Control Drug Delivery System

Controlled / Modified Release Oral Drug Delivery System:

Controlled / Modified Release Oral Drug Delivery System Syed Muhammad Ashhad Halimi Assistant Professor Department of Pharmacy University of Peshawar

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2 Controlled drug delivery is one which delivers the drug at a predetermined rate, locally or systemically, for a specified period of time. Continuous oral delivery of drugs at predictable & reproducible kinetics for predetermined period throughout the course of GIT .

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3 To modify the drug release pattern by either increasing or decreasing its rate. Delivery of a drug at predetermined rate and/or location according to the body need and of disease state, for a definite time period.

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4 Potential Problems Of Conventional Dosage Forms; Lack of temporal delivery Repeated dosage after specific interval. If the interval is not proper there will be large peaks and valleys Patient non compliance Increased untoward effects Such like problems of conventional dosage form stimulates the researchers to develop modified release dosage form.

Plasma concentration time profile:

Plasma concentration time profile 5

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Theoretical plasma concentration after administration of various dosage forms: ( a ) standard oral dose; ( b ) oral overdose; ( c ) IV injection; ( d ) controlled - release system.

Challenges in Oral Drug Delivery:

Challenges in Oral Drug Delivery Development of drug delivery system Delivering a drug at therapeutically effective rate to desirable site. Modulation of GI transit time Transportation of drug to target site. Minimization of first pass elimination

Advantages:

Advantages Total dose is low . Reduced GI side effects . Reduced dosing frequency. Better patient acceptance and compliance . Less fluctuation at plasma drug levels . More uniform drug effect Improved efficacy/safety ratio .

Disadvantages:

Disadvantages 10 Dose dumping. Reduced potential for accurate dose adjustment. Need of additional patient education. Stability problem.

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11 Classification: Delayed Release Extended Release Site Specific Targeting Receptor Targeting Fast Dissolve Drug Delivery System (Flash)

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12 Delayed Release: Example include enteric coated tablets , where a timed release is achieved by barrier coating epeated action tablets or spansules . Extended Release: These include any dosage form that maintains therapeutic blood or tissue level of drug for prolong time. Site Specific Targeting: In such system the drug delivery is targeted adjacent to or in the diseased organ or tissue.

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13 Receptor Targeting In such system the target is a particular receptor with in an organ or tissue. Fast Dissolve Drug Delivery System (Flash) I t is type of solid dosage form that dissolves or disintegrate in the oral cavity without the help of water or chewing. Fast dissolution is achieved by forming loose network ( Zydis , Eli Lilly), or by effervescent agent ( Oraslav , Cima ) or with mixture of disintegrating agent and swelling (Flash Tab, Prographarm )

Mechanism aspects of Oral drug delivery formulation.:

Mechanism aspects of Oral drug delivery formulation. 14 1 . Dissolution : a. Matrix b. Encapsulation 2. Diffusion : a. Matrix b. Reservoir 3. Combination of both dissolution & diffusion. 4. Osmotic Pressure Controlled System. 5. Chemically Controlled Release Systems a. Erodible Systems b. Drugs Covalently linked with polymers Ion-exchange resin controlled released systems Hydrogels

Matrix Type:

Matrix Type 15 Also called as Monolith dissolution controlled system since the drug is homogenously dispersed throughout a rate controlling medium waxes (beeswax, carnuba wax, hydrogenated caster oil etc) which control drug dissolution by controlling the rate of dissolution; 1. Altering porosity of tablet. 2. Decreasing its wettebility . 3. Dissolving at slower rate. Exhibit First order drug release. Drug release determined by dissolution rate of polymer.

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16 SDM Soluble API mixed with SDM

Encapsulation:

Encapsulation 17 Called as Coating dissolution controlled system since the drug encapsulated, with slowly dissolving material like cellulose, PEG, PMA ( polymethylacrylates ) & waxes. Dissolution rate of coat depends upon stability & thickness of coating. Soluble drug Slowly dissolving or erodible coat

Matrix Diffusion Types:

Matrix Diffusion Types 18 Rigid Matrix Diffusion Materials used are insoluble plastics such as PVP & fatty acids. Swellable Matrix Diffusion Also called as Glassy hydrogels . Popular for sustaining the release of highly water soluble drugs. Materials used are hydrophilic gums. Examples : Natural: Guar gum, Tragacanth . Semi-synthetic: HPMC , CMC, Xanthum gum. Synthetic : Polyacrilamides .

Matrix system:

Matrix system 19 Rate controlling step: Diffusion of dissolved drug in matrix.

Matrix Diffusion Types:

Matrix Diffusion Types 20 Drug and excipients are mixed with polymers such as Hydroxypropyl methylcellulose ( HPMC ) and Hydroxypropyl cellulose ( HPC ). Tableted by conventional compression. Release from the tablet takes place by combination of : water diffuses into the tablet, swells the polymer and dissolves the drug. drug may diffuse out to be absorbed.

Reservoir System:

Reservoir System 21 Also called as Laminated matrix device. Hollow system containing an inner core surrounded in water insoluble membrane. Polymer can be applied by coating or micro encapsulation. Rate controlling mechanism - partitioning into membrane with subsequent release into surrounding fluid by diffusion. Commonly used polymers - HPC , ethyl cellulose & polyvinyl acetate.

Reservoir System:

Reservoir System 22 Rate controlling steps : Polymeric content in coating, thickness of coating, hardness of microcapsule.

Dissolution & Diffusion Controlled Release system:

Dissolution & Diffusion Controlled Release system 23 Drug encased in a partially soluble membrane. Pores are created due to dissolution of parts of membrane. It permits entry of aqueous medium into core & drug dissolution. Diffusion of dissolved drug out of system. Ethyl cellulose & PVP mixture dissolves in water & create pores of insoluble ethyl cellulose membrane. Insoluble membrane Pore created by dissolution of soluble fraction of membrane Entry of dissolution fluid Drug diffusion

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24

Osmotic Pressure Controlled System:

Osmotic Pressure Controlled System 25 Drug may be osmotically active, or combined with an osmotically active salt (e.g., NaCl). Semi-permeable membrane usually made from Cellulose acetate. Drug is pumped out continuously because of osmotic pressure gradient. More suitable for hydrophilic drug. Provides zero order release

Osmotic Pressure Controlled System:

Osmotic Pressure Controlled System 26

Osmotic Pressure Controlled System:

Osmotic Pressure Controlled System 27

Chemically Controlled Released Systems:

Chemically Controlled Released Systems 28 Systems that change their chemical structure, when exposed to biological fluids. Mostly, biodegradable polymers, are designed to degrade as a result of hydrolysis of the polymer chains into biologically safe and progressively smaller moieties and thus releasing API. It is of two types; Erodible Systems Pendent Chain System

Chemically controlled released Systems:

Chemically controlled released Systems 29 Erodible Systems Two types; Bulk Erosion : Polymer degradation may occur through bulk hydrolysis. Surface Erosion : Degradation occur at the surface of the polymers e.g. Polyorthoesters & Polyanhydrides , resulting a release rate is proportional to the surface area of the delivery system.

Chemically controlled released Systems:

Chemically controlled released Systems 30 Drug delivery from (a) bulk-eroding (b) surface-eroding biodegradable systems

Chemically Controlled Released Systems:

Chemically Controlled Released Systems 31 Pendent Chain System Consist of linear homo or copolymers with drug attached to its backbone chains. e.g. Hydroxy propyl methyacrylamide etc. Release drug by hydrolysis or enzymatic degradation of the linkages Follows zero order kinetics, cleavage of the drug is rate determining step.

Hydrogels:

Hydrogels 32 Three dimensional structures composed of primarily hydrophilic polymers having chemical or physical cross links which provides a network structure to hydrogels . Insoluble because of network structure and provides desirable protection of liable drugs, peptides and proteins

Hydrogels:

Hydrogels 33 Drug delivery from matrix swelling-controlled release systems

Ion-Exchange Resins Controlled Release Systems:

Ion-Exchange Resins Controlled Release Systems 34 Such system provide control release of an ionic (ionisable) drug. Ionisable drug is absorbed on ion-exchange resins granules and then granules are coated with water permeable polymers using spray drying technique. H + Cl - in the gastric fluid are exchange with cationic and anionic drugs from the ion-exchange resins.

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35 Characteristics Drugs Not effectively absorbed in the lower intestine Riboflavin, Ferrous Sulfate Absorbed and extracted rapidly (short biologic half life i.e. < 1Hr) Penicillin G, Furosemide Long biologic half life i.e. > 12 Hr Diazepam Large doses required (> 1G) Sulfonamides, Sucralfate Drug with low therapeutic index Digitoxin , Warferrin , Phenobarbital Precise dosage to individual is required Anticoagulants No clear advantage for sustained release Griseofulvin If the pharmacological activity of the active compound is not related to its blood levels. Characteristics of Drugs Unsuitable for Peroral Sustained Release

Kinetics:

Kinetics 36 Mathematical models are used to evaluate kinetics and mechanism of drug release from the tablets. Zero Order Release Model First Oder Release Model Hixson-Crowell Release Model Higuchi Release Model Korsmeyer-Peppas Release Model The model that give highest regration value “ r 2 ” is considered as the best fit of the release data.

Zero Order Release Kinetics:

Zero Order Release Kinetics 37 Release kinetics independent of concentration of drugs in the dosage form is described as Zero Order Release Kinetics. Equation for Zero order release is; Q t = Q o + K o t Where Q t = initial amount of drug Q o = cumulative amount of drug at time “t” K o = Zero order release constant t = time in hours

First Order Release kinetics:

First Order Release kinetics 38 Release kinetics dependent on the concentration of drugs in the dosage form is described as First Order Release Kinetics. Equation for First Order release is; log Q t = log Q o + K o t /2.303 Where Q t = initial amount of drug Q o = cumulative amount of drug at time “t” K o = First order release constant t = time in hours

Hexson-Crowell Release Model:

Hexson -Crowell Release Model 39 Describes drug release by dissolution and with changes in surface area and diameter of particles or tablets; Its equation is; - = K HC .t Where Q t = initial amount of drug Q o = cumulative amount of drug at time “t” K HC = Hexson -Crowell release constant t = time in hours

Higuchi Release Model:

Higuchi Release Model 40 Model suggests that the drug is release by diffusion. Its equation; Q = K H t 1 /2 Where Q = cumulative amount of drug at time “t” K H = Higuchi release constant t = time in hours

Korsmeyer-Pappas Release Model:

Korsmeyer -Pappas Release Model 41 Release kinetics dependent on the concentration of drugs in the dosage form is described as First Order Release Kinetics. Equation for First Order release is; F = (M t / M) = K m t n Where F = Fraction of drug release at time “t” M t = Amount of drug release at time “t” M = total amount of drug in dosage form K m = Kinetic constant n = Diffusion or release exponent t = time in hours

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42 Zero Order Kinetics

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43 First Order Kinetics Higuchi Model Kinetics Korsmeyer – Peppas Kinetics Hexson -Crowell Kinetics