Development of Innovative Formulations for Paediatric Use

Children around the world are routinely being treated with medicines that have not been designed and developed for this specific patient population, putting them at risk of inaccurate dosing and side effects. In the view of these considerations, the PhD research project was addressed to the use of specific formulation strategies for the development of innovative paediatric dosage forms. The research has been structured in three case studies, concerning different oral formulations: mucoadhesive buccal films, dispersible granules and complex suspensions. The first part of the research investigated the use of polymeric films for systemic absorption of ondansetron hydrochloride through the buccal mucosa. Several mixtures of hydrophilic polymers were evaluated to optimize the hydration ability of such films, the residence time at the site of application and the drug permeation profile. The second approach was focused on the development of fast dispersible granules for oral administration of praziquantel. Granules represent a flexible dosage form for preschool-aged children that can be given as dispersion in beverages or administered with food, improving the palatability of the formulations and the adherence to therapy. The last part of the work was carried out at the University of Birmingham and faced one of the central challenge associated with paediatric treatment: the taste masking of molecules characterized by bitter taste. To achieve this purpose, polyelectrolyte complexes, composed of whey protein and pectin, and able to encapsulate active substances were developed. Caffeine was selected as model drug for its particularly bitter taste. Finally, the results presented in this thesis demonstrated that specific formulation strategies can be used to overcome the predominant issues related to paediatric administration of medicines, in order to guarantee the complete adherence of children to the therapy and thus the success of the treatment

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 \u3bcm). 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\ub0C/75% RH), at least for the examined time

Development of buccal films as novel dosage form for paediatric use

Introduction: The development of child-appropriated dosage forms represents one of the most important topics of new European regulations and recent WHO recommendations on paediatric medicines. Purpose: The aim of this study was the preparation and characterization of mucoadhesive polymeric films as suitable dosage form for transmucosal drug delivery. Method: An aqueous solution of hyaluronic acid (Mr 1800-2300 kDa; D-glucuronic acid > 42 %) and an acidic solution of chitosan (Mr 150 kDa; deacetylation degree 97 %) were separately added to an aqueous solution of hydroxypropylmethylcellulose (HPMC; methoxyl content 19-24 %; hydroxypropyl content 7-12 %) at different weight ratios (1:1, 3:7, 1:9, 0:10; hyaluronate/HPMC or chitosan/HPMC). Each mixture was stirred at room temperature for 24 hours, spreaded on a Petridish and dried at 50 \ub0C for 6 h. Drug-free films and films with a child-appropriated dose of ondansetron hydrochloride were investigated. Physiochemical properties of the films (thickness, drug content, water uptake ability and mucoadhesion potential) and in vitro drug release were performed. Moreover, in vitro permeation studies will carry out in order to evaluate drug permeation through biological membranes. Results: Films were smooth and transparent, with good flexibility. The thickness was found to be uniform and drug content was close to the theoretical one (1 mg/cm2 for each film). Moreover, films showed good mucoadhesive properties and in particular the presence of hyaluronate allowed the highest mucoadhesion potential. Finally, the inclusion of chitosan in polymeric mixtures enhanced in vitro drug release with respect to the inclusion of hyaluronate, although chitosan/HPMC mixture showed the lowest water uptake. This behaviour could be attibuted to the high viscosity of the hyaluronate/HPMC films in the gel state. Conclusions: Our results indicate that buccal films based on different chitosan/HPMC and hyaluronate/HPMC mixtures could be used as a novel technological platform for paediatric medicines

Buccoadhesive films as a new dosage form for transmucosal delivery of ondansetron

Purpose The lack of appropriate pediatric formulations has been identified as a major obstacle for the study and use of drugs in children. In general, there is a need in pediatrics to develop flexible dosage forms able to allow minimal dosage and frequency, and characterized by minimal impact on lifestyle, and easy and reliable administration. The aim of this study was the development of buccoadhesive polymeric films for transmucosal delivery of ondansetron hydrochloride (ODS), a serotonin 5-HT3 receptor antagonist widely used in the management of nausea and vomiting. Methods An aqueous solution of hyaluronic acid (HA; MW 1800-2300 kDa), an aqueous solution of type B gelatine from bovine skin (GEL; MW 50 kDa) and an acid solution of chitosan (CH; MW 150 kDa) were separately added to an aqueous solution of hydroxypropylmethylcellulose (HPMC) at different weight ratios (10:0, 9:1, 7:3, 5:5, 0:10; HPMC:HA or HPMC:GEL or HPMC:CH). After addition of a child-appropriate dose of ODS, each mixture was stirred at room temperature for 24h, spreaded on a Petri-dish and dried at 50°C for 6h. The films were characterized for their morphology (SEM), physical state (DSC, XRPD), mucoadhesion potential (residence time), water uptake ability (gravimetric method) and drug release (modified “paddle over disk” method). Moreover, in vitro permeation studies will carry out to evaluate drug permeation throught biological membranes (Franz-type diffusion cell). Results All films exhibited a smooth surface and a dense and homogeneous cross-section. Characterization at the solid state indicated an amorphous molecular structure. 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 enhanced in vitro drug release with respect to the inclusion of HA, although HPMC:HA films showed the highest water uptake. This behaviour could be attributed to the high viscosity of the HPMC:HA films in the gel state. Conclusions HPMC can be mixed with HA, GEL and CH to obtain buccal films for the administration of ODS in children. The selection of suitable polymeric mixture and appropriate weight ratio allowed the modulation of film functional properties, suggesting that these formulations could be used as a novel technological platform for pediatric medicines

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

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 20 Hz for 4 h, using 3 spheres of 15 mm 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