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
\nthey are administrated trough conventional pharmaceutical forms. A sustained release
\nfor these drugs could be a usefull tool in order to improve their application in therapy.
\nIn this paper the potential advantages of two sustained release systems for active
\ndrugs on central dopaminergic system are evaluated. In particular, a new system for
\nsustained release of dopamine was proposed for the Parkinson’s disease treatment
\nand a new extended release formulation, already marketed, of the antipsychotic drug
\nquetiapine was accurately analysed trough clinical studies.
\nAn important issue related to the dopamine involvement in the treatment of Parkinson’s
\ndisease, such as the use of its prodrug L-dopa, is the induction of the long term
\nunwanted effects dyskinesias, wearing off and on-off. These effects seem caused by
\nthe fluctuations of dopamine concentration in the brain during the treatment. Controlled
\nrelease systems of dopamine may be therefore useful in limiting this type of problem.
\nThe system designed and characterized for the controlled release of dopamine, during
\nmy PhD studies, consisted on tristearin based solid lipid microparticles (LMs). The
\nsynthesis of a new valeroyl ester of dopamine (3,4-O-divaleroyldopamine, DVD) has
\nbeen necessary to obtain its encapsulation in the microparticles. Studies of DVD
\nstability in human plasma demonstrated that this ester derivative is a suitable
\ndopamine prodrug, being hydrolysed in this physiological fluid. As a consequence,
\nDVD was employed for encapsulation studies. DVD loaded microparticles were able to
\ncontrol the release of the prodrug and to sensibly increase its half life in human plasma.
\nOwing to micronic size of the particles and their optimal biocompatibility for the
\nmucosal tissues, DVD loaded LMs may constitute an useful carrier in enhancing the
\nadministration ways of dopamine.
\nAs for quetiapine, the issue related to its use for schizophrenia treatment is the
\npresence of unwanted effects, suchs as sedation, ipotension, dyzziness and syncope
\ndue to the high drug affinity for H1 and α1 receptors. These effects require to
\nadministrate quetiapine trough a slow titration, with dosages ineffective during the first
\ndays of therapy. As a conseguence, the quetiapine treatment could be inefficacious in
\nthe schizophrenia acute phase. In order to limit these effects, a new extended release
\n(XR) formulation was developed. The XR role was the reduction of quetiapine
\nplasmatic fluctuations with a consequent reduced impact of the drug toward H1 and α1
\nreceptors.
\nDuring my PhD, the in vivo kinetic profiles of XR and immediate release (IR) tablets
\nwere evaluated. In particular, clinical studies evidenced that XR and IR formulations
\nallowed 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
\nof quetiapine than those induced by the IR formulation allowing a slower interaction
\nwith H1 e α1 receptors and so a reduction of adverse events such as sedation and
\nipotension. According to this behaviour, the XR formulation may allow to administrate
\nhigh effective quetiapine dosages and to maintain a good tolerability profile in patients.
\nFurthermore, the XR formulation induced an improvement of the hepatic cytochrome
\nP450 3A4 efficiency in metabolizing quetiapine to N-desalkylquetiapine (norquetiapine),
\nan active metabolite able to induce antidepressant acivity. Consequently, it has been
\nhypothesized that the XR formulation could offer, with respect to the IR tablets, not only
\npotential advantages against schizophrenia, but also against the bipolar depression by
\nenhancing the production of quetiapine metabolite and therefore by improving the
\nantidepressant efficacy of the drug.

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