Particle Engineering Design Research Articles

Design and comprehensive characterization of dry powder inhalation aerosols of simvastatin DPPC/DPPG lung surfactant-mimic nanoparticles/microparticles for pulmonary nanomedicine.

The Rho Kinase (ROCK) pathway is recognized to be involved in changes that lead to remodeling in pulmonary hypertension (PH), particularly cellular processes including signaling, contraction, migration, proliferation, differentiation, and apoptosis. Simvastatin (Sim) has a potent anti-proliferative and pro-apoptotic effect on vasculature smooth muscle cells through the inhibition of the synthesis of isoprenoids intermediates which are essential for the post-translational isoprenylation of Rho, Rac, and Ras family GTPases. Sim targets the underlying mechanism in vascular remodeling. Using bionanomaterials and particle engineering design, this innovative study reports on the advanced inhalable dry powders composed of sim with synthetic phospholipid bionanomaterials, DPPC/DPPG, as a lung surfactant-mimic. These were successfully designed and produced as co-spray dried (Co-SD) nanoparticles and microparticles for nanomedicine delivery as dry powder inhalers (DPIs). Different techniques were used to comprehensively characterize the physicochemical properties of the resulting Co-SD particles. The Next Generation ImpactorTM (NGI™) was used with three different FDA-approved human DPI devices with varying shear stress which were the HandiHaler®, Neohaler®, Aerolizer® DPI devices for aerosol dispersion performance. The formulation-device interactions were examined and correlated. Using human lung cells from different lung regions, in vitro cell viability and transepithelial electrical resistance (TEER) at the air-liquid interface showed biocompatibility of the formulations as a function of dose.

Inhaled Nanoparticulate Systems: Composition, Manufacture and Aerosol Delivery.

An increasing growth in nanotechnology is evident from the growing number of products approved in the past decade. Nanotechnology can be used in the effective treatment of several pulmonary diseases by developing therapies that are delivered in a targeted manner to select lung regions based on the disease state. Acute or chronic pulmonary disorders can benefit from this type of therapy, including respiratory distress syndrome (RDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary infections (e.g. tuberculosis, Yersinia pestis infection, fungal infections, bacterial infections, and viral infections), lung cancer, cystic fibrosis (CF), pulmonary fibrosis, and pulmonary arterial hypertension. Modification of size and surface property renders nanoparticles to be targeted to specific sites, which can serve a vital role in innovative pulmonary drug delivery. The nanocarrier type chosen depends on the intended purpose of the formulation and intended physiological target. Liquid nanocarriers and solid-state nanocarriers can carry hydrophilic and hydrophobic drugs (e.g. small molecular weight drug molecules, large molecular weight drugs, peptide drugs, and macromolecular biological drugs), while surface modification with polymer can provide cellular targeting, controlled drug release, and/or evasion of phagocytosis by immune cells, depending on the polymer type. Polymeric nanocarriers have versatile architectures, such as linear, branched, and dendritic forms. In addition to the colloidal dispersion liquid state, the various types of nanoparticles can be formulated into the solid state, offering important unique advantages in formulation versatility and enhanced stability of the final product. This chapter describes the different types of nanocarriers, types of inhalation aerosol device platforms, liquid aerosols, respirable powders, and particle engineering design technologies for inhalation aerosols.

Advanced Microparticulate/Nanoparticulate Respirable Dry Powders of a Selective RhoA/Rho Kinase (Rock) Inhibitor for Targeted Pulmonary Inhalation Aerosol Delivery.

Pulmonary hypertension (PH) is a progressive disease that eventually leads to heart failure and potentially death for some patients. There are many unique advantages to treating pulmonary diseases directly and non-invasively by inhalation aerosols and dry powder inhalers (DPIs) possess additional unique advantages. There continues to be significant unmet medical needs in the effective treatment of PH that target the underlying mechanisms. To date, there is no FDA-approved DPI indicated for the treatment of PH. Fasudil is a novel RhoA/Rho kinase (ROCK) inhibitor that has shown great potential in effectively treating pulmonary hypertension. This systematic study is the first to report on the design and development of DPI formulations comprised of respirable nanoparticles/microparticles using particle engineering design by advanced spray drying. In addition, comprehensive physicochemical characterization, in vitro aerosol aerosol dispersion performance with different types of human DPI devices, in vitro cell-drug dose response cell viability of different human respiratory cells from distinct lung regions, and in vitro transepithelial electrical resistance (TEER) as air-interface culture (AIC) demonstrated that these innovative DPI fasudil formulations are safe on human lung cells and have high aerosol dispersion performance properties.

Application of SeDeM Expert System in the development of novel directly compressible co-processed excipients via co-processing

BackgroundComputer-aided formulation design is gaining fantastic attention in chemical engineering of high functionality pharmaceutical materials for dosage form manufacture. To accelerate development of novel formulations in a quality-by-design perspective, SeDeM Expert System preformulation algorithm was developed as a tool for the design of solid drug delivery systems and for prediction of direct compression manufacturability of solid formulations. This research aims to integrate SeDeM Expert System into particle engineering design space of co-processing of solid excipients to develop novel composites with optimum direct compression propensity, using corn starch and microcrystalline cellulose powders as model primary excipients.ResultThe data and information generated from the expert system have elucidated the bulk-level characteristics of the primary excipients, enabled computation of the optimum co-processing ratio of the ingredients, and validated the impact of co-processing on material functionality. The experimental flowability (7.78±0.17), compressibility functions (5.16±0.14), parameter profile (0.92), and parametric profile index (6.72±0.27) of the engineered composites, were within the acceptable thresholds. With a reliability constant of 0.961, the net direct compression propensity of the composites expressed as Good Compression Index (6.46±0.26) was superior to that of the primary excipients, but comparable to reference co-processed materials, StarLac® (6.44±0.14) and MicroceLac®100 (6.58±0.03).ConclusionApplication of SeDeM Expert System in particle engineering via co-processing has provided an accelerated upstream proactive mechanism for designing directly compressible co-processed excipients in a quality-by-design fashion. A four-stage systematic methodology of co-processing of solid excipients was postulated. Stage I entails the characterization of CMAs of both defective and corrective excipients, and elucidation of their physicomechanical limitations using SeDeM diagrams. Stage II involves computation of loading capacity of the corrective excipient using dilution potential equation. Stage III entails the selection of co-processing technique based on desired Critical Material Attributes as revealed by the information obtained from Stage I. Stage IV evaluates the impact of co-processing by monitoring the critical behavior of the engineered composites with a decision on either to accept or reject the product.

Impact of process parameters on particle morphology and filament formation in spray dried Eudragit L100 polymer

Spray drying is one of the most broadly applicable and widely used methods of producing amorphous solid dispersions (ASDs). ASDs can improve the oral absorption of poorly water-soluble active pharmaceutical ingredients. Eudragit L100 is an appealing ASD excipient, due to its favorable impact on ASD physical stability and dissolution performance. However, spray drying Eudragit L100 can lead to high-aspect ratio filaments which reduce flowability, density and yield of the resulting powder. This negatively impacts downstream ASD performance and dosage form manufacturability. This work presents a mechanism for filament formation, which results in a particle engineering design space of key processing parameters, defined by a dimensionless parameter for assessing filament formation risk. Specifically, it was found that solution concentration, spray dryer inlet temperature and solvent volatility had the largest impact on controlling filament formation, based on their influence on the relative time scale to atomize versus droplet skinning during drying.

Microparticulate/Nanoparticulate Powders of a Novel Nrf2 Activator and an Aerosol Performance Enhancer for Pulmonary Delivery Targeting the Lung Nrf2/Keap-1 Pathway.

This systematic and comprehensive study reports for the first time on the successful rational design of advanced inhalable therapeutic dry powders containing dimethyl fumarate, a first-in-class Nrf2 activator drug to treat pulmonary inflammation, using particle engineering design technology for targeted delivery to the lungs as advanced spray dried (SD) one-component DPIs. In addition, two-component co-spray dried (co-SD) DMF:D-Man DPIs with high drug loading were successfully designed for targeted lung delivery as advanced DPIs using organic solution advanced spray drying in closed mode. Regional targeted deposition using design of experiments (DoE) for in vitro predictive lung modeling based on aerodynamic properties was tailored based on composition and spray drying parameters. These findings indicate the significant potential of using D-Man in spray drying to improve particle formation and aerosol performance of small molecule with a relatively low melting point. These respirable microparticles/nanoparticles in the solid-state exhibited excellent aerosol dispersion performance with an FDA-approved human DPI device. Using in vitro predictive lung deposition modeling, the aerosol deposition patterns of these particles show the capability to reach lower airways to treat inflammation in this region in pulmonary diseases such as acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), and pulmonary endothelial disease.

High-performing dry powder inhalers of paclitaxel DPPC/DPPG lung surfactant-mimic multifunctional particles in lung cancer: physicochemical characterization, in vitro aerosol dispersion, and cellular studies.

Inhalable lung surfactant-based carriers composed of synthetic phospholipids, dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG), along with paclitaxel (PTX), were designed and optimized as respirable dry powders using organic solution co-spray-drying particle engineering design. These materials can be used to deliver and treat a wide variety of pulmonary diseases with this current work focusing on lung cancer. In particular, this is the first time dry powder lung surfactant-based particles have been developed and characterized for this purpose. Comprehensive physicochemical characterization was carried out to analyze the particle morphology, surface structure, solid-state transitions, amorphous character, residual water content, and phospholipid bilayer structure. The particle chemical composition was confirmed using attenuated total reflectance-Fourier-transform infrared (ATR-FTIR) spectroscopy. PTX loading was high, as quantified using UV-VIS spectroscopy, and sustained PTX release was measured over weeks. In vitro cellular characterization on lung cancer cells demonstrated the enhanced chemotherapeutic cytotoxic activity of paclitaxel from co-spray-dried DPPC/DPPG (co-SD DPPC/DPPG) lung surfactant-based carrier particles and the cytotoxicity of the particles via pulmonary cell viability analysis, fluorescent microscopy imaging, and transepithelial electrical resistance (TEER) testing at air-interface conditions. In vitro aerosol performance using a Next Generation Impactor™ (NGI™) showed measurable powder deposition on all stages of the NGI and was relatively high on the lower stages (nanometer aerodynamic size). Aerosol dispersion analysis of these high-performing DPIs showed mass median diameters (MMADs) that ranged from 1.9 to 2.3 μm with excellent aerosol dispersion performance as exemplified by high values of emitted dose, fine particle fractions, and respirable fractions.

Advanced spray-dried design, physicochemical characterization, and aerosol dispersion performance of vancomycin and clarithromycin multifunctional controlled release particles for targeted respiratory delivery as dry powder inhalation aerosols

Respirable microparticles/nanoparticles of the antibiotics vancomycin (VCM) and clarithromycin (CLM) were successfully designed and developed by novel organic solution advanced spray drying from methanol solution. Formulation optimization was achieved through statistical experimental design of pump feeding rates of 25% (Low P), 50% (Medium P) and 75% (High P). Systematic and comprehensive physicochemical characterization and imaging were carried out using scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Karl Fischer titration (KFT), laser size diffraction (LSD), gravimetric vapor sorption (GVS), confocal Raman microscopy (CRM) and spectroscopy for chemical imaging mapping. These novel spray-dried (SD) microparticulate/nanoparticulate dry powders displayed excellent aerosol dispersion performance as dry powder inhalers (DPIs) with high values in emitted dose (ED), respirable fraction (RF), and fine particle fraction (FPF). VCM DPIs displayed better aerosol dispersion performance compared to CLM DPIs which was related to differences in the physicochemical and particle properties of VCM and CLM. In addition, organic solution advanced co-spray drying particle engineering design was employed to successfully produce co-spray-dried (co-SD) multifunctional microparticulate/nanoparticulate aerosol powder formulations of VCM and CLM with the essential lung surfactant phospholipid, dipalmitoylphosphatidylcholine (DPPC), for controlled release pulmonary nanomedicine delivery as inhalable dry powder aerosols. Formulation optimization was achieved through statistical experimental design of molar ratios of co-SD VCM:DPPC and co-SD CLM:DPPC. XRPD and DSC confirmed that the phospholipid bilayer structure in the solid-state was preserved following spray drying. Co-SD VCM:DPPC and co-SD CLM:DPPC dry powder aerosols demonstrated controlled release of antibiotic drug that was fitted to various controlled release mathematical fitting models. The Korsmeyer-Peppas model described the best data fit for all powders suggesting super case-II transport mechanism of controlled release. Excellent aerosol dispersion performance for all co-SD microparticulate/nanoparticulate DPIs was higher than the SD antibiotic drugs suggesting that DPPC acts as an aerosol performance enhancer for these antibiotic aerosol dry powders. Co-SD VCM:DPPC DPIs had higher aerosol dispersion parameters compared to co-SD CLM:DPPC which was related to differences in the physicochemical properties of VCM and CLM.

Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation

The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.

Design, characterization, and aerosolization of organic solution advanced spray-dried moxifloxacin and ofloxacin dipalmitoylphosphatidylcholine (DPPC) microparticulate/nanoparticulate powders for pulmonary inhalation aerosol delivery

The aim of this study was to design and develop respirable antibiotics moxifloxacin (MOXI) hydrochloride and ofloxacin (OFLX) microparticles and nanoparticles, and multifunctional antibiotics particles with or without lung surfactant 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced by advanced spray-drying particle engineering from an organic solution in closed mode (no water) from dilute solution. Scanning electron microscopy indicated that these particles had both optimal particle morphology and surface morphology, and the particle size distributions were suitable for pulmonary delivery. Comprehensive and systematic physicochemical characterization and in vitro aerosol dispersion performance revealed significant differences between these two fluoroquinolone antibiotics following spray drying as drug aerosols and as cospray-dried antibiotic drug: DPPC aerosols. Fourier transform infrared spectroscopy and confocal Raman microspectroscopy were employed to probe composition and interactions in the solid state. Spray-dried MOXI was rendered noncrystalline (amorphous) following organic solution advanced spray drying. This was in contrast to spray-dried OFLX, which retained partial crystallinity, as did OFLX:DPPC powders at certain compositions. Aerosol dispersion performance was conducted using inertial impaction with a dry powder inhaler device approved for human use. The present study demonstrates that the use of DPPC offers improved aerosol delivery of MOXI as cospray-dried microparticulate/nanoparticulate powders, whereas residual partial crystallinity influenced aerosol dispersion of OFLX and most of the compositions of OFLX:DPPC inhalation powders.

Biodegradable microparticulate drug delivery system of diltiazem HCl

The efficacy of a drug in a specific application requires the maintenance of appropriate drug blood level concentration during a prolonged period of time. Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. The objective of this work is to prepare and evaluate diltiazem HCl loaded albumin microparticles using a factorial design. Albumin (natural polymer) microparticles were prepared by emulsion heat-stabilization method. Selected formulations were characterized for their entrapment efficiency, particle size, surface morphology, and release behavior. Analysis of variance for entrapment efficiency indicates that entrapment efficiency is best fitted to a response surface linear model. Surface morphology was studied by scanning electron microscopy. Scanning electron microscopy of the microparticles revealed a spherical, nonporous and uniform appearance, with a smooth surface. The geometric mean diameter of the microparticles was found to be 2-9 µm, which more than 75% were below 3.5 µm and drug incorporation efficiency of 59.74 to 72.48% (w/w). In vitro release profile for formulations containing diltiazem HCl loaded BSA microparticles with heat stabilization technique shows slow controlled the release of the drug up to 24 hours. The release pattern was biphasic, characterized by an initial burst effect followed by a slow release. All selected microparticles exhibited a prolonged release for almost 24 hours. On comparing regression-coefficient (r²) values for Hixson Crowel, Higuchi and Peppas kinetic models, different batches of microparticles showed Fickian, non-Fickian, and diffusion kinetics. The release mechanism was regulated by D:P ratio. From the statistical analysis it was observed that as the drug:polymer (D:P) ratio increased, there was a significant increase in the encapsulation efficiency. Based on the particle size, entrapment efficiency and physical appearance, DTM-3 formulations were selected for in vivo release study and stability study. The in vivo result of drug loaded microparticles showed preferential drug targeting to liver followed by lungs, kidneys and spleen. Stability studies showed that maximum drug content and closest in vitro release to initial data were found in the formulation stored at 4 ºC. In present study, diltiazem HCl loaded BSA microparticles were prepared and targeted to various organs to satisfactory level and were found to be stable at 4 ºC.

Physicochemical Characterization and Water Vapor Sorption of Organic Solution Advanced Spray-Dried Inhalable Trehalose Microparticles and Nanoparticles for Targeted Dry Powder Pulmonary Inhalation Delivery

Novel advanced spray-dried inhalable trehalose microparticulate/nanoparticulate powders with low water content were successfully produced by organic solution advanced spray drying from dilute solution under various spray-drying conditions. Laser diffraction was used to determine the volumetric particle size and size distribution. Particle morphology and surface morphology was imaged and examined by scanning electron microscopy. Hot-stage microscopy was used to visualize the presence/absence of birefringency before and following particle engineering design pharmaceutical processing, as well as phase transition behavior upon heating. Water content in the solid state was quantified by Karl Fisher (KF) coulometric titration. Solid-state phase transitions and degree of molecular order were examined by differential scanning calorimetry (DSC) and powder X-ray diffraction, respectively. Scanning electron microscopy showed a correlation between particle morphology, surface morphology, and spray drying pump rate. All advanced spray-dried microparticulate/nanoparticulate trehalose powders were in the respirable size range and exhibited a unimodal distribution. All spray-dried powders had very low water content, as quantified by KF. The absence of crystallinity in spray-dried particles was reflected in the powder X-ray diffractograms and confirmed by thermal analysis. DSC thermal analysis indicated that the novel advanced spray-dried inhalable trehalose microparticles and nanoparticles exhibited a clear glass transition (T(g)). This is consistent with the formation of the amorphous glassy state. Spray-dried amorphous glassy trehalose inhalable microparticles and nanoparticles exhibited vapor-induced (lyotropic) phase transitions with varying levels of relative humidity as measured by gravimetric vapor sorption at 25°C and 37°C.

Materials for Pharmaceutical Dosage Forms: Molecular Pharmaceutics and Controlled Release Drug Delivery Aspects

Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development.