ABSTRACT
UNLABELLED: Children with uncomplicated malaria are generally treated with oral medication, except those unable to take oral drugs. Even though quinine has shown to be effective in treatment of African children with uncomplicated malaria its high bitterness limited the paediatric use. This study aimed to develop taste-masked quinine tablets suitable for children and offering dosing flexibility to adjust the quinine dose in function of body weight. METHODS: Insoluble quinine pamoate was used to formulate fast-disintegrating tablets, using a specific tablet design (rectangular tablet which can be divided into 8 subunits) to allow dosing flexibility. The physical properties of tablets were evaluated in vitro, as well as the quinine bioavailability in healthy adults (n=18) and the efficacy for treatment of children with uncomplicated Plasmodium falciparum malaria (n=56) using a 7-day regimen of 8 mg quinine/kg. RESULTS: Quinine pamoate tablets complied with the pharmacopoeial requirements for mass uniformity, friability, content uniformity, breakability, disintegration and dissolution. The quinine pharmacokinetic parameters after single administration of a quinine pamoate tablet were similar to a commercially available quinine sulfate tablet. The fast decline in parasitemia (28.6%/24h), the reduction rate of fever (all children were apyretic after 72 h) and the steady state quinine plasma concentration (5.7-15.8 microg/ml) proved the efficacy of the quinine pamoate tablets against P. falciparum. CONCLUSION: Fast-dispersible and taste-masked quinine pamoate tablets improved dosing accuracy, allowed easy administration and resulted in a high efficacy during the treatment of children with uncomplicated malaria.
Subject(s)
Antimalarials/administration & dosage , Drug Delivery Systems/methods , Malaria, Falciparum/drug therapy , Plasmodium falciparum/isolation & purification , Quinine/administration & dosage , Taste Threshold , Administration, Oral , Adult , Antimalarials/pharmacokinetics , Antimalarials/therapeutic use , Biological Availability , Child, Preschool , Dose-Response Relationship, Drug , Drug Compounding , Excipients/chemistry , Female , Humans , Infant , Malaria, Falciparum/parasitology , Male , Plasmodium falciparum/drug effects , Prospective Studies , Quinine/pharmacokinetics , Quinine/therapeutic use , Solubility , Tablets , Young AdultABSTRACT
In view of the lack of suitable paediatric antiretroviral formulations on the market, a novel fixed dose combination (FDC) tablet containing 300mg zidovudine (AZT) and 160mg lamivudine (3TC) was developed to improve dosing accuracy and allow flexible drug dosing in function of the body weight of paediatric HIV patients as recommended by WHO. Rectangular tablets with multiple fraction bars were designed and each tablet can be broken into 8 subunits, each subunit containing a drug dose corresponding to a body weight of 5kg. These fast-disintegrating subunits can easily be administered to children after dispersion in a liquid or mixing with food. In vitro quality control of the FDC tablets was determined and a crossover bioavailability study using 18 adult volunteers was performed after oral administration of the novel FDC tablet and a Duovir tablet. The results of the study showed that the novel tablets as well as its subunits disintegrated fast (<20s). After 30min dissolution, AZT and 3TC released from Duovir and the novel tablets was above 95%, the similarity factors f2 were above 50 for both AZT and 3TC. A tablet breakability test showed low weight variability (125.1+/-5mg, R.S.D.=4.4%), with limited weight loss (0.3%). There was no significant difference in pharmacokinetic parameters (C(max), t(max) and AUC(0-12h) values) between Duovir and the novel tablets formulated for paediatric applications.
