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Cardoso 20 described the blood brain barrier as being a vibrant and complex interface that separates the blood and the CNS; this barrier is known to control the exchange of molecules between the two regions and plays a key role in protecting the brain from xenobiotics. A significant number of patients on antiepileptics do not receive sufficient benefit from the medication and experience seizures whilst on their medication Halliday et al, 2012. Therapeutic agents have limited access to the central nervous system and as such, a reduced ability to deliver effectively the agents by non-invasive means during treatment (Wong et al, 2012). Most drugs do not readily cross the blood brain barrier and as such targeting is a significant challenge (Wong et al 2012). Various alternative delivery routes have been proposed; the trans-nasal route is non-invasive and involves delivery through the nasal region (Alhenn et al, 2012). Various drugs have been administered and successfully delivered via the olfactory route including peptides like insulin (Bengley, 2004). This route not only bypasses the blood brain barrier, but also hepatic metabolism, drug distribution to other tissues, early elimination and the delayed onset of action of CNS drugs Together with delivery through the olfactory route, 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).
Olazapine (Seju et al, 2011) and risperidone (Kumar et al, 2008) were delivered intranasal in rats, this project focuses on delivering a novel thermoresponsive mucoadhesive gel to deliver quetiapine to the central nervous system. Investigation of the development of the novel mucoadhesive nasal gel system follows a choice of a polymer system. The polymer system utilizes the fusion of two polymers, one with thermoresponsive properties and the other with mucoadhesive properties. Characterisation of the polymers will be based on their gelation temperature, viscosity, rheological and drug release properties.
Following successful polymeric-drug delivery device development, scientific in vivo studies will commence using rat models and then human subjects in clinical trials under the guidelines of the MHRA/EU guidance. To study drug release properties of the drug, the use of natural membranes is necessary (Seju et al, 2011). Humanely killed sheep nasal membranes are excised and the dipped in phosphate buffer; the cartilages are removed and the mucosal membrane of the sheep 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 reconstituted with the phosphate buffer and samples redrawn at suitable intervals to calculate the percentage drug diffusion (Seju et al, 2011). The mucosal membrane is isolated, sectioned into four pieces and treated with the device, PBS, Isopropyl alcohol and the device in PBS; an optical microscope is used to study the mucocillary in histopathological study following pretreatment with hematoxylin and eosin (Seju et al, 2011). To determine the propensity of inducing extra-pyrimidal effects, the paw-test will be performed by utilizing two holes of 4cm and two other holes of 5cm (Kumar et al, 2008). Three swiss albino rats are injected through the tail vein with radiolabled quetiapine and another three rats intranasally administered with the formulated device (Kumar et al, 2008). The rats are humanely killed and organs (brain, liver, spleen, kidney and tail) and blood are collected, treated in saline and radioactivity measured with the shielded well-type gamma scintillation counter and calculated as a fraction of the dose administered (Kumar et al, 2008).
The solution of the formulated drug will be taken through a phase I double-blinded, placebo-controlled randomized clinical trial and will be carried out in 19 healthy male patients with no central nervous disorders (Betancourt et al, 2007). Participants between 18 and 75 years will be randomized between the formulation and a placebo (saline nasal spray); an increasing dose of quetiapine in the device will be used based on the commonly administered doses but specific for direct brain therapy (Betancourt et al, 2007). The adverse effects will be recorded accordingly at varying times (Betancourt et al). Using a placebo drug against 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 and reduction in side effects (extrapyrimidal effects) (Grady, 2008). This trial will incorporate 5000 individuals of a mixed racial population (Grady, 2008).
Ethical issues raised by the project and the hypothetical extension to the project.
The project during its formulation will utilise polymers; they are derived from nature or from chemical synthesis. The thermoresponsive and mucoadhesive polymers utilised require no ethical approval for the commencement of the laboratory pre-clinical phase aspect of this study.
The criteria the animals fall under whether endangered or 'protected' is of ethical importance (ASPA, 2012). Also where the animals intend to breed, obtained from and their housing conditions may raise ethical concerns if not complying with the demands of the act (ASPA, 2012). The procedures used and their severity including nature of killings done, may be of ethical concern if the pain, suffering or distress caused to the animal are not to the lowest threshold such that its mental and social wellbeing of the animals (ASPA, 2012). Record keeping of the animal breeding and care may raise some ethical concerns (ASPA, 2012). The disposal of animal carcass will be an issue that will raise ethical concern (ASPA, 2012). Conflicts of interests and appropriate training to handle the animals may raise concern (ASPA, 2012). Inappropriate application of the 3R's to the project, the maturity, age, gender, training received by the animals and whether they will be reused may raise ethical concerns (ASPA, 2012)
Ethical issues due to the study on humans will be based on the methods chosen for the clinical trial, the number of patients to be recruited, the control of bias, the randomization of the patients among the chosen therapies and other variables (Riis, 2001). The use of placebos in the study may be an ethical issue especially for patients who are already on other CNS medication, since there are already proven therapies, it will be unwise to include placebos (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 or not (Riis, 2001). Because the study will employ healthy volunteers and patients with have a certain form of neurological disorders, their safety and precautions to guard this will need to be proven before, during and after the study (Riis, 2001). Information accessible to the patient and the receipt of their consent is an ethical issue that will be raised (Riis, 2001). Publication ethics and scientist's own ethics (Riis, 2001) need to be considered even well after committee approval. Publication ethical issues have to deal with the outcome of the study and the possibility of abortion of the publication, be it due to quarrels or results contrary to the hypothesis on which the study was based are not only unethical but rather unacceptable because of the inclusion of human subjects in what Riis (2001) describes as vain. The editor responsible for publishing the results, the referees and unrightful authorship of the paper all fall under ethical implications and issues aforementioned well into the publication of the research results (Riis, 2001).
Things needed to be done to commence the project and gain approval. Also things needed to be done considering the hypothetical extension and commencement of the animal and clinical trials.
As already mentioned, the project needs no ethical approval prior to its start however considering the hypothetical extension, various things need to be considered prior to the start of the pre-clinical and clinical trials.
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 to give details of the regulated procedures to be carried out on the animals and the types of animals to be used (ASPA guidance, 2012). To obtain this licence, one must be above 18 years, have completed the adequate training modules and be skilled to handling and looking out for protected animals (ASPA, 2012).
A project licence needs to obtain to authorize the commencement of the project on specific animals at specified locations (ASPA, 2012). Discussion of the project 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 approve and sign the application prior to submission for acceptance ASPA, 2012). Completion of UK modules 1, 2 and 5 are necessary prior to submission of the application for the project licence (ASPA, 2012). The 3R's need to be incorporated and carefully illustrated in the application to encourage a positive response (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. The principles of the 3R's must be followed in the application for the licence (ASPA, 2012).
Since one of the procedure in measuring the drug quantity that targets the brain involves decerebrating the rats; a licence to that effect is needed.
Prior to the commencement of the clinical trial, the application for approval must be submitted to the 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 as specified in the schedule (Clinical trials regulation, 2004).The document of the application should include the following; the ethics committee reference number, allocated number to the trial, trial titles, particulars relating to the trial design, details of the sponsor, financial arrangements of the trial, sources of funding, arrangements to reimburse participants, compensation in event of death or injury to the participants, insurance details, financial agreement details and other documents from recruiting advertisements to letters of invitation (Clinical trials regulation, 2004). Another request in written English must be signed on behalf of the sponsor and with the required fees be sent to the appropriate 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 outway the negative implication (Clinical trials regulation, 2004).Other documents to be submitted to the authorization body include the ethics committee letter of approval, the site address, device description, trial description, manufacturer details as well as protocol description (Clinical trials regulation, 2004).