has the release similarity with commercially available similar preparation.
The present invention is by selecting two kinds or multiple HPMC macromolecular material for use; the granule or the powder viscosity of control felodipine sustained-release tablets before production; in advance production process is controlled; in time adjust the ratio of macromolecular material HPMC in the prescription, guarantee that the felodipine sustained-release tablets of preparation meets drug standard.
The inventor also finds: when the range of viscosities of the granule of felodipine sustained-release tablets (containing two kinds or multiple HPMC macromolecular material) or powder was 2200 ± 200～7040 ± 200 centipoises, felodipine sustained-release tablets had gratifying slow release effect.
Felodipine sustained-release tablets of the present invention; comprise felodipine and HPMC macromolecular material; described felodipine accounts for 2.0%～7.0% of whole particle or powder total amount, and wherein, the granule of the felodipine sustained-release tablets of making or the range of viscosities of powder are 2200 ± 200～7040 ± 200 centipoises.
In felodipine sustained-release tablets of the present invention, the weight of HPMC macromolecular material accounts for the 30%-55% of whole particle or powder total amount, is preferably, and the weight of HPMC macromolecular material accounts for the 33%-42% of whole particle or powder total amount.Described HPMC macromolecular material is among Dow Chemical E5, the E15LV, E50LV, K100LV, E4M CR, E10M CR, K4M CR, K15M CR and the K100M CR that produce two kinds or multiple.
In felodipine sustained-release tablets of the present invention, described HPMC macromolecular material is the HPMC K15M CR that Dow Chemical produces, the mixture of HPMCK4M CR and HPMC K100LV, and three's mixed weight ratio is 2: 1: 4.What can select is, described HPMC macromolecular material is the HPMC K4M CR that produces of Dow Chemical and the mixture of HPMC K100LV, and the mixed weight ratio of the two is 4: 25.Be preferably, described HPMC macromolecular material is the HPMC K15M CR that Dow Chemical produces, the mixture of HPMC K100LV and HPMC E15LV, and three's mixed weight ratio is 3: 8: 6.
The present invention also provides a kind of method that felodipine sustained-release tablets discharges of controlling, and the granule by the control felodipine sustained-release tablets or the viscosity of powder are controlled the release of felodipine sustained-release tablets, and described viscosity is 2200 ± 200～7040 ± 200 centipoises.
Detection method of the present invention is as follows:
A, take by weighing adjuvants such as felodipine, HPMC macromolecular material according to the above ratio, mix homogeneously, (or with the ethanol system soft material of an amount of 30%～95 volume % concentration, drying, 0.8 μ m～2.0 μ m sieve granulate), add an amount of magnesium stearate and/or micropowder silica gel, mix homogeneously, get the powder (or granule) of felodipine sustained-release tablets, tabletting is made felodipine sustained-release tablets, promptly;
B, take by weighing above-mentioned felodipine sustained-release tablets granule or powder, add after hot distilled water disperses, adding distil water is mixed with the solution that contains 1%～3% weight HPMC to constant weight;
C, employing high shearing mixing emulsor or blender fully stirred 30～60 minutes;
E, viscosity are between 2200 ± 200～7040 ± 200 centipoises, and the felodipine sustained-release tablets of preparation discharges and meets the quality standard requirement.
Can also add other conventional additives in the present invention if necessary, its kind and addition those skilled in the art do not need to spend creative work and promptly know.
Beneficial effect of the present invention:
1), the felodipine sustained-release tablets quality conformance with standard of guarantee producing, have the release similarity with commercially available similar preparation.
2), before production, carry out quality control, can reduce and do over again, save production cost, cut down the consumption of energy, enhance productivity.
All raw material of Shi Yonging and additive etc. all are conventional uses in the present invention, can buy from market.In the present invention, refer in particular to as non-, all amount, percentage ratios are unit of weight.
Below in conjunction with embodiment the present invention is carried out concrete description.As known by the technical knowledge, the present invention can realize by other the embodiment that does not break away from its spirit or essential feature.Therefore, following embodiment with regard to each side, all just illustrates, and is not only.All within the scope of the present invention or the change that is equal in the scope of the present invention all be included in the invention.
Description of drawings
Fig. 1 is the evaluation of the embodiments of the invention 1 stripping curve similarity f2 factor;
Fig. 2 is the evaluation of the embodiments of the invention 2 stripping curve similarity f2 factors;
Fig. 3 is the evaluation of the embodiments of the invention 3 stripping curve similarity f2 factors;
Fig. 4 is the evaluation of the embodiments of the invention 4 stripping curve similarity f2 factors;
Fig. 5 is the evaluation of the embodiments of the invention 5 stripping curve similarity f2 factors.
The specific embodiment
Embodiment 1:
(wherein the total amount of HPMC K15M CR, HPMC K4M CR and HPMC K100LV CR accounts for 33% of granule gross weight to take by weighing felodipine sustained-release tablets granule 15.2g; Three's weight ratio is: HPMCK15M CR: HPMC K4M CR: HPMC K100LV CR=2: 1: 4), add the 50g hot distilled water, Glass rod stirs and makes it to disperse, add distilled water 434.8g, high shearing mixing emulsor fully stirred 40 minutes, was mixed with the aqueous solution that contains 1%HPMC, adopted Brookfield LVDV-C digital display viscometer, select the #1 rotor, it is 7040 centipoises that rotating speed 30rpm condition is measured viscosity.This moment, the felodipine sustained-release tablets release of preparation saw Table 1, and Fig. 1 is seen in the evaluation of stripping curve similarity f2 factorization method.
The release of table 1 embodiment 1
| Time (h) | |
Commercial preparation release meansigma methods (%) | Time (h) | |
Commercial preparation release meansigma methods (%) |
| 0.5 | 7.3 | 6.9 | 5 | 59.7 | 70.6 |
| 1 | 14.6 | 13.1 | 7 | 80.7 | 99.7 |
| 2 | 27.9 | 36.0 | 11 | 98.6 | 100.0 |
| 4 | 46.3 | 58.0 | 15 | 100.0 | 100.4 |
Conclusion: embodiment 1 estimates according to the stripping curve similarity f2 factor, and f2=52＞50 judge that its release is similar to the commercial preparation.Meet drug standard so select for use the felodipine sustained-release tablets that contains 33% these three kinds of model HPMC preparations to discharge in the prescription.
Embodiment 2:
(wherein the total amount of HPMC K4M CR and HPMC K100LVCR accounts for 41.4% of granule gross weight to take by weighing felodipine sustained-release tablets granule 12.1g; The weight ratio of the two is: HPMC K4M CR: HPMCK100LV CR=4: 25), add the 50g hot distilled water, Glass rod stirs and makes it to disperse, add distilled water 437.9g, high shearing mixing emulsor fully stirred 40 minutes, was mixed with the aqueous solution that contains 1%HPMC, adopted Brookfield LVDV-C digital display viscometer, select the #1 rotor, it is 2820 centipoises that rotating speed 30rpm condition is measured viscosity.This moment, the felodipine sustained-release tablets release of preparation saw Table 2, and Fig. 2 is seen in the evaluation of stripping curve similarity f2 factorization method.
The release of table 2 embodiment 2
| Time (h) | |
Commercial preparation release meansigma methods (%) | Time (h) | |
Commercial preparation release meansigma methods (%) |
| 0.5 | 8.3 | 6.9 | 5 | 69.6 | 70.6 |
| 1 | 16.8 | 13.1 | 7 | 97.1 | 99.7 |
| 2 | 31.6 | 36.0 | 11 | 99.1 | 100.0 |
| 4 | 62.5 | 58.0 | 15 | 99.7 | 100.4 |
Conclusion: embodiment 2 estimates according to the stripping curve similarity f2 factor, and f2=76＞50 judge that its release is similar to the commercial preparation.Meet drug standard so select for use the felodipine sustained-release tablets that contains 41.4% these two kinds of model HPMC preparations to discharge in the prescription.
Embodiment 3:
(wherein the total amount of HPMC K15M CR, HPMC K100LVCR and HPMC E15LV accounts for 40.1% of granule gross weight to take by weighing felodipine sustained-release tablets granule 12.5g; Three's weight ratio is: HPMCK15M CR: HPMC K100LV CR: HPMC E15LV=3: 8: 6), add the 50g hot distilled water, Glass rod stirs and makes it to disperse, add distilled water 437.5g, high shearing mixing emulsor fully stirred 40 minutes, was mixed with the aqueous solution that contains 1%HPMC, adopted Brookfield LVDV-C digital display viscometer, select the #1 rotor, it is 2200 centipoises that rotating speed 30rpm condition is measured viscosity.This moment, the felodipine sustained-release tablets release of preparation saw Table 3, and Fig. 3 is seen in the evaluation of stripping curve similarity f2 factorization method.
The release of table 3 embodiment 3
| Time (h) | Embodiment 3 release meansigma methodss (%) | Commercial preparation release meansigma methods (%) | Time (h) | Embodiment 3 release meansigma methodss (%) | Commercial preparation release meansigma methods (%) |
| 0.5 | 8.3 | 6.9 | 5 | 70.0 | 70.6 |
| 1 | 18.9 | 13.1 | 7 | 99.5 | 99.7 |
| 2 | 31.8 | 36.0 | 11 | 99.8 | 100.0 |
| 4 | 66.7 | 58.0 | 15 | 100.4 | 100.4 |
Conclusion: embodiment 3 estimates according to the stripping curve similarity f2 factor, and f2=69＞50 judge that its release is similar to the commercial preparation.Meet drug standard so select for use the felodipine sustained-release tablets that contains 40.1% these three kinds of model HPMC preparations to discharge in the prescription.
Embodiment 4:
(wherein the total amount of HPMC K15M CR, HPMC K4M CR and HPMC K100LV CR accounts for 30.2% of granule gross weight to take by weighing felodipine sustained-release tablets granule 16.6g; Three's weight ratio is: HPMC K15M CR: HPMC K4M CR: HPMC K100LV CR=3: 3: 10), add the 50g hot distilled water, Glass rod stirs and makes it to disperse, add distilled water 433.4g, high shearing mixing emulsor fully stirred 40 minutes, was mixed with the aqueous solution that contains 1%HPMC, adopted Brookfield LVDV-C digital display viscometer, select the #1 rotor, it is 1984 centipoises that rotating speed 30rpm condition is measured viscosity.This moment, the felodipine sustained-release tablets release of preparation saw Table 4, and Fig. 4 is seen in the evaluation of stripping curve similarity f2 factorization method.
The release of table 4 embodiment 4
| Time (h) | |
Commercial preparation release meansigma methods (%) | Time (h) | |
Commercial preparation release meansigma methods (%) |
| 0.5 | 13.6 | 6.9 | 5 | 76.4 | 70.6 |
| 1 | 21.9 | 13.1 | 7 | 104.0 | 99.7 |
| 2 | 39.6 | 36.0 | 11 | 103.8 | 100.0 |
| 4 | 58.9 | 58.0 | 15 | 104.1 | 100.4 |
Conclusion: embodiment 4 estimates according to the stripping curve similarity f2 factor, f2=64＞50, judge that its release is similar to the commercial preparation, but according to first time point of release in the drug standard (1h) requirement, its release does not meet drug standard greater than 20% so select for use the felodipine sustained-release tablets that contains 30.2% these three kinds of model HPMC preparations to discharge in the prescription.
Embodiment 5:
(wherein the total amount of HPMC K15M CR, HPMC K4M CR and HPMC K100LV CR accounts for 28.3% of granule gross weight to take by weighing felodipine sustained-release tablets granule 17.7g; Three's weight ratio is: HPMC K15M CR: HPMC K4M CR: HPMC K100LV CR=4: 3: 5), add the 50g hot distilled water, Glass rod stirs and makes it to disperse, add distilled water 432.3g, high shearing mixing emulsor fully stirred 40 minutes, was mixed with the aqueous solution that contains 1%HPMC, adopted Brookfield LVDV-C digital display viscometer, select the #1 rotor, it is 7560 centipoises that rotating speed 30rpm condition is measured viscosity.This moment, the felodipine sustained-release tablets release of preparation saw Table 5, and Fig. 5 is seen in the evaluation of stripping curve similarity f2 factorization method.
The release of table 5 embodiment 5
| Time (h) | |
Commercial preparation release meansigma methods (%) | Time (h) | |
Commercial preparation release meansigma methods (%) |
| 0.5 | 7.9 | 6.9 | 5 | 60.3 | 70.6 |
| 1 | 17.0 | 13.1 | 7 | 78.8 | 99.7 |
| 2 | 28.8 | 36.0 | 11 | 98.9 | 100.0 |
| 4 | 47.5 | 58.0 | 15 | 99.7 | 100.4 |
Conclusion: embodiment 5 estimates according to the stripping curve similarity f2 factor, f2=51＞50, judge that its release is similar to the commercial preparation, but according to the 3rd time point of release in the drug standard (7h) requirement, its release does not meet drug standard less than 80% so select for use the felodipine sustained-release tablets that contains 28.3% these three kinds of model HPMC preparations to discharge in the prescription.
Claims (8)
1, a kind of felodipine sustained-release tablets; it is characterized in that comprising felodipine and HPMC macromolecular material; described felodipine account for whole heavy by 2.0%～7.0%, wherein, the granule of the felodipine sustained-release tablets of making or the range of viscosities of powder are 2200 ± 200～7040 ± 200 centipoises.
2, felodipine sustained-release tablets according to claim 1 is characterized in that the weight of HPMC macromolecular material accounts for the 30%-55% of whole weight.
3, felodipine sustained-release tablets according to claim 1 is characterized in that the weight of HPMC macromolecular material accounts for the 33%-42% of whole weight.
4,, it is characterized in that described HPMC macromolecular material is among Dow Chemical E5, the E15LV, E50LV, K100LV, E4MCR, E10M CR, K4M CR, K15M CR and the K100M CR that produce two kinds or multiple according to the described felodipine sustained-release tablets of one of claim 1-3.
5, felodipine sustained-release tablets according to claim 4, it is characterized in that described HPMC macromolecular material is the HPMC K15M CR that Dow Chemical produces, the mixture of HPMC K4M CR and HPMCK100LV, three's mixed weight ratio is 2: 1: 4.
6, felodipine sustained-release tablets according to claim 4 is characterized in that described HPMC macromolecular material is the HPMC K4M CR of Dow Chemical's production and the mixture of HPMC K100LV, and the mixed weight ratio of the two is 4: 25.
7, felodipine sustained-release tablets according to claim 4, it is characterized in that described HPMC macromolecular material is the HPMC K15M CR that Dow Chemical produces, the mixture of HPMC K100LV and HPMCE15LV, three's mixed weight ratio is 3: 8: 6.
8, a kind ofly control the method that felodipine sustained-release tablets discharges, it is characterized in that the viscosity of granule by the control felodipine sustained-release tablets or powder controls the release of felodipine sustained-release tablets, described viscosity is 2200 ± 200～7040 ± 200 centipoises.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843598A (en) * | 2010-06-07 | 2010-09-29 | 常州制药厂有限公司 | Preparation method of felodipine sustained release tablets |
| CN111603444A (en) * | 2020-07-06 | 2020-09-01 | 浙江工业大学 | Felodipine nano-particles and preparation method thereof |
-
2009
- 2009-06-16 CN CN2009101478700A patent/CN101574324B/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843598A (en) * | 2010-06-07 | 2010-09-29 | 常州制药厂有限公司 | Preparation method of felodipine sustained release tablets |
| CN101843598B (en) * | 2010-06-07 | 2015-10-07 | 常州制药厂有限公司 | The preparation method of felodipine sustained-release tablets |
| CN111603444A (en) * | 2020-07-06 | 2020-09-01 | 浙江工业大学 | Felodipine nano-particles and preparation method thereof |
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