Adsorption onto Mesoporous Silica Using Supercritical Fluid Technology Improves Dissolution Rate of Carbamazepine-a Poorly Soluble Compound.

The purpose of this research was to design and characterize an immediate-release formulation of carbamazepine (CBZ), a poorly soluble anti-epileptic drug, using a porous silica carrier. Carbon dioxide in its supercritical state (2000 psi, 30-35°C) was used as an anti-solvent to precipitate CBZ onto two particle size variants of silica. Adsorption isotherms were used as a pre-formulation strategy to select optimum ratios of silica and CBZ. The obtained drug-silica formulations were characterized by dissolution studies, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). This formulation strategy resulted in a 2.4-fold improvement in dissolution rate when compared to pure drug after 30 min of dissolution testing. PXRD and DSC confirmed the amorphous nature of CBZ in the formulations as well as the differences in polymorphic forms of commercial and supercritical fluid-processed CBZ. Additionally, solid-state NMR spectroscopy showed that the spin-lattice relaxation time for bulk drug (without silica) was ∼7.5 times greater than that for silica-confined CBZ, implying that when CBZ was adsorbed onto mesoporous silica, it is structurally disordered and had higher structural mobility, a characteristic of amorphous solids. The mesoporous silica matrix prevented CBZ crystal growth by imposing spatial constraint on CBZ nuclei and hence resulted in faster dissolution compared to bulk solid drug. Adsorption onto mesoporous silica using supercritical fluid technology may be used as a novel formulation strategy for amorphization of poorly soluble compounds, in turn improving their dissolution rate.

In vivo brain microdialysis as a formulation-screening tool for a poorly soluble centrally acting drug.

OBJECTIVE: Efficacy of a formulation of a poorly soluble centrally acting drug was evaluated by measuring dopamine responses using in vivo brain microdialysis. METHODS: Co-crystals (1:1) of carbamazepine and nicotinamide (CBZ-NCT) were complexed with cyclodextrins (γ-CDs) using supercritical fluid processing. Phase solubility and intrinsic dissolution were studied. Pharmacodynamic studies were performed on rats divided into three groups getting either CBZ-NCT in CD (20 mg/kg CBZ), pure CBZ solution or vehicle. A guide cannula was implanted to attach the microdialysis probe. Dialysate samples were analyzed for dopamine levels, which were compared between groups. RESULTS: The optimized CBZ formulation (5% w/w in γ-CD) with solubility - 10 mg/mL showed stepwise increase in dopamine response (maximum 250% of baseline) compared to neat CBZ or vehicle (p < 0.05). The pharmacokinetics of the drug required 30 min to elicit CNS response, which peaked at about 1.5-2 h. CONCLUSION: Hence, brain microdialysis was successfully used to evaluate a dissolution rate enhancing formulation.

In vivo brain microdialysis to evaluate FITC-dextran encapsulated immunopegylated nanoparticles.

CONTEXT: Delivery of drugs and dyes through intact blood-brain barrier (BBB) is extremely sought-after. A safe and reliable measurement of delivery efficacy in live animals is necessary. OBJECTIVE: To investigate the brain uptake of FITC-dextran MW 4000 (FD4) by CD71/OX-26 coated nanoparticles by microdialysis sampling and fluorescence/confocal microscopy. MATERIALS AND METHODS: Methoxy-poly(ethylene glycol)-poly(lactide) (Met-PEG-PLA) and maleimide-poly(ethylene glycol)-poly(lactide) (Mal-PEG-PLA) nanoparticles were prepared by nanoprecipitation. The surfaces of the prepared nanoparticles were embellished with CD-71/OX-26 antibodies for brain targeting. Male Sprague Dawley rats received 0.4 mg/kg FD4 and equivalent nanoparticulate formulation through lateral tail vein. Animals were euthanized 24 h postadministration, after which the tissues were harvested and analyzed for FD4 concentrations. Tissues were fixed with paraformaldehyde, cryotomed to 20 µm sections, and analyzed by Total Internal Reflection microscopy. RESULTS: Particle sizes of 200 ± 25 nm and zeta potentials of -18 ± 1 mV were obtained. FD4 concentrations, determined using in vivo brain microdialysis, were high on the first day (~360 ng/mL) compared to 60 ng/mL on the following 2 days. The nanoparticle treated animals showed significantly higher (p < 0.05) FD4 concentrations in the brain than pure-FD4 treated animals. Immunopegylated nanoparticles sustained and enhanced Central nervous system (CNS) concentration of hydrophilic dye for at least 3 days. CONCLUSION: Immunopegylated nanoparticles produce enhanced and sustained uptake of brain permeability marker FD4 relative to controls.