Sviluppo di nuove formulazioni di molecole attive sul sistema dopaminergico a livelli centrale

Drugs of recognized clinical efficacy show frequently limits in their clinical use when they are administrated trough conventional pharmaceutical forms. A sustained release for these drugs could be a usefull tool in order to improve their application in therapy. In this paper the potential advantages of two sustained release systems for active drugs on central dopaminergic system are evaluated. In particular, a new system for sustained release of dopamine was proposed for the Parkinson’s disease treatment and a new extended release formulation, already marketed, of the antipsychotic drug quetiapine was accurately analysed trough clinical studies. An important issue related to the dopamine involvement in the treatment of Parkinson’s disease, such as the use of its prodrug L-dopa, is the induction of the long term unwanted effects dyskinesias, wearing off and on-off. These effects seem caused by the fluctuations of dopamine concentration in the brain during the treatment. Controlled release systems of dopamine may be therefore useful in limiting this type of problem. The system designed and characterized for the controlled release of dopamine, during my PhD studies, consisted on tristearin based solid lipid microparticles (LMs). The synthesis of a new valeroyl ester of dopamine (3,4-O-divaleroyldopamine, DVD) has been necessary to obtain its encapsulation in the microparticles. Studies of DVD stability in human plasma demonstrated that this ester derivative is a suitable dopamine prodrug, being hydrolysed in this physiological fluid. As a consequence, DVD was employed for encapsulation studies. DVD loaded microparticles were able to control the release of the prodrug and to sensibly increase its half life in human plasma. Owing to micronic size of the particles and their optimal biocompatibility for the mucosal tissues, DVD loaded LMs may constitute an useful carrier in enhancing the administration ways of dopamine. As for quetiapine, the issue related to its use for schizophrenia treatment is the presence of unwanted effects, suchs as sedation, ipotension, dyzziness and syncope due to the high drug affinity for H₁ and α₁ receptors. These effects require to administrate quetiapine trough a slow titration, with dosages ineffective during the first days of therapy. As a conseguence, the quetiapine treatment could be inefficacious in the schizophrenia acute phase. In order to limit these effects, a new extended release (XR) formulation was developed. The XR role was the reduction of quetiapine plasmatic fluctuations with a consequent reduced impact of the drug toward H₁ and α₁ receptors. During my PhD, the in vivo kinetic profiles of XR and immediate release (IR) tablets were evaluated. In particular, clinical studies evidenced that XR and IR formulations allowed to obtain the same amounts of adsorbed quetiapine in terms of AUC values. On the other hand, the XR formulation induced lower plasmatic fluctuations during time of quetiapine than those induced by the IR formulation allowing a slower interaction with H₁ e α₁ receptors and so a reduction of adverse events such as sedation and ipotension. According to this behaviour, the XR formulation may allow to administrate high effective quetiapine dosages and to maintain a good tolerability profile in patients. Furthermore, the XR formulation induced an improvement of the hepatic cytochrome P450 3A4 efficiency in metabolizing quetiapine to N-desalkylquetiapine (norquetiapine), an active metabolite able to induce antidepressant acivity. Consequently, it has been hypothesized that the XR formulation could offer, with respect to the IR tablets, not only potential advantages against schizophrenia, but also against the bipolar depression by enhancing the production of quetiapine metabolite and therefore by improving the antidepressant efficacy of the drug.