Predicting the environmental emissions arising from conventional and nanotechnology-related pharmaceutical drug products.

Today, environmental pollution with pharmaceutical drugs and their metabolites poses a major threat to the aquatic ecosystems. Active substances such as fenofibrate, are processed to pharmaceutical drug formulations before they are degraded by the human body and released into the wastewater. Compared to the conventional product Lipidil® 200, the pharmaceutical product Lipidil 145 One® and Ecocaps take advantage of nanotechnology to improve uptake and bioavailability of the drug in humans. In the present approach, a combination of in vitro drug release studies and physiologically-based biopharmaceutics modeling was applied to calculate the emission of three formulations of fenofibrate (Lipidil® 200, Lipidil 145 One®, Ecocaps) into the environment. Special attention was paid to the metabolized and non-metabolized fractions and their individual toxicity, as well as to the emission of nanomaterials. The fish embryo toxicity test revealed a lower aquatic toxicity for the metabolite fenofibric acid and therefore an improved toxicity profile. When using the microparticle formulation Lipidil® 200, an amount of 126 mg of non-metabolized fenofibrate was emitted to the environment. Less than 0.05% of the particles were in the lower nanosize range. For the nanotechnology-related product Lipidil 145 One®, the total drug emission was reduced by 27.5% with a nanomaterial fraction of approximately 0.5%. In comparison, the formulation prototype Ecocaps reduced the emission of fenofibrate by 42.5% without any nanomaterials entering the environment. In a streamlined life cycle assessment, the lowered dose in combination with a lowered drug-to-metabolite ratio observed for Ecocaps led to a reduction of the full life cycle impacts of fenofibrate with a reduction of 18% reduction in the global warming potential, 61% in ecotoxicity, and 15% in human toxicity. The integrated environmental assessment framework highlights the outstanding potential of advanced modeling technologies to determine environmental impacts of pharmaceuticals during early drug development using preclinical in vitro data.

Predicting drug release and degradation kinetics of long-acting microsphere formulations of tacrolimus for subcutaneous injection.

Today, tacrolimus represents a cornerstone of immunosuppressive therapy for liver and kidney transplants and remains subject of preclinical and clinical investigations, aiming at the development of long-acting depot formulations for subcutaneous injection. One major challenge arises from establishing in vitro-in vivo correlations due to the absence of meaningful in vitro methods predictive for the in vivo situation, together with a strong impact of multiple kinetic processes on the plasma concentration-time profile. In the present approach, two microsphere formulations were compared with regards to their in vitro release and degradation characteristics. A novel biorelevant medium provided the physiological ion and protein background. Release was measured using the dispersion releaser technology under accelerated conditions. A release of 100% of the drug from the carrier was achieved within 7 days. The capability of the in vitro performance assay was verified by the level A in vitro-in vivo correlation analysis. The contributions of in vitro drug release, drug degradation, diffusion rate and lymphatic transport to the absorption process were quantitatively investigated by means of a mechanistic modelling approach. The degradation rate, together with release and diffusion characteristics provides an estimate of the bioavailability and therefore can be a guide to future formulation development.

A sensitive in vitro performance assay reveals the in vivo drug release mechanisms of long-acting medroxyprogesterone acetate microparticles.

Today, a growing number of subcutaneously administered depot formulations enable continuous delivery of poorly soluble compounds over a longer time period. The modified liberation is considered to be a rate-limiting step in drug absorption and thus impacts therapeutic efficacy and product safety. In the present approach, a mechanism-based pharmacokinetic model of the commercial microparticle formulation depo-subQ provera 104™ (Sauter mean diameter of 5.08 ± 1.63 µm) was established. The model was verified using human pharmacokinetic data from three different clinical trials. Further, the effects of drug release, injection site and patient population on the pharmacokinetic profile were investigated. For this purpose, the drug release was assessed using the novel dispersion releaser technology, whereby a biorelevant medium reflecting major characteristics of the subcutaneous tissue (including ion background, buffer capacity and protein concentration) was used. The established model provided an effective prediction of the key pharmacokinetic parameters, including Cmax, Tmax and AUCall. Only in presence of 55% of fetal bovine serum (using a novel simulated subcutaneous interstitial fluid), the release assay was capable to discriminate between microparticles before and after storage.

Predicting human pharmacokinetics of liposomal temoporfin using a hybrid in silico model.

Over the years, the performance of the liposomal formulations of temoporfin, Foslip® and Fospeg®, was investigated in a broad array of cell-based assays and preclinical animal models. So far, little attention has been paid to the influence of drug release and liposomal stability on the plasma concentration-time profile. The drug release is a key attribute which impacts product quality and the in vivo efficacy of nanocarrier formulations. In the present approach, the in vitro drug release and the drug-protein transfer of Foslip® and Fospeg® was determined using the dispersion releaser technology. To analyze the stability of both formulations in physiological fluids, nanoparticle tracking analysis was applied. A comparable drug release behavior and a high physical stability with a vesicle size of approximately 92 ± 2 nm for Foslip® and at 111 ± 5 nm for Fospeg® were measured. The development of a novel hybrid in silico model resulted in an optimal representation of the in vivo data. Based on the information available for previous formulations, the model enabled a prediction of the performance of Foslip® in humans. To verify the simulations, plasma concentration-time profiles of a phase I clinical trial were used. An absolute average fold error of 1.4 was achieved. Moreover, a deconvolution of the pharmacokinetic profile into different fractions relevant for the in vivo efficacy and safety was achieved. While the total plasma concentration reached a cmax of 2298 ng/mL after 0.72 h, the monomolecular drug accounted for a small fraction of the photosensitizer with a cmax of 321 ng/mL only.

Investigation of L-leucine in reducing the moisture-induced deterioration of spray-dried salbutamol sulfate power for inhalation.

The aim of this study was to investigate the ability of L-leucine (LL) in preventing moisture-induced deterioration in the in vitro aerosolization performance of spray-dried (SD) salbutamol sulfate (SS). Increasing mass fraction of LL (5-80%) were co-spray dried with SS, and the physicochemical properties of the powders were characterized by laser diffraction, X-ray powder diffraction (XRD) and dynamic vapour sorption (DVS). Furthermore, the surface morphology and chemistry of fine particles was analyzed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The in vitro aerosolization performance of powders stored at different relative humidity (RH) was evaluated by a next generation impactor (NGI). The SD SS powders were moderately hygroscopic and amorphous, of which the uptake of moisture upon storage caused a drop in the aerosolization performance. The results showed that 40% (w/w) LL was sufficient to eliminate the effect of moisture on the aerosolization performance at 60% RH. The formulation containing 40% (w/w) LL also maximized the aerosolization performance of SD SS powders (stored in desiccator) with the emitted fraction being 90.0±1.8%, and the fine particle fraction based on the recovered dose (FPFrecovered) and emitted dose (FPFemitted) being 78.0±3.7% and 86.6±2.9%, respectively. The underlying mechanisms were that the crystalline LL increased the degree of particle surface corrugation, and reduced particle fusion and cohesiveness to facilitate dispersion. However, there is still a great challenge to prevent the moisture-induced deterioration in the aerosolization performance at 75% RH due to the recrystallization of SD SS. In conclusion, LL is a potential excipient for reducing moisture-induced deterioration in the aerosolization performance of SD amorphous powders, but still has drawbacks in preventing the recrystallization-induced deterioration.