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Ibuprofen is a small molecular weight hydrophobic drug whereas BSA is a large molecular weight hydrophilic drug. The aim of the project is to develop formulations that will provide sustained release of each. The project will involve determination of solubility in formulations and in vitro release testing.
There will be two aspects to this investigation: formulation of a matrix type release and measuring the effect of drug loading. Silicone will be used as the delivery system due to its biocompatibility and non-biodegradability properties. In the matrix type release silicone will be allowed to bind with required amounts of ibuprofen and BSA separately. Other excipients e.g. polyethylene glycol will also be added to each to obtain a homogenous mixture and giving a uniform distribution. Two model delivery devices will be prepared by placing each formulation containing the silicone and drug in the middle of two glass panels with coins as spacers. For the extraction, the device will be placed in a required amount of dichloromethane. The samples will then be evaporated to dryness and reconstitute the drug sample in a required amount of soluble solution i.e. water for BSA and ethanol or phosphate buffer for ibuprofen.
To measure the effect of drug loading the drug samples containing the drug and excipients will be injected into silicone tubing. The tubing will be cut at equal lengths to form little rods. The tubing's will be placed into required amount of soluble solution i.e. water for BSA and ethanol or phosphate buffer for ibuprofen and then placed in a water bath at 370C. The rods will be left in the water bath for 7 days initially with the possibility of extending to 14 days.Â
For assaying, ibuprofen will be assayed using UV and BSA using bicinchoninic acid (BCA) kit. This will be done daily at same time Â±30mins. When the samples are not in use they will be placed in a fridge. A daily and a cumulative graph will be plotted using the data from the assays. The cumulative will show a drug loading of 10%, 20% and 30%. From the graphs a mean standard deviation and a post hoc analysis will be done.
The hypothetical extension that has to be considered is: the delivery devices being developed can go into clinical trials and can be tested in mice. If successful it can move into human trials which are regulated under EU/MHRA guidelines.
Ethical issues in this project
There are no ethical issues that arise during this project. However, when taking the hypothetical extension into consideration there would be ethical issues that would arise as it may be potentially used in animals and then further into humans.
Ethical issues in research involve the basic bioethical principles: Kavanaugh. (2005).
Respect for persons- subjects are involved voluntarily and should have all the information about the clinical trials
Beneficence- the benefit is maximised while risk is minimised and the subjects are kept assured and are protected from harm
Justice- equal information about the benefits and burdens of the research are distributed between subjects and society
Informed consent- the patient must be able to make a choice of their own i.e understanding the information, risks, benefits and engage in a reasoning process to include alternatives. Patients should be provided with easy to understand information so they can easily make a choice whether they want to take part or not.
These principles link into clinical trials to ensure that they are undertaken ethically. In 2001 the "European Union adopted the EU Clinical Trials Directive (2001/20/EC)" (5)Medical Research Council. (2011) as a management of clinical trials and the clinical trials regulations became law in 2004. The regulations protect the rights, safety and well-being of the subjects taking part in the research. (5)Medical Research Council. (2011).
The stages of clinical trials involve- Preclinical tests (in animals), Phase 1, Phase 2, Phase 3 and Phase 4 trials (in humans).
Preclinical trials involve the use of animals and are used for testing new drugs/devices during teaching and clinical testing. If this device goes into pre clinical trials it may be tested on mice. To protect animals during clinical trials the animals have to be reviewed and the risks and benefits assessed. Research involving animals is always under controversial debates due to the animal rights organisations. Therefore, careful consideration should be undertaken when using animals as they usually bear all the risks/pain while humans realise all the benefits and are the main topics of controversy. To ensure that research with animals is conducted ethically and responsibly, there are rules and regulations in place that involve the use of animals in teaching, testing, and research. Paul et al. (2003)
Before testing the device on the animal, details of the species would need to be provided as well as why that type of animal is chosen, the number of animals used and why other methods could not be employed without the use of animals.
The medical research council (MRC) plays an active role in ensuring that research with animals is undertaken ethically using the 3Rs:
"ReplacementÂ of animals with other alternatives" (6) Medical Research Council. (2011).
"ReductionÂ in the numbers of animals used" (6) Medical Research Council. (2011).
"RefinementÂ of procedures to minimise any pain and suffering the animals" (6) Medical Research Council. (2011).
Standards must be followed taking into consideration of: space and area the animal will be kept in, type and availability of food and water, care in transit and time of exercise. The experiment must be performed under supervision, by trained personnel and have clear limits. Saha and Saha. (2000).
Phase 1-4 clinical trials involve humans. If the device is successful in animal trials and is moved onto human trials there would be ethical issues arising. Some factors would need to be taken into consideration when using human subjects:
Age and sex of patient,
Patient well being, decision, understanding, assurance, knowledge and confidentiality.
How many subjects
Any adverse effects
The trial environment
Safety of patients whilst using device and ease of use.
Risks and benefits
The design of a study is important i.e if hypothesis being tested cannot be accepted nor rejected, it is unethical because the subject is taken into the trial have been put through potential risks for no benefit. Klein. (2010).
Any risks that will be taken should be balanced by the benefits to the subject. When the subject agrees to the trial they are given informed consent which protects certain human rights. The subjects should be competent and able to understand. A full disclosure should be given about the study/ trial and they should understand the risks and benefits. The patients decision should be voluntary. During the trial, the well-being of each volunteer should be closely monitored and if the risks increase the trial should be stopped. All information should be kept confidential about the trial and volunteer Emanuel et al. (2007). Other considerations in clinical trials are the use of placebos in studies. Using placebos can be beneficial i.e. data from placebo controlled studies are definitive and they avoid erroneous bias results Kavanaugh. (2005).
Other ethical issues include: Minimising patients treated at ineffective doses and at toxic doses, difficulty in gaining informed consent from vulnerable patients and toxicity in phase I studies is less than in phase II, but higher variation Ratain et al. (1993)
Obtaining ethical approval
Due to the ethical issues arising the clinical trials of the device ethical approval would need to be attained. According to the Medical Devices Regulations 2002, a Notice of No Objection should be obtained from the Medicines and Healthcare products Regulatory Agency (MHRA) this can be done by using Integrated Research Application System (IRAS).Â In addition, an ethical approval should be obtained from a Research Ethics Committee (REC) to conduct a clinical investigation of a medical device. Before the trial starts each body will need evidence of the other body's approval as a condition of its own approval. Trials through the NHS require management permission from the NHS organisation and are regulated by the Research Governance Framework for Health and Social Care. This involves the use of NHS patients or their tissue/data, NHS facilities and carried out by NHS staff Medicines and Healthcare products Regulatory Agency. (2011).
IRAS is the main system for applying for approvals in the UK and assists with the approval process as it allows researchers to input common information without repetition. IRAS is available at: https://www.myresearchproject.org.uk/. An account would need to be created to login. Once logged in a new project would also need to be created and a project filter will need to be completed, in which relevant forms and questions are generated for different bodies. All common data is automatically populated and can the user can view all forms or individual forms. Using IRAS the MHRA can take the information needed and print out the completed PCA1 and PCA2 forms and sterilisation pro-forma for signing before making a notification. An applications sent on rewritable CD-ROM is recommend with a document index and all documents to be named. In total 8 rewritable CD-ROMS and 1 hard copy of all documentation. Once completed, they are submitted to the bodies either parallel or individually with the relevant fees. All hard copy documents are to be clearly labelled "documentation only" and sent via recorded delivery. Once the payments and relevant documentation are received the 60 day assessment period will begin. Medicines and Healthcare products Regulatory Agency. (2011).
Site-Specific Assessment (SSA) will also be required as part of the ethical opinion. This is done by completing the Site-Specific Information (SSI) Form in IRAS and can be done when the main application form for ethical review has been submitted and accepted for review. There is 25-day clock for reviewing SSAs and the clock cannot be stopped. If there is no objection, the REC will then confirm ethical approval in writing to the Chief investigator. National Research Ethics Service. (2008).Â
NRES run a system of "flagging" of RECs for ethical review of certain types of application, as they are interested in the research area. Medical device research is one of the application types for which RECs may be flagged. Although it is not important, it is advisable to apply to it by arranging a booking through the NRES Central Allocation System (CAS). The application and supporting documentation is submitted to the REC and is reviewed within 4 days of booking. National Research Ethics Service. (2008).Â
In regards to the ethical review the REC assessor validates application within 5 working days and is confirmed by letter. Approximately 17 days after the deadline, the assessors meet and a meeting is held in which the researcher has to attend. The researcher is notified of the Committee's decision after the meeting within 10 working days. To request extra information the assessors will be allowed 14 days through the UK Competent Authority. The 60 day clock will not stop whilst this requested information is being obtained; this is known as no opinion. Provisional opinion is when further information requested and the clock stops during that period. In addition, the assessors may reach a final opinion and can either be favourable or unfavourable. A favourable opinion is when there are no ethical reasons and the trial can proceed. Where as an unfavourable opinion is when trial cannot go ahead and the application can be modified and resubmitted or can appeal against it. It will be essential to obtain all necessary information before the start of the approval to save time. National Research Ethics Service. (2008).Â