Administration of Etoricoxib Using Nanotechnology - Research Proposal Example

Proposal For the Master of Veterinary Science in Pharmacology By Jihad Ibrahim Irbia College of Veterinary Medicine and Animal Resources, King Faisal University Effect of the administration of etoricoxib using nanotechnology for the treatment of experimental arthritis in a rabbit model 1: Summary Inflammation is not only a basic but also a complicated procedure that guards the body by getting rid of both the source together with outcomes of injuries, such as toxins, microbes as well as necrotic cells. Thus, circulating cells, plasma proteins, together with tissue phagocytes (defenders of body against foreign invasion) ought to be engaged to the extra vascular space so as to free the organism of these factors (Kumar et al., 2010).Current developments in nanomedical research have offered scientists with nanocarriers having several distinctive as well as tunable characteristics to meet the particular needs for the treatment of different inflammatory ailments. Etoricoxib, a drug that is non-steroidal anti-inflammatory that selectively restrains isoform 2 of the enzyme cyclooxygenase (cox-2).Apparently, this drug is permitted in over 70 countries globally for the healing of osteoarthritis, rheumatoid arthritis and psoriatic arthritis. Even though it is available for the curing of several inflammatory conditions, its little bioavailability as well as distribution that is not targeted, frequently limit its effectiveness in managing disease symptoms. Neural nanoparticles that are usually smaller in size than vascular-pore’s cutoff are most probably bound to break away from surface opsonisation in addition to having considerably small uptake by the reticuloendothelial system. These particles therefore will make long circulations in the blood and can passively be a target of inflamed tissues. Alternatively, particles intended for macrophages uptake ought to be bigger and containing discrete surface charges so as to make possible their internalisation together with interaction by macrophages (Moghimi et al., 2001).Thus nanoencapsulation of etoricoxib by use of polymeric nanoparticles for etoricoxib delivery will be carried out so as to attain better effectiveness, offer enhanced availability, as well as decrease side effects through careful transportation to targeted sites. Numerous techniques have been depicted so as to organise polymeric nanoparticles. Consequently, polymers ought to be appropriate for the body such as non-antigenicity, non-toxic as well as also being biocompatible and biodegradable. 2: Literature review Nanotechnology also referred to as nanoscience, is an extremely multidisciplinary discipline and also a technology whose intention is to generate, comprehend as well as utilise atomic-and molecular-scale (0.1-100nm) formations, together with fabricating materials or devices that are within the range of nano size. Nanoscience usually applies the standards of electronics, engineering, material in addition to physical science, together with manufacturing to the submicron or molecular level. Nanotechnology has already had considerable influence in the development of new products in industry. Thus several objects of nanostructure, such as nanosensors, nanoparticles (NP), nanowire, nanofibers, nanomesh, and nanosheaf have been made. Generally all these objects have all the 3 dimensions, usually below 100nm (Wang et al., 2009). Nevertheless, several significant nonmaterial have one or several dimension that are more than 100nm, for instance, carbon nanotubes are generally 500nm in length, while as tiny as 2nm in diameter. Several current nanomaterials could be arranged in 4 kinds; metal-based objects, carbon-based objects, dendrimers or polymers and composites. A wide range of other kinds of nanomaterials are anticipated to emerge in the near future (Wang et al., 2009). The distinctive features occurring from the nanoscale proportions of these nanomaterials provide them with novel catalytic, electrical, mechanical, magnetic, imaging or thermal attributes that are extremely attractive for applications in medical, commercial, environmental as well as military sectors. Development plus research on these objects have widened their uses, and several new branches, for instance Nanobiology, nanomedicines, nanotherapeutics, nanobiotechnology, nanosurgery, nanotoxicology together with nanomechanics have been brought up (Wang et al., 2009). Nanobiology is a discipline of nanotechnology that generally has applications in biochemical along with biological fields. It frequently studies existing components of nature so as to engineer new devices. Application of nanotechnology in biology usually leads to nanobiology.On the other hand,nanomechanics is another branch of nanoscience that studies basic mechanical(thermal, elastic as well as kinetic) features of physical systems at the scale of nanometer. The most significant application of nanotechnology in medical field is nanomedicines. The NIH in America recently referred to the application of nanotechnology in diagnosis, treatment, monitoring as well as controlling of biological systems as nanomedicine (Wang et al., 2009). Research into the normal delivery together with targeting of diagnostic, pharmaceutical, as well as therapeutic agents is at the front position of plans in nanomedicines. Finally, nanosystems have got exceptional biological as well as physical features that may be utilised to surmount the drawbacks of molecular imaging together with drug/gene delivery in present years (Wang et al., 2009). Medical application of nanotechnology comprises of new therapies, complicated drug delivery systems as well as in vivo imaging. Another active objective of research is in neuroelectronic interface as well as other nanoelectronics-based sensors. Considerable effort has been made in development of nanotechnology for delivery of drugs since it provides appropriate ways of delivery of little-molecular-weight NP drugs, together with macromolecules like peptides, genes or proteins either by targeted or localised delivery to the tissue of concern(Wang et al., 2009). Nanomaterials that are utilised in drug delivery ought to meet many requirements, which include; drug compatibility, biocompatibility, appropriate for biodegradation kinetics as well as mechanical features, together with easing processing. The past two decades have seen biodegradable polymers that are synthetic being used progressively more in a broad array of strategies to build agents for molecular imaging as well as therapeutic delivering devices for genes and drugs because of their biodegradability and compatibility. Thus polymers might be globular, branched or linear, and there can be tight control of their size (Wang et al., 2009). Co-polymer poly(lactic-co-glycolic acid)(PLGA) is a nanotechnology that has been in development for several years and has gotten approval from the American FDA for the utilisation in delivering drug, applications in addition to diagnostics of basic together with clinical science research, comprising of cancer, cardiovascular disease, vaccine as well as tissue engineering (Wang et al., 2009). Currently, there are several nanotechnology based approaches that are being generated for the curing of inflammatory arthritis (AR).Inflammatory arthritis is a constant systematic ailment, generally affecting 1% of the global population. It is usually typified by constant polyarticular inflammation of the synovial tissues, finally resulting in the complete damaging of bone plus articular cartilage of the joints affected. If not treated, the progressive destruction results in severe functional deterioration, leading to premature death (Christine, 2013). Nanotechnology is mostly a multidisciplinary strategy that utilises a wide array of techniques and tools whose aim is diagnosis of ailment together with delivery of therapeutic agents by utilization of carriers, less than a micrometer in size,nanocarriers.These nanocarriers, unlike, traditional drugs, permit targeted delivering of therapeutic agents particularly to the wanted inflammation sites and possibly individual adjustments can be made depending on alterations in the expression of the disease (Christine, 2013). Apart from their therapeutic activities, these nanocarriers possibly allow non-invasive along with quantitive image-based readouts effects of the drug, which might in future permit practitioners to optimize as well as monitor therapies on the basis of individual responses (Christine, 2013). Nanotechnology started in 1959 when Nobel Prize winner in physics, Richard Feynman, a physicist, illustrated molecular machines created with atomic accuracy in his lecture, commonly referred to as, “There is plenty of room at the bottom,”, which he had presented to the American Physical Society (Sahoo et al., 2007).Nevertheless, the phrase nanotechnology was for the first time ever used by professor Noro Taniguchi, in the year 1974(Kreuter, 2007). In recent times, the term nanotechnology was defined by the medical standing committee of the European Science Foundation as the ,”the science and technology of diagnosing, treating, and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using molecular tools and knowledge of the human body.”(Webster, 2006).Alternatively, the phrase can also be defined as a carrier systems in the nanosize range (if possible 10-100nm) having encapsulated, dispersed, adsorbed, or conjugated drugs as well as imaging agents(Koo et al.,2005). One of the foremost pioneers in the advancement together with assessment of nanoparticles for drug transportation was Professor Peter Speiser, whose approach for controlled release compromised the advancement of miniaturized transportation system (Birrenbach, 1973; Birrenbach and Speiser, 1976).Simultaneously, numerous practical applications of lipossomes in delivery of drugs surfaced from Professor Greg Gregoriadis and collaborators’ research (Gregoriadis and Ryman,1972;Allison and Gregoriadis,1974). On the other hand, albumin nanoparticles were for the very first time developed at the Johns Hopkins Medical institutions in Baltimore, Maryland(Zoolle et al.,1970).The rest of nanoconstructs such as drug polymer conjugates were for the first time proposed in the 1970s(Ringsdorf,1975) and developed pre-clinically in the 80s(Duncan,2006).Patrick Couvreur was another pioneer who illustrated the making of biodegradable nanoparticles made of poly(methylcyanoacrylate) together with poly(ethylcyanoacrylate)(Couvreur et al.,1979).During the same period, other kinds of nanoparticles were also suggested, such as poly(acrylamide)(Ekman et al.,1976) and poly(lactic acid) nanoparticles(Gurny et al.,1981). Professor Kreuter published the first ever review article about nanoparticles(Kreuter,1978),and further suggested a definition of polymeric nanoparticles for purposes of pharmaceutical, which later was taken up by the Encyclopedia of Pharmaceutical Technology(Kreuter,1994) together with the Encyclopedia of Nanotechnology(Kreuter,2004). Currently, over 25 nanomedicines have already been endorsed for use by humans. Different kinds of nanodevices as well as strategies on the basis of nanotechnologies appropriate for delivery of drugs have also been suggested. Generally, these devices may guard a drug from degradation; improve drug absorption by enhancing diffusion via the epithelium, transform pharmacokinetic as well as distribution profiles of drug tissue, in addition to improvement of intracellular infiltration together with distribution (Couvreur and Vauthier, 2006).Additionally, some of these nanodevices have been discovered to enhance the performance of diagnosis and imaging techniques, for instance colloid metals. The most prevalent nanodevices are polymer therapeutics, lipid-based nanodrug transport systems in addition to polymer-based nanoparticulate transport systems (Juan et al, 2011). 3: Research Objectives Nanoscale systems are characterised by both physical as well as chemical features, which give them several merits over conventional parenteral or oral formulation. Thus the possible arrangements as well as chemical compositions of particular monomers in nanoscale systems permit for the encapsulation of a broad range of hydrophobic drugs, peptides, along with oligonucleotides, where the payload is reliant on the general size of the nanocarriers (Cesur et al., 2009; Gao et al., 2011; Kuzmis et al., 2011). Furthermore, the surface and size chemistry of nanosystems can be utilised to accomplish passive as well as active focusing on the inflammation site. It is this focusing capability that leads to buildup of therapeutic agents at inflamed sites in concentrations that are high than in tissues that are healthy. This result assists in reduction of the key unfavorable effects viewed in conservative medicines together with enhancing the effectiveness, pharmacokinetic features, as well as Biodistribution of a particular formulation (Cho et al., 2008). The key objective of this study is evaluation of the effect of etoricoxib as well as the therapeutic advantages of nanomedicines on rheumatoid arthritis by use of polymeric nanoparticles for delivery of drugs. The research will focus on the study of pharmacokinetics and tissue distribution of etoricoxib nanomedicines in rabbit models of experimental arthritis that is stimulated by complete Freund’s adjuvant, with various kinds of polymers in addition to diverse concentrations of the medicine, and then compare the two outcomes. 4: Methods and Procedures 4.1. Materials Etoricoxib (>99% radiochemical purity) will be produced by use of the Labeled Compound Synthesis Group(Merck Research Laboratories, Rahway,NJ).Freund’s adjuvant is completed ,(every milliliter containing I mg of heat-killed as well as dried Mycobacterium tuberculosis, 0.85Ml mineral oil, and O.15Ml mannide monooleate),will be acquired from Sigma. Poly (Lactic-co-glycolic acid)(PLGA) will also be acquired from Sigma,Chitosan. 4.2 Animals Arthritis rabbits that are adjuvant-induced are housed in typical cages under states of optimal light (12:12h light: dark cycle), temperature (251 C), as well as humidity (50-60%), with ad libitum with supply of food and water. In addition all the rabbits are acclimatized to the laboratory for a minimum of three days before any experiments are carried out on them. 4.3: Preparation of polymeric nanoparticles Nanoparticles will be set up by mixing (PLGA) as well as etoricoxib, dissolved in acetic acid together with dichloromethane, correspondingly, with tripolyphosphate .Afterwards; the mixture is then stirred for half an hour (30 min) at 30 C at a speed that is moderate so as to attain spontaneous ionic gelation of the nanoparticles ensuing from the evaporation of organic solvents (Badawi et al., 2008).Thus the size of the resultant nanoparticles will be regulated by adjustment of the ratio of (PLGA) to tripolyphosphate solution. Further, the nonparticles will be brought together by centrifugation at (9000 xg for 30 min alongside washing with water that is distilled so as to get rid of any leftover traces of acetic acid (Wen et al., 2011). 4.4 Experiment There will be random assignment of 15 adjuvant-stimulated arthritis rabbits into 3 groupings of 5 animals each.2 of the groups will be stimulated by intradermal injection of M-tuberculosis that is heat-inactivated in unfinished Freund’s adjuvant into the bottom of the tail (Ishihara et al.,; van den Hoven et al., 2011).Adjuvant-stimulated arthritis rabbits attain quick onset of arthritis (in 10 days),together with the development of healthy, easy to measure polyarticular inflammation marked bone resorption as well as periosteal bone proliferation(Fatma et al.,2012).The last and 3rd grouping of rabbits will act as the control group. 4.5 Biodistribution study For studies involving biodistribution, rabbits will be administered etoricoxib nanoparticles at 10 mg per kg. One grouping of the rabbits will be killed by dislocation of the cervical vertebra. Key organs, comprising of the spleen, liver, kidney, lungs, heart, intestines as well as infected joints will be assembled, weighed and evaluated for radioactivity of drug content by use of a gamma counter. Calculations will be done of the concentrations in the organs and determination of Biodistribution is determined. 4.6. Pharmacokinetic study For studies involving pharmacokinetics, drug-containing nanoparticles will be orally administered. Collection of blood samples will be done after 1, 4, 8 and 24 hours by use of tubes containing anticoagulant like EDTA. The content of the drug will be determined by chromatography, which is a high-performance liquid. Afterwards, plasma concentration-time curves are plotted, and calculation of the area under the curve is done. 4.7. Statistical analysis General Linear Model procedure in SPSS (2004) is used to conduct all analyses. 5: Utilisation/Contribution of Research Results in addressing development issues in the Kingdom of Saudi Arabia Arthritis is a common, chronic inflammatory sickness which involves damaging of various joints in the body. Rheumatoid arthritis, which is the most widespread kind of inflammatory arthritis, is a damaging joint ailment that might have an effect on 0.5-1% of the total populace in industrialised world, resulting in considerable disability as well as a reduction in the quality of life (Lee & Weinblatt, 2001; Smolen & Steiner, 2003). The outcomes of this research will offer a means of enhancing the treatment of rheumatoid arthritis by reducing of effort together with time involved with suboptimal treatment, and as such the exploration proposed here will lead to increased general output of the populace of the Kingdom of Saudi Arabia. References -Allison AG, Gregoriadis G. 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