CN1935139A - Substituted benzimidazole proton pump inhibitor composition, and its preparing method - Google Patents
Substituted benzimidazole proton pump inhibitor composition, and its preparing method Download PDFInfo
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- CN1935139A CN1935139A CN200610096572.XA CN200610096572A CN1935139A CN 1935139 A CN1935139 A CN 1935139A CN 200610096572 A CN200610096572 A CN 200610096572A CN 1935139 A CN1935139 A CN 1935139A
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Abstract
The present invention belongs to the field of medicine preparation, in the concrete, it relates to a composition of substituted benzimidazole proton pump inhibitor and its preparation method. It is characterized by that in said composition the amino acid or glucomethane buffering agent whose pH value is greater than 6.0 is added so as to obtain good therapeutic effect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to contain the composition and method of making the same of substituted benzimidazole proton pump inhibitor.
Background technology
Peptic ulcer is common chronic inflammatory disease, and population of China peptic ulcer rate is common in person between twenty and fifty up to 10～12%, M-F 3: 1, the disease kind that belongs to clinical onset rate height, heals than refractory.
The antiulcer drug product mainly contain three major types at present: the one, and H2-receptor antagonist, representative products have famotidine, cimetidine, ranitidine, and this class drug manufacture is of long duration, domestic production producer is more, low price, doctor and patient accept wide, are the medicines of present large usage quantity; The 2nd, colloidal bismuth, representative products have colloidal bismuth subcitrate, colloidal bismmth pectin, though this class drug price is more cheap, existing market is in atrophy; The 3rd, proton pump inhibitor, representative products have omeprazole, lansoprazole, pantoprazole, RABEPRAZOLE SODIUM.This class drug main will be by specific effect in the gastric mucosa parietal cell, reduce H+/K+-ATP enzymatic activity in the parietal cell, the gastric acid inhibitory secretion, and helicobacter pylori there is unique antibacterial activity, become the strongest competing product of H2-receptor antagonist, become the medicament for resisting peptic ulcer of sales volume first abroad, in world's situation of selling well medicine in 1998,53.26 hundred million dollars of proton pump inhibitor product sales rank the first.Omeprazole (5,200,000,000 dollars) and lansoprazole (3,600,000,000 dollars) rank the 3rd and the 7th respectively in the situation of selling well prescription drugs that 10 ranks in 2002 are occupied the forefront, according to Pharmacast ﹠amp; Beyond prediction U.S. proton pump inhibitor market will rise to 12,600,000,000 dollars in 2010 from 9,900,000,000 dollars in 2000.Omeprazole is a proton pump inhibitor of new generation, is the succedaneum of benzimidazole medicine, no anticholinergic and anti-H
2The histamine characteristic can be attached to the parietal cell surface by suppressing the secretion that the H+/K+-ATP enzyme comes gastric acid inhibitory.This enzyme system is counted as sour proton pump, so the generation that omeprazole blocks gastric acid as the proton pump inhibitor of gastric, this effect becomes positive correlation with dosage.Animal experiment confirmation omeprazole can be measured from blood plasma and gastric mucosa after medication soon.Because of its mechanism of action uniqueness, the specificity height, but the acid effect is strong, the time is lasting, and low price, can be widely used in the welcome for the treatment of the various digestive functional disturbance diseases relevant and being subjected to doctor and patient with sour secretion, entered national medical insurance catalogue in 2004.
But, because substituted benzimidazole proton pump inhibitor structure is unsettled in environment acidity is lower than time period of its pKa, produce acid degradation, therefore make common oral preparation and can degrade, so be made generally in enteric or slow releasing preparation at present for clinical use because of gastric acid.
At present, Missouri, USA university development make the oral quick-acting powder of omeprazole of buffer agent with sodium bicarbonate, its number of patent application is 03806317.4, publication number is CN1735344A., commodity are called Zegerid.This invention is mainly by the combination of sodium bicarbonate and omeprazole, when pharmaceutical composition enters stomach, sodium bicarbonate can in and gastric acid, make pH value in the stomach greater than the pKa of omeprazole, overcoming the degraded of omeprazole in acid, and absorption under one's belt.Though this has solved omeprazole under one's belt because of the unfavorable factor of acid degradation, but also there is certain defective in this technology: (1) makes buffer agent with the 1680mg sodium bicarbonate, promptly be equivalent to contain among the Zegerid of each dosage the sodium (existing) of 460mg with the sodium bicarbonate form, this can not use or use for the patient of sodium content in nephropathy patient and other dietary restrictions and be restricted, and the patient who suffers from the relevant gastrointestinal disorders of acid is in the majority with middle-aged and elderly people, and middle-aged and elderly people trouble nephropathy or poor kidney person are more; (2) sodium bicarbonate should not be used for metabolic alkalosis and hypocalcemia patient; (3) sodium bicarbonate is emitted carbon dioxide with the carbonic acid that the gastric acid effect generates under one's belt rapid the decomposition, makes the patient produce the flatulence sense.
Summary of the invention
The inventor is devoted to seek the new buffer agent that is more suitable for such medicine, and through repetition test and research, pH value relatively is suitable as buffer agent greater than 6.0 aminoacid or meglumine.The safety range of these chemical compounds is big, be considered to nontoxic/or almost non-toxic.Aminoacid is the raw material of human body synthetic protein, the effect that arginine protected the liver and treated male infertility in addition.When these basic amino acids or meglumine and the combination of substituted benzimidazole proton pump inhibitor together arrive stomach, basic amino acid or meglumine can be rapidly in and gastric acid, the substituted benzimidazole proton pump inhibitor is absorbed in a gastric juice that is higher than its pKa value, so neither can be degraded, overcome prior art again and added the negative consequence that sodium bicarbonate causes.
Compositions of the present invention contains substituted benzimidazole proton pump inhibitor and buffer agent, described buffer agent is meglumine or pH value greater than 6.0 aminoacid, and wherein pH value does not comprise lysine (the related pH value of technical solution of the present invention does not all comprise lysine greater than 6.0 aminoacid) greater than 6.0 aminoacid.
The preferred pH value of buffer agent of the present invention is greater than 6.0 aminoacid, pH value is greater than one or more the compositions in preferred group propylhomoserin, arginine, proline or the cysteine in 6.0 the aminoacid, be more preferably the mixture of arginine and histidine, preferred ratio is: 1: 1-20.Test is found: pH value greater than 6.0 aminoacid under the minimum situation of consumption, the pH value of solution, amino acid whose chemical stability, the height of cost etc. is more suitable in buffering requirements in gastric acid such as omeprazoles.
CN02151291.4 mentions with lysine and makes buffer agent, but do not see example.The inventor is through careful investigation, extensively screening and conscientiously test, and lysine not only price is more expensive, and the moisture absorption very easily that main is becomes semisolid with regard to the moisture absorption in pelletization, and 8 hours still be semisolid 50-60 ℃ of drying, can't make dry suspension.Just because of this, lysine is made the hydrochlorate of lysine usually and is kept supplying city's application, and the pH value of lysine hydrochloride is less than omeprazole stable p H-number, is can not be as the buffer agent of omeprazole, therefore and nonbasic substances all be suitable as the buffer agent of such medicine.
On the composition of compositions, because of substituted benzimidazole proton pump inhibitor dosage is very little, to compare with buffer agent, the substituted benzimidazole proton pump inhibitor can be ignored the influence of acid environment in the stomach.Different buffer agents or different simulation preparation are to the influence test of simulated gastric fluid (by generally being estimated as about 200ml, getting its half amount, i.e. 100ml during test) pH, and data see Table 1-2, and curve is seen Fig. 1.
The different buffer agents of table 1 are simulated the test data that influences of artificial Gastric pH to 100ml
| The buffer agent title | Buffer agent consumption and corresponding pH value | ||||||||||||
| Consumption (m mol) | 0 | 6 | 7 | 8 | 8.5 | 9 | 9.5 | 10 | 10.5 | 11 | 12 | 13 | |
| I histidine MW.155.16 | |
6 | 1 | 1 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 1 | 1 | |
| pH | 1.06 | 1.99 | 2.31 | 2.92 | 3.79 | 4.74 | 5.08 | 5.25 | 5.38 | 5.48 | 5.64 | 5.76 | |
| ΔpH | 0.93 | 0.32 | 0.61 | 0.87 | 0.95 | 0.34 | 0.17 | 0.13 | 0.10 | 0.16 | 0.12 | ||
| II arginine-histidine (1: 2 mol ratio) | ΔmEq | 6 | 1 | 1 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 1 | 1 | |
| pH | 1.06 | 2.02 | 2.34 | 2.89 | 3.80 | 4.78 | 5.10 | 5.28 | 5.43 | 5.53 | 5.69 | 5.79 | |
| ΔpH | 0.96 | 0.32 | 0.55 | 0.91 | 0.98 | 0.32 | 0.18 | 0.15 | 0.10 | 0.16 | 0.10 | ||
| III arginine MW.174.20 | |
6 | 1 | 1 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 1 | 1 | |
| pH | 1.15 | 1.99 | 2.24 | 2.51 | 2.68 | 2.84 | 3.07 | 3.43 | 6.96 | 7.77 | 8.24 | 8.46 | |
| ΔpH | 0.84 | 0.25 | 0.27 | 0.17 | 0.16 | 0.23 | 0.36 | 3.53 | 0.81 | 0.47 | 0.22 | ||
| IV meglumine MW.195.22 | ΔmEq | 6 | 1 | 1 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 1 | 1 | |
| pH | 1.16 | 1.61 | 1.80 | 2.19 | 2.86 | 8.24 | 8.60 | 8.81 | 8.95 | 9.05 | 9.21 | 9.32 | |
| ΔpH | 0.45 | 0.19 | 0.39 | 0.67 | 5.38 | 0.36 | 0.21 | 0.14 | 0.10 | 0.16 | 0.11 | ||
| VI sodium bicarbonate MW.84.01 | |
6 | 1 | 1 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 1 | 1 | |
| pH | 1.16 | 1.66 | 1.90 | 2.45 | 4.75 | 5.43 | 5.71 | 5.90 | 6.04 | 6.14 | 6.30 | 6.42 | |
| ΔpH | 0.50 | 0.24 | 0.55 | 2.30 | 0.68 | 0.28 | 0.19 | 0.14 | 0.10 | 0.16 | 0.12 | ||
Two kinds of test datas that wait the simulation preparation of mole buffer agent to simulated gastric fluid pH of table 2
| Omeprazole-sodium bicarbonate | Omeprazole-(arginine-histidine (1: 2)) | ||
| 1680mg (not containing omeprazole) | PH＝5.13 | 3640mg (not containing omeprazole) | PH＝5.21 |
| 1700mg (containing the 20mg omeprazole) | PH＝5.15 | 3660mg (containing the 20mg omeprazole) | PH＝5.18 |
The result shows: the substituted benzimidazole proton pump inhibitor is very little to the influence of simulation gastric acid in the prescription, can ignore.
Test is found, adopt pH value of the present invention greater than 6.0 aminoacid buffer agent as the substituted benzimidazole proton pump inhibitor, such medicine is absorbed under an environment greater than its pK value, and add to compare behind the buffer agent of the present invention and add the compositions that sodium bicarbonate is done buffer agent, present composition related substance in depositing is lower, illustrates that buffer agent of the present invention more helps stability of drug.We with omeprazole respectively with sodium bicarbonate, arginine-histidine (mol ratio 1: 2), histidine, Arg-Pro (1: 2, mol ratio) proline, carry out stability test and detect related substance, the results are shown in Table 3.
The stable key data of the different prescription of table 3 comparative study
| Time (hour) | The contrast project | Sodium bicarbonate | Arginine-histidine (1: 2, mol ratio) | | Proline | |
| 0 | Related substance (normalization method, %) | Do not see | Do not see | Do not see | Do not see | |
| 1 | Related substance (normalization method, %) | 0.04 | 0.04 | 0.03 | 0.04 | |
| 2 | Related substance (normalization method, %) | 0.08 | 0.05 | 0.06 | 0.07 | |
| 4 | Related substance (normalization method, %) | 0.18 | 0.09 | 0.11 | 0.12 | |
| 8 | Related substance (normalization method, %) | 0.28 | 0.13 | 0.16 | 0.18 |
The result shows: pH of the present invention makes buffer agent as the buffer agent of substituted benzimidazole proton pump inhibitor than with sodium bicarbonate greater than 6.0 aminoacid and more helps such stability of drug, and related substance is lower.Therefore the preferred buffer agent of the present invention is pH greater than 6.0 aminoacid.
In the present invention, substituted benzimidazole proton pump inhibitor and meglumine or pH value greater than 6.0 amino acid whose mol ratio be preferably 1: 100～450; Further preferred 1: 170～350.
Research is also found: use histidine or arginine that the effect of good neutralization simulation gastric acid is all arranged separately, but the pH of histidine is on the low side, arginic pH is higher, the capital influences to some extent to the stability of omeprazole, and makes buffer agent when the compositions of arginine-histidine proper proportion (1: 1～20, more preferably 1: 1.1～2), simulation gastric acid can either well neutralize, the assurance omeprazole is stable, and it is minimum that the cost of raw material is dropped to, and is suitable for suitability for industrialized production.
Except that arginine-histidine compositions, the Arg-Pro compositions of proper proportion also has well stablizes the omeprazole effect.But because the pH of proline is lower, in and the ability of gastric acid a little less than, large usage quantity, not as arginine-histidine combination better.Therefore the most preferred buffer agent of the present invention is arginine-histidine.
The preferred omeprazole of substituted benzimidazole proton pump inhibitor, lansoprazole, pantoprazole, rabeprazole, esomeprazole or Pariprazole described in the present invention, or the enantiomer of its these medicines, isomer, free alkali or salt.Be more preferably omeprazole.
When these substituted benzimidazole proton pump inhibitors are prepared into oral formulations, except principal agent and pH value of the present invention greater than 6.0 the aminoacid or meglumine, can also contain pharmaceutically acceptable carrier, these carriers are inert, comprising: suspending agent, filler, binding agent, excipient, correctives, coloring agent etc.Can make tablet pharmaceutically commonly used, dispersible tablet, effervescent tablet, suspension sheet, capsule, granule, powder, dry suspension etc.The preferred dosage form of the present invention is dry suspension and granule.
Through test, by the dry suspension that following component and percentage by weight are formed, suspensoid effect, mouthfeel are all relatively good.
Substituted benzimidazole proton pump inhibitor 0.3-1.6%
Buffer agent 40-80%
Suspensoid 2-5%
Flavoring agent 15-55%
Binding agent 1-4%
Wherein the substituted benzimidazole proton pump inhibitor is selected from omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole or Pariprazole, the buffer agent agent is selected from meglumine, or in the arginine, histidine, proline, cysteine one or more.
Take after the dry suspension of making by above-mentioned prescription adds suitable quantity of water (15ml is to 30ml) suspendible, can be rapidly in and the gastric acid long period keep more than the gastric pH4, keep the stable and fast Absorption of principal agent, play quick-acting effects.
The preferred substituted benzimidazole proton pump inhibitor of the present invention is an omeprazole, and the dry suspension of preferred omeprazole is made up of following component and percentage by weight:
Omeprazole 0.4-1.6%
Arginine and histidine 40-60%
Sodium carboxymethyl cellulose 1.0-5.0%
30 POVIDONE K 30 BP/USP
900.4-5.0%
Icing Sugar or xylitol 35-55%
30 POVIDONE K 30 BP/USP
301-4%
Wherein the mol ratio of arginine and histidine is 1: 1～20.More preferably 1: 1.1～10.Dry suspension suspendible effect, mouthfeel that above-mentioned prescription is made are all relatively good.
The specific embodiment
Omeprazole dry suspension (feeding intake) by 100 bags
Name of material inventory (mg) weight ratio (%)
Omeprazole 20 0.4
Histidine 2,302 46.04
The fine little plain sodium 100 2.0 of carboxylic first
30 POVIDONE K 30 BP/USP
9020 0.4
Icing Sugar or xylitol 2,478 49.56
30 POVIDONE K 30 BP/USP
3080 1.6
Preparation method:
Be not more than at clean and relative humidity under 55% the environment, omeprazole, histidine, the little plain sodium of carboxylic first fibre, 30 POVIDONE K 30 BP/USP
90, Icing Sugar grinds respectively, crosses 80 mesh sieves, gets 30 POVIDONE K 30 BP/USP
30Make binding agent with 50%7 alcohol dissolvings, take by weighing recipe quantity, the principle that increases progressively by equivalent is made soft material with the supplementary material mix homogeneously with adhesive, cross 20 mesh sieves and granulate, in 50～55 ℃ of oven dry (about 3 hours), cross 18 mesh sieve granulate, sampling detects intermediate content, packing, packing, promptly.
Omeprazole dry suspension (100 bags feed intake)
Name of material inventory (mg) weight ratio (%)
Omeprazole 20 0.4
Arginine-histidine (mol ratio, 1: 2) 69,7+1,842 50.78
The fine little plain sodium 100 2.0 of carboxylic first
30 POVIDONE K 30 BP/USP
9020 0.4
Icing Sugar or xylitol 2,241 44.82
30 POVIDONE K 30 BP/USP
3080 1.6
Preparation method is with embodiment 1.
Omeprazole dry suspension (100 bags feed intake)
Name of material inventory (mg) weight ratio (%)
Omeprazole 20 0.4
Arginine 3,640 72.8
The fine little plain sodium 100 2.0 of carboxylic first
30 POVIDONE K 30 BP/USP
9020 0.4
Icing Sugar or xylitol 1,140 22.8
30 POVIDONE K 30 BP/USP
3080 1.6
Preparation method is with embodiment 1.
Omeprazole dry suspension (100 bags feed intake)
Name of material inventory (mg) weight ratio (%)
Omeprazole 20 0.4
Meglumine 3,900 78.0
The fine little plain sodium 100 2.0 of carboxylic first
30 POVIDONE K 30 BP/USP
9020 0.4
Icing Sugar or xylitol 780 17.6
30 POVIDONE K 30 BP/USP
3080 1.6
Preparation method is with embodiment 1.
Embodiment 5
Lansoprazole dry suspension (100 bags feed intake)
Name of material inventory (mg) weight ratio (%)
Lansoprazole 15 0.3
Arginine-histidine (1: 2) 69,7+1,842 50.78
The fine little plain sodium 100 2.0 of carboxylic first
30 POVIDONE K 30 BP/USP
9020 0.4
Icing Sugar or xylitol 2,246 44.92
30 POVIDONE K 30 BP/USP
3080 1.6
Preparation method is with embodiment 1.
Pantoprazole dry suspension (100 bags feed intake)
Composition inventory (mg) weight ratio (%)
Pantoprazole 40 0.8
Arginine-histidine (1: 2) 69,7+1,842 50.78
The fine little plain sodium 100 2.0 of carboxylic first
30 POVIDONE K 30 BP/USP
9020 0.4
Icing Sugar or xylitol 2,221 44.42
30 POVIDONE K 30 BP/USP
3080 1.6
Preparation method is with embodiment 1.
Esso draws azoles dry suspension (100 bags feed intake)
Composition inventory (mg) weight ratio (%)
Esomeprazole 20 0.4
Arginine-histidine (1: 2) 69,7+1,842 50.78
The fine little plain sodium 100 2.0 of carboxylic first
30 POVIDONE K 30 BP/USP
9020 0.4
Icing Sugar or xylitol 2,241 44.82
30 POVIDONE K 30 BP/USP
3080 1.6
Preparation method is with embodiment 1.
Claims (10)
1, a kind of pharmaceutical composition of substituted benzimidazole proton pump inhibitor, contain substituted benzimidazole proton pump inhibitor and buffer agent, it is characterized in that buffer agent is meglumine or pH value greater than 6.0 aminoacid, wherein pH value does not comprise lysine greater than 6.0 aminoacid.
2, the pharmaceutical composition of claim 1, wherein substituted benzimidazole proton pump inhibitor and pH value are 1: 100～450 greater than 6.0 the aminoacid or the mol ratio of meglumine.
3, the pharmaceutical composition of claim 2, wherein substituted benzimidazole proton pump inhibitor and pH value are 1: 170～350 greater than 6.0 the aminoacid or the mol ratio of meglumine.
4, claim 1,2 or 3 pharmaceutical composition, wherein buffer agent is selected from one or more in arginine, histidine, proline, the cysteine.
5, the pharmaceutical composition of claim 4, wherein buffer agent is arginine and histidine, the mol ratio of arginine and histidine is: 1: 1～20.
6, the pharmaceutical composition of claim 5, wherein the mol ratio of arginine and histidine is: 1: 1.1～2.
7, the pharmaceutical composition of claim 1, wherein the substituted benzimidazole proton pump inhibitor is selected from omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole or Pariprazole, or the enantiomer of its these medicines, isomer, free alkali or salt.
8, the pharmaceutical composition of claim 7 also contains pharmaceutically acceptable carrier.
9, a kind of dry suspension of substituted benzimidazole proton pump inhibitor, form by following component and percentage by weight:
Substituted benzimidazole proton pump inhibitor 0.3～1.6%
Buffer agent 40～80%
Suspensoid 2～5%
Flavoring agent 15～55%
Binding agent 1～4%
Wherein the substituted benzimidazole proton pump inhibitor is selected from omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole or Pariprazole; Buffer agent is selected from meglumine, or in the arginine, histidine, proline, cysteine one or more.
10, a kind of omeprazole dry suspension, form by following component and percentage by weight:
Omeprazole 0.4～1.6%
Arginine and histidine 40～60%
Sodium carboxymethyl cellulose 1.0～5.0%
30 POVIDONE K 30 BP/USP 90 0.4～5.0%
Icing Sugar 35～55%
30 POVIDONE K 30 BP/USP 30 1～4%
Wherein the mol ratio of arginine and histidine is 1: 1 to 1: 20.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101991543A (en) * | 2009-08-10 | 2011-03-30 | 杭州赛利药物研究所有限公司 | Omeprazole enteric dried suspension agent and preparation method thereof |
| CN103463636A (en) * | 2013-09-17 | 2013-12-25 | 天津市嵩锐医药科技有限公司 | Pantoprazole sodium medicine composition for injection |
| CN106798750A (en) * | 2017-03-23 | 2017-06-06 | 济宁华能制药厂有限公司 | A kind of preparation method of compound omeprazole dry suspension |
| CN107625736A (en) * | 2017-08-01 | 2018-01-26 | 广州加德恩医药有限公司 | A kind of esomeprazole enteric capsules piece and preparation method thereof |
-
2006
- 2006-09-30 CN CN200610096572A patent/CN100584330C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101991543A (en) * | 2009-08-10 | 2011-03-30 | 杭州赛利药物研究所有限公司 | Omeprazole enteric dried suspension agent and preparation method thereof |
| CN103463636A (en) * | 2013-09-17 | 2013-12-25 | 天津市嵩锐医药科技有限公司 | Pantoprazole sodium medicine composition for injection |
| CN106798750A (en) * | 2017-03-23 | 2017-06-06 | 济宁华能制药厂有限公司 | A kind of preparation method of compound omeprazole dry suspension |
| CN106798750B (en) * | 2017-03-23 | 2019-08-20 | 济宁华能制药厂有限公司 | A kind of preparation method of compound omeprazole dry suspension |
| CN107625736A (en) * | 2017-08-01 | 2018-01-26 | 广州加德恩医药有限公司 | A kind of esomeprazole enteric capsules piece and preparation method thereof |
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Effective date of registration: 20190718 Address after: 210000 No. 5 Qiande Road, Science Park, Jiangning District, Nanjing City, Jiangsu Province Patentee after: NANJING CHENXIANG MEDICAL RESEARCH CO.,LTD. Address before: 210009 Jiangsu Province, Nanjing City Bridge No. 2 building 12 East Patentee before: Xing Weifan |
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