Drug structural features affect drug delivery from hyperbranched polyesteramide hot melt extrudates.

The aim of this study was firstly to evaluate the utility of Hybrane S1200 as a hot melt extrusion (HME) carrier to prepare instant-release multiparticulate systems for very poorly-soluble drugs such as ketoconazole or nifedipine. Hybrane S1200 allows an easy extrusion of its drug mixtures at a relatively low temperature, not higher than 90°C, and with no need of any additional aid. Extrudates containing 10% of nifedipine or ketoconazole form monophasic systems. Nifedipine extrudate shows no drug release in drug dissolution rate tests while ketoconazole extrudate release reaches only 60% of drug content. Additionally, a turbidity in the dissolution medium due to the formation of a kind of polymer vesicles (ranging 3-0.2µm in size) is observed. These facts could suggest a chemical interaction between the polymer and both drugs, triggered by the HME process. Both nifedipine and ketoconazole share characteristic acid-base profiles that could facilitate a degradation processes within the polymer, thus modifying Hybrane's water-solubility and polar nature. Such modified polymer structure, when in aqueous medium, forms the aforementioned stable vesicles that may encapsulate the drugs, thus making its delivery difficult or even preventing it.

Drug dispersion degree and drug dissolution rate in Hybrane S1200-based instant-release matricial particles prepared by hot melt extrusion.

The objective of this study is to evaluate the dissolution of a poorly soluble drug (prednisolone) from different sized matricial particles (from <250 to >1500 µm) with two drug contents (10% or 20%) obtained by hot melt extrusion using the hyperbranched polyesteramide Hybrane S1200 (water-soluble and with a Tg of 45 °C) as the carrier. X-ray diffraction, differential scanning calorimetry and SEM studies permit us to conclude that in 10% prednisolone extrudate, the drug is mainly dispersed within the carrier, whereas in those containing 20% an important fraction of the drug remains in a crystalline state and is accumulated on the surface of the extrudates. On particles proceeding from 10% drug extrudate, the drug dissolution rate is very high and slightly dependant on particle size and in all cases, higher than the pure micronized drug. However, on particles proceeding from 20% prednisolone extrudate particle size have a major effect on drug dissolution rate, attributable to higher proportions of crystalline drug accumulated on the surface, hindering polymer dissolution. Thus, the reduction of the particle size after extrudate grinding creates new surfaces from inside, that leads to strong increments on prednisolone dissolution rate, and becomes higher than the pure micronized drug one when the particle size is <250 µm.

Evaluation of the hyperbranched polymer Hybrane H1500 for production of matricial controlled-release particles by hot-melt extrusion.

Extrudates of the hyperbranched polymer Hybrane H1500 prepared by hot melt extrusion, with five particle sizes (from <250 µm to 1.5-2.0 mm) and three drug content (10, 20 and 30%) of acetaminophen or caffeine, were evaluated in this study as potential multiparticulate controlled release systems. Hybrane H1500 extrudates (of very low porosity), experienced a very slow hydration, with a limited swelling capacity, and they do not behave as true gels when fully hydrated. Hot melt extrusion provokes the conversion of the acetaminophen into an amorphous state inside the extrudates, whereas for those containing caffeine, some crystals remain for the highest drug proportions (20 and 30%). From both drug extrudates a wide range of dissolution profiles are obtained. Drug release rate depends mostly on extrudate particle size, and in those extrudates containing caffeine, a slight effect of the drug proportion is observed. Dissolution profiles' kinetic analysis suggests that drug release is controlled by the diffusion of the drug through the polymeric hydrated structure, although this mechanism is only clearly and efficiently displayed for the greatest extrudate particles (1.5-2.0 mm).

Utility of the hyperbranched polymer Hybrane S1200 for production of instant-release particles by hot melt extrusion.

Particles composed of 90:10 or 80:20 mixtures of the hyperbranched poly(esteramide) Hybrane S1200 and the poorly water-soluble drug hydrochlorothiazide were produced by hot melt extrusion at maximum temperatures of 90°C without any need for addition of a plasticizer. In dissolution rate assays in USP 29 apparatus II, particles of the smallest size category (<250 µm) containing 10% of hydrochlorothiazide released 95% of their load within 5 min. This fast release is attributed to the combination of the high solubility of Hybrane S1200, the dispersion of the drug in non-crystalline form in the polymer matrix (attested to by the results of powder X-ray diffractometry, and scanning electron microscopy), and to the fact that the main interaction between drug and polymer is through hydrogen bonds (attested to by ATR-IR difference spectra).