CN101084903A - Sustained-release preparation containing hydrochlorothiazide and preparation method thereof - Google Patents
Sustained-release preparation containing hydrochlorothiazide and preparation method thereof Download PDFInfo
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- CN101084903A CN101084903A CNA2007100243342A CN200710024334A CN101084903A CN 101084903 A CN101084903 A CN 101084903A CN A2007100243342 A CNA2007100243342 A CN A2007100243342A CN 200710024334 A CN200710024334 A CN 200710024334A CN 101084903 A CN101084903 A CN 101084903A
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Abstract
The invention relates to pharmaceutical preparation field, specifically relates to sustained release medication of hydrochlorothiazide. The inventive sustained release medication comprises quick-release part and sustained release part. After the medicament getting in body, quick-release part quickly releases to get to certain blood concentration, slow-released part slowly releases to keep a certain blood concentration; thereby balancing pressure reducing effect. The invention also discloses the preparation method of the sustained release medication.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to the slow releasing preparation of hydrochlorothiazide medicine, the invention also discloses the preparation method of this slow releasing preparation.
Background technology
Hydrochlorothiazide is a kind of diuretic, and the medication initial stage is a natriuretic diuretic, and blood volume and extracellular fluid are reduced, and cardiac output reduces, blood pressure drops.Continuous use is after several weeks, blood volume and cardiac output recover gradually, blood pressure still continues to reduce, the negative booster of this moment is made as the natriuretic diuretic effect, the content of sodium ion in the arterial wall cell is descended, reduce the reactivity of vascular smooth muscle, Peripheral resistance is descended, induce arterial wall to produce simultaneously and expand angiogenic substance the endogenous vaso-active substance.Can be used for treating mild hypertension, also can be used as basic depressor, share, treatment moderate, severe hypertension with other depressor.
Hydrochlorothiazide is a fat-soluble medicine, absorbs well, and part combines with plasma protein, and the half-life is 6-15h.Used clinically Esidrix is an ordinary tablet at present, three times on the one.Conventional tablet is owing to exist release too fast, and instant blood drug level is too high, and blood drug level is low excessively again after of short duration metabolism, and the former easily produces toxic and side effects, and the latter can make duration of efficacy too short.Patient needed take more than three times in one in addition, and is extremely inconvenient, easily forgets clothes and misses, and curative effect is exerted an influence.
Summary of the invention
The invention discloses a kind of slow releasing preparation that contains the hydrochlorothiazide medicine.Can reach medicine and steadily discharge, blood drug level can maintain fluctuation in the very little scope, has the minimizing administration number of times, and it is steady to take back blood drug level, and toxic and side effects is little, takes characteristics such as safety, reduces administration number of times simultaneously, improves hyperpietic's compliance.
For producing antihypertensive effect rapidly in the back of taking medicine and keeping the long period, therefore, slow releasing preparation of the present invention is made up of rapid release and slow release two parts, after medicine enters in the body like this, immediate release section discharges rapidly, reaches certain blood drug level, the slow-released part slow release, keep certain blood drug level, play the effect of steady blood pressure lowering.
Slow releasing preparation of the present invention, wherein immediate release section contains hydrochlorothiazide 0-7.5mg, and slow-released part contains hydrochlorothiazide 10-40mg.When immediate release section contains hydrochlorothiazide and is 0, promptly do not contain immediate release section, be common slow releasing preparation, medicine is balanced to be discharged.The preferred immediate release section of the present invention contains hydrochlorothiazide 3-7.5mg, and slow-released part contains hydrochlorothiazide 10-40mg.The part medication preparation becomes rapid release, more helps medicine and enters the rapid performance in back drug effect in the body.
Above-mentioned slow releasing preparation can be mixed with into hydrochlorothiazide and slow-release material dosage forms such as slow releasing tablet, granule or micropill, and then contain the immediate release section of hydrochlorothiazide in the granule that makes, micropill or tablet outer wrapping with preparation technique pharmaceutically commonly used.Also immediate release section can be prepared into granule, sheet or micropill, partially mixed with slow release then, incapsulate or tabletting.
Particularity according to hydrochlorothiazide physicochemical property and releasing properties, after preferably being prepared into hydrochlorothiazide after the dosage forms such as slow-releasing granules, slow-release micro-pill or slow release small pieces, mixes by a certain percentage again slow-released part, and then mix with the hydrochlorothiazide immediate release section, the hydrochlorothiazide immediate release section can be prepared into fast-release tablet, micropill or granule etc.Preferably with in incapsulating after slow-released part and the immediate release section mixing.
In the above-mentioned slow-released part, in the slow-released part gross weight, slow-released part preferably is made up of other pharmaceutic adjuvant of 25～60% hydrochlorothiazide, 10～50% slow-release materials and surplus.Further preferred: slow-released part is made up of other pharmaceutic adjuvants of 40～55% hydrochlorothiazide, 10～35% slow-release materials and surplus.
In above-mentioned slow-release material preference card POP, ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, stearic acid, glyceryl monostearate, octadecanol, polyethylene, polypropylene, polysiloxanes, the acrylic resin one or more.Further preference card POP and/or hydroxypropyl methylcellulose.More preferably carbopol and hydroxypropyl methylcellulose.
Above-mentioned other pharmaceutic adjuvant is one or more in filler, disintegrating agent, binding agent, lubricant preferably.
The rapid release hydrochlorothiazide contains hydrochlorothiazide and other pharmaceutic adjuvant.The adjuvant of using always on these adjuvant galenic pharmacies.As: filler, disintegrating agent, binding agent, lubricant etc.
In the preferred lactose of above-mentioned filler, sucrose, starch, pregelatinized Starch, cellulose, Icing Sugar, dextrin, glucose, mannitol, calcium sulfate, the calcium bicarbonate one or more; In the preferred carboxymethyl starch sodium of disintegrating agent, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, the cross-linking sodium carboxymethyl cellulose one or more; In binding agent preferred water, alcohol, polyvinylpyrrolidone, starch slurry, hydroxypropyl methylcellulose aqueous solution, the rubber cement one or more; In the preferred magnesium stearate of lubricant, Pulvis Talci, micropowder silica gel, sodium lauryl sulphate or the magnesium one or more.
Slow releasing preparation of the present invention has changed the single release form of original treatment hypertension drug, and rapid release and slow release are organically combined, and can produce hypotensive effect rapidly and keep the long period in the regular hour.The present invention discharged 10-35% in first hour, can produce hypotensive effect at once, discharged in two kinds of medicine 2-24h afterwards of other 65-90%, and stripping is not less than 60% in pro-8h hour, thereby produced the antihypertensive effect that continues.The invention provides a kind of drug reservoir form, the medicine that contains hydrochlorothiazide can slowly be discharged.
Slow releasing preparation preparation method of the present invention is simple, is example to be prepared into small pieces, and preparation method comprises: after hydrochlorothiazide and auxiliary materials and mixing, directly or after making granule be pressed into hydrochlorothiazide slow release small pieces by powder; Prepare hydrochlorothiazide rapid release small pieces more according to a conventional method.To be poured in the same capsule after slow release and the mixing of rapid release small pieces, preparation becomes slow releasing preparation of the present invention.
According to the Esidrix that technical scheme of the present invention makes, oral back runs into Digestive system in gastrointestinal tract, and hydrochlorothiazide can slowly discharge, and can keep long antihypertensive effect, thereby reduce administration number of times, and patient's compliance improves.The relative ordinary preparation of blood drug level is steady in the body of this slow releasing preparation, therefore, can reduce the toxic and side effects that causes more greatly because of the blood concentration fluctuation.
Slow releasing preparation of the present invention has the characteristic of the slow release of 24h in water, 0.1NHCl, pH6.8 buffer (pressing the configuration of Chinese Pharmacopoeia method) or mimic physiological environment (2-3h in the simulated gastric fluid changes simulated intestinal fluid then over to).
In the hydrochlorothiazide is to discharge index:
Time (h) accumulative total discharges %
1 18-30％
4 35-60％
8 60-90％
12 75-100％
Slow releasing preparation of the present invention not only in dissolution in vitro test release profiles reached slow release effect, also confirmed this slow release effect in the test in animal body.
The specific embodiment
Embodiment 1
Below be by 1000 used amounts
A. hydrochlorothiazide rapid release small pieces
Amounts of components (g)
Hydrochlorothiazide 6
Microcrystalline Cellulose 10
Lactose 12.95
Polyvinylpolypyrrolidone 0.9
Magnesium stearate 0.15
B. hydrochlorothiazide slow release small pieces
Amounts of components (g)
Hydrochlorothiazide 31.5
Hydroxypropyl emthylcellulose 12.5
Carbopol 2
Lactose 8.725
Magnesium stearate 0.275
Preparation technology is as follows:
The supplementary material crushing screening is behind above-mentioned recipe quantity difference mixing, then with mix lubricant.Be pressed into small pieces respectively, be poured in the capsule after the mixing.
Embodiment 2
The consumption of present embodiment is by 1000 used amounts
A. hydrochlorothiazide rapid release small pieces
Amounts of components (g)
Hydrochlorothiazide 6
Microcrystalline Cellulose 10
Lactose 12.95
Polyvinylpolypyrrolidone 0.9
Magnesium stearate 0.15
B. hydrochlorothiazide slow release small pieces
Amounts of components (g)
Hydrochlorothiazide 31.5
Hydroxypropyl emthylcellulose K100 10.2
Carbopol 9.6
Lactose 19.2
Magnesium stearate 0.3
Preparation method is with embodiment 1.
Embodiment 3
The consumption of present embodiment is by 1000 used amounts
A. hydrochlorothiazide rapid release small pieces
Amounts of components (g)
Hydrochlorothiazide 6
Microcrystalline Cellulose 10
Lactose 12.95
Polyvinylpolypyrrolidone 0.9
Magnesium stearate 0.15
B. hydrochlorothiazide slow release small pieces
Amounts of components (g)
Hydrochlorothiazide 31.5
Hydroxypropyl emthylcellulose K15 7.8
Carbopol 1.2
Lactose 19.2
Magnesium stearate 0.3
Preparation method is with embodiment 1.
Embodiment 4
Below be by 1000 used amounts
A. hydrochlorothiazide rapid release small pieces
Amounts of components (g)
Hydrochlorothiazide 7.5
Microcrystalline Cellulose 10
Lactose 12.95
Polyvinylpolypyrrolidone 0.9
Magnesium stearate 0.15
B. hydrochlorothiazide slow release small pieces
Amounts of components (g)
Hydrochlorothiazide 30
Hydroxypropyl emthylcellulose K4 20
Hydroxypropyl emthylcellulose 100cp 10
Hydroxypropyl emthylcellulose K15M 10
Lactose 28.5
Magnesium stearate 0.3
Preparation technology is as follows:
Immediate release section: take by weighing the supplementary material of recipe quantity, add binding agent system soft material after crossing 80 mesh sieve mix homogeneously, cross 20 mesh sieves and granulate, 60 ℃ of dryings, 20 mesh sieve granulate, sneak into lubricant, the 4mm stamping.Slow-released part: take by weighing the supplementary material of recipe quantity, cross 80 mesh sieve mixings, add binding agent system soft material, cross 20 mesh sieves and granulate, 60 ℃ of dryings are crossed 20 mesh sieve granulate, sneak into lubricant, the 5mm stamping.Go in the capsulae vacuus fast-release tablet and slow release are on chip.
Embodiment 5
Below be by 1000 used amounts
A. hydrochlorothiazide rapid release small pieces
Amounts of components (g)
Hydrochlorothiazide 6
Microcrystalline Cellulose 10
Lactose 12.95
Polyvinylpolypyrrolidone 0.9
Magnesium stearate 0.15
B. hydrochlorothiazide slow release small pieces
Amounts of components (g)
Hydrochlorothiazide 31.5
Hydroxypropyl emthylcellulose K15 10.8
Carbopol 2.4
Lactose 15
Magnesium stearate 0.3
Preparation method is with embodiment 4.
Embodiment 6
Below be by 1000 used amounts
A. hydrochlorothiazide rapid release small pieces
Amounts of components (g)
Hydrochlorothiazide 6
Microcrystalline Cellulose 10
Lactose 12.95
Polyvinylpolypyrrolidone 0.9
Magnesium stearate 0.15
B. hydrochlorothiazide slow release small pieces
Amounts of components (g)
Hydrochlorothiazide 31.5
Hydroxypropyl emthylcellulose K15M 17.2
Carbopol 1.4
Lactose 13.8
Magnesium stearate 0.3
Preparation method is with embodiment 4.
Embodiment 7
Below be by 1000 used amounts
A. hydrochlorothiazide rapid release small pieces
Amounts of components (g)
Hydrochlorothiazide 6
Microcrystalline Cellulose 10
Lactose 12.95
Polyvinylpolypyrrolidone 0.9
Magnesium stearate 0.15
B. hydrochlorothiazide slow release small pieces
Amounts of components (g)
Hydrochlorothiazide 31.5
Hydroxypropyl emthylcellulose K4M 30
Carbopol 1.4
Lactose 20
Magnesium stearate 0.1
Preparation method is with embodiment 4.
Embodiment 8
Below be by 1000 used amounts
A. hydrochlorothiazide rapid release small pieces
Amounts of components (g)
Hydrochlorothiazide 6
Microcrystalline Cellulose 10
Lactose 12.95
Polyvinylpolypyrrolidone 0.9
Magnesium stearate 0.15
B. hydrochlorothiazide slow release small pieces
Amounts of components (g)
Hydrochlorothiazide 31.5
Hydroxypropyl emthylcellulose K4M 20
Hydroxypropyl emthylcellulose K15M 10
Ethyl cellulose 5
Lactose 32.5
Magnesium stearate 0.1
Preparation method is with embodiment 4.
Embodiment 9
Below be by 1000 used amounts
Amounts of components (g)
Hydrochlorothiazide 37.5
Hydroxypropyl emthylcellulose K10M 6
Hydroxypropyl emthylcellulose K4M 3
Carbopol 1.3
Lactose 27.65
Magnesium stearate 0.3
Preparation technology is as follows:
Behind the supplementary material crushing screening, take by weighing above-mentioned recipe quantity mixing after, add binding agent system soft material, dry the 18 orders back of granulating, 24 order granulate are sneaked into tabletting behind the lubricant.
The medicine dissolution test
Adopt the cuvette oar method in the Chinese Pharmacopoeia 2005 editions, 75 rev/mins, distilled water or 0.1NHCl150ml are dissolution medium, and the slow releasing preparation experiment stripping result of embodiment 1～9 is as follows
Table 1 dissolution data
| Embodiment 1 (dissolution medium is a water) | Embodiment 2 (dissolution medium is a water) | Embodiment 3 (dissolution medium is 0.1NHCl) | Embodiment 4 (dissolution medium is 0.1NHCl) | |
| Time (h) | Hydrochlorothiazide (%) | Hydrochlorothiazide (%) | Hydrochlorothiazide (%) | Hydrochlorothiazide (%) |
| 1 | 19.3 | 18.9 | 26.5 | 26.4 |
| 4 | 37.6 | 35.9 | 57.1 | 44.6 |
| 8 | 62.7 | 63.5 | 85.2 | 69.9 |
| 12 | 80.1 | 81.5 | 100 | 87.5 |
Table 2 dissolution data
| Embodiment 5 (dissolution medium is 0.1NHCl) | Embodiment 6 (dissolution medium is 0.1NHCl) | Embodiment 7 (dissolution medium is 0.1NHCl) | Embodiment 8 (dissolution medium is 0.1NHCl) | Embodiment 9 (dissolution medium is 0.1NHCl) | |
| Time (h) | Hydrochlorothiazide (%) | Hydrochlorothiazide (%) | Hydrochlorothiazide (%) | Hydrochlorothiazide (%) | Hydrochlorothiazide (%) |
| 1 | 21.6 | 27.3 | 20.3 | 18.8 | 16.4 |
| 4 | 54.5 | 61.2 | 45.5 | 40.7 | 35.5 |
| 8 | 82.0 | 78.4 | 63.8 | 61.4 | 60.4 |
| 12 | 100 | 83.1 | 80.2 | 78.2 | 75.6 |
Claims (7)
1, a kind of slow releasing preparation that contains hydrochlorothiazide is characterized in that being made up of rapid release and slow release two parts, and wherein per unit preparation immediate release section contains hydrochlorothiazide 0-7.5mg, and slow-released part contains hydrochlorothiazide 10-40mg.
2, the slow releasing preparation of claim 1, wherein in the slow-released part gross weight, slow-released part is made up of other pharmaceutic adjuvant of 25～60% hydrochlorothiazide, 10～50% slow-release materials and surplus.
3, the slow releasing preparation of claim 2, wherein in the slow-released part gross weight, slow-released part is made up of other pharmaceutic adjuvants of 40～55% hydrochlorothiazide, 10～35% slow-release materials and surplus.
4, claim 2 or 3 slow releasing preparation, wherein slow-release material is selected from one or more in carbopol, ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, stearic acid, glyceryl monostearate, octadecanol, polyethylene, polypropylene, polysiloxanes, the acrylic resin.
5, the slow releasing preparation of claim 1, wherein immediate release section contains hydrochlorothiazide and other pharmaceutic adjuvant.
6, claim 2,3 or 5 slow releasing preparation, wherein other pharmaceutic adjuvant is selected from one or more in filler, disintegrating agent, binding agent, the lubricant.
7, the slow releasing preparation of claim 6, wherein filler is selected from one or more in lactose, sucrose, starch, pregelatinized Starch, cellulose, Icing Sugar, dextrin, glucose, mannitol, calcium sulfate, the calcium bicarbonate; Disintegrating agent is selected from one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, the cross-linking sodium carboxymethyl cellulose; Binding agent is selected from one or more in water, alcohol, polyvinylpyrrolidone, starch slurry, hydroxypropyl methylcellulose aqueous solution, the rubber cement; Lubricant is selected from one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, sodium lauryl sulphate or the magnesium.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200710024334A CN100581549C (en) | 2007-06-13 | 2007-06-13 | Sustained-release preparation containing hydrochlorothiazide and preparation method thereof |
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|---|---|---|---|
| CN200710024334A CN100581549C (en) | 2007-06-13 | 2007-06-13 | Sustained-release preparation containing hydrochlorothiazide and preparation method thereof |
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| CN101084903A true CN101084903A (en) | 2007-12-12 |
| CN100581549C CN100581549C (en) | 2010-01-20 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519140A (en) * | 2016-06-21 | 2017-12-29 | 北京科信必成医药科技发展有限公司 | A kind of Hydrochioro microplate and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107519140A (en) * | 2016-06-21 | 2017-12-29 | 北京科信必成医药科技发展有限公司 | A kind of Hydrochioro microplate and preparation method thereof |
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Assignee: Shenzhen Xingyin Pharmaceutical Co.,Ltd. Assignor: Hefei Cosource Medicine Technology Co., Ltd. Contract record no.: 2010440020101 Denomination of invention: Sustained-release preparation containing hydrochlorothiazide and preparation method thereof Granted publication date: 20100120 License type: Exclusive License Open date: 20071212 Record date: 20100715 |