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A significant number of patients on antiepileptics do not receive sufficient benefit from their medications. Therapeutic agents have limited access to deliver effectively to the central nervous system (Wong et al, 2012). Most drugs do not readily cross the blood brain barrier and as such, targeting non-invasively is a significant challenge (Wong et al 2012). The burden from neurological disorders according to the WHO (2006) report, make up 6.3% of the worldwide cause of human diseases. The Medicines and healthcare product regulation agency (MHRA) describe antipsychotics as the therapeutic agents used mostly to treat mental (neurological) conditions (MHRA, 2010). Cardoso (2010) described the blood brain barrier as a vibrant and complex interface that controls exchange of molecules and separates the blood and the CNS. Various alternative routes to oral delivery have been proposed; the olfactory route is non-invasive and involves nasal delivery via the olfactory bulb (Alhenn et al, 2012). Various drugs have been successfully delivered via the olfactory route including peptides like insulin (Bengley, 2004). This route not only bypasses the blood brain barrier, but bypasses also, hepatic metabolism, drug distribution to other tissues, early elimination and the delayed onset of action of CNS drugs (Talegagaonkar & Mishra, 2004). Nanotechnology advances have further provided promising solutions to the CNS drug delivery problem (Wong et al, 2012). Polymeric nanoparticles are the focus of this project and they have been extensively investigated as delivery devices for treatment of CNS therapies (Wong et al, 2012).
Investigation of the development of the novel mucoadhesive nasal gel system follows the choice polymer system. The polymer system utilizes the fusion of two polymers, one with thermoresponsive properties and the other carrying mucoadhesive properties. Characterisation of the polymers will be based on their gelation temperature, viscosity, rheological and drug release properties.
Following the successful development of the polymeric-drug delivery device, scientific in vivo studies will commence using animal models and then in human subjects under the guidelines of the MHRA/EU. The MHRA views essential animal research; test tube results of promising therapies may not always be the same in addition to the international Helsinki declaration and the European directive (MHRA, 2010).
To study the release properties of the drug, the use of natural membranes is necessary (Seju et al, 2011). Humanely killed excised sheep nasal membranes will be dipped in phosphate buffer; the cartilages removed and the mucosal membrane dipped in phosphate buffer (Seju et al, 2011). Following the stabilization of two compartments of the nasal membranes, the pure drug and the constituted device will be treated with phosphate buffer and samples; the percentage of drug diffused will be calculated (Seju et al, 2011). An optical microscope will be used to study the mucocillary in what is termed as a histopathological study following pretreatment of the membranes with hematoxylin and eosin (Seju et al, 2011). To determine the propensity of inducing extra-pyrimidal effects, the paw-test will be performed (Kumar et al, 2008). Radiolabled quetiapine will be injected through the tail vein of three swiss albino rats and three other rats will be intranasally treated with the formulated device (Kumar et al, 2008). The rats are then humanely killed with their organs and blood collected, treated in saline and radioactivity measured and calculated as a fraction of the dose administered (Kumar et al, 2008).
Following the success of the animal test; the formulated drug in solution will be taken through a randomized placebo-controlled, phase I double-blinded clinical trial carried out in 19 healthy male patients (Betancourt et al, 2007). Participants between 18 and 75 years will be randomized between the formulation and a placebo (saline nasal spray) using increasing doses (Betancourt et al, 2007). The adverse effects will be recorded accordingly at varying times (Betancourt et al). Using a placebo and the intranasal formulation; a group of 150 patients with central nervous disorders will commence the phase II clinical trial (Grady, 2008). Comparing the effect of standard oral and iv quetiapine against the formulated device, a phase III clinical trial will progress to determine the definite benefit of the intra-nasal formulation against the standard quetiapine in terms of dose variation, efficacy, route and reduction in side effects (extrapyrimidal effects) (Grady, 2008). This trial will incorporate 5000 individuals of mixed racial population (Grady, 2008).
Ethical issues raised by the project and hypothetical extension:
The thermoresponsive and mucoadhesive polymers utilised during the pre-clinical phase require no ethical approval for the commencement of the laboratory pre-clinical phase.
The criteria of animals whether endangered or 'protected' is of ethical importance due to its impact on biodiversity (ASPA, 2012; Anon, 2010). The area of breeding, where they are obtained from (whether from the wild), their welfare and their housing conditions may raise ethical concerns if not complying with the demands of the act of being safe, humane and hygienic (ASPA, 2012; Anon, 2009; Anon, 2010). The procedures used and their severity including whether animals are humanely killed or not, will be an ethical concern if the pain, suffering or distress caused to the animal are not to the lowest threshold such that their mental and social wellbeing is maintained (ASPA, 2012). Record keeping, the nature of disposal of the animal carcass and use of animal tissues or organs will raise ethical concern (ASPA, 2012).The training received by the animals and whether they will be reused or allowed to be free after the project may raise ethical concerns (ASPA, 2012). The experience of the researchers in carrying out the procedures on the animals is of ethical concern (Anon, 2009; Anon, 2010).
The project's compliance with the EU and international guidelines and existence of an 'equipose' hypothesis is ethically important (Riis, 2001). The methods chosen for the clinical trial, the number of patients to be recruited, bias control, patient randomization, existence of conflicting interests and the intended procedure for handling adverse outcomes (Riis, 2001). The use of placebos in the study may be an ethical issue especially for patients who are already on other CNS medication (Riis, 2001). The other ethical issues to be raised will include the evaluation of the safety of the participants; whether the control and treatment groups stand an equal chance of success in this trial (Riis, 2001). Because the study will employ healthy volunteers and patients with neurological disorders, the existence of precautions to guard their safety will need to be proven before, during and after the study (Riis, 2001). Information accessible to the patient (disclosure), competent consent from subjects, volunteerism, confidentiality and the potential offensiveness of the project towards cultural and religious views is an ethical issue (Riis, 2001). Publication ethics and scientist's own ethics (Riis, 2001) need to be considered even well after committee approval.
Ethical approval for project and hypothetical extension: Things to do.
The laboratory phase, (pre-clinical) requires no ethical approval as opposed to the hypothetical extension.
As mentioned in the ASPA guidance (2012), prior to the commencement of a trial involving animals, a personal licence must be obtained from the home office through an application form giving details of the regulated procedures to be carried out on the animals and the types of animals to be used (ASPA, 2012). To obtain this licence, one must be above 18 years, have completed the adequate training modules and be skilled to handling protected animals (ASPA, 2012).
A project licence is to be obtained to authorize the commencement of the project on specific animals at specified locations (ASPA, 2012). The project needs to be discussed with the establishment inspector, NVS, NACWO and reviewed by the local AWERB and the application completed accordingly (ASPA, 2012). In this light, the establishment licence holder needs to approve and sign the application prior to submission (ASPA, 2012).
An establishment licence must be obtained for the place where the project will be conducted, where the animals are bred and supplied from (ASPA, 2012).
The principles of the 3R's must be followed in the application for the licences (ASPA, 2012).
Prior to the commencement of the clinical trial, the application for approval must be submitted to the ethics committee (local research ethics committee) and the approval thereof needs to be endorsed by the licensing body (Clinical trials regulation, 2004). The application to the committee must be a single application only; it must be written, signed by the chief investigator and accompanied with the appropriate documents (Clinical trials regulation, 2004).
Another request in written English must be signed on behalf of the sponsor with the fees sent to the suitable authorizing body for authorization in other to conduct the trial (Clinical trials regulation, 2004). Also, the trial can only commence if the ethics committee and authorizing body conclude that the benefits from the trial outweigh its negative implication (Clinical trials regulation, 2004).Prior to commencing the clinical trial, a notice of no rejection will need to be obtained from the MHRA in support of the non-CE marked device intending to be studied clinically (Medical device regulation, 2007).
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