Lipid-based particle engineering via spray-drying for targeted delivery of antibiotics to the lung.

Pulmonary delivery of antibiotics for the treatment of tuberculosis provides several benefits compared to conventional oral and parenteral administration. API-loaded particles delivered directly to alveolar macrophages, where Mycobacterium tuberculosis resides, can reduce the required dose and decrease the severe side effects of conventional treatment. In this work, lipid-microparticles loaded with rifampicin were engineered via spray-drying to be administered as a carrier-free dry powder for inhalation. Although, it is well-known that spray-drying of lipid-based excipients is strongly limited, a completely lipid-based formulation using diglycerol full ester of behenic acid was produced. The solid state of the lipid, providing high melting temperature, absence of polymorphism and monophasic crystallization, led to high yield of spray-dried particles (83%). Inhalable particles of mass median aerodynamic diameter of 2.36 µm, median geometric size of 2.05 µm, and negative surface (-50.03 mV) were engineered. Such attributes were defined for deep lung deposition and targeted delivery of antibiotics to alveolar macrophages. Superior aerodynamic performance as carrier-free DPI was associated to a high fine particle fraction of 79.5 %. No in vitro cytotoxic effects were found after exposing epithelial cell lines and alveolar macrophages. In vitro uptake of particles into alveolar macrophages indicated the efficiency of their targeted delivery. The use of highly processable and safe lipid-based excipients for particle engineering via spray-drying can extend the availability of materials for functionalized applications for pulmonary delivery.

Mechanically promoted lipid-based filaments via composition tuning for extrusion-based 3D-printing.

Lipid excipients are favorable materials in pharmaceutical formulations owing to their natural, biodegradable, low-toxic and solubility/permeability enhancing properties. The application of these materials with advanced manufacturing platforms, particularly filament-based 3D-printing, is attractive for personalized manufacturing of thermolabile drugs. However, the filament's weak mechanical properties limit their full potential. In this study, highly flexible filaments were extruded using PG6-C16P, a lipid-based excipient belonging to the group of polyglycerol esters of fatty acids (PGFAs), based on tuning the ratio between its major and minor composition fractions. Increasing the percentage of the minor fractions in the system was found to enhance the relevant mechanical filament properties by 50-fold, guaranteeing a flawless 3D-printability. Applying a novel liquid feeding approach further improved the mechanical filament properties at lower percentage of minor fractions, whilst circumventing the issues associated with the standard extrusion approach such as low throughput. Upon drug incorporation, the filaments retained high mechanical properties with a controlled drug release pattern. This work demonstrates PG6-C16 P as an advanced lipid-based material and a competitive printing excipient that can empower filament-based 3D-printing.

Filament-based 3D-printing of placebo dosage forms using brittle lipid-based excipients.

In order to expand the limited portfolio of available polymer-based excipients for fabricating three-dimensional (3D) printed pharmaceutical products, Lipid-based excipients (LBEs) have yet to be thoroughly investigated. The technical obstacle of LBEs application is, however their crystalline nature that renders them very brittle and challenging for processing via 3D-printing. In this work, we evaluated the functionality of LBEs for filament-based 3D-printing of oral dosage forms. Polyglycerol partial ester of palmitic acid and polyethylene glycols monostearate were selected as LBEs, based on their chemical structure, possessing polar groups for providing hydrogen-bonding sites. A fundamental understanding of structure-function relationship was built to screen the critical material attributes relevant for both extrusion and 3D-printing processes. The thermal behavior of lipids, including the degree of their supercooling, was the critical attribute for their processing. The extrudability of materials was improved through different feeding approaches, including the common powder feeding and a devised liquid feeding setup. Liquid feeding was found to be more efficient, allowing the production of filaments with high flexibility and improved printability. Filaments with superior performance were produced using polyglycerol ester of palmitic acid. In-house designed modifications of the utilized 3D-printer were essential for a flawless processing of the filaments.

Drying Behavior and Curcuminoids Changes in Turmeric Slices during Drying under Simulated Solar Radiation as Influenced by Different Transparent Cover Materials.

Dried turmeric is used as a spice and traditional medicine. The common drying methods for turmeric (Curcuma longa L.) are sun drying and solar drying. In this study, turmeric slices with a thickness of 2 mm were dried at 40, 50, 60, and 70 °C in a laboratory hot-air dryer with a simulated solar radiation applied through transparent polycarbonate cover (UV impermeable) and PMMA cover (UV permeable). Air velocity and relative humidity of drying air were fixed at 1.0 M·s-1 and 25 g H2O kg-1 dry air, respectively. Light significantly increased the sample temperature under both covers. Page was the best model to predict the drying characteristics of turmeric slices. Drying rate correlated with the effective moisture diffusivity, which increased at higher temperature. The hue angle (h°) of turmeric was distinctly lower at 70 °C under both covers. The dried products were of intensive orange color. Curcumin, demethoxycurcumin, and total curcuminoids were affected by the cumulated thermal load (CTL). The lowest curcumin content was found at 40 °C under PMMA (highest CTL). The optimum drying condition was 70 °C under polycarbonate cover due to shorter drying time and better preservation of color and curcuminoids in the dried product.

Lipid-microparticles for pulmonary delivery of active pharmaceutical ingredients: Impact of lipid crystallization on spray-drying processability.

Spray-drying is an extensively used technology for engineering inhalable particles. Important technical hurdles are however experienced when lipid-based excipients (LBEs) are spray-dried. Stickiness, extensive wall deposition, or simply inability to yield a solid product have been associated to the low melting points of LBEs. In this work, solutions containing polyglycerol esters of behenic acid (PGFA-behenates), or other high melting point LBEs, were spray-dried to produce ibuprofen (IBU)-loaded inhalable lipid-microparticles. Prior to spray-drying, rational boundaries for the outlet temperature of the process were defined using LBE-IBU phase diagrams. Despite spray-drying the solutions at outlet temperatures below the boundaries, process performance and yield among LBEs were entirely different. Lipid crystallization into polymorphs or multi-phases negatively impacted the yield (10-47%), associated to liquid fractions unable to recrystallize at the surrounding gas temperature in the spray-dryer. The highest yields (76-82%), ascribed to PGFA-behenates, resulted from monophasic crystallization and absence of polymorphism. Lipid-microparticles, composed of a PGFA-behenate, were characterized by a volume mean diameter of 6.586 µm, tap density of 0.389 g/cm3 and corrugated surface. Application as carrier-free dry powder for inhalation resulted in high emitted fraction (90.9%), median mass aerodynamic diameter of 3.568 µm, fine particle fraction of 45.6% and modified release in simulated lung fluid.

Novel approach for overcoming the stability challenges of lipid-based excipients. Part 3: Application of polyglycerol esters of fatty acids for the next generation of solid lipid nanoparticles.

Solid lipid nanoparticles (SLN) are an advantageous carrier system for the delivery of lipophilic active pharmaceutical ingredients (APIs). The use of SLN has been limited due to stability issues attributed to the unstable solid state of the lipid matrix. A novel approach for overcoming this problem is the application of polyglycerol esters of fatty acids (PGFAs) as lipid matrices with stable solid state. PG2-C18 full, a PGFA molecule, was used to develop SLN loaded with dexamethasone as a model API. Dexamethasone-loaded SLN were manufactured via melt-emulsification and high pressure homogenization in the dosage form of a lipid nanosuspension. SLN with median particle size of 242.1 ± 12.4 nm, zeta potential of -28.5 ± 7.8 mV, entrapment efficiency of 90.2 ± 0.7% and API released after 24 h of 81.7 ± 0.7%, were produced. Differential Scanning Calorimetry (DSC) and Small and Wide Angle X-Ray Scattering (SWAXS) analysis of the lipid nanosuspension evidenced the crystallization of PG2-C18 full in a monophasic system in α-form and absence of polymorphism and crystallite growth up to 6 months storage at room temperature. This resulted in stable performance of the SLN after storage: absence of particle agglomeration, no API expulsion, and stable release profile. The potential pulmonary administration of SLN was tested by the nebulization capacity of the lipid nanosuspension. Cellular exposures to SLN did not induce cytotoxicity or immune effect on pulmonary cells. The application of PGFAs as safe and stable lipid matrices provide a promising approach for the development of the next generation of SLN.

Novel approach for overcoming the stability challenges of lipid-based excipients. Part 1: Screening of solid-state and physical properties of polyglycerol esters of fatty acids as advanced pharmaceutical excipients.

The major challenge of conventional lipid-based excipients (LBE) for drug delivery is their unstable solid state, affecting the stability of pharmaceutical product. Polyglycerol esters of fatty acids (PGFAs) are oligomeric hydroxyethers of glycerol fully or partially esterified with fatty acids. Tuning the number of polyglycerol moieties, fatty acids chain length and free hydroxyl groups per molecule results in diverse physicochemical properties, e.g. HLB, melting point, and wettability, which makes these molecules attractive candidates as novel LBE for different pharmaceutical applications. In this first part of our studies the solid state of PGFAs and the stability thereof were profiled on molecular, nano, and microstructural level and the resulting properties as LBE. DSC analysis confirmed the single phase system of PGFAs without phase separation. WAXS patterns revealed the absence of polymorphism and the direct crystallization into a stable α-form; without transition to more dense configurations. SAXS patterns exposed the lamellar arrangement. The lamellae stacks were characterized by the crystallite thickness and growth. The nano, microstructure and physicochemical properties of PGFAs remained stable during storage. The stable solid state and the broad functionality of PGFAs offer a novel approach to overcome the challenges faced by conventional LBE for advanced pharmaceutical applications. Examples for such applications are presented in the next parts of this study.

Novel approach for overcoming the stability challenges of lipid-based excipients. Part 2: Application of polyglycerol esters of fatty acids as hot melt coating excipients.

The application of hot melt coating (HMC) as an economic and solvent-free technology is restricted in pharmaceutical development, due to the instable solid-state of HMC excipients resulting in drug release instability. We have previously introduced polyglycerol esters of fatty acids (PGFAs) with stable solid-state (Part 1). In this work we showed a novel application of PGFAs as HMC excipients with stable performance. Three PGFA compounds with a HLB range of 5.1-6.2 were selected for developing immediate-release formulations. The HMC properties were investigated. The viscosity of molten lipids at 100 °C was suitable for atomizing. The DSC data showed the absence of low solidification fractions, thus reduced risk of agglomeration during the coating process. The driving force for crystallization of selected compounds was lower and the heat flow exotherms were broader compared to conventional HMC formulations, indicating a lower energy barrier for nucleation and lower crystallization rate. Lower spray rates and a process temperature close to solidification temperature were desired to provide homogeneous coating. DSC and X-ray diffraction data revealed stable solid state during 6 months storage at 40 °C. API release was directly proportional to HLB and indirectly proportional to crystalline network density and was stable during investigated 3 months. Cytotoxicity was assessed by dehydrogenase activity and no in vitro cytotoxic effect was observed.

High precision laboratory dryer for thin layer and bulk drying with adjustable temperature, relative humidity and velocity of the drying air.

Convective hot air drying is one of the most common post-harvest processes within the agricultural sector and a standard process in the food industry. The technique is used on fruits and vegetables in order to increase their added value or to extend their shelf life. Drying is highly dependent on the condition of the drying air in terms of temperature, relative humidity and velocity and on the thickness of the product layer. The influence of these drying parameters on the drying behavior and quality is product-specific and has to be investigated in laboratory experiments due to the high costs for full-scale evaluation. For this purpose, a high precision laboratory dryer was developed in order to achieve controlled and stable climate conditions during the drying of light bulk material. To avoid temperature drift of the load cell during drying, a temperature-controlled sensor housing was applied. To further stabilize the signal, it was corrected with the instantaneous temperature. The high precision laboratory dryer HPD TF1 could be potentially useful to establish drying curves for defined temperature, relative humidity and velocity of the drying air. Further potential applications are the establishment of sorption isotherms or the determination of diffusion coefficients of various materials.

In vitro toxicity screening of polyglycerol esters of fatty acids as excipients for pulmonary formulations.

One of the main problems for the development of pulmonary formulations is the low availability of approved excipients. Polyglycerol esters of fatty acids (PGFA) are promising molecules for acting as excipient for formulation development and drug delivery to the lung. However, their biocompatibility in the deep lung has not been studied so far. Main exposed cells include alveolar epithelial cells and alveolar macrophages. Due to the poor water-solubility of PGFAs, the exposure of alveolar macrophages is expected to be much higher than that of epithelial cells. In this study, two PGFAs and their mixture were tested regarding cytotoxicity to epithelial cells and cytotoxicity and functional impairment of macrophages. Cytotoxicity was assessed by dehydrogenase activity and lactate dehydrogenase release. Lysosome function, phospholipid accumulation, phagocytosis, nitric oxide production, and cytokine release were used to evaluate macrophage function. Cytotoxicity was increased with the increased polarity of PGFA molecules. At concentrations above 1 mg/ml accumulation in lysosomes, impairment of phagocytosis, secretion of nitric oxide, and increased release of cytokines were noted. The investigated PGFAs in concentrations up to 1 mg/ml can be considered as uncritical and are promising for advanced pulmonary delivery of high powder doses and drug targeting to alveolar macrophages.

Selective hydroformylation-hydrogenation tandem reaction of isoprene to 3-methylpentanal.

The hydroformylation of isoprene catalysed by rhodium phosphine complexes usually yields a broad mixture of the monoaldehydes, the isomeric methylpentenals, as well as the dialdehyde 3-methyl-1,6-hexandial. Under usual reaction conditions the products of a consecutive hydrogenation are only formed as minor by-products. Surprisingly we discovered now a selective auto-tandem reaction consisting of a hydroformylation and a hydrogenation step if a rhodium complex with the chelate ligand bis(diphenylphosphino)ethane is used as catalyst. If branched aromatic solvents like cumene are applied the conversion of isoprene is nearly quantitatively and the yield of the tandem product 3-methylpentanal amounts to 85%.

Telomerization: advances and applications of a versatile reaction.

The transition-metal catalyzed telomerization of 1,3-dienes with different nucleophiles leads to the synthesis of numerous products, such as sugar ethers, substituted lactones, or terpene derivatives, which can be applied in the cosmetic and pharmaceutical industry as well as in polymers and flavors. The reaction can be controlled by the choice of the catalytic system, the feedstock, and the reaction conditions. Since telomerization was developed in 1967, there have been many efforts to utilize this reaction. Herein we give an overview of the versatility of telomerization based on examples from research and industry, particular emphasis is placed on catalyst and process development as well as mechanistic aspects.