An explorative analysis of process and formulation variables affecting comilling in a vibrational mill: The case of praziquantel.

Praziquantel, a BCS II class anthelmintic drug used for the treatment of schistosome infections, was coground in a vibrational mill with different polymers (linear and crosslinked povidone, copovidone and sodium starch glycolate). An explorative analysis of formulation variables (drug-polymer wt ratio and polymer type) and process parameters (type of grinding media, grinding time and frequency) was carried out with the help of an experimental screening design. The influence of the above mentioned factors on three PZQ characteristics (residual crystallinity, water solubility enhancement and drug recovery) was studied. The variation of carrier amount proved to be by far the most important variable affecting all the experimental responses. A lower impact and, in some cases, rather null effect, had the variation of the process variables. All coground systems were characterized by a high amorphous degree and a solubility significantly higher than the API. A very promising product was obtained by processing at 20Hz for 4h, using 3 spheres of 15mm as grinding media, i.e. a coground having a 50% API content, showing a 4.6-fold greater solubility at 20°C than pure praziquantel. This product maintained the same antischistosomal activity of pure API and was both physically and chemically stable for at least 6 months.

Design and evaluation of buccal films as paediatric dosage form for transmucosal delivery of ondansetron.

In the process of implementation and innovation of paediatric dosage forms, buccal films for transmucosal administration of drug represent one of the most interesting approach. In fact, films are able to provide an extended duration of activity allowing minimal dosage and frequency and offer an exact and flexible dose, associated with ease of handling. The objective of the present study was to develop polymeric films for the sustained release of ondansetron hydrochloride, a selective inhibitor of 5-HT3 receptors indicated in paediatrics for the prevention and treatment of nausea and vomiting caused by cytotoxic chemotherapy or radiotherapy and postoperatively. Films were prepared by casting and drying of aqueous solutions containing different weight ratios of hydroxypropylmethylcellulose (HPMC) with chitosan (CH) or sodium hyaluronate (HA) or gelatin (GEL) and characterized for their physico-chemical and functional properties. The presence of HA, GEL and CH did not improve the mucoadhesive properties of HPMC film. The inclusion of GEL and CH in HPMC film increased in vitro drug release with respect to the inclusion of HA, although films containing HA showed the highest water uptake. Moreover in agreement with the release behaviour, the inclusion of CH and GEL provided higher drug permeation through porcine buccal mucosa with respect to HPMC film and ensured linear permeation profiles of drug.

Development of flexible and dispersible oral formulations containing praziquantel for potential schistosomiasis treatment of pre-school age children.

Praziquantel (PZQ), an anthelmintic drug used in developing countries for the treatment of schistosome infections, was processed using the fluid bed wet granulation technology to prepare fast dispersible granules, as an appropriate and flexible dosage form for pre-school-aged children. Granulation experiments were performed incorporating PZQ either in the powder mixture, according to the traditional way, or in the liquid phase containing wetting agents. In the powder mixture several excipients were tested: Flowlac 100 as filler, Galeniq 721 (isomalt) and Neosorb P 100 T (D-sorbitol) as sweeteners and PVP K30 as binder; while in the liquid phase Lutrol F68, Cremophor RH 40 or Tween 80 as surfactants were investigated. Different formulations loaded with 10% w/w (batches 1-8) and 20% w/w of PZQ (batches 9-13) were produced The majority of granules displayed good flow properties and uniform drug content. X-ray powder diffraction showed that PZQ remained in its original crystalline state, while differential scanning calorimetry and Fourier transform-infrared analysis evidenced the formation of chemical interactions among the ingredients. The solubilisation test performed in non-sink condition to reproduce the actual condition in which a child of 4 years takes the medicine revealed that granules quickly formed a very fine suspension in water (dV90=39.9 µm). Although after the granulation process the solubility of raw PZQ was not increased, adding the aqueous suspension to 500 ml of buffer solution of pH 1.5, simulating the fasted state of a child, 50% of the drug was dissolved after 30 min. After granule manipulation with milk and fruit juices, no PZQ degradation was observed during time. Finally, the selected granule formulation provided evidence to be stable even at hot and very humid climate (30°C/75% RH), at least for the examined time.