CN103860584B - A kind of manufacture method of omeprazole sodium bicarbonate capsule - Google Patents
A kind of manufacture method of omeprazole sodium bicarbonate capsule Download PDFInfo
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- CN103860584B CN103860584B CN201410063761.1A CN201410063761A CN103860584B CN 103860584 B CN103860584 B CN 103860584B CN 201410063761 A CN201410063761 A CN 201410063761A CN 103860584 B CN103860584 B CN 103860584B
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Abstract
The invention provides a kind of manufacture method of omeprazole sodium bicarbonate capsule, wherein, the amount of the supplementary material unit formulation of omeprazole 40mg dosage form is: omeprazole 40mg, sodium bicarbonate 1100mg, cross-linked carboxymethyl cellulose receive 20-30mg, magnesium stearate 1-5mg; The particle size distribution D of described omeprazole
10>=1 μm, D50≤10 μm, D
90≤ 20 μm; The granularity of described sodium bicarbonate crosses 100 orders.The amount of the supplementary material unit formulation of omeprazole 20mg dosage form is: omeprazole 20mg, sodium bicarbonate 1100mg, cross-linked carboxymethyl cellulose receive 20-30mg, magnesium stearate 1-5mg; The particle size distribution D of described omeprazole
10>=1 μm, D50≤10 μm, D
90≤ 20 μm; The granularity of described sodium bicarbonate crosses 100 orders.The invention has the beneficial effects as follows, by the Task-size Controlling of omeprazole a thinner scope, reduce the unit dose of magnesium stearate, improve the therapeutic effect of medicine; And the raw material hybrid technique simplified in manufacturing process.
Description
Technical field
The present invention relates to a kind of manufacture method of omeprazole sodium bicarbonate capsule.
Background technology
The compound preparation that omeprazole sodium bicarbonate capsule is made up of omeprazole and sodium bicarbonate.Omeprazole belongs to the medicine that benzimidazole replaces class gastric acid secretion inhibiting, without cholinolytic or H
2histamine effect, suppresses the H of parietal cell by specificity
+-K
+-ATP enzyme system thus reach the effect of gastric acid secretion inhibiting.Be also called the proton pump on gastric mucosa because of this enzyme system, the proton pump inhibitor so omeprazole is otherwise known as, it can block the final step of gastric acid secretion.Its action intensity is relevant to dosage, has inhibitory action to basis and post-stimulatory gastric acid secretion.Animal experiment shows, omeprazole after quick disappearance, can exist more than one day in blood plasma in gastric mucosa.Omeprazole has acid labile, can by fast degradation in gastric acid, and the sodium bicarbonate in prescription is rapid release composition, can directly fast in and gastric acid improve the pH value of gastric juice, thus stop omeprazole by acid degradation; Meanwhile, sodium bicarbonate can be used for alleviate hyperchlorhydria cause stomachache, heartburn sense, acid regurgitation.
Chinese patent CN 102727516 B discloses a kind of compound omeprazole capsule and preparation method thereof, omeprazole raw material is by 180 orders, sodium bicarbonate granularity is 80 ~ 150 orders, per unit preparation magnesium stearate consumption 6 ~ 10mg, cross-linking sodium carboxymethyl cellulose consumption 6 ~ 18mg.
Chinese patent CN 103006691 A discloses a kind of omeprazole sodium bicarbonate compound capsule, this capsule is even by omeprazole gastric solubleness piller and sodium bicarbonate, disintegrating agent, mix lubricant, filled capsules forms, in hydrochloric acid solution, sodium bicarbonate discharges rapidly, and omeprazole discharges rapidly after sodium bicarbonate release completely again.
Chinese patent CN 101816641 B discloses a kind of method preparing quick-release capsules containing omeprazole, per unit preparation by 20mg omeprazole, 1100mg sodium bicarbonate and appropriate pharmaceutic adjuvant form (solubilizing agent is sodium lauryl sulphate, binding agent is 5% polyvidone, disintegrating agent be croscarmellose sodium, lubricant is magnesium stearate), adopt process for granulation fill capsule.Adjuvant and the production technology of said preparation use are more.
Above shortcoming is, the granularity of omeprazole is comparatively large, and as the magnesium stearate large usage quantity of lubricant, these can have influence on the therapeutic effect of medicine, and hybrid technique in manufacturing process is more loaded down with trivial details.
Summary of the invention
The object of the invention is, a kind of manufacture method of omeprazole sodium bicarbonate capsule is provided, by the Task-size Controlling of omeprazole a thinner scope, reduce the unit dose of magnesium stearate, improve the therapeutic effect of medicine, meanwhile, simplify the raw material hybrid technique in manufacturing process.
One of most preferred embodiment of the present invention: the manufacture method of described a kind of omeprazole sodium bicarbonate capsule, the amount of its supplementary material unit formulation is: omeprazole 40mg, sodium bicarbonate 1100mg, cross-linked carboxymethyl cellulose receive 20-30mg, magnesium stearate 1-5mg; The particle size distribution D of described omeprazole
10>=1 μm, D50≤10 μm, D
90≤ 20 μm; The granularity of described sodium bicarbonate crosses 100 orders; Making step is:
(1) first step premixing: take the omeprazole of full dose and appropriate sodium bicarbonate, be specially sodium bicarbonate: omeprazole=4:1, (weight ratio), mixes 5 minutes;
(2) second step premixing: take appropriate sodium bicarbonate, mixes 5 minutes with step (1) mixture, makes sodium bicarbonate: omeprazole=8:1, (weight ratio);
(3) always mix: get that cross-linked carboxymethyl cellulose in remaining sodium bicarbonate and prescription is received, magnesium stearate, with said mixture mixing 10-30 minute;
(4) gained powder in step (3) is carried out to the detection of intermediate, calculate the loading amount of every capsules;
(5) qualified intermediate powder be directly filled to capsule and get final product.
Most preferred embodiment two of the present invention: a kind of manufacture method of omeprazole sodium bicarbonate capsule, is characterized in that: the amount of its supplementary material unit formulation is: omeprazole 20mg, sodium bicarbonate 1100mg, cross-linked carboxymethyl cellulose receive 20-30mg, magnesium stearate 1-5mg; The particle size distribution D of described omeprazole
10>=1 μm, D50≤10 μm, D
90≤ 20 μm; The granularity of described sodium bicarbonate crosses 100 orders; Making step is:
(1) first step premixing: take the omeprazole of full dose and appropriate sodium bicarbonate, be specially sodium bicarbonate: omeprazole=6:1, (weight ratio), mixes 5 minutes;
(2) second step premixing: take appropriate sodium bicarbonate, mixes 5 minutes with step (1) mixture, makes sodium bicarbonate: omeprazole=12:1, (weight ratio);
(3) always mix: get that cross-linked carboxymethyl cellulose in remaining sodium bicarbonate and prescription is received, magnesium stearate, with said mixture mixing 10-30 minute;
(4) gained powder in step (3) is carried out to the detection of intermediate, calculate the loading amount of every capsules;
(5) qualified intermediate powder be directly filled to capsule and get final product.
The invention has the beneficial effects as follows, by the Task-size Controlling of omeprazole a thinner scope, reduce the unit dose of magnesium stearate, improve the therapeutic effect of medicine; And the raw material hybrid technique simplified in manufacturing process.
Accompanying drawing explanation
Fig. 1 is one of most preferred embodiment of the present invention, pH7.4 phosphate-buffered liquid medium stripping curve figure.
Fig. 2 is one of most preferred embodiment of the present invention, pH4.5 phosphate-buffered liquid medium stripping curve figure.
Fig. 3 is one of most preferred embodiment of the present invention, aqueous medium stripping curve figure.
Fig. 4 is one of most preferred embodiment of the present invention, 0.1mol/L hydrochloric acid solution medium stripping curve figure.
Fig. 5 is preferred embodiment two, pH7.4 phosphate-buffered liquid medium stripping curve figure.
Fig. 6 is preferred embodiment two, pH4.5 phosphate-buffered liquid medium stripping curve.
Fig. 7 is preferred embodiment two, aqueous medium stripping curve figure.
Fig. 8 is preferred embodiment two, pH1.2 hydrochloric acid solution medium stripping curve.
Detailed description of the invention
One of preferred embodiment, as shown in Fig. 1-4, the granularity of omeprazole raw material is comparatively thin, D
90≤ 20 μm, D
50≤ 10 μm, in order to ensure product stripping concordance, and by the granularity D of raw material
10control is greater than 1 μm.
Sodium bicarbonate gastric can fast in and gastric acid, protection omeprazole not by gastric acid degradation, in order to ensure sodium bicarbonate dissolution velocity, we are crossed 100 mesh sieves.
Select magnesium stearate to be lubricant in this prescription, by prescription screening, can reach manufacturing technique requirent when magnesium stearate is 3mg in every capsules, capsule-filling content uniformity is better.
The consumption that in every capsules, cross-linked carboxymethyl cellulose is received is 20mg.
In order to ensure the quality of product, hybrid technique divides three steps, and key step is as follows:
(1) first step premixing: the omeprazole and the appropriate sodium bicarbonate (sodium bicarbonate/omeprazole=4/1) that take full dose, (weight ratio), mixes 5 minutes;
(2) second step premixing: get appropriate sodium bicarbonate, mixes 5 minutes with step (1) mixture, makes sodium bicarbonate/omeprazole=8/1, (weight ratio);
(3) always mix: to get in prescription that cross-linked carboxymethyl cellulose in remaining sodium bicarbonate and prescription is received, magnesium stearate again, mix 20 minutes with said mixture;
(4) gained powder carries out the detection of intermediate in step (3), calculates the loading amount of every capsules;
(5) qualified intermediate powder be directly filled to No. 00 capsule and get final product.
One of preferred embodiment, the prescription of omeprazole sodium bicarbonate capsule is as follows:
| Formulation ingredients | The amount (mg) of the system of unit |
| Omeprazole | 40 |
| Sodium bicarbonate | 1100 |
| Cross-linking sodium carboxymethyl cellulose | 20 |
| Magnesium stearate | 3 |
Get sodium bicarbonate, cross-linking sodium carboxymethyl cellulose crosses 100 mesh sieves, for subsequent use.
Get sieved 200 orders of omeprazole supersonic vibration, and adopt laser particle analyzer to measure the granularity of omeprazole, Task-size Controlling should meet D
90≤ 20 μm, D
50≤ 10 μm, D
10>=1 μm.
| Lot number | 110103 | 110302 | 110304 |
| D 10（μm） | 4.20 | 3.81 | 3.81 |
| D 50（μm） | 8.96 | 8.44 | 8.22 |
| D 90（μm） | 18.60 | 18.11 | 17.26 |
The consumption of magnesium stearate in prescription and cross-linking sodium carboxymethyl cellulose is investigated.In result unit formulation, magnesium stearate consumption is 3mg, during cross-linking sodium carboxymethyl cellulose 20mg, effectively can improve the mobility of powder, not have a significant effect to the disintegrate of capsule.
| Prescription composition and the project of investigation | Prescription 1 | Prescription 2 | Prescription 3 |
| Omeprazole (g) | 4 | 4 | 4 |
| Sodium bicarbonate (g) | 110 | 110 | 110 |
| Cross-linking sodium carboxymethyl cellulose (g) | 3 | 2 | 2 |
| Magnesium stearate (g) | 0.1 | 0.3 | 0.5 |
| Content angle of repose (degree) | 40.1 | 37.7 | 37.0 |
| Disintegration (minute) | 8 | 8 | 9 |
Stockpile density measurement.Result of the test shows, the bulk density of sodium bicarbonate is about 4 times of omeprazole, increases progressively mixing method by equal-volume, and sodium bicarbonate and omeprazole consumption should be 4:1, and sodium bicarbonate divides three steps to add, and adds mixing together when adjuvant in the end always mixes.
| Omeprazole | Sodium bicarbonate | |
| Weight (g) | 3.5 | 13.9 |
| Volume (ml) | 10 | 10 |
| Bulk density (g/ml) | 0.35 | 1.39 |
Through three batches of scale up test process certifications, the omeprazole uniformity of dosage units that result respectively walks hybrid technique meets the requirements (RSD≤5%).
Intermediate detects: by quality standard, measures sodium bicarbonate and omeprazole content in the intermediate powder after total mixing, calculates the loading of capsule by formula [D=(Cmax+Cmin)/2].
| Lot number | 130301 | 130302 | 130303 |
| Omeprazole content (%) | 99.62 | 99.56 | 99.51 |
| Sodium bicarbonate content (%) | 99.83 | 99.90 | 99.99 |
| Capsule loading amount (g/ grain) | 1.165 | 1.164 | 1.163 |
Three batches of finished product detection: the indices measuring finished product by quality standard respectively, result all meets the requirements.
In three batches, test agent and commercially available product stripping curve compare, and 4 kinds of medium stripping curve all similar, can reach rapid release requirement, and dissolution rate are faster than commercially available product as a result.
PH7.4 phosphate-buffered liquid medium stripping curve compares: in three batches, test agent is 15 minutes time, and dissolution is all more than 85%, and own product is similar to commercially available product dissolved corrosion.(accompanying drawing 1)
| Lot number | 0 min | 5min | 10min | 15min | 30min | 45min | 60min |
| 130301 | 0 | 75.23 | 94.72 | 97.48 | 97.52 | 97.53 | 96.19 |
| 130302 | 0 | 76.04 | 95.96 | 98.42 | 98.63 | 98.33 | 97.19 |
| 130303 | 0 | 67.63 | 92.03 | 96.52 | 97.13 | 96.20 | 95.53 |
| Commercially available product | 0 | 55.32 | 85.74 | 94.59 | 96.43 | 96.22 | 96.04 |
PH4.5 phosphate-buffered liquid medium stripping curve compares: in three batches, test agent stripping curve compares with commercially available product, and similar factors is all greater than 50, and own product is similar to commercially available product dissolved corrosion.(accompanying drawing 2)
| Lot number | 0min | 5min | 10min | 15min | 30min | 45min | 60min | f 2Value |
| 130301 | 0 | 62.50 | 81.76 | 84.75 | 81.95 | 79.07 | 75.77 | 75.66 |
| 130302 | 0 | 61.93 | 82.95 | 87.05 | 83.48 | 80.24 | 76.74 | 69.37 |
| 130303 | 0 | 66.70 | 83.86 | 85.08 | 81.78 | 80.82 | 77.41 | 66.60 |
| Commercially available product | 0 | 59.78 | 77.08 | 80.33 | 80.73 | 78.73 | 75.92 | —— |
Aqueous medium stripping curve compares: each batch sample is 15 minutes time, and dissolution is all more than 85%, and own product is similar to commercially available product dissolved corrosion.(accompanying drawing 3)
| Lot number | 0 min | 5min | 10min | 15min | 30min | 45min | 60min |
| 130301 | 0 | 76.03 | 93.83 | 96.97 | 97.02 | 96.71 | 96.60 |
| 130302 | 0 | 75.89 | 94.62 | 97.52 | 97.73 | 97.49 | 97.29 |
| 130303 | 0 | 73.79 | 93.48 | 97.32 | 98.01 | 97.87 | 97.16 |
| Commercially available product | 0 | 67.21 | 90.10 | 94.98 | 97.50 | 97.91 | 98.09 |
0.1mol/L hydrochloric acid solution medium stripping curve compares: in three batches, test agent stripping curve compares with commercially available product, and similar factors is all greater than 50, and own product is similar to commercially available product dissolved corrosion.(accompanying drawing 4)
| Lot number | 0min | 5min | 10min | 15min | 30min | 45min | 60min | f 2Value |
| 130301 | 0 | 15.14 | 9.46 | 7.95 | 5.37 | 4.24 | 3.56 | 80.50 |
| 130302 | 0 | 14.90 | 9.80 | 8.16 | 5.51 | 4.15 | 3.47 | 80.02 |
| 130303 | 0 | 18.06 | 9.84 | 7.76 | 5.16 | 3.95 | 3.20 | 91.46 |
| Commercially available product | 0 | 20.44 | 10.78 | 8.48 | 5.4 | 4.08 | 3.40 | —— |
The quality standard of this product is through Method validation such as related substance, dissolution, omeprazole content, sodium bicarbonate content, microbial limits, and result detection method accurately, reliable, repeatability is good, effectively can control the quality of this product.
Stability study: middle test agent is tested (illumination, high temperature, high humidity) through 10 days influence factors, accelerated and long-term stable experiment for 6 months, result is all in the scope that quality standard specifies, and the index of paper examines project (related substance, dissolution, content etc.) change is very little, the steady quality of product, reliable, effectiveness and the safety of product can be ensured.
Influence factor tests: result of the test shows: (1) this product unlap is placed 10 days under illumination (4500lx ± 500lx) condition, indices is without bright change, show that illumination has no significant effect this product, but in the exposure experiments to light of raw material, illumination has impact to omeprazole, and prompting this product should avoid illumination.(2) this product is tested under high humidity (92.5%) condition, and capsule shells is dissolved, and cannot carry out the detection of product, test under therefore adopting 75% damp condition.This product unlap is placed 10 days under high humidity (RH75% ± 5%) condition, and indices, without bright change, shows that illumination has no significant effect this product, but under the humidity of 92.5%, capsule shells can be softened, and prompting this product should seal preservation.(3) place 10 days under this product unlap high temperature (60 DEG C) condition, the single impurity of omeprazole and total impurities all slightly increase, and other indices, without bright change, show the slightly impact of temperature on this product, and prompting this product answers room temperature preservation.Tested by influence factor, determine that the preservation condition of this product is: shading, sealing, preserves in drying place.
6 months accelerated stability tests: result of the test shows, (1) this product is under commercially available back condition, and through 6 months accelerated tests, every Testing index without significant change, illustrated that this product was placed 6 months samples under acceleration conditions and stablized compared with 0 month.(2) compare the related substance of own product and commercially available product accelerated test, both variation tendencies are basically identical.The dopant species that own product to accelerate after 6 months degraded is consistent with commercially available product impurity, each impurity level and commercially available product impurity basically identical, have no the single contaminant apparently higher than commercially available product, all within the scope of reporting limit.The effect duration of tentative this product is 24 months.
6 months long-term stable experiments: result of the test shows: this product, under commercially available back condition, is placed 6 months through long-term, every Testing index without significant change, illustrated that this product was stable under long-term conditions compared with 0 day.In three batches, test agent long term test is still investigated in continuation, with the result of long term test, finally determines the effect duration of this product.
External acid resisting test: get middle test agent 1, with reference to " Chinese Pharmacopoeia " version in 2010 two annex Ⅹ C second methods, with not containing the simulated gastric fluid 100mL of protease as dissolution medium, rotating speed is 75 turns per minute, operate in accordance with the law, after 2 hours, stop operating, in stripping rotor, precision adds dehydrated alcohol 20mL, within ultrasonic 10 minutes, it is made to dissolve, shake up, filter, measure the content of omeprazole.Result content is all more than 95%, and sodium bicarbonate can the stability of available protecting omeprazole.
By researchs such as prescription composition, production technology, method of quality control, product stability, clinical trials, the production technology of result own product is easy, quality controllable, the effect that can reach rapid release clinically.Compare with commercially available enteric coated preparation, this product can alleviate the clinical symptoms such as stomachache, heartburn sense sooner, has good efficacy to gastrointestinal ulceration disease.
Preferred embodiment two, as shown in Fig. 5-8, the granularity of omeprazole raw material is comparatively thin, D
90≤ 20 μm, D
50≤ 10 μm, in order to ensure product stripping concordance, and by the granularity D of raw material
10control is greater than 1 μm.
Sodium bicarbonate gastric can fast in and gastric acid, protection omeprazole not by gastric acid degradation, in order to ensure sodium bicarbonate dissolution velocity, we are crossed 100 mesh sieves.
Select magnesium stearate to be lubricant in this prescription, by prescription screening, can reach manufacturing technique requirent when magnesium stearate is 3mg in every capsules, capsule-filling content uniformity is better.
The consumption that in every capsules, cross-linked carboxymethyl cellulose is received is 20mg.
In order to ensure the quality of product, hybrid technique divides three steps, and key step is as follows:
(1) first step premixing: the omeprazole and the appropriate sodium bicarbonate (sodium bicarbonate/omeprazole=6/1) that take full dose, (weight ratio), mixes 5 minutes;
(2) second step premixing: take appropriate sodium bicarbonate, mixes 5 minutes with step (1) mixture, makes sodium bicarbonate/omeprazole=12/1, (weight ratio);
(3) always mix: to get in prescription that cross-linked carboxymethyl cellulose in remaining sodium bicarbonate and prescription is received, magnesium stearate again, mix 20 minutes with said mixture;
(4) gained powder carries out the detection of intermediate in step (3), calculates the loading amount of every capsules;
(5) qualified intermediate powder be directly filled to No. 00 capsule and get final product.
Preferred embodiment two, omeprazole sodium bicarbonate capsule prescription is as follows:
| Formulation ingredients | Consumption (mg) |
| Omeprazole | 20 |
| Sodium bicarbonate | 1100 |
| Cross-linking sodium carboxymethyl cellulose | 20 |
| Magnesium stearate | 3 |
Get sodium bicarbonate, cross-linking sodium carboxymethyl cellulose crosses 100 mesh sieves, for subsequent use.
Get sieved 200 orders of omeprazole supersonic vibration, and adopt laser particle analyzer to measure the granularity of omeprazole, Task-size Controlling should meet D
90≤ 20 μm, D
50≤ 10 μm, D
10>=1 μm.
| Lot number | 110302 | 110103 | 110304 |
| D 10（μm） | 4.20 | 3.81 | 3.81 |
| D 50（μm） | 8.96 | 8.44 | 8.22 |
| D 90（μm） | 18.60 | 18.11 | 17.26 |
The consumption of magnesium stearate in prescription and cross-linking sodium carboxymethyl cellulose is investigated.Prescription 1, prescription 2 adopt powder directly to mix respectively, and prescription 3 is granulating process, and in result unit formulation, magnesium stearate consumption is 3mg, and during cross-linking sodium carboxymethyl cellulose 20mg, the good fluidity of powder, does not need to adopt process for granulation.
| Prescription composition and the project of investigation | Prescription 1 | Prescription 2 | Prescription 3 |
| Omeprazole (g) | 2 | 2 | 2 |
| Sodium bicarbonate (g) | 110 | 110 | 110 |
| Cross-linking sodium carboxymethyl cellulose (g) | 3 | 2 | 2 |
| Magnesium stearate (g) | 0.1 | 0.3 | 0.3 |
| 50% ethanol | —— | —— | 40ml |
| Content angle of repose (degree) | 44 | 39 | 36 |
| Disintegration (minute) | 7 | 9 | 8 |
In order to simplify hybrid technique, we design three step mixing methods.Get the sodium bicarbonate mix homogeneously being equivalent to omeprazole 6 times of weight, by incremental method, then add 12 times amount sodium bicarbonate mixing, finally residual sodium bicarbonate and adjuvant are added mix homogeneously together.Through three batches of scale up test process certifications, result omeprazole uniformity of dosage units meets the requirements (RSD≤5%).
Intermediate detects: by quality standard, measures sodium bicarbonate and omeprazole content in the intermediate powder after total mixing, calculates the loading of capsule by formula [D=(Cmax+Cmin)/2].
| Lot number | 120301A | 120302A | 120303A |
| Omeprazole content (%) | 96.87 | 97.10 | 96.01 |
| Sodium bicarbonate content (%) | 100.41 | 100.22 | 100.32 |
| Capsule loading amount (g/ grain) | 1.158 | 1.158 | 1.164 |
Three batches of finished product detection: the indices measuring finished product by quality standard respectively, result all meets the requirements.
In clinical trial sample and three batches, test agent and commercially available product stripping curve compare, 4 kinds of medium stripping curve all similar as a result, dissolution rate and commercially available product is close or slightly fast, all can reach the requirement of release fast.
PH7.4 phosphate-buffered liquid medium stripping curve compares: in (accompanying drawing 5) clinical trial sample and three batches, test agent is 15 minutes time, and dissolution is all more than 85%, and own product is similar to commercially available product dissolved corrosion.
| Lot number | 5min | 10min | 15min | 30min | 45min | 60min |
| 110701A | 69 | 96 | 101 | 102 | 101 | 100 |
| 120301A | 65 | 99 | 101 | 101 | 101 | 100 |
| 120302A | 60 | 93 | 102 | 100 | 99 | 98 |
| 120303A | 64 | 97 | 101 | 101 | 101 | 102 |
| Commercially available product 445772 | 59 | 86 | 93 | 97 | 96 | 98 |
PH4.5 phosphate-buffered liquid medium stripping curve compares: in (accompanying drawing 6) clinical trial sample and three batches, test agent is 15 minutes time, and dissolution is all more than 85%, and own product is similar to commercially available product dissolved corrosion.
| Lot number | 5min | 10min | 15min | 30min | 45min | 60min |
| 110701A | 78 | 93 | 93 | 90 | 86 | 82 |
| 120301A | 62 | 99 | 96 | 93 | 89 | 85 |
| 120302A | 62 | 96 | 96 | 93 | 89 | 85 |
| 120303A | 62 | 96 | 97 | 94 | 90 | 86 |
| Commercially available product 445772 | 61 | 83 | 89 | 91 | 87 | 84 |
Aqueous medium stripping curve compares: in (accompanying drawing 7) clinical trial sample and three batches, test agent is 15 minutes time, and dissolution is all more than 85%, and own product is similar to commercially available product dissolved corrosion.
| Lot number | 5min | 10min | 15min | 30min | 45min | 60min |
| 110701A | 84 | 99 | 101 | 102 | 101 | 102 |
| 120301A | 69 | 100 | 102 | 103 | 103 | 103 |
| 120302A | 74 | 100 | 102 | 103 | 103 | 103 |
| 120303A | 60 | 97 | 101 | 102 | 102 | 102 |
| Commercially available product 445772 | 83 | 98 | 100 | 101 | 101 | 101 |
PH1.2 hydrochloric acid solution medium stripping curve compares: in (accompanying drawing 8) clinical trial sample and three batches, test agent stripping curve compares with commercially available product, similar factors (f
2) being all greater than 50, own product is similar to commercially available product dissolved corrosion.
| Lot number | 5min | 10min | 15min | 30min | 45min | 60min | The f of relative commercially available product 2Value |
| 110701A | 30 | 14 | 8 | 7 | 5 | 4 | 82 |
| 120301A | 36 | 15 | 9 | 6 | 4 | 4 | 67 |
| 120302A | 33 | 14 | 7 | 6 | 4 | 4 | 74 |
| 120303A | 35 | 15 | 8 | 7 | 4 | 4 | 69 |
| Commercially available product 445772 | 25 | 14 | 8 | 6 | 4 | 3 | —— |
The quality standard of this product is through Method validation such as related substance, dissolution, omeprazole content, sodium bicarbonate content, microbial limits, and result detection method accurately, reliable, repeatability is good, effectively can control the quality of this product.
Stability study: middle test agent is tested (illumination, high temperature, high humidity) through 10 days influence factors, accelerated and 12 months long-term stable experiments for 6 months, result is all in the scope that quality standard specifies, and the index of paper examines project (related substance, dissolution, content etc.) change is very little, the steady quality of product, reliable, effectiveness and the safety of product can be ensured.
Influence factor test: result of the test shows: (1) this product unpackaged through illumination after 10 days related substance slightly increase, the content of omeprazole is without significant change, other indices, without significant change, show that illumination slightly affects omeprazole, should avoid illumination during the storage of prompting this product; (2) detection under this product band packaging high humidity RH92.5% condition, results sample weightening finish is 0.05%, and content and related substance, without significant change, show that packaging has good moisture effect to this product; (3) the unpackaged detection under high temperature 60 DEG C of conditions of this product, the content of result display high temperature to omeprazole does not have a significant effect, on the slightly impact of omeprazole related substance.Tested by influence factor, determine that the preservation condition of this product is: shading, sealing, preserves in drying place.
6 months accelerated stability tests: result of the test shows, (1) this product is under commercially available back condition, and through 6 months accelerated tests, every Testing index without significant change, illustrated that this product was placed 6 months samples under acceleration conditions and stablized compared with 0 month.The effect duration of tentative this product is 24 months.
12 months long-term stable experiments: result of the test shows: this product, under commercially available back condition, is placed 12 months through long-term, every Testing index without significant change, illustrated that this product was stable under long-term conditions compared with 0 day.In three batches, test agent long term test is still investigated in continuation, with the result of long term test, finally determines the effect duration of this product.
Clinical pharmacokinetics is tested: after the omeprazole capsule of (1) 12 health volunteer single-dose 20 mg and 40 mg respectively, omeprazole between two dosage
t 1/2 , MRT 0-11 , CL/F, Vd/Fthere is significant difference, and
t maxthere was no significant difference;
c maxwith
aUC 0-11with dosage not proportional,
c maxand
aUC 0-11increasing degree be obviously greater than dosage increasing degree, sex difference does not affect the pharmacokinetics process of omeprazole single-dose in vivo.(2) 12 health volunteer repeatedly oral omeprazole capsule 20 mg, result shows, single, multiple dosing
t 1/2 , CL/F, Vd/Fwith
t ma
x all there is significant difference.After successive administration
with
enlarge markedly, after multiple dosing in identical dosing interval omeprazole body in exposed amount increase.
Bioequivalence, after the meal bioequivalence Journal of Sex Research on an empty stomach, result shows the peak time of this product
t max(0.4 ± 0.2h), obviously faster than enteric reference preparation (1.9 ± 0.7h), reaches peak concentration
c maxalso higher than reference preparation.And bioavailability (AUC
0-∞) equivalent with reference preparation.Diet can reduce omeprazole degree of absorption (
aUC 0-11), blood peak concentration of drug (
c max), and significant prolongation blood medicine peak time (
t max).
Clinical treatment duodenal ulcer multicenter, random, Double-blind double-dummy, parallel check experiment: (1)
During treatment duodenal ulcer, the non-effective percentage being inferior to reference preparation (magnesium omeprazole enteric coatel tablets) of the ulcer healing effective percentage of omeprazole sodium bicarbonate capsule for treating.(2) medication is after 2 weeks, 4 weeks respectively, and clinical symptom remission total effective rate compares with reference preparation, result no difference of science of statistics.The course of therapy duodenal ulcer of (3) 28 days, omeprazole sodium bicarbonate capsule compares with reference preparation, and lenitive ability is suitable.
Test group and matched group adverse events incidence rate comparing difference not statistically significant.Serious adverse events is there is not in clinical trial.
By researchs such as prescription composition, production technology, method of quality control, product stability, clinical trials, the production technology of result own product is easy, quality controllable, the effect that can reach rapid release clinically.Compare with commercially available enteric coated preparation, this product can alleviate the clinical symptoms such as stomachache, heartburn sense sooner, has good efficacy to gastrointestinal ulceration disease.
Claims (2)
1. a manufacture method for omeprazole sodium bicarbonate capsule, is characterized in that: the amount of its supplementary material unit formulation is: omeprazole 40mg, sodium bicarbonate 1100mg, cross-linking sodium carboxymethyl cellulose 20-30mg, magnesium stearate 1-5mg; The particle size distribution D of described omeprazole
10>=1 μm, D50≤10 μm, D
90≤ 20 μm; The granularity of described sodium bicarbonate crosses 100 orders; Making step is:
(1) first step premixing: take the omeprazole of full dose and appropriate sodium bicarbonate, be specially sodium bicarbonate: omeprazole=4:1, weight ratio, mixes 5 minutes;
(2) second step premixing: take appropriate sodium bicarbonate, mixes 5 minutes with step (1) mixture, makes sodium bicarbonate: omeprazole=8:1, weight ratio;
(3) always mix: get cross-linking sodium carboxymethyl cellulose, magnesium stearate in remaining sodium bicarbonate and prescription, with said mixture mixing 10-30 minute;
(4) gained powder in step (3) is carried out to the detection of intermediate, calculate the loading amount of every capsules;
(5) qualified intermediate powder be directly filled to capsule and get final product.
2. a manufacture method for omeprazole sodium bicarbonate capsule, is characterized in that: the amount of its supplementary material unit formulation is: omeprazole 20mg, sodium bicarbonate 1100mg, cross-linking sodium carboxymethyl cellulose 20-30mg, magnesium stearate 1-5mg; The particle size distribution D of described omeprazole
10>=1 μm, D50≤10 μm, D
90≤ 20 μm; The granularity of described sodium bicarbonate crosses 100 orders; Making step is:
(1) first step premixing: take the omeprazole of full dose and appropriate sodium bicarbonate, be specially sodium bicarbonate: omeprazole=6:1, weight ratio, mixes 5 minutes;
(2) second step premixing: take appropriate sodium bicarbonate, mixes 5 minutes with step (1) mixture, makes sodium bicarbonate: omeprazole=12:1, weight ratio;
(3) always mix: get cross-linking sodium carboxymethyl cellulose, magnesium stearate in remaining sodium bicarbonate and prescription, with said mixture mixing 10-30 minute;
(4) gained powder in step (3) is carried out to the detection of intermediate, calculate the loading amount of every capsules;
(5) qualified intermediate powder be directly filled to capsule and get final product.
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| CN104267126B (en) * | 2014-10-14 | 2016-06-15 | 厦门恩成制药有限公司 | A kind of omeprazole sodium bicarbonate capsule has the detection method of related substance |
| KR102080023B1 (en) * | 2018-01-29 | 2020-02-21 | 주식회사 종근당 | Stable pharmaceutical composition comprising esomeprazole and sodium bicarbonate |
| KR102006777B1 (en) | 2018-01-29 | 2019-10-08 | 주식회사 종근당 | Pharmaceutical formulation comprising esomeprazole and sodium bicarbonate |
| CN112022829A (en) * | 2019-06-04 | 2020-12-04 | 厦门恩成制药有限公司 | Method for preparing esomeprazole magnesium sodium bicarbonate capsule |
| CN110585164A (en) * | 2019-10-08 | 2019-12-20 | 苏州弘森药业股份有限公司 | Method for preparing esomeprazole magnesium sodium bicarbonate capsule |
| AU2020377451A1 (en) * | 2019-11-04 | 2022-05-26 | Cinclus Pharma Holding AB | Oral formulation of X842 |
| CN112494451B (en) * | 2020-03-24 | 2022-03-01 | 长春海悦药业股份有限公司 | Esomeprazole magnesium sodium bicarbonate capsule |
| CN112494459B (en) * | 2020-03-24 | 2022-03-01 | 长春海悦药业股份有限公司 | Medicinal preparation and application thereof |
| CN112697688A (en) * | 2020-12-18 | 2021-04-23 | 正大制药（青岛）有限公司 | Acid resistance measuring method of omeprazole chewable tablets |
| CN114028359B (en) * | 2021-12-16 | 2023-03-17 | 厦门恩成制药有限公司 | Pantoprazole quick-release capsule and preparation method thereof |
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| CN102641285A (en) * | 2012-03-12 | 2012-08-22 | 南京海纳医药科技有限公司 | Compound omeprazole capsule and preparation method thereof |
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| CN102641285A (en) * | 2012-03-12 | 2012-08-22 | 南京海纳医药科技有限公司 | Compound omeprazole capsule and preparation method thereof |
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