logging in or signing up Rational design of oral modified-release drug delivery systems keerthi09 Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: Embed: Flash iPad Dynamic Copy Does not support media & animations Automatically changes to Flash or non-Flash embed WordPress Embed Customize Embed URL: Copy Thumbnail: Copy The presentation is successfully added In Your Favorites. Views: 1444 Category: Science & Tech.. License: All Rights Reserved Like it (0) Dislike it (0) Added: October 20, 2010 This Presentation is Public Favorites: 0 Presentation Description No description available. Comments Posting comment... By: quizking (31 month(s) ago) Its a extreamly gud powerpoint. so plz send a copy of the same to me on firstname.lastname@example.org Saving..... Post Reply Close Saving..... 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Introduction : Introduction Drug release modification is a technique or approach by which the delivery pattern of a therapeutic agent is altered via engineering of physical, chemical, and /or biological components into delivery systems for achieving desired/target plasma drug levels defined by clinical pharmacology. Common modes of oral MR delivery include: 1.Delayed release (eg., Using enteric coating) 2.Site specific or timed release (eg., for colonic delivery) 3.extended-relese (eg.., zero-order, first order biphasic release, etc) 4.Programmed release (eg., pulsatile, delayed-extended-release, etc) Oral modified release technologies and drug delivery systems : Oral modified release technologies and drug delivery systems Common-oral modified release systems Matrix systems Reservoir polymeric systems Osmotic pump systems Enteric release Colonic release Pulsatile release Biomodal release Rational design of modified-Release systems : Rational design of modified-Release systems The ability to achieve the desired in vitro and in vivo performance is dependent on • The dose • Physico-chemical • Biopharmaceutical • Pharmacokinetic • Pharmacodynamic... properties of the drug • Proper selection of a delivery technology • Formulation design Slide 7: The successful dosage form • Is dictated by the properties of the compound rather than by the technology platform • All MR products with expired composition of matter patents have been unable to maintain market exclusivity solely based on delivery technology • Performance of the branded products has been matched by their generic counterparts based on similar or different technologies e.g. Procardia XL,Cardizem CD, Concerta, Adalat CC, Wellbutrin XL, Ditropan XL, Glucotrol XL, Glucophage XR, Asacol, Toprol XL etc Slide 8: Stages of designing of MR system 1. to integrate a clinical rationale with the characteristics of the drug for Feasibility evaluation 2. to select an appropriate MR technology Slide 9: Rational design process include: 1. Identify the clinical need and define in vivo target product profile. 2. Conduct a feasibility study through experiments and detailed analysis to assess technical challenges and risk associated with MR delivery based on: a) Characterisation of the molecule with regard to its physico-chemical and biopharmaceutical properties, dose, regional absorption and in vivo disposition b) Pharmacokinetic simulation to prospectively calculate theoretical drug input rate that corresponds to the desired target plasma profile, based on in vivo disposition parameters and certain assumptions. Slide 10: Rational design process 3. If feasible, select an appropriate MR technology and invitro test methods to design and evaluate formulations with different release rates in vitro 4. Test prototype formulations with profiles that bracket the theoretical target absorption profile in vivo in order to: a) Identify a formulation with acceptable in vivo performance or a direction of formulation refinement if iteration is required b) Explore the in vitro – in vivo relationship (IVIVR) or correlation (IVIVC) to aid product development or subsequent rounds of formulation iteration Slide 11: Identification of the clinical need • According to EMEA, development of MR products should be based on a relationship between the pharmacological/toxicological response and the systemic exposure to the drug/metabolites • Usually more emphasis on reducing the dosing frequency or fluctuation of Plasma concentration Slide 12: Identification of the clinical need • Nifedipine: impact of input rate on the efficacy and safety ratio • Rate of increase of nifedipine concentration, rather than aboslute concentration is the dermining factor for the observed haemodynamic effects • Gradual decrease in blood pressure was observed without side-effects (increase in heart rate) with a slow regimen, rapid regimen showed the opposite • It is important to understand the PK-PD relationships to define in vivo target product profile and to make the decision in MR product development Slide 13: Feasibility study • Once the delivery mode and in vivo target product profile are defined and disposition parameters are available, the corresponding theoretical input profile can be obtained by prospective PK simulation e.g. Via adjusting input rate and kinetics to generate in vivo PK profiles or by deconvolution of the target plasma profile • Plasma levels of the MR design should be constantly above the MEC over the dosing interval. when the PKPD data is unavailable, the steady state Cmin of the clinically effective IR counterpart may be used as an estimate of MEC. Slide 14: Feasibility • To evaluate the feasibility of the designed delivery in GI tract • To understand absorption characteristics of the drug in the lower GI tract is crucial to the rational design of an MR dosage form In order to assess technical feasibility and development challenges: • Integrate the physicochemical and biopharmaceutical properties into the context of the total dose, physiological/biological constraints and disposition kinetics Slide 15: Key properties of the drug • Solubility • Lipophilicity • Chemical stability (in GI tract) • Regional permeability (adults/children have different transit times) • Gamma scintigraphic studies, animal models, capsule systems • Gut and hepatic first-pass metabolism, elimination half-life • Therapeutic window and MEC • Whether or not the drug is a substrate of transporters • Susceptibility of the drug to metabolism by gut microflora • PK-PD relationship Slide 16: Selecting the modified-release system • Drug properties (especially solubility) • Dose • Types of delivery profiles • Market needs • Development time • Cost • Commercial production factors (process, equipment, facility, manufacturability, robustness, cost, capacity, environment) Choice of system based on dose and solubility : Choice of system based on dose and solubility Slide 18: Rational product development of MR solid oral dosage forms 1. Preformulation investigation 2. Formulation and process studies 3. In vivo performance evaluation in order to produce high quality, solid product with predefined delivery and pharmacokinetic performance Slide 19: Target product profile • Target PK profile Strength Type Size Drug loading Quality/performance attributes Commercial need IP matters Slide 20: Preformulation investigations • Physicochemical, biopharmaceutical and mechanical properties and compatibility • Quality attributes of the drug substance and excipients are determined • Process feasibility and options should be evaluated Slide 21: Preformulation studies • pH dependent solubility • Degradation in different pH • Solid state characterisation Dosage form development : Dosage form development Slide 23: Choice of manufacturing process • Appropriate manufacturing process should be selected (same delivery systemcan be produced with different methods) • Technological (available technologies and their maturity, process complexity, robustness, scale up challenges, manufacturability and control) • Economical (development cost and time, commercial production efficiency, cost and capacity) • Practical considerations (available equipment, facility and environmental impact) Slide 24: Possible manufacturing processes • Pellets • Extrusion-spheronisation • Drug layering on non-pareil seeds • Spray granulation/spray drying • Spray congealing • Coating • Pan coater • Fluid bed • Compression coating Slide 25: Intellectual property considerations • IP portfolio created in developing dosage forms (MR) is a key strategic element in extending product lifecycle • Robust IP portfolio should be built on continuous development and review of both inhouse and in-licensed opportunities Slide 26: Patentable subject matters • Modifications of structure: new solid phases, salts • Formulation (composition, technology, particle size) • Method of treatment (route of delivery, dosing regimen) • Process • Methods of improving bioavailability with overcoming stability problems • Newly discovered clinical benefits (decreased adverse events, new indication) • Performance (drug release profiles, PK/PD outcomes Slide 27: References • Qiu Y, Chen Y, Zhang, G.G.Z., Developing solid oral dosage forms – pharmaceutical theory and practice, American Press. 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