CN101874775B - Revaprazan hydrochloride nanosuspension and preparation method thereof - Google Patents
Revaprazan hydrochloride nanosuspension and preparation method thereof Download PDFInfo
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- CN101874775B CN101874775B CN 201010186776 CN201010186776A CN101874775B CN 101874775 B CN101874775 B CN 101874775B CN 201010186776 CN201010186776 CN 201010186776 CN 201010186776 A CN201010186776 A CN 201010186776A CN 101874775 B CN101874775 B CN 101874775B
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Abstract
The invention discloses revaprazan hydrochloride nanosuspension and a preparation method thereof, belonging to the technical field of medicines. Revaprazan hydrochloride is a novel proton pump inhibitor and makes an effect of potentially inhibiting basal gastric acid secretion, but in-vivo bioavailability is low due to medicinal slight dissolution. By adopting a nano technology, the particle size of a medicine is reduced to prepare the nano-suspension and evaluate the in-vitro dissolution and the in-vivo bioavailability of the nano-suspension of the medicine. A determining result shows that the nano-suspension can greatly improve the dissolution and the bioavailability of the medicine. The invention further discloses the preparation method of the nano-suspension.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of Revaprazan hydrochloride nanosuspension and preparation method thereof.
Background technology
Peptic ulcer is a kind of commonly encountered diseases, different times, and the sickness rate of different regions can be different, and sickness rate accounts for 10～20% of population usually.Present stage, along with social development, the change of circumstances, the variation of people life style, because of smoking, drink, peptic ulcer rate that nervous and medicine irritation etc. causes increases just gradually, having a strong impact on people's work and life.Medical circle is not clear to its definite pathogenesis now, but gastric acid secretion inhibiting has become the prefered method that this type of disease for the treatment of is generally acknowledged.
Revaprazan hydrochloride is a kind of reversible type proton pump inhibitor of being developed by Korea S Yuhan company, with traditional proton pump inhibitor, compare such as omeprazole, lansoprazole, function with potential inhibition basal gastric acid secretion, great advantage is rapid-action, can not cause the untoward reaction of achlorhydria.
As a kind of fat-soluble medicine newly developed, Revaprazan hydrochloride now only has the tablet list marketing, and because medicine is atomic water-soluble, causes thus bioavailability low, and using dosage is large, and patient compliance is poor.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of Revaprazan hydrochloride nanosuspension and preparation method thereof, thereby improves water solublity and the bioavailability of Revaprazan hydrochloride.
The composition of Revaprazan hydrochloride nanosuspension of the present invention is based on the Revaprazan hydrochloride of 1 weight portion 1nm～1000nm particle diameter; The stabilizing agent of 1～50 weight portion, the antiseptic of the suspending agent of 0.1～10 weight portion and 0.0001～0.0025 weight portion.
Stabilizing agent comprises one of following compounds: polysorbas20, polysorbate60, Tween 80, span 20, sorbester p18, sorbester p17, Myrij 35, sodium laurylsulfate, sodium lauryl sulphate, lecithin, polyvinyl alcohol, polyvinylpyrrolidone, crospolyvinylpyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, ethylene-vinyl acetate copolymer, poloxamer, Polyethylene Glycol, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, carbomer.
Suspending agent comprises one of following chemical compound: methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl starch sodium, arabic gum, tragakanta, carbomer, Polyethylene Glycol, silica sol, sodium alginate.
Antiseptic comprises one of following chemical compound: methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate.
The preparation method of Revaprazan hydrochloride nanosuspension of the present invention is: (1) is dissolved in Revaprazan hydrochloride in the organic solvent, then the organic solution of medicine is poured in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, heated and stirred is even, make organic solvent evaporation to most, drug crystallization is separated out, get Revaprazan hydrochloride nanosuspension.(2) Revaprazan hydrochloride is dissolved in the organic solvent, then the organic solution of medicine is poured in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then place the ultrasonic washing unit ultra-sonic dispersion, along with the volatilization of organic solvent, make drug crystallization separate out to get Revaprazan hydrochloride nanosuspension.(3) Revaprazan hydrochloride is dissolved in the organic solvent, then the organic solution of medicine is poured in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then use the ultrasonic cell disruptor ultra-sonic dispersion, drug crystallization is separated out, get Revaprazan hydrochloride nanosuspension.(4) Revaprazan hydrochloride be scattered in obtain the thick suspensoid of medicine in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then with thick suspensoid by the high pressure nano homogenizer, make the medicament nano suspensoid.(5) Revaprazan hydrochloride be scattered in obtain the thick suspensoid of medicine in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then with the thick suspensoid of medicine by the microjet high pressure homogenizer, make the medicament nano suspensoid.(6) Revaprazan hydrochloride be scattered in obtain the thick suspensoid of medicine in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then with the thick suspensoid of medicine in grinding in ball grinder, make the medicament nano suspensoid.(7) Revaprazan hydrochloride is scattered in obtains the thick suspensoid of medicine in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, the thick suspensoid of medicine is ground in ball mill, make the medicament nano suspensoid.
Revaprazan hydrochloride nanosuspension of the present invention, be different from its common suspensoid: the former or by control drug crystallization size, or by under condition of high voltage, medicine being carried out homogenizing, or grind by long liquid feeding and to make diameter of aspirin particle less, reach Nano grade.The present invention has solved the slightly water-soluble problem of medicine by reducing the drug particle particle diameter.And the adding of stabilizing agent and suspending agent makes the nano suspension dispersion that makes more even, and the stable resting period is longer.Measurement result shows that the present invention has well solved slightly water-soluble and the low problem of bioavailability of Revaprazan hydrochloride, haves laid a good foundation for further developing more preferably the Revaprazan hydrochloride nanometer formulation.
Table 1 has provided the variation of nano suspension particle diameter after preserving 45 days under the drying at room temperature environment of each embodiment of Revaprazan hydrochloride.
The change of size of table 1 Revaprazan hydrochloride nanosuspension storage after 45 days
Description of drawings
Accompanying drawing 1:
Revaprazan hydrochloride coarse powder suspensoid and nanosuspension frozen powder end stereoscan photograph
A is the suspension freeze-dried powder of Revaprazan hydrochloride coarse powder, and B is the Revaprazan hydrochloride nanosuspension freeze-dried powder.
Accompanying drawing 2:
Revaprazan hydrochloride coarse powder suspensoid and nano suspension stripping curve
Series 1 expression Revaprazan hydrochloride coarse powder suspensoid stripping curve, series 2 expression Revaprazan hydrochloride nanosuspension stripping curves.
Accompanying drawing 3:
Curve when Revaprazan hydrochloride coarse powder suspensoid and nano suspension body giving drugs into nose
Curve during series 1 expression Revaprazan hydrochloride coarse powder suspensoid body giving drugs into nose, curve during series 2 expression Revaprazan hydrochloride nanosuspension body giving drugs into nose.
The specific embodiment
Embodiment 1
Take by weighing the Revaprazan hydrochloride of 1g, be dissolved in the 5ml dehydrated alcohol, under agitation pour in the aqueous solution that contains 5g Macrogol 600,3g sodium carboxymethyl cellulose and 0.002g propylparaben, heated and stirred is even under 60 ℃, 100rpm condition, make organic solvent evaporation to the greatest extent, make drug crystallization separate out to get Revaprazan hydrochloride nanosuspension.
Embodiment 2
Take by weighing the 1g Revaprazan hydrochloride, be dissolved in the 5ml dehydrated alcohol, then pour in the aqueous solution of the propylparaben that contains 5g PLURONICS F87,3g hydroxypropyl cellulose and 0.0015g, then place ultrasonic washing unit ultra-sonic dispersion 30min, drug crystallization is separated out, get Revaprazan hydrochloride nanosuspension.
Embodiment 3
Take by weighing the 1g Revaprazan hydrochloride, be dissolved in the 5ml dehydrated alcohol, under agitation pour into and contain in 2g polyvinylpyrrolidone, 3g sodium carboxymethyl cellulose and the 0.001g Pyrusussuriensis aqueous acid, then (the each ultrasonic 10s that uses the ultrasonic cell disruptor ultra-sonic dispersion 30 times, stop 8s), make drug crystallization separate out to get Revaprazan hydrochloride nanosuspension.
Embodiment 4
Take by weighing the 1g Revaprazan hydrochloride, be scattered in to contain and get thick suspensoid in 2g polyvinylpyrrolidone, 3g sodium carboxymethyl cellulose and the 0.001g Pyrusussuriensis aqueous acid, then thick suspensoid is passed through the high pressure nano homogenizer, circulation 20 all Revaprazan hydrochloride nanosuspensions that get under 1500bar pressure.
Take by weighing the 1g Revaprazan hydrochloride, be scattered in the aqueous solution that contains 1g sodium lauryl sulphate, 3g sodium carboxymethyl cellulose and 0.0005g sodium benzoate, get thick suspensoid, again thick suspensoid is passed through the microjet high pressure homogenizer, 15 weeks of circulation get Revaprazan hydrochloride nanosuspension under 1200bar pressure.
Embodiment 6
Take by weighing the 1g Revaprazan hydrochloride, be scattered in the aqueous solution that contains 0.5ml Tween 80,10g hypromellose and 0.0015g ethyl hydroxybenzoate, get thick suspensoid, then thick suspensoid is placed ball mill, under the 200rpm condition, grind 600min, get Revaprazan hydrochloride nanosuspension.
The nano suspension that makes was deposited 45 days at ambient temperature, and remarkable gathering does not occur drug particle, and particle diameter has no obvious increase, saw accompanying drawing 1.This prescription is measured bioavailability in its dissolution in vitro and the male Wistar rat body by Chinese Pharmacopoeia (2005 editions), and curve is seen accompanying drawing 2 and 3 when dissolution curve and medicine.
Embodiment 7
Take by weighing the 1g Revaprazan hydrochloride, be scattered in the aqueous solution that contains 0.5g Poloxamer 127,10g hypromellose and 0.001g ethyl hydroxybenzoate, get thick suspensoid, then thick suspensoid is placed ball mill, under the 600rpm condition, grind 300min, get Revaprazan hydrochloride nanosuspension.
Although by above-described embodiment the present invention is described, the changes and improvements that do not depart from category of the present invention for the present invention carries out it will be apparent to those skilled in the art that.
Claims (6)
1. Revaprazan hydrochloride nanosuspension is characterized in that: take the Revaprazan hydrochloride of 1 weight portion as active component; Be added with the stabilizing agent of 1～50 weight portion, 0.1 the antiseptic of the suspending agent of～10 weight portions and 0.0001～0.0025 weight portion, described stabilizing agent comprises one of following compounds: polysorbas20, polysorbate60, Tween 80, span 20, sorbester p18, sorbester p17, Myrij 35, sodium laurylsulfate, sodium lauryl sulphate, lecithin, polyvinyl alcohol, polyvinylpyrrolidone, crospolyvinylpyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, ethylene-acetate ethylene copolymer, poloxamer, Polyethylene Glycol, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, carbomer; Described suspending agent comprises one of following chemical compound: methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl starch sodium, arabic gum, tragakanta, carbomer, Polyethylene Glycol, silica sol, sodium alginate; Described antiseptic comprises one of following chemical compound: methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate.
2. according to Revaprazan hydrochloride nanosuspension claimed in claim 1, it is characterized in that: described Revaprazan hydrochloride particle diameter is 1 nm～1000nm.
3. the preparation method of a Revaprazan hydrochloride nanosuspension as claimed in claim 1, it is characterized in that: Revaprazan hydrochloride is dissolved in the organic solvent, then the organic solution of medicine is poured in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, heated and stirred is even, make organic solvent evaporation to most, drug crystallization is separated out, get Revaprazan hydrochloride nanosuspension; Or Revaprazan hydrochloride is dissolved in the organic solvent, then the organic solution of medicine is poured in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then place the ultrasonic washing unit ultra-sonic dispersion, volatilization along with organic solvent, drug crystallization is separated out, get Revaprazan hydrochloride nanosuspension;
Or Revaprazan hydrochloride is dissolved in the organic solvent, again the organic solution of medicine is poured in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then use the ultrasonic cell disruptor ultra-sonic dispersion, drug crystallization is separated out, get Revaprazan hydrochloride nanosuspension.
4. the preparation method of a Revaprazan hydrochloride nanosuspension as claimed in claim 1, it is characterized in that: Revaprazan hydrochloride is scattered in obtains the thick suspensoid of medicine in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then thick suspensoid is passed through the high pressure nano homogenizer, make the medicament nano suspensoid;
Or with the thick suspensoid of medicine by the microjet high pressure homogenizer, make the medicament nano suspensoid.
5. the preparation method of a Revaprazan hydrochloride nanosuspension as claimed in claim 1, it is characterized in that: Revaprazan hydrochloride is scattered in obtains the thick suspensoid of medicine in the aqueous solution that contains stabilizing agent, suspending agent and antiseptic, then the thick suspensoid of medicine is placed grinding in ball grinder, make the medicament nano suspensoid;
Or place ball mill to grind the thick suspensoid of medicine, make the medicament nano suspensoid.
6. according to the preparation method of the described Revaprazan hydrochloride nanosuspension of claim 3, it is characterized in that used organic solvent is one of following: dehydrated alcohol, methanol, propylene glycol, acetone, ethyl acetate, dichloromethane, the tert-butyl alcohol.
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| CN103181924B (en) * | 2011-12-27 | 2015-11-18 | 天津药物研究院 | The preparation method of the general pyridine pharmaceutical composition of a kind of Lip river fluorine |
| CN103251556B (en) * | 2013-05-30 | 2015-04-29 | 浙江圣兆药物科技股份有限公司 | Aprepitant nanosuspension and preparation method thereof |
| CN104825410A (en) * | 2015-05-04 | 2015-08-12 | 海南海力制药有限公司 | Revaprazan hydrochloride tablet and preparation method thereof |
| CN107281100B (en) * | 2016-03-30 | 2021-05-07 | 上海现代药物制剂工程研究中心有限公司 | Preparation method of insoluble drug nanosuspension |
| CN108210452B (en) * | 2016-12-11 | 2020-11-13 | 华中农业大学 | Veterinary cyadox nano suspension and preparation method thereof |
| CN114917188A (en) * | 2022-05-06 | 2022-08-19 | 沈阳药科大学 | Celecoxib long-acting nano suspension |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008078922A1 (en) * | 2006-12-22 | 2008-07-03 | Yuhan Corporation | Revaprazan-containing solid dispersion and process for the preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008078922A1 (en) * | 2006-12-22 | 2008-07-03 | Yuhan Corporation | Revaprazan-containing solid dispersion and process for the preparation thereof |
Non-Patent Citations (4)
| Title |
|---|
| 《纳米混悬剂的制备方法及在药剂学中的应用的研究进展》;朱建芬;《中国医药工业杂志》;20061231;第37卷(第3期);全文 * |
| 《纳米混悬剂研究进展》;钱帅;《药学进展》;20071231;第31卷(第1期);全文 * |
| 朱建芬.《纳米混悬剂的制备方法及在药剂学中的应用的研究进展》.《中国医药工业杂志》.2006,第37卷(第3期), |
| 钱帅.《纳米混悬剂研究进展》.《药学进展》.2007,第31卷(第1期), |
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