©上特 - 圈上生 Semisolid dosage forms and transdermal systems Semisolid dosage forms and transdermal systems ·Structure of skin School of pharmacy .Semisolid dosage forms Chen Jian 2013.4 cbenjian.@situ.cdu.cn .Transdermal drug delivery system(patch) 圈生 Structure of skin ©Structure of skin ·Epidermis Stratum corneum/horny layer Viable epidermis .Dermis Network of capillaries Subcutaneous tissue ·Skin appendages 国秋生 国生 ©Stratum corneum Stratum corneum is the principal diffusion barrier for most drugs The outmost layer of skin 62 .The intracellular space of the fully differentiated ·I0-l5 um thickness horny cell is packed full with keratin.Therefore,it is dense and chemically impenetrable. Multilayers,metabolically inactive and flattened Lipid,which is synthesized during a keratinocyte's epidermal transit,becomes a mortar that seals the horny structure. 1
1 Semisolid dosage forms and transdermal systems School of pharmacy Chen Jian 2013.4 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Semisolid dosage forms and transdermal systems • Structure of skin • Semisolid dosage forms • Transdermal drug delivery system (patch) Structure of skin Shanghai Jiao Tong University Structure of skin • Epidermis • Stratum corneum/horny layer • Viable epidermis • Dermis • Network of capillaries • Subcutaneous tissue • Skin appendages Shanghai Jiao Tong University Stratum corneum • The outmost layer of skin • 10-15 μm thickness • Multilayers, metabolically inactive and flattened Shanghai Jiao Tong University Stratum corneum is the principal diffusion barrier for most drugs • The intracellular space of the fully differentiated horny cell is packed full with keratin. Therefore, it is dense and chemically impenetrable. • Lipid, which is synthesized during a keratinocyte’s epidermal transit, becomes a mortar that seals the horny structure
国生 Stratum corneum 国上连 Brick and mortar model:the keratinized corneocytes ©Viable epidermis act as protein“bricks”embedded in a lipid“mortar” ·50-100um .May be the barrier of lipid drugs ©Dermis 0.3 to 4 mm in thickness There are numerous structures embedded within the dermis,including blood vessels,lymphatic vessels, nerve endings,hair follicles,sebaceous glands and sweat glands. 图生一 Process of Drug Absorption via Human Skin ④Skin appendages ·Eccrine sweat glands .Apocrine sweat glands et ·Hair follicles ·Sebaceous glands Less important for drug transport,as this route accounts for less than 0.1% of the total surface area of the skin. 国丝生一 国上人梦 neale Factors affecting percutaneous absorption ·Drug concentration ·Application area Semisolid dosage forms ·Aqueous solubility ·Lipophilicity ·Molecular weight ·Water content in skin ·Anatomical site ·Application time 2
2 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 Viable epidermis • 50~100μm • May be the barrier of lipid drugs Dermis • 0.3 to 4 mm in thickness • There are numerous structures embedded within the dermis, including blood vessels, lymphatic vessels, nerve endings, hair follicles, sebaceous glands and sweat glands. Shanghai Jiao Tong University Skin appendages • Eccrine sweat glands • Apocrine sweat glands • Hair follicles • Sebaceous glands Less important for drug transport, as this route accounts for less than 0.1% of the total surface area of the skin. Process of Drug Absorption via Human Skin Shanghai Jiao Tong University Factors affecting percutaneous absorption • Drug concentration • Application area • Aqueous solubility • Lipophilicity • Molecular weight • Water content in skin • Anatomical site • Application time Semisolid dosage forms
国人生 国生 Semisolids are unique systems used for topically application Semisolid dosage forms Semisolid systems retain their shape until acted .Ointments on by an outside force,whereupon,unlike solids, ·Gels they are easily deformed. .The rheological properties allow semisolids to be ·Pastes spread over the skin to form films that cling ·Rigid foams tenaciously. 国生一 图上生 Semisolid dosage forms Semisolid dosage forms ·Ointment bases(USP) ·Ointment bases(USP) ·Oleaginous bases Oleaginous bases(hydrocarbon bases) ·Absorption bases -Hydrocarbon-based semisolids containing -W/O emulsions dissolved or suspended drugs. .Water-removable bases -Can be made by incorporating high-melting -O/W emulsions waxes into fluid mineral oil at high Water-soluble bases temperature. 国丝生 国生 Semisolid dosage forms Semisolid dosage forms ·Ointment bases(USP) ·Ointment bases(USP) Oleaginous bases(hydrocarbon bases) ·Absorption bases -Effective as occlusive dressings -permit the incorporation of aqueous -Have an emollient effect solutions resulting in the formation of W/O -Remain on the skin for long periods emulsions -Difficult to wash off -limited by the relative insolubility of drug 3
3 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. Shanghai Jiao Tong University Semisolid dosage forms • Ointments • Gels • Pastes • Rigid foams Shanghai Jiao Tong University Semisolid dosage forms • Ointment bases (USP) • Oleaginous bases • Absorption bases – W/O emulsions • Water-removable bases – O/W emulsions • Water-soluble bases Shanghai Jiao Tong University Semisolid dosage forms • Ointment bases (USP) • Oleaginous bases (hydrocarbon bases) – Hydrocarbon-based semisolids containing dissolved or suspended drugs. – Can be made by incorporating high-melting waxes into fluid mineral oil at high temperature. Shanghai Jiao Tong University Semisolid dosage forms • Ointment bases (USP) • Oleaginous bases (hydrocarbon bases) – Effective as occlusive dressings – Have an emollient effect – Remain on the skin for long periods – Difficult to wash off – limited by the relative insolubility of drug Shanghai Jiao Tong University Semisolid dosage forms • Ointment bases (USP) • Absorption bases – permit the incorporation of aqueous solutions resulting in the formation of W/O emulsions
图上人生 图上人生 Semisolid dosage forms Semisolid dosage forms ·Ointment bases(USP) ·Ointment bases(USP) ·Absorption bases -May be used as emollients Water-removable bases(cream) -Not easily removed with water washing -O/W emulsions -Are useful as pharmaceutical adjuncts to -Are easily washed form skin incorporate small volumes of aqueous solutions into hydrocarbon bases. -May be diluted with aqueous solutions -For optimum results,the internal aqueous -Through evaporation,the drug is phase should be close to saturated. concentrated in its forming film. -Can absorb serous discharges 国生一 圈生一 Semisolid dosage forms Semisolid dosage forms ·Ointment bases(USP) ·Gels ·Water-soluble bases Gels are semisolid systems in which a liquid -Polyethylene glycol ointment is a water-soluble phase is trapped within an interlocking,three- system that contains fluid,short-chain dimensional polymeric matrix. polyethylene glycols in a crystalline network of high-melting,long-chain polyethylene glycols. -Liquid polyethylene glycols are fully miscible with water,and many drugs that are insoluble in hydrocarbon vehicles readily dissolve in this base. 国赵生 国生 Semisolid dosage forms Semisolid dosage forms ·Pastes ·Rigid foams Pastes are basically ointments into which a Rigid foams are systems in which air or other high percentage of insoluble particulate solids gas is emulsified in a liquid phase to the point have been added-as much or more than 50% of stiffening. by weight in some instances. The solids containing in the pastes can absorb and neutralize certain noxious chemicals before they ever reach the skin. 4
4 Shanghai Jiao Tong University Semisolid dosage forms • Ointment bases (USP) • Absorption bases – May be used as emollients – Not easily removed with water washing – Are useful as pharmaceutical adjuncts to incorporate small volumes of aqueous solutions into hydrocarbon bases. – For optimum results, the internal aqueous phase should be close to saturated. Shanghai Jiao Tong University Semisolid dosage forms • Ointment bases (USP) • Water-removable bases (cream) – O/W emulsions – Are easily washed form skin – May be diluted with aqueous solutions – Through evaporation, the drug is concentrated in its forming film. – Can absorb serous discharges Shanghai Jiao Tong University Semisolid dosage forms • Ointment bases (USP) • Water-soluble bases – Polyethylene glycol ointment is a water-soluble system that contains fluid, short-chain polyethylene glycols in a crystalline network of high-melting, long-chain polyethylene glycols. – Liquid polyethylene glycols are fully miscible with water, and many drugs that are insoluble in hydrocarbon vehicles readily dissolve in this base. Shanghai Jiao Tong University Semisolid dosage forms • Gels • Gels are semisolid systems in which a liquid phase is trapped within an interlocking, threedimensional polymeric matrix. Shanghai Jiao Tong University Semisolid dosage forms • Pastes • Pastes are basically ointments into which a high percentage of insoluble particulate solids have been added—as much or more than 50% 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 Semisolid dosage forms • Rigid foams • Rigid foams are systems in which air or other gas is emulsified in a liquid phase to the point of stiffening
图上人生 国生 Common constituents of semisolids Common constituents of semisolids ·Oleaginous bases More raw materials are available for use on ·Hydrocarbon the skin than other dosage forms.It is due to -Vaselin -Paraffin and liquid paraffin the type of absorption barrier and physicochemical environment surrounding ·Esters类脂 -Wool fat absorption sites. -Beeswax and spermaceti ·Vegetable oil ·Dimethicones 国丝生一 圈上生 Common constituents of semisolids Common constituents of semisolids ·Emulsion base ·Water soluble bases -Stearic acid,paraffin,beewax,Stearyl PEGs having average molecular weight below alcohols,Liquid paraffin,vaselin, 600 are clear,colorless liquids;those with vegetable oil molecular weight above 1000 are waxlike ·Water with materials. -Water,glycerin,propylene glycol,sorbitol ·Emulsifiers -Soap,Sodium lauryl sulfate,Alcohols and esters,Polyesters.... 国坠生 圈生 Common constituents of semisolids Formulation design of semisolid ·Gelling agents Therapeutic stratification of the skin .Carbomer Physicochemical property of active Carboxymethylcellulose ingredient .Hydroxypropyl methylcellulose ·Property of base ·Tragacanth 5
5 Shanghai Jiao Tong University Common constituents of semisolids • More raw materials are available for use on the skin than other dosage forms. It is due to the type of absorption barrier and physicochemical environment surrounding absorption sites. Shanghai Jiao Tong University Common constituents of semisolids • Oleaginous bases • Hydrocarbon – Vaselin – Paraffin and liquid paraffin • Esters 类脂 – Wool fat – Beeswax and spermaceti • Vegetable oil • Dimethicones 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 Common constituents of semisolids • Gelling agents • Carbomer • Carboxymethylcellulose • Hydroxypropyl methylcellulose • Tragacanth Shanghai Jiao Tong University Formulation design of semisolid • Therapeutic stratification of the skin • Physicochemical property of active ingredient • Property of base
国生一 国上特 “ Preparation of semisolids Transdermal drug delivery ·Fusion method systems ·Emulsion method ·Cold incorporation 国生一 圈生 Transdermal drug delivery involves the application Difference between transdermal delivery and topical of a drug to the skin to achieve systemically active delivery levels of the drug to treat diseases remote from the application site. .Transdermal drug delivery involves the application of a drug to the skin to achieve systemically active levels of Transdermal drug delivery systems (TDDS) the drug to treat diseases remote from the application site. Transdermal therapeutic systems(TTS) Topical drug delivery is to deliver drugs to the local tissues directly under the application site or within tissues under and around the site of application. 国垫生 Worldwido Market for Transdermal Drug DeFvery Systems s700c 国Advantages of TDDS Escape hepatic first-pass effect s6a00 00. Sustained and controlled release s3,000 Minimize the fluctuation of blood level s2,00.0 .Improve patients'compliancy 0 00 Easy for applying and removing 6
6 Shanghai Jiao Tong University Preparation of semisolids • Fusion method • Emulsion method • Cold incorporation Transdermal drug delivery systems Shanghai Jiao Tong University 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 Difference between transdermal delivery and topical delivery • 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. • Topical drug delivery is to deliver drugs to the local tissues directly under the application site or within tissues under and around the site of application. 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 Worldwide Market for Transdermal Drug Delivery Systems $- $1,000.00 $2,000.00 $3,000.00 $4,000.00 $5,000.00 $6,000.00 $7,000.00 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Year Manufacturer Revenue (in millions)
图生 国上生 Transdermal delivery. ©Types of TDDS(patch) ·Drug in adhesive ·Patches Acheste layer 月eehe Sner ·Drug in matrix ·Drug in reservior 国生一 Materials in TDDS preparation Materials in TDDS preparation Membrane and matrix polymer Membrane and matrix polymer .Ethylene vinylacetate copolymer(EVA) .Pressure sensitive adhesives,PSA Polyvinyl chloride(PVC) .Backing laminate ·Polypropylene(Pp) ·Release liner ·Polyethylene(PE) ·Reservoir material polydiethyl phthalate(PET) ④建.Materils in TDDS preparation 圈ft达Materials in TDDS preparation ©Pressure sensitive adhesives,PSA压敏胶 圈Backing laminate Polyisobutylene(PIB) .Polyethylene,aluminum foil etc. ·Polyacrylate ®Release liner .polyethylene,polypropylene,polystyrene ·Silicone ®Reservoir material ·Carbomer,.HPMC,PVA 7
7 Shanghai Jiao Tong University Transdermal delivery . • Patches Shanghai Jiao Tong University Types of TDDS (patch) • Drug in adhesive • Drug in matrix • Drug in reservior Shanghai Jiao Tong University Materials in TDDS preparation • Membrane and matrix polymer • Pressure sensitive adhesives, PSA • Backing laminate • Release liner • Reservoir material Shanghai Jiao Tong University Materials in TDDS preparation Membrane and matrix polymer • Ethylene vinylacetate copolymer (EVA） • Polyvinyl chloride (PVC） • Polypropylene (PP） • Polyethylene (PE) • polydiethyl phthalate (PET） Shanghai Jiao Tong University Materials in TDDS preparation Pressure sensitive adhesives, PSA压敏胶 • Polyisobutylene (PIB) • Polyacrylate • Silicone Shanghai Jiao Tong University Backing laminate • Polyethylene, aluminum foil etc. Release liner • polyethylene, polypropylene, polystyrene Reservoir material • Carbomer, HPMC, PVA Materials in TDDS preparation
国必生 国生 Preparation of TDDS(patch) In vitro evaluation of TDDS Mixing drug with reservoir,matrix,or adhesive Casting into films and drying Parallel permeation cells Laminating with other structural components ·Die cutting Vertical permeation cells ·Final packaging 国生一 国上生一 In vitro evaluation of TDDS In vitro evaluation of TDDS ·Donor solution ·Skin Poorly soluble drug:saturation solution .Soluble drug:10 times higher ·Human skin Receptor solution should maintain a good sink ·Animal skin condition ·Temperature often keep at32±lC .Living skin equivalents 国坠生 Learning objectives Concept:Stratum comeum,TDDS Understand factors affecting drug permeation through the skin The difference between different type of semisolids Preparation of semisolid dosage forms ©Advantages of TDDS 8
8 Shanghai Jiao Tong University Preparation of TDDS (patch) • Mixing drug with reservoir, matrix, or adhesive • Casting into films and drying • Laminating with other structural components • Die cutting • Final packaging Shanghai Jiao Tong University In vitro evaluation of TDDS • Parallel permeation cells • Vertical permeation cells Shanghai Jiao Tong University In vitro evaluation of TDDS • Donor solution • Poorly soluble drug: saturation solution • Soluble drug: 10 times higher • Receptor solution should maintain a good sink condition • Temperature often keep at 32±1℃ Shanghai Jiao Tong University In vitro evaluation of TDDS • Skin •Human skin •Animal skin •Living skin equivalents Shanghai Jiao Tong University Learning objectives Concept: Stratum corneum, TDDS Understand factors affecting drug permeation through the skin The difference between different type of semisolids Preparation of semisolid dosage forms Advantages of TDDS