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Edit Comment Close Premium member Presentation Transcript Basic designs in oral controlled release systems: Basic designs in oral controlled release systems Presented by:- Surya Chandra padman.J M pharmacy pharmaceuticsContents: Contents Introduction Definition Advantages, disadvantages Factors in the design of CRDDS Designs & fabrication of Oral Controlled release systems conclusionIntroduction: Introduction Controlled release products are designed to maintain constant therapeutic plasma concentration of the drug with in therapeutic range of the drug over prolonged period and offer minimum side effects. These products are designed to reduce frequency of dosing by modifying rate of absorptionDefinition : Definition Sustained drug delivery is the one which release the drug at slower than any conventional formulation Controlled drug delivery is the one which delivers the drug at a predetermined rate for a specific period of time Extended release dosage forms are those which due to specialized technology of preparation provided, soon after a single dose administration therapeutic drug levels are maintained for 8-12 hoursPowerPoint Presentation: Plasma Drug Concentration Profiles for Conventional Tablet Formulation, a Sustained Release Formulation and a Zero Order Controlled Release Formulation.Advantages: Advantages Reduced dosing frequency. Reduced fluctuation at plasma drug levels. Reduced GI side effects. Better patient acceptance avoidance of night time dosing Increased safety margin of high potent drugs due to better control of plasma levels.Disadvantages: Disadvantages Dose dumping. Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions Need of additional patient education. Poor in vitro-in vivo correlation. Higher cost of formulationFactors in the design of CRDDS: Factors in the design of CRDDS 1) Biopharmaceutic properties 2)Pharmacokinetic properties 3) Pharmacodynamic propertiesBiopharmaceutic properties: Biopharmaceutic properties Molecular weight of drug: Lower the molecular weight faster and complete absorption – good candidates Large molecular size – poor candidates for oral CR system Aqueous solubility of drug: Good aqueous solubility especially ph-independent are good candidates eg:pentoxifylline Poor aqueous solubility–poor candidates for oral CR system Apparent partition coefficient/ lipophilicity : Greater the apparent partition coefficient of drug,greater the lipophilicity and thus greater its rateand extent of absorptionBiopharmaceutic properties: Biopharmaceutic properties Drug permeability: The three major drug characteristics that determine permeability of drugs for passive transport are a) lipophilicity b) polarity of drug c)molecular size Drug stability: Drugs unstable in GI environment cannot be administered as oral CR formulation eg : nitroglycerine Mechanism and site of absorption : Drugs absorbed by CMT process are poor candidate for CR systemPharmacokinetic properties: Pharmacokinetic properties Absorption rate : Absorption must be efficient since the desired rate-limiting step is rate of drug release Slow absorption- poor candidate since release will result in a pool of unabsorbed drug Elimination half-life: drugs with half-life in the range 2-6hrs are good candidate CR system eg : propranolol Rate of metabolism: drug which is extensively metabolized is suitable for CR system (not too high) Drugs cable of inducing or inhibiting metabolism –poor candidateDosage form index(DI): : Dosage form index(DI): It is defined as the ratio of Css,max to Css,min Goal of CR formulation is improve therapy by reducing DI while maintaining the plasma level with in the therapeutic window Pharmacodynamic properties Drug dose: For oral CR dosage form a dose size of 0.5 to 1.0 gm is consider maximum Higher doses have to be given as liquids. Therapeutic range: drug should be released with in the therapeutic range Plasma concentration-response (PK/PD) relation ship: Drugs such as resepine whose activity is independent of its concentration are poor candidate for CR systemsDesigns & fabrication of Oral Controlled release systems: Designs & fabrication of Oral Controlled release systems Diffusion controlled system Dissolution controlled system Diffusion & Dissolution controlled system Water penetration controlled system Chemically controlled system Hydrogels Ion-exchange resins Diffusion controlled system : Diffusion controlled system In this systems the rate controlling step is diffusion of dissolved drug through the polymeric barrier. There are basically two types of diffusion devices a) Matrix diffusion system b) R eservoir diffusion systemDiffusion controlled system: Diffusion controlled system Matrix systems are also called as monoliths since the drug is homogeneously dispersed through out a rate controlling medium There are two types of matrix devices 1) Insoluble matrix of rigid non swellable hydrophobic materials Drug release from insoluble non swellable matrix involves penetration of fluid followed by dissolution of drug particle and diffusion through fluid filled pores.Diffusion controlled system: Diffusion controlled system Materials used are insoluble plastics such as PVP , PVC & fatty materials like stearic acid, bees wax etc. 2)Soluble swellable hydrophilic substance In swellable matrix , the drug becomes available as matrix swells or dissolves and the dissolved matrix then undergo surface erosion with little or no bulk erosionDiffusion controlled system: Diffusion controlled system 2)Soluble swellable hydrophilic substance 1 ) Insoluble matrix of rigidDiffusion controlled system: Diffusion controlled system Materials used are hydrophilic gums. Examples : Natural- Guar gum, Tragacanth . Semisynthetic - HPMC,CMC,Xanthum gum. Synthetic – Polyacrylamides The drug and matrix materials are granulated together and compressed into CR product Examples : plendil ER (felodipine) agon SR (felodipine) kapanol (morphine sulphate )PowerPoint Presentation: kapanol (morphine sulphate) plendil ER (felodipine) Diffusion controlled system : Diffusion controlled system RESERVOIR CONTROLLED SYSTEM In this system the core of the drug is coated with water insoluble polymer The polymer can be applied by coating or micro encapsulation techniques Diffusion controlled system : Diffusion controlled system The drug release mechanism across the memberane involves diffusion of water through the memberane , dissolution of drug & then diffusion of drug into surrounding fluid Material used in the system are hydroxy propyl cellulose, ethyl cellulose, poly vinyl acetate. Eg :- nio -bid(nitro glycerine ), bronkodyl SR cap( theophylline )Advantages & disadvantages of matrix system: Advantages & disadvantages of matrix system Advantages of Matrix system:- Very easy to fabricate in a wide range of sizes and shapes No danger of dose dumping in the case of rupture Disadvantages:- Achievement of zero order release is difficult Not all drugs can blended with a given polymeric matrixAdvantages & disadvantages of reservoir system: Advantages & disadvantages of reservoir system Advantages :- Achievement of zero order release is easy Very easy to fabricate in a wide range of sizes and shapes Drug inactivation by the polymeric matrix can be avoided Disadvantages:- Rupture can result in dangerous dose dumping Higher cost compared to matrix tablet.Dissolution controlled system: Dissolution controlled system The dissolution controlled formulations are divided into two classes a) Encapsulation dissolution control b) Matrix dissolution controlDissolution controlled system: Dissolution controlled system 1. Encapsulation dissolution control: These methods generally involve coating individual particles or granules of drug with a slowly dissolving material. slowly dissolving materials like cellulose, poly ethylene glycols, polymethacrylates , waxes etcDissolution controlled system: Dissolution controlled system the dissolution rate of coat depends upon the solubility and thickness of the coating. The coated particles can be compressed directly into tablets as in Spacetabs or placed in capsules as in the Spansule Products.Dissolution controlled system: Dissolution controlled system Since the time required for dissolution of the coat is a function of its thickness and aqueous solubility, one can obtain repeat or sustained action by employing a narrow or a wide spectrum of coated particles of varying thicknesses respectivelyEncapsulation dissolution control: Encapsulation dissolution control Examples : Diamox sequels ( acetazolamide ) Ornade spansulesDissolution controlled system: Dissolution controlled system Matrix dissolution control: The drug is homogeneously dispersed throughout a rate controlling medium. The rate of penetration of dissolution fluid into the matrix determines the drug dissolution and release. Controlled dissolution by: 1.Altering porosity of tablet. 2.Decreasing its wettebility . 3.Dissolving at slower rate. drug release is often first orderDissolution controlled system: Dissolution controlled system The drugs with highly water soluble drugs can be formulated as CR products by controlling dissolution rate. This can be achieved by using some of the polymers like Bees wax. Carnauba wax and Hydrogenated Castor oil. The wax embedded drug is generally prepared by dispersing the drug in molten wax and congealing and granulating the same.Dissolution controlled system: Dissolution controlled system Examples: Dimetane extentabs ( bromo phenaramine malate ) Donnatal Extentabs ( Phenobarbital,scopalamine ) Quinidex extentabs ( quinidine )Dissolution & Diffusion Controlled Release system: Dissolution & Diffusion Controlled Release system Drug enclosed in a partial soluble membrane. Pores are created due to dissolution of parts of membrane. It permits entry of aqueous medium into core & drug dissolution.Dissolution & Diffusion Controlled Release system: Dissolution & Diffusion Controlled Release system Diffusion of dissolved drug out of system. Ex- Ethyl cellulose & PVP mixture dissolves in water & create pores of insoluble ethyl cellulose membrane. Water penetration controlled system : Water penetration controlled system Some devices are designed using water as the main agent controlling the release of the drug In these the drug molecules cannot physically diffuse out of the device without water molecules diffusing in. Generally these are of two types:- swelling controlled system osmotic controlled system Water penetration controlled system : Water penetration controlled system Swelling controlled systems:- These systems usually incorporate drugs in a hydrophilic polymer that is stiffy or glassy when dry, but swells when placed in an aqueous environment. Swelling increases the aqueous solvent content with in the formulation as well as the polymer mesh size enabling the drug to diffuse through swollen network in to the external environment Water penetration controlled system : Water penetration controlled system “a” indicates reservoir diffusion swelling. “b” indicates matrix diffusion swelling. OSMOTICALLY CONTROLLED RELEASE SYSTEMS : OSMOTICALLY CONTROLLED RELEASE SYSTEMS Osmotic system utilize the principle of osmotic pressure for drug delivery Osmotic pressure created due to imbibitions of fluid from external environment into the dosage form regulates the delivery of drug from osmotic device OSMOTICALLY CONTROLLED RELEASE SYSTEMS : OSMOTICALLY CONTROLLED RELEASE SYSTEMS The drug is either mixed with the osmotic agent or located in a reservoir The rate of release drug in these products is determined by constant inflow of water across the semi-permeable membrane into resevior which contain osmotic agentOSMOTICALLY CONTROLLED RELEASE SYSTEMS: OSMOTICALLY CONTROLLED RELEASE SYSTEMS The dosage form contain a small hole from which the dissolved drug moves out due to osmotic pressure The rate of release of drug is constant and can be modified by altering the osmotic agent and the size of the hole Water penetration controlled system : Water penetration controlled system OSMOTICALLY CONTROLLED RELEASE SYSTEMS Drugs generally incorporated has short half-life(2-6hr),highly potent, and requires prolonged treatment ex: nifedipine , glipizide,verapamil . Semi-permeable membrane usually made from cellulose acetate. Osmotic agents: HPM, CMC, MC, PVP . KCL,NACL.PowerPoint Presentation: Elementary osmotic pumpPowerPoint Presentation: Examples: Adalat oros(nifidepine) Procardia XL(nifidepine) Glucotrol XL(glipizide)Advantages of osmotic controlled release system:- : Advantages of osmotic controlled release system:- 1. They typically give a zero order release profile after an initial lag. 2. Deliveries may be delayed or pulsed if desired. 3. Drug release is independent of gastric pH 4. The release mechanisms are not dependent on drug. 5. A high degree of in-vitro and in vivo correlationOSMOTICALLY CONTROLLED RELEASE SYSTEMS: OSMOTICALLY CONTROLLED RELEASE SYSTEMS Disadvantages:- 1 Costly 2. If the coating process is not well controlled there is a risk of film defects, which results in dose dumping 3. Size of hole is criticalChemically controlled system : Chemically controlled system chemically controlled release systems are the systems that change their chemical structure, when exposed to biological fluid. When the biodegradable polymer is exposed to water hydrolysis occurs Hydrolysis degrades the large polymers into smaller biocompatible compounds It is of two types and they are Erodible systems Pendent chain systemErodible systems: Erodible systems In erodible systems, the mechanism of drug release occurs by erosion. Erosion may be two types and they are a) Bulk erosion process b) Surface erosion processBulk erosion : Bulk erosion Bulk erosion occur throughout the polymer & process is also called as homogenous erosion Bulk erosion occur when the water is readily able to penetrate the matrix of the device (e.g. poly lactide , polyglycolic acid)Surface erosion : Surface erosion Surface erosion occurs from the surface layer of the device only Surface erosion occurs when water penetration is restricted to device Note these polymer do not swell. (e.g., polyanhydrides )PowerPoint Presentation: “a” indicates bulk erosion “b” indicates surface erosionPendent chain systems: Pendent chain systems Pendent chain systems consists of linear homo or copolymers with the drug attached to the backbone chains. The drug is released from the polymer by hydrolysis or enzymatic degradation of the linkages. Zero order can be obtained and the cleavage of the drug is the rate controlling mechanism. Eg:- for polymers used in pendent chain systems is n-(2-hydroxy propyl) methacrylamide etc.Hydrogels: Hydrogels Hydrogels are water swollen three dimensional structures composed of primarily hydrophilic polymers. They are rendered insoluble because of chemical or physical cross-links. the physical cross-links include crystallites, entanglements or weak associations like hydrogen bonds or vander waals forces. these cross-links provide the physical integrity and network structure.Hydrogels: Hydrogels Hydrogels provide desirable protection of labile drugs, peptides and proteins. Because of their nature , hydrogels can be used in many different types of controlled release systems. These systems are classified according to the mechanism controlling the release of the drug from the devicePowerPoint Presentation: They are classified as follows a) Diffusion controlled systems b) Swelling-controlled systems c) Chemically controlled systemsIon exchange resins: Ion exchange resins drug release characters depends on the ionic state of the environment when a drug is contained in a resin Thus in case of oral administration the drug release is determined by the ionic environment of GIT This principle can be conveniently applied to sustained the release of the drug using ion exchange resinIon exchange resins: Ion exchange resins Resins are water insoluble materials containing anionic or cationic groups in repeating positions on the resin chain This systems are designed to provide the controlled release of an ionic (or ionizable ) drug .Ion exchange resins: Ion exchange resins It is prepared by first absorbing an ionized drug onto the ion-exchange resin granules such as codeine base with Amberlite , and then after filtration from the alcoholic medium, coating the drug resin complex granules with a water permeable polymer e.g. a modified copolymer of polyacrylic and methacrylic ester.Cationic drugs: Cationic drugs A cationic drug forms a complex with an anionic ion-exchange resin e.g. a resin with a SO 3 - group . In the G.I tract Hydronium ion (H + ) in the gastrointestinal fluid penetrates the system and activity the release of cationic drug from the drug resin complex. H + + Resin – SO 3 - Drug + Resin – SO 3 - H + +Drug + .Anionic drugs: Anionic drugs An anionic drug forms a complex with a cationic ion exchange resin, e.g. a resin with a [N (CH 3 ) 3 + ] group. In the GI tract , the Chloride ion ( Cl - ) in the gastrointestinal fluid penetrates the system and activates the release of anionic drug from the drug resin complex. Cl - + Resin –[N (CH 3 ) 3 + ] Drug- Resin –[NCH 3 ) 3 + ] Cl - + Drug-Ion exchange resins: Ion exchange resins Example of ion-exchange resin type of product are duromine (basic drug phenteramine )conclusion: conclusion The controlled release technologies can modulate release profiles to achieve dosing that enhance patient outcome & safety. Oral controlled release systems are in high demand as of today. This is simply because of commercial aim of pharmaceutical companies are now aiming to improve productivity & lower the risks associated with new drug candidates.References: References Advances in drug delivery by Y.madhusudan rao & AV Jithan Controlled drug delivery by joseph R.Robinson Controlled drug delivery by S.p Vyas Bio pharmaceutics & pharmacokinetics by D.M Brahmankar Review articles from IJPPS & IJPSR You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.