Feasability of a new process to produce fast disintegrating pellets as novel multiparticulate dosage form for pediatric use.

Novel orally disintegrating system based on multiparticulate form was developed, offering an alternative to encounter major issues in the design of dosage form for pediatric patients, i.e., the difficulty in swallowing large solid dosage form (tablet or capsule), and the requirement to cover a broad range of doses for different age groups. Microcrystalline cellulose-based pellets containing acetaminophen were prepared via extrusion/spheronization followed by freeze-drying. The in vitro disintegration behavior of these pellets was quantitatively measured with a texture analyzer. Mercury intrusion and gas adsorption techniques, scanning electron microscopy of pellet surface and cross-section were performed in order to characterize their internal porous structure. Pellets characteristics such as size distribution, sphericity, friability and drug release were also determined. The developing process was able to produce pellets containing high drug loading (25, 50 and up to 75%, w/w) with good sphericity (aspect ratio ∼1) and low friability. The pellets exhibited an instantaneous disintegration upon contact with water, which was indicated by two parameters: the disintegration onset was approximating to 0, and the disintegration time less than 5s. The fast disintegration behavior is correlated with the pellet internal structure characterized by a capillary network with pore diameter varying from 0.1 to 10µm. Such a structure not only ensured a rapid disintegration but it also offers to freeze-dried pellets adequate mechanical properties in comparison with conventional freeze-dried forms. Due to pellet disintegration, fast dissolution of acetaminophen was achieved, i.e., more than 90% of drug released within 15min. This novel multiparticulate system offers novel age-appropriate dosage form for pediatric population owing to their facility of administration (fast disintegration) and dosing flexibility (divided and reduced-size solid form).

Use of calcium caseinate in association with lecithin for masking the bitterness of acetaminophen--comparative study with sodium caseinate.

Owing to a variety of structural and functional properties, milk proteins are steadily studied for food and pharmaceutical applications. In the present study, calcium caseinate in association with lecithin was firstly investigated in order to encapsulate the acetaminophen through spray-drying for taste-masking purpose for pediatric medicines. A 2(4)-full factorial design revealed that the spray flow, the calcium caseinate amount and the lecithin amount had significant effects on the release of drug during the first 2 min. Indeed, increasing the spray flow and/or the calcium caseinate amount led to increase the released amount, whereas increasing the lecithin amount decreased the released amount. The "interaction" between the calcium caseinate amount and the lecithin amount was also shown to be statistically significant. The second objective was to compare the efficiency of two caseinate-based formulations, i.e. sodium caseinate and calcium caseinate, on the taste-masking effect. The characteristics of spray-dried powders determined by SEM and DSC were shown to depend on the caseinate/lecithin proportion rather than the type of caseinate. Interestingly, calcium caseinate-based formulations were found to lower the released amount of drug during the early time to a higher extent than sodium caseinate-based formulations, which indicates better taste-masking efficiency.

Optimizing the taste-masked formulation of acetaminophen using sodium caseinate and lecithin by experimental design.

In a previous study of ours, the association of sodium caseinate and lecithin was demonstrated to be promising for masking the bitterness of acetaminophen via drug encapsulation. The encapsulating mechanisms were suggested to be based on the segregation of multicomponent droplets occurring during spray-drying. The spray-dried particles delayed the drug release within the mouth during the early time upon administration and hence masked the bitterness. Indeed, taste-masking is achieved if, within the frame of 1-2 min, drug substance is either not released or the released amount is below the human threshold for identifying its bad taste. The aim of this work was (i) to evaluate the effect of various processing and formulation parameters on the taste-masking efficiency and (ii) to determine the optimal formulation for optimal taste-masking effect. Four investigated input variables included inlet temperature (X1), spray flow (X2), sodium caseinate amount (X3) and lecithin amount (X4). The percentage of drug release amount during the first 2 min was considered as the response variable (Y). A 2(4)-full factorial design was applied and allowed screening for the most influential variables i.e. sodium caseinate amount and lecithin amount. Optimizing these two variables was therefore conducted by a simplex approach. The SEM and DSC results of spray-dried powder prepared under optimal conditions showed that drug seemed to be well encapsulated. The drug release during the first 2 min significantly decreased, 7-fold less than the unmasked drug particles. Therefore, the optimal formulation that performed the best taste-masking effect was successfully achieved.

Development and evaluation of taste-masked drug for paediatric medicines - application to acetaminophen.

The aim of this work was to produce and characterize taste-masked powders of a model drug (acetaminophen) prepared using potentially tolerable and safe excipients for paediatric use, i.e. sodium caseinate and lecithin. The powders were produced by spray-drying aqueous dispersions. The characteristics of taste-masked drug particles were determined by scanning electron microscopy, differential scanning calorimetry and X-ray photoelectron spectroscopy to analyse the surface composition of particles. Taste assessment was approached by an indirect method through drug release studies. We developed a method with a syringe pump using small volumes of aqueous medium and low flow rates, to mimic the behaviour in the mouth. This method was compared to the electronic tongue analysis. SEM, DSC and XPS analysis indicated differences in surface composition of spray-dried particles according to the caseinate/lecithin ratio and to relate it with taste-masking. The "coating" consisting of caseinate and lecithin had a significant role in decreasing the release of drug during the first 2 min and so in taste-masking. Higher content in lecithin results in higher taste-masking efficiency. The association of sodium caseinate and lecithin seems to be promising to mask the bitterness of acetaminophen. A good agreement between release study and electronic tongue analysis was established.