CN102100680A - Benazepril hydrochloride pulse-released tablet and preparation method thereof - Google Patents
Benazepril hydrochloride pulse-released tablet and preparation method thereof Download PDFInfo
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- CN102100680A CN102100680A CN200910250902XA CN200910250902A CN102100680A CN 102100680 A CN102100680 A CN 102100680A CN 200910250902X A CN200910250902X A CN 200910250902XA CN 200910250902 A CN200910250902 A CN 200910250902A CN 102100680 A CN102100680 A CN 102100680A
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- benazepril hydrochloride
- filmogen
- eudragit
- pulse
- label
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Abstract
The invention discloses a benazepril hydrochloride pulse-released tablet and a preparation method thereof. The benazepril hydrochloride pulse-released tablet disclosed by the invention consists of a tablet core and a coating, wherein the tablet core comprises benazepril hydrochloride, a diluent agent, a disintegrating agent, a lubricating agent and the like, and the coating comprises a film forming material, a pore-forming agent and the like. The release table disclosed by the invention is a pulse-released medicine system, releases the medicine according to the preset time and provides an effective blood concentration as required to realize the best curative effect; and the system make the patient ahead take medicine to prevent the disease from attacking according to the rhythm of disease attacking. The invention ensures that the safety, the effectiveness and the adaptability of the medicine are improved.
Description
Technical field
The present invention relates to the drug release formulation art, relate in particular to benazepril hydrochloride pulse release sheet.
Background technology
Recent study shows, blood pressure, heart rate, catecholamine discharge and platelet aggregation all has daily rhythmicity, and active peak has more now in the 6:00-10:00 in morning.Cardiovascular disease in the morning with the period in the morning in M ﹠ M increase with body in relevant neurotransmitter increased activity humorous dependency when being obvious.Coronary resistance and forearm vascular resistance maximum in morning and, these factors can make coronary artery blood flow reduce the period in the morning.Catecholamine discharges to increase and causes that the enhancing of blood vessel allergia causes vascular resistance to increase.Angiography shows that coronary artery disease patient caliber thin at dusk the period in the morning; Obvious when giving its blood vessels caliber increases behind the nitroglycerin amplitude the morning than the afternoon administration, show that arteria coronaria tension force is higher than afternoon in the morning.The performance of this body index daily rhythmicity is the object that chronokinetics is studied.Chronokinetics is that the circadian rhythm of research pharmacokinetic parameters changes.Because the most physiological functions relevant with transport of drug, as cardiac output, liver, renal blood flow, the secretion speed and the pH of various body fluid, gastrointestinal motilities etc. all have circadian rhythm, and this makes one or more pharmacokinetic parameters thereby present round the clock of many medicines change.Clinical practice confirms that also many commonly encountered diseases such as asthma, hypertension, angina pectoris, arthritis all are daily rhythmicity and change.Have tangible daily rhythmicity as human blood-pressure, diastolic pressure (BP) raise rapidly during 6:00-10:00 in morning, significantly reduced at 20:00-2:00.How cardiovascular disease such as the sudden death of existing report cardiac muscle, apoplexy take place in morning.And for most of people, take medicine morning and on compliance, all have certain difficulty, therefore preparation is prepared into the pulse preparation with treating cardiovascular disease, make medicine postpone release in about 4 hours, make patient take medicine before sleeping, the diastolic pressure low value phase medicine before morning 2:00 does not discharge, and avoids the generation of side effect, and reach stable state treatment blood drug level about 6:00 in morning, can improve therapeutic effect greatly.
Benazepril hydrochloride is a kind of precursor medicine, becomes the active substance benazeprilat after the hydrolysis, can suppress Angiotensin-Converting (ACE).Stop angiotensin I to change into Angiotensin II, thereby attenuating is by all effects of Angiotensin II mediation, for example: vasoconstrictive and generation aldosterone, aldosterone promote heavily absorption and the raising cardiac output of renal tubules to sodium and water.This product can weaken the sympathetic reflexive increased heart rate effect that causes because of vasodilation.Has good efficacy for hypertension and congestive heart failure.
It is the benazepril of Novartis that benazepril hydrochloride existing market share is captured more, and domestic also have many companies this product that gone on the market, but all be conventional tablet.Scholars find that benazepril and thiazide diuretic share, and can strengthen hypotensive effect afterwards.Comprise that with other depressor beta-Blocking agent, calcium antagonist share, can further strengthen hypotensive effect.Therefore benazepril, amlodipine compound preparation LOTREL have successively gone on the market, products such as benazepril, hydrochlorothiazide compound preparation LOTENSIN HCT, patent CN200610075610.3 and CN200610075611.8 have also studied the excellent results of benazepril hydrochloride coupling.Retrieval finds that the research of bringing into play the benazepril hydrochloride drug effect from dosage form is also few, particularly fails to prepare dosage form at the temporal rhythm of cardiovascular disease, brings into play better drug effect and reduces side effect.
Benazepril hydrochloride if can be made pulsed release administration preparation, then can more effective prevention and the showing effect of treatment high blood pressure disease.
Summary of the invention
The objective of the invention is to overcome the deficiency of existing benazepril hydrochloride preparation, provide a kind of and can reduce patient and take number of times, and can guarantee the benazepril hydrochloride pulse release sheet of corresponding effective blood drug concentration according to morbidity rhythmicity characteristics.
Adopt the filmogen Eudragit RL and the Eudragit RS of high osmosis to carry out suitable proportioning when discovering tablet coating, control clothing permeability of the membrane, and in filmogen, add porogen Eudragit L, the characteristic of Eudragit L is not dissolve under acid condition, dissolves under the above condition of pH5.5.After tablet entered human body, in tart gastric environment, moisture can not see through film-coat, medicine can't discharge, after entering intestinal, because intestinal juice pH is greater than 5.5, porogen Eudragit L dissolves gradually on the clothing film, moisture infiltrates label gradually, disintegrating agent imbibition in the label, the support of clothing film is big, and drug release hole increases on the clothing film simultaneously, medicine disengages, thereby reaches the purpose of pulse release.Therefore, as long as regulate Eudragit L in coating weightening finish and the clothing membrane material, ratio between Eudragit RS and the Eudragit RL, influence the speed that moisture infiltrates label, thereby control time lag, regulate the consumption of label disintegrating agent on the other hand, the swelling effect of control strip can reach the purpose of medicine pulse release.
Benazepril hydrochloride pulse release sheet of the present invention is by label and be wrapped in the outer coatings of label and form, and coatings accounts for 5%～7% of label gross weight.
Described label is made up of benazepril hydrochloride, filler, disintegrating agent, binding agent, fluidizer, lubricant; Wherein, benazepril hydrochloride accounts for 4%～7% of label gross weight; Described filler is selected from one or more in the following material: microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol, calcium hydrogen phosphate, and preferably microcrystalline cellulose and lactose, its consumption accounts for 45%～75% of label gross weight; Described disintegrating agent is selected from one or more in the following material: crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and preferred carboxymethyl starch sodium, its consumption accounts for 15%～25% of label gross weight; Described binding agent is selected from one or more in the following material: polyvinylpyrrolidone, hydroxypropyl methylcellulose, pregelatinized Starch, and preferred pregelatinized Starch, its consumption accounts for 5%～20% of label gross weight; Described fluidizer is micropowder silica gel, and its consumption accounts for 0.5%～1.0% of label gross weight; Described lubricant is a stearic acid, and its consumption accounts for 1.5%～2.0% of label gross weight.
Described coatings is made up of filmogen, porogen, plasticizer, antiplastering aid; Wherein, described filmogen is made up of Eudragit RS 30D and Eudragit RL 30D, wherein Eudragit RS 30D: the proportioning of EudragitRL 30D is 9: 1～7: 1; Described porogen is Eudragit L 30D-55, and its polymer weight that contains is a total polymer weight 30%～50% in the filmogen; Described plasticizer is a triethyl citrate, and its consumption is a total polymer weight 15%～20% in the filmogen; Described antiplastering aid is selected from glyceryl monostearate, Pulvis Talci, and its consumption is a total polymer weight 5%～50% in the filmogen;
A kind of pulse release sheet that contains benazepril hydrochloride provided by the invention is achieved through the following technical solutions.
Label preparation: with benazepril hydrochloride, filler, add in the mixer and mix, change mixed-powder over to wet granulator.Prepare binding agent with purified water, open granulator, add binding agent and granulate.Use the obtained granule of fluid bed drying, dry back granule changes in the mixer, adds disintegrating agent, mixes, and adds fluidizer and lubricant again, mixes, and tabletting obtains label.
Coating solution preparation: in predetermined prescription ratio mixing Eudragit RS 30D, Eudragit RL 30D, three kinds of aqueous dispersions of Eudragit L 30D, in addition antiplastering aid, plasticizer are poured in the water, used the refiner homogenize, face with before pouring in the aqueous dispersion, mixing filters through 40 mesh sieves, promptly.
Coating: label is inserted in the high-efficiency coating pot, open spray gun, spray into coating solution, continue in the coating process to stir coating solution, dry after coating is finished, obtain finished product.
Relative prior art, benazepril hydrochloride pulsed release tablet provided by the invention is compared with existing benazepril hydrochloride preparation, can discharge medicine to schedule, and effective blood drug level is provided when seizure of disease, to reach the purpose for the treatment of when selecting.The generation that the receptor sensitivity that said preparation has avoided medicine to cause because of lasting high concentration reduces has also reduced the untoward reaction of medicine simultaneously, according to the rhythm and pace of moving things of patient's morbidity, takes medicine in advance, and prevention is fallen ill.
And the clothing membrane material that benazepril hydrochloride pulse release sheet provided by the invention adopts all is an aqueous dispersion, has avoided the use of organic solvent, helps reducing environmental pollution and realizes suitability for industrialized production.
The specific embodiment
Now provide the following example setting forth the present invention, but not the limiting protecting scope in this.
Embodiment 1
The label prescription:
10000 of labels
Benazepril hydrochloride 109g
Carboxymethyl starch sodium 400g
Microcrystalline Cellulose 414g
Lactose monohydrate 827g
Pregelatinized Starch (kind reaching) 200g
Stearic acid 40g
Micropowder silica gel 20g
Coating fluid prescription:
Eudragit?RS?30D 4444g
Eudragit?RL?30D 556g
Eudragit?L?30D-55 2000g
Triethyl citrate 225g
Pulvis Talci 750g
Purified water 2025g
10000g
Method for making
The preparation of label: with benazepril hydrochloride, microcrystalline Cellulose, lactose, add in the mixer and mix, change mixed-powder over to wet granulator.Prepare 18% pregelatinized Starch slurry with purified water, open granulator, add the pregelatinized Starch slurry and granulate.Drying makes granule, changes in the mixer, adds carboxymethyl starch sodium, mixes, and adds stearic acid and micropowder silica gel again, mixes 5min, and tabletting obtains label.
Coating: preparation coating solution: in predetermined prescription ratio mixing Eudragit RS 30D, Eudragit RL 30D, three kinds of aqueous dispersions of Eudragit L 30D-55, in addition Pulvis Talci, triethyl citrate are poured in the water, used the refiner homogenize, face with before pouring in the aqueous dispersion, mixing, filter through 40 mesh sieves, that is, and coating solution clothing membrane material polymer content 15%.
Label is inserted in the high-efficiency coating pot, open spray gun, spray into coating solution, continue to stir coating solution in the coating process, coating dries after coating is finished to coating weightening finish 6%, obtains finished product.
Drug release determination:
" 2005 editions appendix XC second methods of Chinese pharmacopoeia are at the drug release determination that carries out 12 hours under 50 rev/mins in the 900ml simulation medium in use.At first 900ml by USP32 simulated gastric fluid that regulation is joined (not containing enzyme) in stripping 2 hours, then medium is changed into 900ml and joined the simulated intestinal fluid stripping 10 hours by the USP32 regulation.Temperature is controlled to be 37 ℃, and interval takes out 5ml sample determination benazepril hydrochloride content and measures burst size thus on request.Shown in burst size be the meansigma methods of 6 tablets.
Drug release determination is table 1 as a result:
The release of table 1 benazepril hydrochloride pulse release sheet embodiment 1 in the simulation gastro-intestinal Fluid
| Time (h) | Benazepril hydrochloride burst size (%) |
| 0 | 0 |
| 0.5 | 0 |
| 2 | 0 |
| 3 | 2.3 |
| 4 | 9.9 |
| 5 | 45.6 |
| 6 | 92.6 |
| 7 | 94.5 |
| 8 | 94.2 |
| 10 | 93.8 |
| 12 | 93.3 |
The result draws by release, and drug release is lower than 10% in the benazepril hydrochloride pulse release sheet 4h, has 4 hours drug release time lag, the time lag behind complete at 2h left and right sides drug release, the therapeutic purposes of coincidence pulse release.
Embodiment 2
The label prescription:
10000 of labels
Benazepril hydrochloride 109g
Carboxymethyl starch sodium 400g
Microcrystalline Cellulose 281g
Lactose monohydrate 562g
Pregelatinized Starch (kind reaching) 200g
Stearic acid 32g
Micropowder silica gel 16g
Coating fluid prescription:
Eudragit?RS?30D 4667g
Eudragit?RL?30D 667g
Eudragit?L?30D-55 2667g
Triethyl citrate 272g
Glyceryl monostearate 80g
Purified water 1647g
10000g
Label preparation: with embodiment 1
Coating: preparation coating solution: in predetermined prescription ratio mixing Eudragit RS 30D, Eudragit RL 30D, three kinds of aqueous dispersions of Eudragit L 30D-55, in addition glyceryl monostearate, triethyl citrate are poured in the water, used the refiner homogenize, face with before pouring in the aqueous dispersion, mixing, filter through 40 mesh sieves, that is, and coating solution clothing membrane material polymer content 16%.
Label is inserted in the high-efficiency coating pot, open spray gun, spray into coating solution, continue to stir coating solution in the coating process, coating dries after coating is finished to coating weightening finish 5%, obtains finished product.
Drug release determination:
The drug release determination method is with embodiment 1
Drug release determination is table 2 as a result:
The release of table 2 benazepril hydrochloride pulse release sheet embodiment 2 in the simulation gastro-intestinal Fluid
| Time (h) | Benazepril hydrochloride burst size (%) |
| 0 | 0 |
| 0.5 | 0 |
| 2 | 0 |
| 3 | 5.7 |
| 4 | 12.4 |
| 5 | 66.3 |
| 6 | 94.8 |
| 7 | 94.7 |
| 8 | 93.2 |
| 10 | 92.8 |
| 12 | 92.0 |
The result draws by drug release determination, and benazepril hydrochloride pulse release sheet drug release when 4h has the drug release time lag near 4 hours a little more than 10%, and is complete at 2h left and right sides drug release afterwards, the therapeutic purposes of coincidence pulse release.
Embodiment 3
The label prescription:
10000 of labels
Benazepril hydrochloride 109g
Carboxymethyl starch sodium 375g
Microcrystalline Cellulose 564g
Lactose monohydrate 1127g
Pregelatinized Starch (kind reaching) 250g
Stearic acid 50g
Micropowder silica gel 25g
Coating fluid prescription:
Eudragit?RS?30D 3600g
Eudragit?RL?30D 400g
Eudragit?L?30D-55 1200g
Triethyl citrate 240g
Glyceryl monostearate 60g
Purified water 4500g
10000g
Label preparation: with embodiment 1
Coating: coating solution clothing membrane material polymer content 12%, coating is to coating weightening finish 7%, and other is with embodiment 2
Drug release determination:
The drug release determination method is with embodiment 1
Drug release determination the results are shown in following table 3:
The release of table 3 benazepril hydrochloride pulse release sheet embodiment 3 in the simulation gastro-intestinal Fluid
| Time (h) | Benazepril hydrochloride burst size (%) |
| 0 | 0 |
| 0.5 | 0 |
| 2 | 0 |
| 3 | 1.2 |
| 4 | 5.6 |
| 5 | 35.1 |
| 6 | 89.6 |
| 7 | 92.4 |
| 8 | 91.5 |
| 10 | 91.6 |
| 12 | 90.1 |
The result draws by drug release determination, and benazepril hydrochloride pulse release sheet discharges in 4h and is lower than in 10%, has 4 hours drug release time lag, and is fully approaching at 2h left and right sides drug release afterwards, the therapeutic purposes of coincidence pulse release.
Claims (6)
1. benazepril hydrochloride pulse release sheet is characterized in that it is made up of label and coatings, and coatings accounts for 5%～7% of label gross weight.
2. benazepril hydrochloride pulse release sheet as claimed in claim 1, the composition and the weight ratio that it is characterized in that label are: benazepril hydrochloride 4%～7%, filler 45%～75%, disintegrating agent 10%～25%, binding agent 5%～20%, fluidizer 0.5%～1%, lubricant 1.5%～2%, more than each component sum equal 100%; Wherein said filler is selected from one or more in the following material: microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol, calcium hydrogen phosphate; Described disintegrating agent is selected from one or more in the following material: crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose; Described binding agent is selected from one or more in the following material: polyvinylpyrrolidone, hydroxypropyl methylcellulose, pregelatinized Starch; Described fluidizer is micropowder silica gel; Described lubricant is a stearic acid;
Coatings consists of: filmogen, porogen, plasticizer, antiplastering aid; Wherein said filmogen is made up of Eudragit RS 30D and Eudragit RL 30D; Described porogen is selected from Eudragit L 30D-55, and the weight of its polymer is total polymer weight 30%～50% in the filmogen; Described plasticizer is a triethyl citrate, and its consumption is a total polymer weight 15%～20% in the filmogen; Described antiplastering aid is selected from glyceryl monostearate, Pulvis Talci, and its consumption is a total polymer weight 5%～50% in the filmogen.
3. benazepril hydrochloride pulse release sheet according to claim 2 is characterized in that disintegrating agent is selected from carboxymethyl starch sodium.
4. as claim 2 or 3 described benazepril hydrochloride pulse release sheets, it is characterized in that the proportioning of filmogen Eudragit RS 30D and Eudragit RL 30D is 7: 1～9: 1.
5. as the described benazepril hydrochloride pulse release of above-mentioned claim sheet, it is characterized in that antiplastering aid is a glyceryl monostearate, its consumption is a total polymer weight 5% in the filmogen.
6. as the described benazepril hydrochloride pulse release of above-mentioned claim sheet, it is characterized in that antiplastering aid is a Pulvis Talci, its consumption is a total polymer weight 50% in the filmogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910250902XA CN102100680A (en) | 2009-12-18 | 2009-12-18 | Benazepril hydrochloride pulse-released tablet and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910250902XA CN102100680A (en) | 2009-12-18 | 2009-12-18 | Benazepril hydrochloride pulse-released tablet and preparation method thereof |
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| CN102100680A true CN102100680A (en) | 2011-06-22 |
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| Application Number | Title | Priority Date | Filing Date |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103505461A (en) * | 2012-06-19 | 2014-01-15 | 深圳信立泰药业股份有限公司 | Solid medicine composition of lercanidipine and benazepril |
-
2009
- 2009-12-18 CN CN200910250902XA patent/CN102100680A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103505461A (en) * | 2012-06-19 | 2014-01-15 | 深圳信立泰药业股份有限公司 | Solid medicine composition of lercanidipine and benazepril |
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Application publication date: 20110622 |