Innovative Prolonged-Release Oral Alkalising Formulation

www.nature.com/scientificreports OPEN Innovative prolonged‑release oral alkalising formulation allowing sustained urine pH increase with twice daily administration: randomised trial in healthy adults C. Guittet1, C. Roussel‑Maupetit1, M. A. Manso‑Silván 1, F. Guillaumin1, F. Vandenhende2 & L. A. Granier 1* A multi-particulate fxed-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 efect. The specifc release of both types of granules was shown in vitro through their dissolution profles, which indicated that potassium citrate was released within the frst 2–3 h and potassium bicarbonate up to 10–12 h after administration. The long-lasting coverage of ADV7103 was confrmed through a randomised, placebo-controlled, double-blind, two-period study, measuring its efect on urine pH in healthy adults (n = 16) at doses of alkalising agent ranging between 0.98 and 2.88 meq/kg/day. A signifcant 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 efect observed was non-saturating within the range of doses evaluated and the formulation presented a good safety profle. ADV7103 provided an efective prolonged release of alkalising salts to cover a 12-h efect with adequate tolerability and could aford 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. Te absorption of the actives is rapid, generating a peak of high alkaline load, and a short-lived efect. Tese treatments are characterized by inconvenient dosing schemes (3–6 daily doses), difcult day and night coverage and a jerky action leading to a variable efcacy, gastro-intestinal discomfort, and bad taste, which may result in poor acceptability and compliance1,2. Afer oral administration, citrate undergoes oxidative metabolic breakdown to carbon dioxide (CO 2) or bicarbonate. Consequently, a basifying efect is associated with its metabolism 3. Tis 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 pro- duction of CO2 eliminated by the respiratory route. Te remaining bicarbonate not involved in that reaction is rapidly absorbed by the intestinal mucosa6–8. In order to maintain a sustained alkalising efect over 12 h with a good safety profle, ADV7103, a new prolonged-release oral formulation, was designed to maximise absorption of the active substances. ADV7103 formulation consists of potassium citrate (CK) prolonged-release granules and potassium bicarbonate (BK) prolonged-release granules. Afer administration of the drug product, the active substances are released with an optimised release profle for each substance throughout the gastro-intestinal tract. 1Advicenne, Nîmes, France. 2ClinBay, Genappe, Belgium. *email: [email protected] SCIENTIFIC REPORTS | (2020) 10:13960 | https://doi.org/10.1038/s41598-020-70549-2 1 Vol.:(0123456789) www.nature.com/scientificreports/ Te objective of this work was to demonstrate the prolonged-release action of ADV7103 through its in vitro dissolution profle and the long-lasting alkalising efect of ADV7103 administered twice daily in healthy adults by evaluating the pharmacodynamic efect on urine pH values. Methods Formulation development. A new oral formulation, combining the advantages of potassium citrate and potassium bicarbonate was developed. Two types of prolonged-release granules (in practice 2-mm diameter tab- lets) were developed separately, each containing one active substance: green granules containing approximately 67% of potassium citrate (tri-potassium 2-hydroxypropane-1,2,3-tricarboxylate monohydrate) and white granules containing approximately 66% of potassium bicarbonate (potassium hydrogen carbonate). Two diferent colours were used in order to distinguish both types of granules, mainly for quality control purposes. Prolonged release was achieved by coating the granule core with a polymer flm ofering a versatile difusion barrier for both drugs. A pH-independent water-insoluble ethylcellulose flm layer was used as main limiting factor of the difusion of the highly soluble drug substances by virtue of its semi-permeable nature. As the dissolution rate is mainly a function of the thickness of the coating flm, the amount of ethylcellulose was defned for each type of granules to achieve the appropriate dissolution profle and to maximise overall drug absorption. Te respective target dissolution profles were conceived according to the physiological characteristics of their active ingredients in order to avoid an absorption peak and obtain continuous efcacy of the combination during 12 h, in order to allow a twice-a-day administration, while limiting the burst efect. Potassium citrate prolonged-release granules were developed to release potassium citrate within 3 h, to be absorbed mainly in the upper part of the small intestine. Tey were obtained by direct compression involving microcrystalline cellulose as binder, together with lubricants and fowing agents and then coated. Te release mechanism consists in solubilisation of potassium citrate afer difusion of water through the semi-permeable flm layer and then difusion of the active through the polymer at a slow rate. Potassium bicarbonate prolonged-release granules were developed to release potassium bicarbonate within 12 h. Due to the particularly high solubility of potassium bicarbonate, the release mechanism of potassium bicarbonate was based on a combination of the properties of an hypromellose sustained-release matrix and of the ethylcellulose coating. Upon difusion of water through the semi-permeable ethylcellulose flm layer, the hydrophilic hypromellose matrix hydrates on its outer surface to form consecutively degraded gel layers, thus controlling the infux of additional water. Te semi-permeable flm layer, in turn, controls the difusion of the active out of the granules. Potassium bicarbonate granules were obtained by direct compression involving the hypromellose matrix, microcrystalline cellulose as binder, together with lubricants and fowing agents and subsequently coated. In both cases, the coating solution, consisting of ethylcellulose 5% in ethanol, was directly sprayed onto the granules under rotation using a coating pan with a spraying system under predefned and controlled process parameters. Te fnal formulation was obtained as a fxed-dose combination of the two types of granules, containing roughly one part of potassium citrate and two parts of potassium bicarbonate. In vitro dissolution testing. In order to assess the dissolution profle of each type of granules, in vitro dissolution methods were developed on the basis of dissolution tests for prolonged-release solid dosage forms described in the European Pharmacopoeia. Sink conditions were verifed. Approximately 350 granules were placed in each vessel of a USP type 2 rotating paddle dissolution apparatus for a volume of 1 l of purifed water. Tey were stirred at 100 rpm, 37 °C (± 0.5 °C). Samples were drawn afer 15 min, 30 min, 1 h, and 2 h for potassium citrate, and afer 1 h, 5 h, and 10 h for potassium bicarbonate. In both cases the amount of potassium released was measured. For potassium citrate, potassium release was determined afer dilution of the samples with purifed water using an XP fame photometer with a potassium flter (BWB Technologies Ltd, Newbury, UK). For potassium bicarbonate, determination of potassium release was performed by conductivity using an Orion Star Plus meter (Termo Fisher Scientifc, Beverly, MA, USA). Phase I study in healthy adults. A randomised, placebo-controlled, double-blind, two-period study with an adaptive design, was conducted to investigate the pharmacodynamics of the product and its safety and tolerability in healthy adult subjects (trial registration on the 18/09/11 as EudraCT 2011-004679-35). Te study was approved by the French South-East regional independent ethics committee and regulatory authorities, and conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. Signed written informed consent was obtained from all subjects. Te study population consisted of 16 healthy adult subjects, male or female, aged 18–55 years, with a BMI of 18–30 kg/m2, without major medical history or chronic treatment. Te primary objective was to assess the pharmacodynamic efect on urine pH (measure using a validated pH- metre) of six oral doses or dose regimens of ADV7103 versus placebo afer 4–5 days of treatment. Te secondary objectives were to assess the dose–response relationship of ADV7103 on urine pH afer 4–5 days of treatment, to assess the pharmacodynamic efects of

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