Controlled Release Oral Drug Delivery System

1. Controlled Release Oral Drug Delivery System Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Professor of Pharmaceutics Department of Pharmaceutics JN Medical College KEL University, Belgaum- 590010, Karnataka, India E-mail: bknanjwade@yahoo.co.in Cell No: 00919742431000

2. Contents • Overview of Digestive system • Introduction • Advantages • Disadvantages • Mechanisms 1.Dissolution 2.Diffusion 3.Combination of Dissolution & Diffusion 4.Osmotic pressure controlled system • References Nepal Pharmaceutical Ltd., Nepal

3. Digestive System Nepal Pharmaceutical Ltd., Nepal

4. Concept • Controlled drug delivery is one which delivers the drug at a predetermined rate, for locally or systemically, for a specified period of time. • Continuous oral delivery of drugs at predictable & reproducible kinetics for predetermined period throughout the course of GIT. Nepal Pharmaceutical Ltd., Nepal

5. Plasma concentration time profile Nepal Pharmaceutical Ltd., Nepal

6. Challenges in Oral Drug Delivery • Development of drug delivery systemDelivering a drug at therapeutically effective rate to desirable site. • Modulation of GI transit timeTransportation of drug to target site. • Minimization of first pass elimination Nepal Pharmaceutical Ltd., Nepal

7. Advantages • Total dose is low. • Reduced GI side effects. • Reduced dosing frequency. • Better patient acceptance and compliance. • Less fluctuation at plasma drug levels. • More uniform drug effect • Improved efficacy/safety ratio. Nepal Pharmaceutical Ltd., Nepal

8. Disadvantages • Dose dumping. • Reduced potential for accurate dose adjustment. • Need of additional patient education. • Stability problem. Nepal Pharmaceutical Ltd., Nepal

9. Mechanism aspects of Oral drug delivery formulation 1.Dissolution :1.Matrix 2.Encapsulation 2.Diffusion :1.Matrix 2.Reservoir 3.Combination of both dissolution & diffusion. 4.Osmotic pressure controlled system Nepal Pharmaceutical Ltd., Nepal

10. 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. Nepal Pharmaceutical Ltd., Nepal

11. Noyes Whitney Equation dc/dt = kD.A (Cs – C ) dc/dt = D/h A. (Cs – C) dc/dt = Dissolution rate. k= Dissolution rate constant (1st 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. Nepal Pharmaceutical Ltd., Nepal

12. 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 Nepal Pharmaceutical Ltd., Nepal

13. 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 Nepal Pharmaceutical Ltd., Nepal

14. 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. Nepal Pharmaceutical Ltd., Nepal

15. 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 Nepal Pharmaceutical Ltd., Nepal

16. Matrix system Rate controlling step: Diffusion of dissolved drug in matrix. Nepal Pharmaceutical Ltd., Nepal

17. 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. Nepal Pharmaceutical Ltd., Nepal

18. 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 Nepal Pharmaceutical Ltd., Nepal

19. Reservoir System Rate controlling steps : Polymeric content in coating, thickness of coating, hardness of microcapsule. Nepal Pharmaceutical Ltd., Nepal

20. 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 Entry of dissolution fluid Drug diffusion Pore created by dissolution of soluble fraction of membrane Nepal Pharmaceutical Ltd., Nepal

21. Osmotic Pressure Controlled Drug Delivery System • Definition • Procedure • Diagram • Modifications Nepal Pharmaceutical Ltd., Nepal

22. 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 asemipermeable membrane due to difference in concentration of solutes. Nepal Pharmaceutical Ltd., Nepal

23. 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, Nepal Pharmaceutical Ltd., Nepal

24. Equation (Q/t) z = Pw Am/ hm (πs-πe ) (Q/t)= Rate of zero order drug release. Pw, Am & hm= water permeability, effective surface area & thickness of semipermeable membrane. πs= osmotic pressure of saturated solution of osmotically active drug or salt in system. πe = osmotic pressure of GI fluid. Nepal Pharmaceutical Ltd., Nepal

25. Osmotic Pressure Controlled System Nepal Pharmaceutical Ltd., Nepal

26. Osmotic Pressure Controlled System Nepal Pharmaceutical Ltd., Nepal

27. Modifications - Immediate release system. - Osmotically active compartment system

28. 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. Nepal Pharmaceutical Ltd., Nepal

29. 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. Delivery orifice Drug compartment Movable partition Osmotically active compartment Nepal Pharmaceutical Ltd., Nepal

30. 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 ) Nepal Pharmaceutical Ltd., Nepal

31. Some Examples of OCDDS • Propranolol (Inderal LA) • Methyiphenidate HCl (RitalinSR) • Iron (Slow-Fe) • GITS-Prazosin (Minipress) • Morphine sulfate (Roxanol SR) • Decongestant & antihistamine (Resaid SR, Novafed SR Dristan) • Pseudoephedrine HCI (Sudafed SA) • Potassium (Micro-K, Slow-K, Klotrix) • Antitussive combinations (Rescap, Ornade Spansules) • Chlorpheniramine maleate (ChlorTrimeton) • Decongestant, antihistamine and anticholinergic (Dallergy, Supres) Nepal Pharmaceutical Ltd., Nepal

32. Recent Trends : Extended release formulation of Bupropion • Bupropion is used in the treatment of major depressive disorder. • Conventional formulation has to be administered 3 times daily • Initially 150 mg ER formulation was introduced for bid regimen Later on 300 mg ER formulation was introduced for once daily regimen • For ER formulation provide similar Cmax and AUC values as compared to immediate release formulation at steady state. Nepal Pharmaceutical Ltd., Nepal

33. Recent Trends : Extended release formulation of Bupropion Nepal Pharmaceutical Ltd., Nepal

34. Recent Trends: OROS Technology (ALZA corporation) ELEMENTARY OSMOTIC PUMP • Single layer tablet: Drug core (water soluble drug with or without excipients) • Semipermeable membrane with a drilled orifice • Water imbibition by the core because of osmotic action results in drug dissolution, which is released at a controlled rate through the orifice • Not suitable for water insoluble drugs. • Examples: Sudafed 24 hours (Pseudoephedrine); Volmax (Salbutamol) Nepal Pharmaceutical Ltd., Nepal

35. Recent trends: Geomatrix® (SKY Parma) Products in market: Cordicant -uno® Madopar DR SULAR ER • This technology Controls amount, timing and location of release in body. • -Formulation with predictable and • reproducible drug release profile. • Controls rate of drug diffusion • throughout release process, • ensuring 100% release Products Nepal Pharmaceutical Ltd., Nepal

36. References • Novel drug delivery system , volume 50, Y.W.Chien • The theory & practice of industrial pharmacy, Leon Lachman , Herbert A.Lieberman, Joseph L.Kanig,3 rd edition. • The Eastern pharmacist, november 1993. Sustained release drugs, V R.Gudsoorkar & D.Rambhau page 27-32 • Biopharmaceuitics & pharmacokinetics, D M.Brahmankar & Sunil B. Jaiswal. www.google.com Nepal Pharmaceutical Ltd., Nepal

37. Thank you for listening me……… Nepal Pharmaceutical Ltd., Nepal