CN102008476A - 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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- CN102008476A CN102008476A CN201010552708XA CN201010552708A CN102008476A CN 102008476 A CN102008476 A CN 102008476A CN 201010552708X A CN201010552708X A CN 201010552708XA CN 201010552708 A CN201010552708 A CN 201010552708A CN 102008476 A CN102008476 A CN 102008476A
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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 main active alkaloid that contains in the Chinese medicine Semen Strychni, pharmacological research shows, strychnine is that one of effective ingredient of DEVELOPMENT PROSPECT is arranged in the strychnine alkaloid most: 1. the antitumor test shows that the activity of strychnine is significantly higher than the alkaloid component in other Semen Strychni such as strychnine, NSC 118079, different strychnine; 2. the antalgic and inflammation relieving test shows that also strychnine has definite analgesia, arthritis curative effect, but strychnine does not have arthritis and analgesic activity.
Strychnine is a fat-soluble medicine, and the dissolubility in water lower (less than 2mg/mL) is unfavorable for the preparation of its preparation and the bioavailability after the administration.For example in the preparation process of strychnine gel, because dissolubility is low, strychnine can be separated out from hydrogel matrix, has limited the raising of drug level.And for example make injection, need add a large amount of cosolvents, the potential toxicity of cosolvent may be brought hidden danger for clinical application.It is reported, strychnine oral with bioavailability percutaneous dosing only be 30 ~ 35%.And experiment shows that in performance tumor or analgesic and anti-inflammatory effects, there are untoward reaction such as nervus centralis toxicity in strychnine.
In recent years, there have been a plurality of strychnine preparations that are intended to solve dissolubility and bioavailability problem to be in the news, as microemulsion, liposome, nanoparticle etc., as Chinese invention patent: 200510026516.4, a kind of nanometer vauqueline liposome transdermal spray agent and its production and application is disclosed, 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 total alkaloids in Semen Strychni sustained-release dropping pill and preparation method thereof, 02148438.4 disclose 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 disclose a kind of nano vomiting nut medicine and preparation method thereof etc., but above preparation technology is generally complicated, does not also have the research report of strychnine HP-inclusion technique at present.
Summary of the invention
Goal of the invention: the objective of the invention is provides a kind of dissolubility good in order to solve the deficiencies in the prior art, bioavailability height, hydroxypropyl-beta-cyclodextrin inclusion of the strychnine that safety is good and preparation method thereof.
Technical scheme: in order to realize above purpose, the technical scheme that the present invention takes is:
A kind of hydroxypropyl-beta-cyclodextrin inclusion of strychnine, it prepares by the following method:
It is soluble in water to take by weighing HP-, stir to drip strychnine solution down, stirring and evenly mixing, drying, the hydroxypropyl-beta-cyclodextrin inclusion of strychnine, the weight ratio of wherein used strychnine and HP-is 1:1 ~ 100.
As preferred version, the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, the weight ratio of used strychnine and HP-is 1:1 ~ 30; As preferred technical scheme, the weight ratio of used strychnine and HP-is 1:1 ~ 20.The present invention filters out the weight proportion of strychnine, HP-through lot of experiments, and the strychnine and the HP-consumption proportion that adopt the present invention preferably to obtain can guarantee high inclusion rate, improves drug loading.
As preferred version, the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, strychnine with ethanol or acetone as solvent, and the volume ratio of the weight of used strychnine and used ethanol 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 become the hydroxypropyl-beta-cyclodextrin inclusion of strychnine the medicine of injectable powder, injection, oral liquid, exterior-applied gel, ointment, spray or nasal drop dosage form with pharmaceutically acceptable preparing carriers.
Strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention, after the 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 can direct lyophilization prepare injectable powder, and security performance is higher.
When strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention is made injection, get the strychnine hydroxypropyl-beta-cyclodextrin inclusion, add physiological saline solution and add active carbon then, stir, 80 ℃ were heated 30 minutes, filtered, regulate pH value, be filtered to clear and brightly with sintered glass funnel or other filter, fill was made injection in 30 minutes 100 to 115 ℃ of sterilizations.
When strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention is made oral liquid,, filter, add syrup, regulate pH value, make oral liquid the extract adding distil water dissolving of each raw material.
The preparation method of strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention may further comprise the steps:
Take by weighing 1 part of strychnine earlier, be dissolved in the organic solvent, get strychnine solution, standby, take by weighing 1 ~ 100 part of HP-again, be dissolved in the distilled water, under 20 to 60 ℃ of constant temperature magnetic agitation, the strychnine drips of solution is added to and carries out enclose in the HP-aqueous solution, drip the back and continue to stir enclose 0.5 ~ 3 hour, drying promptly gets the strychnine hydroxypropyl-beta-cyclodextrin inclusion.
As preferred version, the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, ethanol or acetone soln that described strychnine solution is strychnine, the volume ratio of the weight of strychnine and ethanol or acetone is 1:2 ~ 10.Used HP-(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 not free strychnine medicine of enclose behind the strychnine HP-enclose through filtering with microporous membrane, and then dry, get the strychnine hydroxypropyl-beta-cyclodextrin inclusion.
As preferred version, the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of above-described strychnine, the strychnine drips of solution is added to the HP-aqueous solution after, adopt supersonic oscillations to carry out enclose, perhaps adopt abrasive method to promote enclose, improve enclose efficient.
As preferred version, after strychnine and HP-enclose are finished, adopt spray drying or vacuum drying method to obtain the hydroxypropyl-beta-cyclodextrin inclusion of strychnine.
The hydroxypropyl-beta-cyclodextrin inclusion of strychnine provided by the invention can be used to prepare anti-inflammation analgesis medicament and antitumor drug.
Beneficial effect: strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention is compared with prior art and is had the following advantages:
1, strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention, the enclose material HP-that adopts is the derivant of beta-schardinger dextrin-, has the tubular molecular structure, very easily water-soluble and do not have a nephrotoxicity, the enclose amount is big, strychnine forms clathrate by means of the intermolecular force enclose enters the cavity in the cyclodextrin molecular, can significantly improve the water solublity of strychnine, experimental result shows, the strychnine hydroxypropyl-beta-cyclodextrin inclusion is compared with strychnine, dissolubility can improve 20 times, thereby can obviously improve the bioavailability after the strychnine administration, not only be suitable for preparing liquid preparation or powder ampoule agent for injection, the oral or external preparation bioavailability of its preparation also can significantly improve; Behind the water solublity that increases strychnine, also have the toxic effect of the strychnine nervus centralis of reduction simultaneously, drug safety is better.
2, strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention, preferred by to strychnine and HP-consumption and concentration, and adopt the prepared of optimizing to obtain the hydroxypropyl-beta-cyclodextrin inclusion of strychnine, experimental result shows the inclusion rate height of strychnine, the drug loading height, good stability, the strychnine hydroxypropyl-beta-cyclodextrin inclusion for preparing, can conveniently be prepared into various dosage forms such as injectable powder, clinical drug safety.
Description of drawings
Fig. 1 is for being the patch of raw material with strychnine, strychnine and HP-physical mixture, strychnine hydroxypropyl-beta-cyclodextrin inclusion respectively, with the blood drug level-time graph of 60mg/kg dosage percutaneous dosing behind rat.
The specific embodiment
Further illustrate the present invention below in conjunction with specific embodiment, should understand these embodiment only is used to the present invention is described and is not used in and limit the scope of the invention, after having read the present invention, those skilled in the art all fall within the application's claims institute restricted portion to the modification of the various equivalent form of values of the present invention.
The preparation of embodiment 1 strychnine hydroxypropyl-beta-cyclodextrin inclusion
Take by weighing strychnine 1g, be dissolved in the 6ml ethanol, get the strychnine alcoholic solution, standby, get HP-6g, be ground into pasty state with the 12ml distilled water, the strychnine alcoholic solution joined carry out enclose in the HP-pasty liquid then, drip the back and ground 2 hours at 40 ℃, vacuum drying, with the dichloromethane flush away strychnine medicine of enclose not, drying promptly gets the strychnine hydroxypropyl-beta-cyclodextrin inclusion.
Prepared strychnine hydroxypropyl-beta-cyclodextrin inclusion is dissolved in prepares the solution that strychnine concentration is 20mg/ml in the distilled water, inclusion rate is 96%.
The preparation of embodiment 2 strychnine hydroxypropyl-beta-cyclodextrin inclusions
Take by weighing strychnine 1g earlier, be dissolved in the 4ml ethanol, get strychnine solution, standby, take by weighing HP-10g again, be dissolved in the 30ml distilled water, under 40 ℃ of constant temperature magnetic agitation, the strychnine drips of solution be added to and carry out enclose in the HP-aqueous solution, drip the back and continued the magnetic agitation enclose 3 hours, spray drying, with the chloroform flush away medicine of enclose not, drying promptly gets the strychnine hydroxypropyl-beta-cyclodextrin inclusion.
Prepared strychnine hydroxypropyl-beta-cyclodextrin inclusion is dissolved in prepares the solution that strychnine concentration is 23mg/ml in the distilled water, inclusion rate is 94%.
The preparation of embodiment 3 strychnine hydroxypropyl-beta-cyclodextrin inclusions
Take by weighing strychnine 1g earlier, be dissolved in the 10ml acetone, get the strychnine acetone soln, standby, take by weighing HP-20g again, be dissolved in the 40ml distilled water, under 40 ℃ of stirrings, the strychnine drips of solution be added to and carry out enclose in the HP-aqueous solution, drip the back and continued the sonic oscillation enclose 1.5 hours, lyophilization, with the ether flush away medicine of enclose not, drying promptly gets the strychnine hydroxypropyl-beta-cyclodextrin inclusion.With this clathrate adding distil water dissolving, filter, add syrup, regulate pH value, make oral liquid.
The preparation of embodiment 4 strychnine hydroxypropyl-beta-cyclodextrin inclusions
Take by weighing strychnine 10g earlier, be dissolved in the 20ml ethanol, get the strychnine alcoholic solution, standby, take by weighing HP-100g again, be dissolved in the 1000ml distilled water, under 50 ℃ of stirrings, the strychnine drips of solution is added to and carries out enclose in the HP-aqueous solution, drip the back and stirred enclose 5 hours down at 50 ℃, make inclusion complex in solution, with 0.45 micron filtering with microporous membrane, in 100 grades of cleaning shops, use 0.22 micron filtering with microporous membrane, packing, lyophilization, gland, packing makes freeze-dried powder.
The preparation of embodiment 5 strychnine hydroxypropyl-beta-cyclodextrin inclusions
Take by weighing strychnine 2g earlier, be dissolved in the 10ml ethanol, get the strychnine alcoholic solution, standby, take by weighing HP-50g again, be dissolved in the 300ml distilled water, under 50 ℃ of stirrings, the strychnine drips of solution be added to and carry out enclose in the HP-aqueous solution, dripped back sonic oscillation enclose 2 hours, make inclusion complex in solution, with 0.45 micron filtering with microporous membrane, vacuum drying gets the strychnine hydroxypropyl-beta-cyclodextrin inclusion again.
Get the strychnine hydroxypropyl-beta-cyclodextrin inclusion for preparing, in the Polyethylene Glycol (PVA) of adding swelling and mixing, sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP), Polyethylene Glycol (PEG) mixed-matrix, coating, dry, cut, make patch.
Embodiment 6
Strychnine hydroxypropyl-beta-cyclodextrin inclusion to embodiment 5 preparations carries out the bioavailability evaluation.With the patch that adopts strychnine, strychnine and HP-physical mixture and strychnine hydroxypropyl-beta-cyclodextrin inclusion to make as raw material respectively, content is 3mg/cm
2Be affixed on rat abdomen by 60mg/kg dosage, the blood drug level of different time points after the administration of HPLC method mensuration, every kind of patch adopts 6 rats to carry out pharmacokinetic experiment, the comparative result of three kinds of patches is seen Fig. 1, result by Fig. 1 shows, in administration after 10 hours, the blood drug level of strychnine hydroxypropyl-beta-cyclodextrin inclusion patch reaches maximum, and show by experimental result, adopt the strychnine hydroxypropyl-beta-cyclodextrin inclusion as the feedstock production patch, relative bioavailability after the administration be directly with strychnine as 186.19% of raw material patch, blood drug level obviously improves, and the blood drug level after strychnine and the administration of HP-physical mixture patch does not significantly improve, explanation can promote the percutaneous of strychnine to absorb after strychnine and HP-are prepared into clathrate, improves bioavailability.More than experiment shows that also strychnine hydroxypropyl-beta-cyclodextrin inclusion provided by the invention has good water solublity, the bioavailability height, and clinical consumption is littler, and after the water solublity increase, can improve the drug loading of strychnine in patch.
Embodiment 7 strychnine hydroxypropyl-beta-cyclodextrin inclusion toxicity tests
Strychnine hydroxypropyl-beta-cyclodextrin inclusion and strychnine to preparation among the embodiment 1 carry out acute toxicity relatively.Both all are dissolved in the solution that is made into same concentrations in the normal saline, and the tail vein injection administration records the LD of strychnine hydroxypropyl-beta-cyclodextrin inclusion and strychnine
50Be respectively 12.2mg/kg and 21.9mg/kg, prove that the strychnine hydroxypropyl-beta-cyclodextrin inclusion can reduce the toxicity of strychnine, clinical application is safer.
The present invention is through the preferred consumption proportion of determining strychnine and HP-, strychnine and have good water solublity and high bioavailability in the preparation-obtained strychnine hydroxypropyl-beta-cyclodextrin inclusion can be prepared into water soluble preparations such as injectable powder.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle 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 (8)
1. the hydroxypropyl-beta-cyclodextrin inclusion of a strychnine is characterized in that, it prepares by the following method:
It is soluble in water to take by weighing HP-, stir to drip strychnine solution down, stirring and evenly mixing, drying, the hydroxypropyl-beta-cyclodextrin inclusion of strychnine, the weight ratio of wherein used strychnine and HP-is 1:1 ~ 100.
2. the hydroxypropyl-beta-cyclodextrin inclusion of strychnine according to claim 1 is characterized in that, the weight ratio of used strychnine and HP-is 1:1 ~ 30.
3. the hydroxypropyl-beta-cyclodextrin inclusion of strychnine according to claim 1 is characterized in that, ethanol or acetone soln that described strychnine solution is strychnine.
4. the hydroxypropyl-beta-cyclodextrin inclusion of each described strychnine of claim 1 to 3, it is characterized in that, the hydroxypropyl-beta-cyclodextrin inclusion of strychnine is become the medicine of injectable powder, injection, oral liquid, exterior-applied gel, ointment, spray or nasal drop dosage form with pharmaceutically acceptable preparing carriers.
5. the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of the described strychnine of claim 1 is characterized in that, may further comprise the steps:
Take by weighing 1 part of strychnine earlier, be dissolved in the organic solvent, get strychnine solution, standby, take by weighing 1 ~ 100 part of HP-again, be dissolved in the distilled water, under 20 to 60 ℃ of constant temperature magnetic agitation, the strychnine drips of solution is added to and carries out enclose in the HP-aqueous solution, drip the back and continue to stir enclose 0.5 ~ 3 hour, drying promptly gets the strychnine hydroxypropyl-beta-cyclodextrin inclusion.
6. the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of strychnine according to claim 5, it is characterized in that, ethanol or acetone soln that described strychnine solution is strychnine, the volume ratio of the weight of strychnine and ethanol or acetone are 1:2 ~ 10.
7. the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of strychnine according to claim 5, it is characterized in that, also remove the not free strychnine medicine of enclose behind the strychnine HP-enclose through filtering with microporous membrane, and then dry, get the strychnine hydroxypropyl-beta-cyclodextrin inclusion.
8. the preparation method of the hydroxypropyl-beta-cyclodextrin inclusion of strychnine according to claim 5 is characterized in that, the strychnine drips of solution is added to the HP-aqueous solution after, adopt supersonic oscillations to carry out enclose.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103222957A (en) * | 2013-04-28 | 2013-07-31 | 华南理工大学 | Strychnine-beta-cyclodextrin polymer liposome, preparation method and applications thereof |
| CN103222956A (en) * | 2013-04-28 | 2013-07-31 | 华南理工大学 | Strychnine-hydroxypropyl-beta-cyclodextrin liposome, preparation method and applications thereof |
| WO2021023099A1 (en) * | 2019-08-02 | 2021-02-11 | 北京盈科瑞创新医药股份有限公司 | Brucine gel formulation and preparation method therefor |
| CN113440480A (en) * | 2021-07-18 | 2021-09-28 | 福建医科大学 | Gelsemii gersfungin-cyclodextrin inclusion compound and gelsmium gersfungin inclusion compound 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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2010
- 2010-11-22 CN CN201010552708.XA patent/CN102008476B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
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| 蔡双霜等: "羟丙基-β-环糊精的应用发展", 《中国药业》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103222957A (en) * | 2013-04-28 | 2013-07-31 | 华南理工大学 | Strychnine-beta-cyclodextrin polymer liposome, preparation method and applications thereof |
| 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 |
| WO2021023099A1 (en) * | 2019-08-02 | 2021-02-11 | 北京盈科瑞创新医药股份有限公司 | Brucine gel formulation and preparation method therefor |
| 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 |
| CN113440480A (en) * | 2021-07-18 | 2021-09-28 | 福建医科大学 | Gelsemii gersfungin-cyclodextrin inclusion compound and gelsmium gersfungin inclusion compound microemulsion composition and preparation method thereof |
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