Development of microparticles for oral administration of the non-conventional radical scavenger IAC and testing in an inflammatory rat model.

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), is an innovative non- radical scavenger used with success in numerous disease models such as inflammation, neurological disorders, hepatitis and diabetes. The pharmacological treatments have been performed by the intraperitoneal route of administration, representing to date, the main limit for the drug use. The aim of this study was to develop a delivery system that allows the oral administration of IAC while maintaining its therapeutic efficacy. Solid Lipid Microparticles (SLMs) containing a theoretical 18% (w/w) of IAC have been produced by the spray congealing technology; three formulations have been tested (A, B and C) using different low melting point carriers (stearic acid, Compritol(®) HD5ATO and carnauba wax) alone or in combination. All IAC loaded SLMs exhibited a spherical shape, encapsulation efficiency higher than 94% and particle size suitable for the oral route. Administered per os at different dosages in an inflammation rat model, all SLMs demonstrated their efficacy in reducing oedema and alleviating pain, compared to the gold standards Indomethacin and Paracetamol. These results suggested that the SLMs are an efficacious delivery system for the oral administration of IAC, potentially useful for the treatment of others diseases related to an over production of free radicals.

Multifunctional liposomes for nasal delivery of the anti-Alzheimer drug tacrine hydrochloride.

The purpose of this study was the development of multifunctional liposomes for nasal administration of tacrine hydrochloride. Liposomes were prepared using traditional excipients (cholesterol and phosphatidylcholine), partly enriched with α-tocopherol and/or Omega3 fatty acids. This approach was chosen in order to obtain at the same time two positive results: an enhanced drug permeation through nasal mucosa and a concomitant neuroprotective effect. Several liposome formulations were prepared using the Reverse Phase Evaporation technique followed by membrane filter extrusion. In particular, liposome capacity to enhance drug permeation was evaluated by means of membrane permeation and cellular uptake studies. Furthermore, liposome effect on neuronal viability and intracellular ROS production was evaluated as well as their cytoprotective effect against oxidative stress. All liposome formulations showed a mean diameter in the range of 175 nm to 219 nm with polydispersity index lower than 0.22, a lightly negative zeta potential and excellent encapsulation efficiency. Moreover, along with good mucoadhesive properties, multifunctional liposomes showed a markedly increase in tacrine permeability, which can be related to liposome fusion with cellular membrane, a hypothesis, which was also supported by cellular uptake studies. Finally, the addition of α-tocopherol without Omega3 fatty acids, was found to increase the neuroprotective activity and antioxidant properties of liposomes.

Layered lipid microcapsules for mesalazine delayed-release in children.

The goal was to make available a delayed-release dosage form of mesalazine to be dispersed in water to facilitate swallowing in adults and children. Mesalazine microparticles containing carnauba wax were prepared by spray-congealing technique. A second step of spray-congealing of carnauba microparticles dispersed in liquefied stearic acid gave rise to mesalazine lipid microcapsules in which several carnauba microparticles remained embedded as cores in a reservoir structure. In order to favor their water dispersion, the lipid microcapsules were dry coated by tumbling them with different ratios of mannitol/lecithin microparticles prepared by spray-drying. Release rate measurements showed a delayed-release behavior, in particular a pH-dependence with less than 10% of drug released in acidic medium and complete release in phosphate buffer pH 7.4 in 4-5h. The layering with hydrophilic excipient microparticles allowed manufacturing of a pH-dependent dosage form suitable for extemporaneous oral use in adults and children.

Albumin nanoparticles carrying cyclodextrins for nasal delivery of the anti-Alzheimer drug tacrine.

Peroral administration of tacrine, the first acetylcholinestearse inhibitor licensed for the treatment of Alzheimer's disease, is associated with low bioavailability, due to an extended first-pass methabolism, short elimination half-life and hepatotoxicity. Nasal drug delivery may reduce the degree of these problems. Tacrine hydrochloride nasal delivery is here investigated by means of albumin nanoparticles carrying beta cyclodextrin and two different beta cyclodextrin derivatives (hydroxypropyl beta cyclodextrin and sulphobutylether beta cyclodextrin). Bovine serum albumin nanoparticles were obtained using a coacervation method, followed by thermal cross-linking, starting from protein solution at alkaline pH. After preparation, nanoparticles were loaded by soaking from solutions of tacrine hydrochloride and lyophilised. Thermal analysis (differential scanning calorimetry and thermogravimetric analysis) supported by Fourier Transform Infrared Spectroscopy were performed in order to confirm protein cross-linking in nanosphere structure and possible drug/carrier interaction occurred after the loading process. Moreover, size, polydispersity, zeta potential and morphology of the nanoparticles were investigated as well as drug loading, mucoadhesion properties and ex-vivo drug permeation ability. Results indicate that all the nanoparticles presented a mean size and a polydispersity lower than 300nm and 0.33nm, respectively, were spherical shaped and negatively charged even after drug loading. Moreover, the presence of the different beta cyclodextrins in the polymeric network affected drug loading and could differently modulate nanoparticle mucoadhesiveness and drug permeation behaviour.

Hydroxypropylmethylcellulose films for prolonged delivery of the antipsychotic drug chlorpromazine.

OBJECTIVES: The aim of this study was to develop transdermal films based on hydroxypropylmethylcellulose with the purpose of improving transdermal permeation of chlorpromazine hydrochloride, an antipsychotic drug used to alleviate the symptoms and signs of psychosis. METHODS: Hydroxypropylmethylcellulose films were prepared and evaluated for their drug content, film thickness, residual water content and bioadhesive properties. In-vitro permeation experiments were performed in the absence and in the presence of permeation enhancers (oleic acid, polysorbate 80, or both) with the purpose of improving drug availability. Other formulative parameters, such as drug and plasticizer concentration and hydroxypropylmethylcellulose type, were investigated. KEY FINDINGS: Both oleic acid and polysorbate 80 had significant effect on drug permeation with respect to the control formulation. In particular films containing a mixture of oleic acid and polysorbate 80 provided the best enhancement activity for chlorpromazine. Moreover, a decrease in propylene glycol or chlorpromazine content or an increase of hydroxypropylmethylcellulose viscosity provided lower cumulative amounts of drug permeated. CONCLUSIONS: The results obtained confirm that chlorpromazine permeation can be easily modulated by varying the composition of hydroxypropylmethylcellulose-based films. These formulations could serve as candidates for transdermal delivery of antipsychotic drugs.

Freeze-dried chitosan/pectin nasal inserts for antipsychotic drug delivery.

The objective of this investigation was the development of chitosan/pectin based nasal inserts to improve bioavailability of antipsychotic drugs in the treatment of psychotic symptoms. In fact, the nasal route of administration ensures systemic availability avoiding the first-pass metabolism and obtaining more efficacious treatments. Chitosan/pectin polyelectrolyte complexes were prepared at pH 5.0 with different polycation/polyanion molar ratios and lyophilized in small inserts in the presence of chlorpromazine hydrochloride. The results show that higher amount of pectin in the complexes, with respect to higher amount of chitosan, produced a more evident porous structure of the nasal inserts, improving water uptake ability and mucoadhesion capacity. Finally, the presence of increasing amounts of pectin allowed the interaction with chlorpromazine hydrochloride inducing the formation of less hydratable inserts thus limiting drug release and permeation. This investigation verifies the formation of polyelectrolyte complexes between chitosan and pectin at pH values in the vicinity of the pKa interval of the two polymers and confirms the potential of these complexes, capable of achieving antipsychotic drug delivery in the nasal cavity.