圆上私修 u 国生 Structure and function of skin Factors affecting drug permeation through the skin Semisolid dosage forms Semisolid dosage forms and transdermal systems .Categories of semisolid dosage forms .Common constituents of dermatological preparations School of pharmacy General methods of preparation In vitro evaluation of TDDS Chen Jian 2012.4 Transdermal drug delivery system(patch) chenjian @situ.edu.cn Design and manufacture of TDDS In vitro evaluation of TDDS 国ft线Structure and function of skin 国生 Stratum corneum ©Structure of skin Brick and mortar model:the keratinized corneocytes act as protein "bricks"embedded in a lipid "mortar" ·Epidermis(表皮) ·Stratum corneum/homy laver(角质层) ·Viable epidermis(活性表皮) ·Dermis(真皮) Network of capillaries ·Subcutaneous tissue(皮下组织) ·Skin appendages 国生一 国生 Factors affecting drug permeation through the skin The process of percutaneous absorption Biological factors affecting percutaneous absorption ·Water content in skin Dissolution of drug in vehicle Diffusion through vehicle Anatomical site variations Transepidermal/transfollicular route ·Integrity of the skin Partitioning into viable epidermis Surface temperature Diffusion through viable epidermis and dermis ·Skin metabolism ·Capillary uptake ·Systemic dilution .Individual difference(age,gender,race et al.) 1
1 Semisolid dosage forms and transdermal systems School of pharmacy Chen Jian 2012.4 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Structure and function of skin Factors affecting drug permeation through the skin Semisolid dosage forms • Categories of semisolid dosage forms • Common constituents of dermatological preparations • General methods of preparation • In vitro evaluation of TDDS Transdermal drug delivery system (patch) • Design and manufacture of TDDS • In vitro evaluation of TDDS Shanghai Jiao Tong University Structure and function of skin Structure of skin • Epidermis (表皮) • Stratum corneum/horny layer（角质层） • Viable epidermis（活性表皮） • Dermis (真皮) • Network of capillaries • Subcutaneous tissue (皮下组织) • Skin appendages Shanghai Jiao Tong University Stratum corneum Brick and mortar model: the keratinized corneocytes act as protein “bricks” embedded in a lipid “mortar” . Shanghai Jiao Tong University The process of percutaneous absorption • Dissolution of drug in vehicle • Diffusion through vehicle • Transepidermal/transfollicular route • Partitioning into viable epidermis • Diffusion through viable epidermis and dermis • Capillary uptake • Systemic dilution Shanghai Jiao Tong University Factors affecting drug permeation through the skin Biological factors affecting percutaneous absorption • Water content in skin • Anatomical site variations • Integrity of the skin • Surface temperature • Skin metabolism • Individual difference (age, gender, race et al.)
圈上开攻达线 Factors affecting drug permeation through the skin 国生 Factors affecting drug permeation through the skin Optimal physiochemical properties for transdermal drug ④Formulation factors candidates ·Dosage form ·Dose deliverable 1 mg ml! ·Melting point <200°C ·Hydrogen bonding <2 国生 Semisolid dosage forms 国线一 Semisolids are unique systems used for topically application Semisolid dosage forms Semisolid systems retain their shape until acted ·Ointments软膏剂 on by an outside force,whereupon,unlike solids, ·Gels凝胶剂 they are easily deformed. .The rheological properties allow semisolids to be ·Pastes糊剂 spread over the skin to form films that cling ·Rigid foams硬泡沫剂 tenaciously 国生一 Semisolids 国秋生 Gels ④Ointment bases(USP) Gels are semisolid systems in which a liquid ·Oleaginous bases油脂性基质 ·Absorption bases吸收性基质 phase is trapped within an interlocking,three- Those permit the incorporation of aqueous solutions dimensional polymeric matrix. resulting in the formation of W/O emulsions ·W/O emulsions ·Water-removable bases易水洗基质 ·O/W emulsions ·Water-soluble bases水溶性基质 2
2 Shanghai Jiao Tong University Factors affecting drug permeation through the skin Optimal physiochemical properties for transdermal drug candidates • Dose deliverable 1 mg ml-1 • Melting point <200°C • Hydrogen bonding <2 Shanghai Jiao Tong University Factors affecting drug permeation through the skin Formulation factors • Dosage form • Base • pH value • Drug concentration and surface area • Percutaneous penetration enhancer Shanghai Jiao Tong University Semisolids are unique systems used for topically application • Semisolid systems retain their shape until acted on by an outside force, whereupon, unlike solids, they are easily deformed. • The rheological properties allow semisolids to be spread over the skin to form films that cling tenaciously. Semisolid dosage forms Shanghai Jiao Tong University Semisolid dosage forms • Ointments 软膏剂 • Gels 凝胶剂 • Pastes 糊剂 • Rigid foams 硬泡沫剂 Shanghai Jiao Tong University Semisolids Ointment bases (USP) • Oleaginous bases 油脂性基质 • Absorption bases 吸收性基质 • Those permit the incorporation of aqueous solutions resulting in the formation of W/O emulsions • W/O emulsions • Water-removable bases 易水洗基质 • O/W emulsions • Water-soluble bases 水溶性基质 Shanghai Jiao Tong University Gels Gels are semisolid systems in which a liquid phase is trapped within an interlocking, threedimensional polymeric matrix
国生 Pastes 国生一 Rigid foams Pastes are basically ointments into which a high Foams are systems in which air or other gas percentage of insoluble particulate solids have is emulsified in a liquid phase to the point been added-as much or more than 25%by of stiffening. weight in some instances. The solids containing in the pastes can absorb and neutralize certain noxious chemicals before they ever reach the skin. 国话t线一Commonnof mid ©生一Commonnofms ⊕Oleaginous bases ©Emulsion base ·0月 ·ydrocarbon烃类 Stearic acid,paraffin,beewax,Stearyl ·Vaselin凡士林 alcohols,Liquid paraffin,vaselin,vegetable ·Paraffin石蜡and liquid paraffin oil ·Esters类脂 ·Water ·Wool fat羊毛脂 .Water,glycerin,propylene glycol,sorbitol ·Beeswax蜂蜡and spermaceti鲸蜡 Emulsifiers ·Vegetable oil Soap,Sodium lauryl sulfate,Alcohols and ·Dimethicones二甲硅油 esters,Polyesters.... 圈t笔Comm onofsemis 国秋生 ©Water soluble bases Formulation design of semisolid PEGs having average molecular weight below Therapeutic stratification of the skin 600 are clear,colorless liquids,those with molecular weight above 1000 are waxlike with Physicochemical property of active ingredient materials. ·Property of base 3
3 Shanghai Jiao Tong University Pastes Pastes are basically ointments into which a high percentage of insoluble particulate solids have been added—as much or more than 25% by weight in some instances. The solids containing in the pastes can absorb and neutralize certain noxious chemicals before they ever reach the skin. Shanghai Jiao Tong University Rigid foams Foams are systems in which air or other gas is emulsified in a liquid phase to the point of stiffening. Shanghai Jiao Tong University Common constituents of semisolids Oleaginous bases • Hydrocarbon烃类 • Vaselin 凡士林 • Paraffin 石蜡and liquid paraffin • Esters 类脂 • Wool fat 羊毛脂 • Beeswax蜂蜡 and spermaceti鲸蜡 • Vegetable oil • Dimethicones 二甲硅油 Shanghai Jiao Tong University Common constituents of semisolids Emulsion base • Oil • Stearic acid, paraffin, beewax, Stearyl alcohols, Liquid paraffin, vaselin, vegetable oil • Water • Water, glycerin, propylene glycol, sorbitol • Emulsifiers • Soap, Sodium lauryl sulfate, Alcohols and esters, Polyesters…. Shanghai Jiao Tong University Common constituents of semisolids Water soluble bases • PEGs having average molecular weight below 600 are clear, colorless liquids; those with molecular weight above 1000 are waxlike with materials. Shanghai Jiao Tong University Formulation design of semisolid • Therapeutic stratification of the skin • Physicochemical property of active ingredient • Property of base
国生一 Preparation of semisolids 圈生一 Evaluation of ointments ©Fusion method 熔合法 ④Drug content ④Melting range ⑥Cold incorporation研和法 ©Viscosity Rheological behavior 国Emulsion method乳化法 Skin irritation ©Stability Transdermal drug delivery systems 国生 Transdermal drug delivery involves the application ©Advantages of TDDS of a drug to the skin to achieve systemically active Escape hepatic first-pass effect levels of the drug to treat diseases remote from the Sustained and controlled release application site. Minimize the fluctuation of blood level .Transdermal drug delivery systems(TDDS) Improve patients'compliancy Transdermal therapeutic systems(TTS) Easy for applying and removing 国生一 国线 Methods enhancing transdermal drug delivery 圈Development of TDDS ·Chemical methods ·Preformulation ·Percutaneous penetration enhancers经皮透过促进剂 .Analytical methodology ·Ion pairs离子对 Determine permeability rate ·Physical methods Select ingredients in TDDS ·lontophoresis离子导入 Pharmacokinetics research ·Sonophoresis超声导入 .Clinical research and quality control procedure ·Microneedles微针技术 4
4 Shanghai Jiao Tong University Preparation of semisolids Fusion method 熔合法 Cold incorporation 研和法 Emulsion method 乳化法 Shanghai Jiao Tong University Evaluation of ointments Drug content Melting range Viscosity Rheological behavior Skin irritation Stability Shanghai Jiao Tong UniversityTransdermal drug delivery systems Transdermal drug delivery involves the application of a drug to the skin to achieve systemically active levels of the drug to treat diseases remote from the application site. • Transdermal drug delivery systems (TDDS) • Transdermal therapeutic systems ( TTS) Shanghai Jiao Tong University Advantages of TDDS • Escape hepatic first-pass effect • Sustained and controlled release • Minimize the fluctuation of blood level • Improve patients’ compliancy • Easy for applying and removing Shanghai Jiao Tong University Methods enhancing transdermal drug delivery • Chemical methods • Percutaneous penetration enhancers 经皮透过促进剂 • Ion pairs 离子对 • Physical methods • Iontophoresis 离子导入 • Sonophoresis 超声导入 • Microneedles 微针技术 Shanghai Jiao Tong University Development of TDDS • Preformulation • Analytical methodology • Determine permeability rate • Select ingredients in TDDS • Pharmacokinetics research • Clinical research and quality control procedure
圈一Selected drugs for TDDS 国生 ©Drugs for cardiovascular diseases心血管药物 Basic structure of a patch ·Nitroglycerine硝酸甘油，Nifedipine硝苯地平 圈Sex homones性激素 ·Estradio雌二醇，Testosterone睾丸激素 Backing laminate ④Analgesics镇痛药 Drug reservoir ·Lidocaine利多卡因，Fentanyl3芬太尼 Adhesive layer ④Antifebrile and Antalgic Drugs解热镇痛药 Release liner ·Diclofenac双氯芬酸，Piroxicam吡罗昔康 国生一 国话t线Preparation of TDDS(patch) Materials in TDDS preparation Manufacture of film material ·Pressure sensitive adhesives,,PSA压敏胶 ·Coating method ·Backing laminate背衬材料 ·Melting method ·Control membrane ·Extrusion method Matrix and reservoir material ·Compressing method ·Release liner防黏材料 ④Treatment of film Combination and formation 圈生一 In vitro evaluation of TDDS 国秋生 Learning objectives ④Instruments Concept:Stratum corneum,TDDS,Percutaneous Parallel permeation cells penetration enhancers Vertical permeation cells Understand factors affecting drug permeation through the skin Preparation of semisolid dosage forms ④Advantages of TDDS 5
5 Shanghai Jiao Tong University Selected drugs for TDDS Drugs for cardiovascular diseases心血管药物 • Nitroglycerine硝酸甘油, Nifedipine硝苯地平 Sex homones性激素 • Estradiol雌二醇, Testosterone睾丸激素 Analgesics镇痛药 • Lidocaine利多卡因, Fentanyl芬太尼 Antifebrile and Antalgic Drugs解热镇痛药 • Diclofenac双氯芬酸, Piroxicam吡罗昔康 Shanghai Jiao Tong University Basic structure of a patch Drug reservoir Adhesive layer Release liner Backing laminate Shanghai Jiao Tong University Materials in TDDS preparation • Pressure sensitive adhesives, PSA压敏胶 • Backing laminate背衬材料 • Control membrane • Matrix and reservoir material • Release liner防黏材料 Shanghai Jiao Tong University Preparation of TDDS (patch) Manufacture of film material • Coating method • Melting method • Extrusion method • Compressing method Treatment of film Combination and formation Shanghai Jiao Tong University In vitro evaluation of TDDS Instruments • Parallel permeation cells • Vertical permeation cells Shanghai Jiao Tong University Learning objectives Concept: Stratum corneum, TDDS, Percutaneous penetration enhancers Understand factors affecting drug permeation through the skin Preparation of semisolid dosage forms Advantages of TDDS