Controlled drug delivery system part II
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The document discusses various approaches to designing controlled release drug delivery systems (CRDDS) based on principles like diffusion, dissolution, and ion exchange. It classifies CRDDS into categories such as rate programmed systems, stimuli-activated systems, and site-targeted systems, each with distinct mechanisms for drug release. Additionally, it elaborates on the components and classifications of these systems, including the advantages and disadvantages of using ion-exchange resins in drug formulations.
Controlled drug delivery system part II
- 1. Approaches to design controlled release formulations based on Diffusion, Dissolution and Ion exchange principles PART - II
- 2. Different approaches for CRDDS • Chemical Approach • Biological approach • Pharmaceutical approach Classification CRDDS can be classified into 1. On the basis of technical sophistication 2. On the basis of route of administration On the basis of technical sophistication 1. Rate programmed DDS 2. Stimuli-activated DDS 3. Site-targeted DDS 4. Feedback-regulated DDS • The drug • The rate controlling element • Energy source that activates the DDS 3 major components
- 3. 1. Rate programmed DDS The release of drug molecules from the delivery systems has been preprogrammed at specific rate profiles 2. Stimuli-activated DDS / Activation modulated DDS The release of drug molecules from the delivery system is activated by some physical, chemical or biochemical processes and/or facilitated by the energy supplied externally. Then the rate of drug release is then controlled by regulating the process applied or energy input 3. Site-targeted DDS It is constructed from a biodegradable polymer backbone having 3 types of attached functional groups • A site-specific targeting moiety that leads the DDS to the vicinity of a target tissue • A solubilizer that enables the DDS to be transported to and preferentially taken up by a target tissue • A drug moiety that is covalently bonded to the polymer backbone through a spacer and contains a cleavable group that can be cleaved only by a specific enzymes at the target tissue 4. Feedback-regulated DDS The release of drug molecules from the delivery system is activated by a triggering agent, such as a biochemical substance in the body and regulated by concentration of triggering agent detected by a sensor in via the feedback-regulated mechanism a. Bioerosion-regulated DDS b. Bioresponsive DDS c. Self-regulating DDS
- 4. Major classes of controlled release drug delivery system
- 5. 1. Rate programmed DDS (Classification of CDDS with reference to release control or mode of drug release ) • Diffusion controlled drug delivery system • Dissolution controlled drug delivery system • Erosion controlled drug delivery system • Combination of dissolution, diffusion and/or erosion controlled drug delivery system 2. Stimuli activated DDS / Smart DDS A. Activation by physical process • Pressure activated DDS • Magnetically activated DDS • Mechanical force activated DDS • Electrically activated DDS • Thermally activated DDS • Photo activated DDS B. Activation by chemical process • pH activated DDS • Ion-activated DDS • Hydrolysis activated DDS • Chelation activated DDS C. Activation by biological systems • Enzyme activated DDS • Antibody interaction- activated DDS • Antigen activated DDS • Inflammation activated DDS
- 7. Rate-programmed DDS These DDS are those from which the drug release has been programmed at specific rate profiles These systems can be designed into • Reservoir systems (membrane-controlled system) • Matrix systems (monolithic- soluble/ erodible/ Swellable/degradable systems) • Hybrid systems (membrane-cum-matrix system) Hybrid system Matrix system Reservoir system • Swellable film • Non- Swellable film (porous) • Hydrophilic Swellable Free swelling Restricted swelling Swellable and erodible • Hydrophobic Erodible Non-Erodible Porous Non-porous Dissolved drug Dispersed drug
- 8. Matrix system • In which the drug is uniformly dissolved or dispersed in a release retarding material • Depending upon the physical properties of the matrix, two types of devices are possible Hydrophilic matrix – • These are porous systems • Release retarding material is water-swellable or swellable and erodible hydrocolloid Ex: High molecular weight HPMCs, HPC, HEC, Xanthan gum, Sodium alginate, Guar gum, Polyethylene oxide and cross-linked polymers of acrylic acid Depending upon the swelling behaviour of hydrophilic polymer, 2 types of matrices are possible Free-swelling matrix: in which polymer swelling is unhindered Restricted-swelling matrix: in which the surface of the device is partially coated with an impermeable polymer film that restricts the hydration of swellable matrix material
- 9. Hydrophobic matrix Release-retarding material is either • Slowly soluble, erodible or digestible Ex: waxes such as glyceryl monostearate, cetyl alcohol, hydrogenated vegetable oils, beeswax, carnauba wax • Insoluble or non-digestible Ex: ethyl cellulose, polymethacrylates Depending upon the manner of incorporation of drug in the matrix, they can be classified into • Porous matrix (heterogeneous) –Release pattern: Higuchis theory In which the drug and release retarding matrix micro particles are simply mixed with each other and compressed into a tablet or The drug is dispersed in the polymer solution followed by evaporation of the solvent • Non-porous matrix (homogenous) In which the release retarding material is first melted and the drug is then incorporated in it by thorough mixing followed by congealing the mass while stirring Dissolved drug non-porous system- drug is dissolved in the molten release retarding matrix material Release pattern: Fick's Second Law Dispersed drug non-porous system-the quantity of the drug is greater than its solubility in molten matrix polymer Release pattern: Fick's First Law
- 10. Hybrid system In which the drug in matrix of release retarding material is further coated with a release controlling polymer membrane. Hence this device combines the constant release kinetics of reservoir system with the mechanical robustness of matrix system Reservoir system In which the drug is present as a core in a compartment of specific shape encased/encapsulated within a rate controlling wall, film or membrane having a well-defined thickness The drug in the core must dissociate from the crystal lattice and dissolve in the surrounding medium, partition and diffuse through the membrane Depending upon the physical properties of the membrane, 2 types of reservoir system exists Non-swelling reservoir system These reservoir type is more common It includes coated drug particles, crystals, granules, pellets, mini-tablets and tablets In which the polymer membrane does not swell or hydrate in an aqueous medium. These materials control drug release owing to their thickness, insolubility or slow dissolution or porosity Ex: ethyl cellulose and polymethacrylates Swelling-controlled reservoir system In which the polymer membrane swells or hydrates upon contact with aqueous medium, so drug release is delayed for the time period required for hydration of barrier and after attaining this, drug release proceeds at a constant rate
- 11. 1. Diffusion controlled drug delivery system Rate controlling step: diffusion of dissolved drug molecule through the rate-controlling element Depending upon the mechanism by which the rate controlling element controls drug diffusion a. Porous matrix-controlled diffusion system Design- Matrix system: In which rate of release is controlled by diffusion of dissolved drug in the matrix, In which rate controlling element is either a Non-swellable water insoluble polymer • Porous • Hydrophobic matrix • Hydrophobic polymers like ethyl cellulose, polymethacrylates • Mechanism: controls drug release through the micropores present in their matrix structure • Porous matrix: In which the drug and release retarding matrix micro particles are simply mixed with each other and compressed into a tablet or the drug is dispersed in the polymer solution followed by evaporation of the solvent
- 12. Water swellable material • Porous • Hydrophilic matrix • Hydrophilic polymers and gums like guar gum, tragacanth, HPMC, HPC, CMC, alginates & Xanthan Gum • Mechanism: Free-swelling matrix: in which polymer swelling is unhindered or Restricted-swelling matrix: in which the surface of the device is partially coated with an impermeable polymer film that restricts the hydration of swellable matrix material
- 13. CONCLUSION
- 15. b. Porous membrane-controlled diffusion system Design- Reservoir System: In which polymer content in coating, thickness of coating & hardness of micro‐capsules control the release of the drug In which the rate controlling element is a Non-swellable water-insoluble polymer • Porous • Hydrophobic polymer membrane • Ex: Ethylcellulose and Polymethacrylate which controls drug release through the micropores present in their membrane • Mechanism: In which the polymer membrane does not swell or hydrate in an aqueous medium. The drug in the core must dissociate from the crystal lattice and dissolve in the surrounding medium, partition and diffuse through the membrane
- 18. 2. Dissolution controlled drug delivery system In which drug is homogeneously dispersed and rate limiting phenomenon responsible for imparting the controlled release characteristics to the DDS is either of a. Drug- Dissolution controlled (Slow dissolution rate of the drug) The drug present in this system may be • Drug with inherently slow dissolution rate Act as natural prolonged release products Ex: Griseofulvin, Digoxin and Nifedipine • Drug that transforms into a slow dissolving form- upon contact with GI fluids Ex: Ferrous sulphate
- 19. b. Polymer-Dissolution controlled (Slow dissolution rate of the reservoir membrane or matrix) The drug present in this system may be the one having high aqueous solubility and dissolution rate Ex: Pentoxifylline and metformin • Embedment in slowly dissolving, degrading or erodible matrix Matrix have low porosity or poor wettability The drug is homogeneously dispersed throughout a rate controlling medium They employ waxes such as beeswax, carnauba wax, hydrogenated castor oil etc which control drug dissolution by controlling the rate of dissolution fluid penetration into the matrix by altering the porosity of tablet, decreasing its wettability or by itself getting dissolved at a slower rate The drug release is often first order from such matrices The wax embedded drug is generally prepared by dispersing the drug in molten wax and solidifying and granulating the same
- 21. • Encapsulation or Coating with slow-dissolving, degrading or erodible substances The rate of dissolution fluid penetration or wettability of the reservoir system are controlled. The drug particles are coated or encapsulated by microencapsulation techniques with slowly dissolving materials like cellulose, poly ethylene glycols, polymethacrylates, waxes etc. The dissolution rate of coat depends upon the solubility and thickness of the coating. Those with the thinnest layers will provide the initial dose. The maintenance of drug levels at late times will be achieved from those with thicker coating.
- 24. Slowly soluble and erodible materials • Hydrophobic substances Ethyl cellulose (containing an added water-soluble release modifying agent such as PVP) Polymethacrylates with pH independent solubility (ex: Eudragit RS and RL 100) Waxes such as Glyceryl monostearate • Hydrophilic materials Ex: Sodium CMC Dissolution-controlled release can be obtained by slowing the dissolution rate of a drug in the GI medium, incorporating the drug in an insoluble polymer and coating drug particles or granules with polymeric materials of varying thickness The rate limiting step for dissolution of a drug is the diffusion across the aqueous boundary layer. The solubility of the drug provides the source of energy for drug release, which is countered by the stagnant-fluid diffusional boundary layer. The rate of dissolution can be approximated by Noyes Whitney's Equation
- 27. Microreservoir Dissolution-Controlled Drug Delivery System • An approach to achieve a constant drug release profile from a matrix- type drug delivery system • These are composed of a homogenous dispersion of numerous microscopic spheres (<30µm) of drug suspension in a solid polymer matrix • These drug-containing spheres exist homogenously throughout the cross- linked polymer matrix as a discrete, immobilized, unleachable liquid compartment • The drug molecules can elute out of the MDD only by; first dissolution in the liquid compartment and partitioning into and diffusion through the polymer matrix, and then partitioning into the surrounding elution solution A cross-section of MDDS. The microscopic liquid compartments, which encapsulate drug particles, are homogenously dispersed as discrete, immobilized, unleachable spheres (with diameter ≤30µm) in a cross- linked polymer matrix. D,P and h are the diffusivity, permeability and thickness respectively. The subscripts p, m and d denote the polymer matrix, polymer coating membrane and diffusion layer respectively
- 28. 3. Dissolution and Diffusion Controlled Release Systems The drug core is enclosed in a partially soluble membrane. Pores are thus created due to dissolution of parts of the membrane which permit entry of aqueous medium into the core and hence drug dissolution and diffusion of dissolved drug out of the system. An example of obtaining such a coating is using a mixture of ethyl cellulose with poly vinyl pyrrolidiene or methylcellulose
- 29. Category: Stimuli-activated Drug Delivery System Sub-category: Activation by chemical process Definition: Ion exchange resins are cross-linked insoluble polymers carrying ionizable functional groups and have the ability to exchange counter-ions within aqueous solutions surrounding them The ion exchange resins are complexed with drug to form resinates by batch or column process. Microencapsulated resinates provides better control over the drug release because of the rate controlling membrane The formulations are developed by embedding the drug molecules in the ion- exchange resin matrix and this core is then coated with a semi-permeable coating material such as ethyl cellulose This system reduces the degradation of drug in the GIT The most widely used and safe ion-exchange resin is Divinylbenzene sulphonate 4. Ion-Exchange Drug Delivery System
- 30. Advantages • Ion-exchange resinates of drugs can help in reducing the dose • Reduced fluctuations in blood and tissue concentrations and maintenance of drug concentration below toxic level can be achieved • Use of ion exchange resins into drug delivery systems have been encouraged because of their physico-chemical stability, inert nature, uniform size, spherical shape assisting coating and equilibrium driven reproducible drug release in ionic environment • Advantageous for the drugs that are highly susceptible to degradation by enzymatic process • Effectively useful in low concentration (5-20%w/w) • Resins have high drug loading capacity • Economic and readily available • Free from local and systemic toxicities Disadvantages • Release rate is proportional to the concentration of the ions present in the area of administration • Release rate of drug can be affected by variability in diet, water intake and individual intestinal content
- 31. Drugs to be formulated into resinates, • Should have in their chemical structure acidic or basic groups • Biological half life should be between the ranges of 2 to 6 hours, drugs with t1/2 < 1hr or > 8hrs are difficult to formulate • It should be well absorbed from all the areas of the gastrointestinal tract • Drugs should be stable sufficiently in the gastric juice Drugs Suitable for Resinate Preparation
- 32. • Cation exchange resins contain covalently bond negatively charged functional groups and exchanges positively charged ions • Anionic exchange resins have positively charged functional groups and it exchange negatively charged ions Acid base strength: The acid base strength of an exchange is dependent on various ionogenic groups, incorporated into the resin • Resin containing sulfonic, phosphonic or carboxylic acid (as an integral part of the resin) exchange groups have approximate pKa values of 1, 2-3 and 4-6 respectively- Cationic- exchangers • Anionic-exchangers are quaternary, tertiary or secondary ammonium groups having apparent pKa values of greater than 13, 7-9 or 5-9 respectively The pKa value of the resin will have a significant influence on the rate at which the drug will be released from resinates in the gastric fluid
- 34. Mechanism and Principle • Anion exchange resins involve basic functional groups capable of removing anions from acidic solutions while Cation exchange resins contain acidic functional group, capable of removing cations from basic solutions • The use of IER to prolong the effect of drug release is based on the principle that positively or negatively charged pharmaceuticals, combined with appropriate resins to yield insoluble polysalt resinates In The Stomach: 1) Drug resinate + HCl ↔ acidic resin + drug hydrochloride 2) Resin salt + HCl ↔ resin chloride + acidic drug In The Intestine: 1) Drug resinate + NaCl ↔ sodium resinate + drug hydrochloride 2) Resin salt + NaCl ↔ resin chloride + sodium salt of drug
- 35. Cross-sectional view of an ion-activated DDS
- 36. Pharmaceutical Applications of Ion-Exchange Resin
- 48. Comparison between Conventional and Controlled release system
- 49. Parameters to be considered while designing into CRDDS