CN102085190B - Pantoprazole sodium freeze-dried powder injection and preparation method thereof - Google Patents
Pantoprazole sodium freeze-dried powder injection and preparation method thereof Download PDFInfo
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- CN102085190B CN102085190B CN 201110030916 CN201110030916A CN102085190B CN 102085190 B CN102085190 B CN 102085190B CN 201110030916 CN201110030916 CN 201110030916 CN 201110030916 A CN201110030916 A CN 201110030916A CN 102085190 B CN102085190 B CN 102085190B
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Abstract
The invention relates to a pantoprazole sodium freeze-dried powder injection and a preparation method thereof. The powder injection is prepared from pantoprazole sodium and mannitol, wherein the consumption ratio of the pantoprazole sodium to the mannitol is (1:0.8)-(1:1.6), and the pH value is 10.5-11.0. In the invention, by lowering the pre-freezing temperature, properly lowering the freezing temperature, maintaining the lowered freezing temperature for a proper time, properly shortening two-stage drying time and carrying out other adjustment processes, good appearance and quality of the product can be kept under the condition that the content of the mannitol is low, the processes are reliable and feasible, and the effect is obvious. The prepared product has low content of related substances and has controllable quality, and the freeze-dried product has good clarity and formability after being redissolved.
Description
Technical field
The present invention relates to a kind of field of pharmaceutical preparations, more particularly the invention provides a kind of Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method.
Background technology
Pantoprazole Sodium, English name: Pantoprazole Sodium, its chemical name is: 5-difluoro-methoxy-2-[[(3,4-dimethoxy-2-pyridine radicals)-methyl] sulfinyl]-1H-benzimidazole sodium-hydrate.The injection Pantoprazole Sodium is applicable to duodenal ulcer, gastric ulcer, AGML, acutes hemorrhage of upper gastrointestinal tract such as plyability gastric ulcer.Pantoprazole is a proton pump inhibitor, through with the H of parietal cell
+-K
+Two site covalent bond of ATP enzyme system and final step that gastric acid inhibitory produces.This effect is dose dependent and the gastric acid secretion under basis and the stimulation state is all suppressed.These article and H
+-K
+The combination of ATP enzyme can cause its anti-gastric acid secretion effect to continue more than 24 hours.Proton pump depressant (PPI) is to treat one of essential drugs that gastric acid abnormal secretion relevant disease uses at most modern age.Pantoprazole (trade name: the appropriate Lip river of Pan
) is by development of German Byk Gulden pharmaceutical factory and development product; Being the proton pump inhibitor of the 3rd listing after omeprazole and lansoprazole, also is the proton pump inhibitor that present unique two kinds of dosage forms (tablet, injection) all obtain drugs approved by FDA.Because substituted radical and omeprazole and the lansoprazole of pantoprazole on pyridine ring and benzimidazole ring is different; Thereby determined its difference at biochemical, pharmacokinetics and pharmacological property; Make it have stronger selectivity and specificity: pantoprazole activates into the speed of activity form one sulfenamide in the cell component (like lysosome and CG) of little acid slower; Thereby itself and the outer sulfydryl reaction of parietal cell are reduced to a minimum, have improved stability of drug.
The document of the freeze-dried powder injection of pantoprazole sodium relevant with the present invention is following in the prior art:
CN1235018 discloses a kind of Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method.To light, heat, oxygen, water etc. stable do not contain water of crystallization, be convenient to operation, be suitable for large-scale production, can supply the intravenous drip administration, the toxic and side effects of avoiding intravenous injection to cause.Described injection is not for containing water of crystallization, and pH value is 9.0～12.5, comprises Pantoprazole Sodium, lyophilized powder proppant, complexing of metal ion agent and PH regulator.Prescription is: 1 part of Pantoprazole Sodium; 1～5 part of lyophilized powder proppant; 0.05～2 part of complexing of metal ion agent.Above-mentioned prescription process filtering charcoal, degerming, lyophilization is carried out in fill.Its freeze-dry process for pre-freeze at first to-55 ℃～-35 ℃, be incubated 1～4 hour, the beginning evacuation in 15～30 hours, rises to 10 ℃～50 ℃ with temperature, continues the maintenance vacuum 3～10 hours; Nitrogen preservation promptly obtains lyophilized injectable powder.
CN101011397 discloses a kind of Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method.Said injectable powder is applicable under acute gastric mucosa damage that digestive ulcerative bleeding, nonsteroidal anti-inflammatory cause and the stress state diseases such as ulcer massive hemorrhage.Said lyophilized injectable powder, pH value is 9.5～11.5, comprises Pantoprazole Sodium, proppant, weak acid strong alkali salt and an amount of inorganic base.Its prescription consists of: 1 part of Pantoprazole Sodium, 0.5～1.0 part of proppant, 0～0.06 part of weak acid strong alkali salt, inorganic salt are an amount of.Its preparation method is characterised in that: proppant and weak acid strong alkali salt are dissolved with water for injection; Transfer pH value to 9.5～11.5 with inorganic base, add Pantoprazole Sodium, pH value to 9.5～11.5 are transferred with inorganic base in the dissolving back; Filter, lyophilization promptly obtains freeze-dried powder injection of pantoprazole sodium.
CN1679563 discloses a kind of freeze-dried powder injection of pantoprazole sodium.Its composition comprises 1 part of Pantoprazole Sodium, 0～0.125 part of excipient, 0.075～0.125 part of weak acid strong alkali salt, 0.025～0.0375 part of disodium edetate, an amount of inorganic base.
In the above-mentioned prescription, the kind and the consumption that add adjuvant are too much, the control of preparation process is required too high, inconvenient operation, freeze-dry process is complicacy comparatively, cost is higher.A large amount of in addition adjuvants possibly interact in storage process influences the stability of product, is unfavorable for promoting.
" China Dispensary "; 2005 the 16th the 2nd phases of volume; " development of pantoprazole sodium freeze-drying injection " discloses a kind of pantoprazole sodium freeze-drying injection, and wherein specifically disclosing by Pantoprazole Sodium, disodium edetate and mannitol is the pantoprazole sodium freeze-drying preparation of feedstock production.Though its prescription is simple relatively, the supplementary product kind of employing is few, those skilled in the art will know that; Disodium edetate can be combined into the complex discharge of solubility with calcium ion, thereby reduces blood calcium, therefore; Add disodium edetate and reduced clinical application safety, should not promote the use of equally.
CN101229138 discloses a kind of Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method.Described injectable powder comprises Pantoprazole Sodium and mannitol, and the two part by weight is 1: 2～5.Its preparation method is: Pantoprazole Sodium and mannitol are mixed, add water for injection and be stirred to whole dissolvings, transferring PH is 9.5～11.0; Adding water for injection to mannitol content is 60～100mg/ml, adds the needle-use activated carbon of total amount 0.05%, stirs 15 minutes; Filtering decarbonization with 0.22 μ m degerming microporous filter membrane fine straining, is measured pH value, content, false add plug with medicinal liquid; Frozen drying obtains freeze-dried powder then.It is sodium bicarbonate, sodium hydroxide or sodium carbonate that its PH regulates used material.Its parameters of freeze-drying process does, freezing period temperature be-40 ℃, the time is 2 hours; The distillation phase, to heat up to make to medicine and freeze the article temperature and remain on-40 ℃～-10 ℃, the time is 25 hours; Dry period is warming up to 25 ℃ gradually with medicine, insulation vacuum drying 3 hours.Above-mentioned freeze-dried powder injection of pantoprazole sodium prescription is simple, few side effects, but because the consumption of adjuvant is excessive, causes the medicinal effects of injectable powder unsatisfactory, has occurred the significant case of side effect in the actual clinical.The consumption of adjuvant too much also influences the pre-freeze of product and drains simultaneously, and therefore the freeze-drying process of above-mentioned freeze-dried powder is greater than 30h.
In view of this, the present invention on the basis of CN101229138, proposed a kind of easy to operate, freeze-dry process is simple, quality controllable, product related substance low and the Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method of favorable reproducibility.
Summary of the invention
The object of the present invention is to provide a kind of freeze-dried powder injection of pantoprazole sodium.Freeze-dried powder injection of pantoprazole sodium related substance provided by the present invention is low, and good stability is quality controllable, good forming ability, and the dried frozen aquatic products solubility is good, solution appearance clarification before freezing, the clarity of lyophilized injectable powder is good.
For realizing above-mentioned purpose, the present invention adopts following technical scheme:
A kind of freeze-dried powder injection of pantoprazole sodium comprises Pantoprazole Sodium and mannitol, said Pantoprazole Sodium: the amount ratio of mannitol is 1: 0.8～1: 1.6, preferred 1: 1-1: 1.4, and more preferably 1: 1.
Described freeze-dried powder injection of pantoprazole sodium specification is 40mg:1.2ml, and every injectable powder contains mannitol 32～64 grams; Another kind of specification is 80mg:2.4ml, and every injectable powder contains mannitol 64～128 grams.
The specification of preferred said freeze-dried powder is 40mg:1.2ml, and every injectable powder contains mannitol 40 grams; Or said freeze-dried powder specification is 80mg:2.4ml, and every injectable powder contains mannitol 80 grams.
Another object of the present invention is to provide the method for preparing of above-mentioned freeze-dried powder injection of pantoprazole sodium.Described method for preparing is following:
Take by weighing the Pantoprazole Sodium and the mannitol of recipe quantity, the water for injection that adds dosing total amount 80% earlier adds the mannitol and the Pantoprazole Sodium of recipe quantity successively in Agitation Tank, stirs to make and is dissolved into clear and bright solution; Replenish water for injection to full dose, mix homogeneously is between sodium hydroxide solution regulator solution pH value to 10.5～11.0; Add the medicinal carbon stirring and adsorbing, through taking off charcoal and 0.22 μ m aseptic filtration for the first time, intermediate detect qualified after; Medicinal liquid basin between medicinal liquid filter pressing to medicinal liquid accepted moves to medicine liquid tank and carries out 0.22 μ m secondary terminals degerming under hundred grades of laminar flow hood of filling machine and filter to medicinal liquor barrel fill; Half tamponade, lyophilization.
Solution temperature when adding Pantoprazole Sodium in the Agitation Tank is controlled at 10～20 ℃, preferred 15 ℃.
The amount that adds medicinal carbon is 0.1% (g/ml), and stirring and adsorbing is after 30 minutes, and decarburization limit, limit circulation 10 minutes is filtered and 0.22 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane, germ tight filter of 0.22 μ m after the decarburization.
Described concentration of sodium hydroxide solution is 5mol/L.
Lyophilization is divided into pre-freeze, primary drying and redrying three phases.
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-35 ± 2 ℃ after, continue insulation 3～5 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 4-8pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-3 ± 2 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 3～5 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 18 ± 2 ℃ with shelf temperature, and insulation 0.5-1h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 37 ± 2 ℃ after, continue insulation 3～5 hours.
Preferred described lyophilization comprises following three phases:
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-35 ℃ after, continue insulation 4 hours, keep that vacuum is 10pa in the case;
The primary drying stage: keeping the interior vacuum of case is 6pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-3 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 4 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 18 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 37 ℃ after, continue insulation 4 hours.
Down in the face of of the present invention describing in detail:
Though disclosed pantoprazole sodium freeze-drying powder pin has prescription simply among the CN101229138; The characteristics that stability is higher; But because the consumption of adjuvant is excessive in its prescription; Cause the medicinal effects of injectable powder general, the holding time, long rear stability was also not so good, had occurred the significant case of side effect in the actual clinical.The consumption of adjuvant too much also influences the pre-freeze of product and drains simultaneously, and therefore the freeze-drying process of above-mentioned freeze-dried powder is greater than 30h.In view of this, the inventor has carried out special research to the prescription and the preparation technology of pantoprazole sodium freeze-drying powder pin.
Pantoprazole Sodium is white or off-white color crystalline powder, in water or methanol, is prone to dissolve, and is almost insoluble in chloroform or ether; It keeps stable in alkaline solution, under acid solution, high light and hot conditions, be prone to degraded.PH value is controlled at 10.5～11.0 according to this.
The present invention follows supplementary product kind equally and the few more good more principle of consumption designs prescription (on the basis stable and controllable for quality, as to satisfy clinical demand); Adjuvant is few; When just meaning production operation; Can reduce batching step, be convenient to operation, the side effect that is difficult to expect that can avoid various adjuvants to bring simultaneously.Owing to the supplementary material source is few, just can reduce the possibility of the related substance increase that brings because of supplementary material.Thereby avoided increasing the curative effect problem descend and bring for hidden danger that patient's drug safety brings and active constituent content to the patient because of related substance.The present invention has continued to use the prescription among the CN101229138, selects mannitol as excipient, and it mainly plays caffolding agent.Mannitol is white crystalline powder, odorless, and it is sweet to distinguish the flavor of; Mannitol is prone to dissolve in water, dissolves in the ethanol part omitted, in ether, does not almost allow.
Because of having only a kind of adjuvant of mannitol, so the ratio of Pantoprazole Sodium and mannitol and freeze-dry process thereof have directly influenced the quality of freeze-dried powder.Prior art it has been generally acknowledged that during the preparation freeze-dried powder injection of pantoprazole sodium, the content of mannitol can not be too low; Point out in application documents like CN101229138: " through experiment in a large number, find that having only the weight ratio of Pantoprazole Sodium and mannitol is 1: during 2-5, the outward appearance of product is loose block; under process conditions of the present invention; solubility has also reached requirement, but wherein portioned product has the phenomenon of cracking slightly (seeing) from top to bottom, but not stratified; Though quality is qualified, outward appearance is good inadequately, will influence the sale of product, and is therefore further preferred to its ratio, and when the two ratio is 1: during 2.5-5, the outward appearance of product, solubility, clarity reach good; From cost-effective consideration, preferably the two ratio is 1: 2.5.Preferably include Pantoprazole Sodium 30-50mg in every injectable powder, preferred 40mg; Specification commonly used is 40mg:1.5ml; Wherein mannitol content must be more than 100mg in every injectable powder, otherwise product appearance atrophy will take place, subsides; Can be referring to experimental example 1; Based on cost consideration, be preferably 100-150mg, most preferably 100mg ".Hence one can see that, in the above-mentioned application in the freeze-dried powder injection of pantoprazole sodium of every 40mg/1.5ml the consumption of mannitol all greater than 100mg.And must guarantee that mannitol just can prepare qualified products greater than 100mg.And find too high stable influential to injectable powder of the content of mannitol in the real process.Therefore, the inventor has done a large amount of experimentatioies to the consumption of mannitol.The result shows that the consumption that appropriateness reduces mannitol possibly obtain qualified lyophilized injectable powder equally.Special; With Pantoprazole Sodium: the amount ratio of mannitol is controlled at 1: 0.8-1: between 1.6; The optimization that simultaneously freeze-dry process is adapted just can significantly improve medicine stability; Make the lyophilized injectable powder outward appearance for preparing, related substance, clarity, solubility etc. all reach requirement, obtain high-quality freeze-dried powder.
As everyone knows, the content of adjuvant is low excessively to be easy to stability of drug is exerted an influence, and causes freeze-dried powder each item index defective, reduces the qualification rate of product.Because the present invention has significantly reduced the consumption of excipient mannitol, therefore, in order stably to obtain high-quality lyophilized injectable powder, the inventor must do a large amount of screening tests to the associative operation that relates in the method for preparing.
The physical and chemical properties of drugs that one skilled in the art will appreciate that the different structure chemical compound is greatly different, so the preparation technology who adopts in the preparation process of different pharmaceutical also varies.Even the chemical compound of same structure, when adopting identical prescription adjuvant, even adjuvant is identical and only be content when difference is arranged, and its preparation method also should be adjusted as the case may be targetedly.Though prior art discloses the pantoprazole sodium freeze-drying powder pin described in background technology, the method for preparing of above-mentioned powder pin also is not suitable for the write out a prescription preparation of Pantoprazole Sodium of the present invention.In addition, though prior art has been launched big quantity research to freeze-dry process, those also only belong to a kind of guiding suggestion.Those skilled in the art to the combination of different drug composition and adjuvant thereof, still need pay a large amount of creative works on the basis of the instruction of prior art.Grope repeatedly and put into practice, could confirm a kind of specific most preferred preparation technology.
One skilled in the art will appreciate that freezing dry process plays the role of a nucleus to the quality of freeze-dried powder.Therefore, of the present inventionly focus on finding a kind of suitable freeze drying process, to solve the illegal technological deficiencies of parameter such as the outward appearance that possibly occur after the very few medicinal liquid lyophilizing of adjuvant and stability.
To prescription of the present invention, the inventor has done the adjustment that adapts to method for preparing on the preparation technology basis of traditional freeze-dried powder; Specifically comprise and select 0.01% needle-use activated carbon stirring and adsorbing 30min in the preparation for use, the circulation of limit decarburization limit is 10 minutes again, and with the degerming of microporous filter membrane secondary; According to the cryodesiccated operating parameter of prescription design, shorten operating process and operating time more as far as possible, control it and be no more than 20h; But can guarantee the quality of freeze-dried powder effectively, the quality of product such as formability, dissolubility, aseptic etc. produce and use in be able to control, can increase the stability of Pantoprazole Sodium like this; Reduce and produce used cost and simplify production technology; Thereby reduce the labor intensity of producing, reduce the side effect odds, guaranteed clinical application safety and convenience to a greater extent.
In order better to explain the method for preparing of pantoprazole sodium freeze-drying powder pin of the present invention, combine embodiment that preparation technology is done further to introduce in detail here.
Confirming of pH value
The present invention studies pH value; Characteristic according to Pantoprazole Sodium easy degraded under acid condition; And guarantee not to be degraded in the Pantoprazole Sodium medicinal liquid process for preparation in process of production, therefore confirm the quality control clearance of liquid PH value through following test.
Experimental technique: the Pantoprazole Sodium and the mannitol that take by weighing each recipe quantity in the following table 1; The water for injection that adds recipe quantity respectively stirs to make and is dissolved into clear and bright solution fully, regulates the solution pH value (result sees table 1) of each prescription with dilute hydrochloric acid and/or diluted sodium hydroxide solution; Each writes out a prescription solution after medicinal carbon is handled; Filter, subsequent filtrate all is filled in the injection bottle by 2.4ml/ bottle branch, makes sample through vacuum lyophilization; Randomly draw quadrat sampling article everywhere respectively, the pH value of test sample solution (result sees table 1).
Table 1 prescription is formed and experimental result
Can know that by result of the test the pH value of these article formulation soln all slightly descends than corresponding original solution pH value.
Basicity value scope in domestic pharmacopeia version drug standard-injection Pantoprazole Sodium exposure draft in 2010 is 9.5～11.0.Combine above result of the test again, the pH value scope of confirming this preparation medicinal liquid is 10.5～11.0.
The absorption research of active carbon
This preparation technology adopts traditional vacuum lyophilization, and in the preparation process, the medicinal liquid preparation needs to add a certain amount of active carbon as removing pyrogen (or bacterial endotoxin) and decolouring remove impurity; And the consumption of active carbon and adsorption time have certain influence to removing pyrogen (or bacterial endotoxin), decolouring remove impurity and drug content.Through following test, confirm consumption and the adsorption time and the suction type of medicinal carbon.
The investigation of medicinal carbon consumption
Carry out adsorption test through following variable concentrations medicinal carbon, investigate the absorption situation of medicinal carbon Pantoprazole Sodium.
Test method: by above-mentioned definite prescription and medicinal liquid compound method preparation pantoprazole sodium solution 100ml; Be divided into 5 equal portions; Get 4 parts of medicinal carbons that add 0.05%, 0.10%, 0.2%, 0.3% (g/ml) respectively; Equal stirring and adsorbing 30min under room temperature; Filter carbon removal, get each subsequent filtrate and another part not adsorbent solution carry out check and analysis, the subsequent filtrate of investigating each medicinal liquid through filter handle after content, pH value, clarity of solution, color, visible foreign matters, the situation of change of bacterial endotoxin of principal agent; See the following form 2.
The investigation of table 2 medicinal carbon consumption
The result shows that the medicinal carbon of variable concentrations all has certain absorption to Pantoprazole Sodium, and all darker without the medicinal liquid clarity and the color of medicinal carbon absorption, bacterial endotoxin is against regulation.Medicinal liquid after medicinal carbon absorption diminishes with respect to the content of the medicinal liquid content before adsorbing with the concentration increase medicinal liquid of active carbon gradually.Medicinal liquid clarity after 0.05% (g/ml) absorption is compared slightly turbid with the purified water that solvent is used; Medicinal liquid clarity is compared with the purified water that solvent is used after 0.1%～0.3% (g/ml) absorption, and is suitable basically.Medicinal liquid color after absorption has clear improvement than all with absorption prodrug liquid phase; Medicinal liquid bacterial endotoxin after the absorption is all up to specification.The pH value of each medicinal liquid does not have significant change before and after the absorption.Consider the influence of active carbon to adsorptivity and other several indexs of Pantoprazole Sodium, selecting concentration of activated carbon is the adsorption concentration of 0.1% (g/ml) as this medicinal liquid.
The investigation of 0.1% activated carbon adsorption mode
According to above result of the test, using concentration is 0.1% medicinal carbon, and through the different adsorption time, the different adsorption mode is investigated the absorption situation of medicinal carbon to Pantoprazole Sodium.
Test method: by above-mentioned medicinal liquid compound method preparation pantoprazole sodium solution 80ml solution, be divided into 4 equal portions, a copy of it conduct is adsorbent solution not; Three parts of medicinal carbons that respectively add 0.10% (g/ml) in addition; Carry out analyzing and testing after respectively at 15min, 30min, 40min three parts of solution being filtered carbon removal, investigate each medicinal liquid of Pantoprazole Sodium through the situation of change of taking off drug content, clarity of solution, color, visible foreign matters, pH value and bacterial endotoxin after charcoal is handled of same concentrations medicinal carbon in different mixings time; See the following form 3.
The investigation of table 3 medicinal carbon adsorption time
Analysis of experiments result shows: in identical medicinal carbon concentration 0.1% (g/ml); Adsorption time 15min～40min; Active carbon is slightly adsorbed to principal agent; Each medicinal liquid bacterial endotoxin after the absorption is up to specification, and clarity of solution, color and visible foreign matters all have clear improvement, and does not have significant change before and after the pH value absorption.Therefore select stirring and adsorbing 30min under the room temperature for use.Further, the inventor has also done correlational study to the suction type of active carbon, and unexpected the discovery, in the process of decarburization, adopts 10 minutes mode of decarburization limit, limit circulation, can make the medicinal liquid dissolving strengthen the absorbability of active carbon uniformly simultaneously.Obtain better adsorption effect.
In addition, in order to produce qualified product, the present invention also improves on follow-up preparation technology, and concrete method for preparing is following:
1. the cleaning of cillin bottle, sterilization
Low Pyrex control injection bottle is removed outer package; The injection bottle is put into the wash bottle transfer dish, and power-on reaches in the bottle washer injection bottle; Be delivered to the tunnel sterilizing oven with purified water, water for injection after cleaning cleaning; Through 350 ℃ of sterilization >=5min of high temperature, the low-temperature space cooling, it is subsequent use to get into the fill chamber.
2. the cleaning of butyl rubber bung, sterilization
Plug is put into full-automatic rubber plug cleaning machine, clean to clean with water for injection; Carry out 121 ℃, 30 minutes sterilization, cooling, drying, it is subsequent use to get into the fill chamber.
3. the cleaning of plastic-aluminum composite cover, sterilization
Aluminium-plastic cap is removed outer package, places 110 ℃ of baking oven sterilizations 90 minutes, and cooling is subsequent use.
4. take by weighing the Pantoprazole Sodium and the mannitol of recipe quantity, add the water for injection (10 ℃～20 ℃) in Agitation Tank of dosing total amount 80% earlier, add the mannitol and the Pantoprazole Sodium of recipe quantity successively, stir to make and be dissolved into clear and bright solution; Replenish water for injection to full dose, mix homogeneously is between sodium hydroxide solution regulator solution pH value to 10.5～11.0 with 5mol/L; 0.10% (g/ml) medicinal carbon that adds the dosing total amount; Stirring and adsorbing 30 minutes, decarburization limit, limit circulation 10 minutes is through taking off charcoal and 0.22 μ m aseptic filtration for the first time; After the intermediate detection is qualified; Medicinal liquid basin between medicinal liquid filter pressing to medicinal liquid accepted moves to medicine liquid tank and carries out 0.22 μ m secondary terminals degerming under hundred grades of laminar flow hood of filling machine and filter to medicinal liquor barrel, supplies fill to use.
The present invention remains Agitation Tank in the dosing process temperature is 10 ℃～20 ℃, preferred 15 ℃.This this temperature range helps the dissolving of Pantoprazole Sodium and mannitol and stablizing of solution PH.
5. fill
The operator will detect qualified solution and insert, and according to the content adjustment loading amount that intermediate detects, fill is in the injection bottle, and half tamponade is in time all used the sample of loading amount adjustment with selective examination again after the secondary aseptic filtration; Fill qualified products rule is positioned on the shelf in the lyophilizing cabinet, installs the thalposis probe after fill finishes on request, closes chamber door.
6. lyophilization
The fill certified products are put into material disc in time put on the dividing plate of freeze drying box, divide three phases to carry out lyophilization.
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-35 ± 2 ℃ after, continue insulation 3～5 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 4-8pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-3 ± 2 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 3～5 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 18 ± 2 ℃ with shelf temperature, and insulation 0.5-1h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 37 ± 2 ℃ after, continue insulation 3～5 hours.
7. roll lid, check.
The freeze-dry process condition plays crucial effects to the quality that guarantees product in the method for preparing of the present invention.The particularly control of the temperature and time when temperature controlling, pre-freeze, distillation.
Pre-freeze speed directly influences the quality of dry rate and product, in order to keep the main performance of Pantoprazole Sodium, obtains the good structure of freezing; The inventor has carried out a large amount of research experiments to the parameters in pre-freeze stage; Experiment is found, when baffle temperature is-50 ℃, puts into goods, and is incubated 3～5 hours; Keeping simultaneously can be thoroughly freezing with medicinal liquid about vacuum 10pa in the case, and can obtain good structure.Put into medicine again and earlier dividing plate is cooled to preset temperature, then can be so that the medicinal liquid fast cooling is freezing, it is more tiny to have guaranteed that medicinal liquid is separated out crystal, is unlikely to again simultaneously to prolong freeze-drying time because too densification causes the distillation difficulty.Freezing sufficient medicinal liquid is the operating time of the whole freeze-drying process of follow-up shortening good basis to be provided.
The primary drying stage of the present invention has been reduced the vacuum in the case, makes it remain on 4-8pa, in the scope of preferred 6pa; Programming rate with 0.25 ℃/min slowly is warming up to shelf-3 ± 2 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 3～5 hours.
Prior art it has been generally acknowledged that mannitol must reach the lyophilized powder that certain content could obtain good form as the proppant of injectable powder.But the inventor finds in the actual fabrication process, and the form of lyophilized powder and the relation of mannitol content are really not so.Mannitol and Pantoprazole Sodium are all water-soluble, all can fully dissolve behind the adding water for injection to form stay-in-grade solution.In the research process; The inventor has reduced the consumption of mannitol, and unexpected the discovery maybe be because the concentration of solution be lower; Dissolve abundant again, intermolecular gap big than prior art; Hydrones a large amount of during sublimation drying can be got rid of rapidly from the gap, and hydrone can only break through the arrange agencie eliminating of surperficial solute molecule when having avoided mannitol concentration high, possibly cause lyophilizing block surface to produce the defective of rough bubble hole shape.In addition, appropriateness reduces vacuum and also helps primary drying, and maintenance vacuum is 4-8pa, the scope of preferred 6pa, and than the operating condition of 10pa, the freeze-dried powder quality of gained will be got well.Concrete reason is still waiting further investigation.
Therefore, as long as experiment proof has been controlled cryodesiccated temperature and time well, and just can obtain more high-quality freeze-dried powder to the adjustment that vacuum adapts.Behind the primary drying, the inventor has done the research and the improvement in a dark step to the operating condition in redrying stage.
Take the technical scheme of two sections intensifications in the present invention of redrying stage; Programming rate with 0.35 ℃/min slowly rises to 18 ± 2 ℃ with shelf temperature earlier, insulation 0.5-1h, and the programming rate with 0.7 ℃/min heats up again; After treating that products temperature reaches 37 ± 2 ℃, continue insulation 3～5 hours.So can further improve the outward appearance of product, make it full, solubility is good, has also shortened the time significantly simultaneously, has improved production efficiency.
The present invention is through having adjusted lyophilisation condition; When reducing the mannitol consumption; The drying means of heating and heat preservation again after elder generation in programming rate, programming rate, temperature retention time and the redrying of the cooling rate through vacuum, pre-freeze in the adjustment freeze-drying process, temperature retention time, distillation heats up and be incubated; Not only can overcome prior art thinks that the content of mannitol is crossed and low must cause the freeze-dried powder atrophy, cave in; Product quality can't be qualified technological prejudice, also significantly shortened freeze-drying time.According to calculating, the cryodesiccated time is lower than 20h among the present invention, compares the cold dry run of prior art, and the time has shortened more than 35%.
Special, be 40mg:1.2ml when the present invention adopts specification, every injectable powder contains mannitol 40 grams; Or specification is 80mg:2.4ml, and every injectable powder contains mannitol 80 grams, in the preparation process of powder pin, adopts following freeze-dry process simultaneously:
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-35 ℃ after, continue insulation 4 hours, keep that vacuum is 10pa in the case;
The primary drying stage: keeping the interior vacuum of case is 6pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-3 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 4 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 18 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 37 ℃ after, continue insulation 4 hours.
The lyophilized injectable powder that adopts two kinds of prepared specifications of above-mentioned prescription and technology is the most preferred embodiment of the present invention.The system the freeze-dried powder outward appearance full, solubility is good, good stability.
In order further to verify preparation technology's according to the invention science and reasonability; The inventor is with Pantoprazole Sodium: the amount ratio of mannitol was respectively 1: 0.8,1: 1,1: 1.2,1: 1.4,1: 1.6; The pantoprazole sodium freeze-drying preparation that has prepared 5 crowdes of 40mg/1.5ml by disclosed method for preparing among the CN101229138; Find in the inspection that in 5 batches of products, most product presents in various degree atrophy, subsides.Result of calculation shows that in above-mentioned 5 batches of products, percent defective is respectively up to 17%, 16%, 15%, 18%, 20%.The result shows, reduce the consumption of mannitol significantly after, adopt freeze-dry process of the prior art to be difficult to obtain the freeze-dried powder of high qualification rate.Therefore in order to keep product appearance good, make solubility, clarity and stability meet related request simultaneously, the inventor must adjust freeze-dry process targetedly.The method for preparing that the present invention requires to protect is finally confirmed after the inventor has done a large amount of experiments; This method can satisfy prescription and be Pantoprazole Sodium: the amount ratio of mannitol is 1: 0.8-1: the preparation of 1.6 freeze-dried powder injection of pantoprazole sodium; And obtain the freeze-dried powder that quality is superior to prior art, realize the object of the invention.
In sum, in the freeze-drying process of Pantoprazole Sodium, through reducing the precooling temperature; Suitably reduce cryogenic temperature and keep reasonable time; Suitably shorten technology adjustment such as two-stage drying time, can under the low situation of mannitol content, keep product good surface appearance and quality; Truly feasible, effect is obvious.
Compared with prior art, the present invention has following advantage:
(1) only adopts a kind of adjuvant, and greatly reduce the consumption of adjuvant on the basis of existing technology.Avoided the potential side effect that brings because of adjuvant more.
(2) the present invention is directed to above-mentioned prescription and optimized method for preparing targetedly; Mannitol consumption, medicinal carbon consumption and adsorption time and parameters of freeze-drying process have been carried out strict control; Prepared freeze-dried powder injection of pantoprazole sodium related substance is low, clarity is good; Good forming ability, favorable solubility, stable and controllable for quality.
(3) the present invention has improved the stability of freeze-dried powder injection of pantoprazole sodium in the preparation process, and the freeze-dried powder injection of pantoprazole sodium impurity (its related substances) of preparation gained is low, and the quality stable homogeneous is stored and transport convenient.The present invention writes out a prescription simply, and adjuvant is few, and technology is simple, and is convenient feasible, good reproducibility, and freeze-drying time is short, and with short production cycle, power consumption is little, is easy to realize industrialized great production, can produce considerable economic and social benefit.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
(1) prescription: specification 40mg:1.2ml
Pantoprazole Sodium (in pantoprazole) 40g
Mannitol 40g
Water for injection adds to 1200ml
Process 1000 bottles
(2) preparation technology:
Take by weighing the Pantoprazole Sodium and the mannitol of recipe quantity, the water for injection (15 ℃) that adds dosing total amount 80% earlier adds the mannitol and the Pantoprazole Sodium of recipe quantity successively in Agitation Tank, stirs to make and is dissolved into clear and bright solution; Replenish water for injection to full dose, mix homogeneously is with the sodium hydroxide solution regulator solution pH value to 10.8 of 5mol/L; 0.10% (g/ml) medicinal carbon that adds the dosing total amount, stirring and adsorbing 30 minutes is through taking off charcoal and 0.22 μ m aseptic filtration for the first time; Intermediate detect qualified after, the medicinal liquid basin between medicinal liquid filter pressing to medicinal liquid accepted moves to medicine liquid tank and carries out 0.22 μ m secondary terminals degerming under hundred grades of laminar flow hood of filling machine and filter to medicinal liquor barrel; Fill, half tamponade, lyophilization.
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-35 ℃ after, continue insulation 4 hours, keep that vacuum is 10pa in the case;
The primary drying stage: keeping the interior vacuum of case is 6pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-3 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 4 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 18 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 37 ℃ after, continue insulation 4 hours.
Inspection vacuum situation of change finishes whole freeze-drying process, total head plug, outlet.
Embodiment 2
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80.0g
Mannitol 80.0g
Water for injection adds to 2400ml
Process 1000 bottles
(2) preparation technology:
Take by weighing the Pantoprazole Sodium and the mannitol of recipe quantity, the water for injection (15 ℃) that adds dosing total amount 80% earlier adds the mannitol and the Pantoprazole Sodium of recipe quantity successively in Agitation Tank, stirs to make and is dissolved into clear and bright solution; Replenish water for injection to full dose, mix homogeneously is with the sodium hydroxide solution regulator solution pH value to 10.8 of 5mol/L; 0.10% (g/ml) medicinal carbon that adds the dosing total amount, stirring and adsorbing 30 minutes is through taking off charcoal and 0.22 μ m aseptic filtration for the first time; Intermediate detect qualified after, the medicinal liquid basin between medicinal liquid filter pressing to medicinal liquid accepted moves to medicine liquid tank and carries out 0.22 μ m secondary terminals degerming under hundred grades of laminar flow hood of filling machine and filter to medicinal liquor barrel; Fill, half tamponade, lyophilization.
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-35 ℃ after, continue insulation 4 hours, keep that vacuum is 10pa in the case;
The primary drying stage: keeping the interior vacuum of case is 6pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-3 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 4 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 18 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 37 ℃ after, continue insulation 4 hours.
Inspection vacuum situation of change finishes whole freeze-drying process, total head plug, outlet.
Embodiment 3
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80.0g
Mannitol 64.0g
Water for injection adds to 2400ml
Process 1000 bottles
(2) preparation technology:
Take by weighing the Pantoprazole Sodium and the mannitol of recipe quantity, the water for injection (18 ℃) that adds dosing total amount 80% earlier adds the mannitol and the Pantoprazole Sodium of recipe quantity successively in Agitation Tank, stirs to make and is dissolved into clear and bright solution; Replenish water for injection to full dose, mix homogeneously is with the sodium hydroxide solution regulator solution pH value to 10.5 of 4mol/L; 0.10% (g/ml) medicinal carbon that adds the dosing total amount, stirring and adsorbing 30 minutes is through taking off charcoal and 0.22 μ m aseptic filtration for the first time; Intermediate detect qualified after, the medicinal liquid basin between medicinal liquid filter pressing to medicinal liquid accepted moves to medicine liquid tank and carries out 0.22 μ m secondary terminals degerming under hundred grades of laminar flow hood of filling machine and filter to medicinal liquor barrel; Fill, half tamponade, lyophilization.
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-33 ℃ after, continue insulation 3 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 4pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-1 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 3 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 16 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 35 ℃ after, continue insulation 3 hours.Finish whole freeze-drying process, total head plug, outlet.
Embodiment 4
(1) prescription: specification 40mg:1.2ml
Pantoprazole Sodium (in pantoprazole) 40g
Mannitol 64g
Water for injection adds to 1200ml
Process 1000 bottles
(2) preparation technology:
Take by weighing the Pantoprazole Sodium and the mannitol of recipe quantity, the water for injection (20 ℃) that adds dosing total amount 80% earlier adds the mannitol and the Pantoprazole Sodium of recipe quantity successively in Agitation Tank, stirs to make and is dissolved into clear and bright solution; Replenish water for injection to full dose, mix homogeneously is with the sodium hydroxide solution regulator solution pH value to 11.0 of 5mol/L; 0.10% (g/ml) medicinal carbon that adds the dosing total amount, stirring and adsorbing 30 minutes is through taking off charcoal and 0.22 μ m aseptic filtration for the first time; Intermediate detect qualified after, the medicinal liquid basin between medicinal liquid filter pressing to medicinal liquid accepted moves to medicine liquid tank and carries out 0.22 μ m secondary terminals degerming under hundred grades of laminar flow hood of filling machine and filter to medicinal liquor barrel; Fill, half tamponade, lyophilization.
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-37 ℃ after, continue insulation 5 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 8pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-5 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 5 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 20 ℃ with shelf temperature, and insulation 1h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 39 ℃ after, continue insulation 5 hours.Finish whole freeze-drying process, total head plug, outlet.
Embodiment 5
(1) prescription: specification 40mg:1.2ml
Pantoprazole Sodium (in pantoprazole) 40g
Mannitol 32g
Water for injection adds to 1200ml
Process 1000 bottles
(2) preparation technology:
Take by weighing the Pantoprazole Sodium and the mannitol of recipe quantity, the water for injection (20 ℃) that adds dosing total amount 80% earlier adds the mannitol and the Pantoprazole Sodium of recipe quantity successively in Agitation Tank, stirs to make and is dissolved into clear and bright solution; Replenish water for injection to full dose, mix homogeneously is with the sodium hydroxide solution regulator solution pH value to 11.0 of 5mol/L; 0.10% (g/ml) medicinal carbon that adds the dosing total amount, stirring and adsorbing 30 minutes is through taking off charcoal and 0.22 μ m aseptic filtration for the first time; Intermediate detect qualified after, the medicinal liquid basin between medicinal liquid filter pressing to medicinal liquid accepted moves to medicine liquid tank and carries out 0.22 μ m secondary terminals degerming under hundred grades of laminar flow hood of filling machine and filter to medicinal liquor barrel; Fill, half tamponade, lyophilization.
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-37 ℃ after, continue insulation 4.5 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 7pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-4 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 4.5 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 19 ℃ with shelf temperature, and insulation 1h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 38 ℃ after, continue insulation 5 hours.Finish whole freeze-drying process, total head plug, outlet.
Embodiment 6
Compare with embodiment 1, distinctive points only is:
(1) prescription: specification 40mg:1.2ml
Pantoprazole Sodium (in pantoprazole) 40g
Mannitol 36g
Water for injection adds to 1200ml
Process 1000 bottles
(2) preparation technology:
Lyophilization:
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-33 ℃ after, continue insulation 3 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 4pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-1 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 3 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 16 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 35 ℃ after, continue insulation 3 hours.Finish whole freeze-drying process, total head plug, outlet.
Embodiment 7
Compare with embodiment 1, distinctive points only is:
(1) prescription: specification 40mg:1.2ml
Pantoprazole Sodium (in pantoprazole) 40g
Mannitol 48g
Water for injection adds to 1200ml
Process 1000 bottles
Lyophilization:
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-34 ℃ after, continue insulation 4 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 5pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-2 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 3 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 16 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 35 ℃ after, continue insulation 4 hours.Finish whole freeze-drying process, total head plug, outlet.
Embodiment 8
Compare with embodiment 7, distinctive points only is:
(1) prescription: specification 40mg:1.2ml
Pantoprazole Sodium (in pantoprazole) 40g
Mannitol 54g
Water for injection adds to 1200ml
Process 1000 bottles
Lyophilization:
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-36 ℃ after, continue insulation 5 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 7pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-4 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 4 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 20 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 35 ℃ after, continue insulation 4 hours.Finish whole freeze-drying process, total head plug, outlet.
Embodiment 9
Compare with embodiment 4, distinctive points only is:
(1) prescription: specification 40mg:1.2ml
Pantoprazole Sodium (in pantoprazole) 40g
Mannitol 62g
Water for injection adds to 1200ml
Process 1000 bottles
Embodiment 10
Compare with embodiment 1, distinctive points only is:
(1) prescription: specification 40mg:1.2ml
Pantoprazole Sodium (in pantoprazole) 40g
Mannitol 64g
Water for injection adds to 1200ml
Process 1000 bottles
Embodiment 11
Compare with embodiment 3, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 72g
Water for injection adds to 2400ml
Process 1000 bottles
Embodiment 12
Compare with embodiment 2, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 78g
Water for injection adds to 2400ml
Process 1000 bottles
Embodiment 13
Compare with embodiment 1, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 84g
Water for injection adds to 2400ml
Process 1000 bottles
Embodiment 14
Compare with embodiment 2, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 96g
Water for injection adds to 2400ml
Process 1000 bottles
Embodiment 15
Compare with embodiment 4, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 102g
Water for injection adds to 2400ml
Process 1000 bottles
Embodiment 16
Compare with embodiment 2, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 108g
Water for injection adds to 2400ml
Process 1000 bottles
Embodiment 17
Compare with embodiment 1, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 112g
Water for injection adds to 2400ml
Process 1000 bottles
Embodiment 18
Compare with embodiment 3, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 120g
Water for injection adds to 2400ml
Process 1000 bottles
Embodiment 19
Compare with embodiment 4, distinctive points only is:
(1) prescription: specification 80mg:2.4ml
Pantoprazole Sodium (in pantoprazole) 80g
Mannitol 124g
Water for injection adds to 2400ml
Process 1000 bottles
Part embodiment product of the present invention is done further check, and the result sees table 4:
Table 4 freeze-dried powder injection of pantoprazole sodium embodiment sample survey result
In addition, embodiments of the invention 5-16 has also been done identical experiment, result and last table data have same trend, no longer enumerate.
Can know that according to above-mentioned data result the freeze-dried powder injection of pantoprazole sodium related substance that the present invention produces is low, process stabilizing, quality controllable, the security performance of medicine is protected effectively.The present invention writes out a prescription simply, and supplementary product kind and consumption are few, and technology is simple, and is convenient feasible, good reproducibility, and with short production cycle, power consumption is little, is easy to realize industrialized great production, can produce considerable economic and social benefit, has very strong practicality.
The present invention also provides following Test Example simultaneously, with the effect of further checking technical scheme of the present invention.
Test Example 1
The influence of freeze-dry process for product investigated in this test, and the result sees table 5.
Compare with embodiment 1, the distinctive points of the technical scheme of sequence number 1-7 only is freeze-dry process.The time that is specially each lyophilizing stage is identical, and distinctive points is freeze temperature.Freeze-dry process like sequence number 1 is: set the pre-freeze temperature and be-35 ℃, primary drying is in the stage, and the programming rate with 0.4 ℃/min rises to-18 ℃ earlier, and the back rises to-3 ℃ with the programming rate of 0.2 ℃/min; Redrying is in the stage, and the programming rate with 0.3 ℃/min rises to 18 ℃ earlier, and the back rises to 35 ℃ with the programming rate of 0.8 ℃/min, and those skilled in the art combine the professional general knowledge of self, can be with reference to the embodiment freeze-drying time of 1 each temperature rise period of adjustment.The result sees table 5.
Table 5, freeze-dry process are for the influence of product
Outward appearance can both obtain high-quality freeze-dried powder to number 6,7,8 embodiment in the last table, and wherein embodiment 6 be the best.The centre is divided into 5 class according to mode of appearance.5 grades best.From table, can find out that freeze-dry process provided by the present invention can obtain higher-quality pantoprazole sodium freeze-drying powder, wherein preferred scheme can further improve the lyophilized powder quality.Some also can access up-to-standard product though adopt other freeze-dry process commonly used of this area, and quality will be well below the lyophilized powder product of the present invention program's preparation.
Test Example 2
This Test Example has been investigated prescription of the present invention and the preparation technology stability influence for formulation products.The result sees table 6,7.
Table 6, for product stability influence (accelerated test)
| 1 month | 2 months | 3 months | 6 months | |
| 1 | 99.93％ | 99.91％ | 99.89％ | 99.85％ |
| 2 | 99.90％ | 99.87％ | 99.85％ | 99.81％ |
| 3 | 99.86％ | 99.80％ | 99.66％ | 99.52％ |
| 4 | 99.87％ | 99.80％ | 99.74％ | 99.63％ |
| 5 | 99.80％ | 99.72％ | 99.63％ | 99.51％ |
Table 7, for product stability influence (stability test)
| 0 month | 3 months | 6 months | 9 months | 12 months | 18 months | |
| 1 | 99.96％ | 99.94％ | 99.91％ | 99.89％ | 99.85％ | 99.83％ |
| 2 | 99.95％ | 99.92％ | 99.89％ | 99.87％ | 99.85％ | 99.81％ |
| 3 | 99.89％ | 99.85％ | 99.80％ | 99.77％ | 99.74％ | 99.71％ |
| 4 | 99.84％ | 99.82％ | 99.79％ | 99.76％ | 99.73％ | 99.69％ |
| 5 | 99.87％ | 99.83％ | 99.78％ | 99.75％ | 99.68％ | 99.65％ |
1 is the product of embodiment 1 in the last table; 2 is the product of the embodiment of the invention 3; 3 for the embodiment 1,4 in the CN1235018 application be commercially available commercially available pantoprazole sodium freeze-drying powder pin (Wuhan Pusheng Pharmaceutical Co., Ltd.) for the embodiment 1,5 of CN101229138 in applying for.
Last table result shows, adopts prescription of the present invention and method for preparing, can obtain higher-quality Pantoprazole Sodium, and the lyophilized powder stability of its preparation is better.Though the higher Pantoprazole Sodium of purity is also arranged in the prior art, through detecting, stability is synthetic resulting poorer than the present invention.Its reason should adopt improved formulation and technology for the present invention, has reduced the kind and the consumption of adjuvant on the one hand, has avoided causing the possibility of side reaction or mass change, thereby has promoted the stability of formulation products greatly.Through optimization, also obtained beyond thought effect on the other hand to freeze-dry process.
Representative several data have only been enumerated in this test, and also all according to testing with quadrat method, the result has and the similar trend of last epiphase other embodiment product.
Test Example 3
This Test Example has been investigated the present invention's prescription of the present invention and the preparation technology influence to the product solubility.The result sees table 8,9.
Wherein 1 is embodiment 1 disclosed product, and 2 is according to embodiment 2 disclosed products; 3 is embodiment 3 disclosed products;
4 are patent application CN101229138 embodiment 1 disclosed product.
5 commercially available pantoprazole sodium freeze-drying powder injection formulations (Wuhan Pusheng Pharmaceutical Co., Ltd.).
Table 8, product redissolution performance-solubility property
| 1 | 2 | 3 | 4 | 5 | |
| 0 month (s) | 3 | 3 | 7 | 10 | 9 |
| 6 months (s) | 4 | 5 | 9 | 18 | 19 |
| 12 months (s) | 6 | 7 | 11 | 19 | 21 |
| 24 months (s) | 12 | 11 | 17 | 32 | 34 |
Table 9, product redissolution performance-solid are separated out
| 1 | 2 | 3 | 4 | 5 | |
| 1 day | Nothing is separated out | Nothing is separated out | Nothing is separated out | Nothing is separated out | Nothing is separated out |
| 3 days | Nothing is separated out | Nothing is separated out | Nothing is separated out | Nothing is separated out | Nothing is separated out |
| 10 days | Nothing is separated out | Nothing is separated out | Nothing is separated out | Separate out trace | Separate out trace |
| 30 days | Nothing is separated out | Nothing is separated out | Nothing is separated out | Separate out a small amount of | Separate out a small amount of |
Can find out that from last table its redissolution speed of freeze-dried powder provided by the present invention can increase substantially, especially after product was placed a period of time, the performance of redissolving significantly was superior to prior art products.More stable after the product that adopts method for preparing of the present invention to prepare in addition dissolves, be difficult for separating out solid matter, improved patient's drug safety greatly.
Above-mentioned experimental example has only been enumerated representative several data, and also all according to testing with quadrat method, the result has the trend similar with The above results to other embodiment product.
Claims (7)
1. the method for preparing of a freeze-dried powder injection of pantoprazole sodium; It is characterized in that; Described method for preparing comprises: the Pantoprazole Sodium and the mannitol that take by weighing recipe quantity; The water for injection that adds dosing total amount 80% earlier adds the mannitol and the Pantoprazole Sodium of recipe quantity successively in Agitation Tank, stir to make to be dissolved into clear and bright solution; Replenish water for injection to full dose, mix homogeneously is between sodium hydroxide solution regulator solution pH value to 10.5～11.0; Add the medicinal carbon stirring and adsorbing, through taking off charcoal and 0.22 μ m aseptic filtration for the first time, intermediate detect qualified after; Medicinal liquid basin between medicinal liquid filter pressing to medicinal liquid accepted moves to medicine liquid tank and carries out 0.22 μ m secondary terminals degerming under hundred grades of laminar flow hood of filling machine and filter to medicinal liquor barrel fill; Half tamponade, lyophilization.
2. the method for preparing of freeze-dried powder injection of pantoprazole sodium according to claim 1 is characterized in that, the solution temperature when adding Pantoprazole Sodium in the Agitation Tank is controlled at 10～20 ℃.
3. the method for preparing of freeze-dried powder injection of pantoprazole sodium according to claim 2 is characterized in that, the solution temperature when adding Pantoprazole Sodium in the Agitation Tank is controlled at 15 ℃.
4. the method for preparing of freeze-dried powder injection of pantoprazole sodium according to claim 1; It is characterized in that; The amount that adds medicinal carbon is 0.1% (g/ml); After the stirring and adsorbing 30 minutes, decarburization limit, limit circulation 10 minutes is filtered and 0.22 μ m secondary terminals aseptic filtration with 0.45 μ m filtering with microporous membrane, germ tight filter of 0.22 μ m after the decarburization.
5. the method for preparing of freeze-dried powder injection of pantoprazole sodium according to claim 1 is characterized in that, described concentration of sodium hydroxide solution is 5mol/L.
6. the method for preparing of freeze-dried powder injection of pantoprazole sodium according to claim 1 is characterized in that, described lyophilization comprises following three phases;
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-35 ± 2 ℃ after, continue insulation 3～5 hours, keep in the case about vacuum 10pa;
The primary drying stage: keeping the interior vacuum of case is 4-8pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-3 ± 2 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 3～5 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 18 ± 2 ℃ with shelf temperature, and insulation 0.5-1h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 37 ± 2 ℃ after, continue insulation 3～5 hours.
7. the method for preparing of freeze-dried powder injection of pantoprazole sodium according to claim 6 is characterized in that, described lyophilization comprises following three phases:
The pre-freeze stage: shelf temperature is reduced to-50 ℃, puts into goods rapidly, treat that products temperature reaches-35 ℃ after, continue insulation 4 hours, keep that vacuum is 10pa in the case;
The primary drying stage: keeping the interior vacuum of case is 6pa; Programming rate with 0.25 ℃/min slowly rises to shelf temperature-3 ℃, after the complete obiteration of goods ice crystal is treated in insulation, continues insulation 4 hours;
The redrying stage: the programming rate with 0.35 ℃/min slowly rises to 18 ℃ with shelf temperature, and insulation 0.5h heats up with the programming rate of 0.7 ℃/min again, treat that products temperature reaches 37 ℃ after, continue insulation 4 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN 201110030916 CN102085190B (en) | 2011-01-28 | 2011-01-28 | Pantoprazole sodium freeze-dried powder injection and preparation method thereof |
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| CN 201110030916 CN102085190B (en) | 2011-01-28 | 2011-01-28 | Pantoprazole sodium freeze-dried powder injection and preparation method thereof |
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| CN102670524B (en) * | 2012-05-04 | 2013-09-18 | 南京正大天晴制药有限公司 | Pantoprazole sodium freeze-dried preparation for injection and preparation method thereof |
| CN103263415A (en) * | 2013-05-22 | 2013-08-28 | 山东罗欣药业股份有限公司 | Levo pantoprazole sodium composition for injection and preparation method thereof |
| CN104414979A (en) * | 2013-08-21 | 2015-03-18 | 哈药集团三精制药股份有限公司 | Pantoprazole sodium freeze-dried powder injection and preparation method thereof |
| CN103550173A (en) * | 2013-10-15 | 2014-02-05 | 海南卫康制药(潜山)有限公司 | Pantoprazole sodium composition freeze-dried powder injection for injection |
| CN104546743A (en) * | 2014-12-29 | 2015-04-29 | 成都通德药业有限公司 | Packaging composition of proton pump inhibitor drug for injection and preparation method of packaging composition |
| CN104546742A (en) * | 2014-12-29 | 2015-04-29 | 成都通德药业有限公司 | Pantoprazole sodium drug for injection and preparation method thereof |
| CN106474076A (en) * | 2015-11-30 | 2017-03-08 | 湖南恒生制药股份有限公司 | The preparation method of Pantoprazole sodium for injection |
| CN106692081B (en) * | 2016-12-30 | 2019-09-13 | 广东健信制药股份有限公司 | A kind of freeze-dried powder injection of pantoprazole sodium and preparation method |
| CN110693821A (en) * | 2019-09-26 | 2020-01-17 | 无锡凯夫制药有限公司 | Method for preparing pantoprazole sodium for injection |
| CN113041226B (en) * | 2021-03-29 | 2022-10-14 | 海南锦瑞制药有限公司 | Preparation process of pantoprazole sodium for injection |
| CN115444826B (en) * | 2022-10-14 | 2023-07-21 | 海南锦瑞制药有限公司 | Preparation method of pantoprazole sodium for injection |
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| CN101229138A (en) * | 2008-01-18 | 2008-07-30 | 山东罗欣药业股份有限公司 | Pantoprazole sodium freeze-dried powder injection and preparing method thereof |
| CN101313894A (en) * | 2008-06-26 | 2008-12-03 | 江苏奥赛康药业有限公司 | Freeze-dried injection of proton pump inhibitor |
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| CN101229138A (en) * | 2008-01-18 | 2008-07-30 | 山东罗欣药业股份有限公司 | Pantoprazole sodium freeze-dried powder injection and preparing method thereof |
| CN101313894A (en) * | 2008-06-26 | 2008-12-03 | 江苏奥赛康药业有限公司 | Freeze-dried injection of proton pump inhibitor |
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Address after: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee after: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Address before: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee before: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. |
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Denomination of invention: Pantoprazole sodium freeze-dried powder injection and its preparation method Effective date of registration: 20230920 Granted publication date: 20120725 Pledgee: Qingdao Qishun Investment Management Co.,Ltd. Pledgor: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980057940 |