Controlled Release Oral Drug Delivery System

1. Controlled Release Oral Drug Delivery System Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D. Dept of Pharmaceutics KLE University College of Pharmacy Belgaum-590010, karnataka, India Cell No: 00919742431000 E-mail: nanjwadebk@gmail.com KLE College of Pharmacy, Nipani.

2. Contents • Overview of Digestive system • Introduction • Advantages • Disadvantages • Dissolution • Diffusion • Combination of Dissolution & Diffusion • Osmotic pressure controlled system • Hydrodynamically balanced systems • pH controlled • Ion exchange controlled systems • References KLE College of Pharmacy, Nipani.

3. 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. KLE College of Pharmacy, Nipani.

4. Controlled Release System Diffusion controlled Matrix Dissolution controlled Matrix Encapsulation Reservoir Reservoir and monolithic Diffusion and dissolution Controlled Release System Chemically controlled Water penetration contrelled Ion-exchange resin hydrogels KLE College of Pharmacy, Nipani.

5. Plasma concentration time profile KLE College of Pharmacy, Nipani.

6. Challenges in Oral Drug Delivery • Development of drug delivery systemDelivering 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 KLE College of Pharmacy, Nipani.

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. KLE College of Pharmacy, Nipani.

8. Disadvantages • Dose dumping. • Reduced potential for accurate dose adjustment. • Need of additional patient education. • Stability problem. KLE College of Pharmacy, Nipani.

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 KLE College of Pharmacy, Nipani.

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. KLE College of Pharmacy, Nipani.

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. KLE College of Pharmacy, Nipani.

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. • Eg. Dimetane extencaps, Dimetapp extentabs. Soluble drug Slowly dissolving matrix KLE College of Pharmacy, Nipani.

13. Matrix devices • In this system the solid drug dispersed in to the insoluble matrix. KLE College of Pharmacy, Nipani.

14. 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. • Eg. Ornade spansules, Chlortrimeton Repetabs Soluble drug Slowly dissolving or erodible coat KLE College of Pharmacy, Nipani.

15. 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. KLE College of Pharmacy, Nipani.

16. 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 KLE College of Pharmacy, Nipani.

17. Matrix system Rate controlling step: Diffusion of dissolved drug in matrix. KLE College of Pharmacy, Nipani.

18. Advantage and Disadvantage of Matrix and Reservoir system Matrix system Reservoir system Degradable reservoir systems may be difficult to design. Rupture can result in dangerous ‘dose dumping’ Achievement of ‘zero order’ release is easy. • Suitable for both non- degradable and degradable system. • No danger of ‘dose dumping’ in case of rupture. • Achievement of ‘zero order’ release is difficult KLE College of Pharmacy, Nipani.

19. Methods to develop the Reservoir devices • Press coating (slowly soluble films and coating) • Air suspension techniques • The microencapsulation process is commonly used procedure • to drug particle incorporated in to tablet or capsule. • In most cases drug is incorporated in coating film as well as in • the microcapsule. • The care should be taken during placement into tablet or • capsule dosage forms to minimize fragmentation or fusion of • the particle both effects will alter release characteristics. KLE College of Pharmacy, Nipani.

20. Factor effecting constant drug release • Polymer ratio in the coating The increase the polymer ratio decrease in drug release due to leaching effect. • Film thickness The drug release rate from an insoluble membrane is expected to increase as the membrane thickness decreases. • Hardness of microcapsule The hardness of microcapsule increase, prolong the time of drug release. KLE College of Pharmacy, Nipani.

21. 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. KLE College of Pharmacy, Nipani.

22. 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 KLE College of Pharmacy, Nipani.

23. Reservoir System Rate controlling steps : Polymeric content in coating, thickness of coating, hardness of microcapsule. KLE College of Pharmacy, Nipani.

24. 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. • Eg. 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 KLE College of Pharmacy, Nipani.

25. Osmotic Pressure Controlled Drug Delivery System KLE College of Pharmacy, Nipani.

26. Introduction • The oral drug delivery has been popular most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs. • The bioavailability of drug from these formulations may vary significantly, depending on factors such as physico-chemical properties of the drug, presence of excipients etc. • The drug release can be modulated by different ways but the most of novel drug delivery systems are prepared using matrix, reservoir or osmotic principle. KLE College of Pharmacy, Nipani.

27. Introduction • Osmotic pressure is used as driving force for these systems to release the drug in controlled manner. Osmotic drug delivery technique is the most interesting and widely acceptable among all other technologies used for the same. • These systems can be used for both route of administration i.e. oral and parenterals. Oral osmotic systems are known as gastro-intestinal therapeutic systems (GITS). KLE College of Pharmacy, Nipani.

28. Principle • Here osmotic pressure is used as the power/source or energy to activate and control the release of drug from the device. In this system, the drug reservoir contains the drug either in the form of solid or as solution, which is enclosed within a semipermiable housing having controlled water permeability. The drug is activated to release in solution form at a constant rate through a special delivery orifice. • The rate of drug release is modulated by controlling the gradient of osmotic pressure.(i.e. differences in osmotic pressure b/w the drug delivery system and the external environment) KLE College of Pharmacy, Nipani.

29. Oral controlled release: Osmotic tablet technology • Once- or twice-daily dosing regimens for crystalline and enhanced-bioavailability drugs is often desired and needed to maximize therapeutic effect, patient safety, and compliance. • Bend Research has developed two proprietary tablet technologies that provide drug release in a predictable, reliable manner. Both dosage forms are driven by osmotic/hydrostatic pressure and provide steady-state, zero-order release that is generally independent of GI pH and agitation. • These attributes minimize patient-to-patient variability and allow accurate prediction of in vivo performance from in vitro dissolution testing. A wide range of release rates is possible. KLE College of Pharmacy, Nipani.

30. Osmotic swellable-core technology • A bi-layer tablet containing an insoluble, semipermeable coating with a delivery orifice • Preferred API and dose: poorly water soluble, or bioavailability-enhanced forms ; low to moderate dose. KLE College of Pharmacy, Nipani.

31. Osmotic asymmetric membrane technology • A single-layer tablet containing an insoluble, asymmetric microporous coating produced by controlled phase separation • Preferred API and dose: water soluble; low to high dose. KLE College of Pharmacy, Nipani.

32. Oral osmotic pumps KLE College of Pharmacy, Nipani.

33. KLE College of Pharmacy, Nipani.

34. Elementary osmotic pump KLE College of Pharmacy, Nipani.

35. Elementary osmotic pump KLE College of Pharmacy, Nipani.

36. Elementary osmotic pump KLE College of Pharmacy, Nipani.

37. Acutrim tablet • It is an oral osmotic pressure controlled G.I. DDS. this systems are fabricated by encapsulating an osmotic drug core containing an osmotically active drug or a combination of an osmotically inactive drug with an osmotically active salt like Nacl, within a semipermiable membrane made from cellulose acetate polymer. • A delivery orifice with a controlled diameter is drilled, using a laser beam, through the coating membrane for controlling the drug release. • The polymer membrane is not only semipermiable in nature but is also rigid & capable of maintaining the structural integrity of the G.I. DDS during the course of drug release. It is permeable to the influx of water in G.I.T. but impermeable to drug solutes. KLE College of Pharmacy, Nipani.

38. Acutrim tablet KLE College of Pharmacy, Nipani.

39. KLE College of Pharmacy, Nipani.

40. Modifications • The external surface of the semipermiable membrane can be coated with a layer of bioerodable polymer like enteric coating, it regulate the penetration of GI fluid through the semipermiable membrane & target the delivery of a drug to the lower region of the GIT. • The coating membrane of the DDS can be constructed from a laminate of two or more semipermiable membranes with differential permeabilities. • The osmotic pressure controlled GI delivery system can be further modified to constitute two compartments separated by a movable partition. The osmotically active compartment absorbs water from GI fluid to creat an osmotic pressure that acts on the partition forces it to move upward and to reduce the volume of the drug reservoir compartment and to release the drug formulation through the delivery orifice . KLE College of Pharmacy, Nipani.

41. Modifications KLE College of Pharmacy, Nipani.

42. Modifications • This system has been applied to the development of a GI-delivery system for the oral controlled delivery of Nifedipine . • Further more, a two compartment GI-delivery system has been applied to the simultaneously GI-controlled delivery of two drugs, such as Oxprenolol sebacinate and Hydralazine HCl, from separate compartment, simultaneously and independently at different delivery rates. KLE College of Pharmacy, Nipani.

43. Push pull osmotic pump • Push pull osmotic pump is a modified EOP. through, which it is possible to deliver both poorly water-soluble and highly water soluble drugs at a constant rate. • This system resembles a standard bilayer coated tablet. One layer (depict as the upper layer) contains drug in a formulation of polymeric, osmotic agent and other tablet excipients. • This polymeric osmotic agent has the ability to form a suspension of drug in situ. When this tablet later imbibes water, the other layer contains osmotic and colouring agents, polymer and tablet excipients. These layer are formed and bonded together by tablet compression to form a single bilayer core. The tablet core is then coated with semipermeable membrane. KLE College of Pharmacy, Nipani.

44. Push pull osmotic pump KLE College of Pharmacy, Nipani.

45. Push pull osmotic pump • After the coating has been applied, a small hole is drilled through the membrane by a laser or mechanical drill on the drug layer side of the tablet. • When the system is placed in aqueous environment water is attracted into the tablet by an osmotic agent in both the layers. The osmotic attraction in the drug layer pulls water into the compartment to form in situ a suspension of drug. • The osmotic agent in the non-drug layer simultaneously attract water into that compartment, causing it to expand volumetrically and the expansion of non drug layer pushes the drug suspension out of the delivery orifice. KLE College of Pharmacy, Nipani.

46. Osmotic pump with non-expanding second chamber • The second category of multi-chamber devices comprises system containing a non-expanding second chamber. This group can be divided into two sub groups, depending on the function of second chamber. • In one category of these devices, the second chamber is used to dilute the drug solution leaving the devices. This is useful because in some cases if the drug leaves the oral osmotic devices in a saturated solution, irritation of GI tract is a risk. KLE College of Pharmacy, Nipani.

47. Osmotic pump with non-expanding second chamber • Example: - The problem that lead to withdrawal of osmosin, the device consist of a normal drug containing porous tablet from which drug is released as a saturated solution. However before the drug can escape from the device it must pass through a second chamber. • Water is also drawn osmotically into this chamber either because of osmotic pressure of drug solution or because the second chamber contain, water soluble diluents such as NaCl. KLE College of Pharmacy, Nipani.

48. Osmotic pump with non-expanding second chamber • This type of devices consist of two rigid chamber, the first chamber contains a biologically inert osmotic agent, such as sugar or a simple salt like sodium chloride, the second chamber contains the drug. In use water is drawn into both the chamber through the surrounding semi permeable membrane. • The solution of osmotic agent formed in the first chamber then passes through the connecting hole to the drug chamber where it mixes with the drug solution before exiting through the micro porous membrane that form a part of wall surrounding the chamber. The device could be used to deliver relatively insoluble drugs. KLE College of Pharmacy, Nipani.

49. Osmotic bursting pump • This system is similar to an EOP except delivery orifice is absent and size may be smaller. When it is placed in an aqueous environment, water is imbibed and hydraulic pressure is built up inside until the wall rupture and the content are released to the environment. • Varying the thickness as well as the area the semipermeable membrane can control release of drug. This system is useful to provide pulsated release. KLE College of Pharmacy, Nipani.

50. Controlled Porosity Osmotic Pumps • In this type two layers of membrane are applied on pumps . • The inner is microporous membrane, which is made up of cellulosic material containing some pore forming agents. A semipermeable membrane cover this layer. • When the system is placed in an aqueous environment the soluble components of first layer of coating dissolve, resulting in a microporous , which provides greater flux of water into the system. KLE College of Pharmacy, Nipani.