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 PDF

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CN100408025C
CN100408025C CN 200610118763 CN200610118763A CN100408025C CN 100408025 C CN100408025 C CN 100408025C CN 200610118763 CN200610118763 CN 200610118763 CN 200610118763 A CN200610118763 A CN 200610118763A CN 100408025 C CN100408025 C CN 100408025C
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self
oil
emulsifying composition
betamethasone
parts
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CN 200610118763
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CN1965808A (en
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坤 刘
朱春柳
杨凌风
杨怡静
勇 甘
莉 甘
韩建生
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上海医药(集团)有限公司;中国科学院上海药物研究所
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Abstract

本发明公开了一种倍他米松β-11物自乳化组合物及其在制备倍他米松中的应用。 The present invention discloses A betamethasone β-11 and their applications betamethasone dipropionate in the manufacture of a self-emulsifying composition. 本发明自乳化组合物包括倍他米松β-11物10份、油相15-55份、助乳化剂15-46份、乳化剂15-55份。 The present invention is a self-emulsifying composition comprising betamethasone β-11 was 10 parts, the oil phase 15-55 parts, 15-46 parts co-emulsifier, 15-55 parts of an emulsifier. 该组合物在制备倍他米松的发酵液中能均匀分散成乳液,粒径均匀;所用试剂、溶剂易得;在增加少量辅料成本的条件下,能够较大程度提高增加倍他米松β-11物向β-12物生物转化步骤中底物的投料量,增加转化率,大大提高产量,降低能耗及成本。 The compositions were prepared in a fermentation betamethasone uniformly dispersed in an emulsion, a uniform particle size; the reagents, readily available solvents; a slight increase in the cost of auxiliary conditions, can be increased to a large extent improved betamethasone β-11 end of the bioconversion step was β-12 was administered quantity thereof, conversion increases significantly increase productivity, reduce energy consumption and costs.

Description

倍他米松P —ll物的自乳化组合物及其制备方法和应用技术领塽本发明涉及自乳化技术和药物制备技术领域,尤其涉及一种含有倍他米松P — ll物的自乳化组合物,以及该组合物的制备方法和在倍他米松制备工艺中的应用。 Betamethasone P -ll was self-emulsifying composition and preparation methods and techniques of the present invention relates to a collar shuang self-emulsifiable pharmaceutical preparation techniques and technologies, and in particular relates containing betamethasone P - self-emulsifying composition thereof ll , and methods for preparing the composition and in the preparation of betamethasone process. 背录技术自乳化系统(Sdf-Emulsifying System)是近年来发展较快的一种技术,是一种包含油相、表面活性剂(乳化剂)和助表面活性剂(助乳化剂)的固体或液体。 Recording technology since back emulsifying system (Sdf-Emulsifying System) is a technique developed rapidly in recent years, an oil phase comprising a solid surfactant (emulsifier) ​​and a co-surfactant (co-emulsifier) ​​or liquid. 其中油相多为脂肪酸酯类和经过结构改造或水解后的植物油类,流动性、溶解性和自乳化性较好;表面活性剂通常为具有较高HLB值的非离子表面活性剂,同时加入适i的辅助表面活性剂能减少主要表面活性剂的用量,减少反复使用表面活性剂引发的安全问题。 Wherein the plurality of the oil phase and the fatty acid esters or after structural modification hydrolyzed vegetable oils, flowability, solubility, and good self-emulsifying; surfactant is typically nonionic surfactant having a high HLB value, while adding i suitable auxiliary surfactants can reduce the amount of primary surfactant, reduces safety problems surfactants used repeatedly initiated. 辅助表面活性剂的分子嵌入表面活性剂的分子中共同形成胶束的界面膜,由此形成的乳滴直径可小于100纳米。 Molecular cosurfactant molecules embedded in the surfactant micelles together form interfacial film, thus formed emulsion droplet diameter may be less than 100 nanometers. 除了在给药系统方面可提高药物生物利用度外,自乳化技术有一显著优势,可提高药物的溶解度。 In addition to the drug delivery system can improve the bioavailability aspect givers, there is a self-emulsifying significant technical advantages, can increase the solubility of the drug. 自乳化系统的基本特征是在环境温度及温和搅拌的情况下能自发形成水包油乳剂。 The basic features of the self-emulsifying system is spontaneously formed oil in water emulsion and at ambient temperature with gentle stirring. 用水稀释后,乳化剂形成乳滴周围的界面膜,从而降低界面能和形成聚集的屏陣。 After dilution with water, the emulsifier forming an interfacial film around the emulsion droplets, thereby lowering the interfacial energy and the formation of aggregates of the matrix screen. 在自乳化系统中,乳化所需要的自由能非常低,所以乳化过程会自然发生。 In the self-emulsifying system, free emulsion needed to be very low, so the emulsification process occurs naturally. 这种自乳化性质对界面结构的要求是进行表面剪切时不需要阻力。 Such unwanted resistance self emulsifying property requirements of the interface structure is cut surface. 当将两相混合物(油/非离子型乳化剂)加入到水中时,形成在油和水之间的界面。 When the two-phase mixture (oil / non-ionic emulsifiers) are added to water to form an interface between oil and water. 随着水分渗入,最终所有靠近界面的成分成为液晶相,液晶相的量依赖于双相混合物中乳化剂的浓度。 With the penetration of moisture into, eventually all of the components become close to the interface of the liquid crystal phase and crystal phase is dependent on the concentration of the emulsifier in the biphasic mixture. 界面液晶相一旦形成,水4Hfi速渗入界面,在轻微的搅拌下,引起界面破裂和乳滴形成。 Once the liquid crystalline phase interface is formed, the water penetration speed 4Hfi interface, under slight stirring, causing interfacial rupture and the emulsion droplets are formed. 目前,已有采用自乳化技术(WO/00/71673, DE3738812A1)、也有微乳技术(WO/00/71672)应用于发酵过程,其目的都主要在于利用自乳化剂中的天然脂肪和油类,以及这类物质的衍生物,如甘油、甘油酯、脂肪酸或脂肪酯,作为微生物的养料,通过增加微生物的养料供给,以提高微生物的工作效率。 At present, self-emulsifying techniques (WO / 00/71673, DE3738812A1), there microemulsion art (WO / 00/71672) is applied to the fermentation process, the purpose of use are primarily self-emulsifying dosage of natural fats and oils , and derivatives of such materials, such as glycerol, glycerides, fatty acids or fatty acid esters, for nutrition of microorganisms, the microorganisms by increasing the supply of nutrients, in order to improve the efficiency of the microorganism. 倍他米松合成反应过程的如式I所示的中间产物(1613-甲基-1, 4-二烯孕酮-17a, 21-二醇-3, 20-二酮-21-乙酸酯",本发明中简称"倍他米松3 一ll物")具有孕甾结构,水溶性较差。在反应过程中(见下式),受其溶解度的影响,其向如式II所示的化合物(16J3-甲基-1, 4-二烯孕酮-lla, 17a, 21-三醇-3, 20-二酮",本发明中简称"倍他米松P—12物")的生物转化率低,反应底物投料量被迫减少;同时所需转化时间长,严重影响倍他米松合<formula>formula see original document page 5</formula>式I倍他米松3 -11物式II倍他米松P -12物成反应的速率。 Betamethasone intermediate (1613- methyl-1,4-dienes of Formula I as shown -17a progesterone synthesis reaction process, the diol 21 -3, 20-dione-21-acetate " in the present invention referred to as "a ll betamethasone was 3") having pregnane structure, poor water solubility. in the course of the reaction (see the following formula), the solubility of the affected, a compound represented by the formula II (16J3- methyl-1, 4-diene progesterone -lla, 17a, 21- triol -3, 20-dione ", the present invention referred to as" P-12 betamethasone objects ") biological conversion low, the reaction substrate was forced to reduce the feeding amount; conversion while longer required, seriously affecting the engagement betamethasone <formula> formula see original document page 5 </ formula> betamethasone formula I formula II 3-11 was betamethasone P -12 was betamethasone rate into the reaction. 因此,解决倍他米松P—ll物水难溶性所致向P—12物生物转化率低的问题成为本领域技术人员长期以来一直试图予以克服的技术难题。 Therefore, the solution betamethasone poorly water-soluble P-ll was due to become skilled in the art to question P-12 biotransformation was low for a long time been trying to be overcome technical problems. 发明内容本发明要解决的技术问题即是上述难题,提供一种倍他米松中间体—— 倍他米松3 —ll物的自乳化组合物,用于提高倍他米松合成反应的速率。 SUMMARY OF THE INVENTION Problem to be solved by the above-mentioned problem, ie, to provide an intermediate betamethasone - betamethasone 3 -ll self-emulsifying composition thereof, for increasing the rate of betamethasone synthesis reaction. 采用本发明自乳化组合物于倍他米松合成反应过程,无需加入额外高速搅拌,通常化学反应的搅拌条件下即能形成纳米级的微粒,增加难溶性甾体类中间药物的溶解度,对于生产有重大意义。 According to the present invention from the emulsion composition to betamethasone synthesis reaction process, without adding an additional high-speed stirring, generally under stirring chemical reactions that can form nanoscale particles, increasing the solubility of a poorly soluble steroid intermediate of drugs, for the production of great significance. 选取合适的油、乳化剂、助乳化剂以及适当优化工艺条件,能增加甾体药物生物转化反应中底物的投入量,在相同生产时间内,仅增加少量乳化剂等辅料成本,就能大大提高最终产品产量,降低生产成本,提髙产品竞争能力。 Select the appropriate oils, emulsifiers, co-emulsifiers, and an appropriate optimum conditions, can be increased in volume steroid drug biotransformation reactions substrate, in the same production time, only a small amount of emulsifier increases the cost of materials and the like, can be greatly improve the final product yield, reduce production costs, improve product competitiveness Gao. 本发明倍他米松中间体自乳化组合物由倍他米松中间体P—ll物、油相、乳化剂、助乳化剂、增稠剂等成分组成。 The present invention is an intermediate fold betamethasone self-emulsifying composition of betamethasone intermediate P-ll, an oil phase, an emulsifier, auxiliary emulsifier, thickeners and other ingredients. 本发明倍他米松e —ll物的自乳化组合物,其可以包括下列重i份的各组份:倍他米松P—11物io份油相15 — 55份乳化剂15—55份助乳化剂13—46份增稠剂0—10份其中,所说油相可以为植物油、脂肪酸酯类或矿物油。 The present invention betamethasone times self-emulsifying composition e -ll thereof, which may include the following parts by weight of the components i: betamethasone P-11 parts oil phase was io 15--55 parts 15-55 parts co-emulsified emulsifier 13-46 parts of a thickener 0-10 parts agent wherein said oily phase may be a vegetable oil, fatty acid esters, or mineral oils. 植物油包括蓖麻油、豆油、花生油、橄槐油,以及它们的混合物;本发明优选蓖麻油。 Vegetable oils include castor oil, soybean oil, peanut oil, olive oil locust, and mixtures thereof; preferably castor oil of the present invention. 脂肪酸酯类包括中链三酸甘油酯,如MCT (三辛酸癸酸甘油酯),Captex 355 (oil) 、 Miglyol 812 (oil)等各种椰子油C8/C10甘油三酯,Captex200 (oil, 椰子油C8/C10丙二醇双酯),CapmulMCM(HLB=5.5〜6.0、椰子油C8/C10 甘油单酯或双酯);和长链脂肪酸甘油酯,如Arlacd80 (油酸山梨醇酯)、 Arlacel86 (油酸甘油酯一丙二醇(重盘比90:10) 〕 、 Peceol (油酸甘油酯)、 Maisine (亚油酸甘油酯)、Myverol48-92 (纯化向日葵油单甘油酯(含90w/w %亚油酸甘油酯)〕、油酸乙酯、Gelucire44/14 (聚乙二醇月桂酸甘油酯) 等;本发明优选MCT、油酸乙酯。矿物油包括白蜡油、液体石蜡等,以及它们的混合物。所述的乳化剂选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、天然植物油甘油三酯(Labrafi产M)、聚乙二醇一8—甘油辛酸廣酸酯(Labrasol)、聚山梨酯类[吐温(Tween)40、 Tween60、 Tween80]、磺化琥珀酸二辛酯钠( Fatty acid esters include medium chain triglycerides, such as the MCT (tricaprylate caprate), Captex 355 (oil), Miglyol 812 (oil), and other coconut oil C8 / C10 triglyceride, Captex200 (oil, coconut oil C8 / C10 propylene glycol diester), CapmulMCM (HLB = 5.5~6.0, coconut oil C8 / C10 mono- or di-esters); and long-chain fatty acid glycerides, such as Arlacd80 (sorbitan oleate ester), Arlacel86 (oil a glycol triglyceride (90:10 weight ratio disc)], Peceol (glycerol oleate), Maisine (glyceryl linoleate), Myverol48-92 (purified sunflower oil monoglyceride (containing 90w / w% linoleic glyceride)], ethyl oleate, Gelucire44 / 14 (glyceryl laurate, polyethylene glycol) and the like; preferably MCT of the present invention, comprises a white mineral oil, ethyl oleate wax, liquid paraffin and the like, and mixtures thereof the emulsifier is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, a natural vegetable oil triglyceride (Labrafi yield M), polyethylene glycol glyceryl caprylate wide ester 8- (Labrasol), polysorbate esters [Tween (Tween) 40, Tween60, Tween80], sodium dioctyl sulfosuccinate ( Aerosol)、 泊洛沙姆F68/188,以及它们的混合物;本发明优选聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油和Tween80中的一种或几种。所述的助乳化剂选自乙醇、丙二醉(1 , 2-丙二醇)、甘油、分子量为200400 的聚乙二醇、Labrafil®M、乙二醉单乙基醚(transcutol P),以及它们的混合物;本发明优选乙醇、丙二醇、Labrafi产M及transcutolP中的一种或几种。所述的增稠剂选用羟丙基甲基纤维素。上述倍他米松e —ll物与油相的重量比优选为0.25-0.33。油相与乳化剂的重:l比优选0.67〜1.2。油相与助乳化剂的重l:比优选0.86〜2.67。本发明还提供上述自乳化组合物的制备方法。其包括将上述自乳化组合物的各组分置于50L配料鐮中,通蒸汽,80'C加热回流0.5h后即得。加至发酵液中,采用激光粒度仪测定,乳滴平均粒径100〜310nm,较佳为100 一200nm,卯%粒径累积值为150〜550nm,优选190—350nm。 Aerosol), poloxamer F68 / 188, and mixtures thereof; preferably a polyoxyethylene castor oil of the present invention, one or more polyoxyethylene hydrogenated castor oil and Tween80 in the co-emulsifier is selected from ethanol. , malonic drunk (1, 2-propylene glycol), glycerin, polyethylene glycol having a molecular weight of 200,400, Labrafil®M, ethylene drunk monoethyl ether (transcutol P), and mixtures thereof; the present invention, preferably ethanol, propylene glycol , producing one or more M and transcutolP Labrafi in. the selection of the thickening agent hydroxypropylmethylcellulose. e -ll by weight of betamethasone was the oil phase ratio is preferably 0.25-0.33. oil heavy phase to the emulsifier:. l oil phase ratio is preferably 0.67~1.2 weight coemulsifiers l:. ratio of preferably 0.86~2.67 present invention also provides a method for preparing the above-mentioned self-emulsifiable composition which comprises the self-emulsifying composition. each component was placed in a 50L sickle ingredients, steaming, 80 'C. is obtained after heating at reflux for 0.5h. was added to the fermentation broth, measured using a laser particle size analyzer, the average particle diameter of emulsion droplets 100~310nm, preferably 100 to 200 nm, d is 150~550nm% cumulative particle diameter, preferably 190-350nm. 发明倍他米松e —ii物的自乳化组合物用于制备倍他米松。即将配制好的自乳化组合物80'C加热、回流后,加入培养好的发酵液中即可。 其中,发酵液的培养采用现有技术,包括:转化培养基:棉籽饼粉0.8w/w%、 Glu(葡萄糖)w/w 4.8%、 KC1 0.024 w/w %、 KNO30.6w/w%,余量为缓冲液;缓冲液配方:MgSO40.05w/w%、 K2HPO40.2w/w%、 KH2PO40.1w/w %、 KNO30.1w/w0/0;把骞菌绿優菌(Metorr/^:'"m )斜面种接入转化培养基进行种子培养, 接种量0.2% (w/w),培养温度28'C,种子长好后,投入底物(倍他米松P 一ll物的自乳化组合物)转化。 Betamethasone invention is a self-emulsifying composition for the preparation thereof e -ii betamethasone. Coming from the formulated emulsion composition 80'C after heating to reflux, was added to the culture broth good. Wherein, the fermentation broth culture prior art, comprising: biotransformation medium: Cottonseed flour 0.8w / w%, Glu (glucose) w / w 4.8%, KC1 0.024 w / w%, KNO30.6w / w%, the balance being a buffer solution; buffer formulation: MgSO40.05w / w%, K2HPO40.2w / w%, KH2PO40.1w / w%, KNO30.1w / w0 / 0; Qian bacteriochlorin preferably the bacteria (Metorr / ^: ' "m) the access ramp species transformed seed culture medium was inoculated amount of 0.2% (w / w), 28'c culture temperature, the seed good long, into the substrate (betamethasone a self-emulsifying composition P was ll) conversion . 种子培养和转化在同一个權中进行。 Seed culture and transformation carried out in the same right. 通常待种子长好后,把一定量泡敌(2-5滴/500ml)加入到底物中混匀后投入到转化培养基中,开始转化。 After the seed is usually longer be good, the amount of bubbles enemy (2-5 drops / 500ml) was added in the end after the conversion into the mixed medium begins to change. 转化45h后,补充损失的缓沖液继续转化至发酵完成。 After transformation 45h, replace lost buffer continues until fermentation is complete conversion. 综上所述,本发明具有如下优点:1. 本发明自乳化组合物,配料易得,配制简单,成本低廉,适宜工业化应用。 In summary, the present invention has the following advantages: 1. The present invention is a self-emulsifying composition ingredients readily available, simple preparation and low cost, suitable for industrial application. 2. 本发明自乳化组合物显著提高倍他米松P —ll物向倍他米松P —12 物的生物转化率。 2. The self-emulsifying composition of the present invention is significantly improved betamethasone dipropionate P -ll was biotransformation product of P -12 to betamethasone. 3. 本发明自乳化组合物克服了倍他米松3 —ll物水溶性差的这一本领域技术人员长期以来一直难以克服的技术难题,提高了倍他米松合成反应速率。 3. The emulsion composition of the present invention to overcome the self betamethasone 3 -ll poorly water-soluble substance present in this art have long insurmountable technical problems, betamethasone increased synthesis reaction rate. 具体实施方式下面用实施例来进一步说明本发明,但本发明并不受其限制。 DETAILED DESCRIPTION The following examples further illustrate the use of the present invention, but the present invention is not limited thereto. 实施例1倍他米松P—11物80g中链三酸甘油酯(MCT) 150g无水乙醇130g1, 2-丙二醇160g聚氧乙烯氢化蓖麻油RH40 250g羟丙基甲基纤维素E15 70g将以上处方l:物质和80ml泡敌混合后加热,80'C回流0.5h,加至每菌(种子)生长好的发酵液中进行转化。 Example 1 Betamethasone was 80g P-11 medium-chain triglyceride (MCT) 150g of anhydrous ethanol 130g1, 2- propylene glycol, 160g of polyoxyethylene hydrogenated castor oil RH40 250g hydroxypropylmethylcellulose E15 70g The above formulation l: 80ml foam material and heating the enemy after mixing, 80'C reflux for 0.5h, added to each bacteria (seed) growth good fermentation broth transformed. 加至发酵液中后,平均粒径200nm,卯%粒径累积值为360nm。 After the addition to the fermentation broth, the average particle diameter of 200 nm, d is 360nm% cumulative particle diameter. 实施例2倍他米松P—11物80g中链三酸甘油酯(MCT) 240gLabrafi产M (助乳化剂) 200g吐温80 80g聚氧乙烯氢化蓖麻油RH40 200g将以上处方l:物质和80ml泡敌混合后加热,80'C回流0,5h,加至雾菌生长好的发酵液中进行转化。 Example 2 Betamethasone was 80g P-11 medium-chain triglyceride (MCT) 240gLabrafi yield M (co-emulsifier) ​​200 g of Tween 80 80g of polyoxyethylene hydrogenated castor oil RH40 200g or more prescription l: 80ml foam material and after the mixture was heated enemy, 80'C reflux for 0,5h, fog was added to the grown bacteria fermentation broth transformed. 加至发酵液中后,平均粒径227nm, 90%粒径累积值为395nm。 After the addition to the fermentation broth, the average particle size of 227nm, 90% cumulative particle diameter is 395nm. 实施例3倍他米松e—ll物80g蓖麻油230g1, 2—丙二醇120gTr咖cutol P 220g聚氧乙烯氡化蓖麻油RH40 250g将以上处方i物质和80ml泡敌混合后加热,80'C回流0,5h,加至籌菌生长好的发酵液中进行转化。 Example 3 Betamethasone e-ll was 80g castor 230g1, 2- 120gTr coffee cutol P 220g propylene glycol, polyoxyethylene castor oil RH40 250g radon the heated material and the above prescription i enemy bubble mixing 80ml, 80'C reflux 0 , 5h, was added to raise the grown bacteria fermentation broth transformed. 加至发酵液中后,平均粒径120nin, 90%粒径累积值为198nm。 After the addition to the fermentation broth, the average particle size 120nin, 90% cumulative particle diameter is 198nm. 实施例4倍他米松e—ll物80g蓖麻油240gTr咖cutolP 110gLabrasol 180g聚氧乙烯萬麻油240g将以上处方i物质和80ml泡敌混合后加热,80'C回流0,5h,加至雾菌生长好的发酵液中进行转化。 Example 4 Betamethasone e-ll was 80g castor 240gTr coffee cutolP 110gLabrasol 180g 240g polyoxyethylene Wan sesame oil heated to the above prescription substance and i enemy bubble mixing 80ml, 80'C reflux for 0,5h, fog was added to the growth of bacteria good fermentation broth transformed. 加至发酵液中后,平均粒径242nm,卯%粒径累积值为474nm。 After the addition to the fermentation broth, the average particle diameter of 242nm, 474nm value of d% cumulative particle diameter. 实施例5倍他米松e—ll物80g 油酸乙酯300g Transcutol P 350g聚氧乙烯氣化蓖麻油RH40 340g将以上处方量物质和80ml泡敌混合后加热,80t:回流0.5h,加至雾菌生长好的发酵液中进行转化。 Example 5 Betamethasone e-ll was 80g 300g Transcutol P 350g ethyl oleate polyoxyethylene castor oil RH40 340g gasifier above the heated formulation material and the amount of mixing 80ml bubble enemy, 80t: at reflux for 0.5h, added to a fog good growth of bacteria fermentation broth transformed. 加至发酵液中后,平均粒径299nm, 90%粒径累积值为500nm。 After the addition to the fermentation broth, the average particle size of 299nm, 90% cumulative particle diameter is 500nm. 实施例6倍他米松e—ll物80g蓖麻油300g大豆油120g无水乙醇120g聚乙二醇400 120g吐温80 100g聚氧乙烯氢化蓖麻油RH40 340g将以上处方量物质和80ml泡敌混合后加热,80"回流0.511,加至雾菌生长好的发酵液中进行转化。加至发酵液中后,平均粒径310nm, 90%粒径累积值为550nm。 实施例7倍他米松e—ll物80g液体石蜡260g无水乙醇130Transcutol P 230g聚氧乙烯蓖麻油120g将以上处方量物质和80ml泡敌混合后加热,80'C回流0,5h,加至籌菌生长好的发酵液中进行转化。加至发酵液中后,平均粒径280nm,卯%粒径累积值为492nm。对照实施例1倍他米松e—ll物80g 无水乙醇400g把以上处方量倍他米松溶于乙酵中,搅拌,溶解后待用。对照实施例2(现有生产使用配方) 倍他米松e—ll物45g 无水乙醇200g 把以上处方量倍他米松溶于乙醉中,搅拌,溶解后待用。 试验实施例1转化率、单位时间产量比较操作 Example 6 After Betamethasone e-ll was castor oil 80g soybean oil 120g 300g 120g of anhydrous ethanol and the amount of material of the above prescription 80ml enemy bubble mixing 120g TWEEN 80 100g 400 polyoxyethylene hydrogenated castor oil RH40 340g polyethylene glycol heating, 80 "0.511 reflux, was added to the grown bacteria fog fermentation broth transformed. was added to the fermentation broth, the average particle size of 310nm, 90% cumulative particle diameter is 550 nm. Example 7 betamethasone e-ll 260g of anhydrous liquid paraffin was 80g ethanol 130Transcutol P 230g 120g Cremophor after the above prescribed amount of substance is heated and mixed 80ml bubble enemy, 80'C reflux for 0,5h, was added to raise the grown bacteria fermentation broth transformed after. was added to the fermentation broth, the average particle diameter of 280 nm, 492nm cumulative value of particle diameter d%. Comparative Example 1 betamethasone e-ll 80g absolute ethanol was above the prescribed amount of 400g was dissolved betamethasone acetate in yeast stirred, and dissolved for use. Comparative Example (conventional production recipe) 2-fold amount or more prescription betamethasone the e-ll 200g 45g was dissolved in absolute ethanol betamethasone acetate drunk, stirred, and dissolved stand test Example 1 the conversion rate, yield per unit time of the comparison operation 将上述实施例的倍他米松e—ll物及处方量的油相、乳化剂、助乳化剂、增稠剂(如有的话)置于50L配料罐中,通蒸汽,80'C加热回流0.5h后,加大配料鐮的压力,将其中回流好的浓縮液体和80ml泡敌混合后压入500L、包括长好后的种子及发酵液的发酵罐中,28'C,空气流量1.0m3/min,搅拌条件(270转/分钟)下反应65小时;将对照实施例1、 2 的倍他米松P—11物的乙醉溶液,压入500L的发酵罐中,28'C,空气流量1.0m3/min,搅拌条件(270转/分钟)下反应65小时或84小时。结果见下表:表1本发明倍他米松P —ll物的自乳化组合物与对比实施例转化结果<table>table see original document page 11</column></row> <table><table>table see original document page 12</column></row> <table>注:瓶号分A、 B便于验证同一样品数据的准确性、重复性。实验结果显示,相同投料量下,本发明自乳化组合物加入发酵液中, The above embodiments of times betamethasone and e-ll was prescribed amount of an oil phase, an emulsifier, auxiliary emulsifier, thickening agent (if any) were placed in a mixing tank 50L, steaming, heating under reflux for 80 'C. after 0.5h, sickle ingredients increase the pressure, in which the good and 80ml concentrated liquid reflux bubble mixing enemy pressed 500L, comprising a fermenter good seed and the length of the fermentation broth, 28'c, air flow rate 1.0 m3 / min, with stirring (270 revolutions / minute) at 65 hours; control Example embodiment 1 times, 2 betamethasone acetate solution drunk P-11 was pressed into the 500L fermenter, 28'c, air flow rate of 1.0m3 / min, with stirring (270 revolutions / min) for 65 hours or 84 hours the reaction results in the table below: table 1 invention Example betamethasone self-emulsifying composition and the composition of Comparative conversion results P -ll < table> table see original document page 11 </ column> </ row> <table> <table> table see original document page 12 </ column> </ row> <table> Note: bottles No. points A, B easy to verify the same the sample data accuracy, repeatability, experimental results show that the same amount of raw materials since the emulsion composition of the present invention is added to the fermentation broth, 形成均一的乳液,没有沉淀出现,稳定性好;无大量泡沫产生,适合工业化生产,反应时间大大縮短。与现有生产产量相比,相同反应时间内转化率和产量均有较大程度增加。且随着乳滴粒径的减少,转化率明显塌加,水解点少。 Form a uniform emulsion, no precipitation occurred, and good stability; without a lot of foam production, suitable for industrial production, the reaction time is shortened compared with the conventional production yield, conversion and yield in the same reaction time were increased to a large extent. and with decreasing particle size of emulsion droplets, increase the conversion rate was significantly collapsed, less hydrolyzed point.

Claims (16)

1. 一种如式I所示的化合物的自乳化组合物,其包括下列重量份的各组份: 式I化合物10份油相15-55份乳化剂15-55份助乳化剂13-46份增稠剂0-10份; id="icf0001" file="C2006101187630002C1.gif" wi="41" he="30" top= "90" left = "75" img-content="drawing" img-format="tif" orientation="portrait" inline="no"/> 式I 所述的油相为植物油、脂肪酸酯或矿物油; 所述的乳化剂选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、天然植物油甘油三酯、聚乙二醇-8-甘油辛酸/癸酸酯、聚山梨酯类、磺化琥珀酸二辛酯钠以及泊洛沙姆中的一种或几种; 所述的助乳化剂选自乙醇、丙二醇、甘油、分子量为200-600的聚乙二醇以及乙二醇单乙基醚中的一种或几种。 1. A self-emulsifying composition comprising a compound of Formula I as illustrated, which includes the following parts by weight of the components: Compound of Formula I 10 parts of oil phase emulsifier 15-55 15-55 parts 13-46 parts co-emulsifier parts of a thickener 0-10 parts; id = "icf0001" file = "C2006101187630002C1.gif" wi = "41" he = "30" top = "90" left = "75" img-content = "drawing" img- format = "tif" orientation = "portrait" inline = "no" /> of formula I according to the oil phase is a vegetable oil, a mineral oil or a fatty acid ester; said emulsifier is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, a natural vegetable oil triglyceride, polyethylene glycol -8- glyceryl caprylate / caprate, polyethylene sorbitan esters, sodium dioctyl sulfosuccinate, and the one or more poloxamers; the co-surfactant selected from ethanol, propylene glycol, glycerin, a molecular weight of 200 to 600 one or more of polyethylene glycol, and the glycol monoethyl ether.
2、 如权利要求1所述的自乳化组合物,其特征在于所述的植物油选自蓖麻油、豆油、花生油和橄榄油。 2, the self-emulsifying composition as claimed in claim 1, wherein said vegetable oil is selected from castor oil, soybean oil, peanut oil and olive oil.
3、 如权利要求1所述的自乳化组合物,其特征在于所述的脂肪酸酯为中链三酸甘油酯或长链脂肪酸甘油酯。 3, the self-emulsifying composition as claimed in claim 1, wherein said fatty acid ester is a medium-chain triglyceride or long chain fatty acid glycerides.
4、 如权利要求3所述的自乳化组合物,其特征在于所述的中链三酸甘油酯选自三辛酸癸酸甘油酯、椰子油C8/C10甘油三酯、椰子油C8/C10甘油单酯或双酯、以及椰子油C8/C10丙二醇双酯。 4, since the emulsion composition as claimed in claim 3, wherein said medium-chain triglyceride is selected from tricaprylate caprate, coconut oil C8 / C10 triglyceride, coconut oil C8 / C10 glycerol mono- or di-esters, and coconut oil C8 / C10 propylene glycol diester.
5、 如权利要求3所述自乳化组合物,其特征在于所述的长链脂肪酸甘油酯选自油酸山梨醇酯、油酸甘油酯一丙二醇、油酸甘油酯、亚油酸甘油酯、 纯化向日葵油单甘油酯、油酸乙酯以及聚乙二醇月桂酸甘油酯。 5, as claimed in the self-emulsifying composition of claim 3, wherein said long chain fatty acid glycerides are selected from sorbitan oleate ester, a propylene glycol oleate, glyceryl oleate, glyceryl linoleate, purification of sunflower oil monoglyceride, ethyl oleate and polyethylene glycol glyceryl laurate.
6、 如权利要求1所述的自乳化组合物,其特征在于所述的矿物油为白蜡油或液体石蜡。 6, self-emulsifying composition as claimed in claim 1, wherein the mineral oil is liquid paraffin or white wax.
7、 如权利要求1所述的自乳化组合物,其特征在于所述的增稠剂为羟丙基甲基纤维素。 7, self-emulsifying composition as claimed in claim 1, wherein said thickening agent is hydroxypropyl methylcellulose.
8、 如权利要求1所述的自乳化组合物,其特征在于式I化合物和油相的重量比为0.25〜0.33。 8, self-emulsifying composition as claimed in claim 1, characterized in that the weight of a compound of formula I and an oil phase ratio of 0.25~0.33.
9、 如权利要求1所述的自乳化组合物,其特征在于该油相与乳化剂的重量比为0.67〜1.2。 9, the self-emulsifying composition of claim 1, wherein the weight ratio of the oil phase to the emulsifier was 0.67~1.2.
10、 如权利要求l所述的自乳化组合物,其特征在于该油相与助乳化剂的重量比为0.86〜2.67。 10, the self-emulsifying composition as claimed in claim l, characterized in that the oil phase coemulsifier weight ratio of 0.86~2.67.
11、 如权利要求l-10任一项所述的自乳化组合物,其特征在于该自乳化组合物的乳滴平均粒径100〜310nm。 11, the self-emulsifying composition as claimed in any one of claims l-10, characterized in that the emulsion composition from the emulsion droplets of average particle diameter of 100~310nm.
12、 如权利要求11所述的自乳化组合物,其特征在于该乳滴平均粒径为100〜200nm。 12, the self-emulsifying composition as claimed in claim 11, characterized in that the average particle size of the emulsion droplets 100~200nm.
13、 如权利要求1-10任一项所述的自乳化组合物,其特征在于该自乳化组合物的90%乳滴粒径累积值150〜550nm。 13, the self-emulsifying composition as claimed in any one of claims 1 to 10, wherein the self-emulsifying composition of 90% cumulative value of particle size emulsion droplets 150~550nm.
14、 如权利要求13所述的自乳化组合物,其特征在于所述的90%乳滴粒径累积值为190〜350nm。 14, the self-emulsifying composition as claimed in claim 13, wherein said cumulative 90% particle diameter of the emulsion droplets is 190~350nm.
15、 如权利要求1-10任一项所述的自乳化组合物的制备方法,其包括以下步骤:把按所述的重量份数的式I化合物,及油相、乳化剂、助乳化剂、 增稠剂置于配料罐中,通蒸汽,8(TC加热回流0.5h。 15. The method for producing a self-emulsifiable composition according to any one of claims 1-10, comprising the steps of: a compound of formula I according to claim parts by weight, and an oil phase, an emulsifier, coemulsifier , thickeners placed in a mixing tank, steaming, 8 (TC was heated at reflux for 0.5h.
16、 如权利要求1-10任一项所述的自乳化组合物在制备倍他米松中的应用。 16, the self-emulsifying composition as claimed in any one of claims 1-10 in the manufacture of betamethasone requirements.
CN 200610118763 2006-11-24 2006-11-24 Self-emulsifying composition of beta-11 betamethasone, preparation process and application thereof CN100408025C (en)

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