CN104306342B - A kind of baicalein freeze-dried powder injection - Google Patents
A kind of baicalein freeze-dried powder injection Download PDFInfo
- Publication number
- CN104306342B CN104306342B CN201410527879.5A CN201410527879A CN104306342B CN 104306342 B CN104306342 B CN 104306342B CN 201410527879 A CN201410527879 A CN 201410527879A CN 104306342 B CN104306342 B CN 104306342B
- Authority
- CN
- China
- Prior art keywords
- lecithin
- preparation
- baicalein
- freeze
- accordance
- 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
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of baicalein freeze-dried powder injection, the method that it is prepared is as follows：By the dissolving of baicalein bulk pharmaceutical chemicals, lecithin and nonionic surfactant in organic solvent, it is then mixed with water rear ultrasonic, lyophilized formulations are made after freeze-dried, mixed micelle system can be formed using preceding redissolved with water for injection, particle diameter is（110±8）nm.This method can overcome baicalein poorly water-soluble, it is difficult to the problem of drug administration by injection, while improve the stability of medicine.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, more particularly to a kind of baicalein freeze-dried powder injection, belongs to medical skill
Art field.
Background technology
Baicalein（Baicalein）The entitled Noroxylin,5,6,7-Trihydroxy flavone of chemistry, is labiate radix scutellariae
（Scutellaria baicalensis Georgi）One of principle active component in dry root, its chemical structural formula is as schemed.
Research in recent years shows, baicalein has an extensive pharmacological action, including antibacterial, antiviral, hepatic cholagogic diuresis, clear
Except free radical and anti-oxidant, anticoagulation and antithrombus formation, suppress enzymatic activity and effect to biomembrane, anticancer, to smooth
The pharmacological actions such as the dual regulation effect of flesh, the expression for suppressing adhesion molecule.Clinically it is mainly used for antiviral, antibacterial anti-inflammatory
With it is anti-infective（Gao Yan, Gu Zhenlun, Jiang little Gang, treasure's traditional Chinese medical science traditional Chinese medicines during Guo time instrument the new development of baicalein pharmaceutical research [J],
2010,07:1765-1767.）.
Baicalein is insoluble in water, and solution degree is only 17.5 μ g/mL in water（Dong Wu armies baicalein phospholipid complexes and its
Research [D] the China Concord Medical Science University of sub-micellar emulsion, 2007.）, to prepare its injection, it is necessary to be carried with suitable method
High-dissolvability.The method of common increase drug solubility has control pH value of solution, latent molten plus surfactant to form micella etc..With
Solution ph rises, and baicalein solubility has increase trend, but works as pH value of solution>When 8.0, pharmaceutical chemistry purity is then with standing time
Extension and substantially reduce, reason is probably that its flavones parent nucleus aoxidizes generation chalcone in alkaline conditions.
Individually use polyethylene glycol 400, the castor oil of polyoxyethylene ether -35, Solutol Hs15 or spit
Warm 80 grades are solubilizer, and drug solubility is significantly improved, but organic solvent content is excessive, there is stronger renal toxicity.It is and independent
Add lecithin, the effect unobvious of medicament solubilization.Using adjusting pH value or add the solubilization method of single surfactant, into
And the method for preparing freeze-dried powder cannot meet radix scutellariae essence injecta prepare require, and there are obvious safety risks because
Element, it is therefore necessary to take other means to improve its dissolubility.
Inventor passes through many experiments, it is determined that lecithin and nonionic surfactant compound under certain condition, shape
Into mixed micelle solution be greatly improved the solubilising and stabilization of medicine.By being used in mixed way for two kinds of surfactants,
Amount when reducing using single auxiliary material, improves surfactant properties.
Freeze drying powder injection is to utilize a kind of sterile preparation of non-final sterilizing made of vacuum drying technique.In aqueous solution not
Stable medicine, is both needed to that powder pin is made.Baicalein is poor to light and pH stability, oxidizable in aqueous solution, and consideration is made into jelly
Dry powder injection, can improve the stability of medicine, beneficial to long-term storage, while solve the problems, such as that oral administration biaavailability is low.
The content of the invention
The technical problems to be solved by the invention are to overcome baicalein not soluble in water, and light and pH stability differences are lacked
Fall into, there is provided a kind of novel form of baicalein, i.e. freeze-dried powder injection, it is characterised in that lecithin and non-ionic surface active
Agent compounds the mixed micelle system of formation under certain condition, it is possible to increase the degree of scatter of medicine, improves the stability of medicine.
Technical problem of the present invention is realized by following technical scheme.
（1）The preparation of organic phase：It is added to by a certain percentage with nonionic surfactant first by lecithin organic molten
In agent, add appropriate baicalein and make its dissolving.
（2）The preparation of water phase：Lecithin is distributed in a certain amount of distilled water, is made into lecithin aqueous dispersion.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, adds lyophilized protect
Agent is protected, is handled through filtering with microporous membrane, baicalein freeze drying powder injection is obtained after freeze-drying.
Preparation method of the present invention, it is characterised in that the lecithin be selected from lecithin S100, lecithin S75,
Lecithin E80.Nonionic surfactant is selected from the castor oil of polyoxyethylene ether -35, the castor oil of polyoxyethylene ether -40, poly- second two
Alcohol lithium 12-hydroxy stearate, Tween 80.Organic solvent is selected from methanol, ethanol, tetrahydrofuran, propane diols.Freeze drying protectant can
Selected from mannitol, trehalose, lactose, sucrose, glucose.
Preferably, step（1）Nonionic surfactant used is Solutol Hs15, You Jirong
Agent is methanol, ethanol.Step（3）Freeze drying protectant used is mannitol, trehalose.
Wherein, step（1）In, the weight ratio of the lecithin and nonionic surfactant is 1:1~5:1, preferably 1:
1~3:1, the dosage of organic solvent use 5 ~ 20 mL organic solvents for every 500 mg baicaleins, preferably 8 ~ 15 mL, baicalein and
The weight ratio of lecithin is 1:10~1:25, preferably 1:13~1:20.
Step（2）In, the concentration of the lecithin aqueous dispersion is 1% ~ 5%, preferably 1% ~ 3%.
Step（2）Described in lecithin aqueous dispersion and step（1）Described in baicalein weight ratio be 400:1~
600:1, preferably 420:1~520:1.
Step（3）In, the ultrasonic power of cell disruptor is the W of 200 W ~ 400, and ultrasonic time is 1 ~ 5 min.
Step（3）In, the concentration of the freeze drying protectant is 3% ~ 10%, is calculated by lyophilized preceding solution weight.
, can be in order to preferably meet medicinal requirements in supplementary material of the present invention, above-mentioned solvent and auxiliary material should all select
Select and meet injection requirement, and be preferred with suitable freeze.
The present invention has found that the using effect after lecithin is compounded with nonionic surfactant is appointed than wherein by screening
A kind of increase dosage of meaning is far better.Preferable nonionic surfactant Solutol Hs15 is a kind of existing
For the solubilizer of high-effect, extremely low toxicity, pass through the authorization for human injection in America ＆ Canada.What is be prepared into is lyophilized
Pharmaceutical preparation, water for injection can obtain particle diameter after redissolving and is（110±8）The mixed micelle system of nm.
Brief description of the drawings
Fig. 1 is grain size distribution after freeze-dried powder prepared by the present invention redissolves
Fig. 2 is freeze-dried powder transmission electron microscope picture prepared by the present invention
Embodiment
In baicalein freeze-dried powder injection preparation process of the present invention, nonionic surfactant used is
Solutol Hs15, organic solvent is methanol, ethanol.Freeze drying protectant is mannitol, trehalose, lactose.
The weight ratio of lecithin and nonionic surfactant is 1:1~3:1, the dosage of organic solvent is yellow for every 500 mg
A kind of reed mentioned in ancient books element use 8 ~ 15 mL organic solvents, and the weight ratio of baicalein and lecithin is 1:10~1:25, preferably 1:13~1:20.
The concentration of lecithin aqueous dispersion is 1% ~ 3%, lecithin aqueous dispersion and step（1）Described in baicalein weight
Amount is than being 420:1~520:1.
The ultrasonic power of cell disruptor is the W of 200 W ~ 400, and ultrasonic time is 1 ~ 5 min.
The concentration of freeze drying protectant is 3% ~ 10%, is calculated by lyophilized preceding solution weight.
With reference to specific embodiment, the present invention is described in further detail.
Embodiment 1
（1）The preparation of organic phase：Take ten dihydroxystearic acid of polyethylene glycol of 5000 mg lecithin S100 and 5000 mg
Lithium is dissolved in 8 mL methanol, adds 500 mg of baicalein, and medicine is complete molten rear spare.
（2）The preparation of water phase：7500 mg lecithin S100 are scattered in 250 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 200 W, 5
Min, adds 8% lactose, crosses 0.22 μm of miillpore filter, freeze-drying.
Embodiment 2
（1）The preparation of organic phase：Take ten dihydroxystearic acid of polyethylene glycol of 9000 mg lecithin S100 and 4500 mg
Lithium is dissolved in 15 mL absolute ethyl alcohols, adds 600 mg of baicalein, and medicine is complete molten rear spare.
（2）The preparation of water phase：5000 mg lecithin S100 are scattered in 265 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 300 W, 3
Min, adds 3% trehalose, crosses 0.22 μm of miillpore filter, freeze-drying.
Embodiment 3
（1）The preparation of organic phase：Take ten dihydroxystearic acid of polyethylene glycol of 16500 mg lecithin S100 and 5500 mg
Lithium is dissolved in 20 mL absolute ethyl alcohols, adds 660 mg of baicalein, and medicine is complete molten rear spare.
（2）The preparation of water phase：3000 mg lecithin S100 are scattered in 274 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 400 W, 1
Min, adds 10% mannitol, crosses 0.22 μm of miillpore filter, freeze-drying.
Embodiment 4
（1）The preparation of organic phase：Take the Solutol Hs15 of 5000 mg lecithin E80 and 5000 mg
It is dissolved in 8 mL methanol, adds 500 mg of baicalein, medicine is complete molten rear spare.
（2）The preparation of water phase：7500 mg lecithin E80 are scattered in 250 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 200 W, 5
Min, adds 5% mannitol, crosses 0.22 μm of miillpore filter, freeze-drying.
Embodiment 5
（1）The preparation of organic phase：Take the Solutol Hs15 of 9000 mg lecithin E80 and 4500 mg
It is dissolved in 15 mL absolute ethyl alcohols, adds 600 mg of baicalein, medicine is complete molten rear spare.
（2）The preparation of water phase：5000 mg lecithin E80 are scattered in 265 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 300 W, 3
Min, adds 10% lactose, crosses 0.22 μm of miillpore filter, freeze-drying.
Embodiment 6
（1）The preparation of organic phase：Take ten dihydroxystearic acid of polyethylene glycol of 16500 mg lecithin E80 and 5500 mg
Lithium is dissolved in 20 mL absolute ethyl alcohols, adds 660 mg of baicalein, and medicine is complete molten rear spare.
（2）The preparation of water phase：3000 mg lecithin E80 are scattered in 274 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 400 W, 1
Min, adds 8% trehalose, crosses 0.22 μm of miillpore filter, freeze-drying.
Embodiment 7
（1）The preparation of organic phase：Take the Solutol Hs15 of 5000 mg lecithin S75 and 5000 mg
It is dissolved in 8 mL methanol, adds 500 mg of baicalein, medicine is complete molten rear spare.
（2）The preparation of water phase：7500 mg lecithin S75 are scattered in 250 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 200 W, 5
Min, adds 5% lactose, crosses 0.22 μm of miillpore filter, freeze-drying.
Embodiment 8
（1）The preparation of organic phase：Take the Solutol Hs15 of 9000 mg lecithin S75 and 4500 mg
It is dissolved in 15 mL absolute ethyl alcohols, adds 600 mg of baicalein, medicine is complete molten rear spare.
（2）The preparation of water phase：5000 mg lecithin S75 are scattered in 265 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 300 W, 3
Min, adds 10% mannitol, crosses 0.22 μm of miillpore filter, freeze-drying.
Embodiment 9
（1）The preparation of organic phase：Take ten dihydroxystearic acid of polyethylene glycol of 16500 mg lecithin S75 and 5500 mg
Lithium is dissolved in 20 mL absolute ethyl alcohols, adds 660 mg of baicalein, and medicine is complete molten rear spare.
（2）The preparation of water phase：3000 mg lecithin S75 are scattered in 274 g water, it is spare.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, cell disruptor ultrasound, 400 W, 1
Min, adds 5% trehalose, crosses 0.22 μm of miillpore filter, freeze-drying.
Using the baicalein freeze-dried powder prepared in embodiment 8, to its particle diameter, form, stability, point in water after redissolution
The situation of dissipating etc. is investigated, as a result as follows.Its particle diameter is（110±8）Nm, micella is spherical in shape under transmission electron microscope.By this specially
After freeze-dried powder is made in the method that profit provides, it can store for a long time.The mixed micelle system formed after being redissolved with water for injection makes medicine
Dispersion degree increases in water（4±0.5）Mg/mL, substantially increases the dispersion degree of medicine in water.
Claims (7)
1. a kind of baicalein freeze-dried powder injection, it is characterised in that be prepared as follows：
（1）The preparation of organic phase：First by lecithin and polyethylene glycol（PEG）Lithium 12-hydroxy stearate adds by a certain percentage
Into organic solvent, appropriate baicalein dissolving is added.
（2）The preparation of water phase：Lecithin is distributed in a certain amount of distilled water, is made into lecithin aqueous dispersion.
（3）The preparation of freeze drying powder injection：Organic phase is slowly poured into water phase, while cell disruptor ultrasound, ultrasonic power are
The W of 200 W ~ 400, ultrasonic time is 1 ~ 5 min, then adds freeze drying protectant, is handled through filtering with microporous membrane, freeze-drying
After obtain baicalein freeze drying powder injection.
2. preparation method described in accordance with the claim 1, it is characterised in that the lecithin is selected from lecithin S100, lecithin
S75, lecithin E80.
3. preparation method described in accordance with the claim 1, it is characterised in that the organic solvent is selected from methanol, ethanol, tetrahydrochysene furan
Mutter, propane diols.
4. preparation method described in accordance with the claim 1, it is characterised in that the freeze drying protectant may be selected from mannitol, seaweed
Sugar, lactose, sucrose, glucose, its concentration are 3% ~ 10%, are calculated by lyophilized preceding solution weight.
5. preparation method described in accordance with the claim 1, it is characterised in that step（1）Described in lecithin and non-ionic surface
The weight ratio of activating agent is 1:1~3:1；The weight ratio of baicalein and lecithin is 1:10~1:25.
6. preparation method described in accordance with the claim 1, it is characterised in that step（2）Described in lecithin aqueous dispersion it is dense
Spend for 1% ~ 3%；The aqueous dispersion and step（1）Described in baicalein weight ratio be 420:1~520:1.
7. preparation method described in accordance with the claim 1, it is characterised in that step（3）The ultrasonic power of middle cell disruptor is
The W of 200 W ~ 400, ultrasonic time is 1 ~ 5 min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410527879.5A CN104306342B (en) | 2014-10-10 | 2014-10-10 | A kind of baicalein freeze-dried powder injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410527879.5A CN104306342B (en) | 2014-10-10 | 2014-10-10 | A kind of baicalein freeze-dried powder injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104306342A CN104306342A (en) | 2015-01-28 |
| CN104306342B true CN104306342B (en) | 2018-04-13 |
Family
ID=52361759
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410527879.5A Expired - Fee Related CN104306342B (en) | 2014-10-10 | 2014-10-10 | A kind of baicalein freeze-dried powder injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104306342B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101912363A (en) * | 2010-07-29 | 2010-12-15 | 蔡海德 | Dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine |
| CN102058528A (en) * | 2009-11-13 | 2011-05-18 | 中国科学院上海药物研究所 | Daidzein micelles and preparation method thereof |
| CN102210706A (en) * | 2011-06-03 | 2011-10-12 | 江苏建中投资有限公司 | Polypeptide donkey-hide gelatine dextran freeze-drying preparation and preparing process thereof |
-
2014
- 2014-10-10 CN CN201410527879.5A patent/CN104306342B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058528A (en) * | 2009-11-13 | 2011-05-18 | 中国科学院上海药物研究所 | Daidzein micelles and preparation method thereof |
| CN101912363A (en) * | 2010-07-29 | 2010-12-15 | 蔡海德 | Dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine |
| CN102210706A (en) * | 2011-06-03 | 2011-10-12 | 江苏建中投资有限公司 | Polypeptide donkey-hide gelatine dextran freeze-drying preparation and preparing process thereof |
Non-Patent Citations (2)
| Title |
|---|
| Flavonoids Loaded in Nanocarriers: An Opportunity to Increase Oral Bioavailability and Bioefficacy;A.R.Bilia,et al;《Food and Nutrition Sciences》;20140831;第5卷;第1212-1227页 * |
| In¯uence of the non-ionic surfactant PEG-660-12-hydroxy stearate on the surface properties of phospholipid monolayers and their effect on lipid emulsion stability;M.Jumaa,et al;《Colloid Polym Sci》;19991231;第277卷;第347-353页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104306342A (en) | 2015-01-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101982168B (en) | Quercetin nano-micelle preparation and preparation method thereof | |
| CN103705469B (en) | A kind of honokiol nanoparticle and preparation method thereof | |
| CN101088524B (en) | Phosphatide composition of active skull cap components and prepn. process and prepn. thereof | |
| CN102008439A (en) | Curcumin coated liposome preparation and preparation method thereof | |
| CN101829061A (en) | Taxol nanoparticle composition and preparation method thereof | |
| CN104163915B (en) | Cholesterol-poloxamer-cholesterol triblock copolymer and its preparation method and application | |
| CN101991593A (en) | Application of quercetin in medicament preparation | |
| CN100415221C (en) | Method for preparing curcumin lyophilized liposome | |
| WO2008052410A1 (en) | A supermolecule composition of water-soluble coenzyme q10 and preparation method thereof | |
| CN103054807A (en) | Curcumin micro-powder composition for intramuscular or hypodermic injection as well as preparation method and application thereof | |
| Liu et al. | Effect of oxymatrine HSPC liposomes on improving bioavailability, liver target distribution and hepatoprotective activity of oxymatrine | |
| CN101088523B (en) | Nanometer solid lipid particle of active skullcap components and its prepn process and prepn | |
| CN104095817A (en) | Nanoparticles containing magnolol or honokiol as well as preparation method and application of nanoparticles | |
| CN105902525A (en) | Application of chlorogenic acid nano powder inhalation in medicine for treating acute lung injury | |
| CN102274188A (en) | Solid lipid nanoparticles comprising andrographolide and preparation method and application thereof | |
| CN104324007A (en) | Preparation technology and application of natural recombinant nanostructured lipid carrier | |
| CN104306342B (en) | A kind of baicalein freeze-dried powder injection | |
| CN103070825A (en) | Curcumin particle suspension used for intramuscular injection and hypodermic injection, preparation method and application | |
| CN104146959A (en) | Oridonin sustained release liposome and preparation method thereof | |
| CN104352427A (en) | Pharmaceutical composition containing andrographolide and use of pharmaceutical composition | |
| CN105012234A (en) | Dimethoxycurcumin polymer micelle, and preparation method and medical application thereof | |
| Gu et al. | Isolation of herpetin from Herpetospermum seed and hepatoprotective activity of liposomal herpetin against carbon tetrachloride-induced liver injury in mice | |
| CN102727793A (en) | Yikunning pharmaceutical composition solid lipid nanosphere preparation | |
| CN111012744B (en) | Platycodon secondary saponin 682 self-assembled nano micelle capable of improving cell membrane permeability | |
| CN104546718B (en) | A kind of long circulating Rabeprazole liposome composition and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180413 Termination date: 20201010 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |