Drug delivery

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  • 1.Introduction to Controlled Drug Delivery 1

2. Classical drug delivery For most of the pharmaceutical industries existence, drug delivery induced simple, fast-acting responses via oral or injection delivery routes Problems associated with this approach 1. Reduced potencies because of partial degradation 2. Toxic levels of administration 3. Increase costs associated with excess dosing2 3. Why control drug delivery? As the cost and complexity of individual drug molecules has risen the problems with the classical delivery strategies over took their benefits. Goal of more sophisticated drug delivery techniques 1. Deploy to a target site to limit side effects 2. Maintain a therapeutic drug level for prolonged periods of time 3. Predictable controllable release rates 4. Reduce dosing frequent and increase patient complianceInjection Toxicity level Therapeutic Level Controlled release Time 3 4. Characteristics and Benefits Long delivery Place of delivery Delivery at the required time New patents and exclusive renewals period production Delivery of specific active ingredients (peptides and proteins) Eliminating the peaks and valleys of blood concentration and reduced side effects 4 5. Drug levels in the blood with (a) traditional drug dosing and (b) controlled-delivery dosing 5 6. Methods of delivery: Use Oily solvents Use sparingly soluble salts drug Use of pretreatment drugs (Prodrugs) Use of non-polymeric carriers (liposomes) Use mechanical drug delivery systems (pumps, drug delivery) Drug molecules bind to specific molecules (monoclonal antibodies, special proteins, PEG) The use of polymeric carriers 6 7. 7 8. Use Ficks law to design drug release8 9. Rate control9 10. Polymers in drug delivery Matrix (Monolithic) devices -films with the drug in a polymer matrix Easy to fabricate, typically by simple mixing of polymer and drugReservoir devices -Drug contained by the polymer Release is usually diffusion controlled (Fickian) i.e. J = -D C where J =flux, C = component of concentration across membrane of defined area, and is a differential vector operatorPolymer drug conjugates -Polymer attached to drug by (covalent) sacrificial linker10 11. Controlled Release Systems Controlled release implies controlled release of drugs from polymer drug delivery systems (DDS) Type of polymer Non-degradable / Degradable Type of DesignReservoirMatrixRelease mechanisms Diffusion / polymer degradation / combination 11 12. Entrapment or Encapsulation During the 1970, scientists first began to encapsulate and entrap drugs within polymers Encapsulation involves surrounding drug molecules with a solid polymer shell polymerdrug Entrapment involves the suspension of drug molecules within a polymer matrix. Drug Polymer 12 13. Drug release by diffusion Early encapsulation and entrapment systems released the drug from within the polymer via molecular diffusion When the polymer absorbs water it swells in size different Swelling created voids throughout the interior polymer Smaller molecule drugs can escape via the voids at a known rate controlled by molecular diffusion (a function of temperature and drug size)Add waterAdd time 13 14. Drug release by erosion Modern delivery systems employ biodegradable polymers When the polymer is exposed to water hydrolysis occurs Hydrolysis degrades the large polymers into smaller biocompatible compounds Bulk erosion process Polymer Surface erosion processWater attacks bondmer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer mer14 15. Bulk erosion: These small compound diffuse out of the matrix through the voids caused by swelling Loss of the small compounds accelerates the formation of voids thus the exit of drug molecules Polymers containing ester, ether, and amide groups, such as poly(lactic acid) (PLA), poly(glycolic acid), poly(caprolactone), polyamide, proteins, and cellulose (and its derivatives), generally exhibit this type of erosion.Add waterAdd time 15 16. Surface erosion: hydrolysis mainly occurs in the region near the surface, whereas the bulk material is only slightly or not at all hydrolyzed. As the surface is eroded and removed. Polymers such as poly(ortho ester)s (POEs), PAHs, and some polycarbonates tend to undergo surface erosion.Add waterAdd time 16 17. How is entrapment or encapsulation obtained? The physical entrapment and encapsulation of drugs within a polymer is complete via one of five techniques 1. 2. 3. 4. 5.Wurster Coacervation Spray drying (or precipitation) Coextrustion Self-assembly methods 17 18. Wurster processing (1949) The Wurstur process is essentially a coating process applied after a drug core is formed. The polymer shell is applied via spraying while the drug cores (liquid or solid) is suspended and recirculated in a gas stream. PolymerDrug PolymerGasDrugGas18 19. STEP #1: Polymer dissolved in a solvent (or oil) Drug dissolved in water STEP #2: STEP # 3: Emulsion from step #2 is mixed rapidly with fresh water Oil droplets within the fresh water phase Oil droplets contain original dispersed water/drug phase Oil diffuses into the fresh water phase precipitating the polymer & entrapping the drugH20 2 liquids are rapidly mixed water droplets form within the solvent19Drug/H20Polymer/OilCoacervation Technique 20. Supercritical fluid precipitation Normal operating conditions: 8.5-MPa, 35CSolvent-polymer solution fr om pumpCO2 from pumpHe a t e xcha nge rFlow str a ighte ne rNozzle Nozzle contr a ction Pr ecipita te Ba ck pr essur e r egula torPoly(l-lactide) ~1-m diameter particles formed by PCA processingGa s outle t 0.2m filter20 21. Co-extrusion processing There are numerous co-extrusion processes but they all share one feature the polymer shell is flowed concentrically around a pipe containing the drug formulation Syringe pump These concentric cylinders then breakup into individual packets either driven by air flow, electrostatic or mechanical vibrationDrug Neg.PolymerHV supply21 22. Self-assembling delivery systems The next advance was to construct materials/polymers that would self assemble with drugs to create controlled drug delivery vehicles Self assembly is typically approach via one of two methods: 1. Using a molecule that has a hydrophilic head and hydrophobic tail to form a shell, or 2. Electrostatic interaction to entrap drug molecules 22 23. Micelles & Bilayers Entrapment by micelle or bilayer formation can be obtained using lipids, surfactants and block copolymersPolar Head Group (hydrophilic)Fatty Tail (hydrophobic)monlayermicelle 23 Bilayer 24. Hydrogels (e.g. polyacrylic acids) Cross-linked, hydrophilic, 3-D polymer networks that are highly permeable Do not swell in the presence of water unless activated Swelling activate by pH, temperature, electric field Drug release happens via void generated & diffusion (diffusion rate is regulated by cross-linking ratio)mer mer mer mer mer mer mer merAdd water + activatormermermermermer mermer mer 24 25. Properties and Structures of Hydrogels Swelling property is influenced by: type and composition of monomers other environmental factors such as : temperature, pH, ionic strength cross-linkingRs = (Ws-Wd) / Wd Rs = swelling ratio Ws = weight of swollen hydrogels Wd = weight of dried hydrogels Cross-linking and/or copolymerization with hydrophobic comonomers density, mechanical strength, swelling property 25 26. Implantable pumps The pumps usually use polymer swelling to drive drug formulations out of a reservoir PolymerDrug/H20Water Drug/H20 Water SwellDrug/H20 26 27. 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