嘉法狮口服solid dosage form_201110Shenyang

Amount of SR matrix (Drug vs. SR matrix ratio) 缓释基质的数量(药物与基质的比例) Amount and nature of diluents selected 所选稀释剂的性质和用量 Porosity of the matrix (compression force used) 骨架的孔隙率(压片时使用的压力)
COMPRITOL® 888 ATO
水溶性药物 难溶性药物
Main Considerations in developing lipidic matrix ? 在研发脂质骨架中主要考虑因素
o
Three key parameters impacting on dissolution profile : 影响溶出曲线的3个主要参数：
将药物加入到熔融 的脂质液体中
Suspension or solution
分散或溶解
Examples of formulation techniques
处方实例
o o
Compression 压片
Capsule filling 填充胶囊
o
Other Methods 其他方法

Melt granulation/ pelletization 热熔制粒 Melt extrusion 热熔挤出 Spray cooling 冷却喷雾 etc…
COMPRITOL® 888 ATO
o Fine white powder : 50µm
白色细粉末，平均粒径为50μm
o Atomized spherical particles 喷雾干燥得球形颗粒
o
o
Tasteless 无味
M.P.熔点 70°C
DSC : Fusion of Compritol 888 ATO
Lipid based formulations
脂类基质处方
Physical mixture 物理混合:
When both active and lipid excipient are solid powders, creation of a lipid barrier around the drug particle by blending and compression
Dispersion/solution of the drug in the carrier 将药物分散或溶解在介质中 Heat is generally involved 通常需进行加热
Solid drug particles
固态药物
Apply Heat 加热
Drug added to molten lipid
Tablet processes with Compritol 888 ATO
使用Compritol 888 ATO制备片剂的工艺
Pre mix
预混百度文库
Solid lipid particles
固体脂质颗粒
Solid drug particles
固态药物
Direct - blend with other excipients
与其他辅料直接混合
Compression
压片
Lipid based formulations
脂类基质处方
Solid dispersion/solution 固体分散/溶液:
Gattefossé in Solid dosage form 嘉法狮脂质辅料在固体制剂中的应用
Shenyang Seminar– Oct. 2011
技术研讨会–沈阳 2011.10
Contents
内容
o
Advanced lipid matrix for sustained release system 缓控释制剂中优良的骨架材料 Advanced Tablet and Capsule Lubricants 优良的片剂和胶囊润滑剂
(C22) 由山嵛酸（C22脂肪酸）与甘油酯化得到
○ Reaction without catalyst and solvent
反应过程不涉及催化剂或溶剂
○ Extremely inert 完全惰性
○
Defined mixture of : Monoglyceride 18 +/- 1.0 (8-22%) 单酸甘油酯 Diglyceride 52 +/- 0.6 (40-60%) 甘油二酯 Triglyceride 28 +/- 1.2 (25-35%) 甘油三酯
o
Hydrophilic matrix （亲水骨架）

Cellulose derived excipients 乙基纤维素: ethylcellulose, hypromellose 羟丙甲纤维素, hydroxypropylcellulose 羟丙基纤维素

Tableting with cellulosic materials 用纤维素类材料包衣
o
o o
，没有原料水解的风险 Avoid burst out effect 避免突释效应
Atomized powders available for direct compression 喷雾干燥
等到的粉末可用于直接压片
o
Kinetics of drug release not influenced by pH changes
Azithromycin/A 阿奇霉素/抗生 素 ntibiotic Doxazosin mesylate 甲磺酸多沙唑嗪
……
Mechanism of release with lipids 脂质基质释放机理
o
Lipids displaying… 脂质显示…

High melting point (solid at RT) and low HLB value 高熔点和低HLB值（室温下固体） Drug release via a Diffusion mechanism 药物通过扩散机理释 放 Medium to high HLB value (> 7) and medium melting point (viscous liquid to semi-solid) 中到高HLB值(>7)和中等熔点(粘稠 液体至半固体) Drug release via an Erosion mechanism药物通过溶蚀机理释 放
o
Lipophilic matrix （脂质骨架）

Partial glycerides displaying high melting point and low HLB 常用到

高熔点、低HLB值的部分甘油酯 : Compritol 888 ATO, Precirol ATO5 Tableting or capsule filling 压片或胶囊灌装
o
SR efficacy： Compritol 888 matrix Compritol 888 ATO + HPMC : simple blending and compression Sophisticated technologies : • Geomatrix TM (multi-layered lipid matrix and HPMC matrix) • Geoclock TM from Skyepharma
药物释放的动力学不受PH值变化的影响
Bypass patents using hydrophilic SR matrix
o
避开亲水骨架缓释制剂的专利
COMPRITOL® 888 ATO
○ Atomized Glyceryl Behenate 粉末状山嵛酸甘油酯 ○ Strictly from vegetable origin 严格的植物来源 ○ Esterification of glycerol with behenic acid
Advantages of lipids to sustain drug release 脂质材料设计缓释处方的优势
o
Use a solid non-water soluble matrix to sustain drug release from dosage form 在缓释制剂中引入固体无水模型 No solvant needed to disperse the lipid 分散脂质不需要溶剂 No drying step, no organic vapors to be handled, no risk of API hydrolysis 无需干燥，无需处理有机溶剂挥发
o
What are the approaches to sustain drug release ?
通常制备缓释制剂的方法
o
Gastro-resistant coating （包衣）


Cellulose acetophtalate, Metacrylate resins 甲基丙烯酸树脂, Hypromellose phtalate Coating film on pellets or tablets made by the dispersion of cellulose in aqueous or organic solution 纤维素类的水溶液或有机 溶液用于片剂或小丸表面包衣- drying step required 需要干燥过程



Repartition of C888ATO matrix in the tablet Compritol 888ATO 在片剂内的分布
Homogeneous distribution of C888Ato within the tablet Creation of lipid network that slows drug release out of tablet
Temperature (° C)
5 -20 0 20 40 60 80 100 120
Heat Flow Endo down (mW)
0
-5
-10
-15
-20
Scanning Electron Micrograph (SEM)
Market references 上市 缓释产品参考
Paroxetine hydrochloride Prednisone Metformin hydrochloride Guanfacine hydrochloride Theophylline Metoprolol succinate Tamsulosin Chlorydrate Felodipin 盐酸帕罗西汀 强的松 盐酸二甲双胍片 盐酸胍法辛 茶碱 琥珀酸美托洛尔 坦洛新 非洛地平 Nisoldipine Bupropion HCl Ropinirole Hydrochloride Nicotinic acid Tilidine Valproic acid 尼索地平 盐酸安非他酮 盐酸罗匹尼罗 烟酸 痛立定 丙戊酸



Tablet processes with Compritol 888 ATO
使用Compritol 888 ATO制备片剂的工艺
Direct compression 直接压片
All ingredients including Compritol 888 ATO should be sieved through a 20 mesh/810 μm sieve 所有物料过筛，20目 o Weigh all ingredients separately 称取各组分 o Mix all ingredients of the internal phase in an appropriate blender (e.g. turbula blending for 10 min at 62 rpm)在合适的混 合器中混合所有物料 o Add the lubricant if necessary 加入润滑剂（如果需要） o Remix (e.g. turbula blending for 1 min at 90 rpm) 再混合 o Transfer the mix to the tableting equipment and compress on an alternative/rotary press 转移至压片机上进行压片 o Curing treatment(if necessarily) 老化（如果需要）