CN103230413A - Compound omeprazole preparation - Google Patents
Compound omeprazole preparation Download PDFInfo
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- CN103230413A CN103230413A CN2013100082859A CN201310008285A CN103230413A CN 103230413 A CN103230413 A CN 103230413A CN 2013100082859 A CN2013100082859 A CN 2013100082859A CN 201310008285 A CN201310008285 A CN 201310008285A CN 103230413 A CN103230413 A CN 103230413A
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Abstract
The invention provides a compound omeprazole preparation. According to the invention, the preparation is composed of micronized proton pump inhibitor omeprazole, an anti-acid agent sodium bicarbonate, and common pharmaceutically acceptable auxiliary materials. According to the invention, micronization process conditions are optimized, and micronization vibration frequency is adjusted, such that medicine particle size rang is effectively controlled. With the method, medicine dissolution rate and bioavailability are improved, and process controllability and stability are enhanced. According to the invention, omeprazole medicine is crushed with an independent micronization method or by combined micronization with the anti-acid agent and/or a filling agent. Particle size distribution is controlled within the range of d90 (20mum), d50 (4mum), and d10 (2mum). Compared with reference preparations in the market, the process stability is high, and dissolution effect is good.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to omeprazole compound medicine micronization and micronization particle size range and distribute.
Background technology
Proton pump inhibitor (PPIs) be in recent years wide clinical application, press down the strongest class medicine of acid effect.Be considered to treat the most effective medicine of stomach relevant disease, developed recently is very fast.First PPI omeprazole (omeprazole) went on the market in Switzerland in 1988, leminoprazole (leminoprazole), pantoprazole (pantoprazole), rabeprazole (rabeprazole), esomeprazole (esomeprazole), Tenatoprazole (tenatoprazole) and Perprazole a series of medicines such as (perprazole) have appearred in lansoprazole (lansoprazole) listing subsequently soon.
Proton pump inhibitor is weakly alkaline benzimidazoles compound, enters the secretory tubyle of parietal cell after the absorption, under the sour environment of official jargon, with H
+In conjunction with further forming activated product, with the proton pump inhibitor irreversible fixation, make the proton pump inactivation, thereby suppress the acid function of secreting of proton pump.
Omeprazole is the benzimidazole succedaneum, is that first is applied to clinical proton pump inhibitor.Can suppress the parietal cell secretase by specificity is to come the gastric acid inhibitory secretion.Be used for gastric ulcer, duodenal ulcer, stress ulcer, reflux esophagitis and Zollinger-Ellison Syndrome (gastrinoma) clinically.
In February, 2006, compound recipe rapid release proton pump depressant omeprazole/sodium bicarbonate 20 mg/1100 mg of drugs approved by FDA Santarus company, 40 mg/1100 mg capsules (trade name: Zegerid) listing, be quick-acting proton pump inhibitors (PPI), be used for the treatment of the symptoms such as heartburn that gastro oesophageal reflux disease (GORD) (GERD) causes, and erosive esophagitis, active stage benign gastric ulcer and active stage duodenal ulcer short term therapy.
This compound recipe omeprazole capsule is the compositions of omeprazole and sodium bicarbonate, the proton pump inhibitor quick releasing formulation that belongs to first listing, this combination is that design is ingenious, sodium bicarbonate not only has the direct effect of gastric acid inhibitory secretion in the side, can also prevent that omeprazole from being degraded by gastric acid, omeprazole quick-release preparation blood medicine peak time can effectively be controlled gastric acid all day in oral back 30 minutes.1 time on the one the Zegerid medicament can be controlled the gastric acid except the daytime, also can control gastric acid at night (night mean ph value 4.1,24 hours in pH value be 4.7) effectively.
The preparation method of the compound preparation of protected US Patent No. 6699885, US6645988, US6489346 and the US7399772 of this product and some relevant patent disclosures a kind of benzimidazole succedaneum proton pump inhibitor and at least a buffer reagent; liquid or solid pharmaceutical dosage form a kind of non-casing or slow release is provided; and provide a kind of by giving the method for the relevant gastrointestinal disorders of solid pharmaceutical dosage formulation therapic acid, but micronization PROCESS FOR TREATMENT proton pump inhibitor is not proposed.
US Patent No. 2,005 0031700 discloses a kind of powder solid preparation, comprises at least a micronized proton pump inhibitor, the manufacture method of at least a antacid and a kind of suspending agent and said preparation.Proton pump inhibitor comprises omeprazole, omeprazole hydrate, esomeprazole, Tenatoprazole, lansoprazole, pantoprazole, free alkalis such as rabeprazole, free acid, salt, hydrate, ester, amide, enantiomer, isomer, tautomer, distortion, or its prodrug.The process micronization processes of proton pump inhibitor, mean diameter 10-200 μ m.
US Patent No. 20100297220 discloses a kind of preparation method of drug oral preparation, and this medicine consists of at least a micronized sour absence of labile protons pump inhibitor and at least a bicarbonate and pharmaceutically uses adjuvant always.Pharmaceutical dosage form comprises: powder, tablet, disintegrating tablet, chewable tablet, capsule, effervescent tablet and suspending agent.Particle diameter more than 80% is not more than 40 μ m.
Above patent has all proposed the micronization mode and has handled the proton pump inhibitor medicine, but and the particle size range in the control particle micronization technical process not yet in effect distributes and degree, thereby cause preparation technology's unstable result, particle is inhomogeneous, dissolubility data changes greatly, unstable product quality, repeatability is relatively poor.
Summary of the invention
In order to overcome the above problems, the invention provides a kind of compound recipe omeprazole preparation, by the proton pump inhibitor omeprazole, the antacid sodium bicarbonate and pharmaceutically adjuvant commonly used form.
Described omeprazole airflow milling is carried out the micronization PROCESS FOR TREATMENT, by regulating the micronization frequency of vibration, effectively controls the particle size range distribution d of medicine
90＜20 μ m, d
50＜4 μ m, d
10＜2 μ m, one side has improved the dissolution rate of medicine, and shows for dynamics test data that through the body giving drugs into nose omeprazole preparation bioavailability of the present invention is higher; On the other hand, strengthened the controllability of technical process, the repeatability height has solved the technology stability problem.
The present invention is optimized the drug micronization particle diameter on original research basis, the micronization process of medicine can adopt multiple medicine material micronization and two kinds of method operations of associating facing-up micronization respectively, generally, can adopt filler or antacid and principal agent omeprazole, add a certain amount of solubilizing agent in the time of necessary and unite the facing-up micronization, to strengthen the controllability of micronization process, reduce operation easier; For the ease of measuring grain size of micropowder, this adopts the omeprazole medicine to pulverize separately.
The present invention, by regulating the micronization vibration frequency, adopt laser particle analyzer that raw material particle size is monitored mensuration (2010 editions pharmacopeia appendix IX E granularity and the particle size distribution method three therapeutic methods of traditional Chinese medicine) in real time, raw material remains in the particle size distribution of stable and consistent after making micropowder, thereby effectively guaranteed result of extraction, good stability, controllability is strong.
Micronization vibration frequency and particle diameter are linear negative correlation within the specific limits, but particle diameter is little after to a certain degree, then easily gather when superfine particle is more, particle diameter after the result gathers is bigger, increased diameter difference between particle, result of extraction is relatively poor, therefore is necessary to determine a suitable particle size range.Explore through a large amount of tests, we have selected a suitable index parameter scope, and it is well-balanced to make that particle diameter distributes, and result of extraction is best.
Particle size range under the various amplitude frequency condition distributes, result such as table 1.
The particle size range of table 1 various amplitude frequency distributes
Annotate: d
10, d
50, d
90Represent the diameter of 10%, 50%, 90% particle respectively; Undressed particle diameter is excessive, measures.
As seen from the above table, do not pass through 200 mesh sieve raw materials of micronization processes, the particle diameter half surpasses 50 μ m, and the particle diameter above 90% reaches more than the 100 μ m; And through micronized drug particle, within the specific limits, along with the reinforcement of micronization shake frequency of vibration, particle diameter reduces gradually, surpasses 50% particle diameter all below 5 μ m, and almost 90% above particle diameter is below 20 μ m.Therefore determine that omeprazole raw material optimum particle size range is distributed as d
90＜20 μ m, d
50＜4 μ m, d
10＜2 μ m.
By contrasting the micronization technology that the present invention adopts, medicine stripping good stability with commercially available similar commodity dissolution test.
Dissolution determination method, install according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C, second method), be release medium with pH7.4 phosphate buffer 900ml, rotating speed is that per minute 75 changes, and operation in accordance with the law is in the time of 30 minutes, getting solution filters, precision is measured subsequent filtrate 5ml, filters, and gets filter filtrate as need testing solution; Precision takes by weighing omeprazole reference substance 20mg in addition, puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, and precision is measured 1ml, puts in the 10ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, in contrast product solution.Get need testing solution and reference substance solution, measure according to the method under the assay item, calculate stripping quantity.
Choose the 32HZ vibration frequency, time 12min carries out omeprazole raw material micronization, and the control particle diameter is distributed as d
90＜20 μ m, d
50＜4 μ m, d
10＜2 μ m, (trade name Zegerid 20mg) compares, and serves as to investigate index with the 30min dissolution, investigates the stability of different technologies technology, the results are shown in Table 2 with commercially available similar commodity.
Table 2 dissolution study on the stability
| ? | 1 | 2 | 3 | 4 | 5 |  | RSD(%) |
| Experimental group | 95.18 | 95.26 | 95.27 | 95.84 | 96.33 | 95.58 | 0.52 |
| Commercially available | 88.76 | 91.39 | 92.48 | 93.65 | 95.22 | 93.70 | 2.64 |
As can be seen from the above table, compare with the drug particles of the present invention's preparation, commercially available group of particle diameter and dissolution stability are all relatively poor, the RSD value is experimental group more than 5 times, experimental group dissolution data unanimity, and the RSD value is below 1%, excellent stability, illustrated that controllability is strong, good stability by the micronization process of particle diameter control.
Further, the invention provides a kind of omeprazole compound preparation, by proton pump inhibitor omeprazole, antacid sodium bicarbonate and pharmaceutically adjuvant commonly used form, described omeprazole is through the micronization PROCESS FOR TREATMENT, particle size range is distributed as d
90＜20 μ m, d
50＜4 μ m, d
10＜2 μ m.
Omeprazole compound preparation of the present invention comprises oral formulations and injection, as tablet, dispersible tablet, effervescent tablet, double-layer tablet, multilayer tablet, slow releasing tablet, soft capsule, hard capsule, granule, powder, pill, dry suspension, suspending agent, syrup etc.Be preferably tablet and capsule.Described injection is selected from injection, injectable sterile powder and concentrated solution for injection, can be used for intramuscular injection, intravenous injection, intravenous drip etc.
In the prepared omeprazole compound preparation of the present invention, in omeprazole, omeprazole content is 20-40mg in the unit formulation.
Adjuvant of the present invention comprises solubilizing agent, disintegrating agent, filler, lubricant, binding agent, antioxidant etc.
Filler is the filler commonly used for the preparation of solid preparation well known in the art in the prepared omeprazole compound preparation of the present invention.Comprise starch, Icing Sugar, dextrin, lactose, pregelatinized Starch (PCS), microcrystalline Cellulose etc., accounting for the principal agent amount is 30-90%.The cohesive of lactose is more intense, and compression forming is good, and pregelatinized Starch makes prepared solid preparation have certain tensile strength.
The prepared available disintegrating agent of omeprazole compound preparation of the present invention accounts for principal agent amount ratio 2-8%.Be selected from microcrystalline Cellulose, pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, dried starch, low-substituted hydroxypropyl cellulose, the gas-producing disintegrant (sodium bicarbonate and citric acid) one or more.
The consumption of the solubilizing agent that the prepared omeprazole compound preparation of the present invention is selected for use is the 0.8-2.5% that accounts for the principal agent amount, is selected from polyoxyethylene sorbitan monoleate, poloxamer, PEG400 and 1000, the sodium lauryl sulphate one or more.
The prepared omeprazole compound preparation binding agent of the present invention can be selected 30 POVIDONE K 30 BP/USP 30 alcoholic solution for use, and is an amount of.
Among the present invention, adopt magnesium stearate 0.5%-1.0% as lubricant.
Description of drawings
Fig. 1 is the stripping curve fitted figure in micronization group and the commercially available reference preparation water;
Fig. 2 is the stripping curve fitted figure in micronization group and the commercially available reference preparation pH6.8 dissolution medium;
Curve chart when Fig. 3 is the pharmacokinetics medicine of omeprazole preparation and commercially available reference preparation.
The specific embodiment
Prescription:
| Omeprazole | 20g |
| Sodium bicarbonate | 1100g |
| Cross-linking sodium carboxymethyl cellulose | 30g |
| Magnesium stearate | 10g |
| Make | 1000 |
(1) 100 mesh sieves are standby excessively respectively to get adjuvant.
(2) get the omeprazole micronization processes, set cross frequence 25 ~ 40HZ, note is made intermediate 1, and is standby.
(3) measure intermediate 1, control its particle size distribution at d
90＜20 μ m, d
50＜4 μ m, d
10In＜2 mu m ranges.
(4) get 1/4 recipe quantity sodium bicarbonate and recipe quantity omeprazole mixing, add 1/4 recipe quantity sodium bicarbonate mixing again, note is made mixed material 1.
(5) get 1/4 recipe quantity sodium bicarbonate and mixed material 1 mixing, note is made mixed material 2; Get 1/4 recipe quantity sodium bicarbonate and recipe quantity cross-linking sodium carboxymethyl cellulose mixing again, note is made mixed material 3; Both mixings again of mixed material 2 and mixed material 3.
(6) add recipe quantity magnesium stearate mixing, note is made intermediate 2.
(7) measure intermediate 2, make intermediate content in 95.0 ~ 105.0% scopes.
(8) fill.
| Component | Content (g) |
| The omeprazole micropowder | 25 |
| Sodium bicarbonate | 1100 |
| Lactose | 140 |
| Pregelatinized Starch | 70 |
| Crospolyvinylpyrrolidone | 52 |
| 5% 30 POVIDONE | In right amount |
| Sodium lauryl sulphate | 15 |
| Magnesium stearate | 7.5 |
The preparation of omeprazole tablet:
(1) get former, adjuvant and cross 100 mesh sieves respectively, standby.
(2) make 5% 30 POVIDONE K 30 BP/USP 30 alcoholic solution, standby.
(3) get 100g sodium bicarbonate and omeprazole associating micronization processes, set cross frequence 25 ~ 40HZ, pulverize time 12min, note is made intermediate 1, and is standby.
(4) measure intermediate 1, control its particle size distribution at d
90＜20 μ m, d
50＜4 μ m, d
10In＜2 mu m ranges.
(5) get 1/2 recipe quantity sodium bicarbonate and above-mentioned micronized particle mixing, note is made mixed material 1, and residual sodium bicarbonate mixes with lactose, pregelatinized Starch, cross linked polyvinyl pyrrolidone, and note is made batch mixing 2.
(6) mixed material 1 adds the soft ability of 5% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution systems with after batch mixing 2 mixes, the granulation of sieving, 60 ℃ of dryings are crossed 18 mesh sieve granulate, add the magnesium stearate mixing after, tabletting.
With unprocessed omeprazole raw material, 200 orders sieve feedstock production sample and commercially available comparing, the micronization frequency is respectively 25HZ, 32HZ, 40HZ, time is set to 12min, monitoring in real time and control drug powder particle diameter are investigated different disposal mode and particle diameter to the influence of drug dissolution, result of the test such as table 3.
Table 3 different-grain diameter sample and commercially available reference preparation dissolution comparing result (pH7.4 dissolution medium)
As can be known from the above table, the overall stripping situation of raw material of undressed raw material, mistake 200 mesh sieves is relatively poor, and the 30min stripping does not all reach 85%, and no longer continues stripping; And all reached 95% stripping level at 30 minutes through micronized and commercially available product.When 45min, three groups of micronized drug particles dissolutions all surpass 98.5%, are higher than the commercially available prod, the result of extraction ideal.
This shows omeprazole raw material micronization particle size range distribution d
90＜20 μ m, d
50＜4 μ m, d
10＜2 μ m, drug dissolution is good, and stability is strong.
(frequency 25 ~ 40HZ) raw materials carry out dissolution comparing result with commercially available reference preparation according to embodiment 1 prepared sample and see Table 4, table 5 in water and pH6.8 dissolution medium to micronization.
In table 4 water with commercially available reference preparation dissolution comparing result
In the table 5 pH6.8 dissolution medium with commercially available reference preparation dissolution comparing result
From table 4,5 as can be seen, in water and pH6.8 dissolution medium, micronization group of frequencies 25HZ is suitable with commercially available reference preparation result of extraction, and for reaching 95%, but two groups are all no longer continued stripping at the dissolution of 30min; High frequency micronization group 32HZ and 40HZ drug dissolution when 30min reaches more than 95%, and continues stripping, and dissolution surpasses 98.5% during 45min, and stripping is more complete.
To high frequency micronization group 32HZ and 40HZ, carry out the stripping curve match with commercially available reference preparation contrast.The results are shown in Figure 1, Fig. 2.
In sum, the omeprazole drug dissolution of micronization PROCESS FOR TREATMENT of the present invention is better than commercially available reference preparation, and result of extraction is good.
Omeprazole preparation of the present invention has good result of extraction, compares with commercially available product, and bioavailability is higher in the body.
As trial target, the capsule of commercially available Zegerid 20mg specification in contrast with the omeprazole capsule medicine of embodiment 1 preparation.Test method is as follows:
6 of beasle dogs, male and female half and half, fasting 12 h before the test are not intake, and do not take other drug, and 4h can take food after the administration.Experimental animal is divided into two groups, gives commercially available capsule 20mg respectively, and note is made R, by the omeprazole self-control capsule that embodiment 1 makes, and 1 of single administration, note is made T.R group is respectively at after the administration 0,0.125,0.25,0.375,0.5,1,1.5,2,3,4,6 hours; T group is respectively at after the administration 0,0.5,0.75,1,1.5,2,3,4, gets the strict lucifuge of blood 3 ml(in 6 hours).Blood sample is put in the heparinization test tube, mixing, centrifugal 15 min of 4000 rpm divide and get blood plasma, and-40 ℃ keep in Dark Place to mensuration, and the concentration of omeprazole is measured with the HPLC method in the blood, and mean plasma concentration-time graph is seen accompanying drawing 3.
As shown in Figure 3, the Tmax meansigma methods of self-control omeprazole capsule is 15 min, and commercially available reference substance is 30 min.The Cmax meansigma methods of self-control omeprazole capsule is 785.4 μ g/mL, and commercially available reference substance is 548.2 μ g/mL.The AUC meansigma methods of self-control omeprazole capsule is 1392.27 μ gh/mL, and commercially available reference substance is 1081.82 μ gh/mL.Result of the test shows, compares with commercially available, and the Tmax of self-control omeprazole capsule is shorter, and Cmax is higher, illustrates that the result of extraction of this product is good, and bioavailability height in the body is higher than commercially available reference substance.
Claims (7)
1. compound recipe omeprazole preparation, by the proton pump inhibitor omeprazole, the antacid sodium bicarbonate and pharmaceutically adjuvant commonly used form, it is characterized in that: the principal agent omeprazole adopts the micronization PROCESS FOR TREATMENT, and particle size range is distributed as d
90＜20 μ m, d
50＜4 μ m, d
10＜2 μ m.
2. the described compound recipe omeprazole of claim 1 preparation is characterized in that: the independent micronization processes of principal agent omeprazole.
3. the described compound recipe omeprazole of claim 1 preparation is characterized in that: micronization process using principal agent omeprazole and antacid associating facing-up micronization.
4. the described compound recipe omeprazole of claim 1 preparation comprises tablet, capsule, dispersible tablet, slow releasing tablet, granule, powder, effervescent tablet, double-layer tablet, multilayer tablet, soft capsule, pill, dry suspension, suspending agent, syrup, injection, injectable sterile powder.
5. the described compound recipe omeprazole of claim 4 preparation comprises tablet, capsule, dispersible tablet, slow releasing tablet, granule.
6. the described compound recipe omeprazole of claim 4 preparation, in omeprazole, omeprazole content is 20-40mg in the unit formulation.
7. the described compound recipe omeprazole of claim 4 preparation, in omeprazole, omeprazole content is 20mg, 25mg in the unit formulation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109364037A (en) * | 2018-12-11 | 2019-02-22 | 湖北舒邦药业有限公司 | Lafutidine Tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050031700A1 (en) * | 2003-07-18 | 2005-02-10 | Sanatarus, Inc. | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders |
| CN101816641A (en) * | 2010-03-11 | 2010-09-01 | 沈阳亿灵医药科技有限公司 | Omeprazole quick-release solid preparation and preparation method thereof |
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2013
- 2013-01-10 CN CN2013100082859A patent/CN103230413A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050031700A1 (en) * | 2003-07-18 | 2005-02-10 | Sanatarus, Inc. | Pharmaceutical formulation and method for treating acid-caused gastrointestinal disorders |
| CN101816641A (en) * | 2010-03-11 | 2010-09-01 | 沈阳亿灵医药科技有限公司 | Omeprazole quick-release solid preparation and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109364037A (en) * | 2018-12-11 | 2019-02-22 | 湖北舒邦药业有限公司 | Lafutidine Tablet and preparation method thereof |
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Application publication date: 20130807 |