D. Voinovich

Spray-dried chitosan/ethylcellulose microspheres for nasal drug delivery: swelling study and evaluation of in vitro drug release properties.

The aim of this study was to develop spray-dried chitosan-based microspheres, suitable for nasal delivery of loratadine, and to evaluate their potential of modifying loratadine release. The microspheres were composed with ethylcellulose (EC) and chitosan (CM) in two different weight ratios, 1:2 and 1:3. One-phase systems (dispersions) and two-phase systems (emulsions and suspensions) were subjected to spray-drying, resulting in conventional and composed microspheres, respectively. The microspheres were evaluated with respect to the yield, particle size, encapsulation efficiency, physical state of the drug in the polymer matrix, swelling properties and in vitro drug release profile. It was shown that particle size, swelling ability and loratadine release from spray-dried microspheres were significantly affected by the polymeric composition and feed concentration in spray-drying process. Emulsifying method to produce composed EC/CM microspheres resulted in improved loratadine entrapment and moderate swelling, when compared to conventional chitosan microspheres. It seems like better formation of EC cores and chitosan coating were obtained when higher feed concentration and ultrasonic homogenization were employed in the preparation of emulsion systems and when EC to CM weight ratio was 1:3.

Theoretical and experimental study on theophylline release from stearic acid cylindrical delivery systems

The purpose of this study is to evaluate the possibility of developing a cylindrical sustained-release dosage form for theophylline directly by means of a ram extrusion process. In particular, the formulations contained: stearic acid as a low melting binder, monohydrate lactose and polyethylene glycol 6000 as hydrophilic fillers. The influence of type and percentage of the components was studied considering different parameters such as the time required for 50% of the drug release (t50%)and the drug diffusion coefficient in the delivery system. The choice of the different formulations to be tested is carried out employing an axial design with constraint domains. The limits of each component were fixed on the basis of preliminary trials. The analysis of the t50% values revealed that the release kinetics is mainly affected by stearic acid and theophylline content, whilst lactose effect is almost negligible. A substantial correspondence between the experimental results and the analysis of the drug release kinetics performed by means of an ad hoc developed mathematical model was found. The proposed mathematical model allows to conclude that wherever the release mechanism is initially ruled by dissolution, then diffusion plays the most important role.

Spray-dried carbamazepine-loaded chitosan and HPMC microspheres: preparation and characterisation.

In this study, the potential of the spray‐drying technique for preparing microspheres able to modify the release profile of carbamazepine was investigated. Low‐, medium‐ and high‐molecular‐weight chitosan and hydroxypropyl methylcellulose (HPMC) in different drug–polymer ratios were used for the preparation of microspheres. The microspheres, characterized by X‐ray powder diffractometry (XRD) and differential scanning calorimetry (DSC), were also studied with respect to particle size distribution, drug content and drug release. The results indicated that the entrapment efficiency (EE), as well as carbamazepine release profile, depended on polymeric composition and drug– polymer ratios of the microspheres prepared. The best entrapment efficiencies were obtained when chitosan of low‐molecular‐weight (CL) or HPMC were used for the microencapsulation. For all types of polymer used, the microspheres with low carbamazepine loading (6.3% w/w) showed better control of drug release than the microspheres with higher drug loadings. The HPMC microspheres showed the slowest carbamazepine release profile with no initial burst effect. Carbamazepine release profiles from ternary systems, carbamazepine–CL–HPMC microspheres, depended mostly on HPMC content and showed similar carbamazepine release profile as CL microspheres when HPMC content was low (9:1 CL–HPMC ratio, w/w). Otherwise, the carbamazepine release from CL–HPMC microspheres was remarkably faster than from either chitosan or HPMC microspheres. The release profile of carbamazepine from the microspheres was highly correlated with the crystalline changes occurring in the matrix.

Study of the solid state of carbamazepine after processing with gas anti-solvent technique

The purpose of this study was to investigate the influence of supercritical CO2 processing on the physico-chemical properties of carbamazepine, a poorly soluble drug. The gas anti-solvent (GAS) technique was used to precipitate the drug from three different solvents (acetone, ethylacetate and dichloromethane) to study how they would affect the final product. The samples were analysed before and after treatment by scanning electron microscopy analysis and laser granulometry for possible changes in the habitus of the crystals. In addition, the solid state of the samples was studied by means of X-ray powder diffraction, differential scanning calorimetry, diffuse reflectance Fourier-transform infrared spectroscopy and hot stage microscopy. Finally, the in vitro dissolution tests were carried out. The solid state analysis of both samples untreated and treated with CO2, showed that the applied method caused a transition from the starting form III to the form I as well as determined a dramatic change of crystal morphology, resulting in needle-shaped crystals, regardless of the chosen solvent. In order to identify which process was responsible for the above results, carbamazepine was further precipitated from the same three solvents by traditional evaporation method (RV-samples). On the basis of this cross-testing, the solvents were found to be responsible for the reorganisation into a different polymorphic form, and the potential of the GAS process to produce micronic needle shaped particles, with an enhanced dissolution rate compared to the RV-carbamazepine, was ascertained.

Solid state mechanochemical simultaneous activation of the constituents of the Silybum marianum phytocomplex with crosslinked polymers

Simultaneous improvement of solubilization kinetics of main flavolignans of Silybum marianum extract was obtained cogrinding with two crosslinked polymers: micronized crospovidone, PVP-CL(R) and sodium carboxymethylcellulose, Ac-Di-Sol(R) in the 1:3 active-to-polymer weight ratio. By this process it was assessed that the main extract components lost its crystalline structure, and the powder surface area was increased by 2.1- and 1.7-fold in the coground products with Ac-Di-Sol(R) and PVP-CL(R), respectively. This activated status of the dry extract remained stable over a period of 2 years. Solubilization kinetics resulted ameliorated both in terms of entire dry extract and in terms of single components. When the 1/3 coground systems with PVP-CL(R) and Ac-Di-Sol(R) were dissolved in saturated conditions they gave a concentration improvement compared to the native product of 8 and 31 times of silybin A, 7 and 27 times of silybin B, whereas in the case of silychristin a double concentration was obtained only using Ac-Di-Sol(R). The in vivo studies on rats confirmed that this solubilization improvement corresponded to an effective oral bioavailability enhancement. The highest bioavailability improvement was obtained with Ac-Di-Sol(R), with a relative bioavailability of 88.6, 17.96, and 16.4 compared to the extract for silybin A, silybine B, and silychristine, respectively.

Synthesis of a new mPEG-dexamethasone conjugate and preliminary bioavailability studies in rabbits

Poly(ethylene glycol) esters have been proposed as a potential oral-controlled drug delivery system for dexamethasone (DXM). The drug was covalently attached to monomethoxypolyethylene glycol amine (mPEG-NH 2 ) (Mw = 10,000 Da) using a succinate linker. A new PEG-based prodrug system was designed using ester derivatives. The drug-polymer conjugate (mPEG-DXM) was freely water soluble at room temperature. First of all, the adduct hydrolytic stability was assessed at physiological pH. Then, the bioavailability was evaluated by orally administering the mPEG-DXM conjugate in rabbits and comparing to that obtained by the intravenous route. The area under the concentration-time curve (AUC) of PEGylated drug was twice as large as that of the parent drug after oral administration. In conclusion, PEGylated DXM was useful for maintaining the DXM concentration in the blood after oral administration.