CN101623258B - Ranitidine hydrochloride lipidosome capsule and new application thereof - Google Patents
Ranitidine hydrochloride lipidosome capsule and new application thereof Download PDFInfo
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Abstract
The invention provides a ranitidine hydrochloride lipidosome capsule and new application thereof. Particularly, certain amounts of yolk lecithin, cholesterin, natrium glycocholicum, tween 80 and an active ingredient ranitidine hydrochloride are combined and are prepared into ranitidine hydrochloride lipidosome by film dispersion technology, and the ranitidine hydrochloride lipidosome is mixed with the general accessories of medicine to prepare the capsule. The ranitidine hydrochloride lipidosome capsule better solves the problems of easy deliquescence, moisture absorption, color change and poor stability of the ranitidine hydrochloride, increases preparation medical effect and biological availability and can be used for treating herpetic stomatitis of childrem.
Description
Technical field
The present invention relates to a kind of liposome methods preparation, be specifically related to a kind of ranitidine hydrochloride lipidosome capsule and new application thereof of the children's's of treatment herpetic stomatitis, belong to medical technical field.
Background technology
Herpetic stomatitis is the common property of a kind of children's disease that is caused by herpes simplex virus, have certain infectiousness and recurrent, do not have obviously seasonality, average 6 days of incubation period, with heating, sialorrhea, oral ulcer is main performance, and infant makes family members anxious because of the refusing to eat of oral ulcer pain.
Ranitidine is a bisfentidine, the treatment herpes simplex effective, may with this product competitive inhibition histamine H2-receptor; the enhancing human body immunity function suppresses microvascular permeability, reduces body fluid and oozes out; protection normal skin mucosa, thus the secretion that suppresses herpes with ooze out relevant.Herpetic stomatitis is that the acute oral mucosa that the incidental herpes simplex virus I-type of children's (HSV-1) causes infects, and also may occur in lip and mouthful all skin separately, and the scholar who has thinks it mainly is relevant with mucocutaneous direct infection through respiratory tract, digestive tract.Primary disease morbidity often after heating, red macule occurred being dispersed in before this, formed on the very fast macule to be dispersed in or the vesicle of Cheng Cong, and red limit is arranged on every side.Just time-out is itched, and pain is arranged then.The very fast diabrosis of blister forms fester and immediately forms a scab, a few days spontaneous recovery that promptly comes off.General Symptoms is light or heavy, and affiliated lymph node is slightly enlargement sometimes.
Ranitidine hydrochloride is deliquescence very easily, causes instability after the moisture absorption, darkens, and content descends, and drug effect descends.Enterprise that the production of ranitidine hydrochloride capsules has adopts powder directly to fill, the not only difficult control of content uniformity, production efficiency is low, and to the humidity requirement of operating environment difficulty reach; The enterprise that has adopts dry pressing to granulate, and grain color becomes dark brown yellow, and moisture resistance can not get improving, and causes poor stability, and mobile poor, so should not adopt.
Chinese patent CN1488345A discloses a kind of production technology of ranitidine hydrochloride capsules, crude drug is that ranitidine hydrochloride, adjuvant are that starch, lubricant are magnesium stearate, supplementary material is through mixed processes, make granule, dry then, through the mixing operation, add lubricant, after filling work procedure is loaded into capsule finished product, supplementary material is made granule through the alcoholic solution that adds 50-90% behind the mixed processes as wetting agent.This patent adopts the alcoholic solution of 50-90% soft and diffusing as the granule that wetting agent makes, granule behind the granulate more than 80% has become powder, it is mobile poor to cause, be difficult for filling, and this patent adopts wet granulation, the crude drug ranitidine hydrochloride is easy to the moisture absorption deliquescence, causes variable color, influences product quality.
Chinese patent CN1795849A discloses a kind of injection prescription of freeze-drying powder of ranitidine hydrochloric acid and preparation method, its prescription is formed and is comprised ranitidine hydrochloride, lyophilized powder proppant, stabilizing agent and pH value regulator, weight fraction is 1 part of a ranitidine hydrochloride, lyophilized powder proppant 0-5 part, stabilizing agent 0-0.04 part, the preparation technology of the freeze-dried powder that employing is conventional.Chinese patent CN1621036A discloses a kind of ranitidine hydrochloride injectable powder and preparation method thereof equally, is made up of the injection supplementary material that allows on ranitidine hydrochloride and the pharmacology.Above-mentioned two patents all provide ranitidine hydrochloride lyophilized injectable powder and preparation method thereof, but because the unstability of ranitidine hydrochloride in aqueous solution, in preparating liquid and freezing dry process, can produce variable color equally, cause end product quality poor, and the production cost height of freeze-dried powder, also high to environmental requirement.
The inventor is through long-term conscientious research, beyond thought discovery is applied to a kind of novel form liposome of targeting drug delivery system in the ranitidine hydrochloride capsules agent, not only solved very easily deliquescence moisture absorption of ranitidine hydrochloride, variable color, the problem of stable difference, improve preparation drug effect and bioavailability, also can be used for treating children's's herpetic stomatitis, thereby finished the present invention.
Summary of the invention
The object of the present invention is to provide a kind of ranitidine hydrochloride lipidosome solid preparation, specifically, the combination of Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC, Tween 80 and active ingredient hydrochloric acid ranitidine by certain content, adopt the thin film dispersion technology to make ranitidine hydrochloride lipidosome, and then and certain adjuvant be mixed and made into capsule, solved very easily deliquescence moisture absorption well, variable color, the problem of stable difference, improve the drug effect and the bioavailability of preparation, obtained gratifying technique effect.
The technical scheme that the present invention solves is as follows:
The invention provides a kind of ranitidine hydrochloride lipidosome, make by ranitidine hydrochloride, Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC and Tween 80, and calculating component by weight is: 1 part of ranitidine hydrochloride, 3～18 parts of Ovum Gallus domesticus Flavus lecithins, 0.3～9 part in cholesterol, 0.5～10 part of NaGC, 0.5～15 part of Tween 80.
As the present invention's one preferred embodiment, above-mentioned described ranitidine hydrochloride lipidosome calculates component by weight and is: 1 part of ranitidine hydrochloride, 5～9 parts of Ovum Gallus domesticus Flavus lecithins, 0.5～5 part in cholesterol, 1～6 part of NaGC, 1～4 part of Tween 80.
As preferably, above-mentioned described ranitidine hydrochloride lipidosome, it is characterized in that making liposome by the method that comprises the steps: (1) is dissolved in Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC in the solvent, mix homogeneously, removing desolvates makes immobilized artificial membrane; (2) add the buffer salt solution stirring and make the complete aquation of immobilized artificial membrane, make the blank liposome suspension; (3) with ranitidine hydrochloride and Tween 80 is water-soluble or buffer salt solution after add in the blank liposome suspension, make the ranitidine hydrochloride lipidosome suspension; (4), promptly get ranitidine hydrochloride lipidosome with suspension lyophilization or spray drying.
Wherein, described buffer salt solution, be preferably the pharmaceutically acceptable buffer salt solution of pH value 4.0～5.0, for example buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, carbonate buffer solution, borate buffer solution, the acetate buffer; The described buffer salt solution of preferred adding is 10～35 weight portions.
Above-mentioned described ranitidine hydrochloride lipidosome, wherein, described solvent is an organic solvent, for example is selected from ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more, preferred solvent is an ethanol.
As preferably, above-mentioned described ranitidine hydrochloride lipidosome wherein, adds buffer salt solution and stirs and make the complete aquation of immobilized artificial membrane in the preferred steps (2), and reuse tissue mashing machine spare matter emulsifying, the one-tenth liposome turbid liquor; Further, preferably wherein in the step (3) with ranitidine hydrochloride and Tween 80 is water-soluble or buffer salt solution after add in the blank liposome suspension, be incubated 55-65 ℃, reuse tissue mashing machine spares matter emulsifying 10-30min, gets the ranitidine hydrochloride lipidosome suspension.
Further, as one of most preferred embodiment of the present invention, above-mentioned described ranitidine hydrochloride lipidosome, be to make by the method that comprises the steps: (1) is dissolved in Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC in the ethanol, mix homogeneously, ethanol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane; (2) add the buffer salt solution stirring and make the complete aquation of immobilized artificial membrane,, make the blank liposome suspension with the even matter emulsifying of tissue mashing machine; (3) ranitidine hydrochloride and Tween 80 is water-soluble, add in the blank liposome suspension, be incubated 55-65 ℃, reuse tissue mashing machine spares matter emulsifying 10-30min, gets the ranitidine hydrochloride lipidosome suspension; (4), promptly get ranitidine hydrochloride lipidosome with suspension lyophilization or spray drying.
As another goal of the invention of the present invention, a kind of ranitidine hydrochloride capsules agent also is provided, it is characterized in that forming by above-mentioned described ranitidine hydrochloride lipidosome and pharmaceutically acceptable other adjuvants; Preferred described capsule is to be made by following component by weight: 1 part of ranitidine hydrochloride lipidosome, 0.2～0.6 part of filler, 0～0.2 part of disintegrating agent, 0.01～0.08 part of binding agent, 0.01～0.03 part of lubricant.
As preferably, wherein:
Described filler is selected from one or more in microcrystalline Cellulose, lactose, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate;
Described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, the cross-linking sodium carboxymethyl cellulose;
Described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, the sodium carboxymethyl cellulose;
Described lubricant is selected from one or more in Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate etc.
Further, the preparation method of above-mentioned described ranitidine hydrochloride capsules agent comprises the steps:
(1) ranitidine hydrochloride lipidosome is pulverized, crossed 80 mesh sieves, standby;
(2) filler, disintegrating agent are pulverized, crossed 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add binding agent system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate;
(4), make the ranitidine hydrochloride capsules agent with the dried granules filled capsules.
The present invention also provides the application of ranitidine hydrochloride lipidosome capsule in treatment children's herpetic stomatitis.
The present invention makes ranitidine hydrochloride lipidosome by suitable excipients and supplementary material proportioning, makes the ranitidine hydrochloride capsules agent with conventional adjuvant pharmaceutically again.Ranitidine hydrochloride lipidosome provided by the invention and ranitidine hydrochloride capsules agent compared with prior art, have beyond thought effect, and major advantage is as follows:
(1) can solve the easy deliquescence moisture absorption of ranitidine hydrochloride simultaneously, poor problem is stablized in variable color, has improved the drug effect and the bioavailability of preparation, has guaranteed product quality;
(2) used Ovum Gallus domesticus Flavus lecithin, cholesterol, Tween 80 and NaGC degradation in vivo, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(3) production technology is simple, and cost is low, can industrial-scale production.
Ranitidine hydrochloride lipidosome capsule provided by the invention carries out stability test and investigates, and accelerated test is 6 months under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, and every detection index does not have significant change.
Ranitidine hydrochloride lipidosome capsule provided by the invention carries out acute toxicity test, abnormal toxicity test and heat source check, and is all up to specification, and safety obtains proof.
The specific embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.
Embodiment 1
The preparation of ranitidine hydrochloride lipidosome
Prescription: ranitidine hydrochloride 150g
Ovum Gallus domesticus Flavus lecithin 750g
Cholesterol 75g
NaGC 150g
Tween 80 150g
Preparation technology
(1) 750g Ovum Gallus domesticus Flavus lecithin, 75g cholesterol, 150g NaGC are dissolved in the 3000ml ethanol, mix homogeneously, ethanol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add pH=4.0 acetic acid-sodium-acetate buffer 1500ml, stir and make the complete aquation of immobilized artificial membrane, the even at a high speed matter emulsifying 20min of reuse tissue mashing machine, rotating speed 12000r/min makes the blank liposome suspension;
(3) 150g ranitidine hydrochloride and 150g Tween 80 are dissolved in the 3000ml water, add in the blank liposome suspension, be incubated 65 ℃, reuse tissue mashing machine spares matter emulsifying 10min, gets the ranitidine hydrochloride lipidosome suspension;
(4), promptly get ranitidine hydrochloride lipidosome with the suspension lyophilization.
Comparative Examples 1
The preparation of ranitidine hydrochloride lipidosome
Prescription: ranitidine hydrochloride 150g
Ovum Gallus domesticus Flavus lecithin 400g
Cholesterol 40g
NaGC 70g
Tween 80 70g
Preparation technology chooses the outer weight portion of component preferable range of the present invention and forms with embodiment 1, makes ranitidine hydrochloride lipidosome.
Embodiment 2
The preparation of ranitidine hydrochloride lipidosome
Prescription: ranitidine hydrochloride 75g
Ovum Gallus domesticus Flavus lecithin 675g
Cholesterol 375g
NaGC 450g
Tween 80 300g
Preparation technology
(1) 675g Ovum Gallus domesticus Flavus lecithin, 375g cholesterol, 450g NaGC are dissolved in the 7500ml ethanol, mix homogeneously, ethanol is removed in decompression on rotary film evaporator, makes immobilized artificial membrane;
(2) add pH=5.0 sodium dihydrogen phosphate-sodium hydrogen phosphate buffer 2500ml, stir and make the complete aquation of immobilized artificial membrane, the even at a high speed matter emulsifying 10min of reuse tissue mashing machine, rotating speed 15000r/min makes the blank liposome suspension;
(3) 75g ranitidine hydrochloride and 300g Tween 80 are dissolved in the 4000ml water, add in the blank liposome suspension, be incubated 55 ℃, reuse tissue mashing machine spares matter emulsifying 30min, gets the ranitidine hydrochloride lipidosome suspension;
(4), promptly get ranitidine hydrochloride lipidosome with the suspension spray drying.
Comparative Examples 2
The preparation of ranitidine hydrochloride lipidosome (preparation technology's difference)
Prescription: ranitidine hydrochloride 75g
Ovum Gallus domesticus Flavus lecithin 675g
Cholesterol 375g
NaGC 450g
Tween 80 300g
Preparation technology
(1) 75g ranitidine hydrochloride, 675g Ovum Gallus domesticus Flavus lecithin, 375g cholesterol, 450g NaGC and 300g Tween 80 are dissolved in the 10000ml ethanol, mix homogeneously, add pH=5.0 sodium dihydrogen phosphate-sodium hydrogen phosphate buffer 2500ml, the even at a high speed matter emulsifying 10min of tissue mashing machine, rotating speed 15000r/min, ethanol is removed in decompression, gets the ranitidine hydrochloride lipidosome suspension;
(2), promptly get ranitidine hydrochloride lipidosome with the suspension spray drying.
Embodiment 3
The preparation of ranitidine hydrochloride capsules
Ranitidine hydrochloride lipidosome (in ranitidine) 75g
Microcrystalline Cellulose 75g
Lactose 50g
30 POVIDONE K 30 BP/USP 30 5g
Pulvis Talci 5g
Preparation technology
(1) liposome that will contain the 75g ranitidine hydrochloride is pulverized, and crosses 80 mesh sieves, and is standby;
(2) take by weighing 75g microcrystalline Cellulose, 50g lactose, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 5% 30 POVIDONE K 30 BP/USP
3080% alcoholic solution 100ml makes soft material, and cross 20 mesh sieves and granulate, 60 ℃ of oven dry, 18 mesh sieve granulate get the ranitidine hydrochloride granule;
(4), make the ranitidine hydrochloride capsules agent with the dried granules filled capsules.
Embodiment 4
The preparation of ranitidine hydrochloride capsules
Ranitidine hydrochloride lipidosome (in ranitidine) 75g
Mannitol 150g
Lactose 225g
Carboxymethylstach sodium 60.5g
30 POVIDONE K 30 BP/USP 30 10g
Colloidality silica 1 5g
Preparation technology
(1) liposome that will contain the 75g ranitidine hydrochloride is pulverized, and crosses 80 mesh sieves, and is standby;
(2) take by weighing 150g mannitol, 225g lactose, 60.5g carboxymethylstach sodium, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 5% 30 POVIDONE K 30 BP/USP
3080% alcoholic solution system soft material is crossed 20 mesh sieves and is granulated, and 55 ℃ of oven dry add 15g colloidality silicon dioxide mix homogeneously, and 18 mesh sieve granulate get the ranitidine hydrochloride granule;
(4), make the ranitidine hydrochloride capsules agent with the dried granules filled capsules.
Embodiment 5
The preparation of ranitidine hydrochloride capsules
Ranitidine hydrochloride lipidosome (in ranitidine) 75g
Microcrystalline Cellulose 185g
Hypromellose 3g
Colloidality silicon dioxide 4g
Pulvis Talci 4g
Preparation technology
(1) liposome that will contain the 75g ranitidine hydrochloride is pulverized, and crosses 80 mesh sieves, and is standby;
(2) take by weighing the 185g microcrystalline Cellulose, cross 80 mesh sieves, mix, standby;
(3) with above-mentioned supplementary material mix homogeneously, add 2% hypromellose, 60% alcoholic solution system soft material, cross 20 mesh sieves and granulate, 65 ℃ of oven dry, add 4g colloidality silicon dioxide and 4g Pulvis Talci magnesium stearate mix homogeneously, 18 mesh sieve granulate get the ranitidine hydrochloride granule;
(4), make the ranitidine hydrochloride capsules agent with the dried granules filled capsules.
Test example 1
The mensuration of envelop rate
Get the Liposomal formulation of embodiment 1-2 and Comparative Examples 1-2 preparation, the total content that high performance liquid chromatography detects ranitidine is M, selects for use column chromatography to separate liposome.
Get 1.5g sephadex G-50, soak more than the swelling 12h with the pH6.8 phosphate buffer, pack in the chromatographic column (200 * 10mm) into, with above-mentioned phosphate buffer flushing balance, getting the ranitidine hydrochloride lipidosome that embodiment 1-2 and Comparative Examples 1-2 obtain respectively is dissolved in water, make the solution that every 1ml contains the about 15mg of ranitidine, get solution 1.8ml adding chromatography respectively and live the top, with phosphate buffer 50ml eluting, flow velocity 1.0ml/min, the eluent of collecting adds rupture of membranes agent (ethanol: 50ml benzyl alcohol=6: 1), mixing, the content M of high performance liquid chromatography detection ranitidine
1
Envelop rate %=M
1/ M * 100%.
Table 1 entrapment efficiency determination result
By above result as can be known, the liposome encapsulation that the present invention makes is very high, meets the actual production requirement substantially; The liposome encapsulation that the Comparative Examples of the Comparative Examples of proportioning and Different Preparation makes and the scope of the invention is write out a prescription outward is very low, has compared tangible gap with embodiment, is not suitable for production requirement.
Test example 2
The detection of particle diameter
Get the liposome of embodiment 1-2 and Comparative Examples 1-2 preparation, adopt micro-image analyzer to measure the particle size distribution of liposome, result such as table 2:
Table 2 particle diameter testing result
By above result as can be known, the liposome that embodiment 1-2 makes shows spherical, ellipticity, and particle diameter is even, and scope is 100-200nm; The liposome shape that Comparative Examples 1-2 makes is indefinite, not of uniform size, and particle diameter is inhomogeneous, and scope is 400-800nm.
Test example 3
Stability test
Get ranitidine hydrochloride capsules agent and (Beijing Qin Wu Tian Pharmaceutical Co., Ltd.'s production of listing preparation ranitidine hydrochloride capsules that embodiment 3-5 makes, lot number 081108), under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the result is as follows:
Table 3 accelerated test is investigated
By above result as can be known, after the accelerated test 6 months, significant change does not take place in sample dissolution, content and the related substance of embodiment of the invention 3-5, and listing formulation content and dissolution decline are bigger, related substance raises obviously, illustrates that the ranitidine hydrochloride lipidosome that the present invention makes has improved its stability of formulation.
Test example 4
Clinical trial
1, case is selected:
This is organized 280 routine infants and all is divided into treatment at random organizes 120 examples after examining, matched group 80 examples, listing matched group 80 examples; Make a definite diagnosis for diagnostic criteria according to Chu Futang " Practical science ".Male 90 examples are organized in treatment, women 30 examples, 8 years old～10 years old 98 example, 10～12 years old 22 example.Matched group man 68 examples, women 12 examples, 8 years old～10 years old 57 example, 10～12 years old 23 example, listing sample sets man 54 examples, women 26 examples, 8 years old～10 years old 52 example, 10～12 years old 28 example.
2, clinical symptoms:
280 routine herpetic infants all have tangible herpesvirus infection symptom, and its clinical manifestation sees Table 4.
Table 4 280 routine herpetic stomatitis symptoms and sign (example, %)
Three groups of patients difference in sex, age and clinical manifestation does not have significance (P＞0.05) and has comparability.
3, therapeutic scheme:
Three groups of patients all give the vitamin B complex injection intravenous drip in treatment, the treatment group adds with XILEI SAN and is coated with mouth, every day 3～5 times, the ranitidine hydrochloride capsules 150mg of the oral embodiment of the invention 3 preparations, 2 times on the one; Listing sample group gives mouth care, the ranitidine hydrochloride capsules (lot number 081108) that simultaneously oral Beijing Qin Wu Tian Pharmaceutical Co., Ltd. produces, each 150mg, 2 times on the one.Continuous use carries out observation of curative effect after 5 days.
4, clinical test results
Efficacy determination
(1) recovery from illness: whole body and local symptom disappear; (2) produce effects: do not have heating, herpes and ulcer sx still have poor appetite; (3) invalid: symptom does not have alleviation.
Three group of 280 routine patient treatment after 5 days its observed result see Table 5.
Three groups of patient's herpetic stomatitis of table 5 therapeutic outcome (routine %)
Annotate: compare with matched group: ★ P＜0.05; Compare with the listing sample: △ P＜0.05.
As seen from the above table: treatment group 99 examples of fully recovering, effective percentage is 99.17%, matched group 50 examples of fully recovering, effective percentage is 78.75%, the treatment group has been compared significant difference with matched group, P＜0.05; Listing sample group 62 examples of fully recovering, effective percentage is 95%, the treatment group has significant difference, P＜0.05 with listing sample group than on cure rate.
In sum, the ranitidine hydrochloride lipidosome capsule determined curative effect of the present invention's preparation can be used for treating herpetic stomatitis.
According to the above embodiments the present invention has been made detailed description.It should be noted that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (11)
1. ranitidine hydrochloride lipidosome, it is characterized in that making by ranitidine hydrochloride, Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC and Tween 80, and calculating component by weight is: 1 part of ranitidine hydrochloride, 5～9 parts of Ovum Gallus domesticus Flavus lecithins, 0.5～5 part in cholesterol, 1～6 part of NaGC, 1～4 part of Tween 80; And make liposome by the method that comprises the steps: (1) is dissolved in Ovum Gallus domesticus Flavus lecithin, cholesterol, NaGC in the solvent, mix homogeneously, and removing desolvates makes immobilized artificial membrane;
(2) add the buffer salt solution stirring and make the complete aquation of immobilized artificial membrane, make the blank liposome suspension;
(3) with ranitidine hydrochloride and Tween 80 is water-soluble or buffer salt solution after add in the blank liposome suspension, make the ranitidine hydrochloride lipidosome suspension; (4), promptly get ranitidine hydrochloride lipidosome with suspension lyophilization or spray drying.
2. ranitidine hydrochloride lipidosome according to claim 1, wherein said buffer salt solution are the pharmaceutically acceptable buffer salt solution of pH value 4.0～5.0.
3. ranitidine hydrochloride lipidosome according to claim 2, wherein said buffer salt solution is selected from one or more in phosphate buffer, citrate buffer, the acetate buffer.
4. according to each described ranitidine hydrochloride lipidosome of claim 1-3, wherein adding described buffer salt solution is 10～35 weight portions.
5. according to each described ranitidine hydrochloride lipidosome of claim 1-3, wherein said solvent is an organic solvent, and is selected from ethanol, methanol, the tert-butyl alcohol, n-butyl alcohol, isopropyl alcohol, acetone, ether, benzyl alcohol, the normal hexane one or more.
6. according to each described ranitidine hydrochloride lipidosome of claim 1-3, wherein, add the buffer salt solution stirring in the step (2) and make the complete aquation of immobilized artificial membrane, reuse tissue mashing machine spares matter emulsifying, becomes liposome turbid liquor; Perhaps, wherein in the step (3) with ranitidine hydrochloride and Tween 80 is water-soluble or buffer salt solution after add in the blank liposome suspension, be incubated 55-65 ℃, reuse tissue mashing machine spares matter emulsifying 10-30min, must the ranitidine hydrochloride lipidosome suspension.
7. ranitidine hydrochloride capsules agent is characterized in that being made up of each described ranitidine hydrochloride lipidosome of claim 1-6 and pharmaceutically acceptable other adjuvants.
8. ranitidine hydrochloride capsules agent according to claim 7, it is made by following component by weight: 1 part of ranitidine hydrochloride lipidosome, 0.2～0.6 part of filler, 0～0.2 part of disintegrating agent, 0.01～0.08 part of binding agent, 0.01～0.03 part of lubricant.
9. ranitidine hydrochloride capsules agent according to claim 8, wherein: described filler is selected from one or more in microcrystalline Cellulose, lactose, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate; Perhaps described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, the cross-linking sodium carboxymethyl cellulose; Perhaps described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, the sodium carboxymethyl cellulose; Perhaps described lubricant is selected from one or more in Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate.
10. method for preparing claim 8 or 9 described ranitidine hydrochloride capsules agent, it comprises the steps: that (1) pulverize ranitidine hydrochloride lipidosome, crosses 80 mesh sieves, and is standby; (2) filler, disintegrating agent are pulverized, crossed 80 mesh sieves, mix, standby; (3) with above-mentioned supplementary material mix homogeneously, add binding agent system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate; (4), make the ranitidine hydrochloride capsules agent with the dried granules filled capsules.
11. be used for the treatment of application in children's's herpetic stomatitis medicine in preparation according to each described ranitidine hydrochloride capsules agent of claim 7-9.
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| CN101816640B (en) * | 2010-04-16 | 2012-01-11 | 海南美大制药有限公司 | Prasugrel liposome solid preparation |
| CN101862329B (en) * | 2010-06-29 | 2012-02-22 | 王明 | Amlodipine besylate and atorvastatin calcium medicine compound liposome solid preparation |
| CN103315970B (en) * | 2013-07-16 | 2015-03-25 | 成都天台山制药有限公司 | Ranitidine hydrochloride powder injection for injection |
| CN104906069A (en) * | 2015-05-26 | 2015-09-16 | 苗怡文 | Medicinal ranitidine hydrochloride composition capsule for treating gastric ulcer |
| CN104873484A (en) * | 2015-05-26 | 2015-09-02 | 苗怡文 | Medicine, namely, ranitidine hydrochloride composition capsule, for treating digestive system disease |
| CN108670959A (en) * | 2018-06-30 | 2018-10-19 | 郑州明泽医药科技有限公司 | A kind of ranitidine hydrochloride capsules and preparation method thereof |
| CN115177598A (en) * | 2022-07-29 | 2022-10-14 | 苏州弘森药业股份有限公司 | Ranitidine hydrochloride capsule and preparation method thereof |
| CN115518049B (en) * | 2022-11-03 | 2023-02-17 | 则正(济南)生物科技有限公司 | Ranitidine hydrochloride capsule and preparation method thereof |
| CN115957192A (en) * | 2023-02-08 | 2023-04-14 | 成都乾坤动物药业股份有限公司 | Preparation method of nitrochlorophenol tablet and nitrochlorophenol compound tablet |
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| CN1488345A (en) * | 2003-07-31 | 2004-04-14 | 雅来（佛山）制药有限公司 | Ranitidine hydrochloride capsule producing process |
| CN1554354A (en) * | 2003-12-23 | 2004-12-15 | 中国药科大学 | Epi-doxorubicine liposome and its preparing method |
| CN1915220A (en) * | 2006-09-05 | 2007-02-21 | 南京康海药业有限公司 | Mitoxantrone or liposome of mitoxantrone hydrochloric acid, and preparation method |
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| CN101623258A (en) | 2010-01-13 |
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