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Paracetamol is a non-selective cyclooxygenase enzyme inhibitor. It is a well-established antipyretic and mild analgesic drug. Maximum daily dose of paracetamol recommended for use is 4gm. Activated carbon is made by thermal decomposition of carbon based material which creates the network of microscopic pores which adsorbs specific material which is based on the type of material to be adsorbed. (Ward and Alexander-Williams, 1999, Andrews RS, 1976)
Activated carbon works by physical adsorption to remove contaminants from water. Carbon's porous nature provides a large surface area for adsorbents to collect. Physical adsorption occurs due to the attractive forces because all molecules exert attractive forces, especially molecules at the surface of a solid (pore walls of carbon), and these surface molecules seek other molecules to adhere to the large surface area of carbon has many attractive forces that work to attract other molecules. Thus, contaminants in water are adsorbed to the surface of carbon by surface attractive forces similar to gravitational forces. Adsorption from solution occurs as a result of differences in adsorbate concentration in the solution and in the carbon pores. Besides physical adsorption, chemical reactions can occur on a carbon surface.(Marsh and Rodríguez-Reinoso, 2006)
Since paracetamol is a poorly soluble drug (Mogal S. A), this research project will explore the development of the poorly soluble drug formulation by activated carbon. The project will investigate how activated carbon affects the drug release and its application as a novel excipient. This project work will investigate the formulation of activated carbon drug using DSC, IR spectroscopy and microscopy.
PROCEDURE OF THE RESEARCH PROJECT AND HYPOTHETICAL EXTENSIONS INVOLVED
The drug (Paracetamol) is mixed with ethanol. The activated carbon is then added to this solution. Due to the large surface area of activated carbon the drug is adsorbed on its surface. The activated carbon and solution is then separated. In the next step, the powdered activated carbon is collected which contains the drug. Then measure the amount of drug present in the powder.
STAGES AND TIMELINE FOR PHARMACEUTICAL FORUMLATION DEVELOPMENT
After all the chemical development of the formulation has been carried out, further studies will be done to access the bioavailability and therapeutic activity of the drug which is done through preclinical trials.
Pre-clinical trial will be done to test the feasibility of the drug formulation in animal models. There is a need of ethical review by the ethics committee before carrying out the pre-clinical trials. The animal ethics is regulated by '' The Animals (Scientific Procedures) Act 1986'' which ensures that a proper procedure is followed in a scientific research so as to lessen the pain, suffering faced by animals. It involves following three types of licensing processes:
Only trained persons who hold a personal license, ensuring that they are qualified and suitable are allowed to carry out the procedures.
The program of work in which the procedures are carried out must be authorized in a project license.
An establishment license must be available for the place at which the work is carried out.
ETHICAL APPROVAL FOR USING ANIMALS
Part of this research involves the testing of the bioavailability of formulation on the animal models, which is divided in to the following two parts:
Oral testing of drug formulation.
Systemic availability of product formulation.
ETHICAL ISSUES RAISED BY THE PROJECT (HYPOTHETICAL EXTENSION)
Ethical issues are to be considered in order to obtain the ethical approval for the use of animals in research work. The issues which are regulated include following:
Modification of the genes of a protected animal, it may be responsible for causing pain, suffering, distress or may cause harm to the animal. For example; breeding animals with harmful genetic defects is a regulated procedure if you intend to keep the animals produced beyond two-thirds of the way through their gestation or incubation period;
An anesthetic, an analgesic will be administered to the animal or certain other measures could be taken in order to sedate or dull the perception of pain in a protected animal.
Removing organs, blood or other tissue under general anesthesia even if the animal is not allowed to recover consciousness.
No animal will be sacrificed or killed during the experiment, only the blood of the animal is extracted during the process.
As, the drug is paracetamol, so a to check its anti-nociceptive activity, 'Hot plate test' would be carried out on the animal in order to test the analgesic effect of the drug.(Ankier, 1974). Its might involve little burn on the feet of animal on which test is conducted; so randomized study will be carried to minimize the pain.
Toxicological studies are carried out on animals to assess the overdose of the drug. Since the aim of the project is to improve the efficiency of paracetamol i.e. less amount of drug is required in order to produce the therapeutic effect due to the presence of activated carbon. So as to test the minimum inhibitory concentration and maximum safe concentration of the new formulation. It is also used to find out compatibility of the new excipient i.e. activated carbon in the organism. For that animals are sacrificed or sedated however care is been taken in excising animal ethically.(Patel, 1992)
Licensing for animal testing:
License for animal testing is given only in those cases where no other alternative is available. The proposed project should have benefits that should outweigh the adversity tolerated by animals. Number of animals required in project should be minimized; also suffering and pain caused to animal due to the experiment must be reduced.
After successful completion of pre clinical trials the dosage of the new formulation is assessed. To obtain ethical approval in UK protocol for clinical trials is sent to National Research Ethics Service, which is a branch of National health services under the category of investigational medicinal products. Clinical Trials for Investigational Medicinal Products (CTIMP) aims at following matters:(Tunis Sr, 2003)
To fathom the pharmacological and new therapeutic activity of the drug.
To find out adverse drug reaction of new formulation.
To carryout the pharmacokinetic study i.e. absorption, dissolution, metabolism, excretion of the new formulation in human subjects.
To choose the subjects for the clinical trials following ethical issues has to be dealt with before carrying forward the project as recommended by Chinese University of Hong Kong (Hong Kong) (Graham, 2007):
"Inclusion Criteria: All patients greater than 16 years selected by clinicians on the basis of their condition related to the acute and chronic pain.
Exclusion Criteria: Patients will be excluded if any of the following cases occur:
1. A history of peptic ulceration or hemorrhage
2. Any case of anticoagulation
3. A case of pregnancy
4. Adverse reaction to paracetamol or ibuprofen
5. Cardiac and renal failure
6. Hepatic problems
7. Rectal bleeding
8. Consumption of Chronic Non-Steroidal Anti-Inflammatory Drug (NSAIDS)
9. Patients suffering from asthma
10. Chronic obstructive pulmonary disease
11. Chronic pain syndromes
12. Prior treatment with analgesia for the same injury"(Graham, 2007)
Clinical trials of the new formulation will be carried out in following four phases provided successful completion of each phase consecutively:(Roberts)
Phase 0 - Pilot study (Pharmacodynamics and Pharmacokinetics)
In this 10 -15 candidates are chosen to know initial data on pharmacodynamics and pharmacokinetics of new formulation.
Phase I - Screening for safety
In this type of study is done to assess the maximum safe concentration of the new formulation in human subjects and also find out the side effects of the drug. This type of study is carried out on healthy individuals. Population of study is 20-80 candidates.
Phase II - Establishing the testing protocol
It includes large group (100-300) of people to check the effectiveness of drug and for the evaluation of drug safety.
Phase III - Final testing
This study includes 1000-3000 subjects that are treated with new formulation and also with conventional formulation to check the efficacy of new drug, confirm the effectiveness and determine the side effects of the drug formulation and finally gather the information that will allow the safe usage of drug.
Phase IV - Post approval studies
After the drug has been launched in the market, post-marketing studies are carried out.