CN100408025C - Self-emulsifying composition of beta-11 betamethasone, preparation process and application thereof - Google Patents
Self-emulsifying composition of beta-11 betamethasone, preparation process and application thereof Download PDFInfo
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- CN100408025C CN100408025C CNB2006101187631A CN200610118763A CN100408025C CN 100408025 C CN100408025 C CN 100408025C CN B2006101187631 A CNB2006101187631 A CN B2006101187631A CN 200610118763 A CN200610118763 A CN 200610118763A CN 100408025 C CN100408025 C CN 100408025C
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Abstract
The invention discloses a self-emulsifying composition of betamethasone beta-11 and its use in preparing betamethasone. The self-emulsifying composition comprises betamethasone beta-11 parts, oil phase 15-55 parts, assistant emulsifier 15-46 and emulsifying agent 15-55 parts.
Description
Technical field
The present invention relates to self emulsifying technology and field of medicine preparing technology, relate in particular to a kind of self-emulsifying composition that contains betamethasone β-11 thing, and the preparation method of said composition and the application in betamethasone preparation technology.
Background technology
Self-emulsifying drug delivery systems (Self-Emulsifying System) is a kind of faster technology of development in recent years, is a kind of solid or liquid that comprises oil phase, surfactant (emulsifying agent) and cosurfactant (co-emulsifier).Plant oil after wherein oil phase mostly is fatty acid ester and passes through structure of modification or hydrolysis, flowability, dissolubility and self emulsifying are better; Surfactant is generally the non-ionic surface active agent with higher HLB value, adds the consumption that an amount of cosurfactant can reduce main surfactant simultaneously, reduces the safety problem of using surfactant to cause repeatedly.The micellar interfacial film of common formation in the molecule of the molecule embedding surfactant of cosurfactant, the emulsion droplet diameter of Xing Chenging can be less than 100 nanometers thus.Except improving aspect drug-supplying system the drug bioavailability, the self emulsifying technology has a significant advantage, can improve the dissolubility of medicine.
The basic feature of self-emulsifying drug delivery systems is can spontaneous formation oil in water emulsion under the situation of ambient temperature and gentle agitation.Behind the dilute with water, emulsifying agent forms the interfacial film around the emulsion droplet, thereby reduces interface energy and form accumulative barrier.In self-emulsifying drug delivery systems, the needed free energy of emulsifying is very low, so emulsion process can spontaneous generation.This self emulsifying character is not need resistance when carrying out surface shear to the requirement of interfacial structure.When two-phase mixture (oil/nonionic emulsifier) when being added to the water, is formed on the interface between oil and the water.Along with moisture infiltrates, finally all one-tenth near the interface are divided into liquid crystalline phase, and the amount of liquid crystalline phase depends on the concentration of emulsifying agent in the biphase mixture.In a single day the interface liquid crystalline phase forms, and moisture infiltrates the interface rapidly, under slight stirring, causes that break in the interface and emulsion droplet forms.
At present, the existing self emulsifying technology (WO/00/71673 that adopts, DE3738812A1), also there is microemulsion technology (WO/00/71672) to be applied to sweat, its purpose all mainly is to utilize natural fat and the oils in the self-emulsifier, and the derivant of this class material, as glycerol, glyceride, fatty acid or fatty ester, as the nutriment of microorganism, supply with by the nutriment that increases microorganism, to improve the work efficiency of microorganism.
The betamethasone synthetic reaction process have pregnant steroid structure suc as formula the intermediate product shown in the I (16 Beta-methyls-1,4-diene progesterone-17 α, 21-glycol-3,20-diketone-21-acetas ", be called for short " betamethasone β-11 thing " among the present invention), water solublity is relatively poor.In course of reaction (formula as follows), be subjected to the influence of its dissolubility, it is to suc as formula (16 Beta-methyls-1 of the chemical compound shown in the II, 4-diene progesterone-11 α, 17 α, 21-triol-3,20-diketone "; be called for short " betamethasone β-12 thing " among the present invention) biological transformation ratio low, the reaction substrate inventory is forced to reduce; Required transformation time is long simultaneously, has a strong impact on betamethasone and closes
Formula I betamethasone β-11 thing formula II betamethasone β-12 thing
Become the speed of reaction.Therefore, solve due to the betamethasone β-11 thing slightly water-soluble and to become those skilled in the art to the low problem of β-12 thing biological transformation ratio and attempt the technical barrier that overcome for a long time always.
Summary of the invention
The technical problem to be solved in the present invention promptly is an above-mentioned difficult problem, and a kind of betamethasone intermediate is provided---the self-emulsifying composition of betamethasone β-11 thing is used to improve the speed of betamethasone synthetic reaction.
Adopt self-emulsifying composition of the present invention in the betamethasone synthetic reaction process; need not to add extra high-speed stirred; usually can form nano level microgranule under the stirring condition of chemical reaction, increase the dissolubility of the middle medicine of slightly solubility steroidal class, be of great importance for production.Choose suitable oil, emulsifying agent, co-emulsifier and suitably optimize process conditions, can increase the input amount of substrate in the steroid drugs bioconversion reaction, in the identical production time, only increase cost of supplementary product such as small amounts of emulsifiers, just can improve final products output greatly, reduce production costs, improve competitive power of product.
Betamethasone intermediate self-emulsifying composition of the present invention is grouped into by one-tenth such as betamethasone intermediate β-11 thing, oil phase, emulsifying agent, co-emulsifier, thickening agents.
The self-emulsifying composition of betamethasone β-11 thing of the present invention, it can comprise the each component of following weight portion:
10 parts of betamethasone β-11 things
Oil phase 15-55 part
Emulsifying agent 15-55 part
Co-emulsifier 13-46 part
Thickening agent 0-10 part
Wherein, said oil phase can be vegetable oil, fatty acid ester or mineral oil.Vegetable oil comprises Oleum Ricini, Oleum Glycines, Oleum Arachidis hypogaeae semen, olive oil, and their mixture; The preferred Oleum Ricini of the present invention.Fatty acid ester comprises MCT, as MCT (three sad caprins), Captex 355 (oil), Miglyol 812 various Oleum Cocois C8/C10 triglyceride such as (oil), Captex 200 (oil, Oleum Cocois C8/C10 propylene glycol dibasic acid esters), Capmul MCM (HLB=5.5～6.0, Oleum Cocois C8/C10 monoglyceride or dibasic acid esters); With the long-chain fat acid glyceride, as Arlacel 80 (oleic acid sorbitol ester), Arlacel 86 (olein-propylene glycol (weight ratio 90: 10)), Peceol (olein), Maisine (glyceryl linoleate), Myverol48-92 (purification Oleum helianthi monoglyceride (containing the 90w/w% glyceryl linoleate)), ethyl oleate, Gelucire 44/14 (Polyethylene Glycol glyceryl laurate ester) etc.; The preferred MCT of the present invention, ethyl oleate.Mineral oil comprises white beeswax oil, liquid paraffin etc., and their mixture.
Described emulsifying agent be selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, crude vegetal triglyceride (
M), Polyethylene Glycol-8-glycerol is sad/decanoin (Labrasol), poly yamanashi esters [tween (Tween) 40, Tween60, Tween80], aerosol-OT (Aerosol), poloxamer F68/188, and their mixture; Among the preferred polyoxyethylene castor oil of the present invention, polyoxyethylene hydrogenated Oleum Ricini and the Tween80 one or more.
Described co-emulsifier be selected from Polyethylene Glycol that ethanol, propylene glycol (1, the 2-propylene glycol), glycerol, molecular weight are 200-600,
M, ethylene glycol monomethyl ether (transcutol P), and their mixture; Preferred alcohol of the present invention, propylene glycol,
Among M and the transcutol P one or more.
Described thickening agent is selected hydroxypropyl emthylcellulose for use.
The weight ratio of above-mentioned betamethasone β-11 thing and oil phase is preferably 0.25-0.33.
The weight ratio of oil phase and emulsifying agent preferred 0.67～1.2.
The weight ratio of oil phase and co-emulsifier preferred 0.86～2.67.
The present invention also provides the preparation method of above-mentioned self-emulsifying composition.It comprises that each component with above-mentioned self-emulsifying composition places the 50L material-compound tank, logical steam, behind 80 ℃ of reflux 0.5h promptly.Add in the fermentation liquid, adopt laser particle analyzer to measure, emulsion droplet mean diameter 100～310nm is preferably 100-200nm, and 90% particle diameter accumulated value is 150～550nm, preferred 190-350nm.
The self-emulsifying composition of betamethasone β-11 thing of the present invention is used to prepare betamethasone.80 ℃ of heating of the self-emulsifying composition that is about to prepare, reflux after, add in the cultured fermentation liquid and get final product.
Wherein, prior art is adopted in the cultivation of fermentation liquid, comprising:
Transform culture medium: cottonseed meal 0.8w/w%, Glu (glucose) w/w 4.8%, KCl 0.024w/w%, KNO
30.6w/w%, surplus is a buffer;
Buffer formulation: MgSO
40.05w/w%, K
2HPO
40.2w/w%, KH
2PO
40.1w/w%, KNO
30.1w/w%;
Mycete green muscardine fungus (Metarrhizium sp.) inclined-plane kind is inserted the conversion culture medium carry out seed culture, inoculum concentration 0.2% (w/w), 28 ℃ of cultivation temperature after seed is grown well, drop into substrate (self-emulsifying composition of betamethasone β-11 thing) and transform.Seed culture and conversion are carried out in same jar.
Usually after treating that seed is grown well, (2-5 drips/500ml) joins to put into behind the mixing in the substrate and transforms in the culture medium, begins to transform a certain amount of bubble enemy.After transforming 45h, the buffer of replenish lost continues to be converted into fermentation to be finished.
In sum, the present invention has following advantage:
1. self-emulsifying composition of the present invention, batching is easy to get, and preparation is simple, and is with low cost, and suitability for industrialized is used.
2. self-emulsifying composition of the present invention significantly improves the biological transformation ratio of betamethasone β-11 thing to betamethasone β-12 thing.
3. these those skilled in the art that self-emulsifying composition of the present invention has overcome betamethasone β-11 thing poorly water-soluble are difficult to the technical barrier that overcomes for a long time always, have improved betamethasone synthetic reaction speed.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1
Betamethasone β-11 thing 80g
MCT (MCT) 150g
Dehydrated alcohol 130g
1,2-propylene glycol 160g
Polyoxyethylene hydrogenated Oleum Ricini RH40 250g
Hydroxypropyl emthylcellulose E15 70g
The enemy mixes post-heating with above recipe quantity material and 80ml bubble, and 80 ℃ of backflow 0.5h add in the good fermentation liquid of mycete (seed) growth and transform.After adding in the fermentation liquid, mean diameter 200nm, 90% particle diameter accumulated value is 360nm.
Embodiment 2
Betamethasone β-11 thing 80g
MCT (MCT) 240g
Tween 80 80g
Polyoxyethylene hydrogenated Oleum Ricini RH40 200g
The enemy mixes post-heating with above recipe quantity material and 80ml bubble, and 80 ℃ of backflow 0.5h add in the good fermentation liquid of fungus growth and transform.After adding in the fermentation liquid, mean diameter 227nm, 90% particle diameter accumulated value is 395nm.
Embodiment 3
Betamethasone β-11 thing 80g
Oleum Ricini 230g
1,2-propylene glycol 120g
Transcutol?P 220g
Polyoxyethylene hydrogenated Oleum Ricini RH40 250g
The enemy mixes post-heating with above recipe quantity material and 80ml bubble, and 80 ℃ of backflow 0.5h add in the good fermentation liquid of fungus growth and transform.After adding in the fermentation liquid, mean diameter 120nm, 90% particle diameter accumulated value is 198nm.
Embodiment 4
Betamethasone β-11 thing 80g
Oleum Ricini 240g
Transcutol?P 110g
Labrasol 180g
Polyoxyethylene castor oil 240g
The enemy mixes post-heating with above recipe quantity material and 80ml bubble, and 80 ℃ of backflow 0.5h add in the good fermentation liquid of fungus growth and transform.After adding in the fermentation liquid, mean diameter 242nm, 90% particle diameter accumulated value is 474nm.
Embodiment 5
Betamethasone β-11 thing 80g
Ethyl oleate 300g
Transcutol?P 350g
Polyoxyethylene hydrogenated Oleum Ricini RH40 340g
The enemy mixes post-heating with above recipe quantity material and 80ml bubble, and 80 ℃ of backflow 0.5h add in the good fermentation liquid of fungus growth and transform.After adding in the fermentation liquid, mean diameter 299nm, 90% particle diameter accumulated value is 500nm.
Embodiment 6
Betamethasone β-11 thing 80g
Oleum Ricini 300g
Soybean oil 120g
Dehydrated alcohol 120g
PEG400 120g
Tween 80 100g
Polyoxyethylene hydrogenated Oleum Ricini RH40 340g
The enemy mixes post-heating with above recipe quantity material and 80ml bubble, and 80 ℃ of backflow 0.5h add in the good fermentation liquid of fungus growth and transform.After adding in the fermentation liquid, mean diameter 310nm, 90% particle diameter accumulated value is 550nm.
Embodiment 7
Betamethasone β-11 thing 80g
Liquid paraffin 260g
Dehydrated alcohol 130
Transcutol?P 230g
Polyoxyethylene castor oil 120g
The enemy mixes post-heating with above recipe quantity material and 80ml bubble, and 80 ℃ of backflow 0.5h add in the good fermentation liquid of fungus growth and transform.After adding in the fermentation liquid, mean diameter 280nm, 90% particle diameter accumulated value is 492nm.
Comparative examples 1
Betamethasone β-11 thing 80g
Dehydrated alcohol 400g
Above recipe quantity betamethasone is dissolved in the ethanol, stirs, the dissolving back is stand-by.
Comparative examples 2 (existing production used prescription)
Betamethasone β-11 thing 45g
Dehydrated alcohol 200g
Above recipe quantity betamethasone is dissolved in the ethanol, stirs, the dissolving back is stand-by.
Experimental example 1 conversion ratio, yield in unit time are relatively
Operation: with the oil phase of betamethasone β-11 thing of the foregoing description and recipe quantity, emulsifying agent, co-emulsifier, thickening agent (if any words) place the 50L material-compound tank, logical steam, behind 80 ℃ of reflux 0.5h, strengthen the pressure of material-compound tank, be pressed into 500L after good concentrated liquid and the 80ml bubble enemy that wherein refluxes mixed, comprise in the long seed and the fermentation tank of fermentation liquid after good, 28 ℃, air mass flow 1.0m
3/ min, stirring condition (270 rev/mins) reacted 65 hours down; Alcoholic solution with betamethasone β-11 thing of comparative examples 1,2 is pressed in the fermentation tank of 500L, and 28 ℃, air mass flow 1.0m
3/ min, stirring condition (270 rev/mins) reacted 65 hours or 84 hours down.The results are shown in following table:
The self-emulsifying composition of table 1 betamethasone β-11 of the present invention thing and comparative example's conversion results are relatively
Annotate: bottle branch A, B are convenient to verify accuracy, the repeatability of same sample data.
Experimental result shows that under the identical inventory, self-emulsifying composition of the present invention adds in the fermentation liquid, forms homogenous emulsion, and precipitation does not occur, good stability; Do not have a large amount of foams and produce, be fit to suitability for industrialized production, the response time shortens greatly.Compare with existing production output, conversion ratio and output all have largely in the same reaction time increases.And along with the minimizing of emulsion droplet particle diameter, conversion ratio obviously increases, and hydrolysis point is few.
Claims (16)
1. the self-emulsifying composition of a compound shown by formula I, it comprises the each component of following weight portion:
10 parts of formula I chemical compounds
Oil phase 15-55 part
Emulsifying agent 15-55 part
Co-emulsifier 13-46 part
Thickening agent 0-10 part;
Formula I
Described oil phase is vegetable oil, fatty acid ester or mineral oil;
Described emulsifying agent be selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, crude vegetal triglyceride, Polyethylene Glycol-8-glycerol sad/in decanoin, poly yamanashi esters, aerosol-OT and the poloxamer one or more;
It is the Polyethylene Glycol of 200-600 and in the ethylene glycol monomethyl ether one or more that described co-emulsifier is selected from ethanol, propylene glycol, glycerol, molecular weight.
2. self-emulsifying composition as claimed in claim 1 is characterized in that described vegetable oil is selected from Oleum Ricini, Oleum Glycines, Oleum Arachidis hypogaeae semen and olive oil.
3. self-emulsifying composition as claimed in claim 1 is characterized in that described fatty acid ester is MCT or long-chain fat acid glyceride.
4. self-emulsifying composition as claimed in claim 3 is characterized in that described MCT is selected from three sad caprins, Oleum Cocois C8/C10 triglyceride, Oleum Cocois C8/C10 monoglyceride or dibasic acid esters and Oleum Cocois C8/C10 propylene glycol dibasic acid esters.
5. as self-emulsifying composition as described in the claim 3, it is characterized in that described long-chain fat acid glyceride is selected from oleic acid sorbitol ester, olein-propylene glycol, olein, glyceryl linoleate, purification Oleum helianthi monoglyceride, ethyl oleate and Polyethylene Glycol glyceryl laurate ester.
6. self-emulsifying composition as claimed in claim 1 is characterized in that described mineral oil is white beeswax oil or liquid paraffin.
7. self-emulsifying composition as claimed in claim 1 is characterized in that described thickening agent is a hydroxypropyl emthylcellulose.
8. self-emulsifying composition as claimed in claim 1, the weight ratio that it is characterized in that formula I chemical compound and oil phase is 0.25～0.33.
9. self-emulsifying composition as claimed in claim 1, the weight ratio that it is characterized in that this oil phase and emulsifying agent is 0.67～1.2.
10. self-emulsifying composition as claimed in claim 1, the weight ratio that it is characterized in that this oil phase and co-emulsifier is 0.86～2.67.
11., it is characterized in that the emulsion droplet mean diameter 100～310nm of this self-emulsifying composition as each described self-emulsifying composition of claim 1-10.
12. self-emulsifying composition as claimed in claim 11 is characterized in that this emulsion droplet mean diameter is 100～200nm.
13., it is characterized in that 90% emulsion droplet particle diameter accumulated value, the 150～550nm of this self-emulsifying composition as each described self-emulsifying composition of claim 1-10.
14. self-emulsifying composition as claimed in claim 13 is characterized in that described 90% emulsion droplet particle diameter accumulated value is 190～350nm.
15. preparation method as each described self-emulsifying composition of claim 1-10, it may further comprise the steps: the formula I chemical compound by described parts by weight, and oil phase, emulsifying agent, co-emulsifier, thickening agent place material-compound tank, logical steam, 80 ℃ of reflux 0.5h.
16. as the application of each described self-emulsifying composition of claim 1-10 in the preparation betamethasone.
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| CNB2006101187631A CN100408025C (en) | 2006-11-24 | 2006-11-24 | Self-emulsifying composition of beta-11 betamethasone, preparation process and application thereof |
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| CN100408025C true CN100408025C (en) | 2008-08-06 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1118351A (en) * | 1994-06-02 | 1996-03-13 | 鲁索-艾克勒夫公司 | New preparation process for a 16SS-methyl steroid and new intermediates |
| CN1338942A (en) * | 1998-12-11 | 2002-03-06 | 药品处理公司 | Self-emulsifying compositions for drugs poorly soluble in water |
| CN1361287A (en) * | 2000-12-27 | 2002-07-31 | 天津药业集团有限公司 | Technological process of producing Betamethasone dehydrogenating material |
| CN1724554A (en) * | 2005-07-15 | 2006-01-25 | 四川大学 | 1,4-pregnandiene 17 alpha, 21'-dihydroxy-3,20-diketone-17 alpha, 21-diacetate |
-
2006
- 2006-11-24 CN CNB2006101187631A patent/CN100408025C/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1118351A (en) * | 1994-06-02 | 1996-03-13 | 鲁索-艾克勒夫公司 | New preparation process for a 16SS-methyl steroid and new intermediates |
| CN1338942A (en) * | 1998-12-11 | 2002-03-06 | 药品处理公司 | Self-emulsifying compositions for drugs poorly soluble in water |
| CN1361287A (en) * | 2000-12-27 | 2002-07-31 | 天津药业集团有限公司 | Technological process of producing Betamethasone dehydrogenating material |
| CN1724554A (en) * | 2005-07-15 | 2006-01-25 | 四川大学 | 1,4-pregnandiene 17 alpha, 21'-dihydroxy-3,20-diketone-17 alpha, 21-diacetate |
Non-Patent Citations (1)
| Title |
|---|
| 简单节杆菌催化17α-羟基-16β-甲基孕甾-4,9(11)二烯-3,20-二酮脱氢动力学研究. 王普等.浙江大学学报（工学版），第38卷第8期. 2004 * |
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