Presentation on theme: "Modulation of drug release from dosage form"— Presentation transcript:
1 Modulation of drug release from dosage form Techniques -Modulation of drug release from dosage form
2 List of contents Introduction Mechanisms of controlled release Intelligent controlled release DDSExamplesRecent advancesReferencesA commercially available responsive drug delivery system – insulin pumps
3 Introduction: Fluctuating plasma level in conventional DF. Development of CR ,SR, TR Etc.A commercially available responsive drug delivery system – insulin pumps
4 Targeted deliveryIt has goal of delivering the drug to specific cell types, tissues or organs.
5 Controlled releaseAssigned to release the DRUG at a PREDETERMINED Rate.
6 Release of drug at a variable rate controlled by Modulated releaseRelease of drug at a variable rate controlled byEnvironmental conditions,Biofeedback,Sensor inputExternal control device.
7 Sustained release (SR) In SR –Drug release is affected by External environment.- Release is slow than conventional DF.In CR – Release is dependant on thedesign of dosage form.
8 ADVANTAGES OF DRUG RELEASE MODULATION Prolonged duration of action.Increase Controlled delivery at predetermined rateIn patient complianceReduction in frequency of dosingReduced fluctuationsMore uniform effect
9 Increased first pass clearance. DISADVANTAGESHigh costPoor IVIVC.Dose dumping.Increased first pass clearance.
10 DRUG RELEASE MODULATION ADVANTAGESDISADVANTAGESDRUGS UNSUITABLE FOR CR
11 Threshold of effectiveness Blue- uncontrolled unsafe doseDotted-uncontrolled safe doseRed-controlled releaseToxic levelDrugThreshold of effectivenessTime
12 Different controlled release systems Burst like releasePulsatile releaseZero order (linear) releaseCumulativereleaseDiffusion controlled releaseLag followed byBurst releaseTime of release
13 FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS Drug relatedBiologicalPhysiologicalPharmacokineticPharmacological
14 FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS partition coefficientaqueous solubilitymolecular sizeDrug relatedprotein bindingdrug stability
15 FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS absorptiondistributiondisease stateBiologicaleliminationside effectsduration of actionmargin of safety
16 FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS variability on GIemptying & motilityprolonged drug absorptionPhysiologicalGI blood flow
17 FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS dose dumpingfirst pass metabolismPharmacokineticvariability of urinary pHeffect on drug elimination
18 FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS changes in drug effectupon multiple dosingPharmacologicalSensitivity / tolerance
19 DRUGS UNSUITABLE FOR CR posses following featuresShort/long elimination half-lifeNarrow therapeutic indexPoor absorptionLarge dosesLow aqueous solubilityExtensive first pass metabolism
20 BASIC PRINCIPLES OF CRDIFFUSIONSWELLINGBIODEGRADABLE or BIOERODIBLE
22 Schematic depiction of various classes of controlled release system Reservoir and monolithicEncapsulationMatrixMatrixDiffusionDissolutionReservoirDiffusion and DissolutionIon exchange resinControlledrelease systemWater penetration controlledcationanionSwellingosmoticallyHydrogelChemically controlledChemicallyDrug linked polymerDiffusionErodibleEnvironmentalSwelling
23 Diffusion controlled release system (monolithic matrix device) In monolithic devices, the drug is uniformly dispersed or dissolved in the polymer, and it is released by diffusion from the polymer as shown in Figure.
24 DIFFUSION CONTROLLED SYSTEMS MONOLITHIC-MATRIX SYSTEMS Drug+polymer
25 MATRIX CHARACTERISTICS MONOLITHIC-MATRIX SYSTEMS Materials used as retardants in matrix tablet formulations :-MATRIX CHARACTERISTICSMATERIALInsoluble, inert matrixPolyethylenePolyvinyl chlorideEthylcelluloseInsoluble, erodableCarnauba waxPolyethylene glycolCastor waxhydrophilicMethyl celluloseCarboxypolymethyleneSodium alginateHPMC
26 Diffusion controlled reservoir system In membrane-controlled reservoir devices, the drug is contained in a core, which is surrounded by a polymer membrane,The drug release limiting structure is the polymer layer surrounding the reservoir
28 RESERVOIR SYSTEMS First layer Of the drug crystals Polymer phase Diffusionlayer
29 DIFFUSION CONTROLLED SYSTEMS Matrix systemAchievement of zero order is difficultSuitable for both degradable & non-degradable systemsNo danger of dose dumpingNot all drugs can be blended with a given polymeric matrixReservoir systemAchievement of zero order is easyDegradable reservoir systems may be difficult to designRupture can result in dangerous dose dumpingDrug inactivation by contact with the polymeric matrix can be avoided
30 Combined reservoir – monolithic system Initially the active agent must diffuse across the membrane , as the time passes the outer layers of the monolithic reservoir are depleted , the agent travels through the monolithic material and the membrane sequentially.This type of system is designated in two phase ( 1, 2)
31 COMBINED RESERVOIR-MONOLITHIC SYSTEMS Phase I – outer membrane layersPhase II – reservoir matrix materialOuter membrane layer (phase I)Dispersed agent in polymer matrix(phase II)
32 COMBINED RESERVOIR-MONOLITHIC SYSTEMS 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 loadedMatrix layerAgent depletedMatrix layer
33 DISSOLUTION CONTROLLED RELEASE SYSTEMS Two classes:Encapsulation dissolution controlMatrix dissolution control
34 DISSOLUTION CONTROLLED SYSTEMS Encapsulation dissolution control systems involve coating of individual particles of drug with a slow dissolving material & the coated particles can be compressed directly into tablets or placed in capsules.
35 Matrix dissolution control In this approach drug is dispersed in slow dissolving matrix consisted of polymer.The rate of penetration of dissolution fluid in to the matrix determines the drug dissolution and subsequent release.
36 Matrix dissolution control Membrane controlledPolymer erosion controlleddrugmembrane
37 DIFFUSION & DISSOLUTION CONTROLLED SYSTEMS Release rate is dependent onsurface areadiffusion coefficient of drug though pore in coatingconc. of drug in dissolution media.membranedrug
38 WATER PENETRATION CONTROLLED SYSTEMS rate control is obtained by penetration of water into the system.classified into 2 parts.swelling controlled systemsosmotically controlled systems
39 SWELLING CONTROLLED SYSTEM The system is initially dry & when placed into any body fluid, it absorbs the fluid & swells.This swelling increases the aqueous solvent content within the formulation & also polymer mesh size & so make the drug to diffuse through the swollen network into the external environment.
40 SWELLING CONTROLLED SYSTEM “Non-fickian case II” type diffusion,solventSwollenmatrixSwelling zoneUnswollenpolymer matrix
41 SWELLING CONTROLLED SYSTEM “Non-fickian case II” type diffusionSwollenmatrixSwelling zoneUnswollenpolymer matrixsolvent
42 CHEMICALLY CONTROLLED SYSTEMS delivery systems that change their chemical structure , when exposed to biological milieuThis 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
43 Biodegradable drug delivery system The polymers used in the formulation and fabrication of biodegradable drug delivery devices erode (with or without changes to the chemical structure) or degrade (breakdown of the main chain bonds) as a result of the exposure to chemicals (water) or biologicals (enzymes)
44 CHEMICALLY CONTROLLED SYSTEMS The polymer degradation by 2 ways:Bulk erosion surface erosion
45 MECHANISM OF POLYMER EROSION Type IA – cleavage of cross linksType IB – disintegration of water soluble polymer backbone
46 MECHANISM OF POLYMER EROSION Type II – Water insoluble macromolecules are converted into water soluble compounds by hydrolysis, ionization or protonation of a pendent group.hydrolysisIonizationprotonationWater insoluble moleculesWater soluble molecules
47 MECHANISM OF POLYMER EROSION Type III – erosion mechanisimHydrolyticcleavageWater insoluble moleculesWater soluble molecules
48 MECHANISM OF DRUG RELEASE bioactive covalently linked to polymer backbone , scission of the bonds connecting the drug to polymer backbone.
49 List of biodegradable polymer Polylactides (PLA).Polyglycolides (PGA).Poly(lactide-co-glycolides) (PLGA).Polyanhydrides.Polyorthoesters.
50 Factors Affecting Biodegradation of Polymers Chemical structure.Chemical composition.Presence of unexpected units or chain defects.Configuration structure.Molecular weight.Molecular-weigh
51 HYDROGELSHydrogels are water swollen three dimensional structures composed of primarily hydrophilic polymers.
53 Advantages Highly biocompatible Applied for both hydrophilic & hydrophobic drugRelease of therapeutics agent regulated controlling water swelling & cross linking agentLow interfacial tension
54 LimitationPoor mechanical strengthToughness after swelling
55 Swelling controlled release HYDROGELSSwelling controlled releaseconsists of drug dispersion within glassy polymer matrix. When the system comes in contact with biofluids, it starts swelling.Drug releaseGlassypolymerSwollen gelwater
56 Environmentally responsive hydrogel systems some polymers show drastic change in their swelling behavior with changes inexternal temp.,pH,ionic strength,enzymatic & chemical reaction,magnetic & chemical stimulus.
57 Environmentally responsive hydrogel systems The changes in network structure in response to external environment are reversible in nature.-TTpH-pH
58 Type of hydrogel Super porous hydrogel pH sensitive hydrogel Temperature sensitive hydrogelGlucose sensitive systemNeutral hydrogelOral insulin hydrogel
59 Electronic microscopic fig of super porous hydrogel Mainly for speedy swellingCarried out by making very fine particle of dried hydrogel having short diffusion path lengthElectronic microscopic fig of super porous hydrogel
60 Recent application of super porous gel in drug delivery DEVELOPMENT OF GASTRICRETENTION DEVICESDevelopment of fast dissolving tabletDevelopment per oral peptide delivery system
62 ION-EXCHANGE RESIN Zero order release obtained kinetics Drug release depends only on the ionic environment of the resins containing drug2 types.- cation exchange resin & anion exchange resin.
63 CATION EXCHANGE RESIN :- Synthesized by copolymerization of divinyl benzene & styrene.divinyl benzenestyrene
64 Anion exchange resinis 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.
66 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.
68 Pulsatile drug delivery system Pulsatile systems are basically time-controlled drug delivery systems in which the system controls the lag time independent of environmental factors like pH, enzymes, gastro-intestinal motility, etc.
69 PULSATILE SYSTEMS :- Electrically regulated systems :- Drug release is due to action of an applied electric field on a rate limiting membrane or directly on the solute & so control the transport across the membrane.
70 PULSATILE SYSTEMS :- Ultrasonically modulated systems :- Because of ultrasound, the polymer erosion is enhanced & therefore, drug release is enhanced .The extent of this enhancement is regulated by the frequency, intensity or duty cycle of the applied ultrasound.
71 PULSATILE SYSTEMS :- Magnetically modulated systems :- No applied fieldField turn onDrug release
72 :- PULSATILE SYSTEMS :- Photoresponsive systems :-Photoresponsive polymer consists of a photoreceptor usually a photochromic chromophore & an functional part. Photoresponsive gels change their physical or chemical characteristics upon exposure to photoradiation.On catching the optical signal, isomerization of the chromophores in the photoreceptor converts it to a chemical signal.
73 :- RESPONSIVE SYSTEMS:- Combination of Biosensors & controlled release systemSense continuously to manage unpredictable conditionImmediate respond with appropriate countermeasureGive the patients more flexibility and less disruption of the daily life
75 RESPONSIVE SYSTEMS:- pH sensitive systems:- Alteration in pH of the environment cause swelling or deswelling of the polymerAn enzyme substrate interaction produces a pH change that is utilized to modulate the erosion of pH sensitive polymer containing a dispersed bioactive.
76 RESPONSIVE SYSTEMS:- Thermo sensitive systems :- Mainly classified in to two classesbased on polymer water interaction & based on polymer-polymer interactions along with polymer water interactions.
77 RESPONSIVE SYSTEMS:- Inflammation responsive systems :- Based on biodegradable hydrogels of cross-linked hyaluronic acid.
79 RESPONSIVE SYSTEMS Glucose sensitive polymers :- Polymer A Polymer B insulinglucosemicrocapsulerelease
80 SYSTEMS UTILIZING ENZYMES a) Urea responsive delivery systems Urea is converted into NH4HCO3 & NH4OH by the action of urease that increases the pH.Hydrogel prepared by immobilizing ureaseIn cross-linked bovine serum albuminN-hyxyl half ester with dispersed drug
81 SYSTEMS UTILIZING ENZYMES b) Glucose responsive insulin delivery :-This system utilizes enzyme-glucose oxidase which converts glucose into gluconic acid.Glucose + O2 gluconic acid + H2OGNR2GluOxGGNR2GHNR2GluOxNR2GluOxGNR2NR2NR2GGluOxNR2
82 SYSTEMS UTILIZING ENZYMES b) Glucose responsive insulin delivery :-GODHOOCCOOHinsulinGOD-OOCCOO-insulinglucoseinsulin
83 SYSTEMS UTILIZING ANTIBODY INTERACTIONS e.g. controlled release of ethinyl estradiol (EE).EE stimulates biosynthesis of sex hormone binding globulin (SHBG).High serum levels of EE stimulates the production of SHBG, which increases the conc. of SHBG attached to the polymer surface & reduces the EE release rate.
84 SYSTEMS UTILIZING CHELATION Concept is based on the property of metals to accelerate the hydrolysis of carboxylate or phosphate esters & amides.Tagging of the chelator to a polymer chain by a covalent ester or amide link prevents its premature loss by excretion & reduces its toxic effects.
85 Insulin pump,Gluco watch Examples:Insulin pump,Gluco watchAn insulin reservoir (like a regular syringe)A small battery operated pumpA computer chip for controlCombination with Glucose sensorsReservoir and pump are incorporated in a plastic case about the size of a beeper.
86 Recent information Polymer therapeutics covers natural or synthetic polymers,which have either inherent therapeutic potential or carry covalently bonded drugs.The covalently bonded drugs have to be released at the desired tissue or cell type. Polymeric therapeutics aree.g.polymeric drugs,polymer-protein conjugates,polymer-DNA complexes,polymer-drug conjugates orpolymeric micelles.
87 Chemo mechanical polymer drug delivery system Chemomechanical polymers, developed by Professor Hans-Jorg Schneider and his team at the University of Saarland, Germany, have greatly improved functionality compared to existing expanding / contracting materials used to perform biomedical functions, and could be used in applications such as actuators, implants, drug release systems and drug screening.
88 New polymer enables near zero order drug release Cavilink TMdHighly porous polymer micro bead
89 Advance technologies in modified release from dosage form TIMERx MASRx & COSRx systemsProcise (comprised of a compression coated core) Drug Delivery Systems Based on Geometric ConfigurationRingcap Technology – tablets
90 Advance technologies in modified release from dosage form Smartrix system – multiple layered tab. Novel Erosion-Controlled Oral Delivery SystemTheriform Technology – novel method of fabrication based on three dimensional printing, a solid freeform fabrication technology- implantsAccudep technology – layered capsules
91 Advance technologies in modified release from dosage form Threeform technology ,- Meltrex technology – melt extrusion processDissocubes –,IDD technology – insoluble drug delivery technologyZydis oral fast dissolving dosage form.Orasolv & Durasolv – efficient technologies for production of orally disintegrating tablets.
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