Formulation study of cysteamine microparticulate systems

Abstract

ABSTRACT

Cysteamine is clinically used for the treatment of nephropathic cystinosis and is orally administered as cysteamine bitartrate. The daily dose of cysteamine (Cystagon®) for treatment of cystinosis in paediatric patients is 50 mg/kg per day, shared in four administrations, meaning that patients are required to awake from sleep. Because of the heavy regimen and the associated symptoms, patient non-adherence to the treatment constituted a major problem, especially among adolescent and young adults. In Procysbi®, the novel orphan product, these problems were faced by the construction of a delayed release formulation. Therefore, the reduction of the frequency of cysteamine dose by formulating a controlled release preparation and the improvement of the taste and smell of the drug would increase the adherence to the therapy. In this PhD research project, a formulation approach differing from the classical coating solutions was proposed. Both for obtaining an intellectual protection and for drug controlled release and taste masking reasons, the novel formulation approach was based on a matrix drug delivery system. Manufacturing processes easy to industrialize and open to patent possibilities were identified in the spray-congealing and spray-drying technologies on which several contract manufacturing companies created their business. Several types of lipid microparticles containing cysteamine bitartrate, using the spray-congealing and spray-drying techniques, were manufactured. Due to the hydrophobic property of the lipid microparticles, they were not well dispersed in the dissolution medium but tended to remain on the surface and this could adversely affect the dissolution process. To improve the wettability of the lipid microparticles, they were mixed with spray-dried mannitol/lecithin or sucralfate/lecithin microparticles. In this way, a hydrophilic layer of the spray-dried excipient microparticles was deposited on the surface of the cysteamine bitartrate lipid microparticles simply by mixing, increasing the wettability of the lipid microparticles. The results of the preliminary phase on a laboratory scale facility proved that the lipid microparticles were promising for the preparation of paediatric extemporaneous dosage forms for taste masking and prolonged release of cysteamine bitartrate. After the initial formulation design on laboratory scale equipment, the scale-up of no-GMP batches was carried out at Xedev bvba (Zelzate, Belgium) production site, with a new facility able to strictly control the process parameters. Based on the results obtained, the regulatory status and the evaluation of ADI (Admitted Daily Intake), different spray-congealing and spray-drying prototypes were investigated and analyzed for the following characteristics: particle size distribution, PXRD (X-ray diffractometry), dissolution (before and after mixing with excipients to avoid floating), DSC, TGA, assay and impurities. Prototypes were stored at two different conditions for 2 weeks to assess the physical and chemical stability. From the results obtained during the research project, it was possible to conclude that cysteamine lipid microparticles proved to be suitable for the industrial no-GMP scale-up manufacturing. The final proposed drug product was an extemporaneous oral powder to be administered in a sachet by suspending it in water or other suitable liquids.

Cysteamine, approved for the treatment of nephropathic cystinosis, was shown to have in vitro potential antimicrobial, anti-biofilm and mucoactive properties in the treatment of cystic fibrosis patient infections. A dry powder inhaler was identified to be the most appropriate inhalation product of cysteamine for this therapeutic objective since the deposition of drug particles could better perform the antimicrobial, anti-biofilm and mucolytic activities, due to the high drug concentration attainable at deposition site. Inhalation powders of cysteamine, as free base or bitartrate, were obtained by spray-drying technique. The design of formulation was to face the hygroscopicity and the poor stability of the active substance by adding appropriate adjuvants that could help in the stabilization of drug and at same time in promoting its respirability. Acidic polymers for particle formation and deaggregating excipients for respirability improvement, both compatible with the inhalation route, were selected. In details, hyaluronic acid was selected as acidic polymer to obtain a stable inhalation spray-dried powder, constituted by the novel cysteamine hyaluronate salt formed during the spray drying process. Cysteamine hyaluronate salts were characterized in terms of drug content determination, solid state investigation (TGA, SEM) and in vitro aerodynamic assessment. In the preformulation study of cysteamine spray-dried powders starting from cysteamine free base, the instability of the drug molecule in environmental conditions was taken into account. From the results of the preformulation study, four formulations of cysteamine hyaluronate microparticles were identified as the most promising in relation to drug content, particle size distribution and fine particle fraction values. These formulations were further investigated in terms of in vitro cytotoxicity assays on different cell lines of the respiratory epithelium where they proved to be non-toxic. Furthermore, rheological experiments were conducted to assess the mucolytic activity of cysteamine. The results showed that the drug was able to provide a reduction of both the viscous and the elastic properties of different mucus mimetic samples. Apart from cysteamine base, also cysteamine bitartrate was investigated for the manufacturing of spray dried microparticles. Excipients like trehalose and cyclodextrins were selected in order to improve cysteamine bitartrate stability during the spray drying process.