CN101422611B - Compound preparation and preparation method thereof - Google Patents
Compound preparation and preparation method thereof Download PDFInfo
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- CN101422611B CN101422611B CN2008102175700A CN200810217570A CN101422611B CN 101422611 B CN101422611 B CN 101422611B CN 2008102175700 A CN2008102175700 A CN 2008102175700A CN 200810217570 A CN200810217570 A CN 200810217570A CN 101422611 B CN101422611 B CN 101422611B
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Abstract
The invention discloses a compound preparation and a preparation method thereof, which have technological problems to be solved that compound medicament constituents are used for forming a compound medicament resin composite proportionally, and the containing components have weight proportions as follows: 0.01 to 20.0 percent of compound activity medicament and 2 to 50.0 percent of ion exchange resin; the ion exchange resin is used as a carrier, and the compound activity medicament forms compound activity medicament resin particles with sizes of 850 to 25Mum by being absorbed on the ion exchange resin. The preparation method comprises the following steps: the compound medicament ion exchange resin particles are prepared and mixed with a disintegrating agent, a flavoring agent, a coloring agent, an aromatic agent and an excipient, and pressed into tablets. Compared with the prior art, the ion exchange resin is used as a carrier, and the compound activity medicament forms the compound activity medicament resin particles by being absorbed on the ion exchange resin proportionally, and the proportions of the compound medicament activity constituents are unchanged, and the prepared formulation products is high in stability, simple in process, low in cost and easy in realizing industrialization.
Description
Technical field
The present invention relates to a kind of chemicals preparation and preparation method thereof, the method for preparing of particularly a kind of compound medicinal formulation and industrial applications thereof.
Background technology
Along with people's deepens continuously to health idea understanding; The medicine closely bound up with health of people receives more concern, and the cry of rational use of drug, safe medication is increasingly high, and the modern medication theory of " with minimum medication amount; reach the highest bioavailability; obtain best therapeutic effect, and drop to the risk of adverse effect minimum " progressively is rooted in the hearts of the people, and then also increasingly high to the requirement of medicine and preparation; Be accompanied by the develop rapidly of the deep of drug delivery system theoretical research and preparation process technology, drug delivery system and route of administration aspect have produced a lot of innovative technologies, for example slow releasing preparation, durative action preparation, targeting drug administration preparation, percutaneous drug delivery preparation etc.Compound preparation can be brought into play the synergism of compound medicine component, and therapeutic effect is much better than single preparations of ephedrine, and reduces the medication number of times, brings great convenience to the patient.Compound slow release preparation is the dosage form of progressively rising in recent years in the compound preparation; Such dosage form has not only that the folk prescription slow releasing preparation improves utilization ratio of drug, reduces drug side effect, the advantage of stabilised blood concentration, prolong drug treatment time etc.; And taking convenience improves patient's compliance, more can bring into play the synergism of compound medicine component; Improve the safety of drug utilization, compound preparation of the present invention includes the slow-release material of weight ratio 0.02～5%.
A kind of compound preparation, the weight ratio ingredient that said compound preparation comprises is: compound active medicine 0.01～1.0%, ion exchange resin 0.1～10.0%; Ion exchange resin is carrier, and the compound active medicine is adsorbed on and forms compound active medical resin microgranule on the ion exchange resin, and compound active medical resin particle size is 250～25 μ m.
Compound preparation of the present invention includes the suspending agent of weight ratio 0.5～30.0%, 0.1～5% acidity regulator, 0.01～5% complexing of metal ion agent, routine dose antiseptic, correctives, coloring agent, and all the other are water.
Compound preparation of the present invention includes the slow-release material of weight ratio 0.001～1%.
A kind of method for preparing of compound preparation may further comprise the steps: one, by weight taking by weighing compound active medicine 0.1～20.0%, after the adding purified water stirs and makes its dissolving; Add ion exchange resin 2～50.0%, with 100～800 rev/mins of stirrings of rotating speed, 1～6 hour time; Do not wash or wash 1～4 time, leave standstill, filter supernatant liquid; Precipitum is subsequent use, or takes out and to place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, obtains compound medicine ion exchange resin microgranule; Two, with the disintegrating agent of compound medicine ion exchange resin microgranule, weight ratio 1～20%, the flavoring agent greater than 0 to 10%, the coloring agent and the aromatic of routine dose, remaining excipient mixes getting mixed material in 10～40 minutes; Three, mixed material is pressed into tablet, or is filled to capsule formulation, or process granule.
Method of the present invention obtains behind the compound medicine ion exchange resin microgranule the slow-release material of weight ratio 0.02%～5.0%, and using isopropyl alcohol or dissolve with ethanol to slow-release material/isopropyl alcohol or alcoholic solution concentration is 0.1%～20%, adds compound medicine ion exchange resin microgranule after precipitum or the dried; Under 30～80 ℃ of conditions; With 100～800 rev/mins of stirrings, 1～6 hour time, do not wash or wash 1～4 time; Sedimentation, filtration; Precipitum is taken out, place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, the back is crossed 80～200 mesh sieve granulate and is obtained compound sustained-released medicine ion exchanger resin microgranule; With the disintegrating agent of weight ratio 1～20%, the flavoring agent greater than 0 to 10%, the coloring agent and the aromatic of routine dose, remaining excipient mixes again.
A kind of method for preparing of compound preparation may further comprise the steps: one, by weight taking by weighing compound active medicine 0.1～20.0%, after the adding purified water stirs and makes its dissolving; Add ion exchange resin 2～50.0%, with 100～800 rev/mins of stirrings, 1～6 hour time; Do not wash or wash 1～4 time, leave standstill then, filter supernatant liquid; Precipitum is subsequent use, or takes out and to place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, obtains compound medicine ion exchange resin microgranule; Two, with the suspending agent of compound medicine ion exchange resin microgranule, weight ratio 1～10.0%, 1～10.0% acidity regulator, the correctives of routine dose, coloring agent and aromatic, and filler mix, and get mixed material; Three, with mixed material by the specification direct packaging or the packing of further granulating, compound dried suspension.
After method of the present invention obtains compound medicine ion exchange resin microgranule, by weight taking by weighing slow-release material 0.02%～5.0%; Using isopropyl alcohol or dissolve with ethanol to slow-release material/isopropyl alcohol or alcoholic solution concentration is 0.1%～20%; Add precipitum or compound medicine ion exchange resin microgranule, under 30 ℃～80 ° degree conditions, stir with 100～800 rev/mins of rotating speeds; 1～6 hour time; Do not wash or wash 1～4 time, precipitum is taken out in sedimentation, filtration; Mistake 80～200 mesh sieve granulate obtain compound sustained-released medicine ion exchanger resin microgranule after placing 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure; With compound medicine slow release ion exchange resin microgranule, the suspending agent of weight ratio 1～10.0%, 1～10.0% acidity regulator, the correctives of routine dose, coloring agent and aromatic, and filler mixes.
A kind of method for preparing of compound preparation may further comprise the steps: one, by weight taking by weighing compound active medicine 0.01～1.0%, after the adding purified water stirs and makes its dissolving; Add ion exchange resin 0.1～10.0%, 100～800 rev/mins of speeds of agitator, 1～6 hour time did not wash or washed 1～4 time; Leave standstill, filter supernatant liquid, precipitum is subsequent use; Or take out and to place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, obtain compound medicine ion exchange resin microgranule; Two, with precipitum or compound medicine ion exchange resin microgranule, the suspending agent of weight ratio 0.5～30.0%, 0.1～5% acidity regulator, 0.01～5% complexing of metal ion agent, antiseptic, correctives and the coloring agent of routine dose and the deionized water of recipe quantity; Be stirred to uniform liquid; By the specification fill, get the compound recipe suspension.
Method of the present invention obtains compound medicine ion exchange resin microgranule; Take by weighing slow-release material by weight 0.001%～1.0%; Using isopropyl alcohol or dissolve with ethanol to slow-release material/isopropyl alcohol or alcoholic solution concentration is 0.1%～20%, and the compound medicine ion exchange resin microgranule after precipitum or the dried is under 30 ℃～80 ° degree conditions; Stirred 1～6 hour with 100～800 rev/mins rotating speeds; Do not wash or wash 1～4 time, leave standstill, sedimentation, filtration, precipitum is subsequent use; Or take out and to place 30～80 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind hot air drying or the drying under reduced pressure to obtain compound sustained-released medicine ion exchanger resin microgranule; With the suspending agent of microgranule, weight ratio 0.5～30.0% after compound sustained-released medicine ion exchanger resin precipitum or the dried, 0.1～5% acidity regulator, 0.01～5% complexing of metal ion agent, antiseptic, correctives and the coloring agent of routine dose, and deionized water, be stirred to uniform liquid; By the specification fill, get compound sustained-released suspension.
The present invention compared with prior art, employing ion exchange resin is carrier, compound active medicine co-absorbed in proportion forms compound active medical resin microgranule on ion exchange resin; The ratio of compound medicine active ingredient no longer changes, the various dosage forms of processing, and product stability can be high; Avoided traditional compound preparation with batch or batch between compound active drug ratios deviation and stripping release degree inconsistent, can also be applied to compound liquid preparation, avoid adverse drug mouthfeel raising patient tolerability; Especially can be applied to the preparation of compound slow release preparation; Significantly reduce that the active ingredient ratio that conventional compound slow release preparation occurs is inconsistent, dissolution time is inconsistent, technology is simple, and cost is low; Easy realization of industrialization more can be applied to the bigger compound recipe liquid slow-release preparation of difficulty and risk.
The specific embodiment:
Below in conjunction with embodiment the present invention is done further explain.Compound preparation of the present invention is carrier with ion exchange resin, and compound active medicine co-absorbed in proportion forms compound active medical resin microgranule on ion exchange resin, and compound active medical resin microgranule and pharmaceutical adjunct are made compound preparation.Compound active medical resin particle size is 850～25 μ m, is preferably between 250～25 μ m, more preferably 150～25 μ m.Compound active medical resin microgranule and other pharmaceutical adjuncts are made various compound recipe dosage forms.Compound recipe dosage form of the present invention is compound recipe general formulation and compound sustained-released dosage form, and the compound recipe general formulation comprises: compound tablet, compound capsule agent, compound granular agent, compound dried suspension, compound recipe suspensoid; Compound sustained-released dosage form comprises compound sustained-released tablet, compound sustained release capsules agent, compound sustained-released granule, compound sustained-released dry suspension and compound sustained-released liquid preparation.
1, compound tablet of the present invention, compound capsule agent, compound granular agent; The weight ratio ingredient that comprises is: active medicine 0.1～20.0%, ion exchange resin 2～50.0%, disintegrating agent 1～20%, flavoring agent 0～10%; Routine dose coloring agent and aromatic, all the other are excipient.Active medicine forms microgranule in prescription ratio co-absorbed on ion exchange resin.
2, compound dried suspension of the present invention; The weight ratio ingredient that comprises is: active medicine 0.1～20.0%, ion exchange resin 2～50.0%, suspending agent 1～10.0%, acidity regulator 1～10%; The antiseptic of routine dose, correctives and coloring agent, other are filler.Active medicine forms microgranule in prescription ratio co-absorbed on ion exchange resin.
3, compound recipe suspensoid of the present invention; The weight ratio ingredient that comprises is: active medicine 0.01%～1.0%, ion exchange resin 0.1%～10.0%, suspending agent 0.5%～30.0%, acidity regulator 0.1%～5%, complexing of metal ion agent 0.01%～5%; Routine dose antiseptic, correctives, coloring agent; All the other form microgranule for the purified water active medicine in prescription ratio co-absorbed on ion exchange resin; The pastille resin particle is evenly distributed in the liquid medium of suspending agent and purified water, and it is aqueous to be suspendible.
4, compound sustained-released tablet of the present invention, compound sustained release capsules agent, compound sustained-released granule; The weight ratio ingredient that comprises is: active medicine 0.1～20.0%, ion exchange resin 2～50.0%, slow-release material 0.02～5%, disintegrating agent 1～20%, flavoring agent 0～10%; Routine dose coloring agent and aromatic, all the other are excipient.Active medicine forms microgranule in prescription ratio co-absorbed on ion exchange resin, be coated with slow-release material.
5, compound sustained-released dry suspension of the present invention; The weight ratio ingredient that comprises is: active medicine 0.～20.0%, ion exchange resin 2～50.0%, slow-release material 0.02～5%, suspending agent 1～10.0%, acidity regulator 1～10%; The antiseptic of routine dose, correctives and coloring agent, other are filler.Active medicine forms microgranule in prescription ratio co-absorbed on ion exchange resin.
6, compound sustained-released liquid preparation of the present invention; The weight ratio that comprises is: active medicine 0.01%～1.0%, ion exchange resin 0.1%～10.0%, suspending agent 0.5%～30.0%, slow-release material 0.001%～1.0%, acidity regulator 0.1%～5%, complexing of metal ion agent 0.01%～5%; Routine dose antiseptic, correctives, coloring agent, all the other are purified water.Active medicine forms microgranule in prescription ratio co-absorbed on ion exchange resin, microgranule is coated with slow-release material, contains in the liquid medium that the medicated resin coated particle is evenly distributed on suspending agent and purified water, and it is aqueous to be suspendible.
Active medicine of the present invention is for use compound medicine always clinically; Preferred half-life of slow releasing preparation is short, is necessary with nicotinic acid, ibuprofen, ketoprofen, flurbiprofen, aspirin, naproxen sodium, the diclofenac sodium of other drug prescription, dissolves dilatory azoles sodium, theophylline, dextromethorphan hydrobromide, cetirizine hydrochloride, pseudoephedrine hydrochloride, galantamine, vincamine, pseudoephedrine sulfate, etodolac, indapamide, codeine phosphate, morphine hydrochloride slow release, morphine hydrochloride slow release, BUPROPIONE HCl, metformin hydrochloride, BUPROPIONE HCl, spectinomycin hydrochloride, the pseudo-numb sulphur alkali of sulphuric acid, tamsulosin hydrochloride, VENLAFAXINE HCL, tramadol hydrochloride, valaciclovir hydrochlordide, Buflomedil Hydrochloride, verapamil hydrochloride, BUPROPIONE HCl, salbutamol sulfate, diltiazem hydrochloride, pseudoephedrine hydrochloride, ambroxol hydrochloride, benproperine phosphate, pentoxifylline, BUPROPIONE HCl, Buflomedil Hydrochloride, nefopam hydrochloride, ditropan XL, gentamycin sulfate, codeine phosphate, alfuzosin hydrochloride, metroprolol succinate, hydrochloric acid Barney, dihydroergotoxine methanesulfonate and suitable prescription medicine thereof.
Preferred drug regimen is loratadine-pseudoephedrine sulfate; Ibuprofen-pseudoephedrine hydrochloride; Isosorbide mononitrate-aspirin; Pseudoephedrine hydrochloride-chlorphenamine maleate; Pseudoephedrine sulfate-chlorphenamine maleate; Codeine phosphate-chlorphenamine maleate; The appropriate sand of codeine phosphate-benzene is quick; Hydrocodone-chlorphenamine maleate; Nicotinic acid-simvastatin; Phenylpropanolamine HC1-chlorphenamine maleate; Cetirizine hydrochloride-pseudoephedrine hydrochloride slow release; Hydrochloric acid non-sofinadine-pseudoephedrine hydrochloride slow release; Metformin hydrochloride-glibenclamide; Codeine phosphate-pseudoephedrine hydrochloride-chlorphenamine maleate; Codeine phosphate-pseudoephedrine sulfate-chlorphenamine maleate; The similar medicine that acidic group or base are different and its combination.
Ion exchange resin adopts more than one in styrene strong-acid ion exchange resin, styrene weak-acid ion exchange resin, styrene strong basic ion exchange resin, styrene weak-base ion-exchange resin, acrylic acid strong-acid ion exchange resin, acrylic acid weak-acid ion exchange resin, methacrylic acid strong-acid ion exchange resin, the methacrylic acid weak-acid ion exchange resin.The styrene storng-acid cation exchange resin has sulfonic group or phosphate functional group; The styrene weak-acid cation-exchange resin has carboxylic acid group or phenolic acid base functional group; The styrene strong basic ion exchange resin has the season amido functional group; The exchange of styrene weakly-basic anion has primary amine groups-NH2, secondary amine-NHR or tertiary amine groups-NR functional group; Acrylic or methacrylic acid weak-acid cation-exchange resin has carboxylic acid group or phenolic acid base functional group, and acrylic or methacrylic acid weak-base anion-exchange resin has amidine functional group.The preferred 50wx2 of styrene storng-acid cation exchange resin, 50wx4,50wx8 (DOW Chemical company limited);
IRP 120, IRP 69 (ROHM AND HAAS Investment Co., Ltd); The preferred DOWEX MAC-3 of styrene weak-acid cation-exchange resin (DOW Chemical company limited);
IRP 64, IRP 88 (ROHM AND HAAS Investment Co., Ltd)); Preferred
IRA 458 of styrene strong basic ion exchange resin,
IRA 400 (ROHM AND HAAS Investment Co., Ltd)); DOWEX 22, MARATHON 550A (OH) (DOW Chemical company limited); The styrene weakly-basic anion exchanges preferred AMBERLITETM ITA67 (ROHM AND HAAS Investment Co., Ltd)), DOWEX MONOSPHERE 66 (DOW Chemical company limited) disintegrating agent adopts: in dried starch carboxylic, methyl starch sodium CMS-Na, low substituted hydroxy-propyl methylcellulose L-HPC, crospolyvinylpyrrolidone PVP, Polyethylene Glycol PEG, the gas-producing disintegrant (by sodium bicarbonate and citric acid combination) two kinds reach more than.
Suspending agent adopts: hydroxypropyl emthylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethyl cellulose, sucrose, propylene glycol, glycerol, sorbitol, maltose alcohol, lactose, Ka Baimu, xanthan gum, tragakanta, polyvidone, polyacrylic acid crosslinked polymer, microcrystalline Cellulose more than one.
Acidity regulator adopts: in sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, citric acid, the sodium citrate more than one.
The complexing of metal ion agent: citric acid, sodium citrate, ethylenediaminetetraacetic acid, disodiumedetate, in calcium disodium chelate, the diethyl pentetic acid calcium disodium more than one.
Sustained-release materials using ion exchange resin capable of matching function with sustained release polymer materials, specifically for the sustained-release materials to meet Chinese Pharmacopoeia (2005 edition) standard polyacrylate resin II, polyacrylic acid resin III, polyacrylic acid Resin IV, poly methyl ammonium acrylate ester I, poly A II or ammonium acrylate ester produced by Degussa AG, Germany
? E100,
? EPO,
? L100-55,?
? L30D-55,
? L100,
? S100,
? RL100,
RLPO,
? RL30D,
? RS100,
? RSPO,
? RS30D,?
? NE30D,
? FS30D in one or more, preferably a functional group having a carboxyl or amine functional group of the polymeric release material.
The method for preparing of compound preparation of the present invention comprises:
1, the method for preparing of compound tablet, compound capsule agent, compound granular agent may further comprise the steps: one, by weight taking by weighing compound active medicine 0.1～20.0%, add and be equipped with in the container of purified water; Stirring makes its dissolving back (Japanese EYELA, MAZELA Z type liquid stirrers), adds ion exchange resin 2～50.0%; 100～800 rev/mins of speeds of agitator, do not wash or wash 1～4 time at 1～6 hour time; Leave standstill then, filter supernatant liquid, precipitum is taken out; Place 30～80 ℃ of temperature to carry out hot air drying (Chongqing four reaches experimental apparatus company limited CS101-2E type electric drying oven with forced convection) or drying under reduced pressure (Japanese EYELA; VOS-451SD type vacuum drying oven), 80～200 mesh sieve granulate are crossed in the back, obtain compound medicine ion exchange resin microgranule; Two, with the disintegrating agent of compound medicine ion exchange resin microgranule, weight ratio 1～20%, the flavoring agent of 1～10 %, the coloring agent and the aromatic of routine dose; Remaining excipient; Put into three-dimensional multinomial mixer (the multinomial movement mixer of SDH-50 type of Jiangyin rarity rubber and plastics machine company limited), mix getting mixed material in 10～40 minutes; Three, mixed material is pressed into tablet (the upright company limited ZP-10A rotary tablet machine of Beijing traditional Chinese medicines dragon) by convas tablet production technology (dry granulation or wet granule compression tablet or direct compression), promptly gets compound tablet by specification cover blister package (DPT130A of Chunguang Packing machinery Co., Ltd., Jinzhou Aluminium-coating Packer); Or press capsule production technology commonly used (granulate and fill or directly filling) and fill suitable capsule formulation (NJP-400B of Zhejiang Fuchang Machinery Co., Ltd. capsule filler), promptly get the compound capsule agent by specification cover blister package (DPT130A of Chunguang Packing machinery Co., Ltd., Jinzhou Aluminium-coating Packer); Or, promptly get the compound granular agent by specification granule racking machine (the Japanese SAMP7-D of Sanko Machinery Co., Ltd. automatic stuffing packager) packing by granule production technology granulation commonly used (SHK-20TS of Beijing Aeronautics Research Inst wet granulator).
2, the method for preparing of compound dried suspension may further comprise the steps: one, by weight taking by weighing compound active medicine 0.1～20.0%, add and be equipped with in the container of purified water; Stirring adds ion exchange resin 2～50.0%, 100～800 rev/mins of speeds of agitator after making its dissolving; 1～6 hour time, do not wash or wash 1～4 time, leave standstill then; Filter supernatant liquid; Precipitum is taken out, place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, the back is crossed 80～200 mesh sieve granulate and is obtained compound medicine ion exchange resin microgranule; Two, with the suspending agent of compound medicine ion exchange resin microgranule, weight ratio 1～10.0%, 1～10.0% acidity regulator; The correctives of routine dose, coloring agent and aromatic; And filler; 100～800 rev/mins of three-dimensional multinomial mixing rotating speeds, get mixed material at 10～40 minutes time (the multinomial movement mixer of SDH-50 type of Jiangyin rarity rubber and plastics machine company limited); Three, with mixed material by dry suspension production technology commonly used, granulate or directly by specification packing (the Japanese SAMP7-D of Sanko Machinery Co., Ltd. automatic stuffing packager), compound dried suspension.
3, the method for preparing of compound recipe suspensoid may further comprise the steps: one, by weight taking by weighing compound active medicine 0.01～1.0%, add and be equipped with in the container of purified water; After stirring makes its dissolving; Add ion exchange resin 0.1～10.0%, 100～800 rev/mins of speeds of agitator, 1～6 hour time; Do not wash or wash 1～4 time; Filter supernatant liquid, precipitum is subsequent use or take out and to place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, and the back is crossed 80～200 mesh sieve granulate and obtained compound medicine ion exchange resin microgranule; Two, with the suspending agent of compound medicine ion exchange resin microgranule, weight ratio 0.5～30.0% after precipitum or the dried, 0.1～5% acidity regulator, 0.01～5% complexing of metal ion agent, antiseptic, correctives and the coloring agent of routine dose and the deionized water of recipe quantity; Be stirred to uniform liquid (Japanese EYELA; MAZELA Z type liquid stirrers); Filling machine gets the compound recipe suspension by specification fill (Jinan fast plant equipment company limited KLG-125 granule filling machine).
4, the method for preparing of compound sustained-released tablet, compound sustained release capsules agent, compound sustained-released granule may further comprise the steps: one, by weight taking by weighing compound active medicine 0.1～20.0%, add and be equipped with in the container of purified water; Stirring adds ion exchange resin 2～50.0%, 100～800 rev/mins of speeds of agitator after making its dissolving; 1～6 hour time; Leave standstill then, do not wash or wash 1～4 time, filter supernatant liquid; Precipitum is subsequent use or take out and to place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, and the back is crossed 80～200 mesh sieve granulate and obtained compound medicine ion exchange resin microgranule; Two, with the slow-release material of weight ratio 0.02%～5.0%; Using isopropyl alcohol or dissolve with ethanol to concentration is 0.1%～20% (slow-release material/isopropyl alcohol or alcoholic solution), and compound medicine ion exchange resin microgranule after adding precipitum or the dried is under 30～80 ℃ of degree conditions; With 100～800 rev/mins of stirrings (MAZELA Z type liquid stirrers Japan EYELA); 1～6 hour time, precipitum is taken out in sedimentation, filtration; Place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, the back is crossed 80～200 mesh sieve granulate and is obtained compound sustained-released medicine ion exchanger resin microgranule; Three, with the disintegrating agent of compound sustained-released medicine ion exchanger resin microgranule, weight ratio 1～20%, 1～10% flavoring agent, the coloring agent and the aromatic of routine dose; And excipient, three-dimensional multinomial mixing 10～40 minutes (the multinomial movement mixer of SDH-50 type of Jiangyin rarity rubber and plastics machine company limited) gets mixed material; Four, mixed material is pressed into tablet by convas tablet production technology (dry granulation or wet granule compression tablet or direct compression), promptly gets compound sustained-released tablet by specification cover blister package; Or press capsule production technology commonly used (granulate and fill or directly filling) and fill suitable capsule formulation, promptly get the compound sustained release capsules agent by specification cover blister package; Or by granule production technology commonly used, granulate, promptly get compound sustained-released granule by the packing of specification granule racking machine.
5, the method for preparing of compound sustained-released dry suspension may further comprise the steps: one, by weight taking by weighing compound active medicine 0.1～20.0%, add and be equipped with in the container of purified water; Stirring adds ion exchange resin 2～50.0%, 100～800 rev/mins of speeds of agitator after making its dissolving; 1～6 hour time; Leave standstill then, do not wash or wash 1～4 time, filter supernatant liquid; Precipitum is subsequent use, or takes out and to place 30～80 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind hot air drying or the drying under reduced pressure to obtain compound medicine ion exchange resin microgranule; Two, by weight taking by weighing slow-release material 0.02%～5.0%; Using isopropyl alcohol or dissolve with ethanol to concentration is 0.1%～20% (slow-release material/isopropyl alcohol or alcoholic solution), adds precipitum or compound medicine ion exchange resin microgranule, under 30 ℃～80 ° degree conditions; Stir (Japanese EYELA with 100～800 rev/mins of rotating speeds; MAZELAZ type liquid stirrers), 1～6 hour time, sedimentation, filtration; Precipitum is taken out, place 30～80 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind hot air drying or the drying under reduced pressure and obtain compound sustained-released medicine ion exchanger resin microgranule; Three, with compound medicine slow release ion exchange resin microgranule, the suspending agent of weight ratio 1～10.0%, 1～10.0% acidity regulator; The correctives of routine dose, coloring agent and aromatic; And filler, three-dimensional multinomial mixing 10～40 minutes (the multinomial movement mixer of SDH-50 type of Jiangyin rarity rubber and plastics machine company limited) gets mixed material; Four, with mixed material by dry suspension production technology commonly used, granulate or directly by specification packing (SAMP7-D automatic stuffing packager, Japanese Sanko Machinery Co., Ltd.), compound sustained-released dry suspension.
6, compound sustained-released liquid preparation; May further comprise the steps: one, by weight taking by weighing compound active medicine 0.01～1.0%, adding and be equipped with in the container of purified water, stirring adds ion exchange resin 0.1～10.0% after making its dissolving; 100～800 rev/mins of speeds of agitator; 1～6 hour time, do not wash or wash 1～4 time, filter supernatant liquid; Precipitum is subsequent use or take out and to place 30～80 ℃ of temperature to carry out hot air drying or drying under reduced pressure, and the back is crossed 80～200 mesh sieve granulate and obtained compound medicine ion exchange resin microgranule; Two, take by weighing slow-release material by weight 0.001%～1.0%; Using isopropyl alcohol or dissolve with ethanol to concentration is 0.1%～20% (slow-release material/isopropyl alcohol or alcoholic solution); The precipitum or the compound medicine ion exchange resin microgranule that add step 1; Under 30 ℃～80 ° degree conditions, stirred 1～6 hour sedimentation, filtration with 100～800 rev/mins rotating speeds; Precipitum is taken out, place 30～80 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind hot air drying or the drying under reduced pressure and obtain compound sustained-released medicine ion exchanger resin microgranule; Three, with the precipitum of step 2 or compound sustained-released medicine ion exchanger resin microgranule, the suspending agent of weight ratio 0.5～20.0%, 0.1～5% acidity regulator, 0.01～5% complexing of metal ion agent, antiseptic, correctives and the coloring agent of routine dose; And deionized water; Be stirred to uniform liquid, filling machine gets compound sustained-released suspensoid by the specification fill.
The compound recipe dosage form of method preparation of the present invention, detection is seen for oneself table 1, and content, release degree, dissolution, granularity and the suspension ability method of inspection are following:
Content and ratio measuring method: press the single taking dose, get 6 units of test sample, drop into the 1000ml volumetric flask respectively; The KCl solution (volume ratio methanol/0.7M KCl solution=1:1), stirred 12 hours, the same solution standardize solution that contain methanol; Get solution 10ml, filter with 0.45 μ m filter membrane, precision is measured subsequent filtrate 20 μ l; Inject chromatograph of liquid, the record chromatogram; Precision takes by weighing preparation single dose active medicine reference substance, and same methanol Klorvess Liquid dissolving standardize solution is got solution 10ml, filters with 0.45 μ m filter membrane, and precision is measured subsequent filtrate 20 μ l, injects chromatograph of liquid, the record chromatogram; In the ratio of external standard method with compound active medicament contg among calculated by peak area the present invention and compound active medicine; Content is not less than sign amount 90%～110%, and the active medicine ratio is not less than 95%～105% of sign amount ratio.
Dissolution method: by " Chinese Pharmacopoeia 2005 editions " appendix XC dissolution method second method, be release medium with 37 ℃ of 0.15M KCl solution, rotating speed is that per minute 75 changes; Got solution 5ml respectively at per 15 minutes and 45 minutes; Filter and instant release medium of in stripping rotor, replenishing equal volume, uniform temp with 0.45 μ m filter membrane, precision is measured subsequent filtrate 20 μ l, injects chromatograph of liquid; The record chromatogram; By external standard method with active medicine among calculated by peak area the present invention in the burst size of different time, 15 minutes stripping quantities are not less than 60%, 45 minute of sign amount and are not less than stripping quantity 75%.
The drug release determination method: by " Chinese Pharmacopoeia 2005 editions " appendix XD drug release determination method first method, adopting dissolution method second subtraction unit, is release medium with 37 ℃ of different ions concentration KCl solution respectively; Rotating speed is that per minute 75 changes, and operation in accordance with the law is when 1 hour, 4 hours and 10 hours; Get solution 5ml respectively, filter with 0.45 μ m filter membrane, and instant release medium of in stripping rotor, replenishing equal volume, uniform temp; Precision is measured subsequent filtrate 20 μ l, injects chromatograph of liquid, the record chromatogram; By external standard method with active medicine among calculated by peak area the present invention in the burst size of different time; 1 hour burst size is that 40%～75%, 10 hours burst sizes that 15%～45%, 4 hours burst sizes of sign amount are the sign amount are not less than knowledge amount 70%.
Particle size detection method: can not and can must not surpass 15% of the examination amount that supplies through a sieve (2000 μ m) through the summation of No. five sieves (180 μ m) by " Chinese Pharmacopoeia 2005 editions " appendix IN granule [granularity] item.The settling volume ratio: by " Chinese Pharmacopoeia 2005 editions " appendix IO oral solution oral suspensions Orally taken emulsion item [settling volume ratio] detection method, the settling volume ratio should be not less than 0.90.
1000 bags of embodiment 1 compound recipe phenylpropanolamine granules (specification phenylpropanolamine HC1 25mg, chlorphenamine maleate 1mg/ bag), prescription:
Phenylpropanolamine HC1 25g
Chlorphenamine maleate 1g
Amberlite?IRP?120 20g
Polyvinylpyrrolidone 10g
Citric acid 10g
Sodium citrate 8g
Sucrose is to 1000g
Technological parameter is seen table 2, and testing result is seen table 3.
The right romilar sheet of embodiment 2 compound recipe hydrobromic acids, 1000 (the right romilar 20mg of specification hydrobromic acid, chlorphenamine maleate 4mg/ sheet), prescription:
The right romilar 20g of hydrobromic acid
Phenyltoloxamine 4g
Amberlite
?IRP?69 40g
Hydroxypropyl emthylcellulose 6g
Carboxymethyl starch sodium 10g
Citric acid 10g
Lactose is to 100g
Technological parameter is seen table 2, and testing result is seen table 3.
Embodiment 3 compound codeine phosphate capsules, 1000 (specification compound codeine phosphate 30mg, phenyltoloxamine 10mg/ grain), prescription:
Codeine phosphate 30g
Phenyltoloxamine 10
DOW?50wx8 100g
Polyvinylpyrrolidone 40g
Magnesium stearate 2g
Differential silica gel 2g
Lactose is to 200g
Technological parameter is seen table 2, and testing result is seen table 3.
1000 bags of embodiment 4 compound recipe phenylpropanolamine sustained-release granular formulations (specification phenylpropanolamine HC1 75mg, chlorphenamine maleate 3mg/ bag), prescription:
Phenylpropanolamine HC1 75g
Chlorphenamine maleate 3g
Amberlite
IRP?120 60g
Gather first ammonium acrylate ester II 0.6g
Polyvinylpyrrolidone 30g
Citric acid 30g
Sodium citrate 24g
Sucrose is to 3000g
Technological parameter is seen table 2, and testing result is seen table 3.
The right romilar slow-release dispersible tablets of embodiment 5 compound recipe hydrobromic acids, 1000 (the right romilar 60mg of specification hydrobromic acid, chlorphenamine maleate 8mg/ sheet), prescription:
The right romilar 60g of hydrobromic acid
Phenyltoloxamine 6g
Amberlite
?IRP?69 100g
Hydroxypropyl emthylcellulose 14g
Gather first ammonium acrylate ester II 6g
Carboxymethyl starch sodium 60g
Citric acid 30g
Lactose is to 300g
Technological parameter is seen table 2, and testing result is seen table 3.
Embodiment 6 compound codeine phosphate slow releasing capsulees, 1000 (specification compound codeine phosphate 90mg, phenyltoloxamine 30mg/ grain), prescription:
Codeine phosphate 90g
Phenyltoloxamine 30g
DOW50wx8 300g
Gather first ammonium acrylate ester II 30g
Polyvinylpyrrolidone 120g
Magnesium stearate 6g
Differential silica gel 6g
Lactose is to 600g
Technological parameter is seen table 2, and testing result is seen table 3.
1000 bags of embodiment 7 compound recipe pseudoephedrine dry suspension (specification pseudoephedrine hydrochloride 30mg, chlorphenamine maleate 1mg/ bag), prescription:
Pseudoephedrine hydrochloride 30g
Chlorphenamine maleate 1g
Amberlite
?IRP?64 20g
Microcrystalline Cellulose 100g
Hydroxypropyl emthylcellulose 4g
Sodium carboxymethyl cellulose 3g
Xanthan gum 3g
Citric acid 10g
Sodium citrate 8g
Sucrose is to 1000g
Technological parameter is seen table 4, and testing result is seen table 5.
1000 bags of embodiment 8 compound recipe pseudoephedrine dry suspension (specification pseudoephedrine hydrochloride 20mg, chlorphenamine maleate 1mg/ bag), prescription:
Pseudoephedrine hydrochloride 20g
Chlorphenamine maleate 1g
Amberlite
?IRP?88 25g
Microcrystalline Cellulose 20g
Hydroxypropyl emthylcellulose 4g
Sodium carboxymethyl cellulose 3g
Xanthan gum 3g
Citric acid 10g
Sodium citrate 6g
Sucrose is to 100g
Technological parameter is seen table 4, and testing result is seen table 5.
1000 bags of embodiment 9 compound recipe pseudoephedrine dry suspension (specification pseudoephedrine hydrochloride 15mg, chlorphenamine maleate 1mg/ bag), prescription:
Pseudoephedrine hydrochloride 15g
Chlorphenamine maleate 1g
DOWEX?MAC-3 100g
Microcrystalline Cellulose 40g
Hydroxypropyl emthylcellulose 4g
Sodium carboxymethyl cellulose 3g
Xanthan gum 3g
Citric acid 10g
Sodium citrate 9g
Sucrose is to 200g
Technological parameter is seen table 4, and testing result is seen table 5.
1000 bags of embodiment 10 compound recipe pseudoephedrine slow-release dry suspensions (specification pseudoephedrine hydrochloride 90mg, chlorphenamine maleate 4mg/ bag), prescription:
Pseudoephedrine hydrochloride 90g
Chlorphenamine maleate 4g
Microcrystalline Cellulose 300g
Hydroxypropyl emthylcellulose 12g
Sodium carboxymethyl cellulose 9g
Xanthan gum 9g
Citric acid 300g
Sodium citrate 24g
Sucrose is to 3000g
Technological parameter is seen table 4, and testing result is seen table 5.
1000 bags of embodiment 11 compound recipe pseudoephedrine slow-release dry suspensions (specification pseudoephedrine hydrochloride 60mg, chlorphenamine maleate 3mg/ bag), prescription:
Pseudoephedrine hydrochloride 60g
Chlorphenamine maleate 3g
?RLPO 3g
Microcrystalline Cellulose 60g
Hydroxypropyl emthylcellulose 12g
Sodium carboxymethyl cellulose 9g
Xanthan gum 9g
Citric acid 30g
Sodium citrate 18g
Sucrose is to 300g
Technological parameter is seen table 4, and testing result is seen table 5.
1000 bags of embodiment 12 compound recipe pseudoephedrine slow-release dry suspensions (specification pseudoephedrine hydrochloride 45mg, chlorphenamine maleate 3mg/ bag), prescription:
Pseudoephedrine hydrochloride 45g
Chlorphenamine maleate 3g
DOWEX?MAC-3 300g
Microcrystalline Cellulose 100g
Hydroxypropyl emthylcellulose 12g
Sodium carboxymethyl cellulose 9g
Xanthan gum 9g
Citric acid 30g
Sodium citrate 27g
Sucrose is to 600g
Technological parameter is seen table 4, and testing result is seen table 5.
100 bottles of embodiment 13 compound recipe codeine suspensions (the every 10ml phosphoric acid of specification codeine 10mg, chlorphenamine maleate 1mg), prescription:
Codeine phosphate 1g
Chlorphenamine maleate 0.1g
Sucrose 100g
Xanthan gum 4g
Microcrystalline Cellulose 1g
Disodiumedetate 0.1g
Citric acid 0.6
Sodium citrate 0.4
Ethyl Hydroxybenzoate 2g
Sodium benzoate 2g
Pigment 0.02g
Essence 0.07g
Purified water is to 1000ml
Technological parameter is seen table 6, and testing result is seen table 7.
Embodiment 14,100 bottles of compound recipe codeine suspensions (the every 5ml phosphoric acid of specification codeine 50mg, chlorphenamine maleate 1mg), and prescription:
Codeine phosphate 10g
Chlorphenamine maleate 0.2g
?IRP?69 100g
Sucrose 250g
Xanthan gum 5g
Microcrystalline Cellulose 40g
Sodium carboxymethyl cellulose 5g
Disodiumedetate 5g
Citric acid 3g
Sodium citrate 2g
Ethyl Hydroxybenzoate 2g
Sodium benzoate 2g
Pigment 0.02g
Essence 0.07g
Purified water is to 1000ml
Technological parameter is seen table 6, and testing result is seen table 7.
100 bottles of embodiment 15 compound recipe codeine suspensions (the every 10ml phosphoric acid of specification codeine 20mg, chlorphenamine maleate 2mg), prescription:
Codeine phosphate 2g
Chlorphenamine maleate 0.2g
50wx8 10g
Sucrose 200g
Xanthan gum 4g
Microcrystalline Cellulose 20g
Disodiumedetate 1g
Citric acid 6g
Sodium citrate 4g
Ethyl Hydroxybenzoate 2.7g
Sodium benzoate 2.0g
Pigment 0.02g
Essence 0.07g
Purified water is to 1000ml
Technological parameter is seen table 6, and testing result is seen table 7.
100 bottles of embodiment 16 compound recipe codeine slow-release suspensions (the every 10ml phosphoric acid of specification codeine 5mg, chlorphenamine maleate 1mg), prescription:
Codeine phosphate 0.5g
Chlorphenamine maleate 0.1g
Sucrose 100g
Xanthan gum 4g
Microcrystalline Cellulose 1g
Disodiumedetate 0.1g
Citric acid 0.6
Sodium citrate 0.4g
Ethyl Hydroxybenzoate 2.7g
Sodium benzoate 2g
Pigment 0.02g
Essence 0.07g
Purified water is to 1000ml
Technological parameter is seen table 6, and testing result is seen table 7.
Embodiment 17,100 bottles of compound recipe codeine slow-release suspensions (the every 5ml phosphoric acid of specification codeine 50mg, chlorphenamine maleate 8mg), and prescription:
Codeine phosphate 10g
Chlorphenamine maleate 0.8g
Sucrose 250g
Xanthan gum 5g
Microcrystalline Cellulose 40g
Sodium carboxymethyl cellulose 5g
Disodiumedetate 5g
Citric acid 3g
Sodium citrate 2g
Ethyl Hydroxybenzoate 2g
Sodium benzoate 2g
Pigment 0.02g
Essence 0.07g
Purified water is to 1000ml
Technological parameter is seen table 6, and testing result is seen table 7.
100 bottles of embodiment 18 compound recipe codeine slow-release suspensions (the every 10ml phosphoric acid of specification codeine 20mg, chlorphenamine maleate 4mg), prescription:
Codeine phosphate 2g
Chlorphenamine maleate 0.4g
50wx8 10g
Sucrose 200g
Xanthan gum 4g
Microcrystalline Cellulose 20g
Disodiumedetate 1g
Citric acid 6g
Sodium citrate 4g
Ethyl Hydroxybenzoate 2g
Sodium benzoate 2g
Pigment 0.02g
Essence 0.07g
Purified water is to 1000ml
Technological parameter is seen table 6, and testing result is seen table 7.
Table 1 test item
| Dosage form | Content and ratio | The release degree | Dissolution | Granularity | Suspension ability |
| Compound tablet | + | — | + | — | — |
| The compound capsule agent | + | — | + | — | — |
| The compound granular agent | + | — | + | + | — |
| Compound dried suspension | + | — | + | — | + |
| Compound sustained-released tablet | + | + | — | — | — |
| The compound sustained release capsules agent | + | + | — | — | — |
| Compound sustained-released granule | + | + | — | + | — |
| Compound sustained-released dry suspension | + | + | — | — | + |
| Compound sustained-released suspensoid | + | + | — | — | + |
(+be detection ,-needn't detection)
Table 2 embodiment 1-6 technological parameter
Table 3 embodiment 1-6 testing result
Table 4 embodiment 7-12 technological parameter
Table 5 embodiment 7-12 testing result
Table 6 embodiment 13-18 technological parameter
Table 7 embodiment 13-18 testing result
Claims (18)
1. compound preparation, it is characterized in that: the every 1000g of said compound preparation is made up of following weight ratio ingredient: phenylpropanolamine HC1 25g, chlorphenamine maleate 1g; Amberlite IRP 12020g, polyvinylpyrrolidone 10g, citric acid 10g; Sodium citrate 8g, all the other are sucrose; Adopt following method to prepare: may further comprise the steps: one, phenylpropanolamine HC1, chlorphenamine maleate are added and be equipped with in the container of purified water, stirring adds Amberlite IRP 120 after making its dissolving; 100 rev/mins of speeds of agitator, leave standstill then at 6 hours time; Filter supernatant liquid, precipitum is taken out, place 80 ℃ of temperature to carry out hot air drying; Cross 80～200 mesh sieve granulate, obtain compound medicine ion exchange resin microgranule; Two,, mix getting mixed material in 40 minutes with compound medicine ion exchange resin microgranule, polyvinylpyrrolidone, citric acid, sodium citrate and sucrose; Three, mixed material is granulated by granule production technology commonly used, obtain the compound granular agent by the packing of specification granule.
2. compound preparation, it is characterized in that: the every 100g of said compound preparation is made up of following weight ratio ingredient: the right romilar 20g of hydrobromic acid, phenyltoloxamine 4g; Amberlite IRP 6940g, hydroxypropyl emthylcellulose 6g, carboxymethyl starch sodium 10g; Citric acid 10g, all the other are lactose; Adopt following method to prepare: may further comprise the steps: one, the right romilar of hydrobromic acid, phenyltoloxamine are added and be equipped with in the container of purified water, stirring adds Amberlite IRP 69 after making its dissolving; 200 rev/mins of speeds of agitator, wash 1 time at 4 hours time; Leave standstill then, filter supernatant liquid, precipitum is taken out; Place the 60C temperature to carry out hot air drying, cross 80～200 mesh sieve granulate, obtain compound medicine ion exchange resin microgranule; Two,, mix getting mixed material in 40 minutes with compound medicine ion exchange resin microgranule, hydroxypropyl emthylcellulose, carboxymethyl starch sodium, citric acid and lactose; Three, mixed material is pressed into tablet by the convas tablet production technology, obtains compound tablet by specification cover blister package.
3. compound preparation, it is characterized in that: the every 200g of said compound preparation is made up of following weight ratio ingredient: codeine phosphate 30g, phenyltoloxamine 10g; DOW 50wx8100g, polyvinylpyrrolidone 40g, magnesium stearate 2g; Differential silica gel 2g, all the other are lactose; Adopt following method to prepare: may further comprise the steps: one, codeine phosphate, phenyltoloxamine are added and be equipped with in the container of purified water, stirring adds DOW 50wx8 after making its dissolving; 400 rev/mins of speeds of agitator, wash 4 times at 3 hours time; Leave standstill then, filter supernatant liquid, precipitum is taken out; Place 40 ℃ of temperature to carry out drying under reduced pressure, 80～200 mesh sieve granulate are crossed in the back, obtain compound medicine ion exchange resin microgranule; Two,, mix getting mixed material in 20 minutes with compound medicine ion exchange resin microgranule, polyvinylpyrrolidone, magnesium stearate, differential silica gel and lactose; Three, mixed material is filled suitable capsule formulation by capsule production technology commonly used, obtain the compound capsule agent by specification cover blister package.
4. compound preparation, it is characterized in that: the every 3000g of said compound preparation is made up of following weight ratio ingredient: phenylpropanolamine HC1 75g, chlorphenamine maleate 3g; Amberlite IRP 12060g; Gather first ammonium acrylate ester II 0.6g, polyvinylpyrrolidone 30g, citric acid 30g; Sodium citrate 24g, all the other are sucrose; Adopt following method to prepare: may further comprise the steps: one, with phenylpropanolamine HC1, chlorphenamine maleate, to add and be equipped with in the container of purified water, after stirring makes its dissolving; Add Amberlite IRP 120,800 rev/mins of speeds of agitator, 1 hour time; Leave standstill then; Filter supernatant liquid, precipitum takes out and places 30 ℃ of temperature to carry out drying under reduced pressure, and the back is crossed 80～200 mesh sieve granulate and obtained compound medicine ion exchange resin microgranule; Two, will gather first ammonium acrylate ester II, using isopropyl alcohol to be dissolved to concentration is 0.1%, adds compound medicine ion exchange resin microgranule; Under 80 ℃ of degree conditions; Reacted 1 hour, precipitum is taken out in sedimentation, filtration; Place 40 ℃ of temperature drying under reduced pressure, the back is crossed 80～200 mesh sieve granulate and is obtained compound sustained-released medicine ion exchanger resin microgranule; Three, with compound sustained-released medicine ion exchanger resin microgranule, polyvinylpyrrolidone, citric acid, sodium citrate and sucrose, three-dimensional multinomial mixing got mixed material in 10 minutes; Four, mixed material is pressed granule production technology commonly used, granulate, obtain compound sustained-released granule by the packing of specification granule racking machine.
5. compound preparation, it is characterized in that: the every 300g of said compound preparation is made up of following weight ratio ingredient: the right romilar 60g of hydrobromic acid, phenyltoloxamine 6g; Amberlite IRP 69100g; Hydroxypropyl emthylcellulose 14g gathers first ammonium acrylate ester II 6g, carboxymethyl starch sodium 60g; Citric acid 30g, all the other are lactose; Adopt following method to prepare: may further comprise the steps: one,, to add and be equipped with in the container of purified water, after stirring makes its dissolving with the right romilar of hydrobromic acid, phenyltoloxamine; Add Amberlite IRP 69,100 rev/mins of speeds of agitator, 6 hours time; Leave standstill then, wash 1 time, filter supernatant liquid; Precipitum takes out and places 80 ℃ of temperature to carry out hot air drying, and the back is crossed 80～200 mesh sieve granulate and obtained compound medicine ion exchange resin microgranule; Two, will gather first ammonium acrylate ester II, using dissolve with ethanol to concentration is 1%, adds compound medicine ion exchange resin microgranule; Under 30 ℃ of degree conditions; Reacted 6 hours, precipitum is taken out in sedimentation, filtration; Place 30 ℃ of temperature to carry out drying under reduced pressure, the back is crossed 80～200 mesh sieve granulate and is obtained compound sustained-released medicine ion exchanger resin microgranule; Three, with compound sustained-released medicine ion exchanger resin microgranule, hydroxypropyl emthylcellulose, carboxymethyl starch sodium, citric acid and lactose, three-dimensional multinomial mixing got mixed material in 10 minutes; Four, mixed material is pressed into tablet by the convas tablet production technology, obtains compound sustained-released tablet by specification cover blister package.
6. compound preparation, it is characterized in that: the every 600g of said compound preparation is made up of following weight ratio ingredient: codeine phosphate 90g, phenyltoloxamine 30g; DOW 50wx8300g; Gather first ammonium acrylate ester II 30g, polyvinylpyrrolidone 120g, magnesium stearate 6g; Differential silica gel 6g, all the other are lactose; Adopt following method to prepare: may further comprise the steps: one, codeine phosphate, phenyltoloxamine are added and be equipped with in the container of purified water, stirring adds DOW 50wx8 after making its dissolving; 200 rev/mins of speeds of agitator; 4 hours time, leave standstill then, wash 4 times; Filter supernatant liquid, precipitum is subsequent use; Two, will gather first ammonium acrylate ester II, using dissolve with ethanol to concentration is 20%, adds precipitum; Under 45 ℃ of degree conditions; Reacted 4 hours, precipitum is taken out in sedimentation, filtration; Place 60 ℃ of temperature to carry out hot air drying, the back is crossed 80～200 mesh sieve granulate and is obtained compound sustained-released medicine ion exchanger resin microgranule; Three, with compound sustained-released medicine ion exchanger resin microgranule, polyvinylpyrrolidone, magnesium stearate, differential silica gel and lactose, three-dimensional multinomial mixing got mixed material in 10 minutes; Four, mixed material is filled suitable capsule formulation by capsule production technology commonly used, obtain the compound sustained release capsules agent by specification cover blister package.
7. compound preparation, it is characterized in that: the every 1000g of said compound preparation is made up of following weight ratio ingredient: pseudoephedrine hydrochloride 30g, chlorphenamine maleate 1g; Amberlite IRP 6420g, microcrystalline Cellulose 100g, hydroxypropyl emthylcellulose 4g; Sodium carboxymethyl cellulose 3g, xanthan gum 3g, citric acid 10g; Sodium citrate 8g, all the other are sucrose; Adopt following method to prepare: may further comprise the steps: one, with pseudoephedrine hydrochloride, chlorphenamine maleate, to add and be equipped with in the container of purified water, after stirring makes its dissolving; Add Amberlite IRP 64,100 rev/mins of speeds of agitator, 6 hours time; Leave standstill then, filter supernatant liquid, precipitum is taken out; Place 80 ℃ of temperature to carry out hot air drying, the back is crossed 80～200 mesh sieve granulate and is obtained compound medicine ion exchange resin microgranule; Two, with compound medicine ion exchange resin microgranule, microcrystalline Cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, xanthan gum, citric acid, sodium citrate and sucrose, mixed 40 minutes, get mixed material; Three, with mixed material by dry suspension production technology commonly used, granulate or, obtain compound dried suspension directly by the specification packing.
8. compound preparation, it is characterized in that: the every 100g of said compound preparation is made up of following weight ratio ingredient: pseudoephedrine hydrochloride 20g, chlorphenamine maleate 1g; Amberlite IRP 8825g, microcrystalline Cellulose 20g, hydroxypropyl emthylcellulose 4g; Sodium carboxymethyl cellulose 3g, xanthan gum 3g, citric acid 10g; Sodium citrate 6g, all the other are sucrose; Adopt following method to prepare: may further comprise the steps: one, pseudoephedrine hydrochloride, chlorphenamine maleate are added and be equipped with in the container of purified water, stirring adds Amberlite IRP 88 after making its dissolving; 200 rev/mins of speeds of agitator, wash 1 time at 4 hours time; Leave standstill then, filter supernatant liquid, precipitum is taken out; Place 60 ℃ of temperature to carry out hot air drying, the back is crossed 80～200 mesh sieve granulate and is obtained compound medicine ion exchange resin microgranule; Two, with compound medicine ion exchange resin microgranule, microcrystalline Cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, xanthan gum, citric acid, sodium citrate and sucrose, mixed 40 minutes, get mixed material; Three, with mixed material by dry suspension production technology commonly used, granulate or, obtain compound dried suspension directly by the specification packing.
9. compound preparation, it is characterized in that: the every 200g of said compound preparation is made up of following weight ratio ingredient: pseudoephedrine hydrochloride 15g, chlorphenamine maleate 1g; DOWEX MAC-3100g, microcrystalline Cellulose 40g, hydroxypropyl emthylcellulose 4g; Sodium carboxymethyl cellulose 3g, xanthan gum 3g, citric acid 10g; Sodium citrate 9g, all the other are sucrose; Adopt following method to prepare: may further comprise the steps: one, pseudoephedrine hydrochloride, chlorphenamine maleate are added and be equipped with in the container of purified water, stirring adds DOWEX MAC-3 after making its dissolving; 400 rev/mins of speeds of agitator, wash 4 times at 3 hours time; Leave standstill then, filter supernatant liquid, precipitum is taken out; Place 40 ℃ of temperature to carry out drying under reduced pressure, the back is crossed 80～200 mesh sieve granulate and is obtained compound medicine ion exchange resin microgranule; Two, with compound medicine ion exchange resin microgranule, microcrystalline Cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, xanthan gum, citric acid, sodium citrate and sucrose, mixed 20 minutes, get mixed material; Three, with mixed material by dry suspension production technology commonly used, granulate or, obtain compound dried suspension directly by the specification packing.
10. compound preparation, it is characterized in that: the every 3000g of said compound preparation is made up of following weight ratio ingredient: pseudoephedrine hydrochloride 90g, chlorphenamine maleate 4g; Amberlite IRP 6460g, Eudragit RL PO0.6g, microcrystalline Cellulose 300g; Hydroxypropyl emthylcellulose 12g, sodium carboxymethyl cellulose 9g, xanthan gum 9g; Citric acid 300g, sodium citrate 24g, all the other are sucrose; Adopt following method to prepare: may further comprise the steps: one, pseudoephedrine hydrochloride, chlorphenamine maleate to be added and be equipped with in the container of purified water; Stirring adds Amberlite IRP 64,800 rev/mins of speeds of agitator after making its dissolving; 1 hour time; Leave standstill then, filter supernatant liquid, place 30 ℃ of temperature to carry out crossing behind the drying under reduced pressure 80～200 mesh sieve granulate and obtain compound medicine ion exchange resin microgranule; Two, with Eudragit RL PO; Using isopropyl alcohol to be dissolved to concentration is 0.1%, adds compound medicine ion exchange resin microgranule, under 80 ° of degree conditions; Reacted 1 hour; Precipitum is taken out in sedimentation, filtration, places 40 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind the drying under reduced pressure and obtains compound sustained-released medicine ion exchanger resin microgranule; Three, with compound medicine slow release ion exchange resin microgranule, microcrystalline Cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, xanthan gum, citric acid, sodium citrate and sucrose, three-dimensional multinomial mixing got mixed material in 10 minutes; Four, with mixed material by dry suspension production technology commonly used, granulate or, obtain compound sustained-released dry suspension directly by the specification packing.
11. a compound preparation is characterized in that: the every 300g of said compound preparation is made up of following weight ratio ingredient: pseudoephedrine hydrochloride 60g, chlorphenamine maleate 3g; Amberlite IRP 8875g, Eudragit RL PO3g, microcrystalline Cellulose 60g; Hydroxypropyl emthylcellulose 12g, sodium carboxymethyl cellulose 9g, xanthan gum 9g; Citric acid 30g, sodium citrate 18g, all the other are sucrose; Adopt following method to prepare: may further comprise the steps: one, pseudoephedrine hydrochloride, chlorphenamine maleate are added and be equipped with in the container of purified water, stirring adds Amberlite IRP 88 after making its dissolving; 100 rev/mins of speeds of agitator; 6 hours time, leave standstill then, wash 1 time; Filter supernatant liquid, mistake 80～200 mesh sieve granulate obtained compound medicine ion exchange resin microgranule after precipitum placed 80 ℃ of temperature to carry out hot air drying; Two, with Eudragit RL PO; Using dissolve with ethanol to concentration is 1%, adds compound medicine ion exchange resin microgranule, under 30 ° of degree conditions; Reacted 6 hours; Sedimentation, washing 1 time, filter, precipitum is taken out, place 30 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind the drying under reduced pressure and obtain compound sustained-released medicine ion exchanger resin microgranule; Three, with compound medicine slow release ion exchange resin microgranule, microcrystalline Cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, xanthan gum, citric acid, sodium citrate and sucrose, three-dimensional multinomial mixing got mixed material in 10 minutes; Four, with mixed material by dry suspension production technology commonly used, granulate or, obtain compound sustained-released dry suspension directly by the specification packing.
12. a compound preparation is characterized in that: the every 600g of said compound preparation is made up of following weight ratio ingredient: pseudoephedrine hydrochloride 45g, chlorphenamine maleate 3g; DOWEX MAC-3300g, Eudragit RLPO 30g, microcrystalline Cellulose 100g; Hydroxypropyl emthylcellulose 12g, sodium carboxymethyl cellulose 9g, xanthan gum 9g; Citric acid 30g, sodium citrate 27g, all the other are sucrose; Adopt following method to prepare: may further comprise the steps: one, pseudoephedrine hydrochloride, chlorphenamine maleate are added and be equipped with in the container of purified water, stirring adds DOWEX MAC-3 after making its dissolving; 200 rev/mins of speeds of agitator; 4 hours time, leave standstill then, wash 4 times; Filter supernatant liquid, precipitum is subsequent use; Two, with Eudragit RLPO; Using dissolve with ethanol to concentration is 20%, adds precipitum, under 40 ° of degree conditions; Reacted 4 hours; Sedimentation, washing 4 times, filter, precipitum is taken out, place 60 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind the hot air drying and obtain compound sustained-released medicine ion exchanger resin microgranule; Three, with compound medicine slow release ion exchange resin microgranule, microcrystalline Cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, xanthan gum, citric acid, sodium citrate and sucrose, three-dimensional multinomial mixing got mixed material in 10 minutes; Four, with mixed material by dry suspension production technology commonly used, granulate or, obtain compound sustained-released dry suspension directly by the specification packing.
13. a compound preparation is characterized in that: the every 1000ml of said compound preparation is made up of following weight ratio ingredient: codeine phosphate 1g, chlorphenamine maleate 0.1g, Amberlite IRP 1201g; Sucrose 100g, xanthan gum 4g, microcrystalline Cellulose 1g, disodiumedetate 0.1g; Citric acid 0.6g, sodium citrate 0.4g, Ethyl Hydroxybenzoate 2g, sodium benzoate 2g; Pigment 0.02g, essence 0.07g, all the other are purified water; Adopt following method to prepare: may further comprise the steps: one, codeine phosphate, chlorphenamine maleate to be added and be equipped with in the container of purified water; After stirring makes its dissolving; Add Amberlite IRP120,100 rev/mins of speeds of agitator, 6 hours time; Filter supernatant liquid, place 80 ℃ of temperature to carry out crossing behind the hot air drying 80～200 mesh sieve granulate and obtain compound medicine ion exchange resin microgranule; Two, with compound medicine ion exchange resin microgranule, sucrose, xanthan gum, microcrystalline Cellulose, disodiumedetate, citric acid, sodium citrate, Ethyl Hydroxybenzoate, sodium benzoate, pigment, essence and purified water; Be stirred to uniform liquid; Filling machine obtains the compound recipe suspension by the specification fill.
14. a compound preparation is characterized in that: the every 1000ml of said compound preparation is made up of following weight ratio ingredient: codeine phosphate 10g, chlorphenamine maleate 0.2g, Amberlite IRP 69100g; Sucrose 250g, xanthan gum 5g, microcrystalline Cellulose 40g, sodium carboxymethyl cellulose 5g; Disodiumedetate 5g, citric acid 3g, sodium citrate 2g, Ethyl Hydroxybenzoate 2g; Sodium benzoate 2g, pigment 0.02g, essence 0.07g, all the other are purified water; Adopt following method to prepare: may further comprise the steps: one, codeine phosphate, chlorphenamine maleate to be added and be equipped with in the container of purified water; Stirring adds Amberlite IRP 69,200 rev/mins of speeds of agitator after making its dissolving; 4 hours time; Wash 1 time, filter supernatant liquid, place 30 ℃ of temperature to carry out crossing behind the drying under reduced pressure 80～200 mesh sieve granulate and obtain compound medicine ion exchange resin microgranule; Two, with compound medicine ion exchange resin microgranule, sucrose, xanthan gum, microcrystalline Cellulose, sodium carboxymethyl cellulose, disodiumedetate, citric acid, sodium citrate, Ethyl Hydroxybenzoate, sodium benzoate, pigment, essence and purified water; Be stirred to uniform liquid; Filling machine obtains the compound recipe suspension by the specification fill.
15. a compound preparation is characterized in that: the every 1000ml of said compound preparation is made up of following weight ratio ingredient: codeine phosphate 2g, chlorphenamine maleate 0.2g, DOW 50wx810g; Sucrose 200g, xanthan gum 4g, microcrystalline Cellulose 20g, disodiumedetate 1g; Citric acid 6g, sodium citrate 4g, Ethyl Hydroxybenzoate 2.7g, sodium benzoate 2.0g; Pigment 0.02g, essence 0.07g, all the other are purified water; Adopt following method to prepare: may further comprise the steps: one, codeine phosphate, chlorphenamine maleate to be added and be equipped with in the container of purified water; Stirring adds DOW 50wx8,800 rev/mins of speeds of agitator after making its dissolving; 1 hour time; Wash 4 times, filter supernatant liquid, precipitum is subsequent use; Two, with precipitum, sucrose, xanthan gum, microcrystalline Cellulose, disodiumedetate, citric acid, sodium citrate, Ethyl Hydroxybenzoate, sodium benzoate, pigment, essence and purified water; Be stirred to uniform liquid; Filling machine obtains the compound recipe suspension by the specification fill.
16. a compound preparation is characterized in that: the every 1000ml of said compound preparation is made up of following weight ratio ingredient: codeine phosphate 0.5g, chlorphenamine maleate 0.1g, Amberlite IRP1201g; Eudragit RS PO 0.01g, sucrose 100g, xanthan gum 4g, microcrystalline Cellulose 1g; Disodiumedetate 0.1g, citric acid 0.6g, sodium citrate 0.4g, Ethyl Hydroxybenzoate 2.7g; Sodium benzoate 2g, pigment 0.02g, essence 0.07g, all the other are purified water; Adopt following method to prepare: may further comprise the steps: one, codeine phosphate, chlorphenamine maleate to be added and be equipped with in the container of purified water; After stirring makes its dissolving; Add Amberlite IRP120,800 rev/mins of speeds of agitator, 1 hour time; Filter supernatant liquid, place 30 ℃ of temperature to carry out crossing behind the drying under reduced pressure 80～200 mesh sieve granulate and obtain compound medicine ion exchange resin microgranule; Two, using isopropyl alcohol to be dissolved to concentration Eudragit RS PO is 0.1%; Add compound medicine ion exchange resin microgranule; Under 80 ° of degree conditions, reacted sedimentation, filtration 1 hour; Precipitum is taken out, place 40 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind the drying under reduced pressure and obtain compound sustained-released medicine ion exchanger resin microgranule; Three, compound sustained-released medicine ion exchanger resin microgranule, sucrose, xanthan gum, microcrystalline Cellulose, disodiumedetate, citric acid, sodium citrate, Ethyl Hydroxybenzoate, sodium benzoate, pigment, essence and purified water; Be stirred to uniform liquid, filling machine obtains compound sustained-released suspension by the specification fill.
17. a compound preparation is characterized in that: the every 1000ml of said compound preparation is made up of following weight ratio ingredient: codeine phosphate 10g, chlorphenamine maleate 0.8g, Amberlite IRP 69100g, EudragitL10010g; Sucrose 250g, xanthan gum 5g, microcrystalline Cellulose 40g, sodium carboxymethyl cellulose 5g; Disodiumedetate 5g, citric acid 3g, sodium citrate 2g, Ethyl Hydroxybenzoate 2g; Sodium benzoate 2g, pigment 0.02g, essence 0.07g, all the other are purified water; Adopt following method to prepare: may further comprise the steps: one, codeine phosphate, chlorphenamine maleate to be added and be equipped with in the container of purified water; Stirring adds Amberlite IRP 69,100 rev/mins of speeds of agitator after making its dissolving; 6 hours time; Wash 1 time, filter supernatant liquid, place 80 ℃ of temperature to carry out crossing behind the hot air drying 80～200 mesh sieve granulate and obtain compound medicine ion exchange resin microgranule; Two, Eudragit L100 being used dissolve with ethanol to concentration is 1%; Add compound medicine ion exchange resin microgranule; Reaction is 6 hours under 30 ° of degree conditions; Sedimentation, washing 1 time, filter, place 30 ℃ of temperature to carry out crossing 80～200 mesh sieve granulate behind the drying under reduced pressure and obtain compound sustained-released medicine ion exchanger resin microgranule; Three, with compound sustained-released medicine ion exchanger resin microgranule, sucrose, xanthan gum, microcrystalline Cellulose, sodium carboxymethyl cellulose, disodiumedetate, citric acid, sodium citrate, Ethyl Hydroxybenzoate, sodium benzoate, pigment, essence and purified water; Be stirred to uniform liquid, filling machine obtains compound sustained-released suspension by the specification fill.
18. a compound preparation is characterized in that: the every 1000ml of said compound preparation is made up of following weight ratio ingredient: codeine phosphate 2g, chlorphenamine maleate 0.4g, DOW 50wx810g; Eudragit S1000.5g, sucrose 200g, xanthan gum 4g, microcrystalline Cellulose 20g; Disodiumedetate 1g, citric acid 6g, sodium citrate 4g, Ethyl Hydroxybenzoate 2g; Sodium benzoate 2g, pigment 0.02g, essence 0.07g, all the other are purified water; Adopt following method to prepare: may further comprise the steps: one, codeine phosphate, chlorphenamine maleate are added and be equipped with in the container of purified water, stirring adds DOW50wx8 after making its dissolving; 200 rev/mins of speeds of agitator, wash 4 times at 4 hours time; Filter supernatant liquid, precipitum is subsequent use; Two, Eudragit S100 being used dissolve with ethanol to concentration is 20%, adds precipitum, and reaction is 4 hours under 45 ° of degree conditions, sedimentation, washing 4 times, filtration; Three, with precipitum, sucrose, xanthan gum, microcrystalline Cellulose, disodiumedetate, citric acid, sodium citrate, Ethyl Hydroxybenzoate, sodium benzoate, pigment, essence and purified water; Be stirred to uniform liquid, filling machine obtains compound sustained-released suspension by the specification fill.
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| CN105250240B (en) * | 2015-08-25 | 2017-05-17 | 江苏先科药业有限公司 | Oral sustained-release preparation containing hydrocodone and chlorpheniramine |
| CN110314234B (en) * | 2018-03-22 | 2023-12-08 | 广东东阳光药业股份有限公司 | Rosuvastatin calcium resin complex and composition thereof |
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Address after: 518110, No. 16, Lan Qing Road, Guanlan new high tech Zone, Longhua New District, Guangdong, Shenzhen Patentee after: Sinopharm (Shenzhen) Pharmaceutical Co., Ltd. Address before: 518029 Bagualing Industrial Zone, Shenzhen, Guangdong, Futian District Patentee before: Zhijun Pharmaceutical Co., Ltd., Shenzhen |