Patheon (Canada)

Advantages of testosterone nasal gel include ease of administration, low dose, and no risk of secondary transference. The efficacy and safety of testosterone nasal gel was evaluated in hypogonadal males. The ninety-day, randomized, open-label, dose-ranging study, included potential dose titration and sequential safety extensions to 1 year. At 39 US outpatient sites, 306 men (mean age 54.4 years) with two fasting morning total serum testosterone levels <300 ng/dL were randomized (n = 228, b.i.d. dosing; n = 78, t.i.d. dosing). Natesto(™) Testosterone Nasal Gel was self-administered, using a multiple-dose dispenser, as two or three daily doses (5.5 mg per nostril, 11.0 mg single dose). Total daily doses were 22 mg or 33 mg. The primary endpoint was the Percentage of patients with Day-90 serum total testosterone average concentration (C(avg)) value within the eugonadal range (≥300 ng/dL, ≤1050 ng/dL). At Day 90, 200/273 subjects (73%; 95% CI 68, 79) in the intent-to-treat (ITT) population and 180/237 subjects (76%; 71, 81) in the per-protocol (PP) population were in the normal range. Also, in the normal range were 68% (61, 74) of ITT subjects and 70% (63, 77) of PP subjects in the titration arm, as well as, 90% (83, 97) of ITT subjects and 91% (84, 98) of PP subjects in the fixed-dose arm. Natesto(™) 11 mg b.i.d. or 11 mg t.i.d. restores normal serum total testosterone levels in most hypogonadal men. Erectile function, mood, body composition, and bone mineral density improved from baseline. Treatment was well tolerated; adverse event rates were low. Adverse event discontinuation rates were 2.1% (b.i.d.) and 3.7% (t.i.d.). This study lacked a placebo or an active comparator control which limited the ability to adequately assess some measures.

AimsThe ACE inhibitor captopril is frequently used for children suffering from hypertension and other conditions such as heart failure. In the EU, however, captopril is available only as a solid dosage form and a proportion of the tablet is required for a therapeutic effect in children. To avoid inaccurate dosing, captopril is formulated as extemporaneous aqueous preparations which suffer from short shelf lives because captopril undergoes oxidative dimerisation to the major degradation product captopril disulphide in aqueous solutions.1 Further, it may also be difficult for the child to swallow a whole solid dosage form.2 For these reasons captopril is usually dispensed as an extemporaneous (unlicensed) oral aqueous formulation made by pharmacies and Specials manufacturers.Given the fragmented and uncertain stability data, this abstract reports a factorial-designed experiment to investigate the effects and interactions of a number of potential variables (pH, captopril concentration and oxygen content) to predict and define precise conditions to achieve a stable product.MethodsParameters investigated included pH (citrate buffer at 3.5 and 5.5), drug concentration (0.75 mg/ml and 3.0 mg/ml), addition/absence of chelating agent (EDTA) and addition/absence of nitrogen purge (N2 Purge), yielding a total of 16 runs (24 design); the apparent first order rate constant (k1) was used as the response factor. Samples were stored under accelerated conditions (50°C) over 14 days and analysed using reversed phase High Performance Liquid Chromatography (HPLC).ResultsStatistical analysis indicated that the main factors of pH, captopril concentration, chelating agent and N2 Purge all significantly influenced the oxidative degradation of captopril to some extent. The two –way interactions, pH×EDTA, pH×captopril concentration, EDTA×captopril concentration and N2 Purge×captopril were found to be significant. The only 3-way interaction found to be significant was pH×EDTA×captopril concentration. Surprisingly, the presence of EDTA was found to degrade captopril at both low and high pH. It is postulated that the addition of EDTA may sequester metal ions which otherwise could have a stabilising effect via a citrate-captopril-metal ion complex.3 The optimised formulation, with lowest degradation, was one which required a low pH (3.5), no EDTA, no N2 Purge and a high concentration of captopril (3.0 mg/ml), and yielded 95% accelerated stability at 50°C for 14 days.ConclusionsWhen developing paediatric formulations one of the many important considerations is to minimise the use of excipients. The fact that EDTA may not be required is an important finding since EDTA is potentially nephrotoxic in chronic conditions.4 Only by using factorial design can such latent complex interactions be identified.