CN103054828A - Ranitidine bismuth citrate intra-gastric floating sustained-release tablet and preparation method thereof - Google Patents
Ranitidine bismuth citrate intra-gastric floating sustained-release tablet and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a ranitidine bismuth citrate intra-gastric floating sustained-release tablet which is composed of a tablet core containing ranitidine bismuth citrate and a coating film wrapped over the tablet core. The tablet core is prepared from raw materials at least containing, by weight, 110 to 120 parts of ranitidine bismuth citrate, 30 to 60 parts of a skeletal material, 5 to 20 parts of a foaming agent and 45 to 130 parts of a bleaching assistant. The coating film accounts for 1 to 5% of the weight of the tablet. The tablet provided by the invention can effectively adjust the rate of constant speed release of the drug ranitidine bismuth citrate and enables a steady and lasting effective plasma concentration to be obtained, so side effects of the drug, frequency of administration and influence of the drug on an in-vivo environment are reduced, and compliance of a patient is improved.
Description
Technical field
The invention belongs to technical field of medicine, being specifically related to a kind of medicine for the treatment of peptic ulcer is bismuth citrate ranitidine intragastric floating tablets and preparation method thereof.
Background technology
Peptic ulcer (peptic ulcer, PU) is a kind of very easily chronic disease of recurrence.Because modern life rhythm and operating pressure strengthen day by day, and the corticosteroids drug dependence, cause the PU sickness rate constantly to rise.The sickness rate of whole world digestive system accounts for the mankind's 10%～12%, and the sickness rate of China's cities and towns digestive system is about 11.43%, with the many developed countries of America and Europe basic simlarity.The effective ways that thorough radical cure is not yet arranged at present, this has become one of emphasis problem of field of medicaments research.Current medicine mainly comprises antacid, anticholinergic, histamine H
2Receptor antagonist, proton pump H
+, K
+-atpase inhibitor, pepsin inhibitor, gastrin receptor antagonist, prostaglandin and derivant (PGE) and inhibition helicobacter pylori medicine etc.Since PU is a state of an illness prolongs continuous complicated, relapse rate is high, the course for the treatment of is long, the common property disease of the prolonged and repeated medication of need, due to illness feelings increase the weight of or treat untimelyly, can cause the consequences such as hemorrhage, perforation, pyloric obstruction and canceration, the serious harm people ' s health.Therefore, people can be detained at gastric for a long time to long-acting, side effect less, and there is urgent demand in the pharmaceutical preparation of playing simultaneously the treatment PU of anti-gastric acid secretion and protection gastric mucosa dual function.
Bismuth citrate ranitidine (RBC) is ranitidine and the formed salt of bismuth citrate chemical combination; it is a kind of novel compound; have unique chemical constitution and physicochemical property; have stronger hygroscopicity, light and heat unstability; clinical practice is the result show, and: RBC has good anti-gastric acid secretion and to the dual function of gastric mucosal protection; can also infecting by eliminating pylorus in conjunction with the use of antibiotics simultaneously, is a kind of effective anti-digestive system and ulcer medicine.Than ranitidine and its advantage of bismuth citrate be: simple bismuth citrate and ranitidine mixture are water-fast suspended matters, the absorption of digestive tract cell membrane can not effectively be seen through after entering gastrointestinal tract, and RBC has the high water soluble energy under low pH value condition, particularly stomach effectively stripping be fully absorbed, improve drug bioavailability, therefore, this medicine has good clinical effectiveness, in a sense, has widely market prospect.
The general formulation of RBC at home and abroad all goes on the market, at first by the development and production of Britain Glaxo-Wellcome company, and commodity Pylorid by name or Tritec.And in nineteen ninety-five at first in Britain listing, obtained the approval of U.S. FDA, domestic RBC(trade name in 1999: auspicious times in 1996) at Discussion on Chinese Listed.20 several countries use RBC in the world at present.The RBC general formulation product that has gone on the market in China mainly contains two pharmaceutical factories, is respectively beautiful pearl pharmacy and Changzhou Lan Ling pharmacy, and it is not long at gastric transit time, and patient's medicining times is more, and poor compliance, current its slow release formulation be listing at home and abroad not.And slow release formulation is compared with ordinary preparation, can reduce the common blood concentration fluctuation phenomenon of ordinary tablet, reaches better therapeutic effect, takes every day once, can reach 24 hours curative effect, and the active chemical in the medicine can relatively more lasting and stably discharge.Therefore developing the RBC slow releasing preparation will have good social effect and economic benefit.
Summary of the invention
The present invention is the weak point that overcomes existing preparation, exploitation day clothes RBC intragastric floating tablets once.Can effectively adjust the speed of medicine constant release, obtain comparatively steady and lasting effective blood drug concentration, thereby reduce the impact of the internal milieu of side effects of pharmaceutical drugs and medicining times and medicine, improve patient's compliance.
A kind of bismuth citrate ranitidine (the following RBC that is called for short) intragastric floating tablets, the coating membrane outer with being wrapped in label by the label that contains bismuth citrate ranitidine forms; By weight, described label is prepared from by the raw material that contains at least 45～130 parts of 110～120 parts of bismuth citrate ranitidines, 30～60 parts of framework materials, 5～20 parts of foaming agents and bleach activators.
Bismuth citrate ranitidine of the present invention (the following RBC of abbreviation) can adopt prior art disclosed any, its preparation method same dawn known to those skilled in the art.Bismuth citrate ranitidine is preferably from the raw material of beautiful pearl synthesis pharmaceutical company limited among the present invention, the accurate word H19991148 of traditional Chinese medicines, its concrete preparation method sees Chinese invention patent " a kind of method for preparing bismuth citrate ranitidine " for details, application number is 200610103786.5, the mandate publication number is CN1903850A, and the applying date is on August 1st, 2006.
Bismuth citrate ranitidine intragastric floating tablets of the present invention, described framework material is selected from one or more in HPMC, ethyl cellulose, the polyvidone; Described foaming agent is selected from one or more in sodium bicarbonate, calcium carbonate, the magnesium carbonate, is preferably sodium bicarbonate; Described bleach activator is one or more in hydrogenated vegetable oil, octadecanol, glyceryl monostearate, the stearic acid, is preferably octadecanol.
As a kind of preferred implementation of the present invention, described label is prepared from by the raw material that contains at least bismuth citrate ranitidine 110-120 part, 40～50 parts of framework materials, bleach activator 80-120 part, foaming agent 6-10 part; Wherein framework material is preferably HPMC15000SR and/or HPMC100000SR, bleach activator is that octadecanol, foaming agent are sodium bicarbonate; More preferably described label is prepared from by the raw material that contains at least 114 parts of bismuth citrate ranitidines, HPMC15000SR30 part, HPMC100000SR15 part, 120 parts of octadecanol, 6 parts of sodium bicarbonate.
The label of RBC intragastric floating tablets of the present invention can only comprise RBC, framework material and be easy to the adjuvant of drug release, but also comprises 1-3 part lubricant and 2-8 part binding agent in order to make the easier molding of preparation, to be preferably.
Described lubricant is one or more in magnesium stearate, Pulvis Talci, stearic acid, the micropowder silica gel, preferred magnesium stearate, Pulvis Talci; Described binding agent is one or more in polyvinylpyrrolidone, water, the dehydrated alcohol, preferred dehydrated alcohol.
Coating membrane of the present invention is dissolved in the solvent with coating material, plasticizer and lubricant and forms coating solution and coating forms to label, described coating membrane account for total sheet heavy 1%～5%, preferred 2-4%.More specifically, preferred described coating material is one or more in Eudragit RS100, EudragitRL100, hydroxyethyl-cellulose, polyvinyl alcohol, cellulose acetate, the ethyl cellulose, and described solvent is one or more in ethanol, water, the acetone; Described plasticizer is triethyl citrate; Described lubricant is Pulvis Talci; More preferably coating material is Eudragit RS100 and RL100; The amount ratio of the two is preferably 1:1.
Described coating solution is with coating material Eudragit RS100 12.5-17.5 part, EudragitRL100 12.5-17.5 part, triethyl citrate 2-4 part, Pulvis Talci 6-9 part, solubilizer ethanol to 500 part is prepared from, preferably with coating material Eudragit RS10030 part, 3 parts of triethyl citrates of 15 parts of addings of RL100,7.5 parts of Pulvis Talci, solubilizer ethanol to 500 part is made coating solution and coating and form coating membrane to label.
Supplementary material used in the present invention is the disclosed commercially available prod of prior art or known product, and the present invention is not particularly limited this.
The present invention adopts take hydroxypropyl methylcellulose (HPMC) as the sustained-release matrix material, take octadecanol as bleach activator, take sodium bicarbonate as foaming agent, take dehydrated alcohol as binding agent, take magnesium stearate as lubricant, take acrylic resin RS100(Eudragit RS100) and acrylic resin RL100(Eudragit RL100) be the sustained release coating material, make hydrogel matrix type intragastric floating tablets, successfully prepare clinical use safety, good stability, long-acting RBC intragastric floating tablets, satisfied clinical needs.
The second purpose of the present invention is to provide a kind of preparation method of RBC intragastric floating tablets, and this preparation method comprises the steps:
(1) preparation of label: bismuth citrate ranitidine, foaming agent and the bleach activator that takes by weighing recipe quantity be the equivalent mix homogeneously that progressively increases respectively, soft material processed or add binding agent after soft material processed; Put baking oven 40-50 ℃ dry 2-3 hour; Granulate behind direct granulate or the adding lubricant mixing; The control tablet hardness is 40-50N, with the stamping of 10-15mm scrobicula, gets label;
(2) take by weighing coating material and be dissolved in an amount of solvent, add plasticizer, get solution; In addition lubricant is dissolved in an amount of solvent, with high-shear homogenate machine homogenize 3-6min, pours in the mentioned solution, solubilizer is to full dose, and the 75-85 order sieves, and namely gets coating solution;
(3) coating.
Wherein said step (1) is preferably: it is for subsequent use that bismuth citrate ranitidine, foaming agent and bleach activator are crossed the 80-120 mesh sieve; Take by weighing the respectively equivalent mix homogeneously that progressively increases of the bismuth citrate ranitidine of recipe quantity and adjuvant, soft material processed or add binding agent after soft material processed; Cross 30 mesh sieves and granulate, put baking oven 40-50 ℃ dry 2-3 hour; Granulate behind direct granulate or the adding lubricant mixing, film-making agent hardness is 40-50N, with the stamping of 10-15mm scrobicula, gets label.
Wherein said step (2) is preferably: take by weighing coating material and be dissolved in an amount of ethanol, add the plasticizer triethyl citrate, get solution; In addition Pulvis Talci is dissolved in an amount of ethanol, with high-shear homogenate machine homogenize 3-6min, pours in the mentioned solution, add ethanol to full dose, the 75-85 order sieves, and namely gets coating solution.
Above-mentioned an amount of specifically be as the criterion to prepare the coating solution that can realize coating for those skilled in the art are understood and grasp, as material to be dissolved is fully dissolved get final product need not specific quantitatively, and the present invention is not particularly limited this.
Wherein said step (3) is preferably: label is placed coating pan, 35 °-45 ° at inclination angle, spray gun apart from the sheet bed apart from 8-12cm, nozzle diameter 0.8-1.2mm is the pancake spraying, 30-35 ℃ of sheet bed tempertaure, jet pressure, 0.12-0.13MPa, hydrojet speed 3-6g/min, coating pan rotating speed 20-30r/min, at the uniform velocity coating to weightening finish accounts for till the heavy 1%-5% of sheet, after coating is finished, slice, thin piece is placed in the tray, place 36-42 ℃ of dry 1.5-2.5h, and get final product.
Further, described step (3) is preferably: label is placed coating pan, 40 ° at inclination angle, apart from 10cm, nozzle diameter 1.0mm is the pancake spraying to spray gun apart from the sheet bed, 30-35 ℃ of sheet bed tempertaure, whiff pressure 0.125MPa, hydrojet speed 5g/min, coating pan rotating speed 25r/min,, at the uniform velocity coating to weightening finish accounts for till the heavy 2%-4% of sheet, after coating is finished, slice, thin piece is placed in the tray, places 40 ℃ of dry 2h.
Because this medicine day, dosage was large, will be prepared into the gastric floating slow-release tablet form simultaneously, showed that in process of preparing is groped film coated slow release effect is better, but floatation characteristic is difficult to control.Although and the control of the release in matrix tablet slow release effect early stage and later stage has technical difficulty, can reach and the ratio of the adjuvant of other screenings is controlled effectively by framework material consumption in the adjustment sheet.Adopt matrix tablet can guarantee prominent releasing in medicine early stage, the interlude release is steady, and the later stage release is complete.So adopt the matrix type slow release method that can satisfy slow release and floating characteristic simultaneously as the slow release method of this medicine.
The increase of lightweight supplementary product consumption is conducive to floating, but is not that consumption is The more the better.Consumption can make too greatly the rate of release of medicine excessively slow, it's the end causes to past human body blood drug level, causes bioavailability and curative effect to descend.Can not realize to adopt foaming agent and lightweight adjuvant use in conjunction when floating when alone lightweight adjuvant, satisfy the demand.The present invention has adopted foaming agent and lightweight adjuvant.
Octadecanol is hydrophobicity and the little aliphatic alcohols of relative density, can not only play floating effect can improve simultaneously slice, thin piece under one's belt hold the power of floating; Sodium bicarbonate is met acid, produces CO
2Gas forms bubble in tablet surface, helps to alleviate the apparent density of tablet, has increased the power of floating; The HPMC water absorption and swelling forms hydrogel, and volume increases, and the tablet apparent density also reduces thereupon, is conducive to keep the power of floating of holding of tablet.
Because the RBC dosage is large, used lightweight adjuvant ratio causes greatly the slice, thin piece poor compressibility simultaneously, the compressibility that increases slice, thin piece is the problem of technological factor significant concern, but increases simultaneously the showy performance that pressure can affect slice, thin piece, so also be very crucial to the control of the hardness of slice, thin piece.
In order to obtain technical scheme of the present invention, the inventor has carried out a large amount of tests, has investigated in the prescription, and the viscosity of HPMC and consumption are on the impact of drug release; Octadecanol, the consumption of sodium bicarbonate is on the impact of drug release; The consumption of bonding agent and lubricant is on the impact of drug release.Full pressed powder and wet granule compression tablet, different hardness and granulation sieve number have been compared in the technological factor to the impact of sustained-release tablets release.Specifically see test example 1 ~ 13.
Adopt technique scheme, the invention has the advantages that: adopt vertical compression and method of granulating that heavy dose of medicine RBC is prepared into slow releasing tablet, by adjusting label and/or coating membrane prescription, can effectively adjust the speed of medicine constant release, obtain comparatively steady and lasting effective blood drug concentration, thereby the side effect that the peak valley phenomenon that reduces medicine blood drug level causes reduces medicining times, improves patient's compliance.
Description of drawings
Fig. 1 is that the proportioning of Eudragit RS100 and RL100 is on the impact (n=6) of release in vitro;
Fig. 2 is that different coating weightening finishes are on the impact (n=6) of release in vitro;
Fig. 3 is that the specification of HPMC is on the impact (n=6) of release in vitro;
Fig. 4 is that the different proportionings of HPMC are on the impact (n=6) of release in vitro;
Fig. 5 is the release profiles of not commensurability HPMC;
Fig. 6 is that different lightweight adjuvants are on the impact of release in vitro;
Fig. 7 is that different foaming agents are on the impact of release in vitro;
Fig. 8 is the release profiles (n=6) of different octadecanol ratio content;
Fig. 9 is that the NaHCO3 consumption is on the impact (n=6) of release in vitro;
Figure 10 is that lubricant quantity is on the impact of drug release;
Figure 11 is that wet granulation and dry granulation are on the impact of drug release;
Figure 12 is that hardness is on the impact of drug release.
The specific embodiment
Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.
The preparation of embodiment 1RBC intra-gastric floating tablet
Label prescription: RBC raw material 228g, octadecanol 240g, HPMC 15000SR 60g, HPMC 100000SR 30g, NaHCO
312g, micropowder silica gel 2g, magnesium stearate 2g, dehydrated alcohol 10g.
The coating membrane coating material is: Eudragit RS100, each 30g of RL100, triethyl citrate 6g, Pulvis Talci 15g, ethanol 919g.
Preparation method:
It is for subsequent use that crude drug and adjuvant are crossed 100 mesh sieves; Take by weighing the respectively equivalent mix homogeneously that progressively increases of the raw material of recipe quantity and adjuvant, it is an amount of to add binding agent, soft material processed.Cross 30 mesh sieves and granulate, put 45 ℃ of dry 2-3 of baking oven hours.24 mesh sieve granulate add lubricant (micropowder silica gel of equivalent and magnesium stearate) mixing; The control tablet hardness is at 40～50N, with the stamping of 12mm scrobicula; Namely get label.
Take by weighing in proportion in the ethanol that coating material is dissolved in 500g, add the 6g triethyl citrate; In addition the 15g Pulvis Talci is dissolved in an amount of ethanol, with high-shear homogenate machine homogenize 5min, pours in the mentioned solution, add ethanol to 1000g, 80 mesh sieves filter, and namely get coating solution.
Label is placed coating pan, inclination angle 40 degree, spray gun apart from the sheet bed apart from 10cm, nozzle diameter 1.0mm is the pancake spraying, 30-35 ℃ of sheet bed tempertaure, whiff pressure 0.125MPa, hydrojet speed 5g/min, coating pan rotating speed 25r/min, at the uniform velocity coating to the weightening finish account for sheet heavy 3% till, after coating is finished, slice, thin piece is placed in the tray, places 40 ℃ of dry 2h, and get final product.
The preparation of embodiment 2RBC intra-gastric floating tablet
Label prescription: RBC raw material 228g, octadecanol 240g, HPMC 15000SR 40g, HPMC 100000SR 20g, NaHCO
312g, magnesium stearate 4g, dehydrated alcohol 10g.
The coating membrane coating material is: Eudragit RS100, each 30g of RL100, triethyl citrate 6g, Pulvis Talci 15g, ethanol 919g.
Preparation method:
It is for subsequent use that crude drug and adjuvant are crossed 80 mesh sieves; Take by weighing the respectively equivalent mix homogeneously that progressively increases of the raw material of recipe quantity and adjuvant, it is an amount of to add binding agent, soft material processed.Cross 30 mesh sieves and granulate, put 50 ℃ of dryings of baking oven 2 hours.24 mesh sieve granulate add the lubricant mixing; The control tablet hardness is at 40～50N, with the stamping of 12mm scrobicula; Namely get label.
Take by weighing in proportion in the ethanol that coating material is dissolved in 500g, add the 6g triethyl citrate; In addition the 15g Pulvis Talci is dissolved in an amount of ethanol, with high-shear homogenate machine homogenize 3min, pours in the mentioned solution, add ethanol to 1000g, 85 mesh sieves filter, and namely get coating solution.
Label is placed coating pan, inclination angle 40 degree, spray gun apart from the sheet bed apart from 10cm, nozzle diameter 1.0mm is the pancake spraying, 30-35 ℃ of sheet bed tempertaure, whiff pressure 0.125MPa, hydrojet speed 5g/min, coating pan rotating speed 25r/min, at the uniform velocity coating to the weightening finish account for sheet heavy 3% till, after coating is finished, slice, thin piece is placed in the tray, places 40 ℃ of dry 2h, and get final product.
The preparation of embodiment 3RBC intra-gastric floating tablet
Label prescription: RBC raw material 228g, octadecanol 240g, HPMC 15000SR 80g, HPMC 100000SR 40g, NaHCO
312g, magnesium stearate 4g, dehydrated alcohol 10g.
The coating membrane coating material is: Eudragit RS100, each 30g of RL100, triethyl citrate 6g, Pulvis Talci 15g, ethanol 919g.
Preparation method:
It is for subsequent use that crude drug and adjuvant are crossed 120 mesh sieves; Take by weighing the respectively equivalent mix homogeneously that progressively increases of the raw material of recipe quantity and adjuvant, it is an amount of to add binding agent, soft material processed.Cross 30 mesh sieves and granulate, put 40 ℃ of dryings of baking oven 3 hours.24 mesh sieve granulate add the lubricant mixing; The control tablet hardness is at 40～50N, with the stamping of 12mm scrobicula; Namely get label.
Take by weighing in proportion in the ethanol that coating material is dissolved in 500g, add the 6g triethyl citrate; In addition the 15g Pulvis Talci is dissolved in an amount of ethanol, with high-shear homogenate machine homogenize 6min, pours in the mentioned solution, add ethanol to 1000g, 75 mesh sieves filter, and namely get coating solution.
Label is placed coating pan, inclination angle 40 degree, spray gun apart from the sheet bed apart from 10cm, nozzle diameter 1.0mm is the pancake spraying, 30-35 ℃ of sheet bed tempertaure, whiff pressure 0.125MPa, hydrojet speed 5g/min, coating pan rotating speed 25r/min, at the uniform velocity coating to the weightening finish account for sheet heavy 3% till, after coating is finished, slice, thin piece is placed in the tray, places 40 ℃ of dry 2h, and get final product.
The preparation of embodiment 4RBC intra-gastric floating tablet
Label prescription: RBC raw material 228g, octadecanol 240g, HPMC 15000SR 60g, HPMC 100000SR 30g, NaHCO
312g, magnesium stearate 4g, polyvinylpyrrolidone 10g.
The coating membrane coating material is: Eudragit RS100, each 30g of RL100, triethyl citrate 6g, Pulvis Talci 15g, ethanol 919g.
Preparation method: by above-mentioned prescription two parts of supplementary materials of parallel preparation respectively, press that preparation method prepares among the embodiment 1, be not both the binding agent that adds in the label and be respectively polyvinylpyrrolidone and water, and get final product.
The preparation of embodiment 5RBC intra-gastric floating tablet
Label prescription: RBC raw material 228g, octadecanol 240g, HPMC 15000SR 60g, HPMC 100000SR 30g, NaHCO
312g, lubricant 4g, dehydrated alcohol 10g.
The coating membrane coating material is:, each 17.5g of hydroxyethyl-cellulose and Polyethylene Glycol, triethyl citrate 4g, Pulvis Talci 12g, ethanol adds to 1000g.
Preparation method: by above-mentioned prescription three parts of supplementary materials of parallel preparation respectively, press that preparation method prepares among the embodiment 1, be not both the lubricant that adds in the label and be respectively Pulvis Talci, stearic acid, micropowder silica gel, and get final product.
The preparation of embodiment 6RBC intra-gastric floating tablet
Label prescription: RBC raw material 220g, octadecanol 90g, HPMC 15000SR 90g, HPMC 100000SR 30g, NaHCO
310g, present embodiment do not add lubricant and binding agent.
The coating membrane coating material is: polyvinyl alcohol, each 12.5g of ethyl cellulose, and triethyl citrate 8g, Pulvis Talci 18g, ethanol adds to 1000g.
Preparation method: by preparation method preparation among the embodiment 1 and get final product.
The preparation of embodiment 7RBC intra-gastric floating tablet
Label prescription: RBC raw material 240g, octadecanol 260g, HPMC 15000SR 40g, HPMC 100000SR 20g, NaHCO
340g, magnesium stearate 4g, dehydrated alcohol 10g.
The coating membrane coating material is: Eudragit RS100, each 30g of RL100, triethyl citrate 6g, Pulvis Talci 15g, ethanol 919g.
Preparation method: by preparation method preparation among the embodiment 1 and get final product.
The preparation of embodiment 8RBC intra-gastric floating tablet
Label prescription: RBC raw material 228g, octadecanol 240g, HPMC 15000SR 60g, HPMC 100000SR 30g, NaHCO
312g, magnesium stearate 2g, dehydrated alcohol 4g.
The coating membrane coating material is: Eudragit RS100, each 30g of RL100, triethyl citrate 6g, Pulvis Talci 15g, ethanol 919g.
Preparation method: by preparation method preparation among the embodiment 1 and get final product.
The preparation of embodiment 9RBC intra-gastric floating tablet
Label prescription: RBC raw material 228g, hydrogenated vegetable oil 240g, HPMC 15000SR 60g, HPMC 100000SR 30g, calcium carbonate 12g, micropowder silica gel 6g, polyvinylpyrrolidone 16g.
The coating membrane coating material is: Eudragit RS100, each 30g of RL100, triethyl citrate 6g, Pulvis Talci 15g, ethanol 919g.
Preparation method: by preparation method preparation among the embodiment 1 and get final product.
The preparation of embodiment 10RBC intra-gastric floating tablet
Label prescription: RBC raw material 232g, glyceryl monostearate 160g, ethyl cellulose 80g, magnesium carbonate 20g, Pulvis Talci 6g, water 12g.
The coating membrane coating material is: Eudragit RS100, each 30g of RL100, triethyl citrate 6g, Pulvis Talci 15g, ethanol 919g.
Preparation method: by preparation method preparation among the embodiment 1 and get final product.
For the further reasonability of checking sustained-release tablet recipe of the present invention and preparation method, the inventor has launched a large amount of special experimental studies, because length is limit, only exemplifies the test example of tool cogency herein.In addition, part test example checking be best-of-breed technology scheme of the present invention, those skilled in the art can predict, in the scope that has comprised the best-of-breed technology scheme, the adjustment of appropriateness or float and also can be used in realization the present invention.
The proportioning of test example 1 coating material is on the impact of drug release
On the basis of embodiment 1 label prescription, fixing Eudragit RS100, the RL100 consumption is for being total to 60g, respectively take the proportioning of Eudragit RS100 and RL100 as 2:3,1:1,3:2, according to embodiment 1 preparation technology, other supplementary material amounts and the constant preparation sustained release coating of technique tablet are measured vitro release according to following " vitro release assay method ", measure flotation property according to following " external flotation property assay method ".
The vitro release assay method: sample thief is an amount of, according to drug release determination method (two appendix XD of 2010 editions pharmacopeia first method), adopt the dissolution method first device, take the hydrochloric acid solution of pH3 as release medium, rotating speed is that per minute 50 turns, in accordance with the law operation, at 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, in the time of 24 hours, get respectively solution 10ml, filter, and in time in stripping rotor, replenish equal volume, the water of uniform temp is got subsequent filtrate, according to ultraviolet visible spectrophotometry (two appendix IVA of 2010 editions pharmacopeia), measure absorbance at the wavelength place of 314nm; It is an amount of that other gets the bismuth citrate ranitidine reference substance, accurately weighed, is dissolved in water and dilutes and make the solution that contains approximately 25 μ g among every 1ml, measures with method.Calculate respectively every in the burst size of different time.Every burst size at 2 hours, 4 hours, 8 hours, 16 hours, 24 hours of this product should be respectively labelled amount 30%, 40%, 60%, 80%, more than 90%.
External flotation property assay method: 6 of sample thiefs, drop in the 1000ml pH3 hydrochloric acid solution, temperature be (37 ± 0.5) ℃, turning the basket rotating speed is 100r/min, observes its flotation property and has comprised the time of floating and lasting floating time.
The result shows: impact has significant difference to the proportioning of Eudragit RS100 and RL100 on drug release.In the certain situation of coating polymer weightening finish, along with the increase of Eudragit RS100 proportion, rate of release slows down.This is because Eudragit RS100 is the polymer to the water hyposmosis, and Eudragit RL100 is the polymer to the high infiltration of water, when two kinds of polymer cladded in the sheet wicking surface jointly, moisture can only enter label by high permeability zones territory (being equivalent to " fenestra ") and dissolve wherein effective ingredient.The ratio of Eudragit RS100 is larger, and formed " fenestra " is just fewer, thereby dissolution rate is just slower.Thereby slice, thin piece works that to float be to enter label and wherein foaming agent by moisture by fenestra to react and produce bubble and slice, thin piece is risen float, so that slice, thin piece works the time of floating is long, floating effect is bad.The release in vitro factor (the f of Eudragit RS100 and the different proportionings of RL100
2) comparative result sees Table 1; The release in vitro curve is seen accompanying drawing 1.
The f of table 1Eudragit RS100 and the different proportionings of RL100
2The factor relatively
The weightening finish of test example 2 coatings is on the impact of drug release
Preparation technology according to embodiment 1, fix other techniques and supplementary material, respectively take the coating weightening finish as 1%, 1.5%, 2%, 2.5%, 3%, preparation sustained release coating tablet, measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: the coating weightening finish has significant difference to drug release.In the certain situation of polymer ratio, coating polymer weightening finish larger (also being that coating is thicker), then dissolution rate is slower.This is because thickening along with coating membrane, a front skim formed " fenestra " is covered by the hyposmosis district of later layer film, thereby effective " fenestra " amount of film is greatly reduced, also can make in addition moisture see through the distance prolongation that film enters label, the effect of this two aspect all makes stripping slow down.The drug release in vitro factor (the f of different coating weightening finish preparations
2) comparative result sees Table 2; The release in vitro curve is seen accompanying drawing 2.
The f of the different coating weightening finishes of table 2
2The factor relatively
The specifications and models of test example 3HPMC are on the impact of drug release
Select the HPMC of four kinds of different sizes, model is respectively HPMC90SH-100SR, 90SH-4000SR, 90SH-15000SR, 90SH-100000SR, and other supplementary material ratios remain unchanged, and prepares slow releasing tablet by preparation technology among the embodiment 1.Measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: the model of HPMC is not obvious on the floating impact of tablet, on the release in vitro impact obviously.The matrix sustained release tablet slow release effect of more low viscous 90SH-100SR, 90SH-4000SR is relatively poor, and the slow release of 90SH-15000SR, 90SH-100000SR is imitated.The speed that generally the larger medicine of water soluble drug HPMC viscosity is discharged from slow releasing tablet is slower.The variation of viscosity becomes very weak to the impact of drug release when HPMC viscosity increases to a certain degree
[21]Because low viscosity HPMC molecular weight is little, the gel skeleton intensity of formation is low to be dissoluted easily, and the gel layer that full-bodied HPMC aquation forms fast is firm, the release that can block the slice, thin piece internal drug.But it is slow that full-bodied HPMC aquation forms the low viscous HPMC of speed ratio of gel, fast in the release in early stage when 90SH-100000SR is found in experiment as gelatum skeleton material, and reason may to fail excessively slowly in time to form the slow release barrier relevant with gel layer formation.And the later stage drug release is too fast when using 90SH-15000SR separately.So consider that both are mixed use regulates rate of releasing drug.The drug release in vitro factor (the f of the specifications and models preparation of different HPMC
2) comparative result sees Table 3; The release in vitro curve is seen accompanying drawing 3.
The f of table 3 different size HPMC
2The factor relatively
The HPMC of test example 4 different proportionings is on the impact of drug release
Fixedly HPMC90SH-15000SR and 90SH-100000SR consumption be sheet heavy 20%, respectively take the proportioning of 90SH-15000SR and 90SH-100000SR as 1:1,1:2,2:1, other supplementary material amounts and technique are constant, prepare slow releasing tablet by preparation technology among the embodiment 1.Measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: HPMC90SH-15000SR and 90SH-100000SR usage ratio change very little on the floating impact of tablet; f
2＜50 explanation HPMC90SH-15000SR and 90SH-100000SR usage ratio have significant difference to drug release.When the ratio of HPMC90SH-15000SR and 90SH-100000SR is 1:1 and 1:2 the early stage release all very fast, burst drug release is obvious.When ratio is adjusted to 2:1, because the percentage ratio that accounts for of HPMC90SH-15000SR is large, can form fast the release of skeleton gel layer blocking medicine early stage in the tablet release, effectively avoid prominent and release.90SH-100000SR and 90SH-15000SR that intermediary and later stages are a small amount of play synergism, have effectively kept the slow release of medicine, are 2:1 so adopt the proportioning of HPMC 90SH-15000SR and 90SH-100000SR.The drug release in vitro factor (the f of the HPMC preparation of different proportionings
2) comparative result sees Table 4; The release in vitro curve is seen accompanying drawing 4.
The f of table 4 HPMC90SH-15000SR and the different proportionings of 90SH-100000SR
2The factor relatively
The consumption of test example 5 HPMC is on the impact of drug release
Select the ratio take HPMC90SH-15000SR:90SH-100000SR as 2:1, investigate respectively the HPMC consumption and be total sheet heavy 10%, 15%, 20%, other supplementary material amounts and technique are constant, prepare slow releasing tablet by preparation technology among the embodiment 1.Measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: along with the increase of HPMC consumption, drug release obviously slows down, and the slice, thin piece rate of releasing drug is too fast early stage when the consumption of HPMC is 10%; But release is excessively slow when the consumption of HPMC reaches 20%; The consumption of HPMC is moderate in the rate of release of 15% medicine, is 15% so select the consumption of HPMC.The drug release in vitro factor (the f of different HPMC consumption preparations
2) comparative result sees Table 5; The release in vitro curve is seen accompanying drawing 5.
Table 5 is the f of commensurability HPMC not
2The factor relatively
Test example 6 different lightweight adjuvants (bleach activator) are on the impact of drug release
Take hydrogenated vegetable oil, octadecanol, glyceryl monostearate, stearic acid as bleach activator, fixedly consumption is 40% of slice, thin piece weight respectively, and other supplementary material amounts and technique are constant, prepares slow releasing tablet by preparation technology among the embodiment 1.Measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: float with the stomach of above-mentioned 4 kinds of bleach activators preparation and delay sheet and all can rise in 5min and float, and the lasting flotation time is all greater than l2h.When stearic acid and glyceryl monostearate were made bleach activator, the release behavior of medicine was similar, discharged also incomplete when the 8h preparation is lower than 40%, 24h.May be that the moisture that slowed down has delayed the stripping of medicine further to the infiltration of label because the two hydrophobicity is stronger, and final drug release be also incomplete.When hydrogenated vegetable oil was made bleach activator, drug release was very fast.And the release in vitro index approaches during with octadecanol, so select octadecanol as bleach activator.The drug release in vitro factor (the f of different lightweight adjuvant preparations
2) comparative result sees Table 6; The release in vitro curve is seen accompanying drawing 6.
The f of the different lightweight supplementary product kinds of table 6
2The factor relatively
Test example 7 different foaming agents are on the impact of drug release
Select three kinds of foaming agents commonly used to be respectively sodium bicarbonate, calcium carbonate, magnesium carbonate, other supplementary material amounts and technique are constant, prepare slow releasing tablet by preparation technology among the embodiment 1.Measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: three kinds of foaming agents, and meet gastric acid and produce CO
2Gas is wrapped in the gel layer of dosage surface, thereby alleviates preparation density, increases buoyancy, can increase again the initial release amount of medicine simultaneously.To affect difference little on floating for three kinds of foaming agent, but on the market medicinal sodium bicarbonate more other two kinds commonly used, be foaming agent so select sodium bicarbonate.The drug release in vitro factor (the f of different foaming agent preparations
2) comparative result sees Table 7; The release in vitro curve is seen accompanying drawing 7.
The f of the different foaming agents of table 7
2The factor relatively
Test example 8 different lightweight adjuvants (bleach activator) consumptions are on the impact of drug release
Other supplementary material amounts and preparation technology are constant, and every amount that contains octadecanol is respectively 30%, 35%, 45%, prepare tablet by preparation technology among the embodiment 1, measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: the octadecanol consumption obviously affects rising of slice, thin piece and floats the time, when the octadecanol consumption is 30%, the slice, thin piece of compacting is put rise in the hydrochloric acid solution of pH3 and is floated difficulty, works the time of floating obviously to prolong.Shorten along with the increase slice, thin piece of octadecanol consumption works the time of floating, when octadecanol content is 45%, works the time of floating and obviously accelerate.But find to have the phenomenon of obvious blocking medicine release, tablet is incomplete in the release of release later stage.So selecting the octadecanol consumption is about 35%.The drug release in vitro factor (the f of different lightweight adjuvant (bleach activator) consumption preparations
2) comparative result sees Table 8; The release in vitro curve is seen accompanying drawing 8.
The f of the different octadecanol ratio of table 8 content
2The factor relatively
Test example 9 different foaming agent NaHCO
3Consumption on the impact of drug release
Other supplementary material amounts and preparation technology are constant, and every contains NaHCO
3Percentage amounts be respectively 0%, 2%, 5%, 10%, prepare tablet by preparation technology among the embodiment 1, measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: do not contain NaHCO3, slice, thin piece works that to float time lengthening obvious, and NaHCO3 works the time of floating 2% all in 10min when above.Along with NaHCO
3Content increases can accelerate drug release, when content is excessive, and NaHCO
3Meet release medium and produce a large amount of CO
2Make the disintegrate of sheet subdivision, more release medium enters label, causes drug release too fast and cause prominent releasing.So NaHCO
3Consumption selects 2% to be advisable.Different foaming agent NaHCO
3The drug release in vitro factor (f of consumption preparation
2) comparative result sees Table 9; The release in vitro curve is seen accompanying drawing 9.
Table 9 different N aHCO
3The f of consumption
2The factor relatively
The kind of test example 10 binding agents is on the impact of drug release
Other supplementary material amounts and preparation technology are constant, to same prescription respectively with 75% ethanol, 95% ethanol and three kinds of binding agent soft materials processed of ethanol solution.Prepare tablet by preparation technology among the embodiment 1, measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: in pelletization, 75% ethanol makes rapidly the HPMC gelation, and the particle viscosity that makes is large, the inhomogeneous and difficulty of sieving of humidity, and dry rear pellet hardness is large, and drug release is slow.During 95% alcohol granulation, the matter soft material still is clamminess, and is bonded at the particle made on the screen cloth into strips.The soft material that makes with dehydrated alcohol becomes puffy, and the pellet hardness that makes is moderate, even particle size distribution, and good fluidity, the tabletting tablet hardness is moderate, and is bright and clean attractive in appearance.So binding agent is selected dehydrated alcohol.
The consumption of test example 11 different lubricants is to the shadow noon of drug release
Other supplementary material amounts and preparation technology are constant, same prescription is granulated, add respectively 0.5%, 1%, 1.5% magnesium stearate as lubricant, prepares tablet by preparation technology among the embodiment 1, measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: magnesium stearate in very little amount ranges on the release of medicine without impact, the magnesium stearate with 0.5% can reach lubricant effect.The drug release in vitro factor (the f of the consumption preparation of different lubricants
2) comparative result sees Table 10; The release in vitro curve is seen accompanying drawing 10.
Table 10 is the f of commensurability lubricant not
2The factor relatively
Test example 12 different method of granulating are to the shadow noon of drug release
The HPMC powder has good compressibility, directly dry powder sheeting.Press preparation technology among the embodiment 1, carry out respectively wet granule compression tablet and direct compression of full-powder, the preparation tablet is measured vitro release according to " vitro release assay method " in the test example 1, and " external flotation property " measures floatation characteristic.
The result shows: both release curve trends are consistent.The rate of releasing drug of dry granulation is slightly faster than wet granulation, but the flowability of dry powder is unfavorable for tabletting not as wet granulation.The powder vertical compression can stick punching because the easy moisture absorption of raw material is clamminess simultaneously.Powder vertical compression slice, thin piece, unilateral brightless clean and tidy, so adopt wet granulation process.The drug release in vitro factor (the f of different method of granulating preparations
2) comparative result sees Table 11; The release in vitro curve is seen accompanying drawing 11.
The f of table 11 wet granulation and dry granulation
2The factor relatively
Test example 13 hardness are to the shadow noon of drug release
Prepare the slow releasing tablet that hardness is respectively 30N, 40N, 50N, 60N with different pressures, it is constant that supplementary material amount and other respectively go on foot preparation technology, prepare tablet by preparation technology among the embodiment 1, measure vitro release according to " vitro release assay method " in the test example 1, " external flotation property " measures floatation characteristic.
The result shows: when medium and soft, hardness is not obvious on the impact of release; The rate of release of medicine slows down to some extent when hardness is larger.Hardness is when 40N-50N, and existing certain anti-fragility has again good drug release characteristic simultaneously.The drug release in vitro factor (the f of different hardness preparation
2) comparative result sees Table 12; The release in vitro curve is seen accompanying drawing 12.
The f of table 12 different hardness
2The factor relatively
The result of above-mentioned test example shows; adopt prescription and the preparation method of bismuth citrate ranitidine intragastric floating tablets of the present invention; the gained preparation has optimal slow release effect; its long-acting side effect is little; can be detained for a long time at gastric; playing simultaneously anti-gastric acid secretion and protection gastric mucosa dual function, is a kind of desirable preparation for being detained peptic ulcer, suitable applying.
Although, above used general explanation, the specific embodiment and test, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a bismuth citrate ranitidine intragastric floating tablets is comprised of the label that contains bismuth citrate ranitidine and the coating membrane that is wrapped in outside the label; It is characterized in that by weight, described label is prepared from by the raw material that contains at least 45～130 parts of 110～120 parts of bismuth citrate ranitidines, 30～60 parts of framework materials, 5～20 parts of foaming agents and bleach activators.
2. bismuth citrate ranitidine intragastric floating tablets according to claim 1 is characterized in that, described framework material is selected from one or more in HPMC, ethyl cellulose, the polyvidone; Described foaming agent is selected from one or more in sodium bicarbonate, calcium carbonate, the magnesium carbonate, is preferably sodium bicarbonate; Described bleach activator is one or more in hydrogenated vegetable oil, octadecanol, glyceryl monostearate, the stearic acid, is preferably octadecanol.
3. bismuth citrate ranitidine intragastric floating tablets according to claim 1 and 2, it is characterized in that, by weight, described label is prepared from by the raw material that contains at least bismuth citrate ranitidine 110-120 part, 40～50 parts of framework materials, bleach activator 80-120 part, foaming agent 6-10 part; Preferred described label is prepared from by the raw material that contains at least 114 parts of bismuth citrate ranitidines, 15 parts of 30 parts of HPMC 15000SR, HPMC 100000SR, 120 parts of octadecanol, 6 parts of sodium bicarbonate.
4. bismuth citrate ranitidine intragastric floating tablets according to claim 1 is characterized in that, described label also comprises 1-3 part lubricant and 2-8 part binding agent; Described lubricant is one or more in magnesium stearate, Pulvis Talci, stearic acid, the micropowder silica gel, preferred magnesium stearate; Described binding agent is one or more in polyvinylpyrrolidone, water, the dehydrated alcohol, preferred dehydrated alcohol.
5. bismuth citrate ranitidine intragastric floating tablets according to claim 1 is characterized in that, described coating membrane account for total sheet heavy 1%～5%; Described coating membrane is dissolved in the solvent with coating material, plasticizer and lubricant and forms coating solution and coating forms to label; Preferred described coating material be Eudragit RS100, Eudragit RL100, hydroxyethyl-cellulose, polyvinyl alcohol, Polyethylene Glycol, cellulose acetate, ethyl cellulose one or more; Described solvent is one or more in ethanol, water, the acetone; Described plasticizer is triethyl citrate; Described lubricant is Pulvis Talci; More preferably coating solution is with coating material EudragitRS100 12.5-17.5 part, EudragitRL100 12.5-17.5 part, triethyl citrate 2-4 part, Pulvis Talci 6-9 part, and solubilizer ethanol to 500 part is prepared from.
6. the preparation method of bismuth citrate ranitidine intragastric floating tablets claimed in claim 1 is characterized in that, comprises the steps:
(1) preparation of label: bismuth citrate ranitidine, bleach activator and the foaming agent that takes by weighing recipe quantity be the equivalent mix homogeneously that progressively increases respectively, soft material processed or add binding agent after soft material processed; Put baking oven 40-50 ℃ dry 2-3 hour; Granulate behind direct granulate or the adding lubricant mixing; The control tablet hardness is 40-50N, with the stamping of 10-15mm scrobicula, gets label;
(2) take by weighing coating material and be dissolved in an amount of solvent, add plasticizer, get solution; In addition lubricant is dissolved in an amount of solvent, with high-shear homogenate machine homogenize 3-6min, pours in the mentioned solution, solubilizer is to full dose, and the 75-85 order sieves, and namely gets coating solution;
(3) coating.
7. preparation method according to claim 6 is characterized in that, described step (1) is: it is for subsequent use that bismuth citrate ranitidine and adjuvant are crossed the 80-120 mesh sieve; Bismuth citrate ranitidine, bleach activator and the foaming agent that takes by weighing recipe quantity be the equivalent mix homogeneously that progressively increases respectively, soft material processed or add binding agent after soft material processed; Cross 30 mesh sieves and granulate, put baking oven 40-50 ℃ dry 2-3 hour; Granulate behind direct granulate or the adding lubricant mixing, film-making agent hardness is 40-50N, with the stamping of 10-15mm scrobicula, gets label.
8. preparation method according to claim 6 is characterized in that, described step (2) is: take by weighing coating material and be dissolved in an amount of ethanol, add the plasticizer triethyl citrate, get solution; In addition the lubricant Pulvis Talci is dissolved in an amount of ethanol, with high-shear homogenate machine homogenize 3-6min, pours in the mentioned solution, add ethanol to full dose, the 75-85 order sieves, and namely gets coating solution.
9. preparation method according to claim 6, it is characterized in that, described step (3) is: label is placed coating pan, 35 °-45 ° at inclination angle, apart from 8-12cm, nozzle diameter 0.8-1.2mm is the pancake spraying to spray gun apart from the sheet bed, 30-35 ℃ of sheet bed tempertaure, jet pressure, 0.12-0.13MPa, hydrojet speed 3-6g/min, coating pan rotating speed 20-30r/min, at the uniform velocity coating to weightening finish accounts for till the heavy 1%-5% of sheet, after coating is finished, slice, thin piece is placed in the tray, place 36-42 ℃ of dry 1.5-2.5h, and get final product.
10. preparation method according to claim 9 is characterized in that, described step (3) is: label is placed coating pan, 40 ° at inclination angle, spray gun apart from the sheet bed apart from 10cm, nozzle diameter 1.0mm, be the pancake spraying, 30-35 ℃ of sheet bed tempertaure, whiff pressure 0.125MPa, hydrojet speed 5g/min, coating pan rotating speed 25r/min, at the uniform velocity coating to weightening finish accounts for till the heavy 2%-4% of sheet, after coating is finished, slice, thin piece is placed in the tray, places 40 ℃ of dry 2h.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103417377A (en) * | 2013-08-23 | 2013-12-04 | 九芝堂股份有限公司 | Bronchitis film-coated tablet and preparation method thereof |
| CN104887641A (en) * | 2015-04-08 | 2015-09-09 | 上海鲁源医药科技有限公司 | Palbociclib gastric-floating tablet and preparation method thereof |
| CN104887641B (en) * | 2015-04-08 | 2017-12-01 | 上海鲁源医药科技有限公司 | Pabuk former times profit cloth gastric floating tablet and preparation method thereof |
| JP2018199630A (en) * | 2017-05-26 | 2018-12-20 | 株式会社ファンケル | Intragastric retentivity tablet |
| CN108057064A (en) * | 2018-01-19 | 2018-05-22 | 浙江中医药大学 | A kind of Corydalis ambigua total alkaloid gastric floating tablet |
| CN108057064B (en) * | 2018-01-19 | 2020-11-03 | 浙江中医药大学 | Corydalis tuber total alkaloid gastric floating tablet |
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