Development and evaluation of a combination analgesic capsule

Abstract

Although the understanding of the pain mechanism has improved significantly over the years, much more is yet to be discovered. Broadening of our knowledge is needed to improve basic and clinical research in this field in order to successfully treat and manage pain in millions of people. Due to the complexities of the process involved in the treatment of pain, many modalities are used to alleviate or reduce pain. Validation of analytical methods is essential but can also be unnecessarily time consuming during the early stages of product development. Various analytical methods are required at different stages of the development life cycle. Although the requirements for method validation of new drug applications are clear, the same is not true for products in early development. Thus in Chapter 2, a method validation by phase development "qualification" was carried out on the methods developed for testing the capsules. This allowed for specific details of some aspects of method validation studies to be delayed during this stage of early development e.g Intermediate precision: during early development, when methods are typically operated in one laboratory and by few analysts, it is not necessary to determine the intermediate precision of an assay method. By phasing method validation, activities and resources can be optimized while maintaining a good scientific approach to pharmaceutical development. In Chapter 3, the rat study proved that there was indeed a super additive effect when using paracetamol, codeine phosphate and meloxicam in a fixed-dose combination. These agents in a combination were effective at doses in which when; used in isolation they would not be effective. This phenomenon of increased efficacy of NSAIDs by using paracetamol, paracetamol in combination with NSAIDs and codeine phosphate and paracetamol has previously been observed when these agents were administered in combination. Although no formal safety studies were carried out in our rat studies, the

rats remained in satisfactory condition and no weight loss was observed during or after the study. The reason for the decrease of codeine phosphate on stability seen in Chapter 4 could not be ascertained. Investigations carried out amongst different samples (including the ones for preformulation) have shown that the reaction is due to the green gelatin capsule shells used. The difference between the sample that still complied (with regards to codeine phosphate) and the one in question is the capsule shell composition and colour. Although the dissolution rate slowed, it was however still within the limits for the requirement of the percentage dissolved in 60 minutes, i.e. 80 %. The exact mechanism or reaction involved between the green gelatin capsules and codeine phosphate could not be established and requires further investigation. There have been reports of possible interactions between codeine and sodium lauryl sulphate. In our case the possibility was eliminated based on the formulations that were explored during the development phase. There was sodium lauryl sulphate in these formulation, including the initial blend of the green gelatin capsules and there was no decrease of codeine phosphate on stability. In Chapter 5, the study to determine the bioavailabilities of the three ingredients of the Triple FDC capsules was carried out according to a randomised, laboratory-blind, single-dose, three-part cross-over study carried out in fasted healthy male/female Caucasian volunteers. Reported inter-ethnic differences in the pharmacokinetics of meloxicam and codeine phosphate was the reason for enrolling only one ethnic group in the study. The bioavailabilities of paracetamol, codeine phosphate and meloxicam, as contained in the Triple FDC capsule were compared with paracetamol and codeine phosphate, as contained in Myprodol® (Adcock Ingram Limited), and meloxicam as contained in Mobic® (Boehringer Ingelheim (Pty) Ltd). The purpose of the study was not to establish bioequivalence but rather to demonstrate that the three drugs do not affect each others respective pharmacokinetic patterns. The results of the study showed that paracetamol and meloxicam, as present in the Triple

FDC capsules, were comparable with those in the reference products in respect of AUCo-t and Cmax- However, codeine phosphate was less bioavailable from Triple FDC capsules than from Myprodol®. The reason for this observation can be linked back to the decrease in assay results of codeine phosphate on stability. It can be concluded that this is clearly a formulation issue. No serious adverse events were reported during the study. Pharmacokinetic studies are particularly important in assessing the clearance of the drug and to anticipate possible accumulation of the parent drug or metabolites and potential drug-drug interactions. The study conducted in Chapter 6 was a multiple dose, double-blind, double-dummy, randomised, placebo and active-controlled cross-over, proof-of-concept study conducted to determine the safety and efficacy of two different doses of the Triple FDC capsule (10 mg codeine phosphate, 250 mg paracetamol, 2.5 mg meloxicam) versus a Double FDC capsule (250 mg paracetamol and 10 mg codeine phosphate) and placebo in females with primary dysmennorhoea, Phase II study. The Triple FDC product was evaluated for analgesic efficacy. It was postulated that a combination of meloxicam, paracetamol and codeine phosphate would act synergistically in providing relief of pain associated with dysmenorrhoea. This postulate was supported by the rat study findings in Chapter 3. Dysmenorrhoea has been shown to be an established model for assessing pain relieving qualities of analgesic candidates with regards to mild to moderate acute pain. To eliminate the inter-subject variability due to the reported inter-ethnic differences in the pharmacokinetics of codeine phosphate and meloxicam, as well as in the pain thresh-hold, only Caucasians were enrolled in this study. Dysmenorrhoea affects more than half of menstruating women. Women have painful menses without demonstrable pelvic abnormalities with dysmenorrhoea. The main objective of the entire study was to gain more information with regards to dose versus response of the Triple FDC and its safety. This objective was attained. The inclusion criteria did however limit extrapolation of the findings to other pain models.

The study reconfirmed the analgesic effect of paracetamol, meloxicam and codeine phosphate for moderate to severe pain. The pain relief does not seem to last longer when combined with meloxicam. The Kaplan-Meier estimator and the cumulative percentage of patients who required rescue medication showed that volunteers on the Triple FDC took longer before using the rescue medication and the percentage of volunteers who took the rescue medication was the least in this group. This suggested that the Triple FDC has a long duration of action when compared to the other treatment groups. One of the main concerns with acute pain treatment when using NSAIDs is decreased renal function. However, no clinically significant abnormal laboratory results were observed during the study even with the administration of meloxicam three times a day with a long half-life. Significantly, more volunteers receiving Triple FDC capsules rated their study medication as good or excellent compared to the other treatment groups. Triple FDC capsules were unequivocally superior to Placebo in relieving pain. Triple FDC capsules/Placebo and the Double FDC capsule groups were marginally better than Placebo, but indistinguishable from one another. The side effects, infections and infestations did not seem to be any less for patients taking 1 Triple FDC versus 2 Triple FDC, i.e. 5 mg versus 2.5 mg meloxicam. This suggests that side effects were not less with a decrease in the dose of meloxicam.