国我私特 国生 Time-controlled drug delivery systems are Time controlled developed to modulate the apparent drug delivery systems absorption and/or alter the site of release of School of Pharmacy drugs,in order to achieve specific clinical Chen Jian 2013.4 objectives that cannot be attained with chenjian@situ.edu.cn conventional dosage forms. 国生一 国话生一 Possible therapeutic benefits of a properly Common modes of oral time-controlled designed time-controlled dosage form delivery include: ·improved efficacy .Delayed release(e.g.,using an enteric coating), reduced adverse events .Site-specific release(e.g.,for colonic delivery), increased convenience .Extended release(e.g,zero-order,first-order), increased patient compliance Programmed release (e.g.,pulsatile,delayed extended-release,etc.). 国生一 ©Other terms: ·Prolonged release ·Sustained release ·Modified release 4 Examples of time controlled release profites
1 Time controlled drug delivery systems School of Pharmacy Chen Jian 2013.4 chenjian@sjtu.edu.cn Shanghai Jiao Tong University Time-controlled drug delivery systems are developed to modulate the apparent absorption and/or alter the site of release of drugs, in order to achieve specific clinical objectives that cannot be attained with conventional dosage forms. Shanghai Jiao Tong University Possible therapeutic benefits of a properly designed time-controlled dosage form • improved efficacy • reduced adverse events • increased convenience • increased patient compliance Shanghai Jiao Tong University Common modes of oral time-controlled delivery include: • Delayed release (e.g., using an enteric coating); • Site-specific release (e.g., for colonic delivery); • Extended release (e.g., zero-order, first-order); • Programmed release (e.g., pulsatile, delayed extended-release, etc.). Shanghai Jiao Tong University Other terms: • Prolonged release • Sustained release • Modified release Shanghai Jiao Tong University Examples of time controlled release profiles
国生一 圈生 Common oral extended-release systems ®Matrix systems In a matrix system,the drug substance is ·Matrix systems homogeneously mixed into the rate-controlling material(s)and other inactive ingredients as a Reservoir polymeric systems crystalline,amorphous or,in rare cases, molecular dispersion. ·Osmotic pump systems Based on the characteristics of the rate- controlling material,the matrix system can be ·Ion-exchange resins divided into: .(a)hydrophilic systems .(b)hydrophobic systems 国生一 国生 Hydrophilic matrix systems Hydrophilic matrix systems The rate-controlling materials The primary rate-controlling nge are water-soluble and /or materials are polymers that hydrate and swell rapidly in an aqueous swellable medium,and form a gel layer on Two competing mechanisms the surface of the system. are involved in the drug Diffusion across the viscous gel release: layer is not the only drug release Fickian diffusional release pathway,as erosion of the matrix 宁 following polymer relaxation also Relaxational release contributes to the overall release. 国生一 国秋生 Hydrophilic matrix systems Characteristics of hydrophilic matrix The continuously changing variables that affect systems drug release make obtaining a mechanistic equation or model describing the release profile ·Advantages imnossible. ·Easier to produce Q=" Can delivery high molecular Q is the fraction of drug released in time t .Complete drug release k is the rate constant incorporating characteristics of the macromolecular network system and the drug ·Disadvantages n is the diffusional exponent. Difficult to control kinetics 2
2 Shanghai Jiao Tong University Common oral extended-release systems • Matrix systems • Reservoir polymeric systems • Osmotic pump systems • Ion-exchange resins Shanghai Jiao Tong University Matrix systems • In a matrix system, 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. • Based on the characteristics of the ratecontrolling material, the matrix system can be divided into: • (a) hydrophilic systems • (b) hydrophobic systems Shanghai Jiao Tong University Hydrophilic matrix systems • The rate-controlling materials are water-soluble and /or swellable • Two competing mechanisms are involved in the drug release: • Fickian diffusional release • Relaxational release Shanghai Jiao Tong University 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. Shanghai Jiao Tong University Hydrophilic matrix systems • The continuously changing variables that affect drug release make obtaining a mechanistic equation or model describing the release profile impossible. • Q is the fraction of drug released in time t • k is the rate constant incorporating characteristics of the macromolecular network system and the drug • n is the diffusional exponent. Shanghai Jiao Tong University Characteristics of hydrophilic matrix systems • Advantages • Easier to produce • Can delivery high molecular • Complete drug release • Disadvantages • Difficult to control kinetics
国生 圈生 Hydrophobic matrix systems Ingestion of tablet Hydrophobic matrix systems In a hydrophobic inert ·Higuchi equation matrix system,the drug is dispersed throughout a M:=[DC,(2A-C)]2 matrix,which involves essentially negligible Mt is the drug released per unit area at time t increase of the device A is the drug loading per unit volume surface or change in ·Cs is drug solubility dimension. D is the diffusion coefficient in the matrix phase 国生一 国话生一 Hydrophobic matrix systems Hydrophobic matrix systems Higuchi equation was derived based on the assumptions In the case of A >>Cs.Higuchi Equation M:[DC,(2A -C)E]/2 reduces to .(1)a pseudo-steady state exists; .(2)the drug particles are small compared to the average distance of diffusion; M,[2DAC,]2 .(3)the diffusion coefficient is constant; Thus,the amount of drug released is .(4)perfect sink conditions exist in the external media; ·(⑤)only the diffusion process occurs; proportional to the square root of time,A, .(6)the drug concentration in the matrix is greater than the drug solubility in the polymer; D,and Cs .(7)no interaction between drug and matrix-takes-pleee. 国线一 国生 Hydrophobic matrix systems Hydrophobic matrix systems A second form of Higuchi equation Similarly,in the case of A>>Cs,it can 4-c4-c4 be reduced 8 is the porosity of the matrix, M-cA-c一M-. .t is the tortuosity of the matrix Da is the drug diffusion coefficient in the release medium. 3
3 Shanghai Jiao Tong University Hydrophobic matrix systems • In a hydrophobic inert matrix system, the drug is dispersed throughout a matrix, which involves essentially negligible increase of the device surface or change in dimension. Shanghai Jiao Tong University Hydrophobic matrix systems • Higuchi equation • Mt is the drug released per unit area at time t • A is the drug loading per unit volume • Cs is drug solubility • D is the diffusion coefficient in the matrix phase Shanghai Jiao Tong University Hydrophobic matrix systems • Higuchi equation was derived based on the assumptions • (1) a pseudo-steady state exists; • (2) the drug particles are small compared to the average distance of diffusion; • (3) the diffusion coefficient is constant; • (4) perfect sink conditions exist in the external media; • (5) only the diffusion process occurs; • (6) the drug concentration in the matrix is greater than the drug solubility in the polymer; • (7) no interaction between drug and matrix takes place. Shanghai Jiao Tong University Hydrophobic matrix systems • In the case of A >>Cs , Higuchi Equation reduces to • Thus, the amount of drug released is proportional to the square root of time, A , D , and Cs Shanghai Jiao Tong University Hydrophobic matrix systems • A second form of Higuchi equation • ε is the porosity of the matrix, • τ is the tortuosity of the matrix • Da is the drug diffusion coefficient in the release medium. Shanghai Jiao Tong University Hydrophobic matrix systems • Similarly, in the case of A >>Cs , it can be reduced
国生 国生 Modulation of drug release profiles Characteristics of hydrophobic matrix systems of matrix systems ·Advantages Can deliver high molecular-weight compounds pH-independent drug release Easier to produce than reservoir devices Solubility enhancement ·Disadvantages Modification of release kinetics Incomplete drug release of hydrophobic matrix Difficult to obtain zero-order release 国生一 国丛生 Reservoir polymeric systems Reservoir polymeric systems A typical reservoir system consists of a core dM =DSK AC containing solid drug d L Drug surrounded by a membrane Mt is the total amount of drug released at time t of a rate-controlling D is the diffusion coefficient of the drug material. S is the effective membrane or barrier surface area for drug ·The only structure diffusion effectively limiting the L is the diffusional pathlength (e.g,thickness of the film) release of the drug is the K is the partition coefficient of drug between the barrier polymer layer surrounding membrane and external aqueous phases the reservoir AC is the drug concentration gradient between the Cs and Ce 国生 国秋生 Reservoir polymeric systems Most of the marketed reservoir systems dM DSK AC M, L DSKAC t=kt L are multi-unit dosage forms. dt The drug release from this type of system follows apparent Minimized risk of dose dumping zero-order kinetics until AC is no longer constant. Because the reservoir system relies on AC as the driving Readily tailored release profiles force for drug diffusion,it is applicable to soluble drugs. For insoluble drugs,the values of Cs may be too low to Lower in vivo variability render adequate driving force,resulting in over-attenuated and incomplete drug release. ·Easy dose adjustment Hydrophilic materials can be added to polymer film to give a porous device. 心
4 Shanghai Jiao Tong University Modulation of drug release profiles of matrix systems • pH-independent drug release • Solubility enhancement • Modification of release kinetics Shanghai Jiao Tong University Characteristics of hydrophobic matrix systems • Advantages • Can deliver high molecular-weight compounds • Easier to produce than reservoir devices • Disadvantages • Incomplete drug release of hydrophobic matrix • Difficult to obtain zero-order release Shanghai Jiao Tong University Reservoir polymeric systems • A typical reservoir system consists of a core containing solid drug surrounded by a membrane of a rate-controlling material. • The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir Shanghai Jiao Tong University Reservoir polymeric systems • 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 pathlength (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 gradient between the Cs and Ce Shanghai Jiao Tong University Reservoir polymeric systems • The drug release from this type of system follows apparent zero-order kinetics until ΔC is no longer constant. • Because the reservoir system relies on ΔC as the driving force for drug diffusion, it is applicable to soluble drugs. • For insoluble drugs, the values of Cs may be too low to render adequate driving force, resulting in over-attenuated and incomplete drug release. • Hydrophilic materials can be added to polymer film to give a porous device. Shanghai Jiao Tong University Most of the marketed reservoir systems are multi-unit dosage forms. • Minimized risk of dose dumping • Readily tailored release profiles • Lower in vivo variability • Easy dose adjustment
国生 国生 Characteristics of a reservoir systems 国Osmotic pump systems ·Advantages .The osmotic pump system contains an osmotic Zero-order delivery is possible .Release rate variable with polymer type agent that acts to imbibe water from the ·Disadvantages surrounding medium via a semipermeable Bad for high-molecular weight compounds membrane. ·Expensive The drug is forced out of an orifice in the device Potential toxicity if system fails by the osmotic pressure generated within the device 国生一 国生 ④Osmotic pump systems ®Osmotic pump systems The rate of water imbibition the amount of drug released at time t 出-华a-△n d 婴出网 dt dV/dt is the rate of water flow When the hydrostatic pressure difference is negligible, k is the hydraulic permeability and there is an excess of solid (saturated solution)in the ·A is the membrane area device ·I is the thickness dM=k△S ·△t is the osmotic pressure difference ·△P is the hydrostatic pressure difference .Therefore,the drug release rate remains constant, delivering a volume equal to the volume of water uptake. 国生一 国秋生 Characteristics of osmotic pump systems ©Osmotic pump systems ·Advantages Zero-order release is obtainable ·one-chamber system Release of drug is independent of environment of the system ·two-chamber system ·Disadvantages requires specialized equipment and complex processes higher cost,longer development time delayed onset of drug release Bare operation quality control is more extensive 5
5 Shanghai Jiao Tong University Characteristics of a reservoir 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 Osmotic pump systems • The osmotic pump system contains an osmotic agent that acts to imbibe water from the surrounding medium via a semipermeable membrane. • The drug is forced out of an orifice in the device by the osmotic pressure generated within the device. Shanghai Jiao Tong University Osmotic pump systems • The rate of water imbibition • dV/dt is the rate of water flow • k is the hydraulic permeability • A is the membrane area • l is the thickness • Δπ is the osmotic pressure difference • ΔP is the hydrostatic pressure difference Shanghai Jiao Tong University Osmotic pump systems • the amount of drug released at time t • When the hydrostatic pressure difference is negligible, and there is an excess of solid (saturated solution) in the device • Therefore, the drug release rate remains constant, delivering a volume equal to the volume of water uptake. Shanghai Jiao Tong University Osmotic pump systems • one-chamber system • two-chamber system Shanghai Jiao Tong University Characteristics of osmotic pump systems • 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
国生 Ion-Exchange Systems Resint-drug +X-resint-X drug Ion-Exchange mechanism ·Resin-drug*+Y+→resin-Y++drug 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 medium or by the presence of competing ions. The resin may release the drug in a certain region of the GIT,due to a pH change or presence of competing ions. 国生一 国丛生 Characteristics of ion-exchange Devices Other common oral time-controlled release ·Advantages systems Offers a protective mechanism for drugs ·Enteric release that are highly susceptible to degradation by enzymatic processes. ·Colonic release ·Disadvantages ·Pulsatile release .The release rate is proportional to the concentration of the ions present in the ·Bimodal release area of administration. 国生一 国秋生 Other common oral time-controlled release systems Other common oral time-controlled release systems ·Enteric release ·Enteric release Enteric release is intended to delay the release Drugs which have an irritant effect on the of the drug (or drugs)until the dosage form stomach,can be coated with an enteric film has passed through the stomach. that will only dissolve in the small intestine. Materials used for enteric coating prevent drug Enteric coating is also used to prevent the release in the stomach,because they are acidic environment of the stomach from typically acidic polymers that are stable degrading certain acid-labile medications. /insoluble at acidic pH. 6
6 Shanghai Jiao Tong University 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 medium or by the presence of competing ions.. • The resin may release the drug in a certain region of the GIT, due to a pH change or presence of competing ions. Ion-Exchange Systems • Resin+-drug- + X- → resin+-X- + drug- • Resin- -drug+ + Y+→ resin- -Y+ + drug+ Shanghai Jiao Tong University Characteristics of 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 Other common oral time-controlled release systems • Enteric release • Colonic release • Pulsatile release • Bimodal release Shanghai Jiao Tong University Other common oral time-controlled release systems • Enteric release • Enteric release is intended to delay the release of the drug (or drugs) until the dosage form has passed through the stomach. • Materials used for enteric coating prevent drug release in the stomach, because they are typically acidic polymers that are stable /insoluble at acidic pH. Shanghai Jiao Tong University Other common oral time-controlled release systems • Enteric release • Drugs which have an irritant effect on the stomach, can be coated with an enteric film that will only dissolve in the small intestine. • Enteric coating is also used to prevent the acidic environment of the stomach from degrading certain acid-labile medications
国生 国生 Other common oral time-controlled release Other common oral time-controlled release systems systems ·Colonic release ·Colonic release .Coated delivery systems using pH- sensitive Colonic delivery systems are essentially .Slow eroding polymers,swelling or delayed-release dosage forms that are osmotic controlled systems for timed release designed to provide either an immediate .Exploitation of carriers that are degraded or sustained release in the large intestine. specifically by colonic bacteria.. 国生一 国生 Other common oral time-controlled release Other common oral time-controlled release systems systems Clinical benefits in pulsatile release ·Pulsatile release .(1)optimizing chronotherapy; .Pulsatile delivery generally refers to release .(2)mimicking natural patterns of endogenous secretion; of a portion of the total payload in a burst, .(3)providing optimal therapy for followed by periods of little or no release toleranceinducing drugs where constant levels cause receptor down-regulation. (lag phase)in a defined temporal pattern. 国生一 国秋生一 Other common oral modified-release systems Materials used for modifying drug release ·Bimodal release Materials for matrix systems Immediate-release followed extended Materials for reservoir systems release or extended release followed immediate-release Materials for osmotic pump systems .Materials for delayed-release systems 7
7 Shanghai Jiao Tong University Other common oral time-controlled release systems • Colonic release • Colonic delivery systems are essentially delayed-release dosage forms that are designed to provide either an immediate or sustained release in the large intestine. Shanghai Jiao Tong University Other common oral time-controlled release systems • Colonic release • Coated delivery systems using pHsensitive • Slow eroding polymers, swelling or osmotic controlled systems for timed release • Exploitation of carriers that are degraded specifically by colonic bacteria.. Shanghai Jiao Tong University Other common oral time-controlled release systems • Pulsatile release • Pulsatile delivery generally refers to release of a portion of the total payload in a burst, followed by periods of little or no release (lag phase) in a defined temporal pattern. Shanghai Jiao Tong University Other common oral time-controlled release systems • Clinical benefits in pulsatile release • (1) optimizing chronotherapy; • (2) mimicking natural patterns of endogenous secretion; • (3) providing optimal therapy for toleranceinducing drugs where constant levels cause receptor down-regulation. Shanghai Jiao Tong University Other common oral modified-release systems • Bimodal release • Immediate-release followed extended release or extended release followed immediate-release Shanghai Jiao Tong University Materials used for modifying drug release • Materials for matrix systems • Materials for reservoir systems • Materials for osmotic pump systems • Materials for delayed-release systems
圆上达生 国生 Materials used for modifying drug release Materials for matrix systems Materials used for modifying drug release .Hydrophilic materials -non-ionic soluble cellulose ethers (HPMC...) Materials for reservoir systems -nonionic homopolymers of ethylene oxide (poly(ethylene oxide)...) -water-soluble natural gums of polysaccharides water insoluble acrylic copolymers (alginate..） -… water insoluble ethylcellulose Hydrophobic materials -Fatty acids,fatty acid esters,fatty alcohols,waxes water insoluble polyvinylacetate -hydrophobic polymers (ethyl cellulose...) 国生一 国话生一 Materials used for modifying drug release Materials used for modifying drug release Materials for osmotic pump systems Materials for delayed-release systems semipermeable membrane .(1)shellac and zein of natural sources; -Cellulose acetate is the most commonly used polymer .(2)derivatives of cellulose and methacrylic ·Osmotic agents acid copolymers containing carboxylic -sodium chloride,... functional groups. ·push layer -poly(ethylene oxide) 国生一 国线 Rational design of time controlled Rational design oftime controlled release DDS release DDS Physicochemical factors ·Dose size Physicochemical factors ·Aqueous solubility ·Biological factors Partition coefficient ·pKa ·Stability 6
8 Shanghai Jiao Tong University Materials used for modifying drug release • Materials for matrix systems • Hydrophilic materials – non-ionic soluble cellulose ethers (HPMC…) – nonionic homopolymers of ethylene oxide (poly(ethylene oxide)…) – water-soluble natural gums of polysaccharides (alginate…) – …… • Hydrophobic materials – Fatty acids, fatty acid esters, fatty alcohols, waxes – hydrophobic polymers (ethyl cellulose…) Shanghai Jiao Tong University Materials used for modifying drug release • Materials for reservoir systems • water insoluble acrylic copolymers • water insoluble ethylcellulose • water insoluble polyvinylacetate Shanghai Jiao Tong University Materials used for modifying drug release • Materials for osmotic pump systems • semipermeable membrane – Cellulose acetate is the most commonly used polymer • Osmotic agents – sodium chloride, … • push layer – poly(ethylene oxide) Shanghai Jiao Tong University Materials used for modifying drug release • Materials for delayed-release systems • (1) shellac and zein of natural sources; • (2) derivatives of cellulose and methacrylic acid copolymers containing carboxylic functional groups. Shanghai Jiao Tong University Rational design of time controlled release DDS • Physicochemical factors • Biological factors Shanghai Jiao Tong University Rational design of time controlled release DDS • Physicochemical factors • Dose size • Aqueous solubility • Partition coefficient • pKa • Stability
国生一 国生 Rational design of time controlled release DDS Evaluation of time controlled release DDS ·Biological factors ·Drug release test ·PK-PD relationship ·Apparatus ·Half-life ·Medium ·Absorption .Criteria ·Metabolism In vitro-in vivo correlation (IVIVC) 国生一 Learning objectives 国生 Learning objectives Understand the mechanisms of different types of Understand physicochemical factors influencing oral sustained release systems time controlled release dosage form design ·Matrix systems ·Dose size .Reservoir polymeric systems ·Aqueous solubility ·Osmotic pump systems Partition coefficient ·pKa ·Stability 9
9 Shanghai Jiao Tong University Rational design of time controlled release DDS • Biological factors • PK-PD relationship • Half-life • Absorption • Metabolism Shanghai Jiao Tong University Evaluation of time controlled release DDS • Drug release test • Apparatus • Medium • Criteria • In vitro-in vivo correlation (IVIVC) Shanghai Jiao Tong University Learning objectives Understand the mechanisms of different types of sustained release systems • Matrix systems • Reservoir polymeric systems • Osmotic pump systems Shanghai Jiao Tong University Learning objectives Understand physicochemical factors influencing oral time controlled release dosage form design • Dose size • Aqueous solubility • Partition coefficient • pKa • Stability
