CN1568961A - Dripping pills of verapamil hydrochloride and its preparation - Google Patents
Dripping pills of verapamil hydrochloride and its preparation Download PDFInfo
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- CN1568961A CN1568961A CNA2004100444475A CN200410044447A CN1568961A CN 1568961 A CN1568961 A CN 1568961A CN A2004100444475 A CNA2004100444475 A CN A2004100444475A CN 200410044447 A CN200410044447 A CN 200410044447A CN 1568961 A CN1568961 A CN 1568961A
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- verapamil hydrochloride
- verapamil
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- polyethylene glycol
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Abstract
The invention discloses am verapamil hydrochloride drop pill prepared through ultramicro disintegration and drop pills manufacturing technique, which has the advantages of improving collapse and dissolving speed, dissolving out speed and degree, quick effect, increased medicament stability, reduced adjuvant consumption, lowered production costs, easiness in carrying and use, oral or swallow administration, It has good compliance, thus is especially suitable for children, the elderly, bedridden patients and dysphagia patients.
Description
Technical field
The present invention relates to a kind of pharmaceutical product and preparation method thereof, specifically verapamil hydrochloride drop pill and preparation method thereof.
Background technology
Verapamil hydrochloride is a calcium ion antagonist.By regulating the flow of calcium ions on myocardium transfer cell, myocardial contraction cell and the vascular smooth muscle cell film, bring into play its pharmacotoxicological effect, but do not change serum calcium cancentration.
The main coronary artery and the small artery of verapamil hydrochloride expansion normal position of heart and ishemic part, antagonism coronary vasospasm spontaneous or that ergometrine brings out has increased sending of coronary vasospasm patient's cardiac muscle oxygen, removes and the prevention coronary vasospasm; Verapamil reduces total peripheral resistance, reduces myocardial oxygen consumption.Can be used for treating variant angina pectoris and unstable angina pectoris.
Verapamil reduces flow of calcium ions, prolongs the effective refractory period of atrioventricular node, and the conduction of slowing down can reduce Chronic Atrial Fibrillation and atrial flutter patient's Ventricular Rate; Reduce the frequency of peroxysmal ventricular tachycardia.Usually verapamil does not influence normal sinus rate, but can cause sick sinus syndrome patient sinus arrest or sino atrial block; Verapamil does not change the action potential or the indoor conduction time in normal atrium, but it reduces the speed of the unpolarized amplitude of repressed human atrial fiber, speed and conduction, may shorten the forward direction effective refractory period of additional bypass passage, quicken the Ventricular Rate that the chamber bypass merges atrial flutter or atrial fibrillation patient, even can bring out ventricular fibrillation.
Verapamil produces the effect of bringing high blood pressure down by reducing body circulation vascular resistance, does not generally cause postural hypotension or reflex tachycardia.
Verapamil alleviates afterload, suppresses myocardial contraction, can improve left chamber diastolic function.In the isometric or dynamic exercise, verapamil does not change the cardiac systolic function of ventricular function normal patient at cardiac muscle.The patient of organic heart disease, the negative inotropic action of verapamil can be lowered the effect of afterload and offset, and cardiac index does not have decline.But the Insufficient patient of severe left ventricular (for example pulmonary wedge pressure greater than 20mmHg or ejection fraction less than 30%), or the patient who takes beta-blocker or other myocardial depressants things, cardiac function may occur and worsen.
The local anesthesia effect of animal experiment prompting verapamil is equimolar 1.6 times an of procaine.
The oral back of verapamil is absorbed more than 90%.Through portal vein first pass effect is arranged.Bioavailability only has 20%～35%.Plasma protein binding rate is about 90%.The oral back of single agent reached peak concentration in 1～2 hour, and effect continues 6～8 hours.Mean half-life is 2.8～7.4 hours, may prolong in the increment phase.Oral for a long time (administration in 6 hours is at least 10 times at interval) half-life increased to 4.5～12.0 hours.Elderly patients' the removing half-life may prolong.
Most of behind the healthy human oral verapamil at liver metabolism.Can detect 13 kinds of metabolites in the urine; Except that nor-verapamil, all metabolites all are micro-.The cardiac vascular activity of Norverapamil is 20% of a verapamil, can reach the essentially identical steady plasma-drug concentration of verapamil hydrochloride.Behind the oral verapamil in 5 days about 70% with metabolite by draining in the urine, 16% or manyly removed by feces, about 3%～4% is discharged by urine with prototype.Verapamil postpones in patient's metabolism of hepatic insufficiency, and the removing half-life extends to 14～16 hours, and apparent volume of distribution increases, and plasma clearance is reduced to liver function normal person's 30%.
The verapamil hydrochloride clinical indication is: 1. angina pectoris: variant angina pectoris; Unstable angina pectoris; The chronic stable angina pectoris.
2. arrhythmia: the Ventricular Rate when share control Chronic Atrial Fibrillation and/or atrial flutter with digoxin; The outbreak repeatedly of prevention paroxysmal supraventricular tachycardia.
3. essential hypertension.
The verapamil hydrochloride odorless, in water, dissolve, but its coated tablet disintegration time is long, dissolution and dissolution rate are low, absorption difference, and bioavailability is low, the supplementary product consumption ratio is big, child, old people, bed patient and dysphagia patients are taken inconvenience, and compliance is poor, have influenced the performance of verapamil hydrochloride therapeutical effect.
The present invention makes the verapamil hydrochloride drop pill by using ultramicro communication technique and dropping pill formulation Technology exactly, thereby overcomes the above defective of verapamil hydrochloride sheet, and the therapeutical effect of verapamil hydrochloride is given full play to.
Summary of the invention
The verapamil hydrochloride drop pill of making by using ultramicro communication technique and dropping pill formulation Technology not only have disintegrate molten loose fast, dissolution and dissolution rate improve, steady quality, the pill volume is little, both can swallow also can buccal, easy to carry and use, onset is rapid, compliance is good, be particularly suitable for the characteristics that child, old people, bed patient and dysphagia patients are taken, but also have working condition and production equipment is simple, production cost is low, compare the advantage that supplementary product consumption reduces with tablet, demonstrated fully the new drug research exploitation spirit that people-oriented.
For achieving the above object, the present invention by the following technical solutions: the verapamil hydrochloride fine powder of 1 weight portion through micronizing is added in 1～10 weight portion molten matrix, fully mixing, dropping preparation method is condensed into ball in coolant, remove coolant, drying, promptly.
The chemical name of verapamil hydrochloride is α-[3-[[2-(3, the 4-dimethoxy phenyl) ethyl] methylamino among the present invention] propyl group]-3,4-dimethoxy-α-cumene acetonitrilehydrochlorate, molecular formula is C
27H
38N
2O
4Hcl, molecular weight are 491.07, and structural formula is
Substrate among the present invention includes but not limited to polyethylene glycol 6000, Macrogol 4000, polyethylene glycol 1500, cetomacrogol 1000, sodium stearate, glycerin gelatine, poloxamer, stearic acid, glycerol monostearate acid, insect wax etc.
Coolant among the present invention includes but not limited to dimethicone, liquid paraffin, vegetable oil, water, alcoholic solution etc.
Below through detecting to beneficial effect of the present invention as directed
One, detects index and method
1. disintegrate (molten loosing) time limit: check according to inspection technique disintegration (two appendix XA of Chinese Pharmacopoeia version in 2000).
2. dissolution rate: sample thief, according to dissolution method (two appendix XC second methods of Chinese Pharmacopoeia version in 2000), 900ml is a solvent with hydrochloric acid solution (9 → 1000), rotating speed is that per minute 50 changes, operation in accordance with the law, in the time of 10,20,30,40 minutes, get solution and filter, get subsequent filtrate as need testing solution; It is an amount of that other gets the verapamil hydrochloride reference substance, and accurate the title decides, and makes the solution that contains 40 μ g among every 1ml approximately, product solution in contrast with above-mentioned dissolution with solvents and quantitative dilution.Get above-mentioned two kinds of solution,, measure trap respectively, obtain trap value (Δ A) separately, calculate stripping quantity at the wavelength place of 278nm and 300nm according to spectrophotography (two appendix IVA of Chinese Pharmacopoeia version in 2000).
Two, commercially available verapamil hydrochloride sheet testing result
1. disintegration time: 48 minutes
2. dissolution rate:
Time (minute) 10 20 30 40
Dissolution (%) 36.7 59.2 78.9 89.3
Three, example 1 sample detection result
1. the molten diffusing time: 3 minutes
2. dissolution rate:
Time (minute) 10 20 30 40
Dissolution (%) 54.5 94.5 99.8 100.4
Four, example 2 sample detection results
1. the molten diffusing time: 3 minutes
2. dissolution rate:
Time (minute) 10 20 30 40
Dissolution (%) 59.7 93.6 99.2 100.6
Five, example 3 sample detection results
1. the molten diffusing time: 4 minutes
2. dissolution rate:
Time (minute) 10 20 30 40
Dissolution (%) 49.3 87.2 98.9 97.3
Six, example 4 sample detection results
1. the molten diffusing time: 4 minutes
2. dissolution rate:
Time (minute) 10 20 30 40
Dissolution (%) 50.0 81.4 98.7 97.2
Seven, example 5 sample detection results
1. the molten diffusing time: 5 minutes
2. dissolution rate:
Time (minute) 10 20 30 40
Dissolution (%) 56.7 88.8 98.5 99.0
Eight, example 6 sample detection results
1. the molten diffusing time: 6 minutes
2. dissolution rate
Time (minute) 10 20 30 40
Dissolution (%) 48.3 86.7 98.5 99.2
The specific embodiment
One, example 1
Prescription:
Verapamil hydrochloride 5g
Polyethylene glycol 6000 15g
Make 1000
Method for making: the verapamil hydrochloride fine powder that the micronizing of learning from else's experience is crossed 200 mesh sieves is added in the fused polyethylene glycol 6000 substrate, stirs evenly, and with the dimethicone coolant, the dropping preparation method pill, drying, promptly.
Two, example 2
Prescription:
Verapamil hydrochloride 5g
Macrogol 4000 15g
Make 1000
Method for making: the verapamil hydrochloride fine powder that the micronizing of learning from else's experience is crossed 200 mesh sieves is added in the fused Macrogol 4000 substrate, stirs evenly, and with the dimethicone coolant, the dropping preparation method pill, drying, promptly.
Three, example 3
Prescription:
Verapamil hydrochloride 5g
Polyethylene glycol 6000 10g
Macrogol 4000 5g
Make 1000
Method for making: the verapamil hydrochloride fine powder that the micronizing of learning from else's experience is crossed 200 mesh sieves is added in fused Macrogol 4000 and the polyethylene glycol 6000 mixed-matrix, stirs evenly, and with the dimethicone coolant, the dropping preparation method pill, drying, promptly.
Four, example 4
Prescription:
Verapamil hydrochloride 5g
Glyceryl monostearate 15g
Make 1000
Method for making: the verapamil hydrochloride fine powder that the micronizing of learning from else's experience is crossed 200 mesh sieves is added in the fused glyceryl monostearate substrate, and mixing is a coolant with the frozen water, the dropping preparation method pill, and drying, promptly.
Five, example 5
Prescription:
Verapamil hydrochloride 5g
Polyethylene glycol 6000 10g
Poloxamer 5g
Make 1000
Method for making: the verapamil hydrochloride fine powder that the micronizing of learning from else's experience is crossed 200 mesh sieves is added in fused polyethylene glycol 6000 and the poloxamer mixed-matrix, stirs evenly, and with the dimethicone coolant, the dropping preparation method pill, drying, promptly.
Six, example 6
Prescription:
Verapamil hydrochloride 5g
Glyceryl monostearate 15g
Poloxamer 1g
Make 1000
Method for making: get the mixing fine powders that verapamil hydrochloride and poloxamer cross 200 mesh sieves through micronizing and be added in the fused glyceryl monostearate substrate, mixing is a coolant with the frozen water, the dropping preparation method pill, and drying, promptly.
Claims (4)
1. verapamil hydrochloride drop pill and preparation method thereof is characterized in that: the verapamil hydrochloride fine powder of 1 weight portion through micronizing is added in 1～10 weight portion molten matrix, fully mixing, dropping preparation method is condensed into ball in coolant, remove coolant, drying, promptly.
2. the chemical name of the described verapamil hydrochloride of claim 1 is α-[3-[[2-(3, the 4-dimethoxy phenyl) ethyl] methylamino] propyl group]-3,4-dimethoxy-α-cumene acetonitrilehydrochlorate, structural formula is
Molecular formula is C
27H
38N
2O
4Hcl, molecular weight are 491.07.
3. the described substrate of claim 1 includes but not limited to polyethylene glycol 6000, Macrogol 4000, polyethylene glycol 1500, cetomacrogol 1000, sodium stearate, glycerin gelatine, poloxamer, stearic acid, glycerol monostearate acid, insect wax etc.
4. the described coolant of claim 1 includes but not limited to dimethicone, liquid paraffin, vegetable oil, water, alcoholic solution etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2004100444475A CN1568961A (en) | 2004-05-13 | 2004-05-13 | Dripping pills of verapamil hydrochloride and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2004100444475A CN1568961A (en) | 2004-05-13 | 2004-05-13 | Dripping pills of verapamil hydrochloride and its preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1568961A true CN1568961A (en) | 2005-01-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004100444475A Pending CN1568961A (en) | 2004-05-13 | 2004-05-13 | Dripping pills of verapamil hydrochloride and its preparation |
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| CN (1) | CN1568961A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107260718A (en) * | 2017-06-26 | 2017-10-20 | 中国科学院心理研究所 | Verapamil is used to prepare the purposes for suppressing to relapse medicine after drug rehabilitation |
-
2004
- 2004-05-13 CN CNA2004100444475A patent/CN1568961A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107260718A (en) * | 2017-06-26 | 2017-10-20 | 中国科学院心理研究所 | Verapamil is used to prepare the purposes for suppressing to relapse medicine after drug rehabilitation |
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| WD01 | Invention patent application deemed withdrawn after publication |