CN1218699C - Method for increasing solubility of parabuxinidine-D injection - Google Patents
Method for increasing solubility of parabuxinidine-D injection Download PDFInfo
- Publication number
- CN1218699C CN1218699C CN 03131627 CN03131627A CN1218699C CN 1218699 C CN1218699 C CN 1218699C CN 03131627 CN03131627 CN 03131627 CN 03131627 A CN03131627 A CN 03131627A CN 1218699 C CN1218699 C CN 1218699C
- Authority
- CN
- China
- Prior art keywords
- injection
- cyclovirobuxinum
- parabuxinidine
- present
- injections
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 16
- 239000007924 injection Substances 0.000 title abstract description 17
- 238000002347 injection Methods 0.000 title abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- GMNAPBAUIVITMI-ABNIRSKTSA-N cyclovirobuxine d Chemical compound CC(C)([C@@H](NC)CC1)[C@H]2[C@@]31C[C@@]13CC[C@]3(C)[C@@H]([C@H](C)NC)[C@H](O)C[C@@]3(C)[C@@H]1CC2 GMNAPBAUIVITMI-ABNIRSKTSA-N 0.000 claims description 28
- 239000008851 cyclovirobuxinum D Substances 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 230000007928 solubilization Effects 0.000 claims description 5
- 238000005063 solubilization Methods 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 16
- 229940090044 injection Drugs 0.000 abstract description 14
- 239000000203 mixture Substances 0.000 abstract description 7
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- 229940093181 glucose injection Drugs 0.000 abstract description 3
- 239000000843 powder Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- 239000008354 sodium chloride injection Substances 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract 1
- 239000000546 pharmaceutical excipient Substances 0.000 abstract 1
- 239000008215 water for injection Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000005352 clarification Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000007731 hot pressing Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a method for increasing the solubility of a parabuxinidine-D injection. The adopted method of the present invention comprises the following steps: parabuxinidine-D is directly mixed with acidic materials, an excipient is added to prepare a powder injection, pH value is maintained from 1 to 6.5, and then, the mixture is stirred and mixed to respectively prepare injections, freeze dried injections, sodium chloride injections and glucose injection preparations. The dissolvability of parabuxinidine-D in acid water solution can reach 100%. The present invention has the advantages of simple technique, short process, low cost, high finished product yield, good therapeutic effect, and convenient and accurate injection use.
Description
Technical field
The present invention relates to a kind of cyclovirobuxinum D ejection preparation and in producing process, increase water miscible processing method.
Background technology
Before the present invention made, cyclovirobuxinum D was a kind of cardiovascular disease to be had the alkaloids medicament of good therapeutic effect and effect, has obtained using widely.Yet the dissolubility of cyclovirobuxinum D in water is little, just because of this, the cyclovirobuxinum D medicine is all made medicinal preparation for oral administration, enters blood through absorption of human body, causes its bioavailability to be lower than injection medicament.For head it off, available technology adopting is made the inorganic salt of cyclovirobuxinum D earlier, i.e. salt-forming reaction, and with after the solution concentration or add organic solvent and make it separate out crystallization, purification refine, assay is used further to the preparation of ejection preparation.Like this, whole process complexity, tediously long, step is many, and the finished product yield is low, causes cost too high.
Summary of the invention
Purpose of the present invention just is to overcome above-mentioned defective, directly utilizes acidic materials that cyclovirobuxinum D is carried out solubilising, and makes injection medicament.
Technical scheme of the present invention is: the solubilization method of cyclovirobuxinum D ejection preparation, its major technique are characterised in that the direct and aqueous solution of citric acid mixed dissolution with cyclovirobuxinum D, add active carbon, stir, filter, degerming.
Its further technical scheme is: its technical characterictic is that pH value is between 2.5～4.5.
Its further technical scheme be: its technical characterictic is the addition of sodium chloride, the addition of glucose, makes its milliosmolarity concentration between 280～320mOsm/L.
Advantage of the present invention and effect are that process is simple, process short, and cost is low, and the cyclovirobuxinum D water solublity strengthens, finished product yield height, and good effect, ejection preparation is easy to use, accurate.
The specific embodiment
Embodiment 1: the preparation of cyclovirobuxinum D injection
Get cyclovirobuxinum D 0.5g, add in advance in the 0.265g citric acid soln with the water for injection preparation, stir and make it dissolving, add water for injection again, measure pH value, adjust pH value 2.5～4.5 with the 0.1M citric acid soln to 800ml; Add about 0.2% needle-use activated carbon, stir; Insulation was placed 30 minutes, and clarification filtration adds the injection water to 1000ml with filtrate; Aseptic filtration is sub-packed in the ampoule of 1ml specification, and sterilization promptly got the cyclovirobuxinum D injection formulation in 30 minutes under 100 ℃ of temperature.Cyclovirobuxinum D dissolubility in acidic aqueous solution can reach 100%.
Embodiment 2: the preparation of cyclovirobuxinum D injectable powder
Get cyclovirobuxinum D 0.5g, add citric acid 0.265g, behind the mix homogeneously, increase progressively mixing method by equivalent and add mannitol 2000g gradually, mix homogeneously, aseptic subpackaged in cillin bottle, seal, make injectable powder.
Embodiment 3: the preparation of cyclovirobuxinum D lyophilized injection
Get cyclovirobuxinum D 0.5g, join the 0.265g citric acid soln of preparing with water for injection in advance, make its dissolving; Add water for injection again to about 800ml, survey pH value, and adjust between the pH value 2.5～6.5 with the 0.1M citric acid soln; Add the mannitol of 20g and 0.2% needle-use activated carbon, stir and make its dissolving, mixing, be incubated 30 minutes, temperature is ℃ clarification filtration; Add water for injection again to 1000ml, aseptic filtration is sub-packed in the 10ml cillin bottle; Send in the drying baker of the freezing in advance freezer dryer to-45 ℃ pre-freeze 2 hours; Evacuation and reach 0.013KPa subsequently; To the shelf heating, make it heat up per hour 2～4 ℃; To rise in 0 ℃, goods moisture entrapment about 5% the time when shelf temperature, can be rapidly heated, and per hour rises 4～10 ℃; Consistent with shelf temperature and in the time of 35～40 ℃ when products temperature, be incubated 4～6 hours, finish heating, outlet makes lyophilizing pin preparation.
Embodiment 4: the preparation of cyclovirobuxinum D sodium chloride injection
Get cyclovirobuxinum D 0.5g, join in advance 0.265g citric acid soln, stir or under heating (25～100 ℃) condition, stir and make its dissolving with the water for injection preparation; Add water for injection again to about 80000ml, survey pH value, and adjust between the pH value 2.5～5.5 with the 0.1M citric acid soln; Add sodium chloride for injection 900g, stir and make its dissolving, the milliosmolarity concentration that makes solution is between 280～320mOsm/L; The needle-use activated carbon of adding 0.2% stirs and makes mix homogeneously; Under 80 ℃ of temperature, be incubated 30 minutes, clarification filtration; Filtrate adds the injection water to 100000ml, and aseptic filtration is sub-packed in the vial of 100ml, jumps a queue, and rolls the aluminum lid; Hot pressing (121 ℃) sterilization 30 minutes promptly gets cyclovirobuxinum D chloride injection liquid formulation.
Embodiment 5: the preparation of cyclovirobuxinum D glucose injection
Get cyclovirobuxinum D 0.5g, join the 0.265g citric acid soln of preparing with water for injection in advance, stir and make its dissolving; Add water for injection again to about 80000ml, survey pH value, and adjust pH value, make them between 2.5～5.5 with the 0.1M citric acid soln; Add glucose for injection 5000g, stir and make its dissolving; The needle-use activated carbon of adding 0.2% stirs and makes mix homogeneously; Under 80 ℃ of temperature, be incubated 30 minutes, clarification filtration; Filtrate adds the injection water, is supplemented to 100000ml; Aseptic filtration is sub-packed in the vial of 100ml, jumps a queue, and rolls the aluminum lid; Hot pressing (121 ℃) sterilization 30 minutes promptly gets the cyclovirobuxinum D glucose injection formulation.
Claims (3)
1. the solubilization method of cyclovirobuxinum D ejection preparation is characterized in that the direct and aqueous solution of citric acid mixed dissolution with cyclovirobuxinum D, adds active carbon, stirs, filters, degerming.
2. the solubilization method of cyclovirobuxinum D ejection preparation according to claim 1 is characterized in that pH value is between 2.5～4.5
3. the solubilization method of cyclovirobuxinum D ejection preparation according to claim 1 is characterized in that the addition of sodium chloride in the step (4), the addition of the middle glucose of step (5), makes its milliosmolarity concentration between 280～320mOsm/L.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03131627 CN1218699C (en) | 2003-06-03 | 2003-06-03 | Method for increasing solubility of parabuxinidine-D injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03131627 CN1218699C (en) | 2003-06-03 | 2003-06-03 | Method for increasing solubility of parabuxinidine-D injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1456165A CN1456165A (en) | 2003-11-19 |
| CN1218699C true CN1218699C (en) | 2005-09-14 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03131627 Expired - Fee Related CN1218699C (en) | 2003-06-03 | 2003-06-03 | Method for increasing solubility of parabuxinidine-D injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1218699C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004112773A1 (en) * | 2003-04-24 | 2004-12-29 | Shin-Jen Shiao | Pharmaceutical compositions used for immune disease treatment and improvement |
-
2003
- 2003-06-03 CN CN 03131627 patent/CN1218699C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1456165A (en) | 2003-11-19 |
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