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 the DRUG at a PREDETERMINED Rate.
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 1. Prolonged duration of action. 2. Increase Controlled delivery at predetermined rate 3. In patient compliance 4. Reduction in frequency of dosing 5. Reduced fluctuations 6. More uniform effect
DISADVANTAGES High cost Poor IVIVC. Dose dumping. Increased first pass clearance.
DRUG RELEASE MODULATION ADVANTAGES DISADVANTAGES DRUGS UNSUITABLE FOR CR
Drug Time Toxic level Threshold of effectiveness Blue- uncontrolled unsafe dose Dotted-uncontrolled safe dose Red-controlled release
Different controlled release systems Time of release Cumulative release Burst like release Pulsatile release Diffusion controlled release Zero order (linear) release Lag followed by Burst release
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS I. Drug related II. Biological III. Physiological IV. Pharmacokinetic V. Pharmacological
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS aqueous solubility protein binding drug stability molecular size partition coefficient Drug related
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS absorption side effects margin of safety elimination distribution duration of action disease state Biological
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS Physiological prolonged drug absorption GI blood flow variability on GI emptying & motility
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS Pharmacokinetic first pass metabolism variability of urinary pH effect on drug elimination dose dumping
FACTORS GOVERNING THE DESIGN OF CR DOSAGE FORMS Pharmacological changes in drug effect upon multiple dosing 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
Schematic depiction of various classes of controlled release system Controlled release system Water penetration controlled Swelling Chemically controlled Erodible Hydrogel Diffusion SwellingEnvironmental Ion exchange resin anion cation Chemically Diffusion Reservoir and monolithic Matrix Reservoir Dissolution Encapsulation Matrix Diffusion and Dissolution osmotically Drug linked polymer
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
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
Oral system RESERVOIR SYSTEMS
First layer Of the drug crystals Polymer phase Diffusion layer
DIFFUSION CONTROLLED SYSTEMS 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 Matrix system o 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
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 )
Phase I – outer membrane layers Phase II – reservoir matrix material COMBINED RESERVOIR-MONOLITHIC SYSTEMS Outer membrane layer (phase I) Dispersed agent in polymer matrix (phase II)
COMBINED RESERVOIR-MONOLITHIC SYSTEMS Monolithic Matrix (phase II) Outer membrane (phase I) Agent loaded Matrix layer Agent depleted Matrix layer 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.
DISSOLUTION CONTROLLED RELEASE SYSTEMS Two classes: Encapsulation dissolution control Matrix 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. DISSOLUTION CONTROLLED SYSTEMS Encapsulation dissolution control
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 solvent Swollen matrix Swelling zone Unswollen polymer matrix Non-fickian case II type diffusion,
SWELLING CONTROLLED SYSTEM solvent Swollen matrix Swelling zone Unswollen polymer matrix Non-fickian case II type diffusion
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 Water insoluble molecules Water soluble molecules Hydrolytic cleavage
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.
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 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 HYDROGELS
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 pH T - -
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
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 –CH 2 Cl groups & forms strong anion exchange resin.
ION-EXCHANGE RESIN Electrolytes In gastric Environment Positively charged Electrolyte. + Anionic resin - Cationic drug
INTELLIGENT CONTROLLED RELEASE DRUG DELIVERY SYSTEMS:- Provide the bioactive in response to the physiological need & shouldsense the changes & manipulate the drug release in response to external stimuli like heat, ultrasound, magnetic field, pH and/or conc. of specific molecules.
CLASSIFICATION: :- CLASSIFICATION: pulsatile systemsresponsive systems systems utilizing chelation systems utilizing enzymes systems utilizing antibodies INTELLIGENT CONTROLLED RELEASE SYSTEMS electically regulated ultrasonically modulated magnetically modulated photoresponsive Glucose sensitive inflammation responsive thermosensitive pH sensitive urea responsive 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 :- 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 Glycosylated insulin glucose Concavalin A Sepharose 4B beads
Glucose sensitive polymers :- insulin microcapsule Polymer A Polymer B release glucose RESPONSIVE SYSTEMS
SYSTEMS UTILIZING ENZYMES a) Urea responsive delivery systems Urea is converted into NH 4 HCO 3 & NH 4 OH 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 + O 2 gluconic acid + H 2 O G G G G HNR 2 GluOx G NR 2 GluOx G NR 2 GluOx G G G
SYSTEMS UTILIZING ENZYMES b) Glucose responsive insulin delivery :- GOD HOOCCOOH insulin GOD - OOCCOO - 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.
An insulin reservoir (like a regular syringe) A small battery operated pump A computer chip for control Combination with Glucose sensors Examples : Insulin pump,Gluco watch
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.
References:- S.P.Vyas, R.K.Khar, Controlled drug delivery- concepts & advances., 1-50, 167 G.S.Banker, Modern Pharmaceutics, 3rd edition, 575 Chien Y.W., Novel fundamentals, developmental concepts, biomedical assessments. Robinson & Lee, controlled drug delivery: fundamentals and applications, 2nd edition. Donald L.Wise, Handbook of Pharmaceutical controlled release technology, 443. Praveen Tyle, drug delivery devices: fundamentals and applications, Marcel Dekker, , James Swarbrick, James C. Boylan, Encyclopedia of Pharmaceutical Technology, Marcel Dekker, III, 282,
References:- Remington: The Science and Practice of Pharmacy, 19 th edition, Leon Lachman, The Theory and Practice of Industrial Pharmacy, third edition, Talukdar M. M., Kinget R., Swelling and drug release behaviour of xanthan gum matrix tablets, Int. J. Pharm. 120 (1995) 63–72. Al-Shamkhani A. and Duncan R. Int. J. Pharm. 122(1995), 107. Brown L., Edelman E., Fishel Ghodsian F. and Langer R. J.Pharm.Sci. 85 (1996), 1341.
References :- Giannos S., Dinh S. and Berner B. J. Pharm. Sci. 84 (1995), 539. Heller J. and Trescony P.V. J. Pharm. Sci. 68 (1979), 919. Hoes C. J. Control. Rel. 38(1996),245. Kabanov A. and Alakhov V. J. Control. Rel. 28 (1994), 15. Kallstrand G. and Ekman B. J. Pharm. Sci. 68 (1976),325. Theeuwes F. and Bayne W. J. Pharm. Sci. 66 (1977), Yokayama M, Okano T., Sakurai Y. and Kataoka K. J.Control. Rel. 32 (1994), 269. Michael J. Rathbone., Modified Release Drug Delivery Technology, volume 126, Marcel Dekker., Pages 1, 216.
References:- Joseph R. Robinson, Sustained release and controlled release drug delivery systems, volume 6,Marcel Dekker. R.E. Notari, J. Pharm. Sci.,62, 865 (1973) G.L.Flynn, S.H. Yalkowsky and T.J. Roseman, J. Pharm. Sci.,63, 479 (1974) S.Motycka and J.G.Naira, J. Pharm. Sci., 67, 500 (1978)
References:- Theeuwes F. Elementary osmotic pump. J Pharm Sci. 1975;64: Zentner GM, Rork GS, Himmelstein KJ. The controlled porosity osmotic pump. J Controlled Rel. 1985;1: Swanson DR, Barclay BB, Wong PS, Theeuwes F. Nifedipine gastrointestinal therapeutic systems. Am J Med. 1987;83(suppl 6B):3-9. Carrigan PJ, Bates TR. Biopharmaceutics of drug administered in lipid- containing dosage forms, part I: GI absorption of griseofulvin from an oil-in-water emulsion in the rat. J Pharm Sci. 1973;62:1477. Noguchi T, Takahashi C, Kimura T, Muranishi S, Sezaki H. Mechanism of the intestinal absorption of drugs from oil-in- water emulsions. Chem Pharm Bull. 1975;23: Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res. 1995;12:156.
References:- Wichterle O, Lim, D. Hydrophilic gels for biological use. Nature. 1960;185: Chen J, Blevins WE, Park H, Park K. Gastric retention properties of superporous hydrogel composites. J Controlled Rel. 2000;64: Shalaby WSW, Blevins WE, Park K. In vitro and in vivo studies of enzyme-digestible hydrogels for oral drug delivery. J Controlled Rel. 1992;19: Shalaby WSW, Blevins WE, Park K. The use of ultrasound imaging and fluoroscopic imaging to study gastric retention of enzyme- digestible hydrogels. Biomaterials. 1992;13: Drews J. Quest of Tomorrow's Medicines. New York, NY: Springer-Verlag; New York; Dorkoosh FA, Borchard G, Rafiee-Tehrani M, Verhoef JC, Junginger HE. Evaluation of superporous hydrogel (SPH) and SPH composite in porcine intestine ex-vivo: assessment of drug transport, morphology effect, and mechanical fixation to intestinal wall. Eur J Pharm Biopharm. 2002;53:
References:- Dorkoosh FA, Verhoef JC, Borchard G, Rafiee-Tehrani M, Junginger HE. Development and characterization of a novel peroral peptide drug delivery system. J Controlled Rel. 2001;71: Dorkoosh FA, Verhoef JC, Ambragts MHC, Rafiee-Tehrani M, Borchard G, Junginger HE. Peroral delivery systems based on superporous hydrogel polymers: release characteristics for the peptide drugs buserelin, octreotide, and insulin. Pharm Sci. (In press). Dorkoosh FA, Verhoef JC, Verheijden JHM, Rafiee-Tehrani M, Borchard G, Junginger HE. Peroral absorption of octreotide in pigs formulated in delivery systems based on superporous hydrogel polymers. Pharm Res. (in press). Chang R-K, Guo X, Burnside BA, Couch RA. Fast-dissolving tablet. Pharm Technol. 2000;24(6): Kallmes DF, Fujiwara NH, Max WF. Angiographic and histologic evaluation of an expandable hydrogel material for aneurysm embolization. Paper 107 presented at the 37th Annual meeting of the American Society of Neuroradiology, April 2-8, 2002; Dallas. Ciceri EF, Dickerson J, Klueznik RP, Moret J, Mawad ME. Embolization of experimental porcine aneurysms with a combination platinum coils and hydrogel material. Paper 106 presented at 37th Annual Meeting of the American Society of Neuroradiology, April 2-8, 2002; Dallas.