A multi-particulate fixed-dose combination product, consisting of a combination of two alkalising salts formulated as prolonged-release granules, ADV7103, was developed to obtain a sustained and prolonged alkalising effect. The specific release of both types of granules was shown in vitro through their dissolution profiles, which indicated that potassium citrate was released within the first 2-3 h and potassium bicarbonate up to 10-12 h after administration. The long-lasting coverage of ADV7103 was confirmed through a randomised, placebo-controlled, double-blind, two-period study, measuring its effect on urine pH in healthy adults (n = 16) at doses of alkalising agent ranging between 0.98 and 2.88 meq/kg/day. A significant increase of urine pH with a positive dose-response in healthy adult subjects was shown. Urine pH above 7 was maintained during 24 h with a dosing equivalent to 1.44 meq/kg twice a day, while urine pH was below 6 most of the time with placebo. The effect observed was non-saturating within the range of doses evaluated and the formulation presented a good safety profile. ADV7103 provided an effective prolonged release of alkalising salts to cover a 12-h effect with adequate tolerability and could afford a twice a day (morning and evening) dosing in patients requiring long-term treatment. Current alkalising treatments in adults and children generally consist of immediate-release forms of citrate or bicarbonate salts. The absorption of the actives is rapid, generating a peak of high alkaline load, and a short-lived effect. These treatments are characterized by inconvenient dosing schemes (3-6 daily doses), difficult day and night coverage and a jerky action leading to a variable efficacy, gastro-intestinal discomfort, and bad taste, which may result in poor acceptability and compliance 1,2. After oral administration, citrate undergoes oxidative metabolic breakdown to carbon dioxide (CO 2) or bicarbonate. Consequently, a basifying effect is associated with its metabolism 3. This salt is mainly absorbed under its divalent form (pH 4.8-6.4), and is thus known to have an absorption window limited to the upper side of the small intestine (duodenum, early part of the jejunum) 4. At physiological blood pH (7.4), citrate is entirely ionized in its trivalent form. Most of the citrate in the blood circulates unbound at relatively low (0.05 to 0.3 mmol/l) concentrations and the remaining quota is bound to calcium, potassium and sodium 5. In contrast, oral bicarbonate is absorbed all over the gastro-intestinal tract, independently of the local pH. A massive elimination of bicarbonate could occur in the stomach, since it neutralizes gastric acid with the production of CO 2 eliminated by the respiratory route. The remaining bicarbonate not involved in that reaction is rapidly absorbed by the intestinal mucosa 6-8. In order to maintain a sustained alkalising effect over 12 h with a good safety profile, ADV7103, a new prolonged-release oral formulation, was designed to maximise absorption of the active substances. ...

Ethosuximide, the first-line therapy for childhood absence epilepsy, is currently formulated as a syrup (Zarontin®, Pfizer) with a bitter taste and high sugar content, poorly adapted to children, and a ketogenic diet. The collaborative European FP7 project KIEKIDS aimed at developing an innovative sugar-free, tasteless formulation convenient for pediatric use. This dual Phase-I study evaluated two granule formulations based on lipid multiparticulate (LMP) technology. Two panels of 6 healthy adult volunteers underwent a randomized, placebo-controlled, partly blinded, 3-way cross-over trial, comparing ethosuximide granules A or B with placebo granules and syrup at single 10 mg/ kg doses. Corresponding plasma pharmacokinetic profiles of ethosuximide were compared, along with palatability, safety, and tolerability. The LMP granule A proved suboptimal due to bitterness and adherence to beaker walls, while the optimized granule B revealed excellent palatability, similar to placebo granules, and low adherence to glass.The relative bioavailability of granules A versus syrup, based on dose-normalized C max and AUC 0-∞ was 93.7% [90% CI: 76.3-115.1] and 96.1% [91.0-101.5], respectively. For granules B it was 87.6% [81.6-94.0] and 92.5% [88.5-96.6], respectively, with slightly delayed t max of 0.75 h [0.5-4.05] compared to syrup 0.5 h [0.3-0.8]. Tolerability visual analog scales revealed a trend for statistically non-significant improvement versus syrup at peak (30 min) for transient dizziness (both granules), fatigue (granules A), and anxiety (granules B). The innovative ethosuximide granule formulation B achieves a suitable