CN105310978A - Drug combination containing conivaptan hydrochloride as active ingredient and preparation of drug combination - Google Patents
Drug combination containing conivaptan hydrochloride as active ingredient and preparation of drug combination Download PDFInfo
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- CN105310978A CN105310978A CN201410377516.8A CN201410377516A CN105310978A CN 105310978 A CN105310978 A CN 105310978A CN 201410377516 A CN201410377516 A CN 201410377516A CN 105310978 A CN105310978 A CN 105310978A
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Abstract
The invention belongs to the technical field of medicine and discloses a drug combination containing conivaptan hydrochloride as an active ingredient and a preparation of the drug combination. The drug combination comprises conivaptan hydrochloride, glucose and a pH regulator, the pH regulator is obtained by taking 5-hydroxymethyl-2-furfura and related substance as indexes for screening, and preferential lactic acid concentration and L-lactic acid are obtained by taking insoluble particles as an index for screening. Researches show that an infusion solution prepared by the drug combination is low in 5-hydroxymethyl-2-furfura, single biggest impurity and total impurity content, small in insoluble particle amount and better in product quality.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of pharmaceutical composition and the preparation thereof that contain active ingredient hydrochloric acid conivaptan.
Background technology
Conivaptan is the non-peptide class dual antagonist of a kind of arginine vasopressin (AVP) V1A and V2 receptor.The Pharmacodynamics effect for the treatment of hyponatremia is the V2 receptor antagonism of AVP in kidney collecting tubule, causes the eliminating of diuretic effect or Free water.Be mainly used in the treatment of the hyponatremia inpatient of normal blood volume and/or Hypervolemia clinically.Modal untoward reaction (incidence rate >=10%) is injection site reaction, heating, hypokalemia, headache and orthostatic hypotension.
In December, 2005, U.S. FDA approval conivaptan such as to be used at the hypovolemic hyponatremia, becomes the AVP receptor antagonist of first application in the world.In February, 2007 is ratified to expand to use in high power capacity hyponatremia by FDA.In October, 2008, FDA ratifies the treatment that conivaptan is used for the hyponatremia inpatient of normal blood volume and/or Hypervolemia, and formally goes on the market in the U.S. in April, 2009.
Take conivaptan as the preparation of raw material be hydrochloric acid conivaptan injection, also not in Discussion on Chinese Listed, the outstanding hydrochloric acid conivaptan injection of quality of research is significant.
Summary of the invention
For these reasons, applicant studies discovery, obtain a kind of new pharmaceutical composition, containing hydrochloric acid conivaptan, glucose and pH adjusting agent in this pharmaceutical composition, wherein pH adjusting agent is certain density lactic acid or Pfansteihl, and under in Pfansteihl, DL-LACTIC ACID content is less than certain numerical value situation, this pharmaceutical composition is prepared in injection, impurity 5 hydroxymethyl furfural content is less than 0.02%, single maximum contaminant content is less than or equal to 0.5%, total impurities content is less than or equal to 1.0%, and particulate matter quantity is few.
Of the present invention meet certain mass standard, certain density Pfansteihl is pH adjusting agent, is again cosolvent, also belongs to the stabilizing agent in hydrochloric acid conivaptan infusion solution simultaneously.In like manner, lactic acid of the present invention is pH adjusting agent, is again cosolvent, also belongs to the stabilizing agent in hydrochloric acid conivaptan infusion solution simultaneously
The present invention is realized by following proposal.
A pharmaceutical composition containing active ingredient hydrochloric acid conivaptan, described pharmaceutical composition comprises hydrochloric acid conivaptan, glucose and pH adjusting agent.
PH adjusting agent described above is lactic acid or Pfansteihl.
Wherein in Pfansteihl, the content of DL-LACTIC ACID is less than or equal to 0.20%.
Pharmaceutical composition containing active ingredient hydrochloric acid conivaptan described above, wherein pH adjusting agent is the lactic acid aqueous solution of concentration 4%-6% (g/ml), or pH adjusting agent is the Pfansteihl aqueous solution of g/ml concentration 4%-6% (g/ml).
Pharmaceutical composition containing active ingredient hydrochloric acid conivaptan described above, wherein pharmaceutical composition comprises hydrochloric acid conivaptan 20 weight portion, glucose 5000 weight portion, concentration is 4%-6% (g/ml) lactic acid aqueous solution (lactic acid is 3.2 weight portion-4.8 weight portions); Or hydrochloric acid conivaptan 20 weight portion, glucose 5000 weight portion, concentration is 4%-6% (g/ml) Pfansteihl aqueous solution (Pfansteihl is 3.2-4.8 weight portion).
The described pharmaceutical composition containing active ingredient hydrochloric acid conivaptan, pharmaceutical composition is prepared into infusion solution.
Wherein the preparation method of infusion solution is:
Get lactic acid aqueous solution or Pfansteihl aqueous solution that concentration is 4%-6%, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at lactic acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, add glucose, mend and inject water to 50% of prescription volume, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit adds to the full amount of water for injection, circulation 20 ~ 30min, and check that the pH value of medicinal liquid is 3.5-3.6, through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, after lamp inspection is qualified, and labeling, packaging, warehouse-in.
The application of pharmaceutical composition containing active ingredient hydrochloric acid conivaptan described above in preparation treatment hyponatremia medicine.
The following test of the present invention is in repeatedly creative experimental basis, the concluding test that the technical scheme for the present invention's protection is carried out.
Hydrochloric acid conivaptan of the present invention is containing C
32h
26n
4o
2hCl is 99.7%, and single maximum contaminant content is 0.12%, and total impurities content is 0.26%; Glucose, pH adjusting agent all meet Chinese Pharmacopoeia version prescription in 2010, all purchased from Weifang Shengtai Medicine Co., Ltd..
One, pH adjusting agent screening test I
Test 1 group: hydrochloric acid conivaptan 2g, glucose 500g, citric acid 0.4g;
Test 2 groups: hydrochloric acid conivaptan 2g, glucose 500g, malic acid 0.4g;
Test 3 groups: hydrochloric acid conivaptan 2g, glucose 500g, tartaric acid 0.4g;
Test 4 groups: hydrochloric acid conivaptan 2g, glucose 500g, acetic acid 0.4g;
Test 5 groups: hydrochloric acid conivaptan 2g, glucose 500g, phosphoric acid 0.4g;
Test 6 groups: hydrochloric acid conivaptan 2g, glucose 500g, lactic acid 0.4g;
Preparation method:
Get different acid, add water to 8mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 5000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 10000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 100 bottles.
[5 hydroxymethyl furfural detection method]
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability octadecyl silane are filler, and mobile phase is acetonitrile/water=10/90 (V/V), and wavelength is 284nm, sample introduction 10 μ l, flow velocity 1.0ml/min, column temperature room temperature.
Algoscopy gets this product as need testing solution, and precision measures 10 μ l, injection liquid chromatography, record chromatogram; Separately get 5 hydroxymethyl furfural reference substance appropriate, accurately weighed, be dissolved in water and quantitatively dilute the solution made about containing 10 μ g in every 1ml, product solution, is measured in the same method in contrast.If any the chromatographic peak consistent with 5 hydroxymethyl furfural retention time in need testing solution chromatogram, its peak area must not be greater than reference substance solution peak area (0.02%).
Result of the test: in table 1:
In the different preparation of table 1,5 hydroxymethyl furfural testing result compares
Test brief summary: above-mentioned result of the test shows, with tartaric acid, phosphoric acid for pH adjusting agent, the conivaptan preparation be prepared into, 5 hydroxymethyl furfural is undesirable, therefore should give up.
Two, pH adjusting agent screening test II
Test method:
Hot test: get and test 1 group, test 2 groups, test 4 groups, test 6 groups of samples, under 60 DEG C of conditions, places 10 days, maximum single impurity, total impurities content is detected in the 10th day, detect 5 hydroxymethyl furfural content, detect hydrochloric acid conivaptan content, the results are shown in Table 2.
Highlight test: get and test 1 group, test 2 groups, test 4 groups, test 6 groups of samples, under illumination 4500Lx ± 500Lx condition, place 10 days, maximum single impurity, total impurities content is detected in the 10th day, detect 5 hydroxymethyl furfural content, detect hydrochloric acid conivaptan content, the results are shown in Table 3.
Determination method
[related substance]
It is appropriate that precision measures this product, as need testing solution; Precision measures need testing solution 1ml and puts in the volumetric flask of 100ml, by 20% dilution in acetonitrile to scale, and solution in contrast.Measure according to the method under assay item, only measuring wavelength is 220nm.Measure contrast solution 50 μ l injection liquid chromatography, conditioning instrumentation sensitivity, makes main constituent chromatograph peak height be about 20% of full scale.Precision measures contrast solution and each 50 μ l of test solution again, respectively injection liquid chromatography, and record chromatogram is to 3 ~ 3.5 times of main peak retention time.As aobvious impurity peaks in need testing solution, except 5 hydroxymethyl furfural, single impurity peak area must not be greater than 0.5 (0.5%) of contrast solution main peak area, and each impurity peak area sum must not be greater than the main peak area (1.0%) of contrast solution.
[assay] hydrochloric acid conivaptan measures according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability octadecyl silane are filler, and with acetonitrile/phosphate buffer=45/55 (V/V) for mobile phase, determined wavelength is 273nm, sample introduction 20 μ l, flow velocity 1.0ml/min, column temperature 30 DEG C.[phosphate buffer: get sodium dihydrogen phosphate dihydrate 7.8g and 1.2g sodium lauryl sulphate is dissolved in water, adds 4ml triethylamine and is settled to 1000ml, adjusts pH to 2.8 with phosphoric acid].
Algoscopy precision measures this product in right amount, and quantitatively dilute the solution made about containing 10 μ g in every 1ml with 20% acetonitrile, precision measures 20 μ l, injection liquid chromatography, record chromatogram; Separately get the hydrochloric acid conivaptan reference substance being dried to constant weight appropriate, accurately weighed, be mixed with the solution about containing 10 μ g in every 1ml with method, be measured in the same method.By external standard method with calculated by peak area, to obtain final product.
Different preparation testing result under table 2 hot conditions
Different preparation testing result under table 3 super-humid conditions
Test brief summary: after 10 days high temperature, highlight test, test 1 group of single maximum contaminant in high temperature, total impurities content and do not meet quality criteria requirements, total impurities content does not meet quality criteria requirements in high light, therefore, should give up; And test 2 groups, test 4 groups after high temperature, highlight test, its 5 hydroxymethyl furfural content is all greater than 0.02%, does not also meet quality criteria requirements, therefore should give up; And take lactic acid as the test 6 groups of pH adjusting agent, indices all meets quality criteria requirements, and applicant selects lactic acid to be adjuvant in pharmaceutical composition.
Three, the screening test of lactic acid
Applicant is in research process, be that adjuvant is tested with lactic acid, the hydrochloric acid conivaptan preparation prepared particulate matter in cold cycle test is too much, in order to the product that preparation quality is more outstanding, applicant carries out deep research and obtains: when in Pfansteihl, DL-LACTIC ACID content is less than certain content, hydrochloric acid conivaptan infusion solution quality more outstanding (particulate matter is few), its result of the test is as follows:
Test 1 group: hydrochloric acid conivaptan 2g, glucose 500g, lactic acid 0.4g.
Test 2 groups: hydrochloric acid conivaptan 2g, glucose 500g, Pfansteihl 0.4g (in Pfansteihl DL-LACTIC ACID content 0.30%).
Test 3 groups: hydrochloric acid conivaptan 2g, glucose 500g, Pfansteihl 0.4g (in Pfansteihl DL-LACTIC ACID content 0.25%).
Test 4 groups: hydrochloric acid conivaptan 2g, glucose 500g, Pfansteihl 0.4g (in Pfansteihl DL-LACTIC ACID content 0.20%).
Test 5 groups: hydrochloric acid conivaptan 2g, glucose 500g, Pfansteihl 0.4g (in Pfansteihl DL-LACTIC ACID content 0.15%).
Formulation preparation method: get pH adjusting agent, add water to 8mL dissolving and obtain acid solution (concentration is 5%) completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 5000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 10000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 100 bottles.
Cold cycle is tested: get above-mentioned different tests group preparation, places 2 days for 1 ~ 10 DEG C, then within two days, is 1 circulation in 40 DEG C of placements, circulates three times, detects.Result of the test is in table 4.
Table 4 cold cycle testing inspection results contrast
Test brief summary: above-mentioned test shows, with lactic acid, or with the trial drug group that Pfansteihl (DL-LACTIC ACID content is greater than 0.2%) is pH adjusting agent, its 5 hydroxymethyl furfural content, maximum single impurity, total impurities, hydrochloric acid conivaptan content, particulate matter all meets the requirements of the standard, but particulate matter is close to limit value, and the group of Pfansteihl (DL-LACTIC ACID content is less than or equal to 0.20%), be more than or equal to 10 μm of microgranules every milliliter and be less than 1, being more than or equal to 25 μm of microgranules every milliliter is 0, obtain the product quality that quality is more outstanding, applicant selects Pfansteihl (DL-LACTIC ACID content is less than or equal to 0.20%) to be pH adjusting agent further.
Four, variable concentrations lactic acid (Pfansteihl) Selection experiment
Test 1 group: hydrochloric acid conivaptan 2g, glucose 500g, lactic acid 0.24g.
Test 2 groups: hydrochloric acid conivaptan 2g, glucose 500g, lactic acid 0.32g.
Test 3 groups: hydrochloric acid conivaptan 2g, glucose 500g, lactic acid 0.48g.
Test 4 groups: hydrochloric acid conivaptan 2g, glucose 500g, lactic acid 0.56g.
Test 5 groups: hydrochloric acid conivaptan 2g, glucose 500g, Pfansteihl 0.24g (DL-LACTIC ACID content 0.10%).
Test 6 groups: hydrochloric acid conivaptan 2g, glucose 500g, Pfansteihl 0.32g (DL-LACTIC ACID content 0.10%).
Test 7 groups: hydrochloric acid conivaptan 2g, glucose 500g, Pfansteihl 0.48g (DL-LACTIC ACID content 0.10%).
Test 8 groups: hydrochloric acid conivaptan 2g, glucose 500g, Pfansteihl 0.56g (DL-LACTIC ACID content 0.10%).
Formulation preparation method: get pH adjusting agent, add water to 8mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 5000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 10000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 100 bottles.
Cold cycle is tested: get above-mentioned different tests group preparation, places 2 days for 1 ~ 10 DEG C, then within two days, is 1 circulation in 40 DEG C of placements, circulates three times, detects.Result of the test is in table 5.
Table 5 cold cycle testing inspection results contrast
Conclusion (of pressure testing), when lactic acid or Pfansteihl concentration are less than 4% (test 1 group, test 5 groups), the microgranule being more than or equal to 10 μm does not meet prescription (2010 editions pharmacopeia, two attached IXC second method microscopic countings); When lactic acid or Pfansteihl concentration are greater than 6% (test 4 groups, test 8 groups), the microgranule being more than or equal to 25 μm does not meet prescription (2010 editions pharmacopeia, two attached IXC); Therefore, applicant's binding tests one to test three, selection concentration is 4%-6% (g/mL).
Preparation embodiment
Embodiment 1
Hydrochloric acid conivaptan 20g, glucose 5000g, lactic acid 3.3g.
Formulation preparation method: extracting lactic acid, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 2
Hydrochloric acid conivaptan 20g, glucose 5000g, lactic acid 4.1g.
Formulation preparation method: extracting lactic acid, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 3
Hydrochloric acid conivaptan 20g, glucose 5000g, lactic acid 4.5g.
Formulation preparation method: extracting lactic acid, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 4
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 3.3g (DL-LACTIC ACID content is 0.15%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 5
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 4.1g (DL-LACTIC ACID content is 0.15%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 6
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 4.5g (DL-LACTIC ACID content is 0.15%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 7
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 3.2g (DL-LACTIC ACID content is 0.08%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 8
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 4.0g (DL-LACTIC ACID content is 0.08%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 9
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 4.8g (DL-LACTIC ACID content is 0.08%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 10
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 4.4g (DL-LACTIC ACID content is 0.08%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 11
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 4.0g (DL-LACTIC ACID content is 0.05%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Embodiment 12
Hydrochloric acid conivaptan 20g, glucose 5000g, Pfansteihl 4.0g (DL-LACTIC ACID content is 0.20%).
Formulation preparation method: get Pfansteihl, add water to 80mL dissolving and obtain acid solution completely, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, adds glucose, mends and injects water to 50000mL, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit injects water to 100000mL, circulation 25min, and through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, and after lamp inspection is qualified, labeling, packaging, warehouse-in, obtains hydrochloric acid conivaptan and infuse 1000 bottles.
Claims (8)
1. the pharmaceutical composition containing active ingredient hydrochloric acid conivaptan, is characterized in that pharmaceutical composition comprises hydrochloric acid conivaptan, glucose and pH adjusting agent.
2. a kind of pharmaceutical composition containing active ingredient hydrochloric acid conivaptan according to claim 1, wherein pH adjusting agent is lactic acid or Pfansteihl.
3. a kind of pharmaceutical composition containing active ingredient hydrochloric acid conivaptan according to claim 1, wherein in Pfansteihl, the content of DL-LACTIC ACID is less than or equal to 0.20%.
4. will remove a kind of pharmaceutical composition containing active ingredient hydrochloric acid conivaptan described in 1 according to right, wherein pH adjusting agent is the lactic acid aqueous solution of concentration 4%-6%, or pH adjusting agent is the Pfansteihl aqueous solution of concentration 4%-6%.
5. a kind of pharmaceutical composition containing active ingredient hydrochloric acid conivaptan according to claim 4, wherein pharmaceutical composition comprises hydrochloric acid conivaptan 20 weight portion, glucose 5000 weight portion, g/ml concentration is 4%-6% lactic acid solution (lactic acid is 3.2 weight portion-4.8 weight portions); Or hydrochloric acid conivaptan 20 weight portion, glucose 5000 weight portion, g/ml concentration is 4%-6%L-lactic acid solution (Pfansteihl is 3.2-4.8 weight portion).
6. a kind of pharmaceutical composition containing active ingredient hydrochloric acid conivaptan according to claim 5, is characterized in that pharmaceutical composition is prepared into infusion solution.
7. a kind of pharmaceutical composition containing active ingredient hydrochloric acid conivaptan according to claim 6, wherein the preparation method of infusion solution is:
Get lactic acid aqueous solution that concentration is 4%-6% or concentration is 4%-6%L-lactic acid aqueous solution, getting hydrochloric acid conivaptan is added in solution, stirring makes hydrochloric acid conivaptan mix at lactic acid solution, adding temperature is 70 ~ 90 DEG C of waters for injection, add glucose, mend and inject water to 50% of prescription volume, add 0.01% active carbon by 50% of cumulative volume, stir 15min; Medicinal liquid is taken off charcoal through titanium rod and 0.65 μm of cartridge type pleated filter; Filtrate benefit adds to the full amount of water for injection, circulation 20 ~ 30min, and check that the pH value of medicinal liquid is 3.5-3.6, through 0.45 μm and 0.22 μm of cartridge type pleated filter fine straining, fill, puts 121 DEG C, sterilizing 15min, after lamp inspection is qualified, and labeling, packaging, warehouse-in.
8. the application of a kind of pharmaceutical composition containing active ingredient hydrochloric acid conivaptan according to any one of claim 1-3 in preparation treatment hyponatremia medicine.
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| CN106442751A (en) * | 2016-08-24 | 2017-02-22 | 蚌埠丰原涂山制药有限公司 | Method for determining content of conivaptan hydrochloride by virtue of high performance liquid chromatography |
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