OCDDS BY RAGHAV modified

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Oral Controlled Drug Delivery systems- Design, Concept, Applications

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 1 ORAL CONTROLLED DRUG DELIVERY SYSTEM PRESNTED BY : RAGHAVENDRA KUMAR GUNDA Assistant. Professor, Department of Pharmaceutics, Narasaraopeta Institute of Pharmaceutical sciences

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 3 BASIC DEFINITIONS DRUG: It is a chemical agent intended for cure, prevention, mitigation, treatment or therapy for a disorder/disease in human being and animal DOSAGE FORM: It is defined as the combination of active drug component along with non drug moieties CONTROLLED RELEASE : One which delivers the drug at a pre-determined rate locally or systemically For specified long period of time SUSTAINED RELEASE: The system of prolonged release either Systemically or locally. CONVENTIONAL RELEASE: Immediate/Prompt release dosage forms

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 4 NEED OF CONTROLLED RELEASE The frequency of administration /dosing interval of any drug depends upon HALF LIFE , MEAN RESIDENCE TIME(MRT), THERAPEUTIC INDEX For conventional release the dosing interval much shorter than it’s halflife so following limitations were observed POOR PATIENT COMPLIANCE PEAKVALLEY PDC VS TIME FLUCTUATIONS IN DRUG LEVELS OVER MEDICATION MISSING OF DOSE C SS IS DIFFICULT FOR NARROW TI DRUGS UNDER MEDICATION

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 5 Reduced potencies because of partial degradation Toxic levels of administration Increase costs associated with excess dosing Compliance issue due to administration pain 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

Why control drug delivery?:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 6 Why control drug delivery? Goal of more sophisticated drug delivery techniques Deploy to a target site to limit side effects Shepard drugs through specific areas of the body without degradation Maintain a therapeutic drug level for prolonged periods of time Predictable controllable release rates Reduce dosing frequent and increase patient compliance Toxicity level Injection Controlled release Therapeutic Level Time As the cost and complexity of individual drug molecules has risen the problems with the classical delivery strategies over took their benefits.

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 7 Hence there is a need to Develop a better, safer drugs with long half-life with larger Therapeutic Index Effective, safer use of existing drugs through Concepts& Techniques of Controlled Release Drug Delivery System OBJECTIVES To minimize the fluctuation in PDC To attain feasibility for CR of drugs Correlation in In-vivo In-vitro aspects& Models To optimize the delivery of medication to achieve good therapeutic response The total amount of drug administered is sed Some times Drug Interactions also prolongs the release Ex:probencid the excretion of PENICILLIN -

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 8 ADVANTAGES REDUCTION IN DOSING FREQUNCY SE FLUCTUATION IN CIRCULATING DRUG LEVEL PATIENT COMPLIANCE AVOIDANCE OF NIGH TIME DOSING MORE UNIFORM EFFECT(PHARMACOLOGICAL) REDUCTION IN GI IRRITATION AND OTHER RELATED SIDE EFECTS IMPROVED EFFICACY/SAFETY RATIO Continuous oral delivery of drugs at predictable & reproducible kinetics for predetermined period throughout the course of GIT.

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 9 DISADVANTAGES Dose dumping. Reduced potential for accurate dose adjustment. Need of additional patient education. Stability problem. Poor Invivo-Invitro correlation Poor systemic availability(depends upon GI residing time) Increased potential for first pass clearance High cost as compared individual Drug reaches to liver via portal vein, higher the oral dose, greater possibility of saturating hepatic metabolism. Smaller dose/ slow release from formulation less chance to saturate

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 10 PLASMA DRUG CONCENTRATION VS TIME PROFILE

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 11 RATE CONTROLLED DRUG DELIVERY SYSTEM RATE PRE PROGRAMMED POLYMER MEMBRANE PERMEATION CONTROL MATRIX DIFFUSION MICRO RESERVOIR PARTITIONED ACTIVATION MODULATED PHYSICAL HYDRATION, IONTOPHORESIS, SONOPHORESIS HYDRODYNAMIC,VAPOUR,OSMATIC PRESSURES MAGNETIC CHEMICAL P H ACTIVATED HYDROLYSIS IONIZATION BIOCHEMICAL ENZYME ACTIVATED BIOCHEMICAL ACTIVATED FEED BACK REGULATED SITE TARGETTED BIO EROSION BIO RESPONSIVE EX: INSULIN CLASSIFICATION OF RATE CDDS

History of Controlled Drug Delivery:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 12 History of Controlled Drug Delivery Wurster technique 1949 Coacervation (liquid encapsulation) 1953 Mircroencapsulation 1960’s 65% of all current drugs use some form of micro-encapsulation Implants 1970’s Transdermal 1980’s Site directed systems 1990’s

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 13 SOME SUBSTANCES AVAILABLE FOR CONTROLLED RELEASE ARE AS FOLLOWS VITAMINS MINERALS HORMONES DRUGS DRUGS DIURETICS & CVS DRUGS ACETAZOLAMIDE, ISOSORBIDE, PAPVERINE ANTIMICROBIAL TETRACYCLIN CNS AMPHETAMINE, CAFFEINE, PHENOBARBITAL, PROCHLORPERAZINE GI BELLADONNA ALKALOIDS, HYOSCINE, TRI DIHEXETHYL CHLORIDE PYRIDO STIGMINE RESPIRATORY AMINOPHYLLINE CPM, BPM

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 14 COMPOUNDS THAT ARE UNSUITABLE FOR CONTROLLED RELEASE DEPEND UPON ELEMINATION HALFLIFE AND DOSE i.e t1/2 < 2.0 hours, larger doses of api . CHARACTERISTIC DRUGS Not effectively absorbed in Lower Intestine IBUPROFEN, FERROUS SALTS Adsorbed, excreted rapidly biological t ½< 1 hr PENICILLIN-G, FUROSEMIDE Long biological t ½ > 12 hr DIAZEPAM, PHENYTOIN Larger doses (> 1 gm) SULPHONAMIDES Cumulative action& un desirable side effects, drugs with low Therapeutic Index PHENOBARBITAL, DIGOXIN Precise dosage titrated to individuals ANTI-COAGULANTS, CARDIAC GLYCOSIDES No clear advantages for CONTROLLED RELEASE GRISEOFULVIN

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 15 Dissolution controlled release Diffusion controlled release Diffusion and dissolution controlled release Ion exchange resins pH independent formulations Osmotically controlled release Altered density formulations. DIFFERENT MECHANISMS INVOLVED IN ORAL CONTROL RELEASE

Dissolution Definition::

2/9/2016 RAGHAVENDRA KUMAR GUNDA 16 16 Dissolution Definition : Solid substances solubilizes in a given solvent. Mass transfer from solid to liquid. Rate determining step: Diffusion from solid to liquid. Several theories to explain dissolution – Diffusion layer theory (imp) Surface renewal theory Limited solvation theory.

Dissolution-Controlled Systems:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 17 Dissolution-Controlled Systems Alternating layers of rate-controlling coats Group of beads with different coatings (Spansule, SmithKline Beecham) dC/dt = kd*A(Cs-C) = D/h*A(Cs-C) dC/dt=dissolution rate, kd=dissolution rate const D=diffusion coefficient, Cs=saturation solubility C=concentration of solute in bulk solution

Types of Dissolution Controlled Systems:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 18 Types of Dissolution Controlled Systems Two types of dissolution- controlled, pulsed delivery systems A: Single bead-type device with alternating drug and rate controlling layer B: Beads containing drug with differing thickness of dissolving coats

Bioerodible and Combination Diffusion and Dissolution System:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 19 Bioerodible and Combination Diffusion and Dissolution System Strictly speaking, therapeutic systems will never be dependent on dissolution only or diffusion only. Bioerodibile devices, however, constitute a group of systems for which mathematical descriptions of release is complex. The complexity of the system arises from the fact that, as the polymer dissolves, the diffusion path length for the drug may change. this usually results in a moving-boundary diffusion system. Zero-order release can occur only if surface erosion occurs and surface area does not change with time. The inherent advantage of such a system is that the bioerodible property of the matrix does not result in a ghost matrix.

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 20 Representation of a Bioerodible Matrix System Drug is dispersed in the matrix before release at time = 0. At time = t, partial release by drug diffusion or matrix erosion has occurred

Characteristics of Bioerodible Matrix Systems:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 21 Characteristics of Bioerodible Matrix Systems Advantages all the advantages of matrix dissolution system removal from implant sites is not necessary Disadvantages difficult to control kinetics owing to multiple processes of release potential toxicity of degraded polymer

Bioerodible and Biodegradable Controlled Release Polymers:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 22 Bioerodible and Biodegradable Controlled Release Polymers These polymers are designed to degrade within the body Polylactides (PLA) Polyglycolides (PGA) Polylactide-co-glycolides (PLGA) Polyanhydrides Polyorthoesters

Degradation of Biodegradable Polymers:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 23 Degradation of Biodegradable Polymers These materials degrade within the body as a result of natural biological processes, eliminating the need to remove a drug delivery system after release of the active agent has been completed Bulk hydrolysis - the polymer degrades in a fairly uniform manner throughout the matrix Surface Eroding - degradation occurs only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system

Biodegradable Polymers:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 24 Biodegradable Polymers Drug delivery from (a) bulk-eroding and (b) surface-eroding biodegradable systems .

Noyes Whitney Equation:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 25 Noyes Whitney Equation dc/dt = kD.A (Cs – C ) dc/dt = D/h A. (Cs – C) dc/dt = Dissolution rate. k= Dissolution rate constant (1 st order). D = Diffusion coefficient/diffusivity Cs = Saturation/ maximum drug solubility. C =Con. Of drug in bulk solution. Cs-C=concentration gradient. h =Thickness of diffusion layer.

Matrix Type:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 26 Matrix Type Also called as Monolith dissolution controlled system. Controlled dissolution by: 1.Altering porosity of tablet. 2.Decreasing its wettebility. 3.Dissolving at slower rate. First order drug release. Drug release determined by dissolution rate of polymer. Examples: Dimetane extencaps, Dimetapp extentabs. Soluble drug Slowly dissolving matrix

Matrix Dissolution Products:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 27 Matrix Dissolution Products

Encapsulation:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 28 Encapsulation Called as Coating dissolution controlled system. Dissolution rate of coat depends upon stability & thickness of coating. Masks colour,odour,taste,minimising GI irritation. One of the microencapsulation method is used. Examples: Ornade spansules, Chlortrimeton Repetabs Soluble drug Slowly dissolving or erodible coat

Encapsulated Dissolution Products:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 29 Encapsulated Dissolution Products

Diffusion:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 30 Diffusion Major process for absorption. No energy required. Drug molecules diffuse from a region of higher concentration to lower concentration until equilibrium is attainded. Directly proportional to the concentration gradient across the membrane.

Matrix Diffusion Types:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 31 Matrix Diffusion Types Rigid Matrix Diffusion Materials used are insoluble plastics such as PVP & fatty acids. Swellable Matrix Diffusion 1. Also called as Glassy hydrogels.Popular for sustaining the release of highly water soluble drugs. 2. Materials used are hydrophilic gums. Examples : Natural- Guar gum,Tragacanth. Semisynthetic -HPMC,CMC,Xanthum gum. Synthetic -Polyacrilamides. Examples: Glucotrol XL, Procardia XL

Matrix system:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 32 Matrix system Rate controlling step: Diffusion of dissolved drug in matrix.

Matrix Diffusional Products:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 33 Matrix Diffusional Products Product Manufacturer Procan SR Parke Davis Desoxyn Abbot Choledyl SA Parke Davis

Higuchi Equation:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 34 Higuchi Equation Q = DE/T (2A.E Cs)Cs.t) 1/2 Where , Q=amt of drug release per unit surface area at time t. D=diffusion coefficient of drug in the release medium. E=porosity of matrix. Cs=solubility of drug in release medium. T=tortuosity of matrix. A=concentration of drug present in matrix per unit volume.

Reservoir System:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 35 Reservoir System 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. Examples: Nico-400, Nitro-Bid

Reservoir diffusion System:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 36 Reservoir diffusion System Rate controlling steps : Polymeric content in coating, thickness of coating, hardness of microcapsule.

Reservoir Diffusional Products:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 37 Reservoir Diffusional Products Product Manufacturer Nico-400 Jones Nitro- Bid Marion Nitrospan Rorer

Dissolution & Diffusion Controlled Release system:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 38 Dissolution & Diffusion Controlled Release system 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. Ex- 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

Osmotic pressure controlled DDS:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 39 Osmosis - Movement of solvent from lower to higher concentration. - The passage of solvent into a solution through semipermeable membrane. Semipermeable Membrane Molecules are permitted only to one component (Water). Osmotic pressure It is the hydrostatic pressure produced by a solution in a space divided by a semipermeable membrane due to difference in concentration of solutes. Osmotic pressure controlled DDS

Osmotic Pressure Controlled System:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 40 Osmotic Pressure Controlled System Provides zero order release Drug may be osmotically active, or combined with an osmotically active salt (e.g., NaCl). Semipermeable membrane usually made from cellulose acetate. More suitable for hydrophilic drug. Examples: Glucotrol XL, Procardia XL,

Equation:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 41 Equation (Q/t) z = Pw Am/ hm ( π s- π e ) (Q/t)= Rate of zero order drug release. Pw, Am & hm= water permeability, effective surface area & thickness of semipermeable membrane. π s= osmotic pressure of saturated solution of osmotically active drug or salt in system. π e = osmotic pressure of GI fluid.

Osmotic Pressure Controlled System:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 42 Osmotic Pressure Controlled System

Osmotic Pressure Controlled System:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 43 Osmotic Pressure Controlled System

Modifications:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 44 Modifications - Immediate release system. - Osmotically active compartment system

Immediate Release System:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 45 Immediate Release System Activation of system is done. Dividing a dose into two parts. One third immediate release. Two third controlled release. Encapsulated into semipermeable membrane. e.g. : Phenyl propanolamine.

Osmotically active system:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 46 Osmotically active system Two compartments separated by movable partition. Osmotically active compartment absorbs water from GIT. Creates osmotic pressure. Partition moves upward & then drug releases. Ex: Nifedipine. Movable partition Delivery orifice Osmotically active compartment Drug compartment

Some Popular Brand names used for OCDDS:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 47 Some Popular Brand names used for OCDDS Spansule capsule ( SK & F ) Sequal capsule (Lederle ) Extentab tablets ( Robins ) Timespan tablet ( Roche ) Dospan tablet ( Merrell Dow ) Chronotab tablet ( Schering ) Plateau capsule ( Marion ) Tempule capsule ( Armour )

Ion exchange resins:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 48 Ion exchange resins It is based on the formation of drug resin complex formed when a ionic solution is kept in contact with ionic resins. The drug from these complex gets exchanged in gastrointestinal tract and released with excess of Na+ and Cl- present in gastrointestinal tract. Resin + - Drug - + Cl- goes to resin + Cl- + Drug- Where x- is cl- conversely Resin - - drug+ + Na +goes resin – Na+ + Drug These systems generally utilize resin compounds of water insoluble cross – linked polymer. They contain salt – forming functional group in repeating positions on the polymer chain. The rate of drug diffusion out of the resin is sustained by the area of diffusion, diffusional path length and rigidity of the resin which is function of the amount of cross linking agent used to prepare resins

PH -independent formulations:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 49 PH -independent formulations Drugs administered oraly encountered pH ranging from 7 in mouth,1 to 4 in stomach, and 5 to 7 in small intestine.since most of the drugs are eighter weak acids or weak bases,their release from sustained formulations is P H dependent. However buffer can be added to the formulation to help maintain a constant PH there by rendering pH-independent release. To this end,salts of amino acids,citric acid,phthalic acid,phosphoric acid or tartrate acid are commonly used because of their physiological acceptibility. e.g. propoxyphene in a buffered sustained release formulation, which significantly increase reproducibility

Altered density formulations:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 50 Altered density formulations 1.High desity approch : the density of the pellets must exceed that of normal stomach content(1.04g/cm3) and should be atleast 1.4 In preparing such formulations,drug can be coated on a heavy core or mixed with heavy inert materials such as barium sulfate,titanium dioxide ,iron oxide. 2.low density approch : Globular shells which have an apparen density lower than that of gastric fluid can be used as a carrier of drug for sustained release purpose.polysterol,poprice,and even popcorn are all good condidates as carriers. The surface of these empty shells is undercoated with sugar or with a polymeric material such as methacrylic polymer and cellulose acetate pthalate.the undercoated shell is then coated by a mixture of drug with polymers such as ethylcellulose and hydroxypropylcellulose.Final product floats on GIT fluid.

Conclusion:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 51 Conclusion By and large, these are based on the principles diffusion, dissolution, or ion exchange and, only recently, on the principle of osmosis. Regardless of the mechanism of sustained release, however, more and more of these systems are becoming polymer based. There are also those which are based on the bioadhesion principle whose goal is to promote the retention of a delivery system, hence drug release, at a specific region in the GI tract Though CDDS appears appear to be feasible, The Timing for practical development is difficult to predict; safety, cost, efficacy are those factors need to be evaluated.

BIBLIOGRAPHY:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 52 BIBLIOGRAPHY Novel drug delivery system , volume 50, Y.W.Chien, pg nos 1-55 Novel drug delivery system by N.K.jain 4 th edition, pg no1-4,54-61 The theory & practice of industrial pharmacy, Leon Lachman , Herbert A.Lieberman, Joseph L.Kanig,3 rd edition. Pg no 430-445 The Eastern pharmacist, november 1993. Sustained release drugs, V R.Gudsoorkar & D.Rambhau ,page 27-32 Biopharmaceuitics & pharmacokinetics, D M.Brahmankar & Sunil B. Jaiswal, 1 st edition 1995, pg nos 220-235, 3335-371 Li. V.H., "Influence of drug properties and routes of drug administration on the design of sustained and controlled release systems" Chapter 1 in "Controlled drug delivery : fundamentals and applications" edited by Robinson J.R., VincentLee,2 nd edition,Marcel Dekker Inc., Volume 29, 1978: 5-36pp

Continue……………:

2/9/2016 RAGHAVENDRA KUMAR GUNDA 53 Continue…………… Hui ho-wah, "Design and fabrication of oral controlled release drug delivery systems“ chapter 9 in "Controlled drug delivery; fundamentals and applications", edited by Robinson J.R., Vincent Lee, 2nd edition, Marcel Dekker Inc., Volume 29, 1978: 391-420pp.

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2/9/2016 RAGHAVENDRA KUMAR GUNDA 54 Joseph.R.Robinson pointed out the importance of drug delivery system “Unless a drug can be delivered to it’s target area at a rate and concentration that minimize the side effects and maximize the therapeutic effect of drug will not be maximally beneficial to patient and in the extreme an otherwise useful drug may be discarded ”

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