CN102008476B - Hydroxypropyl-beta-cyclodextrin inclusion of strychnine and preparation method thereof - Google Patents
Hydroxypropyl-beta-cyclodextrin inclusion of strychnine and preparation method thereof Download PDFInfo
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- CN102008476B CN102008476B CN201010552708.XA CN201010552708A CN102008476B CN 102008476 B CN102008476 B CN 102008476B CN 201010552708 A CN201010552708 A CN 201010552708A CN 102008476 B CN102008476 B CN 102008476B
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Abstract
The invention discloses a hydroxypropyl-beta-cyclodextrin inclusion of strychnine and a preparation method thereof. The inclusion is prepared from the strychnine and hydroxypropyl-beta-cyclodextrin in weight ratio of 1: (1-100) by using the preferential inclusion process. Experimental results show that the hydroxypropyl-beta-cyclodextrin inclusion of the strychnine has the advantages of high inclusion rate, great drug loading and good stability, and can significantly improve the water solubility of the strychnine, lead the solubility in water to be more than 20 times that of the strychnine, significantly improve the bioavailability after administration of the strychnine, play a role in reducing the toxicity of the strychnine and lead the clinical application to be safer.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to cyclodextrin clathrate of a kind of strychnine and preparation method thereof.
Background technology
Strychnine is the chief active alkaloid contained in Chinese medicine Semen Strychni, pharmacological research shows, strychnine is most one of effective ingredient having DEVELOPMENT PROSPECT in strychnine alkaloid: 1. antitumor test shows, the activity of strychnine is significantly higher than the alkaloid component in other Semen Strychni such as strychnine, NSC 118079, different strychnine; 2. antalgic and inflammation relieving test also shows, strychnine has definite analgesia, arthritis curative effect, but strychnine does not have arthritis and analgesic activity.
Strychnine is fat-soluble medicine, the dissolubility in water lower (being less than 2mg/mL), is unfavorable for the bioavailability after the preparation of its preparation and administration.Such as in the preparation process of strychnine gel, because dissolubility is low, strychnine can be separated out from hydrogel matrix, limits the raising of drug level.And for example make injection, need to add a large amount of cosolvent, the potential toxicity of cosolvent may bring hidden danger for clinical application.It is reported, strychnine is oral is only 30 ~ 35% with the bioavailability of percutaneous dosing.And experiment shows that strychnine is while performance tumor or analgesic and anti-inflammatory effects, exists the untoward reaction such as Central neurotoxicity.
In recent years, multiple strychnine preparation being intended to solve dissolubility and bioavailability concerns has been had to be in the news, as microemulsion, liposome, nanoparticle etc., as Chinese invention patent: 200510026516.4, disclose a kind of nanometer vauqueline liposome transdermal spray agent and its preparation method and application, 200810236293.8 disclose a kind of strychnine composite phospholipid liposome and preparation method thereof and the application in pharmacy, 200910235087.X disclose a kind of sustained-release pill of total alkaloids from strychnos and preparation method thereof, 02148438.4 discloses a kind of Semen Strychni slow releasing preparation and preparation method, 200510026515.X disclose a kind of nanometer vauqueline liposome and preparation method thereof, 01100654.4 discloses a kind of nano vomiting nut medicine and preparation method thereof etc., but above preparation technology is general more complicated, the research of strychnine HP-β-CD inclusion technique is not also had to report at present.
Summary of the invention
Goal of the invention: the object of the invention is to solve the deficiencies in the prior art, provide a kind of dissolubility good, bioavailability is high, hydroxypropyl-beta-cyclodextrin inclusion of the strychnine that safety is good and preparation method thereof.
Technical scheme: in order to realize above object, the technical scheme that the present invention takes is:
A hydroxypropyl-beta-cyclodextrin inclusion for strychnine, it prepares by the following method:
Take HP-β-CD soluble in water, stir lower dropping strychnine solution, stirring and evenly mixing, dry, obtain the hydroxypropyl-beta-cyclodextrin inclusion of strychnine, wherein used strychnine and the weight ratio of HP-β-CD are 1:1 ~ 100.
Preferably, the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, used strychnine and the weight ratio of HP-β-CD are 1:1 ~ 30; As preferred technical scheme, used strychnine and the weight ratio of HP-β-CD are 1:1 ~ 20.The present invention filters out the weight proportion of strychnine, HP-β-CD through lot of experiments, and the strychnine adopting the present invention preferably to obtain and HP-β-CD consumption proportion, can ensure high inclusion rate, improves drug loading.
Preferably, the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, strychnine is using ethanol or acetone as solvent, and the volume ratio of the weight of used strychnine and ethanol used or acetone is 1:2 ~ 10, strychnine has good dissolubility in ethanol and acetone
The hydroxypropyl-beta-cyclodextrin inclusion of strychnine of the present invention, can be prepared into the medicine of injectable powder, injection, oral liquid, exterior-applied gel, ointment, spray or nasal drop dosage form by the hydroxypropyl-beta-cyclodextrin inclusion of strychnine and pharmaceutically acceptable carrier.
Strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention, after depyrogenation, through aseptic filtration, lyophilization, obtains injection strychnine hydroxypropyl-beta-cyclodextrin inclusion injectable powder.Strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention does not need to add freeze drying protectant direct lyophilization can prepare injectable powder, and security performance is higher.
When strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention makes injection, get strychnine hydroxypropyl-beta-cyclodextrin inclusion, add physiological saline solution and then add active carbon, stir, 80 DEG C are heated 30 minutes, filter, adjust ph, with sintered glass funnel or other frit to clear and bright, fill, makes injection in 30 minutes 100 to 115 DEG C of sterilizings.
When strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention is made oral liquid, the extract adding distil water of each raw material is dissolved, filter, add syrup, adjust ph, make oral liquid.
The preparation method of strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention comprises the following steps:
First take strychnine 1 part, be dissolved in organic solvent, obtain strychnine solution, for subsequent use, then take HP-β-CD 1 ~ 100 part, be dissolved in distilled water, under 20 to 60 DEG C of temperature constant magnetic stirrings, strychnine solution is added drop-wise in HP-β-CD aqueous solution and carries out enclose, drip rear continuation and stir enclose 0.5 ~ 3 hour, dry, obtain strychnine hydroxypropyl-beta-cyclodextrin inclusion.
Preferably, the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, described strychnine solution is ethanol or the acetone soln of strychnine, and the volume ratio of the weight of strychnine and ethanol or acetone is 1:2 ~ 10.Used HP-β-CD (weight) is 1:2 ~ 10 with the ratio of water (volume).
As further preferred version, the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, also remove the free strychnine medicine of non-enclose through filtering with microporous membrane after strychnine HP-β-CD enclose, and then dry, obtain strychnine hydroxypropyl-beta-cyclodextrin inclusion.
Preferably, the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, after strychnine solution is added drop-wise to HP-β-CD aqueous solution, adopts supersonic oscillations to carry out enclose, or adopt the method for grinding to promote enclose, improve enclose efficiency.
Preferably, after strychnine and HP-β-CD enclose complete, spraying dry or vacuum drying method is adopted to obtain the hydroxypropyl-beta-cyclodextrin inclusion of strychnine.
The hydroxypropyl-beta-cyclodextrin inclusion of strychnine provided by the invention may be used for preparing anti-inflammation analgesis medicament and antitumor drug.
Beneficial effect: compared to the prior art strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention has the following advantages:
1, strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention, the enclose material HP-β-CD adopted is the derivant of beta-schardinger dextrin-, there is tubular molecular structure, very easily water-soluble and there is no nephrotoxicity, enclose amount is large, strychnine forms clathrate by means of intermolecular force enclose enters the cavity in cyclodextrin molecular, the water solublity of strychnine can be significantly improved, experimental result shows, strychnine hydroxypropyl-beta-cyclodextrin inclusion is compared with strychnine, dissolubility can improve 20 times, thus the bioavailability can obviously improved after strychnine administration, not only be suitable for preparing liquid preparation or powder ampoule agent for injection, its oral or external preparation bioavailability prepared also can significantly improve, simultaneously when after the water solublity increasing strychnine, also have the effect reducing strychnine Central neurotoxicity, drug safety is better.
2, strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention, preferred by strychnine and HP-β-CD consumption and concentration, and adopt the technique optimized to prepare the hydroxypropyl-beta-cyclodextrin inclusion of strychnine, experimental result shows that the inclusion rate of strychnine is high, drug loading is high, good stability, the strychnine hydroxypropyl-beta-cyclodextrin inclusion prepared, conveniently can be prepared into the various dosage forms such as injectable powder, clinical drug safety.
Accompanying drawing explanation
Fig. 1 is respectively with the patch that strychnine, strychnine and HP-β-CD physical mixture, strychnine hydroxypropyl-beta-cyclodextrin inclusion are raw material, with the blood concentration-time curve of 60mg/kg dosage percutaneous dosing after rat.
Detailed description of the invention
The present invention is illustrated further below in conjunction with specific embodiment, these embodiments should be understood only be not used in for illustration of the present invention and limit the scope of the invention, after having read the present invention, the amendment of those skilled in the art to the various equivalent form of value of the present invention has all fallen within the application's claims limited range.
The preparation of embodiment 1 strychnine hydroxypropyl-beta-cyclodextrin inclusion
Take strychnine 1g, be dissolved in 6ml ethanol, obtain strychnine alcoholic solution, for subsequent use, get HP-β-CD 6g, be ground into pasty state with 12ml distilled water, then strychnine alcoholic solution joined in HP-β-CD pasty liquid and carry out enclose, 40 DEG C of grindings 2 hours after dripping, vacuum drying, the strychnine medicine of non-enclose is washed away with dichloromethane, dry, obtain strychnine hydroxypropyl-beta-cyclodextrin inclusion.
Be dissolved in distilled water by obtained strychnine hydroxypropyl-beta-cyclodextrin inclusion and prepare the solution that strychnine concentration is 20mg/ml, inclusion rate is 96%.
The preparation of embodiment 2 strychnine hydroxypropyl-beta-cyclodextrin inclusion
First take strychnine 1g, be dissolved in 4ml ethanol, obtain strychnine solution, for subsequent use, take HP-β-CD 10g again, be dissolved in 30ml distilled water, under 40 DEG C of temperature constant magnetic stirrings, strychnine solution be added drop-wise in HP-β-CD aqueous solution and carry out enclose, drip rear continuation magnetic agitation enclose 3 hours, spraying dry, the medicine of non-enclose is washed away with chloroform, dry, obtain strychnine hydroxypropyl-beta-cyclodextrin inclusion.
Be dissolved in distilled water by obtained strychnine hydroxypropyl-beta-cyclodextrin inclusion and prepare the solution that strychnine concentration is 23mg/ml, inclusion rate is 94%.
The preparation of embodiment 3 strychnine hydroxypropyl-beta-cyclodextrin inclusion
First take strychnine 1g, be dissolved in 10ml acetone, obtain strychnine acetone soln, for subsequent use, take HP-β-CD 20g again, be dissolved in 40ml distilled water, under stirring at 40 DEG C, strychnine solution be added drop-wise in HP-β-CD aqueous solution and carry out enclose, drip rear continuation sonic oscillation enclose 1.5 hours, lyophilization, the medicine of non-enclose is washed away with ether, dry, obtain strychnine hydroxypropyl-beta-cyclodextrin inclusion.This clathrate adding distil water is dissolved, filters, add syrup, adjust ph, make oral liquid.
The preparation of embodiment 4 strychnine hydroxypropyl-beta-cyclodextrin inclusion
First take strychnine 10g, be dissolved in 20ml ethanol, obtain strychnine alcoholic solution, for subsequent use, take HP-β-CD 100g again, be dissolved in 1000ml distilled water, under stirring at 50 DEG C, strychnine solution is added drop-wise in HP-β-CD aqueous solution and carries out enclose, at 50 DEG C, enclose is stirred 5 hours after dripping, obtained inclusion complex in solution, with 0.45 micrometer Millipore membrane filtration, in 100 grades of cleaning shops, use 0.22 micrometer Millipore membrane filtration, subpackage, lyophilization, gland, packaging, obtained freeze-dried powder.
The preparation of embodiment 5 strychnine hydroxypropyl-beta-cyclodextrin inclusion
First take strychnine 2g, be dissolved in 10ml ethanol, obtain strychnine alcoholic solution, for subsequent use, take HP-β-CD 50g again, be dissolved in 300ml distilled water, under stirring at 50 DEG C, strychnine solution be added drop-wise in HP-β-CD aqueous solution and carry out enclose, drip rear sonic oscillation enclose 2 hours, obtained inclusion complex in solution, with 0.45 micrometer Millipore membrane filtration, then vacuum drying, obtain strychnine hydroxypropyl-beta-cyclodextrin inclusion.
Get the strychnine hydroxypropyl-beta-cyclodextrin inclusion prepared, add swelling and the Polyethylene Glycol (PVA) of mixing, sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP), in Polyethylene Glycol (PEG) mixed-matrix, coating, dry, cut, make patch.
Embodiment 6
Evaluation On The Bioavailability is carried out to strychnine hydroxypropyl-beta-cyclodextrin inclusion prepared by embodiment 5.Using the patch adopting strychnine, strychnine and HP-β-CD physical mixture and strychnine hydroxypropyl-beta-cyclodextrin inclusion to make as raw material respectively, content is 3mg/cm
2, rat abdomen is affixed on by 60mg/kg dosage, the blood drug level of different time points after the administration of HPLC method mensuration, often kind of patch adopts 6 rats to carry out pharmacokinetic experiment, the comparative result of three kinds of patches is shown in Fig. 1, shown by the result of Fig. 1, in administration after 10 hours, the blood drug level of strychnine hydroxypropyl-beta-cyclodextrin inclusion patch reaches maximum, and shown by experimental result, strychnine hydroxypropyl-beta-cyclodextrin inclusion is adopted to prepare patch as raw material, relative bioavailability after administration is directly using strychnine as 186.19% of raw material patch, blood drug level significantly improves, and the blood drug level after strychnine and HP-β-CD physical mixture patch delivery does not significantly improve, the percutaneous absorbtion that can promote strychnine after strychnine and HP-β-CD are prepared into clathrate is described, improve bioavailability.More than test and also show that strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention has good water solublity, bioavailability is high, and quantity is less, and after water solublity increase, can improve the drug loading of strychnine in patch.
Embodiment 7 strychnine hydroxypropyl-beta-cyclodextrin inclusion toxicity test
Carry out acute toxicity to the strychnine hydroxypropyl-beta-cyclodextrin inclusion prepared in embodiment 1 and strychnine to compare.Both are all dissolved in normal saline the solution being made into same concentrations, tail vein injection administration, record the LD of strychnine hydroxypropyl-beta-cyclodextrin inclusion and strychnine
50be respectively 12.2mg/kg and 21.9mg/kg, prove that strychnine hydroxypropyl-beta-cyclodextrin inclusion can reduce the toxicity of strychnine, clinical application is safer.
The present invention is through preferably determining the consumption proportion of strychnine and HP-β-CD, strychnine in preparation-obtained strychnine hydroxypropyl-beta-cyclodextrin inclusion and the water solublity had and high bioavailability, can be prepared into the water soluble preparations such as injectable powder.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (1)
1. the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of strychnine, is characterized in that, comprises the following steps:
First take strychnine 1 part, be dissolved in organic solvent, obtain strychnine solution, for subsequent use, then take HP-β-CD 1 ~ 100 part, be dissolved in distilled water, under 20 to 60 DEG C of temperature constant magnetic stirrings, strychnine solution is added drop-wise in HP-β-CD aqueous solution and carries out enclose, drip rear supersonic oscillations enclose 0.5 ~ 3 hour, then remove the free strychnine medicine of non-enclose through filtering with microporous membrane, drying, obtains strychnine hydroxypropyl-beta-cyclodextrin inclusion;
Described strychnine solution is ethanol or the acetone soln of strychnine, and the volume ratio of the weight of strychnine and ethanol or acetone is 1:2 ~ 10.
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| CN103222956A (en) * | 2013-04-28 | 2013-07-31 | 华南理工大学 | Strychnine-hydroxypropyl-beta-cyclodextrin liposome, preparation method and applications thereof |
| CN103222957B (en) * | 2013-04-28 | 2014-12-03 | 华南理工大学 | Strychnine-beta-cyclodextrin polymer liposome, preparation method and applications thereof |
| CN112386565A (en) * | 2019-08-02 | 2021-02-23 | 北京盈科瑞创新医药股份有限公司 | Strychnine gel preparation and preparation method thereof |
| CN113440480B (en) * | 2021-07-18 | 2023-03-17 | 福建医科大学 | Gelsemii Elegantis seed-cyclodextrin clathrate, gelsemii Elegantis seed clathrate microemulsion composition, and preparation method thereof |
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|---|---|---|---|---|
| CN101810597A (en) * | 2010-04-26 | 2010-08-25 | 南京中医药大学 | Transdermal patch containing vauqueline and preparation method and application thereof |
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| CN101810597A (en) * | 2010-04-26 | 2010-08-25 | 南京中医药大学 | Transdermal patch containing vauqueline and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 羟丙基-β-环糊精的应用发展;蔡双霜等;《中国药业》;20081231;第17卷(第10期);第78-79页 * |
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