Effect of Caffeine on Pharmacokinetics of Paracetamol in Healthy Human Volunteers: a Case Study of Panadol Extra®
CHAPTER ONE
Objectives Of Study
The objectives of the study were to:
- Determine the quality of the samples parameters according to British Pharmacopoiea (2009) Standard.
- Determine the effect of caffeine on pharmacokinetics of paracetamol in Panadol Extra® tablets using healthy human.
CHAPTER TWO
LITERATURE REVIEW
History and Chemistry of Paracetamol
Antipyretic agents were used in ancient and medieval times as compounds contained in white willow bark from the family of chemicals known as Salicins, which led to the development of aspirin and compounds contained in cinchona bark. A lot of efforts to refine and isolate salicin and salicylic acid took place throughout the 19th century, and this was accomplished by Bayer chemist Felix Hoffmann (French chemist Charles Frédéric Gerhardt 40 years earlier worked on it, but abandoned the work when he thought it was impractical) until the cinchona tree became scarce in the 1880s, and alternatives were sought (Lester et al., 1947). Two alternative antipyretic agents were later developed in the 1880s known as acetanilide in 1886 and phenacetin in 1887 (Lester et al., 1947).
Brodie and Axelrod in 1949 linked the use of acetanilide with methemoglobinemia, showed that the analgesic effect of acetanilide was due to its active metabolite paracetamol and so they advocated the use of paracetamol, since it did not have the toxic effects of acetanilide (Brodie and Axelrod, 1949).
Paracetamol was first synthesized in 1873 by Harmon Northrop Morse through the reduction of p-nitrophenol with tin in glacial acetic acid. It was not used medically for two decades until in 1893 when it was discovered in the urine of individuals who had taken Phenacetin, and was concentrated into a white, crystalline compound with a bitter taste (Morse, 1878). In 1899, Paracetamol was found to be a metabolite of acetanilide but the discovery was not built on and ignored (Lester et al,. 1947).
Paracetamol was first sold in the United States in 1955 under the brand name Tylenol® while in 1956; 500 mg tablets of paracetamol were sold in the United Kingdom under the trade name Panadol®, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc.
Panadol® was originally available only by prescription, for the relief of pain and fever. It was advertised as being “gentle to the stomach,” since all other analgesic agents at the time contained aspirin that was a stomach irritant. The children’s formulation named Panadol Elixir® was later released in June 1958 (Milton et al., 1992).
In 1963, paracetamol was added to the British Pharmacopoeia, and has since gained popularity as an analgesic agent with few side-effects and with little interaction with other pharmaceutical agents (Milton et al., 1992).
CHAPTER THREE
MATERIALS AND METHOD
Materials
Study site
The Faculty is located opposite the University sick bay and adjacent to Faculty of Veterinary Medicine. It is one out of 12 faculties in the university. The Faculty comprises of five (5) Departments and five (5) tiers of classes with a population of 854 undergraduate students.
Human volunteers
Twelve (12) healthy adult volunteers between the ages of 20-29 years, seven (7) females and five (5) males participated in the study. They were undergraduate students of the Faculty of Pharmaceutical Sciences of Ahmadu Bello University, Zaria.
Recruitment of human volunteers
Prior to the study, the 400L and 500L undergraduate classes were briefed on the study, about 20 students showed interest in the exercise but after complete orientation on the design and protocol, they were subjected to the inclusion and exclusion criteria, we were able to get 12 volunteers that satisfied the inclusion criteria.
Inclusion criteria
Students who were able to satisfy the following criteria were enrolled:
- Non smokers or non alcoholics
- Not taken Paracetamol or any drug with paracetamol for the preceeding two weeks
- Had no apparent liver disease
- Agreed to fast over night before the exercise begins; and throughout the period of sample collection
CHAPTER FOUR
RESULTS
Uniformity of weight test of Paracetamol tablets
The result of uniformity of weight test is shown in table 4.1. It shows that in the weight uniformity test the deviation from the mean was 1.5% for sample A1, 2.4% for A2, 1.1% for A3 and 1.7%, 1.4% and 1.7% for samples B1, B2 and B3 respectively.
Friability Test
The percentage friability of Samples A1, A2 and A3 were found to be 0.17%, 0.42% and 0.43% respectively, while those of samples B1 and B2 had 0.74% and 0.33% respectively. However, Sample B3 had 5.83% which was greater than 1% and so had failed the test (Table 4.2)
CHAPTER FIVE
DISCUSSION
The in vitro weight uniformity test ensures that the formulation is of similar thickness (mass). The samples used for this study all passed the weight uniformity test. B.P (2009) stated that not more than two of the individual weights (for tablet of average weight of 250mg or more) deviates from the average weight by more than 5% and none deviates by more than twice that percentage. The significance of this test is to ascertain its quality and was cofirmed.
Tablet formulations are consistently subjected to mechanical stress from the point of production, through handling and transportation till it is consumed. The samples analysed passed the friability test except for sample B3 (Panadol Extra® tablets). This could be due to insufficient binder in the mixture and/or insufficient compression strength, as all samples of B3 were very soft. It correlated with values of disintegration test where it disintegrated in the least mean time of 30 seconds that is less than one minute. The aim of the test is to ensure that tablets will withstand the mechanical stress during handling; transportation and they will not break or lose significant weight to abrasions. The loss of any part of the tablet results in loss of active ingredient in the formulation.
SUMMARY AND CONCLUSION
Summary
The samples of Panadol® and Panadol Extra® tablets used in this study have passed the official tests for identification and percentage content of active ingredient, weight uniformity/variation, disintegration and dissolution based on the B.P 2009 specifications. However, Panadol Extra® tablets sample (B3) failed friability test, though other test samples passed this test. These tests have shown that both sampled products are chemically equivalent in their paracetamol component and have been manufactured based on good manufacturing practice. However the pharmacokinetic parameters calculated indicated varying values and only the peak saliva concentration levels was statistically significant at p ≤ 0.05.
Conclusion
The study revealed that the drugs used were chemically equivalent and significantly higher saliva paracetamol levels recorded for Panadol Extra® tablets as compared to Panadol® tablets and may be concluded that caffeine in panadol Extra® is responsible.
Recommendation
Further studies should be carried out to compare pharmacokinetics of the combination of caffeine with paracetamol at varying doses since not all the pharmacokinetic parameters showed significant differences to affect the bioavailability and pharmacological activity.
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