CN103202816B - Pantoprazole sodium freeze-dried powder injection - Google Patents
Pantoprazole sodium freeze-dried powder injection Download PDFInfo
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- CN103202816B CN103202816B CN201310167087.7A CN201310167087A CN103202816B CN 103202816 B CN103202816 B CN 103202816B CN 201310167087 A CN201310167087 A CN 201310167087A CN 103202816 B CN103202816 B CN 103202816B
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Abstract
The invention relates to pantoprazole sodium freeze-dried powder injection, in particular to freeze-dried powder injection which contains pantoprazole sodium, mannitol, citric acid and optional pH regulator. The invention further relates to a method for preparing the pantoprazole sodium freeze-dried powder injection disclosed by the invention. The pantoprazole sodium freeze-dried powder injection disclosed by the invention can be used for treating stomach diseases and has anticipated good properties.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of lyophilized injectable powder that can be used for treating gastropathy, particularly relate to a kind of lyophilized injectable powder that comprises Pantoprazole Sodium.Lyophilized injectable powder of the present invention has the good nature of expectation.
Background technology
Digestive system disease is common, frequently-occurring disease, is also a kind of very easily chronic disease of recurrence simultaneously, not yet has so far the effective means of thorough radical cure, and oneself becomes one of emphasis problem of pharmaceutical field research for this.Statistical analysis shows: the sickness rate of global digestive system accounts for the mankind's 10～12%, and the sickness rate of China's cities and towns digestive system disease is 11.43%, substantially similar to the many developed countries of America and Europe.Due to dietary structure, Shelter in South China Cities and southwest resident's prevalence is more higher, and the incidence rate of middle-aged and elderly people peptic ulcer is more, has been the main consumer of medicine for digestive system.
The new action pathway of medicament for resisting peptic ulcer has been opened up in the appearance of proton pump inhibitor (Proton Pump Inhibitors, referred to as PPIs), and it rises abruptly in the eighties in 20th century.First generation proton pump inhibitor product pantoprazole is synthetic in 1979, within 1988, goes on the market in Switzerland.Its Acidinhibitor does not also lie in the various receptors of blocking-up, but enters in the high acid environment of parietal cell secretory tubyle and H
+in conjunction with forming activated sulfenic acids and sulfenamide, with H
+/ K
+the sulfydryl dehydration coupling of-ATP enzyme, causes H in body
+/ K
+-atpase activity is forever suppressed.This medical instrument has high selectivity, and no matter the final step can gastric acid inhibitory forming, so be to basal gastric acid secretion or to various forms of irritability gastric acid secretions.All can effectively suppress.This medicine presses down acid completely, and effect is strong, and the persistent period is permanent.Curative effect to peptic ulcer is higher, and the course for the treatment of is also shorter, and the time of ulcer healing is compared H
2receptor antagonist is fast.
Pantoprazole Sodium is the third generation proton pump inhibitor after omeprazole, lansoprazole, Pantoprazole Sodium is parietal cell proton pump inhibitor, relatively stable under neutral and weak basic condition, activation rapidly under acid condition, the activation characteristic that its pH relies on, makes its effect to H+, K+-ATP enzyme have better selectivity.This product can suppress H+, the K+-ATP enzyme on secreted microtubule and intracytoplasmic tubular foam that parietal cell top film forms specifically, causes the inhibition of this enzyme irreversibility, thus the secretion of gastric acid inhibitory effectively.Because H+, K+-ATP enzyme are last processes that parietal cell secretes acid, therefore that this product presses down sour ability is powerful.It can not only noncompetitive suppresses the gastric acid secretion that gastrin, histamine, choline cause, and can suppress the part basal gastric acid secretion that not affected by choline or heart receptor blocking agent.This product and 5 used times of other drug, have advantages of that drug drug interaction is little.This product is carried out metabolism by the I system of the cytochrome P 450 Enzyme in hepatocyte, also can carry out metabolism by II system simultaneously.In the time being the drug combination of metabolism with other by P450 enzyme, the metabolic pathway of this product can be undertaken by II enzyme system, thereby is difficult for occurring the competitiveness effect of drug metabolism enzyme system, reduces the interaction between drug disposition.Without mutagenesis, carcinogenic and teratogenesis.
The chemistry of Pantoprazole Sodium is by name: 5-difluoro-methoxy-2-[[(3,4-dimethoxy-2-pyridinyl)-methyl]-sulfinyl]-1H-benzimidazole sodium-hydrate, English by name: Pantoprazole Sodium, molecular formula: C
16h
14f
2n
3naO
4sH
2o, molecular weight: 423.4, structural formula is as follows:
Pantoprazole Sodium can high selectivity H in ground and parietal cell
+/ K
+the combination of-ATP enzyme, loses activity it, thereby controls and block the final tache of gastric acid secretion, makes the H in parietal cell
+can not be transported in stomach, be a powerful gastric acid secretion inhibitor.Be applicable to the acute hemorrhage of upper gastrointestinal tract that duodenal ulcer, gastric ulcer, AGML, plyability gastric ulcer etc. cause.After also can be used for clinically the generation of Hemorrhage of ulcer under acute gastric mucosal lesion that nonsteroidal antiinflammatory drug causes and stress state and general anesthesia or major operation and weak comatose patient prevent that regurgitation of gastric juice from merging aspiration pneumonitis.
The Protonix form of listing has the peroral dosage forms such as multiple, such as tablet, capsule, micropill at present.Due to pantoprazole poorly water-soluble, in the time being made into ejection preparation, need to use the salt of pantoprazole as active component.Pantoprazole and sodium hydroxide can form Pantoprazole Sodium soluble in water under certain condition, and it is the main medicinal forms of freeze-dried pantoprazole powder pin.The freeze-dried powder injection of pantoprazole sodium of listing mostly is intravenous drip at present, and clinical data demonstration intravenous drip stable curative effect, and effect is rapider than the oral other administration route that waits.
Pantoprazole is proton pump inhibitor; there is sulfonyl benzimidazole chemical constitution; stability is subject to the impact of the many factors such as pH, light, metal ion, temperature; particularly in the time of acid condition; pantoprazole chemical constitution easily changes; there is polymerization and metachromatism, so should not make injection.Therefore, lyophilized injectable powder is the first-selected dosage form that Pantoprazole Sodium is made injection.Studies show that, pantoprazole poorly water-soluble, and salify is soluble in water under alkali condition.Therefore in the time that Pantoprazole Sodium is made to ejection preparation, must strengthen the control of basicity, conventionally also need to add other adjuvants to improving the stability of preparation, but the stability of gained preparation still be difficult to reach the requirement storing steady in a long-term.
In prior art, there are a large amount of research work to be devoted to the development of freeze-dried pantoprazole injectable powder.For example, the Chinese patent application of application number 201210442823.0 (Nanjing is just wide) discloses a kind of freeze-dried powder injection of pantoprazole sodium, described Pantoprazole Sodium is raceme or levo form Pantoprazole Sodium, and described lyophilized injectable powder is made up of Pantoprazole Sodium, lecithin, alpha-tocopherol, sodium citrate and sodium hydroxide.Again for example, the Chinese patent application of application number 201110398553.3 (Shandong greenery) discloses a kind of Pantoprazole sodium drug composition and preparation method thereof, the Pantoprazole sodium drug composition being specifically related to is counted and is comprised by weight: 1 part of Pantoprazole Sodium, 0.3～0.6 part of sucrose, 0.005～0.05 part of complexing of metal ion agent and inorganic base are appropriate.Again for example, the Chinese patent application of application number 201210350519.3 (Asia-Pacific, Zhejiang) discloses a kind of pantoprazole sodium freeze-drying preparation, comprises the raw material of following weight portion: 1 part of Pantoprazole Sodium; 0.5～1.2 part, mannitol; 0.02～0.1 part of disodium edetate; 0.03～0.06 part of sodium sulfite; 0.01～0.02 part of sodium hydroxide; 50 parts of waters for injection.Again for example, the Chinese patent application of application number 201210135474.8 (Nanjing is honest to be become a fine day) discloses a kind of injection pantoprazole sodium freeze-drying preparation and preparation method thereof, and this lyophilized formulations is dissolved in and is mixed with medicinal liquid lyophilizing after water for injection and forms by the component that contains following weight portion: Pantoprazole Sodium 60-80 part, glycine 100-300 part, glucose 50-100 part and appropriate sodium hydroxide.Again for example, the Chinese patent application of application number 200810001189.0 (Shandong Luo Xin) discloses a kind of freeze-dried powder injection of pantoprazole sodium, comprise Pantoprazole Sodium and mannitol, the part by weight of the two is 1: 2-5, formula is simple, few side effects, and has taked advanced freeze drying process, and the product appearance making is full, solubility is good, best in quality.Visible, in prior art multiplex mannitol as proppant, EDTA as chelating agent, and with being adjusted to alkalescence.
But the clinical for example injection Pantoprazole Sodium lyophilization injectable powder of Protonix with Good Pharmacy performance that provides is still provided those skilled in the art.
Summary of the invention
The object of the invention be to provide a kind of have some/lyophilized injectable powder that comprises Pantoprazole Sodium of certain good nature, expect that it has one or more good pharmaceutical properties.The inventor finds unexpectedly, and the lyophilized injectable powder that comprises Pantoprazole Sodium with special formulation has makes us the desirable features expected.Therefore the present invention is accomplished.
Therefore, first aspect present invention provides a kind of lyophilized injectable powder, wherein comprises Pantoprazole Sodium.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, wherein comprise Pantoprazole Sodium, mannitol, citric acid, methionine, disodiumedetate and optional acid-base modifier.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the material wherein comprising is in the Pantoprazole Sodium of every 40 weight portions, and the amount of mannitol is 50-200 weight portion, for example 75-150 weight portion, for example 100-150 weight portion.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the material wherein comprising is in the Pantoprazole Sodium of every 40 weight portions, and the amount of citric acid is 1-10 weight portion, for example 2-8 weight portion, for example 2-6 weight portion.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the material wherein comprising is in the Pantoprazole Sodium of every 40 weight portions, and the amount of methionine is 1-10 weight portion, for example 2-8 weight portion, for example 3-7 weight portion.Methionine is L-methyl methyllanthionine, is also called L-Methionine.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the material wherein comprising is in the Pantoprazole Sodium of every 40 weight portions, the amount of disodiumedetate (available EDTA-2Na represents) is 0.5-5 weight portion, for example 0.75-3 weight portion, for example 1-2 weight portion.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for example 1M hydrochloric acid solution or 1M sodium hydroxide solution.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, wherein comprise: Pantoprazole Sodium 40 weight portions, mannitol 50-200 weight portion (for example 75-150 weight portion, for example 100-150 weight portion), citric acid 1-10 weight portion (for example 2-8 weight portion, for example 2-6 weight portion), methionine 1-10 weight portion (for example 2-8 weight portion, for example 3-7 weight portion), disodiumedetate 0.5-5 weight portion (for example 0.75-3 weight portion, for example 1-2 weight portion) and optional acid-base modifier.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, wherein also comprise the trometamol of effective dose.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the material wherein comprising is in the Pantoprazole Sodium of every 40 weight portions, and the amount of trometamol is 2-15 weight portion, for example 3-10 weight portion, for example 4-8 weight portion.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, wherein comprise Pantoprazole Sodium, mannitol, citric acid, methionine, trometamol, disodiumedetate and optional acid-base modifier.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, wherein comprise: Pantoprazole Sodium 40 weight portions, mannitol 50-200 weight portion (for example 75-150 weight portion, for example 100-150 weight portion), citric acid 1-10 weight portion (for example 2-8 weight portion, for example 2-6 weight portion), methionine 1-10 weight portion (for example 2-8 weight portion, for example 3-7 weight portion), trometamol 2-15 weight portion (for example 3-10 weight portion, for example 4-8 weight portion), disodiumedetate 0.5-5 weight portion (for example 0.75-3 weight portion, for example 1-2 weight portion), with optional acid-base modifier.
As everyone knows, the lyophilization injectable powder (conventionally referred to as lyophilized injectable powder or freeze-dried powder) obtaining through freezing-vacuum drying, it is first by each dissolution with solvents for material (being typically with water dissolution), be mixed with a solution, then make this solution carry out freezing, carry out again evacuation, distillation, dry and Powdered thing or the block of the one substantially anhydrous (typically water content, lower than 5%, is particularly usually less than 3%) that obtains.Therefore, the acid-base value of this solid lyophilized products is controlled by the pH value of process for preparation regulator solution conventionally; Or can adjust so that the solid lyophilized products obtaining is controlled the pH value of this dissolve/dilute liquid under the dissolve/dilute degree of regulation and control (this is called the acid-base value of controlling solid lyophilized products) by prescription; A rear mode is more generally used conventionally, for example in pharmacopeia, contained many lyophilized injectable powders are all controlled the acid-base value of goods in this way, and the acid-base value of this mode control product recipe quantity of concrete regulation acid-base modifier not conventionally, and only specify the acid-base value of finished product.Be equally applicable to be of the present inventionly, according to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the amount of wherein said optional acid-base modifier is, the amount of the pH value of this solution in 9.5～11.5 scopes while making described lyophilized injectable powder water for injection be dissolved into the solution containing Pantoprazole Sodium 40mg/ml concentration, the amount of the pH value of for example this solution in 10.0～11.0 scopes.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, it is by comprising prepared by following step substantially:
(a) take Pantoprazole Sodium and mannitol, citric acid, methionine, disodiumedetate and the optional trometamol of recipe quantity, add appropriate water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, be adjusted to pH10.5～12.0 with acid-base modifier if desired, preferably pH11.0～11.5;
(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, and tamponade to obtain final product.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is to be 3～20% (w/v), preferably 3～15% (w/v), more more preferably 3～10%.
According to the lyophilized injectable powder described in the arbitrary embodiment of first aspect present invention, wherein also optionally comprise the acceptable excipient of other pharmacy.Described excipient is such as but not limited to mannitol, lactose, sucrose, glucose, sorbitol, glycine, dextran, sodium chloride and combination thereof.
Further, second aspect present invention provides the method for the lyophilized injectable powder described in the arbitrary embodiment of preparation first aspect present invention, and it consists essentially of following steps:
(a) take Pantoprazole Sodium and mannitol, citric acid, methionine, disodiumedetate and the optional trometamol of recipe quantity, add appropriate water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, be adjusted to pH10.5～12.0 with acid-base modifier if desired, preferably pH11.0～11.5;
(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, and tamponade to obtain final product.
According to the method described in the arbitrary embodiment of second aspect present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is to be 3～20% (w/v), preferably 3～15% (w/v), more more preferably 3～10%.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein the described appropriate water for injection of step (a) is approximately 70～90% of water for injection recipe quantity.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein in step (b) water for injection of described " recipe quantity " in " benefit injects water to its recipe quantity " be Pantoprazole Sodium weight 10-50 doubly, for example 20-30 times, for example approximately 25 times.The amount of this water for injection can be passed through solid content described in step (c) and easily control.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein the described activated carbon dosage of step (a) is 0.02%～0.5% (w/v) of solution weight, preferably 0.05%～0.2%.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein described in step (b), acid-base modifier is the aqueous solution that is selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.The concentration of these aqueous solutions is well known to a person skilled in the art, for example 1～10%, for example 2%～5%.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, for example 1M hydrochloric acid solution or 1M sodium hydroxide solution.
According to the method described in the arbitrary embodiment of second aspect present invention, wherein in step (d), remove after moisture content in gained lyophilization material water content lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.
In the step of the above-mentioned preparation method of the present invention, although the step of the concrete steps of its description in some details or described in the preparation example of language description up and down literary composition detailed description of the invention part distinguished to some extent, but, detailed open the above method step of completely can summarizing of those skilled in the art's full text according to the present invention.
Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characterictic goes for this technical characterictic in other embodiment, as long as they there will not be contradiction.
The invention will be further described below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
According to lyophilized injectable powder of the present invention, active component is wherein the compound with following formula structure:
At above-claimed cpd of the present invention, also by any individual isomer that comprises that it may exist, or any 2 the above isomers that may exist of described compound are with the mixture of arbitrary proportion.
According to the present invention, term " excipient " also can be described as adjuvant, filler etc.
" the acceptable excipient of pharmacy " used herein refers to the excipient that can be used for compounding pharmaceutical, it there is no harmful effect to organism, and normally organism can tolerate.
In the present invention, preferred lyophilized injectable powder of the present invention is made in every 1ml and is contained after the solution of formula I compound 4mg at water, then is that pH value algoscopy is measured according to the method under two annex VI H items of Chinese Pharmacopoeia version in 2010.
Although those skilled in the art understand, excipient of the present invention can be that any can be used for cryodesiccated excipient, particularly mannitol, lactose, sucrose, glucose, sorbitol, glycine, dextran, sodium chloride and combination thereof, but in the present invention, particularly preferred excipient is mannitol, lactose, dextran etc.
The preparation process of lyophilization injectable powder is to well known to a person skilled in the art pharmaceutical technology, for example two kinds of schematic freeze-drying curves shown in following freeze-drying curve A and freeze-drying curve B:
In the instantiation of below preparing in lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.
Water content in lyophilization injectable powder is generally below 8%, preferably lower than 5%, more preferably less than 3%.Moisture control can be controlled by suitable adjustment lyophilization program.Water content in this lyophilization injectable powder can be measured according to many known methods, for example dry weight-loss method.
In the present invention, in order to regulate where necessary the pH value of medicinal liquid, can in compositions, add suitable pH adjusting agent.Although the inventor only regulates with not having the strong acid of buffer capacity or for example sodium hydrate aqueous solution of strong base solution and an aqueous hydrochloric acid solution, but, those skilled in the art understand, if can meet the pH requirement of system with this pH adjusting agent processing of not having buffer capacity, the pH adjusting agent with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can regulate pH value, and can stablize pH value.Therefore the listed arbitrary pH adjusting agent of the present invention or its combination include in spirit and scope of the invention.
In preparation, when lyophilized injectable powder of the present invention, in the medicinal liquid of preparing, solid content is to be 3～20% (w/v), preferably 3～15% (w/v), more more preferably 3～10%.Because normally carrying out lyophilization in tubulose cillin bottle, lyophilized injectable powder obtains, those skilled in the art understand this product and are obtaining finished product even before for doctor, conventionally all present a round pie, although lecture is than the volume of original aqueous solution few (slightly dwindling) in the volume theory of this cake, but this dwindling can not narrow down to former aqueous solution volume 50% conventionally conventionally, conventionally can be between the 80-120% of former aqueous solution volume, be more typically between the 90-100% of former aqueous solution volume, and can be observed former aqueous solution liquid level vestige in finished product cillin bottle, (main body cake remains in the liquid level vestige on bottle wall dwindling because of lyophilizing, even if the dried frozen aquatic products in cillin bottle is former thereby be Powdered because a variety of causes for example collides etc., conventionally still can retain original liquid level vestige), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still can roughly estimate it in the time preparing according to this injectable powder, the at least medicine liquid volume before lyophilization starts, according to the weight of the dry end-product in this volume and cillin bottle estimating, also can calculate in the time of preparation lyophilized injectable powder of the present invention the content of the solid content in the medicinal liquid of preparing.Therefore, according to the lyophilized injectable powder of first aspect present invention, its solid content at the medicinal liquid in when preparation is to be 3～20% (w/v), preferably 3～15% (w/v), more more preferably 3～10%.
Term " solid content " refers to solid matter (for example reactive compound of the present invention and whole excipient used, weight/gram) for example join, in solvent (water for injection), after dissolving, obtain a solution, the weight of described solid matter for example, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.For example in the present invention, add appropriate aqueous solution for injection with mannitol, citric acid, methionine, trometamol, the EDTA-2Na of 40mg reactive compound and total 135mg, be mixed with the solution that final volume is 1000ml, its solid content is 4.4%.
In the present invention, symbol %, the linguistic context using according to it, can have those skilled in the art and hold intelligible implication.For example, in the time mentioning solid content, this symbol represents the percent (w/v, for example g/100ml) of weight/volume; For example in the time of " water content " mentioned in lyophilization injectable powder, for example water content is below 8% again, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking,, in the time that solid is dispersed in liquid, % represents weight/volume percent; Solid be dispersed in solid or liquid dispersion in solid for example, when (water content of powder pin), % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.
In the time of preparation medicinal liquid of the present invention, as well known to those skilled in the art, can example according to appointment the microporous filter membrane of 0.45um carry out coarse filtration filtration, by liquid medicine filling to before in cillin bottle, can example according to appointment the microporous filter membrane of 0.22um carry out fine straining filtration with degerming, can filter repeatedly if desired.
According to lyophilized injectable powder of the present invention, it is lyophilization injectable powder.In one embodiment, this lyophilization injectable powder is single-dose preparations (injectable powder that for example XiLin is bottled), the amount of reactive compound in per unit dosage (it is all converted in the present invention if not otherwise indicated in pantoprazole) can be such as but not limited to about 10mg, about 20mg, about 40mg, about 60mg, about 80mg, about 100mg.
According to lyophilized injectable powder of the present invention, it redissolves with water for injection, and the time of typically redissolving is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.
According to lyophilized injectable powder of the present invention, its water is made in every 1ml and is measured containing the solution of reactive compound 4mg and according to the method under two annex VI H items of Chinese Pharmacopoeia version in 2005, and the pH value of this solution is 9.5～11.5.In one embodiment, pH value is 9.5～11.0.In one embodiment, pH value is 10.0～11.0.
Lyophilized injectable powder provided by the invention can, preserving at least 24 months at 25 DEG C of following dry places, can meet the Storage Requirement of general lyophilization injectable powder.
Obtained freeze-drying injectable powder of the present invention particularly lyophilization injectable powder is generally lyophilizing block or its fragment or its powder of white or off-white color, and odorless, bitter in the mouth are soluble in water.
Pantoprazole is the racemic mixture of a pair of active optical antimer, and nationality is reduced the secretion of gastric acid by the mechanism of action of high targeted, is the specific inhibitor of sour pump in parietal cell.This product effect is rapid, the secretion that dosage once a day can reversible gastric acid inhibitory.Pantoprazole is a kind of alkalescence material, in parietal cell, in this peracidity environment of tubule, is concentrated and is converted into active substance, suppresses H
+/ K
+-ATP enzyme (proton pump).This inhibitory action to gastric acid formation final step is dosage correlation, and highly suppresses basal gastric acid secretion and zest gastric acid secretion, but irrelevant with stimulus object.Human vein gives pantoprazole, is the gastric acid secretion inhibiting of dosage correlation, in order to reach rapidly and the repeatedly effect of oral 20 milligrams of identical reduction Acidity in the stomachs, advises that intravenous gives 40 milligrams of pantoprazole first.40 milligrams of pantoprazole of quiet note reduce rapidly Acidity in the stomach, average decline 90% in 24 hours.The gastric acid secretion inhibiting effect of pantoprazole is relevant to area under drug-time curve (AUC), and blood drug level during with administration is irrelevant.Helicobacter pylori is relevant with sour digestion disease, comprises duodenal ulcer and gastric ulcer, relevant with helicobacter pylori infections with gastric ulcer with 70% duodenal ulcer by 95% respectively.Helicobacter pylori is the principal element that causes gastritis.Helicobacter pylori is the principal element that causes peptic ulcer together with gastric acid.Pantoprazole and antibiotic share can eradicate helicobacter pylori, this is relevant to rapid relief of symptoms, gastric mucosa repair rate long-term remission high and peptic ulcer disease, and therefore reduced the complication such as gastrointestinal hemorrhage, also reduce the anti-needs of secreting sour medicine treatment of long-term use simultaneously.Any method, comprises that gastric acid reduces due to proton pump inhibitor, all increases the quantity of normal flora in gastrointestinal tract, and with antisecretory treatment, salmonella and campylobacter infect gastrointestinal danger may slightly increase.Give for a long time in the research of pantoprazole rat, observe stomach ECL cell and increase and benign tumor, this is the result that persistence hypergastrinemia suppresses because of gastric acid.With after bisfentidine, proton pump inhibitor therapy and part Bottoming is postoperative also a similar discovery.Obviously these change the not direct effect of said medicine.
Pantoprazole Sodium is generally used for the alternative medicine when the inapplicable epidemy at present of oral therapy disease: duodenal ulcer, gastric ulcer, reflux esophagitis and Zollinger-Ellison syndrome.Especially, Pantoprazole Sodium can be used for digestive ulcerative bleeding, stoma ulcer is hemorrhage; Concurrent Acute Gastric Mucosal infringement when stress state, and the acute gastric mucosal injury that causes of nonsteroidal antiinflammatory drug; Also be usually used in preventing after seriously disease (as cerebral hemorrhage, severe trauma etc.) stomach operation prevention hemorrhage etc. again; After general anesthesia or major operation and weak comatose patient prevent regurgitation of gastric juice merge aspiration pneumonitis.
Detailed description of the invention
Can conduct further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.In example below, the pH adjusting agent (in the present invention that is acid-base modifier) using, unless otherwise noted, 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is while making to prepare injectable powder, make the pH value of the solution of preparing before lyophilization be adjusted to a certain setting or scope, this setting or scope are value or the scopes that lyophilization gained dry powder water for injection is diluted to the pH value of measuring containing the solution of active component 4mg/ml.The below object of preparation process in order to give an example, and comparability based on respectively giving an example and making some specific description, those skilled in the art can therefrom summarize according to existing knowledge the method that the present invention prepares lyophilized injectable powder that obtains completely.Dosing is prepared in various compositionss below, and if not otherwise indicated, total dosing amount of every batch is 1000ml, but while listing formula, all illustrates with the amount of pantoprazole 40mg containing Pantoprazole Sodium in every bottle.
assay method:
The assay of various samples (comprising injectable powder of the present invention) can carry out (can be described as [HPLC method A] herein) according to following methods:
[HPLC method A]
[assay] measured according to high performance liquid chromatography (annex V D);
Chromatographic condition and system suitability: with octadecylsilane chemically bonded silica be filler; Taking 0.01mol/L dipotassium hydrogen phosphate solution (with phosphorus acid for adjusting pH value to 7.0)-acetonitrile (65:35) as mobile phase; Detection wavelength is 289nm; Number of theoretical plate calculates and is not less than 2500 by pantoprazole peak;
Algoscopy: get with the lyophilization injectable powder test sample of the present invention of glass bottle (if not otherwise indicated, every bottle containing 40mg pantoprazole) 4 bottles, solubilizer [0.001mol/L sodium hydroxide solution-acetonitrile (1:1)] dissolves and is quantitatively transferred in same 100ml measuring bottle and is diluted to scale, shake up, precision measures in right amount, makes with the quantitative dilution of above-mentioned solvent the solution that approximately contains pantoprazole 40ug in every 1ml, and precision measures 20ul, injection liquid chromatography, records chromatogram; Separately get Pantoprazole Sodium reference substance appropriate, accurately weighed, be measured in the same method; Press external standard method with calculated by peak area, and result is multiplied by 0.9457, to obtain final product; Crude drug also can be measured similarly.
The related substance of various samples (comprising injectable powder of the present invention) can carry out (can be described as [HPLC method B] herein) according to following methods:
[HPLC method B]
Measure according to high performance liquid chromatography (annex V D);
Solvent mixture: acetonitrile: 40mg/l sodium hydroxide solution (50:50V/V);
Test solution: the test sample that contains 23mg Pantoprazole Sodium (it can be crude drug or injectable powder of the present invention) is dissolved in above-mentioned solvent mixture and with it and is diluted to 50.0ml;
Reference solution (a): 1.0ml test solution is diluted to 100.0ml with solvent mixture, this solution 1.0ml is diluted to 10.0ml with solvent mixture, to obtain final product;
Reference solution (b): a bottle system employment and suitability test (E & ST) is dissolved in 1.0ml solvent mixture with the content (wherein containing impurity A, B, C, D and E) of pantoprazole, obtains final product;
Chromatographic column:
Size: long 125mm,
immobile phase: (5 μ m) for octadecylsilane chemically bonded silica; Column temperature: 40 ° of C.
Mobile phase:
Mobile phase A: 1.74g/l dipotassium hydrogen phosphate solution (it is adjusted to pH7.00 ± 0.05 with 330g/l phosphoric acid solution);
Mobile phase B: acetonitrile;
Gradient:
| Time (min) | Mobile phase A (%, V/V) | Mobile phase B (%, V/V) |
| 0-40 | 80—>20 | 20—>80 |
| 40-45 | 20—>80 | 80—>20 |
Flow velocity: 1.0ml/min;
Detector: ultraviolet detection 290nm, detects at 305nm place for impurity C;
Sample size: 20 μ l;
Impurity is determined: the chromatogram that the chromatogram that use system suitability obtains with pantoprazole and reference solution (b) obtain is determined the ownership of impurity A, B, C, D+F and E;
Relative retention time: with respect to pantoprazole (its retention time is about 11min): impurity C approximately 0.6, impurity A approximately 0.9, impurity D and F approximately 1.2, impurity E approximately 1.3, impurity B approximately 1.5;
System suitability: reference solution (b)
-separating degree: be at least 1.5 between impurity E and D+F chromatographic peak;
The chromatogram that-chromatogram obtains with pantoprazole to system suitability is similar;
Limit (requirement of this area general provision):
-impurity A: 2 times (0.2%) that are no more than main peak area in reference solution (a) gained chromatogram;
-impurity D and F summation: 2 times (0.2%) that are no more than main peak area in reference solution (a) gained chromatogram;
-impurity B, C, E: be no more than main peak area (0.1%) in reference solution (a) gained chromatogram;
-nonspecific impurity (also can be described as unknown impuritie): be no more than separately main peak area (0.1%) in reference solution (a) gained chromatogram;
-total impurities (specific impurities and nonspecific impurity summation): 5 times (0.5%) that are no more than main peak area in reference solution (a) gained chromatogram.
Wherein, each impurity A, B, C, D, E, F structural formula or chemical name are as follows:
Impurity A: X=SO2 in above formula, chemical name: 5-(difluoro-methoxy)-2-[[(3,4-dimethoxy-pyridine-2-yl) methyl] sulfonyl]-1H-benzimidazole,
Impurity B: X=S in above formula, chemical name: 5-(difluoro-methoxy)-2-[[(3,4-dimethoxy-pyridine-2-yl) methyl] sulfenyl]-1H-benzimidazole,
Impurity C:5-(difluoro-methoxy)-1H-benzimidazolyl-2 radicals-mercaptan,
and isomer
Impurity D: R=OCHF2 in above formula, R '=H, chemical name: 5-(difluoro-methoxy)-2-[(RS)-[(3,4-dimethoxy-pyridine-2-yl) methyl] sulfinyl]-1-methyl isophthalic acid H-benzimidazole,
Impurity F: R=H in above formula, R '=OCHF2, chemical name: 6-(difluoro-methoxy)-2-[(RS)-[(3,4-dimethoxy-pyridine-2-yl) methyl] sulfinyl]-1-methyl isophthalic acid H-benzimidazole,
Impurity E: 6,6 '-bis-(difluoro-methoxy)-2,2 '-bis-[[(3,4-dimethoxy-pyridine-2-yl) methyl] sulfinyl]-1H, 1 ' H-5, the mixture of the stereoisomer of 5 '-Lian benzimidazolyl.
Above-mentioned each impurity as well known to those skilled in the art is the important impurity of pantoprazole or its salt, and its existence has important harmful effect to the quality of pantoprazole product, and it is valuable therefore controlling them.
chemical stability investigation method:
This method can be for investigating the particularly chemical stability of stability under the various product simulation Long-term Storage of the present invention condition.Concrete grammar is: the lyophilization injectable powder making is placed 4 months under 45 ° of C, measure content [45 ° of C4 months of pantoprazole in sample, can be described as high temperature average content, mg/ bottle, measures the meansigma methods of 10 bottles] while processing the corresponding time with respect to this sample under 20 ° of C the content of pantoprazole [20 ° of C4 months, can be described as room temperature average content, mg/ bottle, measure the meansigma methods of 10 bottles] percent, can be referred to as residual content (%), calculating formula is as follows:
Wherein, high temperature average content (mg/ bottle) and room temperature average content (mg/ bottle) are sample is measured pantoprazole in every bottle that obtains content (averages of 10 bottles) through [HPLC method A].
In addition, also measure the related substance in sample according to [HPLC method B], measure their each specific impurities content, total specific impurities content (being impurity A, B, C, D, E, F summation) and total impurities content (being the summation of above-mentioned specific impurities and unknown impuritie).For each sample, calculate respectively each specific impurities content and increase percent (%, can be referred to as " certain special assorted increment "), total specific impurities content increases percent (%, can be referred to as " total special assorted increment ") and total impurities content increase percent (%, can be referred to as " always assorted increment "), three's calculating formula is as follows:
the injectable powder that preparation example 1, preparation comprise Pantoprazole Sodium
Formula:
| pantoprazole Sodium | 40mg, |
| mannitol | 120mg, |
| citric acid | 4mg, |
| methionine | 5mg, |
| eDTA-2Na | 1.5mg, |
| pH adjusting agent | to pH10.5, |
| water for injection | in right amount, add to 4ml. |
Preparation method:
(1) take principal agent and the adjuvant (except pH adjusting agent) of recipe quantity, be placed in stainless steel cask, add the water for injection of recipe quantity approximately 80%, make each components dissolved, add again the active carbon of 0.1% (w/v) by liquor capacity, stir 30 minutes, filtering decarbonization, mends and injects water to approaching prescription full dose.
(2) filtrate sampling, measure pH value, be adjusted to setting (this setting is the value that lyophilization gained dry powder water for injection is diluted to the pH value of measuring containing the solution of active component 4mg/ml, lower same) by pH adjusting agent if desired, then benefit injects water to prescription full dose.
(3) medicinal liquid is first used 0.45um filtering with microporous membrane, then uses 0.22um filtering with microporous membrane 2 times.
(4) with every bottle of liquid drug 4ml fill, in 12ml cillin bottle, (in following example, while quoting this preparation example method, if not otherwise indicated, liquid drug amount is the medicine liquid volume that comprises 40mg reactive compound; If liquid drug volume obviously increases or obviously reduces in other example, can rule of thumb suitably adjust the volume of cillin bottle), false add plug.
(5) carry out lyophilization according to freeze-drying curve A described herein, to moisture lower than 3%; After lyophilizing finishes, carry out hydraulic pressure and jump a queue; Prick aluminium lid, to obtain final product.The sample of preparation example 1 can be referred to as Ex1 in the present invention; The sample of other preparation example also can similarly represent.
Supplement preparation example 1: with reference to the method for above preparation example 1, different is that the amount of methionine is wherein adjusted, be respectively 0mg, 1mg, 2mg, 3mg, 4mg, 6mg, 7mg, 8mg, 9mg, 10mg, 15mg, 20mg, the injectable powder numbering obtaining is respectively Ex100, Ex101, Ex102, Ex103, Ex104, Ex106, Ex107, Ex108, Ex109, Ex110, Ex115, Ex120.
Supplement preparation example 2: with reference to the method for above preparation example 1, different is that citric acid is wherein replaced with to equivalent sodium citrate or deletes citric acid, and the injectable powder obtaining numbering is respectively Ex131, Ex132.
Prior art goods 1: according to CN101810588A (Chinese Patent Application No. 200910223918.1, Luo Cheng) prescription and the method for making of description [0086] to [0100] section embodiment 1 are prepared (active component of every bottle of subpackage is counted 40mg by pantoprazole), the injectable powder numbering CN588A obtaining, its preparation prescription proportioning is:
study on the stability example:
Measure sample prepared by above embodiment 1 part according to this paper chemical stability investigation method and place the chemical stability after 4 months under 45 ° of C, particularly measure their residual content (%), total special assorted increment (%) and total assorted increment (%), result as shown in the following Table 1.
Table 1
| Sample | Residual content (%) | Total special assorted increment (%) | Total assorted increment (%) |
| Ex100 | 95.8 | 325 | 386 |
| Ex101 | 96.6 | 256 | 324 |
| Ex102 | 97.7 | 165 | 236 |
| Ex103 | 99.3 | 54 | 81 |
| Ex104 | 99.4 | 45 | 69 |
| Ex1 | 99.3 | 41 | 70 |
| Ex106 | 99.5 | 45 | 81 |
| Ex107 | 99.3 | 47 | 74 |
| Ex108 | 98.1 | 62 | 98 |
| Ex109 | 97.6 | 68 | 141 |
| Ex110 | 97.5 | 73 | 164 |
| Ex115 | 97.0 | 86 | 195 |
| Ex120 | 96.6 | 97 | 203 |
| Ex131 | 96.3 | 175 | 253 |
| Ex132 | 96.4 | 195 | 244 |
| CN588A | 95.4 | 181 | 261 |
Result shows, in the scope that is 3mg～7mg in the amount of methionine, injectable powder of the present invention is higher at content after high-temperature process, and total special assorted increment (%) and total assorted increment (%) occupy reduced levels, but in the time that the amount of methionine is lower, total special assorted increment (%) and total assorted increment (%) occupy higher level, show that product obviously can not be satisfied with aspect chemical stability, and in the time that the amount of methionine is higher, total special assorted increment (%) is although occupy reduced levels, but the total assorted increment (%) of these samples has the trend obviously increasing, in the scope that the amount that is presented at methionine is 3mg～7mg, injectable powder of the present invention has good stability.
In addition, when not adding citric acid in formula or changing citric acid into methionine, total special assorted increment (%) and total assorted increment (%) all increase obviously, are presented at the performance that exists lower methionine inhibition of impurities to increase without citric acid and can not get performance.In addition, inventor also finds in calculating, the main contributions person of total special assorted increment (%) and total assorted increment (%) is impurity A, in total special assorted increment (%) and total assorted increment (%), the increment of impurity A is more obvious, accounts for the assorted increment (%) of total spy and total assorted the more than 40% of increment (%).Beat all discovery, by adding the effectively increase of inhibition of impurities A of methionine.In addition, the injectable powder that prior art prepares at total special assorted increment (%) with aspect the increment (%) two of always mixing also all not as powder pin ideal of the present invention.
In addition, at these in the redissolution solution of the sample of high-temperature process, the yellow of Ex110, Ex115, Ex120 three's showed different, and methionine amount is larger, color is darker.
performance example: the outward appearance of injectable powder and dissolubility are measured
Get respectively each sample injectable powder of preparation in embodiment 1, open bottle cap plastic top, inject water for injection (consumption is about 3 times of liquor capacity respective sample lyophilization) from bottle stopper puncture with syringe, record the redissolution time with stopwatch, every batch sample test 5 times, averages.
Result, the redissolution time of the whole samples in table 1 is all in the scope of 30～65 seconds, the redissolution time of for example Ex1 is 35 seconds, the redissolution time of for example Ex103, Ex104, Ex106, Ex107 all, in the scope of 30～45 seconds, shows that these samples have clinical substantially acceptable redissolution performance faster; The redissolution time of other sample in table 1, the redissolution time of for example Ex120 and CN588A was respectively 48 seconds and 53 seconds all in the scope of 40～65 seconds.
In addition, the outward appearance of Ex103, Ex104, Ex1, Ex106, these samples of Ex107 is all solid, complete round pie, without abnormal conditions such as cleavage block, spray bottles.There is cleavage block, spray bottle in various degree in Ex115, Ex120.
preparation example 2, injectable powder of the present invention
Prescription and method for making are with reference to preparation example 1, and different is only to change mannitol consumption wherein into 100mg or 150mg, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex20, Ex21.
Prescription and method for making are with reference to preparation example 1, and different is only to change citric acid consumption wherein into 2mg or 6mg, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex22, Ex23.
Prescription and method for making are with reference to preparation example 1, and different is only to change EDTA-2Na consumption wherein into 1mg or 2mg, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex24, Ex25.
Prescription and method for making are with reference to preparation example 1, and different is is only 10.0 or 11.0 by pH value control wherein, and uses freeze-drying curve B described herein to carry out lyophilization, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex26, Ex27.
Prescription and method for making be with reference to preparation example 1, and different is only, and the amount adjustment of water for injection is wherein made to the solid content of step (3) gained filtrate is 3%, 10%, obtains the powder pin of two lot numbers, numbers and is designated as respectively Ex28, Ex29.
That measures these samples of Ex20 to Ex29 places the chemical stability after 4 months under 45 ° of C, result residual content is all in 99.1～99.7% scopes, total special assorted increment (%) is all in 35～55% scopes, and always assorted increment (%) is all in 60～85% scopes.The redissolution time of whole samples, outward appearance was all solid, complete round pie all in the scope of 8～15 seconds, without abnormal conditions such as cleavage block, spray bottles.
preparation example 3, injectable powder of the present invention
Formula:
| pantoprazole Sodium | 40mg, |
| mannitol | 120mg, |
| citric acid | 4mg, |
| methionine | 5mg, |
| trometamol | 6mg, |
| eDTA-2Na | 1.5mg, |
| pH adjusting agent | to pH10.5, |
| water for injection | in right amount, add to 1ml. |
Preparation method: the method with reference to preparation example 1 is carried out, the powder pin obtaining numbering is designated as Ex3.
With reference to prescription and the method for making of above sample Ex3, different is that wherein trometamol amount changes 4mg or 8mg into, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex31, Ex32.
With reference to prescription and the method for making of above sample Ex3, different is that wherein methionine amount changes 3mg or 7mg into, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex33, Ex34.
With reference to prescription and the method for making of above sample Ex3, different is that wherein EDTA-2Na amount changes 1mg or 2mg into, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex35, Ex36.
With reference to prescription and the method for making of above sample Ex3, different is that wherein pH value changes 10.0 or 11.0 into, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex37, Ex38.
With reference to prescription and the method for making of above sample Ex3, different is that wherein mannitol amount changes 100mg or 150mg into, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex39, Ex40.
With reference to prescription and the method for making of above sample Ex3, different is that wherein citric acid amount changes 2mg or 6mg into, obtains the powder pin of two lot numbers, and numbering is designated as respectively Ex41, Ex42.
That measures Ex3 and these samples of Ex31 to Ex42 places the chemical stability after 4 months under 45 ° of C, result residual content is all in 99.2～99.7% scopes, total special assorted increment (%) is all in 35～58% scopes, and always assorted increment (%) is all in 63～90% scopes.All the outward appearance of sample is all solid, complete round pie, without abnormal conditions such as cleavage block, spray bottles.
In Performance test mentioned above, have been surprisingly found that, all the redissolution time of sample is all in the scope of 3～9 seconds, the redissolution time of for example Ex3 is 5 seconds, the redissolution time of Ex32 is 3 seconds, the redissolution time of Ex31 is 95 seconds, shows to add trometamol to have gratifying result for obtaining the good powder needle set of solubility property in the present invention's formula.
long-term stable experiment:
Get powder pin sample of the present invention: Ex103, Ex104, Ex1, Ex106, Ex107, Ex20 to Ex29, Ex3, Ex31 to Ex42.These samples are placed 3 years under the room temperature condition of 20 ± 2 ° of C, and with reference to the chemical stability method of investigationing above, " room temperature " result that different is was wherein with the result replacement of 0 month.Result shows, the present invention's above-mentioned powder pin sample and control sample all have good stability, for example residual content (%) is in 95～98% scopes (content (%) of measuring 0 month time is all in 98～101% scopes of labelled amount) all, all in this product standard (Chinese Pharmacopoeia two of versions " injection Pantoprazole Sodium " in 2010, this standard is applicable to the quality control of the commercially available injection Pantoprazole Sodium that effect duration is defined as 2 years (the accurate word H200662277 of traditional Chinese medicines, Chengdu Tiantaishan Pharmaceutical Co., Ltd. produces)) in 90～110% scopes of regulation.The acid-base value (dissolving the solution of making containing the about 4mg/ml of active component with water for injection) of measuring these injectable powder according to this standard method, pH is all in 10.0～10.7 scopes, all in 9.5～11.0 scopes of standard regulation.Measure the related substance of these injectable powder according to this standard method, maximum single contaminant was all less than for 0.25% (standard regulation should be less than 0.5%), total impurities was all less than for 0.44% (standard regulation should be less than 1.0%), showed that these samples still have good stability in long-term placement after 3 years.For example under Ex1 room temperature condition, placing residual content after 3 years (%, compared with 0 month) is 98.3%, and maximum single contaminant is 0.17%, and total impurities is 0.38%, and other index all meets the regulation in standards of pharmacopoeia.
Claims (1)
1. a lyophilized injectable powder, it is made up of Pantoprazole Sodium, mannitol, citric acid, methionine, disodiumedetate and optional acid-base modifier; The material wherein comprising is in the Pantoprazole Sodium of every 40 weight portions, and the amount of mannitol is 100-150 weight portion, and the amount of citric acid is 2-6 weight portion, and the amount of methionine is 3-7 weight portion, and the amount of disodiumedetate is 1-2 weight portion; The amount of described optional acid-base modifier is, the amount of the pH value of this solution in 10.0 ~ 11.0 scopes while making described lyophilized injectable powder water for injection be dissolved into the solution containing Pantoprazole Sodium 40mg/ml concentration.
2. according to the lyophilized injectable powder of claim 1, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.
3. according to the lyophilized injectable powder of claim 1, wherein water content is lower than 5%.
4. according to the lyophilized injectable powder of claim 1, wherein water content is lower than 3%.
5. according to the lyophilized injectable powder of claim 1, in its solution before lyophilization, solid content is 3 ~ 20% (w/v).
6. according to the lyophilized injectable powder of claim 1, in its solution before lyophilization, solid content is 3 ~ 15% (w/v).
7. according to the lyophilized injectable powder of claim 1, in its solution before lyophilization, solid content is 3 ~ 10% (w/v).
8. a lyophilized injectable powder, it consists of: Pantoprazole Sodium 40 weight portions, mannitol 100-150 weight portion, citric acid 2-6 weight portion, methionine 3-7 weight portion, trometamol 4-8 weight portion, disodiumedetate 1-2 weight portion and optional acid-base modifier; The amount of described optional acid-base modifier is, the amount of the pH value of this solution in 10.0 ~ 11.0 scopes while making described lyophilized injectable powder water for injection be dissolved into the solution containing Pantoprazole Sodium 40mg/ml concentration.
9. lyophilized injectable powder according to Claim 8, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.
10. lyophilized injectable powder according to Claim 8, wherein water content is lower than 5%.
11. lyophilized injectable powders according to Claim 8, wherein water content is lower than 3%.
12. lyophilized injectable powders according to Claim 8, in its solution before lyophilization, solid content is 3 ~ 20% (w/v).
13. lyophilized injectable powders according to Claim 8, in its solution before lyophilization, solid content is 3 ~ 15% (w/v).
14. lyophilized injectable powders according to Claim 8, in its solution before lyophilization, solid content is 3 ~ 10% (w/v).
The method of the lyophilized injectable powder described in 15. preparation claim 1 to 7 any one, it comprises the following steps:
(a) take the Pantoprazole Sodium of recipe quantity and mannitol, citric acid, methionine, disodiumedetate, add appropriate water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, be adjusted to pH11.0～11.5 with acid-base modifier if desired;
(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, and tamponade to obtain final product.
The method of the lyophilized injectable powder described in 16. preparation claim 8 to 14 any one, it comprises the following steps:
(a) take Pantoprazole Sodium and mannitol, citric acid, methionine, disodiumedetate and the trometamol of recipe quantity, add appropriate water for injection, make to dissolve, then add active carbon, stir filtering decarbonization;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, be adjusted to pH11.0～11.5 with acid-base modifier if desired;
(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, and tamponade to obtain final product.
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| CN104666254A (en) * | 2015-03-23 | 2015-06-03 | 山东北大高科华泰制药有限公司 | Pantoprazole sodium freeze-dried powder injection pharmaceutical composition and preparation method thereof |
| CN109061011B (en) * | 2018-10-18 | 2021-06-29 | 成都天台山制药有限公司 | Pantoprazole sodium freeze-dried powder injection pharmaceutical composition and preparation method thereof |
| CN113125583B (en) * | 2019-12-30 | 2022-06-21 | 成都百裕制药股份有限公司 | Method for detecting content of genotoxic impurities in pantoprazole sodium for injection |
| US12102624B2 (en) | 2020-08-26 | 2024-10-01 | Nivagen Pharmaceuticals, Inc. | Pantoprazole compositions and methods |
| 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 |
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