©上特 “-wls 国上人生 Capsule Solid dosage form in which the drug substance and excipients are enclosed within a hard or soft-elastic Capsules capsule ·Hard capsules ·Soft capsules School of Pharmacy Chen Jian 20123 Sustained release capsules chenjian@sjtu.edu.cn Controlled release capsules ·Enteric capsules 图上生一 Hard Capsules 国生一 ©Advantages ·Conceal the smell .Improve drug stability .Bioavailability is generally good Flexibility in formulation in comparison to tablets Solidify the liquid drug .Obtain sustained-release or targeted-release .Ideal or clinical trials and widely used for preliminary drug trials 国垫生 ©f达Manufacture of Hard Capsules Disadvantages ®Shell composition .Number of suppliers of shells is limited .Gelatin Filling equipment slower than tableting ·Plasticizer .Generally more costly than tablets ·Colorants Not suitable for some kinds of drugs ·Opaquing agents Water or alcohol solution of drugs ·Preservatives .Efflorescent materials ·Water .Hygroscopic materials Extremely soluble materials 1
1 Capsules School of Pharmacy Chen Jian 2012.3 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Capsule Solid dosage form in which the drug substance and excipients are enclosed within a hard or soft-elastic capsule • Hard capsules • Soft capsules • Sustained release capsules • Controlled release capsules • Enteric capsules Shanghai Jiao Tong University Hard Capsules Shanghai Jiao Tong University Advantages • Conceal the smell • Improve drug stability • Bioavailability is generally good • Flexibility in formulation in comparison to tablets • Solidify the liquid drug • Obtain sustained-release or targeted-release • Ideal or clinical trials and widely used for preliminary drug trials Shanghai Jiao Tong University Disadvantages • Number of suppliers of shells is limited • Filling equipment slower than tableting • Generally more costly than tablets • Not suitable for some kinds of drugs • Water or alcohol solution of drugs • Efflorescent materials • Hygroscopic materials • Extremely soluble materials Shanghai Jiao Tong University Manufacture of Hard Capsules Shell composition • Gelatin • Plasticizer • Colorants • Opaquing agents • Preservatives • Water
图生 Gelatin 国上人生 Gelatin Although some other materials could be used. Type A gelatin contributes plasticity and clarity Manufactured from pork skin gelatin is the most popular component to prepare capsule shells. Produced by acid hydrolysis .Isoelectric point:7-9 Gelatin is prepared by the hydrolysis of collagen obtained from animal connective Type B gelatin contributes firmness Manufactured from bone tissue,bones,skin,and sinew. Produced by alkaline hydrolysis Isoelectric point:4.7-5.2 国生一 Manufacture of Hard Capsules Evaluation of gelatin Shell composition ·Gel strength冻力强度 Gelatin Plasticizer:glycerin ·Viscosity ·Thicker Opaquing agents ·Preservatives ·Colorants Water 国生一 Manufacture of Hard Capsules Manufacture of Hard Capsules ©Shell manufacture Properties of empty capsules ·Gelatin dissolution ·Appearance: ·Dipping ·Size ·Smel .Rotation Moisture content:13.0-16.0% ·Drying ·Friability ·Stripping ·Dissolution rate .Trimming ·Ash test ·Joining .Microbiological test 2
2 Shanghai Jiao Tong University Gelatin Although some other materials could be used, gelatin is the most popular component to prepare capsule shells. Gelatin is prepared by the hydrolysis of collagen obtained from animal connective tissue, bones, skin, and sinew. Shanghai Jiao Tong University Gelatin Type A gelatin contributes plasticity and clarity • Manufactured from pork skin • Produced by acid hydrolysis • Isoelectric point: 7-9 Type B gelatin contributes firmness • Manufactured from bone • Produced by alkaline hydrolysis • Isoelectric point: 4.7-5.2 Shanghai Jiao Tong University Evaluation of gelatin • Gel strength 冻力强度 • Viscosity Shanghai Jiao Tong University Manufacture of Hard Capsules Shell composition • Gelatin • Plasticizer: glycerin • Thicker • Opaquing agents • Preservatives • Colorants • Water Shanghai Jiao Tong University Manufacture of Hard Capsules Shell manufacture • Gelatin dissolution • Dipping • Rotation • Drying • Stripping • Trimming • Joining Shanghai Jiao Tong University Manufacture of Hard Capsules Properties of empty capsules • Appearance: • Size • Smell • Moisture content: 13.0–16.0% • Friability • Dissolution rate • Ash test • Microbiological test
图生_Manufacture of Hard Capsules ®i生_Manufacture of Hard Capsules ©Size ④Self-locking closure ·Eight size::000,00,0,1,2,3,4,5 Hard capsules are made self-locking by forming indentations or grooves 空数01234 on the inside of the cap 0750.550.400200.25015 and body portions 圈t生Manufacture of Hard Capsules Manufacture of Hard Capsules ©Storage of shells ©Rectification Avoid extremely temperature(s37C) Separation of caps from bodies Maintain a relative humidity of 50% Dosing of fill material ④Stability of shells Replacement of caps and ejection of filled capsules Moisture transfer between content and shell ·Trace aldehydes 8-ee-9-ggg-月-3 Manufacture of Hard Capsules 国生 Manual Filling Machines ®Powder filling ·Choice of shell ·Power filling Sealing 3
3 Shanghai Jiao Tong University Manufacture of Hard Capsules Size • Eight size: 000, 00, 0, 1, 2, 3, 4, 5 Shanghai Jiao Tong University Manufacture of Hard Capsules Self-locking closure • Hard capsules are made self-locking by forming indentations or grooves on the inside of the cap and body portions Shanghai Jiao Tong University Manufacture of Hard Capsules Storage of shells • Avoid extremely temperature(≤ 37℃) • Maintain a relative humidity of 50% Stability of shells • Moisture transfer between content and shell • Trace aldehydes Shanghai Jiao Tong University Manufacture of Hard Capsules Rectification Separation of caps from bodies Dosing of fill material Replacement of caps and ejection of filled capsules Shanghai Jiao Tong University Manufacture of Hard Capsules Powder filling • Choice of shell • Power filling • Sealing Shanghai Jiao Tong University Manual Filling Machines
Powder filling ®生Design of Powder Formulation 柱塞 General Considerations ·Lubricity 1防 ·Compactibility 。Fluidity 填充管 ]T仔单位重药指块 放表 @卢t生Design of Powder Formulation Manufacture of Hard Capsules ©Excipients ©Nonpowder filling ·Fillers ·Beads/pellets ·Glidants ·Microtablets 。Lubricants ·Liquid ·Disintegrants 国垫生 ©f达Soft Gelatin Capsules(softgels) Alternatives to Gelatin Capsules ·Starch capsules The moisture content of the capsules is 14%. ·HPMC capsules Lower moisture content than gelatin capsules The moisture is tighter bound 4
4 Powder filling Shanghai Jiao Tong University Design of Powder Formulation General Considerations • Lubricity • Compactibility • Fluidity Shanghai Jiao Tong University Design of Powder Formulation Excipients • Fillers • Glidants • Lubricants • Disintegrants Shanghai Jiao Tong University Manufacture of Hard Capsules Nonpowder filling • Beads/pellets • Microtablets • Liquid Shanghai Jiao Tong University Alternatives to Gelatin Capsules • Starch capsules • The moisture content of the capsules is 14%. • HPMC capsules • Lower moisture content than gelatin capsules • The moisture is tighter bound Shanghai Jiao Tong University Soft Gelatin Capsules (softgels)
国必生 Soft Capsules 国上生 Soft Capsules Capsule filling material Advantages of soft capsule ·Single liquid Solidify the liquid drug ·Liquid blends Improved bioavailability ·Drug solution Enhanced drug stability ·Suspensions .Pharmaceutical elegance Superior patient compliance ·Semisolids Excellent dose uniformity 国生一 Soft Capsules 国生 Soft Capsules Disadvantages of soft capsule ©Plasticizer Not suitable for some kinds of drugs Glycerin,sorbitol,propylene glycol Specialized manufacturing equipment requirements ·Ratio:0.4-0.6 Higher manufacturing cost as compared to tablets .Stability concers with compounds susceptible to hydrolysis. 国坠生 Soft Capsules 国生 Soft Capsules Requirements of filling material ©The types of vehicles Water content lower than 5% .Water-immiscible liquids No low MW water soluble and volatile ·Vegetable oils organic compounds .Aliphatic and aromatic hydrocarbons No aldehyde .Water-miscible,nonvolatile liquids ·PEG The pH of the liquids can be between 2.5 and 7.5 All liquids used for filling must flow by gravity at a temperature of 35'C or less. 5
5 Shanghai Jiao Tong University Soft Capsules Capsule filling material • Single liquid • Liquid blends • Drug solution • Suspensions • Semisolids Shanghai Jiao Tong University Soft Capsules Advantages of soft capsule • Solidify the liquid drug • Improved bioavailability • Enhanced drug stability • Pharmaceutical elegance • Superior patient compliance • Excellent dose uniformity Shanghai Jiao Tong University Soft Capsules Disadvantages of soft capsule • Not suitable for some kinds of drugs • Specialized manufacturing equipment requirements. • Higher manufacturing cost as compared to tablets • Stability concerns with compounds susceptible to hydrolysis. Shanghai Jiao Tong University Soft Capsules Plasticizer • Glycerin, sorbitol, propylene glycol • Ratio: 0.4-0.6 Shanghai Jiao Tong University Soft Capsules Requirements of filling material • Water content lower than 5% • No low MW water soluble and volatile organic compounds • No aldehyde • The pH of the liquids can be between 2.5 and 7.5 Shanghai Jiao Tong University Soft Capsules The types of vehicles • Water-immiscible liquids • Vegetable oils • Aliphatic and aromatic hydrocarbons • Water-miscible, nonvolatile liquids • PEG All liquids used for filling must flow by gravity at a temperature of 35℃ or less
因人生 Soft Capsules 国生 Soft Capsules ©Base adsorption ©Manufacture ·Drug suspensions ·Rotary die process压制法 Base adsorption=weight of base/weight of solid drug ·Bubble method滴制法 RE 胶帮 片国 国达生 国生 ©Enteric Capsules ©Evaluation .The shell of enteric capsules is soluble in ·Appearance intestine and insoluble in stomach Weight variation The content of enteric capsules is soluble in ·Disintegration test intestine and insoluble in stomach ·Dissolution test .Water content Packaging and Storage 6
6 Shanghai Jiao Tong University Soft Capsules Base adsorption • Drug suspensions • Base adsorption=weight of base/weight of solid drug Shanghai Jiao Tong University Soft Capsules Manufacture • Rotary die process 压制法 • Bubble method 滴制法 Shanghai Jiao Tong University Enteric Capsules • The shell of enteric capsules is soluble in intestine and insoluble in stomach • The content of enteric capsules is soluble in intestine and insoluble in stomach Shanghai Jiao Tong University Evaluation • Appearance • Weight variation • Disintegration test • Dissolution test • Water content Packaging and Storage
国丝 速效感冒胶囊（硬胶囊剂） 国生一维生素AD胶丸（软胶囊剂） ©处方：对乙酰氨基酚300g 推生素C 100g 围处方：推生素A3000单位 雏生素D 300单位 胆汁粉 100g 知啡因 3g 明胶 100份 甘油 55-66份 氯萃事敏 39 10%淀粉浆 通量 水 120份 鱼肝油或精炼食用植物油适量 食用色素 量 共制成硬胶囊剂1000粒 思制备： 制备： ·取上述各药物，分别粉碎，过0目筛 A为标 示量的90.0120.0%、含谁生煮 ·将10%淀物浆分为A,B.C三份：A红刷，B黄柳，C白柳 ·将对乙酰氨基酚分为三份 ·囊材的制备：甘油及水如热至7080℃。如入明胶，搅排溶化，保温 12小时，除去上浮的泡沫，滤过（保持温度） 。一经与氢装配错湿匀后相入红期 。一份与胆汁粉、 生素C湿匀后如入黄 ‘ 用布拭去酷附的冷 一与如啡因漫匀后加入白 吹冷风4小时，于2535℃下烘4小时， ·分别制成款材后，过14目尼龙筛制粒，70℃干燥至水分3%以下 用g %乙醇洗漆 ·将上述三种颜色的颗粒混合均匀后，填入空较囊中，即得。 -次，最后在30-35℃烘干约2小时，即得。 国生一 Learning Objectives 国上1修 in neh Advantages and disadvantages of hard capsules Shell composition of capsules Suppository Size of hard capsule shells Advantages and disadvantages of soft capsules School of Pharmacy Chen Jian Manufacture methods of soft capsules 2012.3 chenjian@sjtu.edu.cn 国达生 国生 ©Concepts ©Suppository(栓剂) Components A small plug of medication designed to melt or solve in fluid within a body cavity,especially the ©Formulation design rectum or vagina Preparation ·Local effect ·Systemic effect ©Evaluation 7
7 Shanghai Jiao Tong University 速效感冒胶囊（硬胶囊剂） 处方：对乙酰氨基酚 300g 维生素C 100g 胆汁粉 100g 咖啡因 3g 氯苯那敏 3g 10%淀粉浆 适量 食用色素 适量 共制成硬胶囊剂1000粒 制备： • 取上述各药物，分别粉碎，过80目筛 • 将10%淀粉浆分为A、B、C三份： A红糊，B黄糊，C白糊 • 将对乙酰氨基酚分为三份 • 一份与氯苯那敏混匀后加入红糊 • 一份与胆汁粉、维生素C混匀后加入黄糊 • 一份与咖啡因混匀后加入白糊 • 分别制成软材后，过14目尼龙筛制粒，70℃干燥至水分3%以下 • 将上述三种颜色的颗粒混合均匀后，填入空胶囊中，即得。 Shanghai Jiao Tong University 维生素AD胶丸（软胶囊剂） 处方：维生素A 3000单位 维生素D 300单位 明胶 100份 甘油 55～66份 水 120份 鱼肝油或精炼食用植物油适量 制备： • 内容物的制备：取维生素A与维生素D，加鱼肝油或精炼食用植物油溶 解，并调整浓度至每丸含维生素A为标示量的90.0~120.0%、含维生素 D为标示量的85.0%以上，作为药液待用 • 囊材的制备：甘油及水加热至70~80℃，加入明胶，搅拌溶化，保温 1~2小时，除去上浮的泡沫，滤过（保持温度） • 胶丸的制备：采用滴制法制备，将囊材和内容物分别加入滴丸剂的料槽 中滴制，以液状石腊为冷却液，收集冷凝的胶丸，用纱布拭去黏附的冷 却液，在室温下吹冷风4小时，放于25~35℃下烘4小时，再经石油醚洗 涤两次（每次3~5分钟），除去胶丸外层液状石腊，再用95%乙醇洗涤 一次，最后在30~35℃烘干约2小时，即得。 Shanghai Jiao Tong University Learning Objectives Advantages and disadvantages of hard capsules Shell composition of capsules Size of hard capsule shells Advantages and disadvantages of soft capsules Manufacture methods of soft capsules Suppository School of Pharmacy Chen Jian 2012.3 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Concepts Components Formulation design Preparation Evaluation Shanghai Jiao Tong University Suppository （栓剂） • A small plug of medication designed to melt or solve in fluid within a body cavity, especially the rectum or vagina • Local effect • Systemic effect
国以生 国上人连 ④Local action ©Systemic action Rectal suppositories intended for local are most frequently Drugs inactivated by the pH or enzymatic activity used to relieve constipation or the pain,irritation, of the stomach or intestines itching and inflammation associated with hemorrhoids Drugs irritating to the stomach 疮 Drugs destroyed by the liver .Vaginal suppositories intended for local effects are Patients who are unable or unwilling to swallow employed mainly as contraceptives孕s药，antiseptics. medication. Patients with vomiting. 图生 国生 栓剂基质 Components of suppositories Requirement of bases ·Active Ingredients Solid at room temperature Solve or suspend in base Soft,melt,or dissolve at body temperature ·Suppositories base Physical and chemical stability ·Fatty base Acid value,Saponification value,lodine value ·Water soluble base ·High water number ·Additive 国坠生一 国生 ©Fatty Base ©Water soluble base ·Cocoa butter可可豆脂 Gelatin glycerin(gelatin:glycerin: ·Semi--synthetic fatty glyeerides半合成甘油酯 water=-20:70:l0) ·PEG ·Polysorbate6l聚山梨酯6l ·Polyoxyl40 stearate聚氧乙烯单硬脂酸酯 ·Poloxamer 8
8 Shanghai Jiao Tong University Local action • Rectal suppositories intended for local are most frequently used to relieve constipation便秘 or the pain, irritation, itching and inflammation associated with hemorrhoids痔 疮. • Vaginal suppositories intended for local effects are employed mainly as contraceptives避孕药, antiseptics. Shanghai Jiao Tong University Systemic action • Drugs inactivated by the pH or enzymatic activity of the stomach or intestines • Drugs irritating to the stomach • Drugs destroyed by the liver • Patients who are unable or unwilling to swallow medication. • Patients with vomiting. Shanghai Jiao Tong University Components of suppositories • Active Ingredients • Solve or suspend in base • Suppositories base • Fatty base • Water soluble base • Additive Shanghai Jiao Tong University 栓剂基质 Requirement of bases • Solid at room temperature • Soft, melt, or dissolve at body temperature • Physical and chemical stability • Acid value, Saponification value, Iodine value • High water number Shanghai Jiao Tong University Fatty Base • Cocoa butter可可豆脂 • Semi-synthetic fatty glycerides 半合成甘油酯 Shanghai Jiao Tong University Water soluble base • Gelatin glycerin (gelatin: glycerin: water=20:70:10 ) • PEG • Polysorbate 61 聚山梨酯61 • Polyoxyl 40 stearate 聚氧乙烯单硬脂酸酯 • Poloxamer
国以生 Additives 国认生 ④Surfactant ④Formulation desigr 国Antioxidant抗氧剂 Local effect:Sustained release ©Hardening agent硬化剂and viscosity ·Systemic effect: modifier增稠剂 ·Rapid release ©Absorption enhancer吸收促进剂 .Reduce first-pass effect 国生一 国生一 Something about rectum ·Aout15 em long Factors affecting drug absorption from rectal No villi or microvilli suppositories Small amount of fluid with a pH about 7 Low enzymatic activity Physiological factors Abundant vascularization with blood and lymphatic vessels ·The inferior hemorrhoidal vein直肠下静眯-bypass the liver ·The middle hemorrhoidal ven直中静脉-bypass the liver Physicochemical factors ·The superiot hemorthoidal vein直肠上静脉.into the liver Lymphatic circulation also assists in absorption 国必线 国生 Physiological factors Physicochemical factors ·Colonic content .Oil/water partition coefficient ·Circulation route .Water soluble base for hydrophobic drug Fatty base for hydrophilic drug pH and lack of buffering capacity of rectal fluids ·Particle size Nature of the base 9
9 Shanghai Jiao Tong University Additives Surfactant Antioxidant抗氧剂 Hardening agent 硬化剂 and viscosity modifier 增稠剂 Absorption enhancer 吸收促进剂 Shanghai Jiao Tong University Formulation design • Local effect: Sustained release • Systemic effect: • Rapid release • Reduce first-pass effect Shanghai Jiao Tong University Something about rectum • About 15 cm long • No villi or microvilli • Small amount of fluid with a pH about 7 • Low enzymatic activity • Abundant vascularization with blood and lymphatic vessels • The inferior hemorrhoidal vein直肠下静脉- bypass the liver • The middle hemorrhoidal vein 直肠中静脉 -bypass the liver. • The superior hemorrhoidal vein直肠上静脉- into the liver • Lymphatic circulation also assists in absorption Shanghai Jiao Tong University Factors affecting drug absorption from rectal suppositories • Physiological factors • Physicochemical factors Shanghai Jiao Tong University Physiological factors • Colonic content • Circulation route • pH and lack of buffering capacity of rectal fluids Shanghai Jiao Tong University Physicochemical factors • Oil/water partition coefficient • Water soluble base for hydrophobic drug • Fatty base for hydrophilic drug • Particle size • Nature of the base
国生一 国上人生 ©Preparation 国Fusion method热熔法 ·Cold compression method冷压法 ·Melting of the base .Incorporating of medicament ·Fusion method热熔法 Pouring the melt into molds .Cooling the melt and congeal in to suppositories Removing the formed suppositories 圈生 Lubrication of the mold Some kinds of suppository molds need lubrication before the melt is poured to facilitate clean and easy removal of the molded suppositories. Lubrication is not necessary when the base is cocoa butter or PEG,as these materials contract sufficiently on cooling 4U+ to separate from the inner surfaces and allow easy removal. 0-00n 下aktu supp 国坠生 国生 ④It is better to Determination of the amount of base required ·Displacement value(DV,置换价) Chill the molds in refrigerator W Keep the melt near the congealing point DV=- G-(M-W) y x=(G--)·n DV 10
10 Shanghai Jiao Tong University Preparation • Cold compression method 冷压法 • Fusion method 热熔法 Shanghai Jiao Tong University Fusion method 热熔法 • Melting of the base • Incorporating of medicament • Pouring the melt into molds • Cooling the melt and congeal in to suppositories • Removing the formed suppositories Shanghai Jiao Tong University Shanghai Jiao Tong University Lubrication of the mold • Some kinds of suppository molds need lubrication before the melt is poured to facilitate clean and easy removal of the molded suppositories. • Lubrication is not necessary when the base is cocoa butter or PEG, as these materials contract sufficiently on cooling to separate from the inner surfaces and allow easy removal. Shanghai Jiao Tong University It is better to • Chill the molds in refrigerator • Keep the melt near the congealing point Shanghai Jiao Tong University Determination of the amount of base required • Displacement value（DV，置换价） W DV= —————— G -（M-W） y x=（G - — ）• n DV