CN103479593B - Preparation method for omeprazole enteric coated tablet - Google Patents
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Abstract
The invention relates to a preparation method for an omeprazole enteric coated tablet. The components comprise in percents by weight: 10-50% of omeprazole, 1.25-6.25% of superfine silica powder, 30-78% of lactose, 2-3% of copolyvinylpyrrolidone, 5-12% of crospovidone, 1.5-2.0% of sodium octadecyl fumarate and 0.5-1.0% of magnesium stearate. The preparation method comprises: uniformly mixing micronized omeprazole and superfine silica powder, sieving; sieving copolyvinylpyrrolidone, crospovidone, lactose and sodium octadecyl fumarate, uniformly mixing with omeprazole and superfine silica powder, adding into a drying-method granulator, granulating for 3-4 times, screening out integrated particles with a 60 mesh sieve and obtaining dry particles; blending uniformly the dry particles and magnesium stearate by a three-dimensional mixer, adding into a tablet press for pressing tablets; and then coating to obtain the omeprazole enteric coated tablet. The formula is simple; the preparation method helps to solve the industrialized production problem of omeprazole enteric coated tablet high-specification products such as a product with a specification of 40 mg/tablet; and the preparation is controllable in quality, the product is good in uniformity, and impurity content is low.
Description
Technical field:
The preparation method that the present invention relates to a kind of Omeprazole Enteric-coated Tablets, belongs to field of medicine preparing technology.
Background technology:
In digestive tract, contact the limitation that the internal film tissue of gastric juice part occurs damaged, comprise lower esophagus, gastroduodenal first paragraph, conventionally claim gastric ulcer and duodenal ulcer, general name peptic ulcer, erosive gastritis can develop into Peptic Ulcers, and motherland's medical science claims gastric abscess.Aspect epidemiology, peptic ulcer is a commonly encountered diseases, and its sickness rate is at different times, and different regions difference is larger, and total sickness rate accounts for 10～20% of population.U.S. peptic ulcer patient approximately 10%, Germany is 12.3%; China is according to the investigation of minority area, and digestive tract disease sickness rate is 11.43%, and wherein peptic ulcer rate is 4.54%.Only country of the U.S., has just reached 13,900,000,000 dollars for the medical expense of peptic ulcer every year.
At present along with Chinese society development, the change of circumstances, the variation of population structure and people life style, main because of smoking, drink, peptic ulcer rate that the factor such as nervous, medicine irritation causes increases gradually, become a kind of commonly encountered diseases and frequently-occurring disease, bring great misery to patient, cause patients ' life quality to decline.For these reasons, the treatment of peptic ulcer more and more receives publicity clinically and payes attention to, therefore Development and Production safely and effectively medicament for resisting peptic ulcer receive publicity, and become one of the emphasis of current drug development research and focus.
Anti-ulcer medicament has H
2receptor antagonist (representing medicine ranitidine), antacid (representing medicine hydrotalcite), proton pump inhibitor (representing medicine omeprazole) etc., but from the listing of proton pump inhibitor omeprazole, due to determined curative effect, omeprazole becomes rapidly topmost anti-ulcer medicament.Omeprazole grinds by AstraZeneca is former, and omeprazole enteric-coated capsules from 1992 (trade name losec) goes on the market at home, and because curative effect is outstanding, Market reaction is good.Domestic production producer, in the time it being domesticized to research, has researched and developed Omeprazole Enteric-coated Tablets.Omeprazole Enteric-coated Tablets design sheet footpath is
ensure that tablet passes through rapidly pylorus (pylorus tranquillization diameter 12.8 ± 7mm) in the time of gastric emptying, arrival intestinal release medicine enters blood circulation and plays a role, with traditional antacid, anticholinergic agent, H
2receptor antagonist compare there is higher selectivity, better curative effect (strong 2-7 doubly).As long as be administered once and can reach therapeutic purposes morning every day, in the 2-4 week course for the treatment of, particularly can thoroughly kill helicobacter pylori with antimicrobial drug drug combination and reach therapeutic purposes.
At present, Omeprazole Enteric-coated Tablets production technology is mainly wet granulation, the wet granulation technology that Chinese patent 201010109148.0 and 201210530305.4 all adopts.Because omeprazole principal agent itself is met wet, heat, chance acid is all perishable, in technique preparation, should avoid contacting the environment such as water, high temperature, acid, to reduce the impact in preparation process, main constituent being caused.But in fact, due to adding of binding agent, and large in batches while producing greatly, be difficult in process of production control moisture and the impact of high temperature on omeprazole, thereby make omeprazole degraded and produce impurity, affect the treatment and drug safety.Detect and find through impurity, its total impurities of the product after wet granulation obviously improves compared with raw material, if Shop floor control is bad, and the as easy as rolling off a log prescribed limit that exceedes of impurity.And as easy as rolling off a log viscosity of bringing out omeprazole itself after wet granulation technology, easily there is the phenomenon of sticking during as the product tabletting of 40mg/ sheet in the product of high standard, its plain sheet hardness is not high yet, the requirement that does not reach coating.Therefore wet granulation and be not suitable for Omeprazole Enteric-coated Tablets technique preparation, particularly high standard cannot realize suitability for industrialized production by wet granulation as the Omeprazole Enteric-coated Tablets of 40mg/ sheet.
Because omeprazole character is special, be insoluble in water, need be carried out micronization to improve the stripping of medicine, if adopt the method for direct powder compression, the physical propertys such as bulk density, granularity and the particle size distribution of the medicine after micronization and the selected adjuvant of direct powder compression fall far short, and carrying out in the process of supplementary material mixing, the principal agent after micronization is difficult to and other auxiliary materials and mixing, its uniformity of dosage units is wayward, therefore can not use direct powder compression.
The present invention is by a large amount of experimentatioies, invented a kind of formula simple, adopted dry granulation to produce feasible, the reasonably large production method of Omeprazole Enteric-coated Tablets, the method both can avoid meeting the damp and hot principal agent that affects aborning, the impurity content that ensures medicine is lower, and release is better; Jointly mix by principal agent and micropowder silica gel the Electrostatic Absorption problem that has solved omeprazole again, by adding adjuvant sodium stearyl fumarate to ensure that granular mass good in dry granulation process is applicable to the problem of tabletting, thereby ensured the practical feasibility of large production, the preparation of producing can be realized quality controllable.Use the present invention can prepare high standard as the Omeprazole Enteric-coated Tablets of 40mg/ sheet specification simultaneously.
Summary of the invention:
The object of the invention is to overcome the shortcoming of prior art, a kind of preparation method of the solid composite medicament that contains omeprazole is provided.Said composition has been carried out preferably, uses and has significantly improved omeprazole release with polyvinylpolypyrrolidone and copolyvidone pairing; Adopt dry granulation technique, can effectively improve the stability of preparation, by adding adjuvant sodium stearyl fumarate to ensure that granular mass good in dry granulation process is to be more suitable for tabletting; Simple process of the present invention, easily operation, be suitable for suitability for industrialized production.
In order to realize foregoing invention object, the preparation method of a kind of Omeprazole Enteric-coated Tablets of the present invention, using omeprazole as principal agent, taking micropowder silica gel, lactose, copolyvidone, polyvinylpolypyrrolidone, sodium stearyl fumarate, magnesium stearate as adjuvant, it is as follows that the each component of tablet accounts for tablet weight percentage ratio:
Active component omeprazole accounts for 10～50%;
Filler micropowder silica gel accounts for 1.25～6.25%;
Filler lactose accounts for 30～78%;
Binding agent copolyvidone accounts for 2～3%;
Disintegrating agent polyvinylpolypyrrolidone accounts for 5～12%;
Filler sodium stearyl fumarate accounts for 1.5～2.0%;
Magnesium stearate lubricant accounts for 0.5～1.0%;
Wherein, the weight ratio of copolyvidone and polyvinylpolypyrrolidone is 1:2.5～1:4;
Operation in accordance with the following steps: adopt dry granulation technique, will jointly mix 200 mesh sieves with 1.25～6.25% micropowder silica gel after 10～50% omeprazole micronization; 2～3% copolyvidone, 5～12% polyvinylpolypyrrolidone, 30～78% lactose, 1.5～2.0% sodium stearyl fumarate are crossed after 200 mesh sieves, mixed homogeneously with omeprazole, micropowder silica gel; The material of mix homogeneously is added in dry granulating machine and granulated, 10 hertz of filler speed in frequency, 30 hertz of granulation speed in frequency, granulation pressure 2-3MPa, granulation screen sizes approximately 30 orders, through 3-4 granulation, with 60 mesh sieve granulate, obtain dry granule appropriate; By dry granule, 0.5～1.0% magnesium stearate three-dimensional mixer mix homogeneously, add in tablet machine loading hopper tabletting; Plain sheet after tabletting is carried out to coating, make Omeprazole Enteric-coated Tablets of the present invention.
The present invention screens formula, and because omeprazole belongs to the material of slightly solubility, preferably polyvinylpolypyrrolidone and copolyvidone pairing are used as the adjuvant of raising omeprazole release, and wherein, polyvinylpolypyrrolidone uses as disintegrating agent.Polyvinylpolypyrrolidone can show rapidly high capillary activity and excellent hydration capability, the almost tendency of gel-free as tablet disintegrant.Polyvinylpolypyrrolidone is done after disintegrating agent compacting in flakes, and disintegration is short, and dissolution rate is high; Stability is strong, not can through time and become, be called as super-disintegrant.It has had the character of PVP and PVAC concurrently copolyvidone molecule.Copolyvidone has retained good water solublity, caking property and the film property of PVP, has relatively much lower water absorption and more broad solubility property, better plasticity and stronger surface activity again than PVP.Therefore copolyvidone is a kind of good tablet binder, applies its tablet making and have the characteristic of low friability, and under wet condition, film-making can less bond, and is particularly useful for high dose, poorly water-soluble and the film-making to water sensitive medicine and pelletize.To polyvinylpolypyrrolidone, copolyvidone, pairing is used as disintegrating agent and binding agent, finds, when copolyvidone and polyvinylpolypyrrolidone weight ratio are the release that 1:2.5～1:4 can significantly improve omeprazole through experimental study.
The present invention is in dry granulation technical study process, and in discovery omeprazole dry granulation, pellet hardness causes more greatly the difficulty of tabletting.By adjusting existing filler and adding traditional lubrication agent to fail effectively to address this problem.Find after deliberation to add sodium stearyl fumarate can effectively solve omeprazole granule in dry granulation process problem that is difficult to molding in tabletting process that causes really up to the mark, ensured the feasibility of large production.
The present invention adopts in dry granulation technical study process, consider the problem that mixes of omeprazole in actual production process, all adjuvants except magnesium stearate lubricant are crossed to 200 mesh sieves, ensure that omeprazole can fully mix in the time mixing, the uniformity of dosage units of principal agent can meet the requirements.
The present invention is in dry granulation technical study process, find that omeprazole easily produces Electrostatic Absorption, therefore after selecting micropowder silica gel and omeprazole jointly to mix, after 200 mesh sieves, ensure the granularity of omeprazole, can eliminate the Electrostatic Absorption problem of omeprazole self simultaneously.
The present invention, by a large amount of experimentatioies, has invented a kind of formula simple, adopts dry granulation to produce feasible, the reasonably large production method of Omeprazole Enteric-coated Tablets.Dry granulation makes omeprazole avoid touching moisture, can solve the problem that uprises of omeprazole impurity that Omeprazole Enteric-coated Tablets occurs in producing.Meanwhile, the present invention has also solved Omeprazole Enteric-coated Tablets high standard as the suitability for industrialized production problem of 40mg/ sheet specification product.At present listing Omeprazole Enteric-coated Tablets only has two kinds of 10mg and 20mg specifications, and 40mg Omeprazole Enteric-coated Tablets cannot be realized suitability for industrialized production, and this is all to adopt wet granulation technology due to Omeprazole Enteric-coated Tablets at present, and Omeprazole Enteric-coated Tablets design sheet diameter is
sheet heavy fixing (should be not more than 90mg/ sheet) substantially, as developed the Omeprazole Enteric-coated Tablets of 40mg specification, its main constituent approaches the half that accounts for whole formulation weight, by as easy as rolling off a log viscosity of bringing out omeprazole itself after wet granulation technology, when tabletting, easily there is the phenomenon of sticking, the requirement that does not reach coating.And adopting dry granulation of the present invention, the sheet that can make omeprazole is heavy smaller, adopts dry granulation can make the Omeprazole Enteric-coated Tablets of 40mg.
Detailed description of the invention:
Below by specific embodiment, the preparation method of medicine of the present invention is further elaborated.
Embodiment 1,
Medicine specification: 10mg
Fill a prescription as follows:
Preparation method: pharmaceutical formulation is the same.
1, omeprazole crude drug micronization, after jointly mixing with micropowder silica gel after 200 mesh sieves; Lactose, copolyvidone, polyvinylpolypyrrolidone, sodium stearyl fumarate are crossed 200 mesh sieves, and magnesium stearate is crossed 100 mesh sieves, for subsequent use;
2, the supplementary material except magnesium stearate is mixed 60 minutes to mix homogeneously;
3, the material of mix homogeneously is added in dry granulating machine and granulated, 10 hertz of filler speed in frequency, 30 hertz of granulation speed in frequency, granulation pressure 2-3MPa, granulation screen sizes approximately 30 orders, through 3-4 granulation, with 60 mesh sieve granulate, obtain dry granule appropriate;
4, dry granule, magnesium stearate are joined to three-dimensional mixer, mix 20 minutes to evenly, add in tablet machine loading hopper tabletting;
5, by plain sheet bag contagion gown and enteric coating after tabletting, make Omeprazole Enteric-coated Tablets of the present invention.
Embodiment 2,
Medicine specification: 20mg
Fill a prescription as follows:
| Element slice prescription | Ratio (percentage by weight) | 1000 slice prescription amounts (g) |
| Omeprazole | 25.00％ | 20.00 |
| Micropowder silica gel | 3.13％ | 2.50 |
| Lactose | 60.12％ | 48.10 |
| Copolyvidone | 2.50％ | 2.00 |
| Polyvinylpolypyrrolidone | 7.00％ | 5.60 |
| Sodium stearyl fumarate | 1.50％ | 1.20 |
| Magnesium stearate | 0.75％ | 0.60 |
| Amount to | 100％ | 80 |
Preparation method: pharmaceutical formulation is the same.
1, omeprazole crude drug micronization, after jointly mixing with micropowder silica gel after 200 mesh sieves; Lactose, copolyvidone, polyvinylpolypyrrolidone, sodium stearyl fumarate are crossed 200 mesh sieves, and magnesium stearate is crossed 100 mesh sieves, for subsequent use;
2, the supplementary material except magnesium stearate is mixed 60 minutes to mix homogeneously;
3, the material of mix homogeneously is added in dry granulating machine and granulated, 10 hertz of filler speed in frequency, 30 hertz of granulation speed in frequency, granulation pressure 2-3MPa, granulation screen sizes approximately 30 orders, through 3-4 granulation, with 60 mesh sieve granulate, obtain dry granule appropriate;
4, dry granule, magnesium stearate are joined to three-dimensional mixer, mix 20 minutes to evenly, add in tablet machine loading hopper tabletting;
5, by plain sheet bag contagion gown and enteric coating after tabletting, make Omeprazole Enteric-coated Tablets of the present invention.
Embodiment 3,
Medicine specification: 40mg
Fill a prescription as follows:
| Element slice prescription | Ratio (percentage by weight) | 1000 slice prescription amounts (g) |
| Omeprazole | 45.45％ | 40.00 |
| Micropowder silica gel | 5.68％ | 5.00 |
| Lactose | 36.21％ | 31.86 |
| Copolyvidone | 2.05％ | 1.80 |
| Polyvinylpolypyrrolidone | 7.95％ | 7.00 |
| Sodium stearyl fumarate | 1.75％ | 1.54 |
| Magnesium stearate | 0.91％ | 0.80 |
| Amount to | 100％ | 88 |
Preparation method: pharmaceutical formulation is the same.
1, omeprazole crude drug micronization, after jointly mixing with micropowder silica gel after 200 mesh sieves; Lactose, copolyvidone, polyvinylpolypyrrolidone, sodium stearyl fumarate are crossed 200 mesh sieves, and magnesium stearate is crossed 100 mesh sieves, for subsequent use;
2, the supplementary material except magnesium stearate is mixed 60 minutes to mix homogeneously;
3, the material of mix homogeneously is added in dry granulating machine and granulated, 10 hertz of filler speed in frequency, 30 hertz of granulation speed in frequency, granulation pressure 2-3MPa, granulation screen sizes approximately 30 orders, through 3-4 granulation, with 60 mesh sieve granulate, obtain dry granule appropriate;
4, dry granule, magnesium stearate are joined to three-dimensional mixer, mix 20 minutes to evenly, add in tablet machine loading hopper tabletting;
5, by plain sheet bag contagion gown and enteric coating after tabletting, make Omeprazole Enteric-coated Tablets of the present invention.
Embodiment of the present invention sample simulation listing packaging also grinds with former the investigation experimentation that keeps sample for a long time together with medicine, commercially available Omeprazole Enteric-coated Tablets (wet granulation technology), and 0,3,6,9,12,18,24,30 month sample analysis after placing.By the requirement of two Omeprazole Enteric-coated Tablets quality standards of " Chinese Pharmacopoeia " version in 2010, investigate project release, related substance, content, the investigation result of the test that keeps sample for a long time sees the following form.
Conclusion (of pressure testing): medicine of the present invention is through keeping sample and investigate 30 months for a long time, indices is all normal after testing, all meet two quality standard requirements of Omeprazole Enteric-coated Tablets " Chinese Pharmacopoeia " version in 2010, related substance, content and release index are all better than former grind medicine and the listing Omeprazole Enteric-coated Tablets agent through wet granulation technology.
Claims (1)
1. the preparation method of an Omeprazole Enteric-coated Tablets, it is characterized in that using omeprazole as principal agent, taking micropowder silica gel, lactose, copolyvidone, polyvinylpolypyrrolidone, sodium stearyl fumarate, magnesium stearate as adjuvant, it is as follows that the each component of tablet accounts for tablet weight percentage ratio: active component omeprazole accounts for 10～50%; Filler micropowder silica gel accounts for 1.25～6.25%; Filler lactose accounts for 30～78%; Binding agent copolyvidone accounts for 2～3%; Disintegrating agent polyvinylpolypyrrolidone accounts for 5～12%; Filler sodium stearyl fumarate accounts for 1.5～2.0%; Magnesium stearate lubricant accounts for 0.5～1.0%; Wherein, the weight ratio of copolyvidone and polyvinylpolypyrrolidone is 1:2.5～1:4; Operation in accordance with the following steps: adopt dry granulation technique, will jointly mix 200 mesh sieves with micropowder silica gel after omeprazole micronization; Copolyvidone, polyvinylpolypyrrolidone, lactose, sodium stearyl fumarate are crossed after 200 mesh sieves, mixed homogeneously with omeprazole, micropowder silica gel; The material of mix homogeneously is added in dry granulating machine and granulated, 10 hertz of filler speed in frequency, 30 hertz of granulation speed in frequency, granulation pressure 2-3MPa, granulation screen sizes 30 orders, through 3-4 granulation, with 60 mesh sieve granulate, obtain dry granule; By dry granule, magnesium stearate three-dimensional mixer mix homogeneously, add in tablet machine loading hopper tabletting; By plain sheet bag contagion gown and enteric coating after tabletting, make Omeprazole Enteric-coated Tablets.
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Inventor after: Geng Shixia Inventor after: Ni Zhiwei Inventor after: Jiang Jinxiao Inventor after: Yang Shanshan Inventor after: Lu Dafeng Inventor before: Geng Shixia Inventor before: Li Cunfu Inventor before: Ni Zhiwei Inventor before: Jiang Jinxiao Inventor before: Yang Shanshan |
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Free format text: CORRECT: INVENTOR; FROM: GENG SHIXIA LI CUNFU NI ZHIWEI JIANG JINXIAO YANG SHANSHAN TO: GENG SHIXIA NI ZHIWEI JIANG JINXIAO YANG SHANSHAN LU DAFENG |
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Address after: 266108, 2 whale Road, Liuting Industrial Park, Chengyang District, Shandong, Qingdao Patentee after: Qingdao Shuangwhale Pharmaceutical Co.,Ltd. Address before: 266108, 2 whale Road, Liuting Industrial Park, Chengyang District, Shandong, Qingdao Patentee before: QINGDAO DOUBLE WHALE PHARMACEUTICAL Co.,Ltd. |
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