CN100333727C - Budesonide target-direction microball and preparation thereof - Google Patents

Budesonide target-direction microball and preparation thereof Download PDF

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CN100333727C
CN100333727C CN 200410072871 CN200410072871A CN100333727C CN 100333727 C CN100333727 C CN 100333727C CN 200410072871 CN200410072871 CN 200410072871 CN 200410072871 A CN200410072871 A CN 200410072871A CN 100333727 C CN100333727 C CN 100333727C
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pellets
layer
budesonide
weight
applicator
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CN1778301A (en )
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张秀珍
李宏玲
马晓勇
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天津药业研究院有限公司
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Abstract

本发明公开了一种布地奈德的结肠靶向微丸制备方法,它采用了以β-环糊精(β-cyclodextrins)等辅料将水不溶性的药物活性成分布地奈德制备成亲水性前体药物的方法,从而实现了采用水性包衣的生产工艺制备布地奈德微丸。 The present invention discloses a method for preparing pellets colon targeting one kind of budesonide, which uses a cyclodextrin to β- (β-cyclodextrins), and other accessories water-insoluble pharmaceutically active distribution of budesonide was prepared hydrophilic prodrug method using an aqueous coating in order to achieve a production process of the preparation of budesonide pellets. 由于本发明制备布地奈德微丸的工艺中分散相均为水,没有使用任何有机溶媒,生产设备和在生产过程中无需采用防爆装置或防爆措施,生产安全性大大提高;同时简化了生产工艺、降低了生产成本。 Since the present invention was prepared in the process of budesonide pellets are dispersed in water without using any organic solvent, in the production equipment and production processes without the use of explosion-proof or explosion-proof means measures the production of security is greatly enhanced; while simplifying the manufacturing process and reduce production costs.

Description

布地奈德靶向微丸及其制备方法 Budesonide pellets and its preparation method of the targeted

技术领域 FIELD

本发明涉及布地奈德的圆粒结肠靶向微丸及其制备方法。 The present invention relates to targeting of budesonide pellets colon pellets and its preparation method. 尤其是涉及将水不溶性的布地奈德采用一定制剂手段转化为亲水性后以流化床喷涂方式制备结肠靶向微丸。 Particularly it relates to a water-insoluble budesonide formulations using certain hydrophilic after conversion means colon pellets prepared in a fluidized bed spraying.

背景技术 Background technique

布地奈德(budesonide)是一种甾体皮质激素类药物,其性质为几乎不溶于水,因而,目前以布地奈德为药物活性成分的制剂,在生产制备中均采用极性有机溶媒(一般为乙醇)为分散相。 Budesonide (budesonide) is a corticosteroid steroid drug, the nature of which is practically insoluble in water, therefore, currently budesonide as active ingredient in pharmaceutical formulation, are used in the preparation of the production of a polar organic solvent (typically ethanol) a dispersed phase.

2001年10月2日,美国食品及药物管理局FDA批准了AstraZeneca公司研制的一种用于治疗轻、中度局限性肠炎的布地奈德口服固体制剂,该产品由布地奈德与乙基纤维素制备而成,该产品在国外市场上的商品名为“Entocort EC”。 October 2, 2001, the US Food and Drug Administration (FDA) approved the oral solid formulation of budesonide for the treatment of mild to moderate Crohn's disease for AstraZeneca company developed the product by the budesonide and ethyl cellulose Su prepared from the product in foreign markets under the trade name "Entocort EC". 但未见该产品相关专利或其他文献报道。 The product-related but no patents or other literature.

国内文献Journal of China Pharmaceutical University 2003,34(5):419~422报道了一种布地奈德结肠定位微丸的制备方法,此方法是采用锅包衣制备载药微丸,并进行乙基纤维素有机溶液包覆及EUDRAGITFS30D水分散体包衣。 Domestic literature Journal of China Pharmaceutical University 2003,34 (5): 419 ~ 422 reported a method for preparing a budesonide pellets of Colon, this method is the use of drug-loaded pellets prepared pan coating, and ethylcellulose The organic solution was coated prime and EUDRAGITFS30D aqueous dispersion coating.

Rodriguez等人在Chemical Abstracts 63-Pharmaceuticals Vol.130,NO.9,1999等刊物上报道了一种新型的用于治疗结肠炎的圆球型(pellet)微丸制剂,该微球制剂主要由载药丸芯(布地奈德、昂丹司琼和纤维丁酸酯组成,简称:CAB微丸)和用EUDRAGIT S材料包衣而成的、对PH敏感的微丸。 Rodriguez et al reported the ball type (a pellet) pellet preparation for treating colitis a novel in Chemical Abstracts 63-Pharmaceuticals Vol.130, NO.9,1999 other publications, the microsphere preparation contained mainly by pellet core (budesonide, ondansetron butyrate and fiber composition, referred to as: CAB pellets) and a coating made of a material with EUDRAGIT S, PH sensitive to pellets. 该载药微丸的制备工艺是将布地奈德、昂丹司琼溶于有机溶媒,添加高分子材料纤维丁酸酯,然后蒸发掉有机溶媒而得。 Preparation of the drug pellets is budesonide, ondansetron was dissolved in an organic solvent, adding a polymer fiber material butyrate, and then the organic solvent was evaporated off to give.

发明内容 SUMMARY

由于布地奈德(budesonide)的水溶性极差,因而以布地奈德为药物活性成分的微丸制剂,在生产制备中一般均采用有机溶媒为分散相,而本发明采用以β-环糊精(β-cyclodextrins)、增溶剂、抗粘剂等,将水不溶性的药物活性成分布地奈德制备成亲水性前体药物,从而实现了采用水性包衣的生产工艺制备布地奈德微丸。 Since budesonide (budesonide) poor water solubility, and thus to the formulation Budesonide pellets as a pharmaceutically active ingredient, in the preparation of the production of an organic solvent generally used as dispersed phase, and the present invention is employed to β- cyclodextrin (β-cyclodextrins), solubilizers, anti-adherents, etc., the water-insoluble pharmaceutically active Ned distributed to the front aqueous drug married prepared, using an aqueous coating in order to achieve the production process of the preparation of budesonide pellets. 以本发明方法制备布地奈德微丸时,分散相均为水,没有使用任何有机溶媒,生产设备和在生产过程中无需采用防爆装置或防爆措施,生产安全性大大提高;同时简化了生产工艺、降低了生产成本。 When Budesonide pellets prepared in the process of the present invention, the dispersed phase are water, without using any organic solvent, in the production equipment and production processes without the use of explosion-proof or explosion-proof means measures the production of security is greatly enhanced; while simplifying the manufacturing process and reduce production costs.

本发明布地奈德的圆粒结肠靶向微丸,是由不含活性成分的空白核芯、含活性成分布地奈德的涂药层和肠溶包衣层构成。 Desonide present Mingbu round pieces colon targeted pellets, containing no active ingredient is a blank core, containing the active ingredient distributed desonide applicator layer and an enteric coating layer. 所述的涂药层是由布地奈德、β-环糊精、增溶剂、抗粘剂和丙烯酸甲酯共聚物组成,在涂药层中各物料所占重量百分比可以是:布地奈德0.1%~20%,β-环糊精1%~40%,增溶剂5%~70%,抗粘剂1%~30%,丙烯酸甲酯共聚物10%~80%。 The applicator of the layer is made of budesonide, [beta] -cyclodextrin, solubilizers, anti-adherents and methyl acrylate copolymer, each layer of material in the applicator proportion by weight percentage may be: budesonide 0.1 % ~ 20%, β- cyclodextrin 1% to 40%, solubilizer 5% to 70%, anti-tack agent 1% to 30% methacrylate copolymer 10 to 80%. 所述的肠溶包衣层是由丙烯酸甲酯共聚物、抗粘剂和增塑剂组成,在包衣层中各物料所占重量百分比可以是丙烯酸甲酯共聚物60%~99%,抗粘剂0.5%~30%,增塑剂0.1%~25%。 The enteric coating layer is formed from methyl acrylate copolymer, a plasticizer and anti-adherent, coating layer of each material in the proportion by weight methyl acrylate copolymer may be 60% to 99%, anti- agent 0.5% to 30%, from 0.1% to 25% of a plasticizer.

本发明优选下列物料和配比制备:涂药层(重量比):布地奈德5%~15%,β-环糊精10%~30%,增溶剂15%~40%,抗粘剂3%~10%,丙烯酸甲酯共聚物20%~45%。 Preferably these materials and the preparation of the present invention, the ratio: applicator layer (weight ratio): Budesonide 5% ~ 15%, β- cyclodextrin 10% to 30%, increasing to 40% solvent 15, anti-tack agent 3 to 10%, 20% methyl acrylate copolymer and 45%.

肠溶包衣层(重量比):丙烯酸甲酯共聚物75%~95%、抗粘剂3%~15%、增塑剂5%~12%。 The enteric coating layer (weight ratio): methyl acrylate copolymer, 75% to 95%, 3% anti-tack agent to 15% plasticizer, 5% to 12%. 最优选为:涂药层(重量比):布地奈德10.9%、β-环糊精23.9%、增溶剂23.9%、抗粘剂6.5%、丙烯酸甲酯共聚物34.8%。 And most preferably: applicator layer (weight ratio): budesonide 10.9%, β- cyclodextrin 23.9%, 23.9% solubilizing agent, anti-adherent 6.5%, 34.8% methyl acrylate copolymer.

结肠包衣层(重量比):丙烯酸甲酯共聚物83.3%、抗粘剂8.3%、增塑剂8.4%。 Colonic coating layer (weight ratio): 83.3% methyl acrylate copolymer, anti-adherent 8.3%, 8.4% plasticizer.

所述涂药层中的增溶剂可选用聚乙二醇6000、聚乙二醇4000或它们的混合物,优选聚乙二醇6000;所述涂药层或肠溶包衣层中的抗粘剂优选用滑石粉;所述肠溶包衣层中的增塑剂可选用柠檬酸三乙酯、癸二酸二乙酯或1,2-丙二醇,优选柠檬酸三乙酯。 The solubilizing agent layer applicator optional polyethylene glycol 6000, polyethylene glycol 4000, or mixtures thereof, preferably polyethylene glycol 6000; the applicator layer or an enteric coating layer of the anti-tack agent preferably talc; the enteric coating layer can be selected plasticizer triethyl citrate, diethyl sebacate or 1,2-propylene glycol, triethyl citrate is preferable.

为了达到较好的成品质量,涂药层、肠溶包衣层与空白核芯之间要保持一定的重量比。 In order to achieve a better quality of the finished product, the applicator layer, enteric layer between the core and the blank to maintain a certain weight ratio.

涂药层应是空白核芯的1%~130%(重量比),更优选是空白核芯的5%~20%(重量比),最优选是空白核芯的9.2%(重量比)。 Applicator layer should be 1% to 130% of the core blank (weight ratio), more preferably from 5% to 20% of the core blank (weight ratio), most preferably 9.2% of the core blank (weight ratio).

肠溶包衣层应是空白核芯的2%~90%(重量比),更优选是空白核芯的5%~20%(重量比),最优选是空白核芯的14.4%(重量比)。 Enteric coating layer should be 2% to 90% of the core blank (weight ratio), more preferably from 5% to 20% of the core blank (weight ratio), most preferably 14.4% of the core blank (weight ratio ).

其中,所述空白核芯的粒度为0.01mm~2mm,更优选为0.1mm~1mm,最优选为0.5mm~0.7mm。 Wherein the particle size of the core blank 0.01mm ~ 2mm, and more preferably is 0.1mm ~ 1mm, and most preferably 0.5mm ~ 0.7mm.

本发明靶向微丸的释放度完全满足中国国家标准规定的靶向制剂释放度要求。 Targeted release pellets of the present invention is to fully meet the requirements of targeted release formulation of the Chinese national standard.

释放度的测定方法如下:取本品按释放度测定方法(中国药典2000年版二部附录XC第一法),前两小时以0.1mol/1盐酸溶液为溶剂,以后用PH7.0的磷酸盐缓冲液为释放介质,转速每分钟100转,依法操作,于2小时、3小时、4小时、6小时、8小时、10小时、12小时及24小时取溶液滤过,照分光光度法(中国药典2000年版二部附录IVA)在236nm波长处测定吸收度,按C25H24O6的吸收度为对照,计算出靶向微丸的释放度。 Release determination method is as follows: Take this product measured by the method of release (China Pharmacopoeia 2000 Appendix XC method), two hours prior to 0.1mol / 1 hydrochloric acid solution as solvent, after using phosphate PH7.0 buffer was release medium, the rotational speed of 100 revolutions per minute, according to operations at 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours and 24 hours the solution was filtered to take, according to spectrophotometry (China Pharmacopoeia 2000 Appendix IVA) measuring absorbance at a wavelength of 236nm, the absorption of the control of C25H24O6, calculated targeted release pellets. 前两小时释放量小于10%,4小时为40~60%,6小时为55~80%,8小时为70~85%,12小时大于75%,24小时90%以上。 Two hours before release of less than 10%, four hours from 40 to 60% 6 hours 55 to 80% at 8 hours 70% to 85% for 12 hours more than 75%, 90% more than 24 hours.

附图说明 BRIEF DESCRIPTION

图1:用高效液相色谱法测定原料药(1)和靶向微丸制剂(2)的含量图谱。 Figure 1: Determination of drug (1) and a targeting pellet preparation (2) content by HPLC pattern.

图2:实施例1~6的释放度图谱。 Figure 2: Release profiles Example 1-6.

图3:实施例7~11相同涂药层,不同包衣厚度的释放度图谱。 Figure 3: Examples 7 to 11 the same embodiment applicator layer, different release profiles of the coating thickness.

具体实施方式 detailed description

本发明布地奈德结肠靶向微丸,可以采用一般的制备方法制备,优选按下列方法制备:在室温下,按前面所述的重量比称取布地奈德、β-环糊精、增溶剂、抗粘剂和丙烯酸甲酯共聚物等涂药层各物料及相当于涂药层各物料总重量0.5倍至10倍的水,将布地奈德、β-环糊精、增溶剂和抗粘剂分别加入到水中制成水分散混悬液,将该混悬液在搅拌下缓缓加入到前述称取的丙烯酸甲酯共聚物中,混合,将该混合液过120目筛,制备成涂药用水分散混悬液,采用流化床包衣方法将该混悬液喷洒于前面所述重量比的蔗糖空白微丸核芯上形成涂药层制备含药微丸。 Mingbu present colon budesonide pellets can be prepared by using general methods, preferably prepared by the following methods: at room temperature, the ratio by weight of the foregoing weighed budesonide, [beta] -cyclodextrin, solubilizers , anti-adherents and methacrylate copolymers and the like of each layer of material and the applicator on the total weight of each layer of material corresponds to the applicator 0.5 to 10-fold water, budesonide, [beta] -cyclodextrin, solubilizing agents and anti-stick agent were added to the aqueous dispersion made in water suspension, the suspension was slowly added to the weighed methacrylate copolymer under stirring and mixing, the mixture through a 120 mesh sieve to prepare a coating drug dispersed water suspension, and the suspension was sprayed on the sucrose core blank pellets formed in front of the applicator layer weight ratio of drug-containing pellets prepared using a fluidized bed coating method.

按前面所述的重量比称取丙烯酸甲酯共聚物、抗粘剂和增塑剂肠溶包衣层各物料及相当于包衣层各物料总重量0.1倍至2倍的水,将抗粘剂和增塑剂分散于水中制成水分散混悬液,然后将该混悬液在搅拌下缓缓加入到前述称取的丙烯酸甲酯共聚物中,混合后将该混合液过120目筛,制成肠溶包衣用水分散混悬液。 The ratio by weight of the foregoing materials were weighed each methyl acrylate copolymer, a plasticizer and an anti-enteric coating agent layer, and each corresponds to the total weight of coating material 0.1 to 2 times the water, the anti-stick and a plasticizer are dispersed in water to prepare an aqueous dispersion of a suspension, then the suspension was slowly added to the weighed methacrylate copolymer under stirring, after mixing the mixture through a 120 mesh sieve to prepare the enteric coating suspension is dispersed with water. 采用与喷洒涂药层相同的工艺条件,将该肠溶包衣混悬液喷洒在前述制备的含药微丸上,在其外部形成结肠包衣层制备成结肠靶向微丸。 The spray applicator layer using the same process conditions, the enteric coating suspension is sprayed onto the drug-containing pellets prepared above, to form a coating layer prepared colon colon targeting pellets outside thereof.

流化床的条件可以根据产品最终需要按常规确定,例如可以将流化床的条件设定为:进风量85m3/h,空气压3.0帕,进风温度36~40℃,排风温度30~33℃,品温(样品温度)28~31℃,喷嘴直径1mm,喷雾速度5~10ml/min,干燥时间5分钟。 Fluidized bed conditions required by the final product can be routinely determined, for example, fluidized bed conditions set as follows: inlet air volume 85m3 / h, air pressure of 3.0 Pa, the intake air temperature 36 ~ 40 ℃, exhaust temperature of 30 to 33 ℃, product temperature (sample temperature) 28 ~ 31 ℃, nozzle diameter 1mm, spraying rate 5 ~ 10ml / min, the drying time of 5 minutes.

制备好的圆整微丸置40~50℃干燥条件下干燥2~4小时即可。 Pellets prepared rounded set to 2 to 4 hours and dried at 40 ~ 50 ℃ drying conditions.

为了能更好地理解本发明,下面通过实施例对本发明作进一步的描述,但并不限制本发明。 For better understanding of the present invention, the following examples further describe the present invention, but do not limit the present invention.

在本发明的以下实施例中,丙烯酸甲酯共聚物均选用由Degussa Rohm公司生产的EUDRAGITFS30D,该产品是以甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯制备的共聚物的混悬液,在实施例中所述的EUDRAGITFS30D的量均指其固含量。 Embodiment, the acrylate copolymers are made by the Degussa Rohm EUDRAGITFS30D produced in the following embodiment of the present invention, the product is suspended copolymers prepared methacrylic acid, methyl acrylate and methyl methacrylate liquid, in the embodiment EUDRAGITFS30D solids content refers to the volume.

实施例1~11中所用的不含活性成分的空白微丸核芯均为粒度是0.5-0.7mm的蔗糖型药用微丸丸芯,丸芯重量500克。 Pellets empty core containing no active ingredient in Examples 1 to 11 are used in the embodiment of sucrose particle size 0.5-0.7mm type of pellet cores medicinal pellets, pellet core weight of 500 grams.

实施例1称取1克布地奈德、8克β-环糊精、5克聚乙二醇6000、1克滑石粉,在搅拌下将上述物料分散于40克水中;将该混悬液在搅拌下缓缓分散于10克EUDRAGITFS30D(以固含量计)聚合物混悬液中,过120目筛制备成涂药用水分散混悬液(简称<1>液);另称取滑石粉3克、柠檬酸三乙酯5克,加入水20克混匀制成水分散混悬液,将该混悬液在搅拌下缓缓加入到称取的25克EUDRAGITFS30D中形成水分散混悬液,并将该混合液过120目筛,制备成结肠包衣液(简称<2>液)。 Example 1 1 Kebu budesonide weighed 8 grams of β- cyclodextrin, 5 g of polyethylene glycol 6000,1 g of talc, stirring the above materials were dispersed in 40 g of water; the suspension stirring slowly dispersed in 10 g EUDRAGITFS30D (as solid content) of polymer suspension, through a 120 mesh sieve to prepare a water dispersion applicator suspension (referred to as & lt; 1 & gt; solution); the other weighed 3 g of talc, 5 g triethyl citrate, 20 g of water was added to prepare an aqueous mixed dispersion of a suspension, the suspension was added slowly to 25 g EUDRAGITFS30D weighed under stirring to form water dispersing the suspension, and the mixture is through a 120 mesh sieve to prepare a coating solution colon (referred to as & lt; 2 & gt; solution). 采用流化床包衣方法,将<1>、<2>液喷洒于糖芯微丸上制备结肠靶向微丸。 Fluidized bed coating methods, the & lt; 1 & gt;, & lt; 2 & gt; was sprayed onto the sugar core pellets prepared colon pellets. 对所制备的微丸进行含量测定,结果为:原料药(对照品)的双峰达峰时为18.298分和20.132分;微丸细粉的达峰时间为18.282分和20.148分,与对照品基本相同。 The pellets were prepared for the determination, the result is: drug (control) bimodal peak of 18.298 min and 20.132 time points; fines pellets peak time 18.282 minutes and 20.148 minutes, with the control basically the same. 测定结果见图1。 The measurement results shown in Figure 1.

实施例2称取40g布地奈德、110gβ-环糊精、100g聚乙二醇6000、100g聚乙二醇4000、18g滑石粉,在搅拌下将上述物料分散于600g水中;将该混悬液在搅拌下缓缓分散于150g的EUDRAGITFS30D(以固含量计)聚合物混悬液中,过120目筛制备成涂药用水分散混悬液(简称<1>液);另称取滑石粉18g、柠檬酸三乙酯3g,加入水30g混匀制成水分散混悬液,将该混悬液在搅拌下缓缓加入到称取的包衣材料EUDRAGITFS30D(以固含量计)215g中形成水分散混悬液,并将该混合液过120目筛,制备成结肠包衣液(简称<2>液)。 Example 2 weighed 40g budesonide, 110gβ- cyclodextrin, polyethylene glycol 6000,100g 100g 4000,18g talc, polyethylene glycol, with stirring 600g The above materials were dispersed in water; the suspension stirring slowly dispersed in 150g of EUDRAGITFS30D (as solid content) of polymer suspension, through a 120 mesh sieve to prepare a water dispersion applicator suspension (referred to as & lt; 1 & gt; solution); otherwise known as take talc 18g, triethyl citrate 3g, 30g water was added to prepare an aqueous mixed dispersion of a suspension, the suspension was slowly added with stirring to weighed coating material EUDRAGITFS30D (solid content meter) suspension of 215g of the aqueous dispersion is formed, and the mixture is through a 120 mesh sieve to prepare a coating solution colon (referred to as & lt; 2 & gt; solution). 采用流化床包衣方法,将<1>、<2>液喷洒于糖芯微丸上制备结肠靶向微丸。 Fluidized bed coating methods, the & lt; 1 & gt;, & lt; 2 & gt; was sprayed onto the sugar core pellets prepared colon pellets. 所测释放度见图2。 The measured release of Figure 2.

实施例3称取30g布地奈德、60gβ-环糊精、15g聚乙二醇6000、45g聚乙二醇4000、18g滑石粉,在搅拌下将上述物料分散于300g水中;将该混悬液在搅拌下缓缓分散于40g的EUDRAGITFS30D(以固含量计)聚合物混悬液中,过120目筛制备成涂药用水分散混悬液(简称<1>液);另称取滑石粉5g、柠檬酸三乙酯10g,加入水60g混匀制成水分散混悬液,将该混悬液在搅拌下缓缓加入到称取的包衣材料EUDRAGITFS30D150g中形成水分散混悬液,并将该混合液过120目筛,制备成结肠包衣液(简称<2>液)。 Example 3 30g of said embodiment budesonide, 60gβ- cyclodextrin, polyethylene glycol 15g 6000,45g 4000,18g talc, polyethylene glycol, with stirring 300g The above materials were dispersed in water; the suspension stirring slowly dispersed EUDRAGITFS30D 40g (in solid content) of polymer suspension, through a 120 mesh sieve to prepare a water dispersion applicator suspension (referred to as & lt; 1 & gt; solution); otherwise known as take talc 5g, triethyl citrate 10g, 60g water was added to prepare an aqueous mixed dispersion of a suspension, the suspension was slowly added to the coating material EUDRAGITFS30D150g weighed under stirring to form an aqueous dispersion suspension, and the mixture is through a 120 mesh sieve to prepare a coating solution colon (referred to as & lt; 2 & gt; solution). 采用流化床包衣方法,将<1>、<2>液喷洒于糖芯微丸上制备结肠靶向微丸。 Fluidized bed coating methods, the & lt; 1 & gt;, & lt; 2 & gt; was sprayed onto the sugar core pellets prepared colon pellets. 测定释放度结果见图2。 Determination of dissolution results shown in Figure 2.

实施例4称取5g布地奈德、3gβ-环糊精、8g聚乙二醇4000、10g滑石粉,在搅拌下将上述物料分散于100g水中;将该混悬液在搅拌下缓缓分散于10g的EUDRAGITFS30D聚合物混悬液中,过120目筛制备成涂药用水分散混悬液(简称<1>液);另称取滑石粉5g、柠檬酸三乙酯2g,加入水60g混匀制成水分散混悬液,将该混悬液在搅拌下缓缓加入到称取的包衣材料EUDRAGITFS30D(以固含量计)90g中形成水分散混悬液,并将该混合液过120目筛,制备成结肠包衣液(简称<2>液)。 5g of budesonide said Example 4, 3gβ- cyclodextrin, 8g 4000,10g talc, polyethylene glycol, with stirring 100g The above materials were dispersed in water; the suspension is slowly dispersed under stirring in EUDRAGITFS30D 10g of polymer suspension, through a 120 mesh sieve to prepare a water dispersion applicator suspension (referred to as & lt; 1 & gt; solution); the other weighed talc 5g, triethyl citrate 2g, was added mixing 60g water to prepare an aqueous dispersion of a suspension, the suspension was slowly added to the coating material EUDRAGITFS30D weighed (in solid content) 90g is formed in aqueous dispersion under stirring suspension, and the mixture is through a 120 mesh sieve to prepare a coating solution colon (referred to as & lt; 2 & gt; solution). 采用流化床包衣方法,将<1>、<2>液喷洒于糖芯微丸上制备结肠靶向微丸。 Fluidized bed coating methods, the & lt; 1 & gt;, & lt; 2 & gt; was sprayed onto the sugar core pellets prepared colon pellets. 测定释放度结果见图2。 Determination of dissolution results shown in Figure 2.

实施例5称取5g布地奈德、11gβ-环糊精、11g聚乙二醇6000、3g滑石粉,在搅拌下将上述物料分散于80g水中;将该混悬液在搅拌下缓缓分散于16g的EUDRAGITFS30D(以固含量计)聚合物混悬液中,过120目筛制备成涂药用水分散混悬液(简称<1>液);另称取滑石粉3g、柠檬酸三乙酯10g,加入水60g混匀制成水分散混悬液,将该混悬液在搅拌下缓缓加入到50g的EUDRAGITFS30D中形成水分散混悬液,并将该混合液过120目筛,制备成结肠包衣液(简称<2>液)。 Example 5 weighed 5g budesonide, 11gβ- cyclodextrin, polyethylene glycol 6000,3g 11g talc, stirring the above materials were dispersed in 80g of water; the suspension is slowly dispersed under stirring 16g of EUDRAGITFS30D (as solid content) of polymer suspension, through a 120 mesh sieve to prepare a water dispersion applicator suspension (referred to as & lt; 1 & gt; solution); the other weighed talc 3g, citric acid triethyl 10g, 60g water was added to prepare an aqueous mixed dispersion of a suspension, the suspension was slowly added to EUDRAGITFS30D 50g of an aqueous dispersion under stirring to form a suspension, and the mixture over 120 mesh sieve to prepare a coating solution colon (referred to as & lt; 2 & gt; solution). 采用流化床包衣方法,将<1>、<2>液喷洒于糖芯微丸上制备结肠靶向微丸。 Fluidized bed coating methods, the & lt; 1 & gt;, & lt; 2 & gt; was sprayed onto the sugar core pellets prepared colon pellets. 测定释放度结果见图2。 Determination of dissolution results shown in Figure 2.

实施例6称取3g布地奈德、9gβ-环糊精、23g聚乙二醇6000、3g滑石粉,在搅拌下将上述物料分散于100g水中;将该混悬液在搅拌下缓缓分散于42g的EUDRAGITFS30D(以固含量计)聚合物混悬液中,过120目筛制备成涂药用水分散混悬液(简称<1>液);另称取滑石粉5g、柠檬酸三乙酯5g,加入水60g混匀制成水分散混悬液,将该混悬液在搅拌下缓缓加入到50g的EUDRAGITFS30D(以固含量计)中形成水分散混悬液,并将该混合液过120目筛,制备成结肠包衣液(简称<2>液)。 Example 6 3g weighed budesonide, 9gβ- cyclodextrin, 23g 6000,3g talc, polyethylene glycol, with stirring 100g The above materials were dispersed in water; the suspension is slowly dispersed under stirring in 42g of EUDRAGITFS30D (as solid content) of polymer suspension, through a 120 mesh sieve to prepare a water dispersion applicator suspension (referred to as & lt; 1 & gt; solution); the other weighed talc 5g, citric acid triethyl 5g, 60g water was added to prepare an aqueous mixed dispersion of a suspension, the suspension was slowly added to EUDRAGITFS30D 50g (in solid content) in the aqueous dispersion formed suspension under stirring, and the mixture is through a 120 mesh sieve to prepare a coating solution colon (referred to as & lt; 2 & gt; solution). 采用流化床包衣方法,将<1>、<2>液喷洒于糖芯微丸上制备结肠靶向微丸。 Fluidized bed coating methods, the & lt; 1 & gt;, & lt; 2 & gt; was sprayed onto the sugar core pellets prepared colon pellets. 测定释放度结果见图2。 Determination of dissolution results shown in Figure 2.

以下实施例7-11六个实施例中的靶向微丸,涂药层与实例5完全相同,但结肠包衣层厚度不同,各例分别测定释放度,见图3。 Examples 7-11 The following Examples six pellets targeting embodiment, applicator identical layer in Example 5, but with different layer thicknesses coating colon, release of each example were measured, shown in Figure 3.

实施例7称取滑石粉6g,柠檬酸三乙酯6g,加入水30g混匀制成水分散混悬液,将该混悬液在搅拌下缓缓加入到60g的EUDRAGITFS30D中形成水分散混悬液,并将该混合液过120目筛,制备成结肠包衣液制备<2>液,并按与实施例5相同的操作制备微丸。 Example 7 weighed talc 6g, triethyl citrate 6g, 30g water was added to prepare an aqueous mixed dispersion of a suspension, the suspension was slowly added to 60g of EUDRAGITFS30D under stirring to form an aqueous dispersion suspension, and the mixture is through a 120 mesh sieve to prepare a coating liquid was prepared colon & lt; 2 & gt; solution, and the same operation as in Example 5 preparation of pellets.

实施例8称取EUDRAGITFS30D 30g,水40g,滑石粉2g,柠檬酸三乙酯8g,同实施例7的操作制备<2>液,并按与实施例5相同的操作制备微丸。 Example 8 weighed EUDRAGITFS30D 30g, water 40g, talc 2g, triethyl citrate 8g, prepared following Example 7 & lt same embodiment; 2 & gt; solution, in accordance with the same operation as in Example 5 was prepared pellets.

实施例9称取EUDRAGITFS30D30g,水40g,滑石粉2g,癸二酸二乙酯8g,同实施例7的操作制备<2>液。 Example 9 weighed EUDRAGITFS30D30g, water 40g, talc 2g, diethyl sebacate 8g, prepared as described in Example & lt 7 of operation; 2 & gt; solution. 按实施例5相同的操作制备成微丸实施例10称取EUDRAGITFS30D40g,水60g,滑石粉5g,1,2-丙二醇5g,同实施例7的操作制备<2>液,并按与实施例5相同的操作制备微丸。 The same operation as in Example 5 was prepared as in Example 10 was weighed pellets EUDRAGITFS30D40g, water, 60g, 5g of talc embodiment, 5g 1,2-propanediol, & lt operating Preparation Example 7 in the same embodiment; 2 & gt; solution, and press the same operation as in Example 5 was prepared pellets.

实施例11称取EUDRAGITFS30D60g,水80g,滑石粉10g,柠檬酸三乙酯10g,同实施例7的操作制备<2>液,并按与实施例5相同的操作制备微丸。 Example 11 weighed EUDRAGITFS30D60g, water 80g, talc 10g, triethyl citrate 10g, prepared following Example 7 & lt same embodiment; 2 & gt; solution, and the same operation as in Example 5 Preparation of pellets.

Claims (9)

  1. 1.一种含布地奈德的结肠靶向微丸,由不含活性成分的空白核芯和含活性成分布地奈德的涂药层及肠溶包衣层构成,其特征在于所述的涂药层重量百分比组成为:布地奈德0.1%~20%,β-环糊精1%~40%,增溶剂5%~70%,抗粘剂1%~30%,丙烯酸甲酯共聚物10%~80%;所述的肠溶包衣层重量百分比组成为:丙烯酸甲酯共聚物60%~99%、抗粘剂0.5%~30%、增塑剂0.1%~25%;所述丙烯酸甲酯共聚物是以甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯制备的共聚物。 A colon targeting containing budesonide pellets, containing no active ingredient and the applicator layer and the core blank enteric coating layer containing the active constituent budesonide composition distribution, wherein said coated the drug layer weight percent composition: budesonide 0.1% ~ 20%, β- cyclodextrin 1% to 40%, solubilizer 5% to 70%, anti-tack agent 1% to 30%, 10 methacrylate copolymer to 80%; the percentage by weight of the enteric coating layer consisting of: methyl acrylate copolymer of 60% to 99%, anti-adherent 0.5% to 30%, from 0.1% to 25% of a plasticizer; the acrylic methacrylate copolymers are copolymers prepared from methacrylic acid, methyl acrylate and methyl methacrylate.
  2. 2.按照权利要求1所述的靶向微丸,其特征在于所述涂药层的重量是空白核芯的1%~130%;所述肠溶包衣层的重量是空白核芯的2%~90%;所述空白核芯的粒度为0.01mm~2mm。 2. The targeted pellets according to claim 1, characterized in that the weight of the applicator layer 1 is 130% of the core blank; weight of the enteric coating layer of the core blank 2 % ~ 90%; particle size of the core blank is 0.01mm ~ 2mm.
  3. 3.按照权利要求1所述的靶向微丸,其特征在于所述涂药层的重量百分比组成为:布地奈德5%~15%,β-环糊精10%~30%,增溶剂15%~40%,抗粘剂3%~10%,丙烯酸甲酯共聚物20%~45%;所述肠溶包衣层的重量百分比组成为:丙烯酸甲酯共聚物75%~95%、抗粘剂3%~15%、增塑剂5%~12%。 3. The targeted pellets according to claim 1, wherein the weight percentage of the applicator layer is composed of: Budesonide 5% ~ 15%, β- cyclodextrin 10% to 30% solubilizer 15% to 40%, anti-tack agent 3% to 10% methyl acrylate copolymer, 20% to 45%; by weight of the enteric coating layer of the percentage composition: methyl acrylate copolymer, 75% to 95%, anti-adherents 3% to 15% plasticizer, 5% to 12%.
  4. 4.按照权利要求3所述的靶向微丸,其特征在于所述涂药层的重量是空白核芯的5%~20%;所述肠溶包衣层的重量是空白核芯的5%~20%,所述空白核芯的粒度为0.1mm~1mm。 4. The targeted pellets according to claim 3, characterized in that the weight of the applicator layer is from 5% to 20% of the core blank; weight of the enteric coating layer of the core blank 5 % to 20%, particle size of the core blank is 0.1mm ~ 1mm.
  5. 5.按照权利要求1所述的靶向微丸,其特征在于所述涂药层的重量百分比组成为:布地奈德10.9%、β-环糊精23.9%、增溶剂23.9%、抗粘剂6.5%、包衣材料丙烯酸甲酯共聚物34.8%;所述肠溶包衣层的重量百分比组成为:丙烯酸甲酯共聚物83.3%、抗粘剂8.3%、增塑剂8.4%。 5. Pellets according to claim 1 targeted, characterized in that the weight percentage of the applicator layer is composed of: budesonide 10.9%, β- cyclodextrin 23.9%, 23.9% solubilizing agent, anti-tack agent 6.5% methyl acrylate copolymer coating material 34.8%; by weight of the enteric coating layer of the percentage composition: 83.3% methyl acrylate copolymer, anti-adherent 8.3%, 8.4% plasticizer.
  6. 6.按照权利要求5所述的靶向微丸,其特征在于所述涂药层的重量是空白核芯的9.2%;所述肠溶包衣层的重量是空白核芯的14.4%;所述空白核芯的粒度为0.5mm~0.7mm。 6. The targeted pellets claim 5, characterized in that the applicator layer weight was 9.2% of the core blank; weight of the enteric coating layer was 14.4% of the core blank; the said core blank size is 0.5mm ~ 0.7mm.
  7. 7.按照权利要求1、3或5所述的靶向微丸,其特征在于所述涂药层中的增溶剂为聚乙二醇6000、聚乙二醇4000或它们的混合物;所述涂药层或肠溶包衣层中的抗粘剂为滑石粉;所述肠溶包衣层中的增塑剂为柠檬酸三乙酯、癸二酸二乙酯或1,2-丙二醇。 7. The pellets of claim 3 or targeting 5, characterized in that the applicator solubilizing agent layer is polyethylene glycol 6000, polyethylene glycol 4000, or mixtures thereof; said coating drug or an enteric layer coating layer resistant agent talc; the enteric coating layer of the plasticizer is triethyl citrate, diethyl sebacate or 1,2-propanediol.
  8. 8.按照权利要求1、3或5所述的靶向微丸,所述涂药层中的增溶剂为聚乙二醇6000、所述涂药层或肠溶包衣层中的抗粘剂为滑石粉,所述肠溶包衣层中的增塑剂为柠檬酸三乙酯;所述空白核芯为蔗糖型药用微丸。 8. The pellets as claimed in claim 1, 3 or 5 the targeting of solubilizing the applicator layer is polyethylene glycol 6000, the anti-tack agent layer applicator or enteric coating layer talc, the enteric coating layer of the plasticizer is triethyl citrate; the core blank is sucrose type pharmaceutical pellets.
  9. 9.按照权利要求1至8中任一权利要求所述的靶向微丸的制备方法,它包括下列步骤:1)、室温下,按所述重量百分比称取涂药层的各物料:布地奈德、β-环糊精、增溶剂,抗粘剂和丙烯酸甲酯共聚物;2)、取涂药层各物料总重量0.5倍至10倍的水,将布地奈德、β-环糊精、增溶剂、抗粘剂加入到水中制备成水分散混悬液:3)、将步骤2)制得的混悬液在搅拌下缓缓加入到步骤1)中称取的丙烯酸甲酯共聚物中,混合,将该混合液过120目筛,制备成涂药用水分散混悬液;4)、按所述重量百分比称取肠溶包衣层的各物料:丙烯酸甲酯共聚物、抗粘剂和增塑剂;5)、取肠溶包衣层各物料总重量0.1倍至2倍的水,将步骤4)中称取的抗粘剂和增塑剂分散于水中成混合液;6)将步骤5)制得的混合液在搅拌下缓缓加入到在步骤4)中称取的丙烯酸甲酯共聚物中,混合,将该混合液过12 9. A method of preparing a targeting pellets of any one of 1 to 8 claim in accordance with claim 1, which comprises the following steps: 1) at room temperature, according to the weight percentage of each said layer of material taken applicator: budesonide Ned, [beta] -cyclodextrin, solubilizers, anti-adherents and methyl acrylate copolymers; 2), taking the total weight of the respective layer material applicator 0.5 to 10-fold water, budesonide, [beta] -cyclodextrin fine, solubilizers, anti-sticking agents added to water to prepare an aqueous suspension dispersion: 3), step 2) obtained suspension was under stirring slowly added to the step 1) is taken, said acrylate copolymer were mixed, the mixture through a 120 mesh sieve to prepare a water dispersible suspension applicator; 4), each of said percentages by weight of the material taken enteric layer: methacrylate copolymers, anti-sticking agents and plasticizers; 5), taking the total weight of the enteric layer each 0.1 to 2 times the mass of water in step 4) the anti-tack agent was weighed and dispersed in water as a plasticizer mixture ; 6) in step 5) obtained mixed was added slowly with stirring to weighed in step 4) is methyl acrylate copolymer, mixed, the mixture over 12 0目筛,制备成包衣用水分散混悬液;7)、使用流化床底喷方式,将步骤3)制备的水分散混悬液喷涂在用糖制成的空白核芯上,制备成含药微丸;流化床条件:进风量85m3/h,空气压3.0帕,进风温度36~40℃,排风温度30~33℃,样品温度28~31℃,喷嘴直径1mm,喷雾速度5~10ml/min,干燥时间5分钟;8)、采用与步骤7)相同的条件,将在步骤6)制备的包衣用水分散混悬液喷涂在步骤7)制备的含药微丸上,制备成圆粒结肠靶向微丸;9)、制备好的微丸置40~50℃干燥条件下干燥2~4小时。 0 mesh sieve to prepare a water dispersion coating suspension; 7), using a fluidized bed bottom spray mode, Step 3) Preparation of aqueous dispersion suspension is sprayed onto the blank core made of sugar, prepared drug-containing pellets; fluidized bed conditions: inlet air flow 85m3 / h, air pressure of 3.0 Pa, the intake air temperature 36 ~ 40 ℃, exhaust air temperature 30 ~ 33 ℃, sample temperature of 28 ~ 31 ℃, nozzle diameter 1mm, spray rate 5 ~ 10ml / min, drying time 5 min; 8) used in step 7) the same conditions, the coating water prepared in step 6) dispersing the drug-containing suspension was sprayed on the pellets prepared in step 7), pellets prepared pellets colon; 9), opposite the prepared pellets dried at 40 ~ 50 ℃ dried for 2 to 4 hours.
CN 200410072871 2004-11-25 2004-11-25 Budesonide target-direction microball and preparation thereof CN100333727C (en)

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US5932249A (en) * 1993-09-23 1999-08-03 Dr. Falk Pharma Gmbh Budesonide pellets with a controlled released pattern and process for producing the same
CN1243434A (en) * 1997-01-20 2000-02-02 阿斯特拉公司 New formulation for inhalation having a poured bulk density of from 0.28 to 0.38 g/ml, comprising budesonide
CN1284869A (en) * 1998-02-09 2001-02-21 乔尔·博朗尼克 Treatment of chronic inflammatory disorders of gastrointestinal tract

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US5932249A (en) * 1993-09-23 1999-08-03 Dr. Falk Pharma Gmbh Budesonide pellets with a controlled released pattern and process for producing the same
CN1243434A (en) * 1997-01-20 2000-02-02 阿斯特拉公司 New formulation for inhalation having a poured bulk density of from 0.28 to 0.38 g/ml, comprising budesonide
CN1284869A (en) * 1998-02-09 2001-02-21 乔尔·博朗尼克 Treatment of chronic inflammatory disorders of gastrointestinal tract

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