Modulation of drug release from dosage form Techniques - Modulation of drug release from dosage form

List of contents Introduction Mechanisms of controlled release Intelligent controlled release DDS Examples Recent advances References A commercially available responsive drug delivery system – insulin pumps

Introduction: Fluctuating plasma level in conventional DF. Development of CR ,SR, TR Etc. A commercially available responsive drug delivery system – insulin pumps

Targeted delivery It has goal of delivering the drug to specific cell types, tissues or organs.

Controlled release Assigned to release the DRUG at a PREDETERMINED Rate.

Release of drug at a variable rate controlled by Modulated release Release of drug at a variable rate controlled 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.

ADVANTAGES OF DRUG RELEASE MODULATION Prolonged duration of action. Increase Controlled delivery at predetermined rate In patient compliance Reduction in frequency of dosing Reduced fluctuations More uniform effect

Increased first pass clearance. DISADVANTAGES High cost Poor IVIVC. Dose dumping. Increased first pass clearance.

DRUG RELEASE MODULATION ADVANTAGES DISADVANTAGES DRUGS UNSUITABLE FOR CR

Threshold of effectiveness Blue- uncontrolled unsafe dose Dotted-uncontrolled safe dose Red-controlled release Toxic level Drug Threshold of effectiveness Time

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

DRUGS UNSUITABLE FOR CR posses following features Short/long elimination half-life Narrow therapeutic index Poor absorption Large doses Low aqueous solubility Extensive first pass metabolism

BASIC PRINCIPLES OF CR DIFFUSION SWELLING BIODEGRADABLE or BIOERODIBLE

CONTROLLED RELEASE – MECHANISM Diffusion controlled Dissolution controlled diffusion & dissolution controlled Water penetration controlled Chemically controlled Hydrogels Ion exchange resins

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 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 . 

DIFFUSION CONTROLLED SYSTEMS MONOLITHIC-MATRIX SYSTEMS Drug + polymer

MATRIX CHARACTERISTICS MONOLITHIC-MATRIX SYSTEMS Materials used as retardants in matrix tablet formulations :- MATRIX CHARACTERISTICS MATERIAL Insoluble, inert matrix Polyethylene Polyvinyl chloride Ethylcellulose Insoluble, erodable Carnauba wax Polyethylene glycol Castor wax hydrophilic Methyl cellulose Carboxypolymethylene Sodium alginate HPMC

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

RESERVOIR SYSTEMS Oral system

RESERVOIR SYSTEMS First layer Of the drug crystals Polymer phase Diffusion layer

DIFFUSION CONTROLLED SYSTEMS Matrix system 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 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

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)

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 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

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.

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.

Matrix dissolution control Membrane controlled Polymer erosion controlled drug membrane

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 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.

SWELLING CONTROLLED SYSTEM “Non-fickian case II” type diffusion, solvent Swollen matrix Swelling zone Unswollen polymer matrix

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

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)

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.

Factors Affecting Biodegradation of Polymers Chemical structure. Chemical composition. Presence of unexpected units or chain defects. Configuration structure. Molecular weight. Molecular-weigh

HYDROGELS Hydrogels are water swollen three dimensional structures composed of primarily hydrophilic polymers.

Classification:- 1) Diffusion controlled release 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

Advantages Highly biocompatible Applied for both hydrophilic & hydrophobic drug Release of therapeutics agent regulated controlling water swelling & cross linking agent Low interfacial tension

Limitation Poor mechanical strength Toughness after swelling

Swelling controlled release HYDROGELS Swelling controlled release consists of drug dispersion within glassy polymer matrix. When the system comes in contact with biofluids, it starts swelling. Drug release Glassy polymer Swollen gel water

Environmentally responsive hydrogel systems some polymers show drastic change in their swelling behavior with changes in external temp., pH, ionic strength, enzymatic & chemical reaction, magnetic & chemical stimulus.

Environmentally responsive hydrogel systems The changes in network structure in response to external environment are reversible in nature. - T T pH - pH

Type of hydrogel Super porous hydrogel pH sensitive hydrogel Temperature sensitive hydrogel Glucose sensitive system Neutral hydrogel Oral insulin hydrogel

Electronic microscopic fig of 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

Per oral octreotide 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.

ION-EXCHANGE RESIN - - - - - + + Electrolytes + In gastric + Environment - + + - - + + Cationic drug + Anionic resin - Positively charged Electrolyte. +

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.

electically regulated :- 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 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.

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.

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.

PULSATILE SYSTEMS :- Magnetically modulated systems :- No applied field Field turn on Drug release

:- 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.

:- RESPONSIVE SYSTEMS:- Combination of Biosensors & controlled release system Sense continuously to manage unpredictable condition Immediate respond with appropriate countermeasure Give the patients more flexibility and less disruption of the daily life

RESPONSIVE SYSTEMS:- Commercially available Responsive Noninvasive reverse iontophoresis devices Implantable fusion pumps Duros implant technology controlled release Responsive Closed loop Smart polymers

RESPONSIVE SYSTEMS:- pH sensitive systems:- Alteration in pH of the environment cause swelling or deswelling of the polymer An enzyme substrate interaction produces a pH change that is utilized to modulate the erosion of pH sensitive polymer containing a dispersed bioactive.

RESPONSIVE SYSTEMS:- Thermo sensitive systems :- Mainly classified in to two classes based on polymer water interaction & based on polymer-polymer interactions along with polymer water interactions.

RESPONSIVE SYSTEMS:- Inflammation responsive systems :- Based on biodegradable hydrogels of cross-linked hyaluronic acid.

RESPONSIVE SYSTEMS Glucose sensitive polymers :- Glucose in Glycosylated insulin out Polymer membrane Concavalin A Sepharose 4B beads glucose Glycosylated insulin

RESPONSIVE SYSTEMS Glucose sensitive polymers :- Polymer A Polymer B insulin glucose microcapsule release

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 urease In cross-linked bovine serum albumin N-hyxyl half ester with dispersed drug

SYSTEMS UTILIZING ENZYMES b) Glucose responsive insulin delivery :- This system utilizes enzyme-glucose oxidase which converts glucose into gluconic acid. Glucose + O2  gluconic acid + H2O G NR2 GluOx G G NR2 G HNR2 GluOx NR2 GluOx G NR2 NR2 NR2 G GluOx NR2

SYSTEMS UTILIZING ENZYMES b) Glucose responsive insulin delivery :- GOD HOOC COOH insulin GOD -OOC COO- insulin glucose insulin

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.

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.

Insulin pump,Gluco watch Examples: Insulin pump,Gluco watch An insulin reservoir (like a regular syringe) A small battery operated pump A computer chip for control Combination with Glucose sensors Reservoir and pump are incorporated in a plastic case about the size of a beeper.

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 are e.g. polymeric drugs, polymer-protein conjugates, polymer-DNA complexes, polymer-drug conjugates or polymeric micelles.

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.

New polymer enables near zero order drug release Cavilink TMd Highly porous polymer micro bead

Advance technologies in modified release from dosage form TIMERx MASRx & COSRx systems Procise (comprised of a compression coated core) Drug Delivery Systems Based on Geometric Configuration Ringcap Technology – tablets

Advance technologies in modified release from dosage form Smartrix system – multiple layered tab. Novel Erosion-Controlled Oral Delivery System Theriform Technology – novel method of fabrication based on three dimensional printing, a solid freeform fabrication technology- implants Accudep technology – layered capsules

Advance technologies in modified release from dosage form Threeform technology ,- Meltrex technology – melt extrusion process Dissocubes –,IDD technology – insoluble drug delivery technology Zydis oral fast dissolving dosage form. Orasolv & Durasolv – efficient technologies for production of orally disintegrating tablets.

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