CN105640877A - Liquid preparation containing Vonoprazan - Google Patents
Liquid preparation containing Vonoprazan Download PDFInfo
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- CN105640877A CN105640877A CN201610051170.1A CN201610051170A CN105640877A CN 105640877 A CN105640877 A CN 105640877A CN 201610051170 A CN201610051170 A CN 201610051170A CN 105640877 A CN105640877 A CN 105640877A
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- liquid preparation
- nuolazan
- injection
- fumaric acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a liquid preparation containing Vonoprazan, relates to the field of medicines and in particular to a preparation method and stability study of multiple liquid preparations containing the Vonoprazan. The liquid preparation further contains a pH regulator, a metal ion complexing agent and inorganic salt except the active ingredient Vonoprazan. The relatively stable liquid preparation products are determined by studying the Vonoprazan liquid preparations prepared by adopting different prescriptions and processes.
Description
Technical field
The present invention relates to field of medicaments, specifically, relate to the system of the liquid preparation of the multiple Wo Nuolazan of containingPreparation Method, and investigate its stability.
Technical background
Fumaric acid Wo Nuolazan is the competitive acid of a kind of potassium ion by Japanese Wu Tian company (Takeda) developmentRetarding agent (P-CAB), external activity experiment shows that the ability of this compound inhibition proton pump is Lansoprazole400 times, it is with respect to Na+, K+-ATPase selectively more than 500 times. The rabbit gastric gland tissue of cultivatingIn, TAK-438 demonstrates higher accumulation rate and slower clearance rate than Lansoprazole, and this has it in vivoStronger usefulness and more lasting Acidinhibitor.
Fumaric acid Wo Nuolazan has excellent gastric acid secretion inhibitory action (particularly proton pump inhibitory action).Itself and conventional proton pump inhibitor are (as Omeprazole, Lansoprazole etc. and half Guang ammonia of H+/K+-ATP enzymeAcid residue formation covalent bond irreversibly inhibitory enzyme activity) difference, fumaric acid Wo Nuolazan is with reversible inhibitionProton pump (H+/K+-APT enzyme) activity, with K+ antagonist suppressor mode gastric acid secretion inhibiting, so it hasTime be called the competitive hydrochloric acid in gastric juice retarding agent of potassium: P-CAB or hydrochloric acid in gastric juice pump antagonist (ACPA or APA)),So it can provide drug composition effective clinically, for preventing and/or treating peptic ulcer (exampleAs, gastric ulcer, the gastric ulcer that postoperative irritability (postoperativestress) causes, duodenal ulcer,Marginal ulcer (anastomoticulcer), the ulcer that non-steroidal anti-inflammatory agent causes, postoperative irritability causesUlcer etc.); Zuo-Ai syndrome; Gastritis; Erosive esophagitis; Reflux esophagitis fluidity as anti-in erosiveEsophagitis etc.; Symptomatic gastroesophageal reflux disease (symptomatic GERD) is as the reflux disease of Non-erosive(non-erosiverefluxdisease) or without gastroesophageal reflux disease of esophagitis etc.; Functional dyspepsia FD;Cancer of the stomach (comprising that the il-1 β promoting with the gene pleiomorphism owing to il-1 produces relevant cancer of the stomach);Stomach MALT lymthoma; Hyperchlorhydria; Or due to the UGB of peptic ulcer, acute answeringSwash ulcer, hemorrhagic gastritis or invasive stress reaction are (as all needed separately to strengthen the major operation requirement for the treatment ofThe stress reaction that causes of postoperative centralized management, cranial vascular disease, head trauma, MOF and large areaBurn) inhibitor etc. And fumaric acid Wo Nuolazan can be used for preventing and/or treating airways disorders, heavy breathingPreanesthetic medication, the elimination of helicobacter pylori or the auxiliary elimination etc. such as breathe heavily. Due to fumaric acid Wo Nuolazan toolIt has hypotoxicity and water-soluble, body internal dynamics and effect to express excellent, so can be used for doing drug regimenThing.
Because Japanese Wu Tian company develops and the fumaric acid Wo Nuolazan sheet that goes on the market is conventional oral administration administration, medicineIt is obvious that the rapid property of effect is not so good as injection, in the time of some acute diseases of reply, and the stomach that for example postoperative irritability causesUlcer, duodenal ulcer, marginal ulcer, oral medication cannot reach good effect. Therefore the fertile promise of exploitationDraw the formulation of praising drug administration by injection approach to there are good Clinical significance of MG and market prospects.
Summary of the invention
The present invention aims to provide a kind of stable liquid preparation that contains Wo Nuolazan, in described liquid preparation, removesOutside active component Wo Nuolazan, also should comprise pH adjusting agent, complexing of metal ion agent and inorganic salts.
The Wo Nuolazan liquid preparation that the present invention prepares by investigating different prescriptions and technique, to determine relativelyStable liquid preparation product.
The Wo Nuolazan bulk drug of the present invention protection, comprises itself and the salt of inorganic acid or organic acid generation and moltenAgent or hydrate. Wo Nuolazan salt used in the present invention is fumaric acid Wo Nuolazan salt.
Preparation provided by the invention is liquid preparation, comprising but be not limited to injection.
Liquid preparation technique provided by the present invention is liquid preparation conventional process.
Liquid preparation stability study provided by the present invention is mainly divided into five aspects, and first aspect is anti-goldBelonging to ion complexation-pH investigates; Second aspect anti-complexing of metal ion-EDTA-Na consumption investigated. The 3rd sideFace stabilizing agent-inorganic salts consumption is investigated. The selection of the 4th aspect sterilizing parameter. The 5th aspect sterilizing parameterSelection.
In anti-complexing of metal ion research, find that metal ion network once appearred in proton pump inhibitor in the time of compatibilityThe phenomenon of closing, for example Lansoprazole powder pin should be furnished with the filter that aperture is 1.2 μ m in the time that drip-feed is used,So that issuable sediment in removal infusion process. The situation that precipitation occurs, analysis is the not homogeneity of being infusedThe impact that water gaging is flat, in the principal component of medicine and transfusion (0.9% sodium chloride injection and 5% glucose injection)Some metal ion generation complex reactions, produce sediment separate out, cause occurring clinical adverse.
The present invention, in the time of the formulation and technology of this product of design, exists and asks in this regard for solving domestic production enterpriseTopic, on the basis of lot of experiments screening, selects fumaric acid Wo Nuolazan and EDTA-2Na to be used in combination,The two ratio is 3: 0.01～0.5; Be preferably 3: 0.05～0.3; More preferably 3: 0.2, noOnly the particulate matter of product self obtains fine raising and control, meanwhile, has also effectively prevented from dripping quietMetal ion in Lansoprazole and transfusion in journey (0.9% sodium chloride injection and 5% glucose injection) is sent outRaw complex reaction, avoids producing Precipitation, asks thereby solved this product clinical drug safety in this regardTopic.
In inorganic salts stability study, find Wo Nuolazan there is parahelium group, when high nucleophilicity withThe pharmacy activity component of uncle or secondary amino group is dissolved or suspended in suitable solvent (for example, distilled water for injection, electricitySeparate matter solution etc.) in time, have greatly may with α, beta-unsaturated carbonyl compound (especially α, β-Unsaturated carboxylic acid, for example fumaric acid etc.) there is Michael addition reaction (what be connected with electron-withdrawing substituentThe nucleophilic addition occurring on the end carbon of conjugated system).
Thus, in liquid preparation of the present invention, add salt as stabilizing agent. Described stabilizing agent passes through imitated α,Beta-unsaturated carbonyl compound (especially α, beta-unsaturated carboxylic acid) is lived with the pharmacy with uncle's ammonia or secondary amino groupAmino in property composition reacts and makes preparation stabilization. In liquid preparation, salt is for carrying uncle or secondary amino groupPharmacy activity component and organic acid product produce inhibition. Salt provided by the present invention is halideSalt, particularly metal halide salt, preferably sodium chloride.
In liquid preparation of the present invention, carry uncle or the pharmacy activity component of secondary amino group and the mol ratio of salt and be1:0.01～1:1000, preferably 1:0.1～1:100. Wo Nuolazan liquid preparation in scope of the present inventionMatter is stable, can store for a long time use.
In sum, compared with prior art, substantial advantage is in the present invention:
1. in the present invention program, adopt the EDTA-Na prescription of different pH and different amounts, to guarantee that it is as best steadyQualitative prescription.
2. the present invention adopts conventional inorganic salts as stabilizing agent, and auxiliary material is simple and easy to get, and process stabilizing is controlled, and it is improvingStability aspect has clear superiority.
Wo Nuolazan mainly contains the formulations such as tablet, capsule, injection for clinical at present, and these formulations are at intestines and stomachDissolution rate is poor, and bioavilability is not high. The invention provides a kind of stable Wo Nuolazan freeze-dried powder and system thereofPreparation Method, described Wo Nuolazan freeze-dried powder auxiliary material is less, good stability, clinical safety in utilization is higher.
Detailed description of the invention:
Embodiment mono-(anti-complexing of metal ion-pH investigates)
Prescription
| Supplementary material title | Effect | Recipe quantity |
| Fumaric acid Wei Nuolazan | Active material | 26.72mg |
| NaOH | PH adjusting agent | In right amount |
| Water for injection | Solvent | To 5ml |
According to above formula preparation injection, investigate the anti-metal ion activity under different pH, prescription pH dividesWei not write out a prescription 1 (pH4.0), prescription 2 (pH5.0), prescription 3 (pH6.0), prescription 4 (pH7.0),Prescription 5 (pH8.0).
Technique
Prescription 1～prescription 5 techniques are all consistent, are only pH difference, and concrete technology is as follows:
In glass beaker, weigh fumaric acid Wei Nuolazan, add water for injection, stir this mixing with agitatorThing, dissolves them. Add 1mol/L sodium hydrate aqueous solution, this mixture is adjusted to prescription analog value.
This test has been investigated the fumaric acid Wei Nuolazan injection placement content of 30 days and has been separated out situation.
| Prescription title | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 |
| pH | 4.0 | 5.0 | 6.0 | 7.0 | 8.0 |
| Place 10 days | There is solid to separate out | There is solid to separate out | Separate out without solid | Separate out without solid | Separate out without solid |
| Place 20 days | There is solid to separate out | There is solid to separate out | There is solid to separate out | Separate out without solid | Separate out without solid |
| Place 30 days | There is solid to separate out | There is solid to separate out | There is solid to separate out | There is solid to separate out | There is solid to separate out |
From above result, the anti-metal ion activity of the preparation of pH7.0 and pH8.0 is higher than lower pH'sPreparation, and pH7.0 and the anti-metal ion activity difference of pH8.0 preparation little, therefore select neutral pH 7.0 preparationsDo follow-up investigation.
Embodiment bis-(anti-complexing of metal ion-EDTA-Na consumption is investigated)
Prescription
| Supplementary material title | Effect | Prescription 6 | Prescription 7 |
| Fumaric acid Wei Nuolazan | Active material | 26.72mg | 26.72mg |
| EDTA-Na | Complexing of metal ion agent | 5mg | 25mg |
| NaOH | PH adjusting agent | In right amount | In right amount |
| Water for injection | Solvent | To 5ml | To 5ml |
Prescription 6～prescription 7 techniques are all consistent, are only EDTA-Na usage variance, and concrete technology is as follows:
In glass beaker, weigh fumaric acid Wei Nuolazan, EDTA-Na, add water for injection, use agitatorStir this mixture, they are dissolved. Add 1mol/L sodium hydrate aqueous solution, this mixture is adjusted to7.0。
This test has been investigated the fumaric acid Wei Nuolazan injection placement content of 30 days and has been separated out situation.
| Prescription title | Prescription 4 | Prescription 6 | Prescription 7 |
| EDTA-Na consumption | 0 | 5mg | 25mg |
| Place 10 days | Separate out without solid | Separate out without solid | Separate out without solid |
| Place 20 days | Separate out without solid | Separate out without solid | Separate out without solid |
| Place 30 days | There is solid to separate out | Separate out without solid | Separate out without solid |
From above result, in the time that pH is 7.0, EDTA-Na consumption only uses 5mg (0.1%w/v) to expireThe anti-complexing of metal ion effect of foot is 0.1%w/v therefore the present invention adopts EDTA-Na consumption.
Embodiment tri-(investigation of stabilizing agent-inorganic salts consumption)
Prescription
In glass beaker, weigh fumaric acid Wei Nuolazan, EDTA-Na, halide, add water for injection,Stir this mixture with agitator, they are dissolved. Add 1mol/L sodium hydrate aqueous solution, by this mixingThing is adjusted to 7.0.
60 DEG C of placements of fumaric acid Wei Nuolazan injection related substance situation of change of 30 days has been investigated in this test.
From above result, use sodium bromide and sodium chloride not to make significant difference for preparation stability, sodium chlorideConsumption is remarkable for stability influence, can play good steady in the time that sodium chloride consumption is 9mg (0.18%)Tailor-made use is 0.18%w/v therefore the present invention adopts sodium chloride consumption.
Wo Nuolazan liquid preparation of the present invention, by investigating anti-metal ion activity agent high-temperature stable Journal of Sex Research,Whole optimization steady quality, simple formulation and technology, it is easy operating not only, and greatly reducesProduction cost, has good directive significance.
Embodiment tetra-(ph regulates the investigation of the solubility of sodium hydrate aqueous solution)
Prescription
| Supplementary material title | Prescription 12 | Prescription 13 | Prescription 14 |
| Fumaric acid Wei Nuolazan | 26.72mg | 26.72mg | 26.72mg |
| EDTA-Na | 5mg | 5mg | 5mg |
| NaOH | 1mol/L | 0.5mol/L | 0.1mol/L |
| Sodium chloride | 9mg | 9mg | 9mg |
| Water for injection | To 5ml | To 5ml | To 5ml |
Prescription 12～prescription 14 techniques are all consistent, are only to regulate the solubility of the sodium hydrate aqueous solution of ph to differCause, in glass beaker, weigh fumaric acid Wei Nuolazan, EDTA-Na, sodium chloride, add water for injection,Stir this mixture with agitator, they are dissolved. Add respectively 1,0.5,0.1mol/L NaOH water-solubleLiquid, is adjusted to 7.0 by this mixture.
60 DEG C of placements of fumaric acid Wei Nuolazan injection related substance situation of change of 30 days has been investigated in this test.
From above result, the stability of writing out a prescription when naoh concentration is 0.1mol/L is best, therefore this0.1mol/L sodium hydrate aqueous solution is selected in bright ph adjustment agent.
Embodiment five (selection of sterilizing parameter)
Prescription
| Supplementary material title | Prescription 15 | Prescription 16 | Prescription 17 |
| Fumaric acid Wei Nuolazan | 26.72mg | 26.72mg | 26.72mg |
| EDTA-Na | 5mg | 5mg | 5mg |
| Sterilizing parameter | 121℃15min | 121℃20min | 121℃30min |
| Sodium chloride | 9mg | 9mg | 9mg |
| Water for injection | To 5m | To 5ml | To 5ml |
Prescription 15～prescription 17 techniques are all consistent, are only the difference under sterilising conditions.
In glass beaker, weigh fumaric acid Wei Nuolazan, EDTA-Na, sodium chloride, add water for injection,Stir this mixture with agitator, they are dissolved. Add 0.1mol/L sodium hydrate aqueous solution, this is mixedCompound is adjusted to 7.0. At 121 DEG C, heat respectively 15min, 20min, 30min.
60 DEG C of placements of fumaric acid Wei Nuolazan injection related substance situation of change of 30 days has been investigated in this test.
From above result, the stability of writing out a prescription in the time of 121 DEG C of 15min of sterilising conditions is best, therefore the present inventionSelect sterilizing under 121 DEG C of 15min conditions.
Embodiment six (preparation technology of powder pin)
Prescription
| Fumaric acid Wei Nuolazan | 20g |
| Sweet mellow wine | 3g |
| EDTA-Na | 1.5g |
| Valine | 0.5g |
| Sodium chloride | 8g |
| PH adjusting agent | To 7.0 |
| Water for injection | 1000ml |
Preparation technology:
1, get recipe quantity valine, EDTA-Na adds the water for injection of 50% amount, is heated to 50～55 DEG C,Stirring is dissolved it, and the fumaric acid Wei Nuolazan that gets recipe quantity adds in solution, continues to stir 15 after stirring and dissolvingMinute.
2, get sodium chloride and the sweet mellow wine of recipe quantity, add the water for injection of 40% amount, stir and make its dissolving.
3,1,2 solution are merged, measure pH value, be adjusted to setting by pH adjusting agent if desired.Add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 25 minutes, filter decarburization, centreHealth check-up is looked into, qualified rear use 0.22 μ m membrane filtration degerming.
4, filtrate is poured in cillin bottle, carry out freeze drying, obtain freeze-dried powder, after the assay was approved, packaging.
Embodiment seven
The production technology prescription of Wo Nuolazan injection
| Fumaric acid Wei Nuolazan | 10kg |
| Sodium dihydrogen phosphate | In right amount |
| NaOH | In right amount |
| EDTA | 50g |
| Sodium chloride | 500g |
| Water for injection | Add to 380L |
| Make altogether | 100000 |
Preparation technology
1) take the injection fumaric acid Wei Nuolazan raw material of 10kg through being up to the standards, in Sheng bulk drugAfter packaging bag vacuumizes, slowly inflated with nitrogen is to more than 3/4 sealing of packaging bag volume. Additional one deck black bagAfter pack vacuumizes, inflated with nitrogen is to more than 3/4 sealing of packaging bag volume. Sack is put into outer packaging barrelAfter vacuumizing, inflated with nitrogen seals for subsequent use to expiring bung on bonnet. Surplus stock medicine is anti-according to aforesaid operations stepVacuumize again-inflated with nitrogen is preserved.
2) in material-compound tank, add 300L water for injection, open vacuum, vacuum in tank is reached-0.085～0.09Mpa, is filled with the nitrogen of purity 99.99% to normal pressure, is repeatedly operated to water for injection in tankIn be no more than 0.1ppm containing dissolved oxygen and (adopt dissolved oxygen analytic instrument Winkler method to detect the oxygen in parenteral solutionContent). In the situation that constantly filling nitrogen, water for injection is heated to 70 DEG C, drop into 500g and close through inspectionThe sodium chloride of lattice, after stirring and dissolving, adds recipe quantity fumaric acid Wei Nuolazan raw material, is stirred to dissolve, and uses phosphorusAcid dihydride sodium, sodium hydroxide solution regulates, and pH should be between 5.0～8.0. Add place to above-mentioned solutionMeasure EDTA and then add the medicinal carbon of cumulative volume 0.1% (g/ml) side, mends to inject water to and criticizeAmount, stirs, and 80 DEG C of insulation 10min are back to clear and bright through the de-charcoal of titanium rod filter. Dosing whole process is filledNitrogen protection.
3) intermediate standard detection is pressed in sampling, and pH is controlled at 7.3～7.8, intermediate contentBeing controlled at containing fumaric acid Wei Nuolazan is between 95.0～105.0mg/ml, in tank, in water for injection, contains and dissolvesOxygen is no more than 0.1ppm.
3. embedding
Intermediate, through using after the assay was approved the filter aseptic filtration of 0.22 μ m, checks in visible foreign matters, bacteriumAfter toxin is qualified, upper streamline carries out filling, ensures water for injection in ampoule by vacuumize-inflated with nitrogen modeIn be no more than 0.1ppm containing dissolved oxygen, after vacuumize-inflated with nitrogen, seal.
4. sterilizing
Ampoule semi-finished product good embedding are sent into steam sterilization cabinet sterilizing, sterilising conditions: 121 DEG C of hot pressing steam sterilizings 12Minute, sterilizing program: 12 DEG C/min heats up, and rises to 121 DEG C, sterilizing 12min in 10min; Compression5 DEG C/min of air cooling, is cooled to 80 DEG C in 8min, water drenches 2.5 DEG C/min cooling, in 12minBe cooled to 50 DEG C, condition is in accordance with regulations hunted leak, is offerd for sale.
5. inspection
By sample light signal inspection after sterilizing, check visible foreign matters. Lamp is examined to qualified sample packaging, inspection, warehouse-in.
Embodiment eight
Detailed process is with embodiment seven, and different is the processing of vacuumize-Tong of fumaric acid Wei Nuolazan nitrogen, residueAlso vacuumize-Tong of raw material nitrogen is processed directly and is preserved, and process for preparation and embedding process do not vacuumize, only logicalNitrogen is processed 25 minutes.
Embodiment nine
Detailed process is with embodiment seven, and different is that sterilization process steam sterilizing does not adopt gradient cooling program, butDirectly cooling water drip washing quenching cooling.
Embodiment ten
Detailed process is with embodiment seven, and different is that sterilization process adopts gradient cooling program, 3.4 DEG C of compressed air/ min cooling, is cooled to 80 DEG C in 12min, water drenches 2 DEG C/min cooling, is cooled to 50 DEG C in 15min.
Embodiment 11
Detailed process is with embodiment seven, and that different is 60 DEG C of insulation 10min of process for preparation.
Embodiment 12
Detailed process is with embodiment seven, and that different is 40 DEG C of insulation 30min of process for preparation.
Claims (9)
1. contain the liquid preparation that active component is Wo Nuolazan, it is characterized in that, it comprises: (1)Active component Wo Nuolazan and salt thereof; (2) pH adjusting agent; (3) complexing of metal ion agent; (4) inorganicSalt.
2. liquid preparation claimed in claim 1, is characterized in that, described Wo Nuolazan salt is that fumaric acid is fertileNola praises, and wherein comprises fumaric acid Wo Nuolazan 1～1000mg, preferably 10～500mg.
3. liquid preparation claimed in claim 1, is characterized in that, described pH adjusting agent comprises biphosphateSodium, potassium phosphate,monobasic, NaOH/hydrochloric acid; PH value scope is 3.0～10.0, preferably 5.0～8.0.
4. liquid preparation claimed in claim 1, is characterized in that, described complexing of metal ion agent is EDTAAnd EDETATE SODIUM, amount ranges is 0.001%～5%, wherein preferably 0.005%～0.05%.
5. liquid preparation claimed in claim 1, is characterized in that, described inorganic salts comprise sodium chloride, sulfuric acidHydrogen potassium, sodium hydrogen phosphate. Amount ranges is 0.1%～10%, wherein preferably 0.5%～5%.
6. liquid preparation claimed in claim 1, is characterized in that, fumaric acid Wo Nuolazan and EDTA-2NaBe used in combination, the two ratio is 3: 0.01～0.5; Be preferably 3: 0.05～0.3; More preferably3∶0.2。
7. liquid preparation claimed in claim 1, is characterized in that, carries the pharmaceutical active of uncle or secondary amino groupThe mol ratio of composition and salt is 1:0.01～1:1000, preferably 1:0.1～1:100.
8. the arbitrary liquid preparation described in claim 1-7, is characterized in that, comprising but be not limited to notePenetrate agent.
9. the preparation method of the liquid preparation described in claim 1-8, comprises the steps:
(1) get recipe quantity valine, EDTA-Na adds the water for injection of 50% amount, is heated to 50～55 DEG C,Stirring is dissolved it, and the fumaric acid Wei Nuolazan that gets recipe quantity adds in solution, continues to stir after stirring and dissolving10-30 minute.
(2) get sodium chloride and the sweet mellow wine of recipe quantity, add the water for injection of 40% amount, stir and make its dissolving.
(3) 1,2 solution are merged, measure pH value, be adjusted to regulation by pH adjusting agent if desiredValue. Add to the full amount of water for injection, add 0.15% needle-use activated carbon, stir 15-50 minute, filter decarburization,Intermediate checks, qualified rear use 0.22 μ m membrane filtration degerming.
(4) filtrate is poured in cillin bottle, carry out freeze drying, obtain freeze-dried powder, after the assay was approved, bagDress.
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| CN201610051170.1A CN105640877A (en) | 2016-01-26 | 2016-01-26 | Liquid preparation containing Vonoprazan |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113350271A (en) * | 2020-03-04 | 2021-09-07 | 广东东阳光药业有限公司 | Composition of proton pump inhibitor and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104582687A (en) * | 2012-06-27 | 2015-04-29 | 武田药品工业株式会社 | Liquid preparations of amines and organic acids stabilized by salts |
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