CN1813825A - Ginkgolide emulsion for injection - Google Patents
Ginkgolide emulsion for injection Download PDFInfo
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- CN1813825A CN1813825A CN 200510022338 CN200510022338A CN1813825A CN 1813825 A CN1813825 A CN 1813825A CN 200510022338 CN200510022338 CN 200510022338 CN 200510022338 A CN200510022338 A CN 200510022338A CN 1813825 A CN1813825 A CN 1813825A
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- injection
- bilobalide
- oil
- injectable emulsion
- emulsifying agent
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Abstract
The present invention discloses a bilobalide (mixture or ginkgo extract) emulsion for injection, in particular, it relates to a bilobalide (including single bilobalide A, B and C, etc.) injection emulsion for curing angiocardiopathy and cerebrovascular disease. It is made up by using bilobalide and medicinal auxiliary material according to a certain ratio through the processes of dissolving, heating, uniformly mixing, emulsifying, cooling and filling to obtain the invented product.
Description
Technical field
The present invention relates to a kind of bilobalide (mixture or Semen Ginkgo extrac) Emulsion of injection, especially relate to a kind of bilobalide (comprising single ginkalide A, B, C etc.) injectable emulsion that is used for cardiovascular and cerebrovascular disease.
Background technology
Semen Ginkgo extrac, it has been carried out extensive studies both at home and abroad, pharmacological research deeply, mechanism is clear and definite, main active is a bilobalide, comprise ginkalide A, ginkalide B, ginkalide C etc. and bilobalide, PAF is a kind of endogenous phospholipid that platelet and multiple inflammation tissue secretion produce, the generation of it and numerous disease, development are closely related, and bilobalide is the PAF antagonist of clinical practice most worthy so far, develops this product and can go to the world for the medicine of China people's health and China and make bigger contribution.Wherein capsule, tablet and injection are widely used in treatment brain and peripheral blood flow circulatory disturbance, acute and chronic brain insufficiency and sequela thereof clinically, and ear's blood flow and neurological disorder etc. have demonstrated due clinical effectiveness.
The gingko leaf extract injection of listing mainly contains the Ginaton injection that the big pharmaceutical factory of home-made SHUXUENING ZHUSHEYE and German Weil-McLain Shu Pei produces both at home and abroad.Home-made SHUXUENING ZHUSHEYE only requires to detect the content of ginkalide A; Ginaton injection does not pass a test because of preparation process, and the bilobalide major part is destroyed, does not detect bilobalide in the finished product standard, and ginkalide B, content of bilobalide are very low in investigating above two products.
Documents and materials by retrieval, because bilobalide is poorly soluble, water insoluble in the Folium Ginkgo extract, so the oral formulations bioavailability is low, the product curative effect is relatively poor relatively, makes injection and improves curative effect with expectation.But it is bigger to make the injection difficulty, some also is unfavorable for the reservation of effective ingredient, add the alkali salify as utilization and (mostly be meglumine or sodium hydroxide etc., number of patent application 00115134.7,02134223.7 etc.), adding the alkali salify is under alkali condition, make the open loop of bilobalide part, the lactone dissolubility increases after the open loop, make injection, yet the closed-loop structure form of bilobalide is only main activity form, structural deterioration after the open loop, reduced activity, as patent: as described in the US Patent, No:5798342.And the injection of ginkgolide B of French Beaufour-Ipsen company exploitation, code name: BN52021, it is exactly the freeze-dried powder of part open loop form, clinical efficacy is with regard to fall flat [Brochet B, etal:J Neurology, Neurosurgery and Psychiatry.1995,58:360-362].Utilize [number of patent applications: 97107809.2 such as organic solvent Polyethylene Glycol, ethanol in addition; 03137720.3].But the organic solvent zest is big, and safety is that problem to be solved is arranged.
How to develop a kind of integrity that can keep the bilobalide structure, do not add organic solvent again, the injection of making is stable again, has become the task of top priority.
Summary of the invention
Drug effect reduced, uses organic solvent toxic reaction problem after the present invention was intended to overcome the bilobalide open loop of above-mentioned injection, the neither open loop of a kind of bilobalide is provided, toxic reaction and zest are little, and effective drug duration is long, and have the ginkgolide emulsion of persistence and targeting.Especially relate to a kind of bilobalide (comprising single ginkalide A, B, C etc.) injectable emulsion that is used for cardiovascular and cerebrovascular disease and preparation method thereof.This injectable emulsion can also reach the effect of supplying with patient's energy, thereby improve patient's life quality effectively when being used for the treatment of.
The present invention also provides the preparation method of this injectable emulsion simultaneously.
A kind of bilobalide injectable emulsion, it comprises active component bilobalide (mixture or Semen Ginkgo extrac) and medicinal organic adjuvant, it is characterized in that: it is to be mixed with 1000 milliliters of injection by following weight proportion:
Bilobalide (mixture or Semen Ginkgo extrac) 1.0～50.0g
Injection vegetable oil 50～300g
Emulsifying agent 5～20g
Isoosmotic adjusting agent 20～60g
Water for injection adds to 1000ml
The optimization formula of above-mentioned injectable emulsion is: be mixed with 1000 milliliters of injection by following weight proportion:
Bilobalide (mixture or Semen Ginkgo extrac) 10.0～25.0g
Injection vegetable oil 100～200g
Emulsifying agent 10～15g
Isoosmotic adjusting agent 22.5～55g
Water for injection adds to 1000ml
A kind of bilobalide injectable emulsion, it comprises active component bilobalide (as single ginkalide A, B etc.) and pharmaceutic adjuvant, and it is characterized in that: it is to be mixed with 1000 milliliters of injection by following weight proportion:
Ginkalide B 0.01～30.0g
Injection vegetable oil 50～250g
Emulsifying agent 5～20g
Isoosmotic adjusting agent 20～60g
Water for injection adds to 1000ml
The optimization formula of above-mentioned injectable emulsion is: be mixed with 1000 milliliters of injection by following weight proportion:
Ginkalide B 0.1～20.0g
Injection vegetable oil 100～150g
Emulsifying agent 10～15g
Isoosmotic adjusting agent 22.5～55g
Water for injection adds to 1000ml
Also can add membrane stabilizer in the described injectable emulsion, as oleic acid or enuatrol.
Also can add antioxidant vitamin E etc. in the described injectable emulsion.
Described injection vegetable oil is selected from a kind of in soybean oil, safflower oil, Semen Maydis oil, olive oil, the Semen Sesami wet goods vegetative grease.
Described emulsifying agent is selected at least a in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, cholesterol, the poloxamer (Poloxamer) etc. for use.
Described isoosmotic adjusting agent is selected a kind of in glycerol, xylitol, sorbitol, the fructose etc. for use.
Route of administration of the present invention mainly adopts the intravenous injection mode.
The invention has the advantages that:
1, injectable emulsion of the present invention, bilobalide do not use to add the alkali salifying method and add organic solvent with the form dissolving of not open loop, have kept its complete structure and biological activity, have novelty.
2, injectable emulsion of the present invention, the stability of bilobalide improves greatly, has also improved safety and effectiveness.
3, injectable emulsion of the present invention be with Emulsion as carrier, its breast grain has special affinity to inflammation tissue, and bilobalide is concentrated in this tissue, suppresses it and secretes PAF, the generation of antagonism disease and development help rehabilitation of patients.
4, injectable emulsion of the present invention be with lipomul as carrier, and just like wherein one or more such as soybean lecithin, Ovum Gallus domesticus Flavus lecithin, cholesterol as emulsifying agent, dosage form has novelty.
5, owing to soybean oil, Flos Carthami wet goods composition as oil phase, and all nontoxic as the compositions such as phospholipid of emulsifying agent to human body, and its clinical application is for many years, and is safe and reliable, and can be the metabolism of human body institute.
6, after bilobalide is made into Emulsion, the directionality of lymph and the harmonicity of cancerous cell have been increased, so increase in the abundance of reticuloendothelial system, inflammation part, tumor body and brain, and prolong action time in vivo, thereby improved curative effect, reduced dosage, alleviated toxic and side effects.
7, owing to compositions such as injection soybean oil and/or soybean lecithin have used as fat milk transfusion, therefore injectable emulsion of the present invention is when giving to treat, can also play the dual function of supplying with patient's energy, positive role has been played in the raising of medical effect and medical level.
The present invention also provides the preparation method of this injectable emulsion simultaneously, but is not limitation of the present invention.
The specific embodiment
Embodiment 1
Bilobalide (mixture) 2.0g, glycerol 22.5g are dissolved in the water for injection, refining soybean lecithin 12.0g is dissolved in the refined soybean oil, is heated to 50 ℃ respectively, mixing, earlier in tissue mashing machine's mid score emulsifying, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml, cooling, fill promptly gets the bilobalide injectable emulsion.This technology is the prescription of 1000ml, and production can enlarge, and needs nitrogen protection in the production process.
Embodiment 2
Bilobalide 5.0g, sorbitol 25.0g are dissolved in the water for injection, and refined lecithin 10g is dissolved in the refined maize oil, is heated to 45 ℃ respectively, mixing, earlier in tissue mashing machine's mid score emulsifying, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml.
Embodiment 3
Semen Ginkgo extrac 10.0g, xylitol 55.5g are dissolved in the water for injection, and refined lecithin 15.0g is dissolved in the refining Oleum sesami, is heated to 60 ℃ respectively, mixing, earlier in tissue mashing machine's mid score emulsifying, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml.
Embodiment 4
With bilobalide 20.0g, refine yolk lecithin 10.0g is dissolved in the refining safflower oil of 100g, and glycerol 22.5g is dissolved in the water for injection, is heated to 65 ℃ respectively, mixing, dispersion and emulsion in tissue mashing machine earlier, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml.
Embodiment 5
With ginkalide B 0.4g, refining soybean lecithin 15.0g is dissolved in the 100.0g refined soybean oil, and glucose 50.0g is dissolved in the water for injection, be heated to 55 ℃ respectively, mixing, first dispersion and emulsion in tissue mashing machine, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml.
Embodiment 6
With Ovum Gallus domesticus Flavus lecithin 12.0g, be dissolved in the solution that contains glycerol 25.0g, be heated to 55 ℃, earlier with tissue mashing machine after 8000～12000 rev/mins of stirrings disperse for three times, oil solution with ginkalide B and refined soybean oil 100.0g adds again, under same speed conditions, stir and carry out emulsifying for three times and disperse, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml.
Embodiment 7
With soybean lecithin 15.0g, be dissolved in the solution that contains glycerol 22.5g, be heated to 45 ℃, earlier with tissue mashing machine after 8000～12000 rev/mins of stirrings disperse for three times, oil solution with ginkalide B and refining olive oil 100.0g adds again, under same speed conditions, stir and carry out emulsifying for three times and disperse, again through the emulsifying of high speed dispersing emulsification machine to meeting the preparation particle diameter.Add the injection water to 1000ml.
Stability test
20050501) and commercially available product (SHUXUENING ZHUSHEYE, lot number: 050401-4 with the Emulsion that makes (lot number:; Ginaton injection, lot number: 1908064) carried out comparative study, investigated and the results are shown in following table.(40 ℃) 6 months stability tests
| Lot number | Time (moon) | Outward appearance | Bilobalide labelled amount (%) | Lactone A labelled amount (%) | Lactone B labelled amount (%) |
| 20050501 | 0 | Milky | 100.0 | 100.0 | 100.0 |
| 1 | Milky | 98.6 | 98.9 | 99.3 | |
| 2 | Milky | 98.0 | 98.2 | 98.5 | |
| 3 | Milky | 97.5 | 97.7 | 97.4 | |
| 6 | Milky | 97.1 | 96.8 | 97.0 | |
| 050401-4 | 0 | Yellow liquid | 79.2 | 98.3 | 72.7 |
| 1 | Yellow liquid | 64.3 | 94.5 | 69.8 | |
| 2 | Yellow liquid | 50.2 | 89.0 | 48.2 | |
| 3 | Yellow liquid | 43.7 | 68.7 | 41.5 | |
| 6 | Yellow liquid | 23.9 | 58.4 | 38.2 | |
| 1908064 | 0 | Yellow liquid | 70.2 | 78.3 | 62.7 |
| 1 | Yellow liquid | 54.3 | 64.5 | 49.8 | |
| 2 | Yellow liquid | 40.2 | 49.0 | 41.2 | |
| 3 | Yellow liquid | 33.7 | 38.7 | 30.5 | |
| 6 | Yellow liquid | 24.0 | 30.4 | 28.7 |
Illustrate: 1, above test is the data based on labelled amount of the present invention 0 month;
2, homemade SHUXUENING ZHUSHEYE of some index and import Ginaton injection do not require detection.
Studies show that by last table:
1, the Emulsion that makes of the present invention makes all complete reservation of composition of bilobalide, and structure is not destroyed.From the gained data analysis, can satisfy the relevant medicine requirement of country through accelerated test measured result of the present invention, and the listing product content of contrast is very low, the accelerated test tamper indicating is serious.
2, the Emulsion that makes of the present invention makes suitable stable of the composition of bilobalide, and this is a surprised part of the present invention, and with respect to the aqueous solution of making, this is a big miracle.
Claims (7)
1, a kind of bilobalide injectable emulsion, it comprises active component bilobalide (mixture or Semen Ginkgo extrac) and medicinal organic adjuvant, it is characterized in that: it is to be mixed with 1000 milliliters of injection by following weight proportion:
Bilobalide (mixture or Semen Ginkgo extrac) 1.0～50.0g
Injection vegetable oil 50～300g
Emulsifying agent 5～20g
Isoosmotic adjusting agent 20～60g
Water for injection adds to 1000ml
The optimization formula of above-mentioned injectable emulsion is: be mixed with 1000 milliliters of injection by following weight proportion:
Bilobalide (mixture or Semen Ginkgo extrac) 10.0～25.0g
Injection vegetable oil 100～200g
Emulsifying agent 10～15g
Isoosmotic adjusting agent 22.5～55g
Water for injection adds to 1000ml
2, a kind of bilobalide injectable emulsion according to claim 1, it comprises active component bilobalide (as single ginkalide A, B etc.) and pharmaceutic adjuvant, and it is characterized in that: it is to be mixed with 1000 milliliters of injection by following weight proportion:
Ginkalide B 0.01～30.0g
Injection vegetable oil 50～250g
Emulsifying agent 5～20g
Isoosmotic adjusting agent 20～60g
Water for injection adds to 1000ml
The optimization formula of above-mentioned injectable emulsion is: be mixed with 1000 milliliters of injection by following weight proportion:
Ginkalide B 0.1～20.0g
Injection vegetable oil 100～150g
Emulsifying agent 10～15g
Isoosmotic adjusting agent 22.5～55g
Water for injection adds to 1000ml
3, also can add membrane stabilizer in the injectable emulsion according to claim 1, as oleic acid or enuatrol.
4, also can add antioxidant vitamin E etc. in the injectable emulsion according to claim 1.
5, be selected from a kind of in soybean oil, safflower oil, Semen Maydis oil, olive oil, the Semen Sesami wet goods vegetative grease according to the described described injection vegetable oil of claim 1.
6, emulsifying agent according to claim 1 is selected at least a in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, cholesterol, the poloxamer (Poloxamer) etc. for use.
7, emulsifying agent isoosmotic adjusting agent according to claim 1 is selected a kind of in glycerol, xylitol, sorbitol, the fructose etc. for use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510022338 CN1813825A (en) | 2005-12-21 | 2005-12-21 | Ginkgolide emulsion for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510022338 CN1813825A (en) | 2005-12-21 | 2005-12-21 | Ginkgolide emulsion for injection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1813825A true CN1813825A (en) | 2006-08-09 |
Family
ID=36906257
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510022338 Pending CN1813825A (en) | 2005-12-21 | 2005-12-21 | Ginkgolide emulsion for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1813825A (en) |
-
2005
- 2005-12-21 CN CN 200510022338 patent/CN1813825A/en active Pending
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