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Techniques - Modulation of drug release from dosage form . List of contents. Introduction Mechanisms of controlled release Intelligent controlled release DDS Examples Recent advances References. Introduction:. Fluctuating plasma level in conventional DF. Development of CR ,SR, TR Etc.
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Techniques - Modulation of drug release from dosage form
List of contents • Introduction • Mechanisms of controlled release • Intelligent controlled release DDS • Examples • Recent advances • References
Introduction: • Fluctuating plasma level in conventional DF. • Development of CR ,SR, TR Etc.
Targeted delivery • It has goal of delivering the drug to specific cell types, tissues or organs.
Controlled release • Assigned to release theDRUG at a PREDETERMINEDRate.
Modulated release • Release of drug at a variable ratecontrolled by • Environmental conditions, • Biofeedback, • Sensor input • External control device.
Sustained release (SR) • In SR –Drug release is affected by External environment. - Release is slow than conventional DF. In CR – Release is dependant on the design of dosage form.
DRUG RELEASE MODULATION • ADVANTAGES • DISADVANTAGES • DRUGS UNSUITABLE FOR CR
Different controlled release systems Burst like release Pulsatile release Zero order (linear) release Cumulative release Diffusion controlled release Lag followed by Burst release Time of release
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS • Drug related • Biological • Physiological • Pharmacokinetic • Pharmacological
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS partition coefficient aqueous solubility molecular size Drug related protein binding drug stability
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS absorption • distribution disease state Biological • elimination side effects duration of action margin of safety
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS variability on GI emptying & motility prolonged drug absorption Physiological GI blood flow
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS dose dumping first pass metabolism Pharmacokinetic variability of urinary pH effect on drug elimination
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS changes in drug effect upon multiple dosing Pharmacological Sensitivity / tolerance
BASIC PRINCIPLES OF CR • DIFFUSION • SWELLING • BIODEGRADABLE or BIOERODIBLE
Schematic depiction of various classes of controlled release system Reservoir and monolithic Encapsulation Matrix Matrix Diffusion Dissolution Reservoir Diffusion and Dissolution Ion exchange resin Controlled release system Water penetration controlled cation anion Swelling osmotically Hydrogel Chemically controlled Chemically Drug linked polymer Diffusion Erodible Environmental Swelling
DIFFUSION CONTROLLED SYSTEMSMONOLITHIC-MATRIX SYSTEMS Drug + polymer
MONOLITHIC-MATRIX SYSTEMSMaterials used as retardants in matrix tablet formulations :-
RESERVOIR SYSTEMS Oral system
RESERVOIR SYSTEMS First layer Of the drug crystals Polymer phase Diffusion layer
Reservoir system Achievement of zero order is easy Degradable reservoir systems may be difficult to design Rupture can result in dangerous dose dumping Drug inactivation by contact with the polymeric matrix can be avoided Matrixsystem Achievement of zero order is difficult Suitable for both degradable & non-degradable systems No danger of dose dumping Not all drugs can be blended with a given polymeric matrix DIFFUSION CONTROLLED SYSTEMS
COMBINED RESERVOIR-MONOLITHIC SYSTEMS Phase I – outer membrane layers Phase II – reservoir matrix material Outer membrane layer (phase I) Dispersed agent in polymer matrix (phase II)
COMBINED RESERVOIR-MONOLITHIC SYSTEMS Monolithic Matrix (phase II) Outer membrane (phase I) Initially the release rate of diffusion through the phase 1 ,as the time progress ,a layer depleted from the active agent is generated in phase 11 reservoir material immediately adjacent to the membrane layer. Agent loaded Matrix layer Agent depleted Matrix layer
DISSOLUTION CONTROLLED RELEASE SYSTEMS • Two classes: • Encapsulation dissolution control • Matrix dissolution control
membrane drug Membrane controlled Polymer erosion controlled Matrix dissolution control
DIFFUSION & DISSOLUTION CONTROLLED SYSTEMS Release rate is dependent on • surface area • diffusion coefficient of drug though pore in coating • conc. of drug in dissolution media. membrane drug
WATER PENETRATION CONTROLLED SYSTEMS • rate control is obtained by penetration of water into the system. • classified into 2 parts. • swelling controlled systems • osmotically controlled systems
SWELLING CONTROLLED SYSTEM • “Non-fickian case II” type diffusion Swollen matrix Swelling zone Unswollen polymer matrix solvent
CHEMICALLY CONTROLLED SYSTEMS • delivery systems that change their chemical structure , when exposed to biological milieu • This system include biodegradable polymer that degrade within body as a result of natural biological process ,eliminating the need to remove the delivery system after exhausting of active agent from system
CHEMICALLY CONTROLLED SYSTEMS • The polymer degradation by 2 ways: Bulk erosion surface erosion
MECHANISM OF POLYMER EROSION Type IA – cleavage of cross links Type IB – disintegration of water soluble polymer backbone
MECHANISM OF POLYMER EROSION Type II – Water insoluble macromolecules are converted into water soluble compounds by hydrolysis, ionization or protonation of a pendent group. hydrolysis Ionization protonation Water insoluble molecules Water soluble molecules
MECHANISM OF POLYMER EROSION Type III –erosion mechanisim Hydrolytic cleavage Water insoluble molecules Water soluble molecules
MECHANISM OF DRUG RELEASE • bioactive covalently linked to polymer backbone , scission of the bonds connecting the drug to polymer backbone.
List of biodegradable polymer • Polylactides (PLA). • Polyglycolides (PGA). • Poly(lactide-co-glycolides) (PLGA). • Polyanhydrides. • Polyorthoesters.
HYDROGELS • Hydrogels are water swollen three dimensional structures composed of primarily hydrophilic polymers.
HYDROGELS • Classification:- 1) Diffusion controlled release - reservoir - matrix 2) Chemically controlled release - biodegradable polymers - covalently linked drug & polymer 3) Swelling controlled release 4) Environmentally responsive hydrogel systems
HYDROGELS Swollen gel water Drug release Glassy polymer Swelling controlled release • consists of drug dispersion within glassy polymer matrix. When the system comes in contact with biofluids, it starts swelling.
T T pH pH Environmentally responsive hydrogel systems • The changes in network structure in response to external environment are reversible in nature. - -
Type of hydrogel • Super porous hydrogel • pH sensitive hydrogel • Temperature sensitive hydrogel • Glucose sensitive system • Neutral hydrogel • Oral insulin hydrogel
Super porous hydrogel • Mainly for speedy swelling • Carried out by making very fine particle of dried hydrogel having short diffusion path length • Electronic microscopic fig of super porous hydrogel
Recent application of super porous gel in drug delivery • DEVELOPMENT OF GASTRIC • RETENTION DEVICES • Development of fast dissolving tablet • Development per oral peptide delivery system
ION-EXCHANGE RESIN • Zero order release obtained • kinetics Drug release depends only on the ionic environment of the resins containing drug • 2 types.- cation exchange resin & anion exchange resin.
CATION EXCHANGE RESIN :- • Synthesized by copolymerization of divinyl benzene & styrene. divinyl benzene styrene
Anion exchange resin • is prepared by chloromethylation of benzene rings of three dimensional styrene-divinyl benzene copolymer network leading to insertion of –CH2Cl groups & forms strong anion exchange resin.
INTELLIGENT CONTROLLED RELEASE DRUG DELIVERY SYSTEMS:- • Provide the bioactive in response to the physiological need & should ‘sense’ the changes & manipulate the drug release in response to external stimuli like heat, ultrasound, magnetic field, pH and/or conc. of specific molecules.
:-CLASSIFICATION: pH sensitive electically regulated thermosensitive pulsatile systems responsive systems ultrasonically modulated inflammation responsive magnetically modulated INTELLIGENT CONTROLLED RELEASE SYSTEMS Glucose sensitive photoresponsive urea responsive systems utilizing enzymes systems utilizing chelation systems utilizing antibodies glucose responsive
PULSATILE SYSTEMS :- • Magnetically modulated systems:- No applied field Field turn on Drug release
RESPONSIVE SYSTEMS • Glucose sensitive polymers:- Glycosylated insulin out Glucose in Polymer membrane Concavalin A Sepharose 4B beads glucose Glycosylated insulin