Zidovudine-Poly(l-Lactic Acid) Solid Dispersions with Improved Intestinal Permeability Prepared by Supercritical Antisolvent Process

Abstract

A supercritical antisolvent (SAS) process for obtaining zidovudine-poly(L-lactic acid) (PLLA) solid dispersions (SDs) was used to attain a better intestinal permeation of this drug. A 3(2) factorial design was used, having as independent variables the ratio 3'-azido-2'3'-dideoxythymidine (AZT)-PLLA and temperature/pressure conditions, as dependent variables the process yield and particle macroscopic morphology. AZT-PLLA production batches were carried out by the SAS process, and the resulting products evaluated via scanning electron microscope, X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared analyses. From the nine possible combinations of tests performed experimentally, only one combination did not produced a solid. The L3 batch of SD, produced with 1:2 (AZT-PLLA) ratio, resulted in a 91.54% yield, with 40% AZT content. Intestinal permeability studies using the AZT-PLLA from L3 batch led to an AZT permeability of approximately 9.87%, which was higher than that of pure AZT (∼3.84%). AZT remained in crystalline form, whereas PLLA remained in semicrystalline form. AZT release is controlled by a diffusion mechanism. It has been demonstrated that it is possible to use PLLA carrier and SAS process to obtain SD, in a single step.

Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies

“…Glibenclamide ASDs prepared by the SAS were shown to have similar solubility as those prepared by solvent evaporation using a rotary evaporator 208 . A recent study further demonstrated improved permeability of zidovudine-poly (l-lactic acid) solid dispersions relative to the pure crystalline drug when tested in an ex vivo everted rat intestinal sac model 224 . The observed effect was attributed to the enhanced poly ( l -lactic acid) (polymer) plasticization which increased the extent of drug diffusion in the polymer matrix.…”

PLA/PLGA-Based Drug Delivery Systems Produced with Supercritical CO2—A Green Future for Particle Formulation?

“…Although the EE was higher for the drug:polymer ratio of 1:2, ex vivo experiments that evaluated the intestinal permeability proved higher zidovudine permeation for the 1:1 ratio. This result indicates that the use of SAS method allows the modification of suitable polymeric carrier systems in terms of absorption and dissolution properties of the drug [102].…”

“…In another study, anti-retroviral drugs presenting low permeability, high dissolution rate and low bioavailability such as zidovudine (3 -azido-2 3 -dideoxythymidine) were considered for their encapsulation into PLLA using SAS, to obtain solid dispersions that improve intestinal absorption [102]. Briefly described, three different zidovudine:PLLA ratios (2:1, 1:1 and 1:2) were formulated in ethanol using three different pressures (P = 135, 100 and 85 bar) while keeping the temperature constant at 45 • C for all runs.…”

Supercritical Antisolvent Process for Pharmaceutical Applications: A Review

“…In reverse, the drug release is prolonged using a polymer with a hydrophobic behavior, as occurs, for example, by selecting zein [17,[46][47][48][49]. Similarly, a sustained or prolonged release of the active compound was observed from particles based on polylactic acid (PLA) and poly (L-lactic acid) (PLLA) [32,67,98,99,111,112,[118][119][120][121], which, until now, has been mostly employed to deliver anticancer drugs.…”

“…PVP is currently the most used polymer and is considered one of the best carriers [8,9,11,31,33,35,65,70,80,81,93,94,97,103,[115][116][117]123] since it is often allowed to obtain regular and spherical composite particles. PVP is followed by PLA [45,108,124] and PLLA [41,67,98,99,[111][112][113][118][119][120][121][125][126][127] that are also suitable carriers often employed. Recently, zein [17,46] is also established as a good polymeric carrier for SAS coprecipitation; moreover, β-CD [22,128] seems to be a promising polymer, but its use has to be further investigated given the very few existing papers.…”