©上特 “-Bl✉ 国上人生 The design objective for modifying oral drug release Oral Modified-release is to alter the rate of drug input(dissolution /absorption)in GIT to achieve a predetermined Drug Delivery Systems plasma profile. School of Pharmacy Chen Jian 2012.3 chenjian@sjtu.edu.cn 图生 国生一 Possible therapeutic benefits of a properly Common modes of oral MR delivery include: designed MR dosage form ·Delayed release ·improved efficacy reduced adverse events Site-specific release increased convenience ·Extended release increased patient compliance ·Programmed release 国坠生 圆话达生 Mechanism of sustained release Dissolution-controlled mechanism .Dissolution-controlled mechanism Decrease the rate of dissolution .Diffusion-controlled mechanism Noyes-Whitney Equation Bioerodible-controlled mechanism =G-0术-品 t Osmotically-controlled mechanism lon-Exchange mechanism Prepare appropriate salts or derivatives Control particle size of active ingredient 1
1 Oral Modified-release Drug Delivery Systems School of Pharmacy Chen Jian 2012.3 chenjian@sjtu.edu.cn Shanghai Jiao Tong University The design objective for modifying oral drug release is to alter the rate of drug input (dissolution /absorption) in GIT to achieve a predetermined plasma profile. Shanghai Jiao Tong University Possible therapeutic benefits of a properly designed MR dosage form • improved efficacy • reduced adverse events • increased convenience • increased patient compliance. Shanghai Jiao Tong University Common modes of oral MR delivery include: • Delayed release • Site-specific release • Extended release • Programmed release Shanghai Jiao Tong University Mechanism of sustained release • Dissolution-controlled mechanism • Diffusion-controlled mechanism • Bioerodible-controlled mechanism • Osmotically-controlled mechanism • Ion-Exchange mechanism Shanghai Jiao Tong University Dissolution-controlled mechanism • Decrease the rate of dissolution • Noyes-Whitney Equation • Prepare appropriate salts or derivatives • Control particle size of active ingredient
因上人生 国上认生 Reservoir difusion device Diffusion-controlled mechanism Membrane Membrane Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion C through an inert membrane barrier. ·Reservoir Devices Drug Reservoir ·Matrix Devices Reservoir Devices are characterized by a core of drug,the reservoir surrounded by a polymeric membrane. 图生Reservor difo device 圈话生Reservoirdiffusion device Fick's first law of diffusion 4M=DSK AC For a given molecule and system composition,D, dt L S,K,L,and AC are constant in equation under M,is the total amount of drug released at time t sink conditions.Thus the amount of drug released .D is the diffusion coefficient of the drug as a function of time can be obtained by S is the effective membrane or barrier surface area for integration: drug diffusion .L is the diffusional path length(e.g.,thickness of the M,==M film) L K is the partition coefficient of drug between the barrier membrane and external aqueous phases k is the release rate constant. AC is the drug concentration 国生一 图达生 Characteristics of a Reservoir Diffusional Systems Diffusion-controlled mechanism ·Advantages Matrix Devices Zero-order delivery is possible Release rate variable with polymer type The drug substance is homogeneously mixed into ·Disadvantages the rate-controlling material(s)and other inactive Bad for high-molecular weight compounds ingredients as a crystalline,amorphous or,in rare ·Expensive cases,molecular dispersion.Drug release occurs Potential toxicity if system fails either by drug diffusion and /or erosion of the matrix system. 2
2 Shanghai Jiao Tong University Diffusion-controlled mechanism • Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion through an inert membrane barrier. • Reservoir Devices • Matrix Devices Shanghai Jiao Tong University Reservoir diffusion device L Cm(L) C(L) Reservoir Devices are characterized by a core of drug, the reservoir surrounded by a polymeric membrane. Shanghai Jiao Tong University Reservoir diffusion device Fick’s first law of diffusion • Mt is the total amount of drug released at time t • D is the diffusion coefficient of the drug • S is the effective membrane or barrier surface area for drug diffusion • L is the diffusional path length (e.g., thickness of the film) • K is the partition coefficient of drug between the barrier membrane and external aqueous phases • ΔC is the drug concentration Shanghai Jiao Tong University Reservoir diffusion device For a given molecule and system composition, D, S, K, L , and ΔC are constant in equation under sink conditions. Thus the amount of drug released as a function of time can be obtained by integration: • k is the release rate constant. Shanghai Jiao Tong University Characteristics of a Reservoir Diffusional Systems • Advantages • Zero-order delivery is possible • Release rate variable with polymer type • Disadvantages • Bad for high-molecular weight compounds • Expensive • Potential toxicity if system fails Shanghai Jiao Tong University Diffusion-controlled mechanism • Matrix Devices • The drug substance is homogeneously mixed into the rate-controlling material(s) and other inactive ingredients as a crystalline, amorphous or, in rare cases, molecular dispersion. Drug release occurs either by drug diffusion and /or erosion of the matrix system
国生Diffusion--onmhnis 图4生_Hydrophobie marixsystems Based on the characteristics of the rate-controlling Ingestion of tablet (as is or in capsule) material,the matrix system can be divided into: .Hydrophobic systems(rate-controlling materials consists of a water-insoluble inert matrix with minimum swelling). Hydrophilic systems(rate-controlling materials are water- Continued water soluble and /or swellable)Bioerodible-controlled eeonandthg mechanism Complete drug release Higuchiequation Q=kt 国生一 Hydrophobic matrix systems Assumptions: ·Advantages .Apseudo-steady state is maintained during drug release can deliver high molecular-weight compounds ·A>>S easier to produce than reservoir devices .The bathing solution provides sink conditions at all times ·Disadvantages The diameter of the drug particles <the drug diffusion Incomplete drug release distance cannot obtain zero-order release The diffusion coefficient D of drug in the matrix remains constant 国秋生 Bioerodible-controlled mechanism 国达生一 Bioerodible-controlled mechanism Bioerodible-controlled mechanism Hydrophilic matrix systems Hydrophilic matrix systems(rate-controlling materials are The primary rate-controlling materials are polymers that water-soluble and /or swellable) hydrate and swell rapidly in an aqucous medium,and form a gel layer on the surface of the system.Diffusion tablet (is or in capeule) across the viscous gel layer is not the only drug release pathway,as erosion of the matrix following polymer relaxation also contributes to the overall release. The mathematical descriptions of release can be complex. 3
3 Shanghai Jiao Tong University Diffusion-controlled mechanism Based on the characteristics of the rate-controlling material, the matrix system can be divided into: • Hydrophobic systems (rate-controlling materials consists of a water-insoluble inert matrix with minimum swelling). • Hydrophilic systems (rate-controlling materials are watersoluble and /or swellable) Bioerodible-controlled mechanism Shanghai Jiao Tong University Hydrophobic matrix systems Higuchi equation Q=kt1/2 Assumptions: • A pseudo-steady state is maintained during drug release • A＞＞S • The bathing solution provides sink conditions at all times • The diameter of the drug particles ＜the drug diffusion distance • The diffusion coefficient D of drug in the matrix remains constant Shanghai Jiao Tong University Hydrophobic matrix systems • Advantages • can deliver high molecular-weight compounds • easier to produce than reservoir devices • Disadvantages • Incomplete drug release • cannot obtain zero-order release Shanghai Jiao Tong University Bioerodible-controlled mechanism Bioerodible-controlled mechanism • Hydrophilic matrix systems (rate-controlling materials are water-soluble and /or swellable) Shanghai Jiao Tong University Bioerodible-controlled mechanism Hydrophilic matrix systems • The primary rate-controlling materials are polymers that hydrate and swell rapidly in an aqueous medium, and form a gel layer on the surface of the system. Diffusion across the viscous gel layer is not the only drug release pathway, as erosion of the matrix following polymer relaxation also contributes to the overall release. • The mathematical descriptions of release can be complex
因上人生 国生9 Osmotically-controlled mechanism Characteristics of Bioerodible Matrix Systems Osmotically-controlled mechanism Advantages .The osmotic pump system is similar to a reservoir device, ·Easier to produce but contains an osmotic agent that acts to imbibe water Can delivery high molecular from the surrounding medium via a semipermeable Complete drug release membrane. Disadvantages .Osmotic pressure provides the driving force to generate Difficult to control kinetics controlled release of drug instead of drug concentration Potential toxicity of degraded polymer gradient. 国生 Osmotically-controlled mechanism OnW nat6g ·dVd=KA(△x-AP)h◆dV/dt=Ak△xh ·dQ/di==CsXdV/dt=kA△rCsh=K'Cs K=membrane permeability A=area of the membrane h=membrane thickness An=osmotic pressure difference AP=hydrostatic pressure difference 国生 国生 Ion-Exchange mechanism Osmotically-controlled mechanism ·Advantages Ion-Exchange mechanism Zero-order release is obtainable Ion exchange resins can form ionic complexes with Release of drug is independent of environment oppositely charged drugs. of the system ·Disadvantages The interactions between resin and drugs are strongly requires specialized equipment and complex governed by the pH of the. processes The resin may release the drug in a certain region of the higher cost,longer development time delayed onset of drug release GIT,due to a pH change or presence of competing ions. quality control is more extensive 4
4 Shanghai Jiao Tong University Characteristics of Bioerodible Matrix Systems • Advantages • Easier to produce • Can delivery high molecular • Complete drug release • Disadvantages • Difficult to control kinetics • Potential toxicity of degraded polymer Shanghai Jiao Tong University Osmotically-controlled mechanism Osmotically-controlled mechanism • The osmotic pump system is similar to a reservoir device, but contains an osmotic agent that acts to imbibe water from the surrounding medium via a semipermeable membrane. • Osmotic pressure provides the driving force to generate controlled release of drug instead of drug concentration gradient. Shanghai Jiao Tong University Osmotically-controlled mechanism • dV/dt= KA (P) /h dV/dt= Ak /h • dQ/dt=CS×dV/dt= kA CS /h=K’CS K=membrane permeability A=area of the membrane h=membrane thickness = osmotic pressure difference P =hydrostatic pressure difference Shanghai Jiao Tong University Osmotically-controlled mechanism • Advantages • Zero-order release is obtainable • Release of drug is independent of environment of the system • Disadvantages • requires specialized equipment and complex processes • higher cost, longer development time • delayed onset of drug release • quality control is more extensive Shanghai Jiao Tong University Ion-Exchange mechanism Ion-Exchange mechanism • Ion exchange resins can form ionic complexes with oppositely charged drugs. • The interactions between resin and drugs are strongly governed by the pH of the. • The resin may release the drug in a certain region of the GIT, due to a pH change or presence of competing ions
图生_lon-Exchange Systems 国 ©Resin'-drug+X→resint-X.+drug Resin-drug*+Y+-resin-Y++drug" H'C and Drugs and atorpon Excretion and elminabon 国生一 国生一 Rational design of oral MR DDS Ion-exchange Devices Physicochemical factors influencing oral .Advantages Offers a protective mechanism for drugs that are sustained-release dosage form design highly susceptible to degradation by enzymatic processes. ·Dose size ·Disadvantages .pKa,lonization and aqueous solubility The release rate is proportional to the concentration of the ions present in the area of Partition coefficient administration. ·Stability 国生Rational design of oral MR DDS 国生 Biological factors influencing oral sustained- Design of sustained-release Systems Choose suitable active materials release dosage form design General requirements ·Half-life ·Bioavailabilty ·Absorption ·Cma/Cmm ·Metabolism ·Dose calculation 5
5 Shanghai Jiao Tong University Ion-Exchange Systems Resin+-drug- + X- → resin+-X- + drugResin- -drug+ + Y+→ resin- -Y+ + drug+ Shanghai Jiao Tong University Shanghai Jiao Tong University Ion-exchange Devices • Advantages • Offers a protective mechanism for drugs that are highly susceptible to degradation by enzymatic processes. • Disadvantages • The release rate is proportional to the concentration of the ions present in the area of administration. Shanghai Jiao Tong University Rational design of oral MR DDS Physicochemical factors influencing oral sustained-release dosage form design • Dose size • pKa, Ionization and aqueous solubility • Partition coefficient • Stability Shanghai Jiao Tong University Rational design of oral MR DDS Biological factors influencing oral sustainedrelease dosage form design • Half-life • Absorption • Metabolism Shanghai Jiao Tong University Design of sustained-release Systems • Choose suitable active materials • General requirements • Bioavailabilty • Cmax/Cmin • Dose calculation
图生 国i生_Ea-release products Design of Sustained-release Systems In vitro-Dissolution test Excipients for sustained release ·Apparatus Matrix material ·Media -Hydrogel .Requirement of drug release -Non-erodible First time point ensures against dose dumping(0.5~2h) -Bioerodible Final time point demonstrates complete release (>75%) Intermediate time points prove control of the ·Coating material release(50%) -Insoluble coating material Dynamics of drug release -Enteric coating material ·Thickener Evaluation of sustained-release products Evaluation of sustained-release products In vivo-Bioavailability In vitro-in vivo correlation ·Volunteers A predictive mathematical model describing Reference formulation the relationship between an in vitro property ·Analysis methods ·Single dose (usually the extent or rate of drug release), ·Multidose and a relevant in vivo response(e.g,plasma ·Statistic analysis concentration or amount of drug absorbed) 国丝生 Learning objectives Learning objectives Understand the mechanisms of different types of Understand factors influencing oral sustained-release dosage form design sustained release systems .Physicochemical factors Dissolution-controlled mechanism ·Dose size Diffusion-controlled mechanism pKa,lonization and aqueous solubility Partition coefficient Bioerodible-controlled mechanism ·Stability .Osmotically-controlled mechanism ·Biological factors ·Half-life lon-Exchange mechanism .Absorption ·Metabolism 6
6 Shanghai Jiao Tong University Design of Sustained-release Systems • Excipients for sustained release • Matrix material – Hydrogel – Non-erodible – Bioerodible • Coating material – Insoluble coating material – Enteric coating material • Thickener Shanghai Jiao Tong University Evaluation of sustained-release products In vitro-Dissolution test • Apparatus • Media • Requirement of drug release • First time point ensures against dose dumping( 0.5~2h) • Final time point demonstrates complete release ( ＞ 75%) • Intermediate time points prove control of the release( 50%). • Dynamics of drug release Shanghai Jiao Tong University Evaluation of sustained-release products In vivo-Bioavailability • Volunteers • Reference formulation • Analysis methods • Single dose • Multidose • Statistic analysis Shanghai Jiao Tong University Evaluation of sustained-release products In vitro-in vivo correlation • A predictive mathematical model describing the relationship between an in vitro property (usually the extent or rate of drug release), and a relevant in vivo response (e.g., plasma concentration or amount of drug absorbed). Shanghai Jiao Tong University Learning objectives Understand the mechanisms of different types of sustained release systems • Dissolution-controlled mechanism • Diffusion-controlled mechanism • Bioerodible-controlled mechanism • Osmotically-controlled mechanism • Ion-Exchange mechanism Shanghai Jiao Tong University Learning objectives Understand factors influencing oral sustained-release dosage form design • Physicochemical factors • Dose size • pKa, Ionization and aqueous solubility • Partition coefficient • Stability • Biological factors • Half-life • Absorption • Metabolism