CN100417378C - Oridonin clathrate compound, and medicinal prepn. thereof - Google Patents
Oridonin clathrate compound, and medicinal prepn. thereof Download PDFInfo
- Publication number
- CN100417378C CN100417378C CNB2006100722268A CN200610072226A CN100417378C CN 100417378 C CN100417378 C CN 100417378C CN B2006100722268 A CNB2006100722268 A CN B2006100722268A CN 200610072226 A CN200610072226 A CN 200610072226A CN 100417378 C CN100417378 C CN 100417378C
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- CN
- China
- Prior art keywords
- rubescensine
- cyclodextrin
- clathrate
- injection
- preparation
- 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.)
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An inclusion compound of rebescensine A is prepared from the rebescensine A as active component and cyclodextrin as including material in the weight ratio of 1: (0.5-50). A medicine containing said inclusion compound is also disclosed.
Description
Technical field
The present invention relates to the pharmaceutical preparation of rubescensine A, relate in particular to and adopt rubescensine A clathrate that cyclodextrin inclusion technique obtains and the related drugs preparation that utilizes this clathrate preparation as the treatment effective ingredient.
Background technology
Rubescensine A is a kind of alkene class diterpene that extracts from Rabdosia rubescens.Rabdosia rubescens Rabdosiarubescens (Hemsl) Ha ra calls the Asia of cracking rice, and the snowflake grass is a Labiatae Herba Coriandri platymiscium, is a kind of traditional Chinese herbal medicine, has the effect of heat-clearing and toxic substances removing, anti-inflammatory analgetic.China Ministry of Public Health approval in 1991 is dried leaf and aerial parts as Chinese crude drug, income health Chinese crude drug standard promulgated by the ministries or commissions of the Central Government.China has carried out big quantity research to chemical constituent, pharmacological action and the clinical practice of Rabdosia rubescens from twentieth century the seventies.
Rubescensine A (Rubescensin A), molecular formula C
20H
28O
6, molecular weight 364.42, structure such as figure below.Rubescensine A separated acquisition first from the Rabdosia rubescens leaf of Jiyuan in 1977, and identify through elementary analysis and spectroscopy, determine that itself and Japanese scholar rattan Tian Rongyi prolong from equal plant that to separate the diterpene oridonin that obtains the life careless (Isodonjaponicus) be same chemical compound.So rubescensine A is called oridonin again.In addition, in the fragrant bar dish (T.macrophylla) of equal plant Da Ye, comospore Herba Rabdosiae glaucocalycis (Isodon trichocarpus) etc., also contain this chemical compound.
Clinical research shows that this chemical compound has uniqueness and tangible anticancer effect, especially malignant tumor such as the esophageal carcinoma, carcinoma of gastric cardia is had specially good effect.No matter rubescensine A is the oral or injection of decoct when using separately, all has anti-tumor activity, particularly the esophageal carcinoma and carcinoma of gastric cardia etc. is had specially good effect.In the body or experiment in vitro studies show that, rubescensine A is to the strain of multiple transplantability mouse tumor, as sarcoma 180 ascitic type, ehrlich carcinoma and solid type, hepatic ascites and solid type etc., human cancer cell with In vitro culture, as human body esophageal carcinoma 109 cell strains, human hepatocellular BEL-7402 cell strain, human body esophageal squamous cell carcinoma cell strain CaEs-17, hepatocarcinoma and histiocytosarcoma solid type, L1210, P388, ehrlich carcinoma ECA, S180 ascitic type etc., wherein, esophageal carcinoma CaEs-17 and adenocarcinoma of stomach MGC80-3 are the most responsive.Result of study shows that also rubescensine A is not that all cancerous cell lines are all had effect, and as to mouse leukemia L615 and No. 1 ascitic type of lymphosarcoma (L1) etc., human body the lung pulse cancer SPC-A1 and lung squamous cancer LTEP-78 etc. do not have obviously active.
The effect of rubescensine A in the clinical research of anti-tumor disease and treatment is by extensive concern, because rubescensine A is a kind of white crystalline powder, water solublity is bad, biological half-life is short, bioavailability is low, how producing the pharmaceutical preparation of quick and stable performance drug effect, is the key of present rubescensine A medicinal application.A kind of technology for preparing Oridonin emulsion is provided in the Chinese patent 200310110304.5, and has illustrated that this technology can be disperseed active component fast, all had good stability and high bioavailability as injection and oral formulations.200510046253.3 of Chinese patent application provide a kind of rubescensine A liposome at above-mentioned Oridonin emulsion drug loading and envelop rate defective on the low side, illustrate that it can improve the drug loading of medicament.
Can see from the record of above-mentioned patent formerly, make preparation stabilization, the preparation Oridonin emulsion need add oils and fats, emulsifying agent and the isotonic agent of relatively large amount, introduces some sensitization compositions easily.Kai Fa Oridonin emulsion is exactly because contain a large amount of ethanol and oils and fats the earliest, and sensitization obviously can not be used during clinical use.Preparing the rubescensine A liposome then needs the packaging material (phospholipid) of relatively large amount, stabilizing agent, water-solubility carrier etc.; Angle from suitability for industrialized production, the pharmaceutical preparation of preparation microemulsion and liposome form requires very high to production equipment, especially need to use high-power emulsifying device that encapsulation object is highly dispersed after with the principal agent parcel, for example high pressure homogenize equipment causes the technical process more complicated; In addition, the primary raw material or the lecithin that in liposome preparation, use at present, its quality has a significant impact for final liposome, so the used lecithin of pharmacy industry is also based on import.
So, in present stage rubescensine A is processed into appropriate formulations, the technology that it is complicated, the equipment of high investment and expensive raw material have constituted restriction for the less pharmacy corporation of some scale strength.
Summary of the invention
The invention provides a kind of rubescensine A clathrate, come the hydrotropy rubescensine A by adopting cyclodextrin inclusion technique, the clathrate that obtains can have good stable and envelop rate, and technology is simple, and production cost is low, helps industrialized mass production.
The present invention also provides the preparation method of this rubescensine A clathrate.
The present invention also provides the rubescensine A pharmaceutical preparation that utilizes this clathrate to obtain as the principal agent carrier.
The front mentions that the rubescensine A water solublity is relatively poor, and biological half-life is short, bioavailability is low, and cyclodextrin (Cyclodextrin) is a kind of cyclic oligomer sugar compounds, has special ring-type hollow cylinder type structure, can form clathrate with medicine under certain condition.The applicant studies show that, rubescensine A can significantly improve dissolubility and bioavailability behind cyclodextrin inclusion compound, improves stability of drug, and reduces the zest of medicine, improves curative effect, reduces toxic and side effects.
So, rubescensine A clathrate provided by the present invention, for rubescensine A by the product of all or part of enclose of cyclodextrin, the weight ratio of rubescensine A and cyclodextrin is 1 in this clathrate: 0.5-50.
The cyclodextrin that adopts in the rubescensine A clathrate of the present invention comprises alpha-cyclodextrin, r-cyclodextrin, beta-schardinger dextrin-or beta-cyclodextrin derivative; Especially can be cyclodextrin is r-cyclodextrin, beta-schardinger dextrin-or beta-cyclodextrin derivative.Wherein, described beta-cyclodextrin derivative comprises DM-, TM-, HP-(for example, 2-HP-, 3-HP-etc.), G 1-CD, G 2-CD, G 3-, 2G1-or 2G2-etc.
In the rubescensine A clathrate of the present invention, the weight ratio scope of rubescensine A and cyclodextrin can be 1: 0.5-50 is preferably 1: 1-50.
Rubescensine A clathrate of the present invention is a kind of molecular level enclose, in case after determining suitable cyclodextrin, preparation process can be very simple.Because the water solublity of rubescensine A own is bad, so when the preparation clathrate, rubescensine A can be dissolved in earlier and make alcohol soluble substance in the adequate amount of ethanol, cyclodextrin is made solution with water dissolution.As the pharmaceutical pack compound, preferably use water for injection or deionized water to make cyclodextrin aqueous solution, the two mixing is back can be finished room temperature-80 ℃ following a stirring in 0.5-8 hour.
Adopt differential thermal analysis that rubescensine A clathrate of the present invention is identified: to use differential thermal analysis meter, to rubescensine A, cyclodextrin and clathrate scanning, the scanning temperature range is 50-450 ℃, scanning speed is 20 ℃/min, rubescensine A has absworption peak at 256.7 ℃, be the fusing point peak, and the rubescensine A clathrate does not have 256.7 ℃ of absworption peaks, illustrating does not have the rubescensine A monomer in the clathrate, by enclose.
The present invention also provides the pharmaceutical composition that contains rubescensine A, and it comprises above-mentioned rubescensine A clathrate and pharmacy adjuvant.Pharmaceutical composition of the present invention adopts suitable pharmaceutical technology, can obtain various pharmaceutical preparatioies, so can be rubescensine A injection or rubescensine A oral formulations.The content of described rubescensine A clathrate (also claiming to contain drug carrier) can be 1-99%.The concrete content of this rubescensine A clathrate in different preparations can be by to requiring to determine as the conversion of the rubescensine A content of therapeutic activity composition and the routine of pharmaceutical technology, promptly, should comprise the rubescensine A for the treatment of effective dose in the described pharmaceutical composition, it is to exist with the cyclodextrin clathrate form in preparation.The dosage of rubescensine A medicament of the present invention in clinical treatment can be 20-100mg/ days (in rubescensine A).
From the drug safety angle, the cyclodextrin that is used for the rubescensine A clathrate of rubescensine A injection of the present invention is preferably beta-cyclodextrin derivative, the indefiniteness example has: DM-(for example 2, the 6-DM-), TM-, HP-(for example, 2-HP-, 3-HP-etc.), G 1-CD, G 2-CD, G 3-, 2G1-or 2G2-etc.
Wherein, more preferably adopt HP-and DM-.
The preferred range of the weight ratio of rubescensine A and cyclodextrin is 1: 1.5-50, more preferably scope is 1: 2-10.
Above-mentioned rubescensine A injection comprises the various regular dosage forms in the pharmaceutics,, comprises injection, intravenous fluid, spray powder pin or freeze-dried powder that is.
For the rubescensine A freeze-dried powder, pharmacy adjuvant (excipient) wherein can comprise one or more in low-molecular-weight dextran, PEG400, polyethylene glycol 6000, mannitol, lactose, glucose, sucrose, sodium chloride and the sorbitol.Can finish through lyophilization after the rubescensine A clathrate of recipe quantity and adjuvant handled according to the routine preparation.
For rubescensine A spray powder pin, pharmacy adjuvant (excipient) wherein comprises one or more in low-molecular-weight dextran, mannitol, lactose, glucose, sucrose, sodium chloride and the sorbitol.Make sterilized powder through lyophilization or spray drying after the rubescensine A clathrate of recipe quantity and adjuvant handled according to the routine preparation, carry out aseptic subpackaged can finishing then.
Described rubescensine A injection can also be glucose injection or sodium chloride injection.For example, the rubescensine A glucose injection can be with the rubescensine A injection of glucose as the large volume of osmotic pressure regulator, after 115-121 ℃ of pressure sterilizing 20-30 minute and get.The rubescensine A sodium chloride injection is with the rubescensine A injection of sodium chloride as the large volume of osmotic pressure regulator, after 115-121 ℃ of pressure sterilizing 20-30 minute and get.
Utilize the pharmaceutical composition that comprises the rubescensine A clathrate of the present invention can also obtain the rubescensine A oral formulations, comprise tablet, granule, hard capsule, soft capsule and oral liquid, described rubescensine A clathrate is for containing drug carrier, and the pharmacy adjuvant is blank carrier.
According to rubescensine A oral formulations of the present invention, the cyclodextrin in the rubescensine A clathrate is preferably beta-schardinger dextrin-or beta-cyclodextrin derivative.The weight ratio of rubescensine A and cyclodextrin is preferably 1 in the rubescensine A clathrate: 1.5-50, more preferably 1: 2-10.
Comprised the cyclodextrin clathrate and the pharmaceutics adjuvant of above-mentioned rubescensine A in the composition of rubescensine A oral formulations of the present invention, in different dosage form, the selection of pharmaceutics adjuvant is different, but the present invention does not have particular determination to this.
When this oral formulations was the rubescensine A sheet, adjuvant comprised filler, wetting agent or binding agent, disintegrating agent, lubricant.Wherein the selection of filler comprises lactose, microcrystalline Cellulose, starch, pregelatinized Starch, dextrin, sucrose, glucose, mannitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate etc.; Wetting agent can comprise water, ethanol etc.; Binding agent comprises starch slurry, dextrin, sucrose, glucose, hypromellose, hyprolose, carboxymethyl starch sodium, polyvidone, methylcellulose, pregelatinized Starch, sodium carboxymethyl cellulose, polyvinyl alcohol, gelatin, arabic gum etc.; Disintegrating agent comprises microcrystalline Cellulose, starch, pregelatinized Starch, hyprolose, carboxymethyl starch sodium, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone etc.; Lubricant comprises silicon dioxide, magnesium stearate, Pulvis Talci, Polyethylene Glycol, hydrogenated vegetable oil, aluminium hydroxide, liquid paraffin, calcium stearate, sodium stearate, stearic acid, stearyl alcohol, paraffin, Cera Chinensis etc.
In the described tablet, the rubescensine A cyclodextrin clathrate is as containing drug carrier, and preferred content is a 1-90% weight; More preferably content is 5-85% weight; Optimum content is a 10-70% weight.
When described oral formulations was rubescensine A capsule (hard capsule), adjuvant comprised filler, wetting agent or binding agent, disintegrating agent, lubricant.Wherein filler comprises lactose, microcrystalline Cellulose, starch, pregelatinized Starch, dextrin, sucrose, glucose, mannitol, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate etc.; Wetting agent comprises water, ethanol; Binding agent comprises starch slurry, dextrin, sucrose, glucose, hypromellose, hyprolose, carboxymethyl starch sodium, polyvidone, methylcellulose, pregelatinized Starch, sodium carboxymethyl cellulose, polyvinyl alcohol, gelatin, arabic gum etc.; Disintegrating agent comprises microcrystalline Cellulose, starch, pregelatinized Starch, hyprolose, carboxymethyl starch sodium, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone etc.Lubricant comprises silicon dioxide, magnesium stearate, Pulvis Talci, Polyethylene Glycol, hydrogenated vegetable oil, aluminium hydroxide, liquid paraffin, calcium stearate, sodium stearate, stearic acid, stearyl alcohol, paraffin, Cera Chinensis etc.
The rubescensine A clathrate is present in the capsule as containing the amount of drug carrier with 1% to 99% weight.Preferably, the described content that contains drug carrier is 1-95% weight; Be preferably 1-90% weight; Containing the optimum content of drug carrier in hard capsule is 5-85% weight.
The rubescensine A clathrate is present in the granule as containing the amount of drug carrier with 1% to 99% weight.Preferably, the described content that contains drug carrier is 1-95% weight; Be preferably 1-90% weight; Containing the optimum content of drug carrier in granule is 5-85% weight.
Described oral agents can also be the rubescensine A soft capsule, capsule skin raw material can comprise gelatin, soybean oil or oil with hydrogenated soybean, and plasticizer (for example glycerol, yellow beeswax), antiseptic (for example methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sorbitol etc.), food coloring etc., and the processing technology of capsule skin is a routine techniques.Rubescensine A clathrate as active component can carry out suitable emulsifying before the capsule skin of packing into, for example add in the Polyethylene Glycol and mix.This rubescensine A clathrate is preferably 10-85% weight as containing the content of drug carrier in soft capsule.
Described oral formulations can also be the rubescensine A oral liquid, and the rubescensine A clathrate is preferably 1-85% weight as containing drug carrier content therein.Adjuvant can have sucrose or glucose, antiseptic (for example methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, sorbitol etc.), sweeting agent (for example stevioside, aspartame, cyclamate etc.) and essence etc.
Rubescensine A clathrate of the present invention is compared with liposome with Emulsion has following characteristics:
1, the biological half-life and the availability of medicine have been increased.Emulsion is to utilize the surface activity of emulsifying agent that water-fast rubescensine A is distributed in the oils and fats to go, and forms small oil droplet; Liposome also is to utilize the emulsification of lecithin, poloxamer etc. rubescensine A to be distributed in the oil phase such as stearic acid to form translucent emulsion.Rubescensine A clathrate of the present invention be utilize cyclodextrin ring-type hollow cylinder type structure with the rubescensine A embedding wherein, can better reach the effect of slow release, thereby prolong half-life improves dissolubility and bioavailability.
Solubility test:
Rubescensine A clathrate and rubescensine A are added respectively in the volumetric flask of 50m1, be diluted with water to scale, form supersaturated solution, measure absorbance at the 234nm place with ultraviolet spectrophotometer, adopt standard curve method to calculate rubescensine A concentration in the solution, the result shows that rubescensine A has all increased more than 10 times (specifically can referring to the record of the embodiment of the invention) through dissolubility behind the cyclodextrin inclusion compound.
Bioavailability and prolong half-life test:
Test method: test with healthy white big ear rabbit male and female dual-purpose, body constitution amount 1.87-2.23kg, fasting 12h before the administration freely drinks water, be divided into 3 groups at random, respectively with rubescensine A clathrate freeze-dried powder, the rubescensine A emulsion, rubescensine A liposome intravenously administrable, the dosage of rubescensine A all calculate by 20mg/kg, injection back 20,30,40,50,60,80,100,120,140,160 and 180min offside ear vein blood drawing 1ml, wait to separate out serum and centrifugal 10min after the placement, draw serum 10 μ L sample introductions, (with the octadecylsilane chemically bonded silica is filler to adopt high effective liquid chromatography for measuring; With acetonitrile-water (40: 60) is mobile phase; The detection wavelength is 240nm; Flow velocity is 0.8ml/min) rubescensine A content, can draw as calculated, rubescensine A clathrate freeze-dried powder is (133.5 ± 5.4) % with respect to the relative bioavailability of emulsion, is (119.2 ± 2.7) % (specifically can referring to the record of the embodiment of the invention) with respect to the relative bioavailability of liposome.
Result of the test also demonstrates rubescensine A clathrate freeze-dried powder peak time (t
Max) longer than emulsion and liposome.
2, improved stability of drug.Rubescensine A illumination and weak acid, a little less than subtract under the condition unstable, and the rubescensine A clathrate to expose be cyclodextrin under external environment, rubescensine A stability is improved.
Rubescensine A and rubescensine A clathrate are placed in the culture dish respectively, spread out into the thin layer of 3-4mm, in lighting box, in illumination is under the condition of 45001x ± 5001x, placed 5 days, sampling, (with the octadecylsilane chemically bonded silica is filler to adopt high effective liquid chromatography for measuring; With acetonitrile-water (40: 60) is mobile phase; The detection wavelength is 240nm; Flow velocity is 0.8ml/min), find that new impurity peaks appears in rubescensine A, and rubescensine A clathrate stable (specifically can referring to the record of the embodiment of the invention).
3, production technology is simple, is easy to industrialization.Clathrate of the present invention can adopt conventional reactor to mix, and vacuum drying or lyophilization get product then.
Need to prove, the present invention is on the basis of the cyclodextrin clathrate that a kind of rubescensine A is provided, all kinds of rubescensine A preparations that adopt this clathrate preparation also are provided, but only needing to get final product according to existing result of study is definite in the industry for the concrete content of rubescensine A in these medicaments, is not research contents of the present invention.
The present invention adopts cyclodextrin to prepare the rubescensine A clathrate by inclusion technique, compare with liposome product with the Emulsion that report is arranged, it is the molecular level enclose product that adopts cyclodextrin, it is simple to have technology, the characteristics that raw material sources are abundant, the suitability for industrialized production that is beneficial to the rubescensine A medicine is promoted.The cyclodextrin that the present invention uses is the industrialization product, wide material sources not only, continually developing to enforcement of the present invention of various in recent years cyclodextrin and derivant product thereof provides wide in range choice, select targetedly to use according to the characteristic of types of formulation, also the safety for medication provides guarantee.
The specific embodiment
Below introduction by the specific embodiments beneficial effect that further discloses technical characterstic of the present invention and produced, be intended to help the reader to understand technical spirit of the present invention and characteristics better, but do not constitute any qualification the scope of the present invention.
Rubescensine A in following examples and various adjuvant, reagent are all from being purchased product.
The preparation of embodiment 1 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 10.0g |
| 2, the 6-DM- | 20.0g |
| Ethanol | 20ml |
| Water for injection | 300ml |
Preparation methods of cyclodextrin inclusion complexes is as follows:
Take by weighing the rubescensine A of 10.0g, be dissolved in the 20ml ethanol; Take by weighing 20.0g 2, the 6-DM-is dissolved in the water for injection (also can use deionized water) of 300ml.After the two mixing, stirring reaction 4h, the control temperature is about 60 ℃, stirring reaction 4h.Left standstill 3 days, and filtered, drying, promptly.
The solubility experiment result shows that the dissolubility of this clathrate improves more than 10 times than rubescensine A.Stability after the illumination also significantly improves.
The preparation of embodiment 2 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 10.0g |
| TM- | 100.0g |
| Ethanol | 10ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 1.
The preparation of embodiment 3 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 1.0g |
| G 1-CD | 50.0g |
| Ethanol | 15ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 1.
The preparation of embodiment 4 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 2.0g |
| Three G 2-CDs | 50.0g |
| Ethanol | 15ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 1.
The preparation of embodiment 5 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 2.5g |
| G 3- | 50.0g |
| Ethanol | 25ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 1.
The preparation of embodiment 6 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 5.0g |
| 2G1- | 50.0g |
| Ethanol | 25ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 1.
The preparation of embodiment 7 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 10.0g |
| 2G2- | 50.0g |
| Ethanol | 25ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 1.
The preparation of embodiment 8 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 20.0g |
| HP- | 50.0g |
| Ethanol | 25ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 1.
The preparation of embodiment 9 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 0.1g |
| HP- | 0.5g |
| Ethanol | 5ml |
| Water for injection | 100ml |
Preparation technology is referring to embodiment 1.
The preparation of embodiment 10 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 10.0g |
| HP- | 100.0g |
| Ethanol | 25ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 1.
The clathrate that obtains is measured dissolubility according to the method for introducing previously, shows that the dissolubility than rubescensine A improves about 13 times; With this clathrate and rubescensine A illumination simultaneously experiment, adopt high-performance liquid chromatogram determination according to preceding method, show that clathrate has good stable.
The preparation of embodiment 11 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 10.0g |
| Alpha-cyclodextrin | 50.0g |
| Ethanol | 50ml |
| Water for injection | 300ml |
Preparation methods of cyclodextrin inclusion complexes is as follows:
Take by weighing the rubescensine A of 10.0g, be dissolved in the 50ml ethanol; Take by weighing the 50.0g alpha-cyclodextrin, be dissolved in the water for injection of 300ml.After the two mixing, stirring reaction 4h, the control temperature is about 60 ℃, stirring reaction 4h.Left standstill 3 days, and filtered, drying, promptly.
The preparation of embodiment 12 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 10.0g |
| The r-cyclodextrin | 100.0g |
| Ethanol | 10ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 11.
The preparation of embodiment 13 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 1.0g |
| Beta-schardinger dextrin- | 50.0g |
| Ethanol | 15ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 11.
The preparation of embodiment 14 rubescensine A cyclodextrin clathrate
Proportioning raw materials:
| Rubescensine A | 2.5g |
| Beta-schardinger dextrin- | 50.0g |
| Ethanol | 25ml |
| Water for injection | 300ml |
Preparation technology is referring to embodiment 11.
Embodiment 15 rubescensine A injection
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| Ethanol | 25ml |
| Water for injection | In right amount |
The preparation method of rubescensine A injection is as follows:
Take by weighing the rubescensine A of recipe quantity, be dissolved in the ethanol of recipe quantity; Take by weighing the hydroxypropyl of recipe quantity, be dissolved in the water for injection of 300ml.After the two mixing, stirring reaction 4h, the control temperature is about 60 ℃.Put coldly, regulate pH to 7.0, add the injection water to 1000ml; Add active carbon 5g, be heated to 60 ℃, stirred 30 minutes, filter and take off charcoal, add the injection water to 1000ml, through 0.45 μ m microporous filter membrane, filter, embedding is in the ampere bottle, 115-121 ℃ of pressure sterilizing 30 (or 15) minute promptly, can supply intramuscular injection, or add the Glucose Liquid used for intravenous injection.
Embodiment 16 injection rubescensine A (freeze-dried powder)
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| PEG400 | 100ml |
| Dextran-40 | 75g |
| Ethanol | 25ml |
| Water for injection | In right amount |
The preparation method of injection rubescensine A (freeze-dried powder) is as follows:
Take by weighing the rubescensine A of recipe quantity, be dissolved in the ethanol of recipe quantity; Take by weighing the HP-of recipe quantity, be dissolved in the water for injection of 300ml.After the two mixing, stirring reaction 4h, the control temperature is about 60 ℃.Add PEG400 100ml and 75g dextran-40, put coldly, regulate pH to 7.0, add the injection water to 1000ml; Add active carbon 5g, be heated to 60 ℃, stirred 30 minutes, filter and take off charcoal, add the injection water to 1000ml, through 0.22 μ m microporous filter membrane, Entkeimung, packing, lyophilizing, promptly.
Detect the bioavailability of this freeze-dried powder according to the method for introducing previously, and compare with liposome with the rubescensine A emulsion of identical drug loading respectively, this lyophilized injectable powder is (133.5 ± 5.4) % with respect to the relative bioavailability of the emulsion of equal drug loading, is (119.2 ± 2.7) % with respect to the relative bioavailability of the liposome of equal drug loading.
Embodiment 17 injection rubescensine A (freeze-dried powder)
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| PEG400 | 100ml |
| Mannitol | 60g |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 16.
Embodiment 18 injection rubescensine A (freeze-dried powder)
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 60.0g |
| PEG400 | 100ml |
| Lactose | 40g |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 16.
Embodiment 19 injection rubescensine A (freeze-dried powder)
Proportioning raw materials:
| Rubescensine A | 5.0g |
| Hydroxypropyl | 50.0g |
| PEG400 | 100ml |
| Glucose | 40g |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 16.
Embodiment 20 injection rubescensine A (freeze-dried powder)
Proportioning raw materials:
| Rubescensine A | 5.0g |
| Hydroxypropyl | 60.0g |
| PEG400 | 100ml |
| Sucrose | 40g |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 16.
Embodiment 21 injection rubescensine A (freeze-dried powder)
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 60.0g |
| PEG400 | 100ml |
| Sorbitol | 50g |
| Ethanol | 25m1 |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 16.
Embodiment 22 injection rubescensine A (freeze-dried powder)
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| Dextran-40 | 10g |
| PEG400 | 80ml |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 16.
Embodiment 23 injection Rebescensine A powder injections
Proportioning raw materials:
| Rubescensine A | 5.0g |
| Hydroxypropyl | 50.0g |
| Dextran-40 | 45g |
| Ethanol | 25ml |
| Water for injection | In right amount |
The preparation method of injection rubescensine A is as follows:
Take by weighing the rubescensine A of recipe quantity, be dissolved in the ethanol of recipe quantity; Take by weighing the HP-of recipe quantity, be dissolved in the water for injection of 300ml.After the two mixing, stirring reaction 4h, the control temperature is about 60 ℃.Add the 45g dextran-40, put coldly, regulate pH to 7.0, add the injection water to 500ml; Add active carbon 5g, be heated to 60 ℃, stirred 30 minutes, filter and take off charcoal, add the injection water to 500ml, through 0.22 μ m microporous filter membrane, Entkeimung, aseptic spray drying is by the packing of design dosage, promptly.
Embodiment 24 injection Rebescensine A powder injections
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| Mannitol | 20g |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 23.
Embodiment 25 injection Rebescensine A powder injections
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| Lactose | 40g |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 23.
Embodiment 26 injection Rebescensine A powder injections
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| Sucrose | 40g |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 23.
Embodiment 27 injection Rebescensine A powder injections
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| Sorbitol | 40g |
| Ethanol | 25ml |
| Water for injection | In right amount |
Preparation technology is referring to embodiment 23.
Embodiment 28 rubescensine A glucose injections
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| Glucose | (medicinal liquid cumulative volume 5%) |
| Ethanol | 25ml |
| Water for injection | In right amount |
The preparation method of this rubescensine A glucose injection:
Take by weighing the rubescensine A of recipe quantity, be dissolved in the ethanol of recipe quantity; Take by weighing the HP-of recipe quantity, be dissolved in the water for injection of 300ml.After the two mixing, stirring reaction 4h, the control temperature is about 60 ℃.Add glucose an amount of (be medicinal liquid cumulative volume 5%), put coldly, regulate pH to 7.0, add and inject water to 50 liter; Add active carbon, be heated to 60 ℃, stirred 30 minutes, filter and take off charcoal, add injection water to 50 liter, 0.45 microporous filter membrane filters, and lid is rolled in fill, 115-121 ℃ of pressure sterilizing 30 minutes, that is, and injection for intravenous usefulness.
Embodiment 29 rubescensine A sodium chloride injections
Proportioning raw materials:
| Rubescensine A | 5.0g |
| HP- | 50.0g |
| Sodium chloride | (medicinal liquid cumulative volume 0.9%) |
| Ethanol | 25ml |
| Water for injection | In right amount |
The preparation method of this rubescensine A sodium chloride injection:
Take by weighing the rubescensine A of recipe quantity, be dissolved in the ethanol of recipe quantity; Take by weighing the HP-of recipe quantity, be dissolved in the water for injection of 300ml.After the two mixing, stirring reaction 4h, the control temperature is about 60 ℃.Add sodium chloride an amount of (be medicinal liquid cumulative volume 0.9%), put coldly, regulate pH to 7.0, add and inject water to 25 liter; Add active carbon, be heated to 60 ℃, stirred 30 minutes, filter and take off charcoal, add injection water to 25 liter, the filtration of 0.45 microporous filter membrane, lid is rolled in fill, 115-121 ℃ of pressure sterilizing 30 minutes, promptly.Injection for intravenous is used.
Embodiment 30 rubescensine A sheets
Proportioning raw materials:
| The rubescensine A cyclodextrin clathrate | 150g |
| Hypromellose | 1g |
| Carboxymethylstach sodium | 8g |
| Silicon dioxide | 1.6g |
| Magnesium stearate | 1.44g |
| 3% hypromellose, 50% alcoholic solution | In right amount |
| Make | 1000 |
Preparation method: take by weighing cyclodextrin clathrate (embodiment 10) and hypromellose, in add the carboxymethylstach sodium mix homogeneously, it is an amount of to add 3% hypromellose, 50% alcoholic solution, makes soft material, pushes 16 mesh sieves, makes wet granular.Wet granular is put into 70 ℃ of oven dry of convection oven, adds behind the dried granule 16 mesh sieve granulate to add carboxymethylstach sodium, silicon dioxide, magnesium stearate mix homogeneously.The drift punch die is installed, and adjustment sheet heavily reaches pressure, tabletting, promptly.
Embodiment 31 rubescensine A sheets
Proportioning raw materials:
| The rubescensine A cyclodextrin clathrate | 100g |
| Microcrystalline Cellulose | 170g |
| Hyprolose | 20g |
| Magnesium stearate | 2g |
| 2.0% hypromellose, 50% alcoholic solution | In right amount |
| Make | 1000 |
Preparation method: take by weighing cyclodextrin clathrate (embodiment 10) and microcrystalline Cellulose, in add the hyprolose mix homogeneously, it is an amount of to add 2.0% hypromellose, 50% alcoholic solution, makes soft material, pushes 14 mesh sieves, makes wet granular.Wet granular is put into 70 ℃ of oven dry of convection oven, adds behind the dried granule 16 mesh sieve granulate to add hyprolose, magnesium stearate mix homogeneously.The drift punch die is installed, and adjustment sheet heavily reaches pressure, tabletting, promptly.
Embodiment 32 rubescensine A sheets
Proportioning raw materials:
| The rubescensine A cyclodextrin clathrate | 150g |
| Lactose | 73g |
| Hypromellose | 1g |
| Carboxymethylstach sodium | 20g |
| Silicon dioxide | 2g |
| Magnesium stearate | 1.8g |
| 3.0% hypromellose, 50% alcoholic solution | In right amount |
| Make | 1000 |
Preparation method: take by weighing cyclodextrin clathrate (embodiment 10) and lactose, hypromellose, in add the carboxymethylstach sodium mix homogeneously, it is an amount of to add 3.0% hypromellose, 50% alcoholic solution, makes soft material, pushes 14 mesh sieves, makes wet granular.Wet granular is put into 70 ℃ of oven dry of convection oven, adds behind the dried granule 16 mesh sieve granulate to add carboxymethylstach sodium, silicon dioxide, magnesium stearate mix homogeneously.The drift punch die is installed, and adjustment sheet heavily reaches pressure, tabletting, promptly.
Embodiment 33 rubescensine A capsules
Proportioning raw materials:
| The rubescensine A cyclodextrin clathrate | 150g |
| Hypromellose | 1g |
| Carboxymethylstach sodium | 4g |
| Silicon dioxide | 1.6g |
| Magnesium stearate | 1.44g |
| 3% hypromellose, 50% alcoholic solution | In right amount |
| Make | 1000 |
Preparation method:
Take by weighing cyclodextrin clathrate (embodiment 10) and hypromellose, carboxymethylstach sodium mix homogeneously, it is an amount of to add 3% hypromellose, 50% alcoholic solution, makes soft material, pushes 16 mesh sieves, makes wet granular.Wet granular is put into 70 ℃ of oven dry of convection oven, adds silicon dioxide, magnesium stearate mix homogeneously behind the dried granule 16 mesh sieve granulate.Regulate the capsule loading amount, fill, polishing, polishing are promptly.
Embodiment 34 rubescensine A capsules
Proportioning raw materials:
| The rubescensine A cyclodextrin clathrate | 150g |
| Microcrystalline Cellulose | 170g |
| Hyprolose | 10g |
| Magnesium stearate | 2g |
| 2.0% hypromellose, 50% alcoholic solution | In right amount |
| Make | 1000 |
Preparation method:
Take by weighing cyclodextrin clathrate (embodiment 10) and microcrystalline Cellulose, the third cellulose mix homogeneously, it is an amount of to add 2.0% hypromellose, 50% alcoholic solution, makes soft material, pushes 14 mesh sieves, makes wet granular.Wet granular is put into 70 ℃ of oven dry of convection oven, adds the magnesium stearate mix homogeneously behind the dried granule 16 mesh sieve granulate.Regulate the capsule loading amount, fill, polishing, polishing are promptly.
Embodiment 35 rubescensine A capsules
Proportioning raw materials:
| The rubescensine A cyclodextrin clathrate | 200g |
| Lactose | 73g |
| Hypromellose | 1g |
| Carboxymethylstach sodium | 10 |
| Silicon dioxide | 2g |
| Magnesium stearate | 1.8g |
| 3.0% hypromellose, 50% alcoholic solution | In right amount |
| Make | 1000 |
Preparation method:
Take by weighing cyclodextrin clathrate (embodiment 10) and lactose, hypromellose, carboxymethylstach sodium mix homogeneously, it is an amount of to add 3.0% hypromellose, 50% alcoholic solution, makes soft material, pushes 14 mesh sieves, makes wet granular.Wet granular is put into 70 ℃ of oven dry of convection oven, adds silicon dioxide, magnesium stearate mix homogeneously behind the dried granule 16 mesh sieve granulate.Regulate the capsule loading amount, fill, polishing, polishing are promptly.
Embodiment 36 rubescensine A soft capsules
(1) content prescription
| The rubescensine A cyclodextrin clathrate | 150g |
| PEG400 | 150ml |
| Make | 1000 |
(2) prescription of soft capsule peel
| Gelatin | 305.0g |
| Glycerol | 249.5g |
| Purified water | 443.5g |
| Methyl parahydroxybenzoate | 0.99g |
| Propyl p-hydroxybenzoate | 0.50g |
| Iron oxide red | 0.01g |
| Titanium dioxide | 0.60g |
| Full dose | 1000g |
Preparation method:
Take by weighing cyclodextrin clathrate (embodiment 10), measure PEG400, mix homogeneously promptly gets the content of soft capsule.
It is standby that titanium dioxide and iron oxide red are crossed 100 mesh sieves.Take by weighing in the purified water of methyl parahydroxybenzoate, propyl p-hydroxybenzoate adding recipe quantity, heated and stirred makes dissolving, and glycerol, gelatin, titanium dioxide, iron oxide red are added in the solution, stirs, and heats little boiling and boils, and replenishes scattering and disappearing of part moisture.
Content, the rubber cement of soft capsule are respectively charged in the hopper separately of semi-automatic soft capsule manufacturing filling machine, and it is promptly rolling to start shooting.
Embodiment 37 rubescensine A cyclodextrin inclusion compound composition soft capsules
(1) content prescription
| The rubescensine A cyclodextrin clathrate | 100g |
| PEG400 | 200ml |
| Make | 1000 |
(2) prescription of soft capsule peel
| Gelatin | 305.0g |
| Glycerol | 249.5g |
| Purified water | 443.5g |
| Methyl parahydroxybenzoate | 0.99g |
| Propyl p-hydroxybenzoate | 0.50g |
| Iron oxide red | 0.01g |
| Titanium dioxide | 0.60g |
| Full dose | 1000g |
Preparation method:
Take by weighing cyclodextrin clathrate (embodiment 10), measure PEG400, mix homogeneously promptly gets the content of soft capsule.
It is standby that titanium dioxide and iron oxide red are crossed 100 mesh sieves.Take by weighing in the purified water of methyl parahydroxybenzoate, propyl p-hydroxybenzoate adding recipe quantity, heated and stirred makes dissolving, and glycerol, gelatin, titanium dioxide, iron oxide red are added in the solution, stirs, and heats little boiling and boils, and replenishes scattering and disappearing of part moisture.
Content, the rubber cement of soft capsule are respectively charged in the hopper separately of semi-automatic soft capsule manufacturing filling machine, and it is promptly rolling to start shooting.
Embodiment 38 rubescensine A cyclodextrin clathrate oral liquids
Proportioning raw materials:
| The rubescensine A cyclodextrin clathrate | 150g |
| PEG400 | 100ml |
| Sucrose | 4000g |
| Ethylparaben | 10g |
| Fructus Citri Limoniae essence | In right amount |
| Deionized water | To 10000ml |
| Make | 1000 |
Preparation method:
Precision takes by weighing rubescensine A cyclodextrin clathrate (embodiment 10), PEG400, sucrose, ethylparaben and Fructus Citri Limoniae essence, add in the 10000ml deionized water, stirring makes dissolving, the pH value of regulator solution, pH value should be 6.0, the needle-use activated carbon that adds amount of liquid medicine 0.05%, 70 ℃ adsorbed 30 minutes.Coarse filtration is removed active carbon, uses 0.8 μ m microporous filter membrane fine straining, and filtrate pours in the 10ml oral liquid bottle, rolls lid.Sample is put into the sterilization cabinet, 100 ℃ of flowing steam sterilizations 30 minutes, promptly.
Embodiment 39 rubescensine A cyclodextrin clathrate oral liquids
Proportioning raw materials:
| The rubescensine A cyclodextrin clathrate | 100g |
| PEG400 | 200ml |
| Glucose | 400g |
| Stevioside | 60g |
| Ethylparaben | 10g |
| Fructus Citri Limoniae essence | In right amount |
| Deionized water | To 10000ml |
| Make | 1000 |
Preparation method:
Precision takes by weighing rubescensine A cyclodextrin clathrate (embodiment 10), PEG400, glucose, stevioside, ethylparaben and Fructus Citri Limoniae essence, add in the 10000ml deionized water, stirring makes dissolving, the pH value of regulator solution, pH value should be 6.0, the needle-use activated carbon that adds amount of liquid medicine 0.05%, 70 ℃ adsorbed 30 minutes.Coarse filtration is removed active carbon, uses 0.8 μ m microporous filter membrane fine straining, and filtrate pours in the 10ml oral liquid bottle, rolls lid.Sample is put into the sterilization cabinet, 100 ℃ of flowing steam sterilizations 30 minutes, promptly.
Claims (7)
1. rubescensine A clathrate, its be rubescensine A by the product of all or part of enclose of cyclodextrin, the weight ratio of rubescensine A and cyclodextrin is 1 in this clathrate: 5-1: 10.
2. the described rubescensine A clathrate of claim 1, wherein, described cyclodextrin is alpha-cyclodextrin, r-cyclodextrin, beta-schardinger dextrin-or beta-cyclodextrin derivative, and described beta-cyclodextrin derivative comprises DM-, TM-, HP-, G 1-CD, G 2-CD, G 3-, 2G1-or 2G2-.
3. the preparation method of claim 1 or 2 described rubescensine A clathrates, it comprises: rubescensine A is dissolved in makes alcohol soluble substance in the ethanol, cyclodextrin is made solution with water dissolution, and the two mixes the back and ℃ stirred 0.5-8 hour down in room temperature-80.
4. pharmaceutical composition that contains rubescensine A, it comprises claim 1 or 2 described rubescensine A clathrate and pharmacy adjuvants.
5. the described pharmaceutical composition of claim 4, it is injection or oral formulations.
6. the described pharmaceutical composition of claim 5, wherein, described injection is injection, spray powder pin or freeze-dried powder, and pharmacy adjuvant wherein comprises one or more in low-molecular-weight dextran, PEG400, polyethylene glycol 6000, mannitol, lactose, glucose, sucrose, sodium chloride and the sorbitol.
7. the described pharmaceutical composition of claim 5, wherein, described oral formulations comprises tablet, granule, hard capsule, soft capsule and oral liquid.
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| CNB2006100722268A CN100417378C (en) | 2006-04-12 | 2006-04-12 | Oridonin clathrate compound, and medicinal prepn. thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102755379A (en) * | 2012-07-17 | 2012-10-31 | 河南大学 | Novel preparation technology of rabdosia rubescens tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101181260B (en) * | 2007-11-28 | 2010-06-02 | 贾儒 | Rabdosia nail element clathrate and pharmaceutical preparation containing the same |
| CN103768616B (en) * | 2014-01-08 | 2015-08-05 | 中国科学院昆明植物研究所 | Eriocalyxin B cyclodextrin clathrate, pharmaceutical composition containing this clathrate, its preparation method and application |
| CN107281167B (en) * | 2017-07-21 | 2018-04-13 | 安士制药（中山）有限公司 | A kind of benzonatate soft capsule and preparation method thereof |
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| CN1554334A (en) * | 2003-12-30 | 2004-12-15 | 乔文晖 | Rebescensine A emulsion and its preparing method |
| CN1650855A (en) * | 2004-12-09 | 2005-08-10 | 中国科学院武汉植物园 | Rabdosia rubescens injection agent and its preparation technology |
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| CN1554334A (en) * | 2003-12-30 | 2004-12-15 | 乔文晖 | Rebescensine A emulsion and its preparing method |
| CN1650855A (en) * | 2004-12-09 | 2005-08-10 | 中国科学院武汉植物园 | Rabdosia rubescens injection agent and its preparation technology |
| CN1686106A (en) * | 2005-04-15 | 2005-10-26 | 沈阳药科大学 | Rabdosia rubescens A microglobule medicinal agent and its preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102755379A (en) * | 2012-07-17 | 2012-10-31 | 河南大学 | Novel preparation technology of rabdosia rubescens tablet |
| CN102755379B (en) * | 2012-07-17 | 2014-07-09 | 河南大学 | Novel preparation technology of rabdosia rubescens tablet |
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Owner name: JILIN A-THINK PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: JILIN YIXIN PHARMACEUTICAL CO., LTD. |
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Address after: 130616 Jilin province Changchun Shuangyang Economic Development Zone on the road No. 1 Patentee after: SINOPHARM A-THINK PHARMACEUTICAL Co.,Ltd. Address before: 130616 Jilin province Changchun Shuangyang Economic Development Zone on the road No. 1 Patentee before: Jilin Yixin pharmaceutical Limited by Share Ltd. |
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