PROFESSOR VINESS PILLAY & DR. YAHYA E. CHOONARA Department of Pharmacy and Pharmacology at the University of the Witwatersrand

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1 PROFESSOR VINESS PILLAY & DR. YAHYA E. CHOONARA Department of Pharmacy and Pharmacology at the University of the Witwatersrand NRF/DST South African Research Chair: Pharmaceutical Biomaterials and Polymer-Engineered Drug Delivery Technologies Director: Platform Institutional Director: Wits Hub of the MRC/Wits National Medical Devices Innovation Platform

2 In a nutshell: Drug carriers Modification of drug release and ADME properties Drug targeting Common types of drug delivery systems: Conventional dosage forms Modified release systems Gastroretentive systems Microstructures Nano-Enabled systems

3 Nanostructures cannot be considered superior as they do form part of larger systems/devices Is it a case where Microtechnology has just gotten smaller so what is the big deal?... Microtechnology is also very small and has shrunk to the point that it is now nano anyway Many times Nanotechnology is built upon Microtechnology via modified microfabrication This may imply Nanotechnology is not yet mature and should remain as Nanoscience. There is plenty good Nanoscience, but not yet much in the way of viable Nanotechnology Our limited understanding of the complexities indicate that molecular modeling simulations and chemometrics would win in predictive power and assisting in rational systems design Describing nanotechnology based on merely size is pointless since the usefulness of drug delivery systems are not based only on size Nevertheless, it is the largest potential growth sector of the pharmaceutical industry and is spurring researchers to take that leap in enabling the generation of innovative nanomedicines An exceptionally large economic force set to reach an annual global market worth USD1 trillion

4 For a freely soluble drug, S is not critical: large C s large k large dc/dt For a poorly soluble drug, k is small dc/dt is highly responsive to S dc dt = DS Vh ( C C) S For e.g. 5cm 3 about 1.7cm per side of material divided 24 times will produce 1nm cubes and spread in a single layer could cover the field at Soccer City

5 Nanomedicines may be less favored due to safety concerns with pulmonary disposition leading to inflammation or even tumor formation Globally, including SA legislation is under development on the handling of hazards/exposure and there is a need for risk assessment and risk management of nanomaterials Size, shape and morphology play a key role in determining safety Little attention has been placed on requiring approval from the US Food and Drug Administration (FDA) grey area The main challenge with current methods are low drug-loading capacity and poor ability to control the size distribution Pharma industry is slow to utilize the new systems with components that are not Generally Regarded As Safe (GRAS) The future depends on the ability of scale-up production by nano-manufacturing Re-engineering of clinical research through translational research is required to advance basic discoveries to clinical studies

6 Speaks of the control of matter that can be used to design systems to serve specific therapeutic needs The nanocrystal story demonstrates how a simple technique can improve the performance of poorly water-soluble drugs Essentially the physicochemical principles in terms of interactions with surfaces, diffusion behavior and hydrodynamics are modified This overcomes anatomical and physiological barriers to provide efficacious drug delivery Characterized by high surface-area to mass ratio and stabilized against agglomeration Typically prepared by molecular deposition/complexation ( bottom up ) or attrition of larger materials ( top down ) Range in size from nm for many pharmaceutical applications

7 According to the US National Institute of Health s Nanomedicine Roadmap Initiative, nanotech will offer innovative medical intervention for diagnosis, prevention and treatment of diseases The secret is to manipulate supramolecular structures to produce programmed nanodevices Nano-manufacturing processes that can churn out nano drug delivery systems for e.g. soft gelatin capsules at the nano-scale will revolutionize drug therapy. Development of nanodevices for both diagnosis and therapy (theragnosis) using the same device hold great promise in personalized medicine

8 Nanocrystals Nanospheres Nanoparticles Nanocapsules Nanocapsules Dandelions Nanofibers Nanoliposomes Nanotubes Nanorods Nanogels CNT Dendrimers Nanogels Nanosuspensions Nanomicelles Nanotubes Nanomicelles Nanosuspensions Nanofibers Platform Porphyrins

9 Spray freezing into liquid (SFL) Emulsification Precipitation with a compressed fluid antisolvent (PCA) Rapid expansion from a liquefied-gas solution (RESS) Evaporative precipitation into aqueous solution (EPAS) High-pressure homogenization Microfluidization High-energy wet milling

10 Professor William Pardridge, M.D. UCLA, Brain Research Institute, Los Angeles, CA, USA (Drug Discovery Today, 12, 54-61, 2007) Considering the potential size of the global CNS pharmaceutical market, and considering that so few drugs cross the BBB, one would expect that the development of BBB drug delivery technologies would be a high priority in the pharmaceutical industry and in the academic sciences. In fact, there is not a single medium or large pharmaceutical company in the world today that has a BBBdrug-targeting technology program. Even if Big Pharma wanted to change this situation, there would be no staff to hire because there are so few BBB scientists being trained in academia. In the USA, there is not a single academic neuroscience program that has any emphasis on BBB drug targeting technology. One routinely reads summaries of workshops in either the USA or Europe that are devoted to various CNS diseases such as Alzheimer s and Parkinson's disease, brain cancer or stroke, and the issue of BBB drug delivery is not even mentioned Drug delivery to the brain is limited by the BBB <2% of small molecules cross the BBB (400Da; lipophilic) 100% of large molecules do not cross the BBB Rely on specialized transport mechanisms at the BBB interface CNS conditions are escalating in the young and old...need breakthroughs now!!!

11 Mechanisms for localized CNS drug delivery employing various nano-enabled polymeric devices Transcranial C/S of BBB Capillary Receptor Mediation Our aim is to achieve site-specific delivery via intracranial implantation of the device to increase the accumulation of drug molecules at the target Intrathecal Osmotic Disruption Nano-Lipidization

12 Nanopharmaceutical Products Currently on the Market Nanoparticles/Crystals Dendrimers Liposomes Micelles