CN101732282B - Omeprazole enteric capsule and preparation method thereof - Google Patents
Omeprazole enteric capsule and preparation method thereof Download PDFInfo
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- CN101732282B CN101732282B CN2010101237764A CN201010123776A CN101732282B CN 101732282 B CN101732282 B CN 101732282B CN 2010101237764 A CN2010101237764 A CN 2010101237764A CN 201010123776 A CN201010123776 A CN 201010123776A CN 101732282 B CN101732282 B CN 101732282B
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Abstract
The invention belongs to the technical field of medicines, particularly to an omeprazole enteric capsule and a preparation method thereof. The omeprazole enteric capsule is characterized in that an enteric solid dispersion body containing an omeprazole clathrate compound comprises omeprazole, clathrate materials, an enteric solid dispersion body carrier, a disintegrating agent and an excipient. The invention has the advantages of simple and convenient production process, strong operation controllability, stable process parameters, and releases in intestines rapidly and can be suitable for industrialized production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of omeprazole enteric-coated capsules and preparation method thereof.
Background technology
Omeprazole is a proton pump inhibitor class antiulcerative, can treat duodenal ulcer, gastric ulcer and esophagitis, and can eliminate the intractable ulcer crisis, and treatment Zhuo-Ai two syndromes are also very effective.It is powerful and lasting to press down the acid effect, splendid to peptic ulcer and the backflow curative effect of ulcer of serious esophagus that routine treatment can not onset, and side effect is rarely found.
The omeprazole instability, chemical name 5-methoxy foundation stone-[(4-methoxyl group-3,5-dimethyl-2-pyridine radicals)-and methyl] sulfenyl-1H-benzimidazole, in acid and neutral medium, be easy to degraded, its stability also is subjected to the influence of light, humidity, heat, organic solvent, even under normal storage service condition, because the degraded of omeprazole also can be found the variable color of preparation; There is the slow problem of onset in the omeprazole poor solubility simultaneously.
WO9852564 discloses the proton pump inhibitor granule, and it comprises the medicated layer that active substance combines with alkaline matter, and the barrier layer of being made up of lyophobic dust and the inert core of enteric coat layer.CN1093855C discloses new containing unsettled omeprazole composition of acid and preparation method, and it comprises inner core, intermediate layer and the enteric coat layer that contains the unsettled omeprazole active component of acid.CN1114405C discloses a kind of omeprazole microgranule, wherein each self-contained medicated layer and the stomach protective layer that contains stomach protectiveness reagent.CN100425235C discloses a kind of omeprazole enteric coated pellets formulation and preparation method thereof, and the ball core of described omeprazole enteric coated pellets formulation contains omeprazole and pharmaceutical excipient, and is surrounded by intermediate isolating layer and enteric coating protective layer on described core.CN100490790C discloses a kind of enteric coated micropill and preparation method thereof, and it includes celphere, contains pharmaceutically active layer, sealing coat and the enteric coating layer of alkaline components.
Above-mentioned patented technology has all adopted the method for the clothing of double-baging at least to suppress omeprazole degraded under one's belt, but there are the following problems: (1) causes the production process complexity owing to adopt the granule coating technology, and operation controllability is poor, technological parameter is difficult to fix, and difference is big between criticizing and criticizing.(2) multiple coatings technology because of the slow dissolving of coatings in intestinal delayed the rapid release of medicine at the duodenum position, has influenced curative effect of medication.
Summary of the invention
For overcoming the deficiency that prior art exists, the invention provides a kind of omeprazole enteric-coated capsules, this capsule can discharge rapidly in intestinal, and it is easy to have production process, and operation controllability is strong, the advantage that technological parameter is stable; The invention provides in addition and can be fit to the preparation method that industrialization is produced.
Omeprazole enteric-coated capsules preparation provided by the invention contains the enteric solid dispersion of omeprazole clathrate, is made up of omeprazole, enclose material, enteric solubility solid dispersion carrier, disintegrating agent, excipient etc., and concrete weight proportion is as follows:
1 part of omeprazole
0.5～5 part of enclose material
Disintegrating agent 0.3-1 part
1～10 part in enteric solubility solid dispersion carrier
0.5～20 part of excipient
Wherein above-mentioned enclose material is selected from one or more in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, hydroxyethyl-, the HP-, preferably beta-schardinger dextrin-.
Wherein above-mentioned enteric solubility solid dispersion carrier material is selected from one or more in Hydroxypropyl Methylcellulose Phathalate, polyacrylic resin, the cellulose acetate-phthalate, preferably polyacrylic resin.
Wherein above-mentioned disintegrating agent is selected from one or more in carboxymethyl starch sodium, crosslinked carboxymethyl fecula sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, the starch.
Other wherein above-mentioned excipient are selected from one or more in filler, binding agent, the lubricant.
Wherein above-mentioned filler is selected from one or more in lactose, microcrystalline Cellulose, calcium hydrogen phosphate, starch, pregelatinized Starch, dextrin, calcium sulfate, mannitol, glucose, sorbitol, sucrose, calcium carbonate, the calcium phosphate.
Wherein above-mentioned binding agent is selected from one or more in polyvidone, hydroxypropyl level methylcellulose, ethyl cellulose, the methylcellulose.
Wherein above-mentioned lubricant is selected from one or more in magnesium stearate, micropowder silica gel, hydrogenated vegetable oil, Pulvis Talci, sodium lauryl sulphate, calcium stearate, zinc stearate, the stearic acid.
Omeprazole enteric-coated capsules preparation provided by the invention, its preparation method is as follows:
(1) preparation of omeprazole cyclodextrin clathrate
Cyclodextrin, omeprazole are dissolved in the alcoholic acid 0.3-1% ammonia spirit of 30-85% (V/V) 40 ℃-60 ℃ of preparation temperature; The mixed liquor of above-mentioned gained is carried out drying with spray drying method, collect the omeprazole cyclodextrin clathrate, wherein the spray drying parameter is: 40 ℃-60 ℃ of inlet temperatures, spray velocity 2-10ml/min, atomisation pressure are 1-5bar;
(2) the enteric solubility solid dispersion of preparation clathrate
Take by weighing omeprazole clathrate, solid dispersion carrier, the disintegrating agent of recipe quantity, join in an amount of 30-85% (V/V) ethanol, 40～60 ℃ of following stirring and dissolving keep 40～60 ℃ of decompression rotary evaporation solvents, the preparation solid dispersion;
(3) with prepared solid dispersion drying, sieve, conventional method prepares granule or directly incapsulates with pharmaceutics auxiliary materials and mixing commonly used, must omeprazole enteric-coated capsules.
For solving the problems of the prior art, we have carried out experiment targetedly, intend adopting solid dispersions technique, and omeprazole and carrier material are prepared into the enteric solubility solid dispersion, but omeprazole structure neutral and alkali group is more, the character of enteric coating material is acidic materials, and is water insoluble, also is insoluble in the acidic buffer, in intestinal, dissolve, if omeprazole and enteric coatings material are directly prepared solid dispersion, because acid-base reaction can cause the omeprazole degraded.
We find unexpectedly in experimentation, at first adopt the method for cyclodextrin inclusion compound to prepare the omeprazole clathrate, on this basis clathrate is made the enteric solubility solid dispersion then, so both avoided the degraded of omeprazole, can guarantee that again medicine is at the enteral rapid release.Reason may be that omeprazole is molecularity after by enclose, has therefore improved the dissolubility of omeprazole, and omeprazole can be discharged rapidly in intestinal; The omeprazole molecule is enclosed in the cavity in the cyclodextrin molecular, has improved the stability of omeprazole, has avoided the reaction of omeprazole and enteric solubility solid dispersion material.
Adopt solid dispersion technology, the omeprazole cyclodextrin clathrate is become the enteric solubility solid dispersion with enteric solubility solid dispersion preparing carriers, surrounded by the stomach insoluble support around making clathrate, the control medicine discharges in small intestinal, utilize the bag of clathrate carrier to cover effect simultaneously, delay the degraded of omeprazole.
Omeprazole enteric-coated capsules prepared in accordance with the present invention, hydrochloric acid solution with sodium chloride (is got sodium chloride 1g, add hydrochloric acid 3.5ml, adding water to 500ml) 500ml is dissolution medium, rotating speed is 100 commentaries on classics, and through 2 hours, this preparation did not have significant change in appearance, acid-resistant strength reaches more than 95%, is higher than 90% of 2010 editions pharmacopeia requirements; The release test shows, the slurry method, 100 change, in the hydrochloric acid solution 500ml of 37 ± 0.5 ℃ of sodium chloride after 2 hours, adding is preheated to 37 ℃ 0.235mol/l disodium phosphate soln 400ml, and in the time of 15 minutes, sampling records release and reached more than 85%, far above 45 minutes of the pharmacopeia requirement, release was more than 80%; Related substance is about 0.4%, is lower than 2% of 2010 editions pharmacopeia requirements.
Omeprazole enteric-coated capsules prepared in accordance with the present invention quickens to investigate 6 months in 40 ± 2 ℃, the climatic chamber of relative humidity 75 ± 5%, and the appearance character of enteric coated capsule, related substance, release and content were compared with 0 day, did not all have significant difference.
The specific embodiment
Embodiment 1
1 part of omeprazole
1.5 parts of alpha-cyclodextrins
0.3 part of carboxymethyl starch sodium
3 parts of polyacrylic resin L100-55
20 parts of microcrystalline Cellulose
Preparation technology:
(1) alpha-cyclodextrin, omeprazole are dissolved in alcoholic acid 0.3% ammonia spirit of 30% (V/V) 40 ℃ of preparation temperature; To get above-mentioned mixed liquor and carry out drying with spray drying method, wherein the spray drying parameter is: 40 ℃ of inlet temperatures, and spray velocity 2ml/min, atomisation pressure are 1bar, collect dry good omeprazole cyclodextrin clathrate at last;
(2) take by weighing omeprazole clathrate, polyacrylic resin L100-55, the carboxymethyl starch sodium of recipe quantity, join in an amount of 30-85% (V/V) ethanol 40 ℃ of following stirring and dissolving; Insulation, rotary evaporation, preparation solid dispersion;
(3) with prepared solid dispersion drying, sieve, again with the microcrystalline Cellulose mixing of recipe quantity, in incapsulating, omeprazole enteric-coated capsules.
Embodiment 2
1 part of omeprazole
2 parts of beta-schardinger dextrin-s
1 part of polyvinylpolypyrrolidone
5 parts of cellulose acetate-phthalates
5 parts of lactose
0.02 part of magnesium stearate
Preparation technology:
(1) beta-schardinger dextrin-, omeprazole are dissolved in alcoholic acid 0.4% ammonia spirit of 60% (V/V) 50 ℃ of preparation temperature; The mixed liquor of gained is carried out drying with spray drying method, and wherein the spray drying parameter is: 50 ℃ of inlet temperatures, and spray velocity 2ml/min, atomisation pressure are 5bar, collect dry good omeprazole cyclodextrin clathrate at last;
(2) take by weighing omeprazole clathrate, cellulose acetate-phthalate, the polyvinylpolypyrrolidone of recipe quantity, join in an amount of 75% (V/V) ethanol 40 ℃ of following stirring and dissolving; Insulation, rotary evaporation, preparation solid dispersion;
(3) with prepared solid dispersion drying, sieve, again with lactose, the magnesium stearate mixing of recipe quantity, in incapsulating, omeprazole enteric-coated capsules.
Embodiment 3
1 part of omeprazole
2 parts of gamma-cyclodextrins
1 part of cross-linking sodium carboxymethyl cellulose
4 parts of polyacrylic resin L30-D55
4 parts of lactose
2% 30 POVIDONE K 30 BP/USP, 30 aqueous solutions are an amount of
Preparation technology:
(1) gamma-cyclodextrin, omeprazole are dissolved in alcoholic acid 1% ammonia spirit of 85% (V/V) 52 ℃ of preparation temperature; The mixed liquor of gained is carried out drying with spray drying method, and wherein the spray drying parameter is: 52 ℃ of inlet temperatures, and spray velocity 6ml/min, atomisation pressure are 5bar, collect dry good omeprazole cyclodextrin clathrate at last;
(2) take by weighing omeprazole clathrate, polyacrylic resin L30-D55, the cross-linking sodium carboxymethyl cellulose of recipe quantity, join in an amount of 85% (V/V) ethanol 40 ℃ of following stirring and dissolving; Insulation, rotary evaporation, preparation solid dispersion;
(3) with prepared solid dispersion drying, sieve, again with the lactose mixing of recipe quantity, it is an amount of to add 2% 30 POVIDONE K 30 BP/USP, 30 aqueous solutions, granulate, drying, in incapsulating, omeprazole enteric-coated capsules.
Embodiment 4
1 part of omeprazole
2.5 parts of beta-schardinger dextrin-s
1 part of polyvinylpolypyrrolidone
5 parts of cellulose acetate-phthalates
5 parts of microcrystalline Cellulose
0.02 part of magnesium stearate
Preparation technology:
(1) beta-schardinger dextrin-, omeprazole are dissolved in alcoholic acid 0.4% ammonia spirit of 70% (V/V) 50 ℃ of preparation temperature; The mixed liquor of gained is carried out drying with spray drying method, and wherein the spray drying parameter is: 50 ℃ of inlet temperatures, and spray velocity 2ml/min, atomisation pressure are 5bar, collect dry good omeprazole cyclodextrin clathrate at last;
(2) omeprazole clathrate, cellulose acetate-phthalate, the polyvinylpolypyrrolidone that takes by weighing recipe quantity joins in an amount of 75% (V/V) ethanol 40 ℃ of following stirring and dissolving; Insulation, rotary evaporation, preparation solid dispersion;
(3) with prepared solid dispersion drying, sieve, again with microcrystalline Cellulose, the magnesium stearate mixing of recipe quantity, in incapsulating, omeprazole enteric-coated capsules.
Experimental example 1
Commercially available capsule and the made capsule of the present invention are carried out accelerated test, condition: 40 ℃ of relative humiditys 75% of temperature, the result is as follows.
| 0 day | 6 months | |
| Commercially available capsule | Labelled amount 99.8%, related substance 0.55%, 15min release 75.2% | Labelled amount 95.2%, related substance 1.55%, 15min release 65.2% |
| Embodiment 1 | Labelled amount 99.4%, related substance 0.48%, 15min release 92.9% | Labelled amount 98.2%, related substance 0.74%, 15min release 91.1% |
| Embodiment 2 | Labelled amount 99.6%, related substance 0.45%, 15min release 93.5% | Labelled amount 98.7%, related substance 0.69%, 15min release 92.9% |
| Embodiment 3 | Labelled amount 99.5%, related substance 0.49%, 15min release 92.6% | Labelled amount 98.8%, related substance 0.71%, 15min release 91.8% |
| Embodiment 4 | Labelled amount 99.7%, related substance 0.44%, 15min release 94.6% | Labelled amount 98.4%, related substance 0.76%, 15min release 91.6% |
It can be seen from the table, the self-control capsule adopts the enteric solid dispersion of making behind the cyclodextrin inclusion technique, and its related substance does not have to increase substantially, and content, dissolution change little; Commercially available capsule related substance increases obviously, and content, dissolution descend more, therefore, the more commercially available capsule of self-control capsule, stability is higher.
Claims (1)
1. omeprazole enteric-coated capsules preparation is characterized in that containing the enteric solid dispersion of omeprazole cyclodextrin clathrate, form and weight proportion as follows:
1 part of omeprazole
As 1～5 part of the cyclodextrin of enclose material
Disintegrating agent 0.3-1 part
1～10 part in enteric solubility solid dispersion carrier
0.5～20 part of excipient
Described excipient is selected from one or more in filler, binding agent and the lubricant.
2. omeprazole enteric-coated capsules preparation according to claim 1 is characterized in that described enclose material is selected from one or more in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, hydroxyethyl-and the HP-.
3. omeprazole enteric-coated capsules preparation according to claim 1 and 2 is characterized in that described enclose material is a beta-schardinger dextrin-.
4. omeprazole enteric-coated capsules preparation according to claim 1 is characterized in that described enteric solubility solid dispersion carrier is selected from one or more in Hydroxypropyl Methylcellulose Phathalate, polyacrylic resin L100-55, polyacrylic resin L30D-55, polyacrylic resin L100 and the cellulose acetate-phthalate.
5. omeprazole enteric-coated capsules preparation according to claim 1 is characterized in that described disintegrating agent is selected from one or more in carboxymethyl starch sodium, crosslinked carboxymethyl fecula sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and the starch.
6. omeprazole enteric-coated capsules preparation according to claim 1 is characterized in that described filler is selected from one or more in lactose, microcrystalline Cellulose, calcium hydrogen phosphate, starch, pregelatinized Starch, dextrin, calcium sulfate, mannitol, glucose, sorbitol, sucrose, calcium carbonate and the calcium phosphate.
7. omeprazole enteric-coated capsules preparation according to claim 1 is characterized in that described binding agent is selected from one or more in polyvidone, hydroxypropyl emthylcellulose, ethyl cellulose and the methylcellulose.
8. omeprazole enteric-coated capsules preparation according to claim 1 is characterized in that described lubricant is selected from one or more in magnesium stearate, micropowder silica gel, hydrogenated vegetable oil, Pulvis Talci, sodium lauryl sulphate, calcium stearate, zinc stearate and the stearic acid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010101237764A CN101732282B (en) | 2010-02-09 | 2010-02-09 | Omeprazole enteric capsule and preparation method thereof |
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|---|---|---|---|
| CN2010101237764A CN101732282B (en) | 2010-02-09 | 2010-02-09 | Omeprazole enteric capsule and preparation method thereof |
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| CN101732282B true CN101732282B (en) | 2011-08-31 |
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| CN102274204B (en) * | 2011-08-04 | 2013-03-27 | 悦康药业集团有限公司 | Omeprazole enteric-coated capsule and preparation method theroef |
| CN103127017A (en) * | 2013-03-01 | 2013-06-05 | 南京正宽医药科技有限公司 | Entecavir dispersible tablet and preparation method |
| CN107595845A (en) * | 2017-10-14 | 2018-01-19 | 南京正宽医药科技有限公司 | A kind of omeprazole enteric-coated capsules of gastric acid secretion inhibiting |
| CN111821337B (en) * | 2020-08-30 | 2022-05-17 | 扬子江药业集团广州海瑞药业有限公司 | Process for preparing pharmaceutical composition |
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