CN103230373A - Dexlansoprazole freeze-drying powder for injection and preparation method thereof - Google Patents
Dexlansoprazole freeze-drying powder for injection and preparation method thereof Download PDFInfo
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- CN103230373A CN103230373A CN2013101262577A CN201310126257A CN103230373A CN 103230373 A CN103230373 A CN 103230373A CN 2013101262577 A CN2013101262577 A CN 2013101262577A CN 201310126257 A CN201310126257 A CN 201310126257A CN 103230373 A CN103230373 A CN 103230373A
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Abstract
The invention provides a dexlansoprazole freeze-drying powder for injection and preparation method thereof, and the freeze-drying powder comprises dexlansoprazole, tromethamine and mannitol in weight ratio of 3 to 1-4 to 12-20. The preparation method comprises the following steps: dissolving tromethamine and mannitol by adding water, adjusting pH, resolving dexlansoprazole, filtering with filter membrane, charging, cooling to -45-35 DEG C at the speed of 0.8-1.2 DEG C/min, insulating and refrigerating for 2-4 hours, vacuuming to 10-20 Pa, heating to -15-5 DEG C within 1-3 hours at a uniform speed, insulating for 3-7 hours, and heating to 5-15 DEG C within 3-5 hours at a uniform speed, insulating for 2-4 hours, and then heating to 35-45 DEG C within 1-3 hours, insulating and drying for 35-45 DEG C, and then packing and warehousing after the product is detected qualified. The product prepared by the method has the advantages of low water content, good appearance, high stability and easy storage transportation.
Description
Technical field
The invention belongs to medical technical field, relate to class proton pump inhibitor class medicine and preparation method thereof, is a kind of R-lansoprazole for injection lyophilized powder and preparation method thereof in particular.
Background technology
The chemical structural formula of R-lansoprazole (dexlansoprazole) is:
Chemistry is by name: (+)-2-[(R)-[[3-methyl-4-(2; 2; the 2-trifluoro ethoxy)-the 2-pyridine radicals] methyl] sulfinyl]-1H-benzimidazole R-lansoprazole be behind esomeprazole (Esomeprazole) exploitation another draw azole optical voidness proton pump inhibitor class (proton pump inhibitors, PPIs) antiulcerative.R-lansoprazole be the interior onset composition of body of lansoprazole, thereby dosage is lower than lansoprazole, and then side effect still less as the optical voidness medicine of racemization lansoprazole.It acts on the H of parietal cell
+/ K
+-ATP enzyme makes the H of parietal cell
+Can't be transported to stomach, make that the gastric acid amount greatly reduces in the gastric juice, be used for the treatment of duodenal ulcer, gastric ulcer, reflux esophagitis, a left side-Ai (Zollinger-Ellison) syndrome clinically, evident in efficacy, helicobacter pylori also there is inhibitory action.Oral formulations by the listing of Japan military field pharmaceutical factory, does not all have the listing of R-lansoprazole injection both at home and abroad at present at the beginning of 2009.
After making oral formulations, drug absorption need be passed through the disintegrate dispose procedure, though the enteric solubility solid preparation can effectively solve gastric acid to the destruction of medicine, still bioavailability is lower.Simultaneously clinically, all need drug administration by injection in the surgical operation as complexity such as gastric cancer, intestinal cancer, liver, spleen, cancer of pancreas, craniocerebral operations, the gastric mucosa that causes with prevention stress state (the intestines and stomach stress) damages and stress ulcer; And for digestive ulcerative bleeding, the patient that stoma ulcer is hemorrhage because not taking food, has the pathological changes of stomach adhesion widely again, so also be more suitable in using injection.Therefore the R-lansoprazole injection is an urgent demand of clinical practice.From pharmacology, pharmacokinetics angle analysis, by muscle or intravenous injection medication, can avoid R-lansoprazole oral destroyed in gastric acid, can make R-lansoprazole rapidly by blood absorption or directly enter blood again, improve the blood drug level of R-lansoprazole and shorten peak time, utilized by human body rapidly, can reach the purpose of rapid onset and raising bioavailability.
Yet, there is the chemical constitution of sulfinyl benzimidazole in the R-lansoprazole structure, be subject to light, heavy metal ion, oxidisability and the reproducibility influence of various factors that becomes to grade.Especially when acid condition, R-lansoprazole is extremely unstable, is prone to variable color and polymerism, and its properties of Aqueous Solution is also very unstable, does not tolerate moist heat sterilization, thereby these product often are prepared into powder ampoule agent for injection.Because the unstability of itself character is subject to various Effect of Environmental, make that the development difficulty of its prescription, technology is bigger.
Having adopted a large amount of sodium thiosulfate or sodium pyrosulfite etc. among the CN200910259365 is antioxidant, and because this kind antioxidant does not have strict quality standard in China, a large amount of use has bigger drug safety hidden danger.
Adopting arginine among the CN200410036486 is stabilizing agent, and lactose is excipient, carries out lyophilizing and handles.Because, adding a large amount of lactose to lactose intolerance in the injection, Chinese more are easy to generate serious adverse.Simultaneously, arginine is unstable under alkali condition, and its pH will certainly influence arginic stability up to about 11.
Add EDTA among the CN200510040368 as stabilizing agent, and EDTA understands the calcium ion in the complexation blood, thereby cause the danger of low blood calcium.
Adopt meglumine as cosolvent among the CN200810001185, obtained the license of Lansoprazole freeze-dried injection, the large usage quantity of mannitol in its prescription, and mannitol has dehydration, the high infiltration of Chang Zuowei depressor uses, therefore the amount that adds of mannitol is excessive, make it possess certain pharmacologically active after, easily increase the risk that clinical adverse takes place.
Summary of the invention
One of the object of the invention is to provide a kind of R-lansoprazole for injection lyophilized powder.
Another purpose of the present invention is to provide a kind of preparation method of R-lansoprazole for injection lyophilized powder.
To achieve these goals, the technical solution used in the present invention is:
A kind of R-lansoprazole for injection lyophilized powder, described lyophilized powder component is: principal agent R-lansoprazole, stabilizing agent trometamol and excipient mannitol, the weight ratio of R-lansoprazole, trometamol and mannitol are 3:1-4:12-20.
The weight batching of above-mentioned R-lansoprazole, trometamol and mannitol is than being 3:2:12.
A kind of preparation method of R-lansoprazole for injection lyophilized powder noted earlier comprises following processing step:
(1), dosing: by R-lansoprazole: the weight ratio of trometamol: mannitol=3:1-4:12-20 is got trometamol and mannitol, join in the dosing cylinder, add water for injection again and be stirred to whole dissolvings, to 10-12, add R-lansoprazole with the sodium hydroxide adjust pH, add water for injection to liquor capacity and be R-lansoprazole 135 times;
(2), filter: filtrate is surveyed pH value to 10-12 with 0.22 μ m degerming filtering with microporous membrane, filtrate, packing false add plug;
(3) lyophilizing:
1., pre-freeze: the medicinal liquid that branch is installed is cooled to-45 ~-35 ℃ by 0.8-1.2 ℃ of/minute speed, is incubated freezing 2-4 hour;
2., distillation: will freeze good medicinal liquid and be evacuated to 10-20Pa, and in 1-3 hour, at the uniform velocity be warming up to-15--5 ℃, and be incubated 3-7 hour, and in 3-5 hour, at the uniform velocity be warming up to 5-15 ℃ again, and be incubated 2-4 hour;
3., drying: the distillation medicinal liquid of stage after finishing that finish risen to 35-45 ℃ in 1-3 hour, heat preservation and dryness 3-5 hour, detects qualified back packing and put in storage.
In the above-mentioned preparation method, step (2) is not taken off charcoal, but usually reach the endotoxin of controlling final products by the endogenous toxin of control supplementary material, so not only improved stability of drug, and shortened preparation time, active carbon has the back suction phenomenon under high pH condition simultaneously, introduces uncertain influence to medicine, and this preparation method has been avoided the generation of this kind situation.
In the above-mentioned preparation method, in the step (3) 1. described cooling rate of pre-freeze stage be 0.8-1.2 ℃/minute, make that medicinal liquid can quick freezing, it is little to produce crystalline volume, avoided cooling rate to cross slow simultaneously and cause R-lansoprazole to be separated out, or produced and concentrate effect and make product structure inhomogeneous.The present invention cools the temperature to when pre-freeze-35--45 ℃, guarantee that medicinal liquid is thoroughly frozen.
In the above-mentioned preparation method, step (3) if in 2. sublimation stage process vacuum is excessive then influence heat passagely because having eliminated cross-ventilation, if too small then influence distillation effect, through overtesting, the present invention is limited to 20Pa with it, has perfectly solved this problem.Sublimation process is divided into two stages, can shorten the time when guaranteeing the distillation effect, has improved distillation efficient.
In the above-mentioned preparation method, in the step (3) 3. dry run temperature is risen to 40 ℃, guarantee that moisture is evaporated to greatest extent, can not influence product quality simultaneously.
According to foregoing preparation method, in the step (3) 1. the described cooling rate of sublimation stage be 1.0 ℃/minute.
According to above-mentioned preparation method, 1. described being cooled to-40 ℃ in the step (3).
According to above-mentioned preparation method, in the step (3) 2. described sublimation stage process be: the medicinal liquid that pre-freeze is good is evacuated to 20Pa, at the uniform velocity is warming up to-10 ℃ in 2 hours, is incubated 5 hours, at the uniform velocity is warming up to 10 ℃ again in 4 hours, is incubated 3 hours.
According to above-mentioned preparation method, R-lansoprazole: trometamol: mannitol equals 3:2:12.
According to above-mentioned preparation method, it is specially: trometamol and mannitol are added in the Agitation Tank, add water for injection and be stirred to whole dissolvings, regulate pH10-12 with sodium hydroxide, add R-lansoprazole and be stirred to whole dissolvings, add water for injection to liquor capacity and be R-lansoprazole 135 times, with 0.22 μ m degerming filtering with microporous membrane, filtrate is surveyed pH value, content, packing false add plug, the medicinal liquid that branch is installed is cooled to-40 ℃ by 1.0 ℃ of/minute speed, be incubated freezing 3 hours, open vacuum valve and be evacuated to 20Pa, in 2 hours, at the uniform velocity be warming up to-10 ℃, be incubated 5 hours, in 4 hours, at the uniform velocity be warming up to 10 ℃ again, be incubated 3 hours, medicinal liquid was risen to 40 ℃ in 2 hours, heat preservation and dryness 4 hours detects qualified back packing warehouse-in.
According to above-mentioned preparation method, it more specifically is: trometamol 10g and mannitol 60g are added in the Agitation Tank, add 1800ml water for injection and be stirred to whole dissolvings, regulate pH11.5 with sodium hydroxide, add R-lansoprazole 15g and be stirred to whole dissolvings, add water for injection to 2000ml, with 0.22 μ m degerming filtering with microporous membrane, filtrate is surveyed pH value, content, be distributed into 1000 bottles, the false add plug, the medicinal liquid that branch is installed is cooled to-40 ℃ by 1.0 ℃ of/minute speed, is incubated freezing 3 hours, open vacuum valve and be evacuated to 20Pa, in 2 hours, at the uniform velocity be warming up to-10 ℃, be incubated 5 hours, in 4 hours, at the uniform velocity be warming up to 10 ℃ again, be incubated 3 hours, medicinal liquid was risen to 40 ℃ in 2 hours, heat preservation and dryness 4 hours detects qualified back packing warehouse-in.
R-lansoprazole lyophilized powder provided by the present invention and preparation method thereof has following advantage:
(2) R-lansoprazole lyophilized powder provided by the present invention adopts the consumption of excipient mannitol few, and product appearance is full, and solubility is good, has satisfied the principle of as far as possible using adjuvant in the pharmaceutical preparation less.
(3) preparation method of R-lansoprazole lyophilized powder provided by the present invention is taked dissolving adjuvant earlier, behind adjusting pH to 10 ~ 12, dissolves R-lansoprazole again, and this technology not only makes R-lansoprazole dissolve sooner, and medicine is more stable.
(4) preparation method of R-lansoprazole lyophilized powder provided by the present invention takes to control by control supplementary material bacterial endotoxin level the endotoxin of final products, rather than adopt the method take off charcoal, this technology has not only shortened preparation time, and avoided simultaneously the attached effect of back suction of active carbon again, make medicine have higher stability.
(5) R-lansoprazole method for preparing freeze-dried powder provided by the present invention takes rapidly fluid temperature to be down to the pre-freeze temperature, and heat up stage by stage, not only obtain full, the up-to-standard product of outward appearance under this technology, possessed higher production efficiency simultaneously, at utmost reduced energy consumption.
(6) R-lansoprazole lyophilized powder steady quality provided by the present invention, easy to use, be beneficial to storing, its preparation method is simple, operability is high, be easy to suitability for industrialized production.
For further embodying the stability of R-lansoprazole for injection of the present invention, the present invention has been carried out study on the stability according to the R-lansoprazole for injection that embodiment 1 prepares.Be evaluation index with outward appearance, pH value, related substance, content, investigated it at 25 ℃ ± 2 ℃, RH 60% ± 10% and 40 ℃ ± 2 ℃ are placed 6 months stability under RH 75% ± 5% condition, the results are shown in Table 1.Concrete test operation carries out according to related content in 2010 editions two appendix of Chinese Pharmacopoeia " pharmaceutical preparation stability test guideline ".
Table 1 R-lansoprazole for injection embodiment 1 stability of sample of the present invention is investigated information slip
Stability result explanation, R-lansoprazole for injection of the present invention were placed 6 months under RH 75% ± 5% condition at 40 ℃ ± 2 ℃, and significant change does not all take place for its outward appearance, pH and content, and related substance has increase slightly; At 25 ℃ ± 2 ℃, to place 6 months under RH 60% ± 10% condition, significant change does not all take place in its outward appearance, pH, related substance and content, and R-lansoprazole for injection steady quality of the present invention is described, thereby infers that it must possess certain clinical drug safety.
Description of drawings
Fig. 1 is R-lansoprazole for injection lyophilized powder preparation flow.
The specific embodiment
The following examples will be done to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
Embodiment 1
A kind of preparation method of R-lansoprazole for injection lyophilized powder, be that trometamol 50g and mannitol 300g are added in the dosing cylinder, add 9L water for injection and be stirred to whole dissolvings, regulate pH10 ~ 12 with sodium hydroxide, add R-lansoprazole 75g and be stirred to whole dissolvings, add water for injection to 10L, filtrate is surveyed pH value with 0.22 μ m degerming filtering with microporous membrane, filtrate, content, be distributed into 5000 bottles, the false add plug, the medicinal liquid that branch is installed is cooled to-40 ℃ by 1.0 ℃ of/minute speed, is incubated freezing 3 hours, open vacuum valve and be evacuated to 20Pa, at the uniform velocity slowly be warming up to-10 ℃ then in 2 hours, heat preservation and dryness 5 hours at the uniform velocity was warming up to 10 ℃ again in 4 hours, heat preservation and dryness 3 hours, then medicinal liquid at the uniform velocity was warming up to 40 ℃ in 2 hours, heat preservation and dryness 4 hours detects qualified back packing warehouse-in.
Embodiment 2
A kind of preparation method of R-lansoprazole for injection lyophilized powder, be that trometamol 25g and mannitol 300g are added in the dosing cylinder, add 9L water for injection and be stirred to whole dissolvings, regulate pH10 ~ 12 with sodium hydroxide, add R-lansoprazole 75g and be stirred to whole dissolvings, add water for injection to 10L, filtrate is surveyed pH value with 0.22 μ m degerming filtering with microporous membrane, filtrate, content, be distributed into 5000 bottles, the false add plug, the medicinal liquid that branch is installed is cooled to-45 ℃ by 1.2 ℃ of/minute speed, is incubated freezing 2 hours, open vacuum valve and be evacuated to 15Pa, at the uniform velocity slowly be warming up to-15 ℃ then in 2 hours, heat preservation and dryness 6 hours at the uniform velocity was warming up to 15 ℃ again in 5 hours, heat preservation and dryness 2 hours, then medicinal liquid at the uniform velocity was warming up to 40 ℃ in 2 hours, heat preservation and dryness 3 hours detects qualified back packing warehouse-in.
Embodiment 3
A kind of preparation method of R-lansoprazole for injection lyophilized powder, be that trometamol 100g and mannitol 300g are added in the dosing cylinder, add 9L water for injection and be stirred to whole dissolvings, regulate pH10 ~ 12 with sodium hydroxide, add R-lansoprazole 75g and be stirred to whole dissolvings, add water for injection to 10L, filtrate is with 0. 22 μ m degerming filtering with microporous membranes then, and filtrate is surveyed pH value, content, be distributed into 5000 bottles, the false add plug, the medicinal liquid that branch is installed is cooled to-35 ℃ by 1.1 ℃ of/minute speed, is incubated freezing 3 hours, open vacuum valve and be evacuated to 10Pa, at the uniform velocity slowly be warming up to-5 ℃ then in 2 hours, heat preservation and dryness 4 hours at the uniform velocity was warming up to 5 ℃ again in 3 hours, heat preservation and dryness 4 hours, then medicinal liquid at the uniform velocity was warming up to 40 ℃ in 2 hours, heat preservation and dryness 5 hours detects qualified back packing warehouse-in.
Embodiment 4
A kind of preparation method of R-lansoprazole for injection lyophilized powder, be that trometamol 50g and mannitol 500g are added in the dosing cylinder, add 9L water for injection and be stirred to whole dissolvings, regulate pH10 ~ 12 with sodium hydroxide, add R-lansoprazole 75g and be stirred to whole dissolvings, add water for injection to 10L, filtrate reuse 0.22 μ m degerming filtering with microporous membrane then, filtrate is surveyed pH value, content, be distributed into 5000 bottles, the false add plug, the medicinal liquid that branch is installed is cooled to-40 ℃ by 0.9 ℃ of/minute speed, is incubated freezing 4 hours, open vacuum valve and be evacuated to 15Pa, at the uniform velocity slowly be warming up to-15 ℃ then in 2 hours, heat preservation and dryness 6 hours at the uniform velocity was warming up to 15 ℃ again in 5 hours, be incubated 2 hours, then medicinal liquid at the uniform velocity was warming up to 40 ℃ in 2 hours, heat preservation and dryness 3 hours detects qualified back packing warehouse-in.
Embodiment 5
A kind of preparation method of R-lansoprazole for injection lyophilized powder, be that trometamol 25g and mannitol 500g are added in the dosing cylinder, add 9L water for injection and be stirred to whole dissolvings, regulate pH10-12 with sodium hydroxide, add R-lansoprazole 75g and be stirred to whole dissolvings, add water for injection to 10L, filtrate reuse 0.22 μ m degerming filtering with microporous membrane then, filtrate is surveyed pH value, content, be distributed into 5000 bottles, the false add plug, the medicinal liquid that branch is installed is cooled to-35 ℃ by 0.8 ℃ of/minute speed, is incubated freezing 4 hours, open vacuum valve and be evacuated to 20Pa, at the uniform velocity slowly be warming up to-5 ℃ then in 2 hours, heat preservation and dryness 5 hours at the uniform velocity was warming up to 5 ℃ again in 3 hours, heat preservation and dryness 4 hours, then medicinal liquid at the uniform velocity was warming up to 40 ℃ in 2 hours, heat preservation and dryness 4 hours detects qualified back packing warehouse-in.
Embodiment 6
A kind of preparation method of R-lansoprazole for injection lyophilized powder, be that trometamol 100g and mannitol 500g are added in the dosing cylinder, add 9L water for injection and be stirred to whole dissolvings, regulate pH10 ~ 12 with sodium hydroxide, add R-lansoprazole 75g and be stirred to whole dissolvings, add water for injection to 10L, filtrate reuse 0.22 μ m degerming filtering with microporous membrane then, filtrate is surveyed pH value, content, be distributed into 5000 bottles, the false add plug, the medicinal liquid that branch is installed is cooled to-45 ℃ by 1.1 ℃ of/minute speed, is incubated freezing 2 hours, open vacuum valve and be evacuated to 15Pa, at the uniform velocity slowly be warming up to-5 ℃ then in 2 hours, heat preservation and dryness 4 hours at the uniform velocity was warming up to 5 ℃ again in 3 hours, heat preservation and dryness 5 hours, then medicinal liquid at the uniform velocity was warming up to 40 ℃ in 2 hours, heat preservation and dryness 3 hours detects qualified back packing warehouse-in.
For verifying the reasonability of R-lansoprazole for injection lyophilized powder prescription of the present invention and preparation method thereof, the inventor once tested in a large number, and it is as follows now to enumerate part:
Test example 1 acidity scope is determined
According to listing kind and R-lansoprazole raw material properties, this product is stablized pH value is 10.0 ~ 12.0 scopes in, based on the dissolubility of R-lansoprazole and the toleration influence factor of human body, the basicity of this product is decided to be pH value 10.0 ~ 12.0.
The screening of test example 2 excipient
Requirement to excipient is: (1) no antigen, avirulence.(2) dry back rehydration is good.(3) in lyophilizing and duration of storage product there is protective effect, does not produce chemical reaction with property of medicine composition, do not influence the activity of property of medicine composition.(4) the not detection of interference products.(5) height that should try one's best of its disintegrate temperature.According to above principle and R-lansoprazole quality standard, selecting mannitol commonly used for use is excipient.Its consumption screening sees Table 2.
The screening of table 2 amount of excipient
1 sample of writing out a prescription is shaped undesirable, atrophy occurs subsiding; Prescription 3 is white block, and quality is loose, fine and smooth, and nothing is subsided, and does not have the bottle of extension phenomenon; 2 samples of writing out a prescription are white block, and quality is loose, fine and smooth, and nothing is subsided, and do not have the bottle of extension phenomenon, and the mannitol consumption are few, is suitable prescription, and we select to write out a prescription 2.
The investigation of test example 3 dissolving situations
R-lansoprazole is insoluble in water, adds the dissolving situation that suitable stabilizers and suitable dissolving method can improve R-lansoprazole, and result of the test sees Table 3.
The investigation of table 3 dissolving situation
Prescription 1 does not add trometamol, after the supplementary material dissolving, transfers pH to 10.0 ~ 12.0, and dissolving is slow; Prescription 2 adds the more amount trometamol, after the supplementary material dissolving, transfers pH to 10.0 ~ 12.0, and dissolving is very fast; Prescription 3 adds a small amount of trometamol, after the adjuvant dissolving, transfers pH to 10.0 ~ 12.0, dissolves crude drug again, dissolves very soon, is suitable prescription and dissolving method, and we select to write out a prescription 3 and dissolving method.
The 4 endotoxic investigations of test example
Under gnotobasis, press recipe quantity preparation R-lansoprazole solution, with 0.22 μ m microporous filter membrane aseptic filtration, investigate sample endotoxin and medicament contg, result of the test sees Table 4.
The endotoxic investigation of table 4
| ? | Sample 1 | Sample 2 | Sample 3 |
| Content (%) | 99.3 | 100.2 | 99.7 |
| Endotoxin | Up to specification | Up to specification | Up to specification |
The result shows: process for preparation does not take off charcoal, is feasible but control the endotoxic technology of finished product by reinforcement supplementary material quality, raising process control level, and endotoxin is all up to specification.Therefore, we do not take off charcoal at layoutprocedure, still can satisfy prescription, have shortened preparation time simultaneously, have also avoided the back suction of active carbon attached, further cause the raising of medicine stability.
The research of test example 5 lyophilisation conditions
The screening of lyophilisation condition:
Designed three kinds of lyophilization conditions (seeing Table 5) according to freeze-drying process and carried out test and Selection, different lyophilizing the results are shown in Table 6.
Table 5 freeze-dry process
The result of the different lyophilization conditions of table 6
| Sequence number | Evaluation of result |
| 1 | Formability is bad, water content height (5.7%), and solubility is undesirable. |
| 2 | Formability is good, water content higher (3.4%), solubility ideal. |
| 3 | Formability is good, water content low (1.2%), solubility ideal. |
By The above results as can be known: sequence number 1 sample formability is bad, the water content height, and solubility is undesirable; Sequence number 2 sample formabilities are good, and water content is higher, redissolve desirable; Sequence number 3 sample good moldability, water content is low, redissolves desirable.Screening by lyophilisation condition, we have determined the best freeze-dry process of this product, select sequence number 3: be cooled to-40 ℃ by 1.0 ℃ of/minute speed, be incubated freezing 3 hours, evacuation at the uniform velocity slowly was warming up to-10 ℃ in 2 hours, heat preservation and dryness 5 hours, in 4 hours, at the uniform velocity be warming up to 10 ℃ again, heat preservation and dryness 3 hours at the uniform velocity is warming up to 40 ℃ in 2 hours then, heat preservation and dryness 4 hours.
Correlated quality index comparative test before and after 6 lyophilizing of test example
In order to confirm whether freeze-dry process influences the every index of quality of medicine, get the qualified sample of basic investigation project and compared some physical and chemical indexs of lyophilizing front and back, the results are shown in Table 7.
Comparative test before and after table 7 lyophilizing
The result shows: sample related substance, content have no significant change, and pH slightly descends, so freeze-dry process does not influence this product quality.
Test example 7 stability studies
This product is according to relevant requirements in 2010 editions two appendix of Chinese Pharmacopoeia " pharmaceutical preparation stability test guideline ", this product carried out the stability study of accelerated test, long term test.The result shows: R-lansoprazole for injection is at 40 ℃ ± 2 ℃, placed 6 months under RH75% ± 5% condition, significant change does not all take place in its character, pH, clarity and content, and related substance has increase slightly, but far below the quality standard limit of commercially available Lansoprazole for injecting; R-lansoprazole for injection was placed 6 months under RH60% ± 10% condition at 25 ℃ ± 2 ℃, and significant change does not all take place for its character, pH, clarity, related substance and content, and the R-lansoprazole for injection steady quality among the present invention is described.
Claims (4)
1. a R-lansoprazole for injection lyophilized powder is characterized in that being prepared into by R-lansoprazole, stabilizing agent trometamol and excipient mannitol, and the weight proportion of R-lansoprazole, trometamol and mannitol is 3:1-4:12-20.
2. a kind of R-lansoprazole for injection lyophilized powder according to claim 1, the weight ratio that it is characterized in that described R-lansoprazole, trometamol and mannitol is 3:2:12.
3. the preparation method of a R-lansoprazole for injection lyophilized powder is characterized in that comprising following processing step:
(1) by R-lansoprazole: the weight ratio of trometamol: mannitol=3:1-4:12-20 is got R-lansoprazole, trometamol and mannitol, and earlier trometamol and mannitol are joined in the dosing cylinder, add water for injection again and be stirred to whole dissolvings, to 10-12, add R-lansoprazole with the sodium hydroxide adjust pH, add water for injection to liquor capacity and be R-lansoprazole 135 times;
(2), filter: filtrate is surveyed pH value to 10-12 with 0.22 μ m degerming filtering with microporous membrane, filtrate, packing false add plug;
(3) lyophilizing:
1., pre-freeze: the medicinal liquid that branch is installed is cooled to-45 ~-35 ℃ by 0.8-1.2 ℃ of/minute speed, is incubated freezing 2-4 hour;
2. distillation: will freeze good medicinal liquid and be evacuated to 10-20Pa, and in 1-3 hour, at the uniform velocity be warming up to-15 ~-5 ℃, and be incubated 3-7 hour, and in 3-5 hour, at the uniform velocity be warming up to 5-15 ℃ again, and be incubated 2-4 hour;
3. dry: the distillation medicinal liquid of stage after finishing that finish risen to 35-45 ℃ in 1-3 hour, heat preservation and dryness 3-5 hour, namely.
4. the preparation method of a kind of R-lansoprazole for injection lyophilized powder according to claim 3 is characterized in that, in the step (3) 1. described cooling rate of pre-freeze stage be 1.0 ℃/minute; Be cooled to-40 ℃;
In the step (3) 2. described sublimation stage process be: the medicinal liquid that pre-freeze is good is evacuated to 20Pa, at the uniform velocity is warming up to-10 ℃ in 2 hours, is incubated 5 hours, at the uniform velocity is warming up to 10 ℃ again in 4 hours, is incubated 3 hours;
In the step (3) 3. described drying stage process be: the distillation medicinal liquid of stage after finishing that finish risen to 40 ℃, heat preservation and dryness 4 hours in 2 hours.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN109394706A (en) * | 2018-12-07 | 2019-03-01 | 杭州上禾健康科技有限公司 | A kind of Lansoprazole freeze-dried powder for injection and preparation method thereof |
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| CN109394706A (en) * | 2018-12-07 | 2019-03-01 | 杭州上禾健康科技有限公司 | A kind of Lansoprazole freeze-dried powder for injection and preparation method thereof |
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