CN101181259A - Sustained-release agent of nitric acid dinitrate and preparation method thereof - Google Patents
Sustained-release agent of nitric acid dinitrate and preparation method thereof Download PDFInfo
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Abstract
An isosorbide dinitrate sustained-release preparation is a tablet which consists of isosorbide dinitrate, sustained-release materials and other pharmaceutical excipients, wherein, the sustained-release materials are selected from hypromellose (E4M) and carmellose sodium. As the drug is released in digestive tract according to the procedure after the oral administration, the effective plasma drug concentration in human body can be maintained stably and sustainedly, therefore the invention has the advantages of good healing efficacy, long drug effect, less side effects, small number of the times of the administration of the patients, convenient usage and so on; the invention not only has the function of treating and alleviating angina symptoms, but also has the special advantages of preventing sudden onset and protecting the daily lives of the patients and safely passing through the incidence peak of the diseases, therefore, the invention provides reliable means and great convenience for the treatment of the patients and the self-prevention of sudden onset; the price of the drug is cheap, which is conductive to the administration of ordinary patients.
Description
Technical field
The present invention relates to a kind of medicament slow release preparation, exactly is a kind ofly to be used for the treatment of anginal sustained-release agent of nitric acid dinitrate, and the preparation method of this slow releasing agent.
Technical background
Angina pectoris is the common clinical syndrome in the cardiovascular emergency case, and most of patients has coronary disease disease or myocardium sufferer concurrently, and its characteristics of incidence is to show effect very soon, if can not get timely and correct treatment, will form serious threat or SUD to patient's life security.Traditional Therapeutic Method is to adopt Isosorbide sheet treatment angina pectoris, and dosage form is generally conventional tablet.The angina pectoris patient is through being everlasting night 1～(peak period in early morning) morbidity after 3 points (peak period in morning) and patient get up, because the conventional tablet drug half-life is short, be generally 1.8～2 hours, duration of efficacy is short, need repeatedly repeat administration every day, side effect is big and be difficult to prevent sudden onset, therefore to patient's rest, work and travel, go out to have increased difficulty and inconvenient.The different Pyrusussuriensis slow releasing tablet of single nitric acid though cost an arm and a leg with this product effect is close, is not suitable for a large amount of general patients.
Summary of the invention
The objective of the invention is to overcome above-mentioned defective; Isosorbide is made the slow release long-acting sheet; make it when having the effect of treatment allevating angina pectoris symptom; have concurrently and protect patient's daily life, degree of safety to cross onset peak period, a kind of sustained-release agent of nitric acid dinitrate of prevention sudden onset effect and preparation method thereof.
The present invention seeks to be realized by following technical scheme: a kind of sustained-release agent of nitric acid dinitrate is characterized in that each composition weight per distribution ratio is:
Isosorbide 10%,
Slow-release material 20%～35%
Other pharmaceutic adjuvant surplus.
Wherein the per unit preparation contains 20 milligrams of Isosorbides, the heavy 0.2g/ sheet of theoretical sheet.
Isosorbide (ISDN) is used for the prevention of angina pectoris; Anginal treatment behind the myocardial infarction; With Folium Digitalis Purpureae class medicine and (or) the diuretic use in conjunction, the treatment chronic heart failure.Its main pharmacological is lax vascular smooth muscle.ISDN metabolism in vivo generates the different Pyrusussuriensis of single nitric acid (ISMN), the latter discharges nitrogen oxide (NO), NO is identical with the endothelium relaxing factor, activate guanylate cyclase, cyclic guanylic acid (cGMP) in the smooth muscle cell is increased, thereby lax vascular smooth muscle makes peripheral arterial and venectasia, and is stronger to the venous dilating effect.Venectasia makes blood retention in periphery, and returned blood volume reduces, and left ventricular end diastolic is pressed and pulmonary capillary wedge pressure PCWP presses (preload) to lower.Arteriectasia lowers peripheral vascular resistance, SAP and mean arterial pressure (afterload).Coronary artery expansion increases the coronary perfusion amount.Total effect is that myocardial oxygen consumption is reduced, and oxygen-supplying amount increases, and angina pectoris is alleviated.
Slow-release material is selected hypromellose (E4M) and sodium carboxymethyl cellulose for use.Adopting E4M high viscosity type hypromellose to prepare sustained-release preparation as framework material, to have controllability strong, and the characteristics of stable storing are share with sodium carboxymethyl cellulose and can be made this product reach the national drug standards.Sodium carboxymethyl cellulose is available as suspending agent, thickening agent, emulsifying agent in liquid preparation, can make gel-type vehicle in semi-solid preparation.In tablet, can make binding agent, disintegrating agent and slow-release auxiliary material.
Hypromellose (E4M) and sodium carboxymethyl cellulose weight ratio are: 1: 0.66～1: 0.2.
Other pharmaceutic adjuvant is selected filler and lubricant for use.
Filler is selected microcrystalline Cellulose and lactose for use; Or Icing Sugar and microcrystalline Cellulose and lactose; Or L-hydroxypropyl cellulose and lactose; Or Icing Sugar and L-hydroxypropyl cellulose and lactose; Or Icing Sugar and L-hydroxypropyl cellulose and lactose and microcrystalline Cellulose.Because microcrystalline Cellulose and L-hydroxypropyl cellulose are the modified cellulose of native cellulose after hydrolysis, belong to chemical inertness, can combine with all active component, owing to have good flowability, have cohesive and good plastic deformation ability again, in tablet, be used as binding agent, can improve the hardness of tablet, have the effect that promotes disintegrate again.In wet granulation, can add, also can be used for the dry adhesive of direct compression of full-powder, also can be used as capsular diluent.
Lubricant is selected magnesium stearate for use; Or micropowder silica gel; Or magnesium stearate and micropowder silica gel; Or magnesium stearate and Pulvis Talci; Or magnesium stearate and Pulvis Talci and micropowder silica gel.
A kind of preparation method of sustained-release agent of nitric acid dinitrate:
1. get the raw materials ready according to above-mentioned formulation components, supplementary material is pulverized according to pharmaceutical grade and sieved;
2. with Isosorbide, slow-release material and other pharmaceutic adjuvant mix according to each weight percentages of components of above-mentioned each described preparation;
3. will granulate behind each component mix homogeneously;
4. above-mentioned granule is used prior art and make tablet.
Supplementary material sieves and selects 80～120 order stainless steel sifts for use, adopts dry granulation behind each component mix homogeneously, granulates at 16～24 mesh sieve granulate.
Because oral back follow procedure in digestive tract discharges medicine, the intravital effective blood drug concentration of stable and persistent maintenances people, so have good effect, drug effect is long, side effect is little, patient takes number of times and reaches advantages such as easy to use less; The effect of existing treatment allevating angina pectoris symptom more has the prevention sudden onset concurrently, and protection patient's daily life and degree of safety are crossed the distinct advantages of onset peak period, reliable means and great convenience is provided for patient's treatment and self prevention sudden onset; Because selecting for use of material makes drug price cheap, is beneficial to common patient and takes.
The specific embodiment
Embodiment 1
Slow releasing tablet of the present invention is formulated by the following weight proportion raw material:
Isosorbide 10%
Hypromellose (E4M) 15%
Sodium carboxymethyl cellulose 10%
Microcrystalline Cellulose 30%
Lactose 30%
Micropowder silica gel 4%
Magnesium stearate 1%
Wherein, hypromellose (E4M), sodium carboxymethyl cellulose are slow releasing agent, and lactose, microcrystalline Cellulose are filler, and micropowder silica gel, magnesium stearate are lubricant.
With supplementary material pulverize, sieve, weighing mixing, granulation, tabletting, Isosorbide is pulverized with 100 order stainless steel meshs, preserves standby; Take by weighing Isosorbide, slow-release material and other pharmaceutic adjuvant by formula ratio, and with the abundant mix homogeneously of three-dimensional blender device; With the component of above-mentioned mix homogeneously, adopt dry granulation machine dry granulation, 22 mesh sieve granulate; With above-mentioned whole good granule mix homogeneously in the three-dimensional blender device, with 37A tablet machine tabletting.
Embodiment 2
Slow releasing tablet of the present invention is formulated by the following weight proportion raw material:
Isosorbide 10%
Hypromellose (E4M) 20%
Sodium carboxymethyl cellulose 7.5%
Microcrystalline Cellulose 27.5%
Lactose 30%
Micropowder silica gel 5%
Wherein, hypromellose (E4M), sodium carboxymethyl cellulose are slow releasing agent, and lactose, microcrystalline Cellulose are filler, and micropowder silica gel is a lubricant.
With supplementary material pulverize, sieve, weighing mixing, granulation, tabletting, Isosorbide is pulverized with 100 order stainless steel meshs, preserves standby; Take by weighing Isosorbide, slow-release material and other pharmaceutic adjuvant by formula ratio, and with the abundant mix homogeneously of three-dimensional blender device; With the component of above-mentioned mix homogeneously, adopt dry granulation machine dry granulation, 24 mesh sieve granulate; With above-mentioned whole good granule mix homogeneously in the three-dimensional blender device, with 40C tablet machine tabletting.
Embodiment 3
Slow releasing tablet of the present invention is formulated by the following weight proportion raw material:
Isosorbide 10%
Hypromellose (E4M) 20%
Sodium carboxymethyl cellulose 5%
Microcrystalline Cellulose 25%
Lactose 25%
Icing Sugar 10%
Micropowder silica gel 4%
Magnesium stearate 1%
Wherein, hypromellose (E4M), sodium carboxymethyl cellulose are slow releasing agent, and lactose, Icing Sugar, microcrystalline Cellulose are filler, and micropowder silica gel, magnesium stearate are lubricant.
With supplementary material pulverize, sieve, weighing mixing, granulation, tabletting, Isosorbide is pulverized with 110 order stainless steel meshs, preserves standby; Take by weighing Isosorbide, slow-release material and other pharmaceutic adjuvant by formula ratio, and with the abundant mix homogeneously of three-dimensional blender device; With the component of above-mentioned mix homogeneously, adopt dry granulation machine dry granulation, 20 mesh sieve granulate; With above-mentioned whole good granule mix homogeneously in the V-type blender, with 37A tablet machine tabletting.
Embodiment 4
Slow releasing tablet of the present invention is formulated by the following weight proportion raw material:
Isosorbide 10%
Hypromellose (E4M) 25%
Sodium carboxymethyl cellulose 5%
L-hydroxypropyl cellulose 25%
Lactose 30%
Micropowder silica gel 4%
Magnesium stearate 1%
Wherein, hypromellose (E4M), sodium carboxymethyl cellulose are slow releasing agent, and lactose, L-hydroxypropyl cellulose are filler, and micropowder silica gel, magnesium stearate are lubricant.
With supplementary material pulverize, sieve, weighing mixing, granulation, tabletting, Isosorbide is pulverized with 120 order stainless steel meshs, preserves standby; Take by weighing Isosorbide, slow-release material and other pharmaceutic adjuvant by formula ratio, and with the abundant mix homogeneously of three-dimensional blender device; With the component of above-mentioned mix homogeneously, adopt dry granulation machine dry granulation, 24 mesh sieve granulate; With above-mentioned whole good granule mix homogeneously in the V-type blender, with 40C tablet machine tabletting.
Embodiment 5
Slow releasing tablet of the present invention is formulated by the following weight proportion raw material:
Isosorbide 10%
Hypromellose (E4M) 25%
Sodium carboxymethyl cellulose 5%
L-hydroxypropyl cellulose 25%
Icing Sugar 10%
Lactose 20%
Micropowder silica gel 4%
Magnesium stearate 1%
Wherein, hypromellose (E4M), sodium carboxymethyl cellulose are slow releasing agent, and lactose, L-hydroxypropyl cellulose, Icing Sugar are filler, and micropowder silica gel, magnesium stearate are lubricant.
With supplementary material pulverize, sieve, weighing mixing, granulation, tabletting, Isosorbide is pulverized with 90 order stainless steel meshs, preserves standby; Take by weighing Isosorbide, slow-release material and other pharmaceutic adjuvant by formula ratio, and with the abundant mix homogeneously of three-dimensional blender device; With the component of above-mentioned mix homogeneously, adopt dry granulation machine dry granulation, 22 mesh sieve granulate; With above-mentioned whole good granule mix homogeneously in the three-dimensional blender device, with 37A tablet machine tabletting.
Embodiment 6
Slow releasing tablet of the present invention is formulated by the following weight proportion raw material:
Isosorbide 10%
Hypromellose (E4M) 25%
Sodium carboxymethyl cellulose 10%
L-hydroxypropyl cellulose 15%
Microcrystalline Cellulose 15%
Icing Sugar 5%
Lactose 15%
Micropowder silica gel 4%
Magnesium stearate 1%
Wherein, hypromellose (E4M), sodium carboxymethyl cellulose are slow releasing agent, and lactose, microcrystalline Cellulose, Icing Sugar, L-hydroxypropyl cellulose are filler, and micropowder silica gel, magnesium stearate are lubricant.
With supplementary material pulverize, sieve, weighing mixing, granulation, tabletting, Isosorbide is pulverized with 80 order stainless steel meshs, preserves standby; Take by weighing Isosorbide, slow-release material and other pharmaceutic adjuvant by formula ratio, and with the abundant mix homogeneously of three-dimensional blender device; With the component of above-mentioned mix homogeneously, adopt dry granulation machine dry granulation, 16 mesh sieve granulate; With above-mentioned whole good granule mix homogeneously in the three-dimensional blender device, with 37A tablet machine tabletting.
Embodiment 7
Slow releasing tablet of the present invention is formulated by the following weight proportion raw material:
Isosorbide 10%
Hypromellose (E4M) 20%
Sodium carboxymethyl cellulose 7.5%
Microcrystalline Cellulose 27.5%
Lactose 30%
Pulvis Talci 4%
Magnesium stearate 1%
Wherein, hypromellose (E4M), sodium carboxymethyl cellulose are slow releasing agent, and lactose, microcrystalline Cellulose are filler, and Pulvis Talci, magnesium stearate are lubricant.
With supplementary material pulverize, sieve, weighing mixing, granulation, tabletting, Isosorbide is pulverized with 120 order stainless steel meshs, preserves standby; Take by weighing Isosorbide, slow-release material and other pharmaceutic adjuvant by formula ratio, and with the abundant mix homogeneously of three-dimensional blender device; With the component of above-mentioned mix homogeneously, adopt dry granulation machine dry granulation, 24 mesh sieve granulate; With above-mentioned whole good granule mix homogeneously in the three-dimensional blender device, with 37A tablet machine tabletting.
Embodiment 8
Slow releasing tablet of the present invention is formulated by the following weight proportion raw material:
Isosorbide 10%
Hypromellose (E4M) 20%
Sodium carboxymethyl cellulose 7.5%
Microcrystalline Cellulose 27.5%
Lactose 30%
Micropowder silica gel 2%
Pulvis Talci 2%
Magnesium stearate 1%
Wherein, hypromellose (E4M), sodium carboxymethyl cellulose are slow releasing agent, and lactose, microcrystalline Cellulose are filler, and micropowder silica gel, Pulvis Talci, magnesium stearate are lubricant.
With supplementary material pulverize, sieve, weighing mixing, granulation, tabletting, Isosorbide is pulverized with 90 order stainless steel meshs, preserves standby; Take by weighing Isosorbide, slow-release material and other pharmaceutic adjuvant by formula ratio, and with the abundant mix homogeneously of three-dimensional blender device; With the component of above-mentioned mix homogeneously, adopt dry granulation machine dry granulation, 20 mesh sieve granulate; With above-mentioned whole good granule mix homogeneously in the three-dimensional blender device, with 37A tablet machine tabletting.
Pharmacodynamic analysis of the present invention:
1. the detection of bioavailability of the present invention, its method is as follows: 10 healthy male single oral dose and multiple dose Isosorbide slow releasing tablet (20mg/ sheet), and make comparisons with oral ordinary tablet (5mg/ sheet), use gas chromatograph for determination blood drug level, try to achieve relevant pharmacokinetic parameter.The result: analyze by statistics, the Cmax of slow releasing tablet and ordinary tablet, Tmax and MRT have significant difference.When stable state, the slow releasing tablet of single dose and multiple dose (20mg) bioavailability is respectively (104.0 ± 18.3) % and (98.6 ± 12.4) % with respect to ordinary tablet (5mg * 4).
Conclusion: the present invention and ordinary tablet bioequivalence, but only need day clothes 1 time, make things convenient for the patient to use.
2. pharmacokinetics of the present invention relatively, its method is as follows: adopt gas chromatography, the slow releasing tablet that slow releasing capsule of producing with the happy company of German Mike and Switzerland Aktiebolaget Astra produce compares, with the p-nitrophenyl acetonitrile is interior mark, measure the plasma concentration of Isosorbide (5-ISMN) in the subject, calculate pharmacokinetic parameter.The range of linearity of method is: 10～1000 μ gL-1, and the response rate is (100 ± 3) %; Precision RSD is 2.3%.The result: this product and slow releasing capsule compare, AUC, and Cmax, T1/2, MRT, MAT (P＞0.05), and at C10min, C20min, C30min, C45min, C60min, Tmax, Tlag (P＜0.05).Compare with slow releasing tablet, AUC, Cmax, Tmax, T1/2, Tlag, MAT (P＞0.05), and at MRT, C20min, C30min (P＜0.05).
Conclusion: absorption of the present invention is significantly faster than 2 kinds of control formulation.
3. the curative effect of the slow releasing capsule treatment angina pectoris of the happy company of the present invention and German Mike production compares, and its method is as follows: coronary disease with angina pectoris 58 examples, be divided into slow releasing tablet group 30 examples at random, and give slow releasing tablet 60mg, po, qd, 4wk altogether; Slow releasing capsule group 28 examples are given slow releasing capsule 50mg, po, qd, 4wk altogether.The result: slow releasing tablet group angina pectoris effective percentage and electrocardiogram improvement rate are respectively 93% and 57%; The slow releasing capsule group is followed successively by 93% and 61%, compares difference nonsignificance (P＞0.05) between group.The untoward reaction of two kinds of medicines is all slight.
Conclusion: the curative effect of the slow releasing capsule treatment angina pectoris that the happy company of the present invention and German Mike produces is basic identical.
After testing, 45～70%, 12 hours release in vitro degree＞70% of 20～45%, 6 hours release in vitro degree of 1 hour of the present invention release in vitro degree.
Do not observe carcinogenic and the mutagenesis phenomenon through zoopery.
Because release procedure timing, quantitative release medicine are pressed in oral back in digestive tract, make the intravital effective blood drug concentration of people keep more stable and persistent state.Therefore have: good effect, drug effect is long, side effect is little, patient takes number of times and reaches advantages such as easy to use less.The effect of existing treatment allevating angina pectoris symptom more has the prevention sudden onset concurrently, and protection patient's daily life and degree of safety are crossed the distinct advantages of onset peak period, reliable means and great convenience is provided for patient's treatment and self prevention sudden onset.
Claims (8)
1. sustained-release agent of nitric acid dinitrate is characterized in that each composition weight per distribution ratio is:
Isosorbide 10%,
Slow-release material 20%～35%
Other pharmaceutic adjuvant surplus.
2. sustained-release agent of nitric acid dinitrate according to claim 1 is characterized in that slow-release material selects hypromellose (E4M) and sodium carboxymethyl cellulose for use.
3. sustained-release agent of nitric acid dinitrate according to claim 2 is characterized in that hypromellose (E4M) and sodium carboxymethyl cellulose weight ratio are: 1: 0.66～1: 0.2.
4. sustained-release agent of nitric acid dinitrate according to claim 1 is characterized in that other pharmaceutic adjuvant selects filler and lubricant for use.
5. sustained-release agent of nitric acid dinitrate according to claim 4 is characterized in that filler selects microcrystalline Cellulose and lactose for use; Or Icing Sugar and microcrystalline Cellulose and lactose; Or L-hydroxypropyl cellulose and lactose; Or Icing Sugar and L-hydroxypropyl cellulose and lactose; Or Icing Sugar and L-hydroxypropyl cellulose and lactose and microcrystalline Cellulose.
6. sustained-release agent of nitric acid dinitrate according to claim 4 is characterized in that lubricant selects magnesium stearate for use; Or micropowder silica gel; Or magnesium stearate and micropowder silica gel; Or magnesium stearate and Pulvis Talci; Or magnesium stearate and Pulvis Talci and micropowder silica gel.
7. the preparation method of a sustained-release agent of nitric acid dinitrate:
1. get the raw materials ready according to each described formulation components of claim 1～6, supplementary material is pulverized according to pharmaceutical grade and sieved;
2. with Isosorbide, slow-release material and other pharmaceutic adjuvant mix according to each weight percentages of components of each described preparation of claim 1-6;
3. will granulate behind each component mix homogeneously;
4. above-mentioned granule is used prior art and make tablet.
8. the preparation method of sustained-release agent of nitric acid dinitrate according to claim 7 is characterized in that supplementary material sieves to select 80～120 order stainless steel sifts for use, adopts dry granulation behind each component mix homogeneously, granulates at 16～24 mesh sieve granulate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112121025A (en) * | 2019-06-24 | 2020-12-25 | 翰宇药业（武汉）有限公司 | Isosorbide mononitrate sustained-release tablet and preparation method thereof |
| CN115487162A (en) * | 2022-10-13 | 2022-12-20 | 山东力诺制药有限公司 | Preparation method of isosorbide mononitrate sustained-release tablets |
| CN115590830A (en) * | 2021-07-08 | 2023-01-13 | 武汉熙瑞医药科技有限公司（Cn） | Broglitazone sustained-release preparation and preparation method thereof |
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2007
- 2007-11-19 CN CN2007101141774A patent/CN101181259B/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112121025A (en) * | 2019-06-24 | 2020-12-25 | 翰宇药业（武汉）有限公司 | Isosorbide mononitrate sustained-release tablet and preparation method thereof |
| WO2020258472A1 (en) * | 2019-06-24 | 2020-12-30 | 深圳翰宇药业股份有限公司 | Isosorbide mononitrate sustained release tablet and preparation method therefor |
| CN112121025B (en) * | 2019-06-24 | 2022-05-31 | 翰宇药业（武汉）有限公司 | Isosorbide mononitrate sustained-release tablet and preparation method thereof |
| CN115590830A (en) * | 2021-07-08 | 2023-01-13 | 武汉熙瑞医药科技有限公司（Cn） | Broglitazone sustained-release preparation and preparation method thereof |
| CN115487162A (en) * | 2022-10-13 | 2022-12-20 | 山东力诺制药有限公司 | Preparation method of isosorbide mononitrate sustained-release tablets |
| CN115487162B (en) * | 2022-10-13 | 2023-10-13 | 山东力诺制药有限公司 | Preparation method of isosorbide mononitrate sustained release tablet |
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