Amélie Bochot

Intravitreal administration of antisense oligonucleotides: potential of liposomal delivery.

Antisense oligonucleotides are short synthetic fragments of genes that are able to inhibit gene expression after being internalized by cells. They can therefore be used as antiviral compounds particularly, for the treatment of ocular viral infections (i.e. Herpes simplex virus or Cytomegalovirus, CMV). Antisense oligonucleotides are however poorly stable in biological fluids and their intracellular penetration is limited. Although oligonucleotides are now currently used in therapeutics for the treatment of CMV by intravitreal injection (Vitravene) their main drawbacks impose to repeat the number of administrations which can be very harmful and damaging. A system that is able to permit a protection of oligonucleotides against degradation and their slow delivery into the vitreous would be more favorable for improving patient compliance. The use of liposomes for intravitreal administration can be very promising since these lipid vesicles are able to protect oligonucleotides against degradation by nucleases and they allow to increase the retention time of many drugs in the vitreous. In this review, the potentialities of liposomes for the intravitreal delivery of oligonucleotides will be discussed.

Direct Formation of Nanospheres from Amphiphilic β-Cyclodextrin Inclusion Complexes

AbstractPurpose. The aim of this work was to develop and characterize a highly loaded nanoparticulate system based on amphiphilic β-cyclodextrins (CDs) to facilitate the parenteral administration of poorly soluble antifungal model drugs bifonazole and clotrimazole.nMethods. Inclusion complexes were characterized with spectroscopic techniques. Particle size distribution of nanospheres were determined by photon correlation spectroscopy (PCS). Nanospheres were assessed for hemolytic activity. Entrapped and released drug quantities were determined and minimum inhibitory concentration (MIC) values of drugs, amphiphilic β-CDs, and drug loaded nanospheres were evaluated.nResults. 1:1 inclusion complexes of model drugs with amphiphilic β-CDs gave nanospheres <300 nm (polydispersity index < 0.15) by nanoprecipitation technique without using surfactants. By direct preparation from preformed inclusion complexes, loading was increased 2- to 8-fold depending on CD type and loading technique. Conventionally loaded CD nanospheres displayed immediate release whereas preloaded and highly loaded nanospheres liberated model drugs over a period of 1 h reducing the initial burst effect. MIC values of bifonazole and clotrimazole were lowered significantly when associated to amphiphilic β-CD nanospheres.nConclusion. Amphiphilic β-CDs form nonsurfactant, highly loaded nanospheres with lower hemolytic activity than that of natural CDs directly from inclusion complexes. They enhanced solubility and subsequently therapeutic efficacy of the model drugs.

Non-surfactant nanospheres of progesterone inclusion complexes with amphiphilic β-cyclodextrins

Amphiphilic beta-cyclodextrins were formulated as nanospheres and characterised by particle size, zeta potential and TEM following freeze-fracture. The nanospheres were loaded with progesterone with different loading techniques involving the spontaneous formation of nanospheres from pre-formed inclusion complexes of amphiphilic beta-cyclodextrins modified on the primary or secondary face with progesterone. Inclusion complexes were characterised with various techniques including Differential Scanning Calorimetry (DSC), Fast Atom Bombardment Mass Spectrometry (FAB MS) and 1H NMR spectroscopy; and progesterone was believed to be partially included in the CD cavity. Loading properties of conventionally-loaded nanospheres were compared with those prepared directly from pre-formed inclusion complexes and loading technique was found to enhance associated drug percentage significantly (P<0.05). Although both amphiphilic beta-cyclodextrins (6-N-CAPRO-beta-CD and beta-CDC6) were capable of high progesterone loading, beta-CDC6 displayed slightly higher entrapment efficiency due to the possible higher affinity of progesterone to the 14 alkyl chains surrounding this molecule resulting in higher drug adsorption to particle surface. Progesterone was released within a period of 1 h from all formulations. Progesterone-loaded amphiphilic beta-CD nanospheres were proved to be a promising non-surfactant injectable delivery system providing high-quantity of water-insoluble progesterone rapidly within 1 h.