Effect of PLGA raw materials on in vitro and in vivo performance of drug-loaded microspheres.

Poly(lactide-co-glycolide) and poly(lactic-co-glycolic acids) (PLGAs) play a critical role in the development of commercial long-acting injectable microsphere formulations. However, very little information is available describing the impact of PLGA manufacturer and monomer distribution along the polymer chain (e.g., glycolic blockiness (Rc) and average lactic block length (LL)) on the degradation and release behavior of PLGA drug carriers in vitro and in vivo. Here, we compared the in vitro and in vivo performance of (a) four leuprolide-loaded microsphere formulations prepared from similar low-molecular-weight acid-capped PLGAs (10-14 kD, i.e., Expansorb® DLG 75-2A, Purasorb® PDLG 7502A, Resomer® RG 752H and Wako® 7515) and (b) two triamcinolone acetonide-loaded (Tr-A) microsphere formulations from similar medium-molecular-weight ester-capped PLGAs (i.e., Expansorb® DLG 75-4E and Resomer® RG 753S). Lupron Depot® and Zilretta® were used as reference commercial products. The six 75/25 PLGAs displayed block lengths that were either above or below values expected from a random copolymer. Drug release and polymer degradation were monitored simultaneously in vitro and in vivo using a cage implant system. The four leuprolide-loaded formulations showed similar release and degradation patterns with some notable differences between each other. Microspheres from the Expansorb® polymer displayed lower LL and higher Rc relative to the other 3 PLGA 75/25 microspheres, and likewise exhibited distinct peptide release and degradation behavior compared to the other 3 formulations. For each formulation, leuprolide release was erosion-controlled up to about 30% release after the initial burst followed by a faster than erosion release phase. In vitro release was similar as that in vivo over the first phase but notably different from the latter release phase, particularly for the most blocky Expansorb® formulation. The Purasorb® and Wako® formulations displayed highly similar performance in release, degradation, and erosion analysis. By contrast, the two ester-capped Expansorb® DLG 75-4E and Resomer® RG 753S used to prepare Tr-A microspheres shared essentially identical LL and higher Rc and behaved similarly although the Expansorb® degraded and released the steroid faster in vivo, suggestive of other factors responsible (e.g., residual monomer). The in vivo release performance for both drugs from the six microsphere formulations was similar to that of the commercial reference products. In summary, this work details information on comparing the similarities and differences in in vitro and in vivo performance of drug-loaded microspheres as a function of manufacturing and microstructural variables of different types of PLGA raw materials utilized and could, therefore, be meaningful in guiding the source control during development and manufacturing of PLGA microsphere-based drug products. Future work will expand the analysis to include a broader range of LL and higher Rc, and add additional important formulation metrics (e.g., thermal analysis, and residual monomer, moisture, and organic solvent levels).

Bioinspired zwitterionic triblock copolymers designed for colloidal drug delivery: 2 - Biological evaluation.

In this work, poly(lactide) nanoparticles were equipped with a bioinspired coating layer based on poly[2-(methacryloyloxy)ethyl phosphorylcholine] and then evaluated when administered to the lungs and after intravenous injection. Compared to the plain counterparts, the chosen zwitterionic polymer shell prevented the coated colloidal formulation from aggregation and conditioned it for lower cytotoxicity, protein adsorption, complement activation and phagocytic cell uptake. Consequently, no interference with the biophysical function of the lung surfactant system could be detected accompanied by negligible protein and cell influx into the bronchoalveolar space after intratracheal administration. When injected into the central compartment, the coated formulation showed a prolonged circulation half-life and a delayed biodistribution to the liver. Taken together, colloidal drug delivery vehicles would clearly benefit from the investigated poly[2-(methacryloyloxy)ethyl phosphorylcholine]-based polymer coatings.

Bioinspired zwitterionic triblock copolymers designed for colloidal drug delivery: 1 - Synthesis and characterization.

This study describes the synthesis and characterization of triblock copolymers composed of poly[2-(methacryloyloxy)ethyl phosphorylcholine]-block-poly(propylene glycol)-block-poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PMPC-b-PPG-b-PMPC) intended for, but not limited to, applications in colloidal drug delivery. Atom transfer radical polymerization led to a library of well-defined PMPC-b-PPG-b-PMPC triblock copolymers with varying overall molecular weight (ranging from ∼5 to ∼25 kDa) and composition (weight fraction of the hydrophobic PPG block ranged from ∼10 to ∼50 wt%). The properties of the synthesized triblock copolymers were linked to the PPG to bioinspired PMPC block(s) ratio, where the more hydrophilic species showed adequate aqueous solubility, surface activity and biocompatibility (non-toxicity) in in vitro cell culture. Their amphiphilic nature makes them adsorb efficiently onto polymer nanoparticles, what improves colloidal stability under stress conditions and, furthermore, depletes proteins from unwanted adsorption to the underlying surface. The current findings strengthen our insights into structure-function relationships of PMPC-based coatings leading to protecting shells on relevant polymer nanoparticle formulations. PMPC-b-PPG-b-PMPC triblock copolymers composed of a hydrophobic PPG block of 2-4 kDa flanked by two hydrophilic PMPC blocks each of 5-10 kDa seem to be most promising to enhance colloidal drug delivery vehicles.

Analytical techniques for the characterization of nanoparticles for mRNA delivery.

Nanotechnology-assisted RNA delivery has gotten a tremendous boost over the last decade and made a significant impact in the development of life-changing vaccines and therapeutics. With increasing numbers of emerging lipid- and polymer-based RNA nanoparticles progressing towards the clinic, it has become apparent that the safety and efficacy of these medications depend on the comprehensive understanding of their critical quality attributes (CQAs). However, despite the rapid advancements in the field, the identification and reliable quantification of CQAs remain a significant challenge. To support these efforts, this review aims to summarize the present knowledge on CQAs based on the regulatory guidelines and to provide insights into the available analytical characterization techniques for RNA-loaded nanoparticles. In this context, routine and emerging analytical techniques are categorized and discussed, focusing on the operation principle, strengths, and potential limitations. Furthermore, the importance of complementary and orthogonal techniques for the measurement of CQAs is discussed in order to ensure the quality and consistency of analytical methods used, and address potential technique-based differences.

In vitro degradation and erosion behavior of commercial PLGAs used for controlled drug delivery.

Copolymers of lactic (or lactide) and glycolic (or glycolide) acids (PLGAs) are among the most commonly used materials in biomedical applications, such as parenteral controlled drug delivery, due to their biocompatibility, predictable degradation rate, and ease of processing. Besides manufacturing variables of drug delivery vehicles, changes in PLGA raw material properties can affect product behavior. Accordingly, an in-depth understanding of polymer-related "critical quality attributes" can improve selection and predictability of PLGA performance. Here, we selected 19 different PLGAs from five manufacturers to form drug-free films, submillimeter implants, and microspheres and evaluated differences in their water uptake, degradation, and erosion during in vitro incubation as a function of L/G ratio, polymerization method, molecular weight, end-capping, and geometry. Uncapped PLGA 50/50 films from different manufacturers with similar molecular weights and higher glycolic unit blockiness and/or block length values showed faster initial degradation rates. Geometrically, larger implants of 75/25, uncapped PLGA showed higher water uptake and faster degradation rates in the first week compared to microspheres of the same polymers, likely due to enhanced effects of acid-catalyzed degradation from PLGA acidic byproducts unable to escape as efficiently from larger geometries. Manufacturer differences such as increased residual monomer appeared to increase water uptake and degradation in uncapped 50/50 PLGA films and poly(lactide) implants. This dataset of different polymer manufacturers could be useful in selecting desired PLGAs for controlled release applications or comparing differences in behavior during product development, and these techniques to further compare differences in less reported properties such as sequence distribution may be useful for future analyses of PLGA performance in drug delivery.

Characterization of commercial PLGAs by NMR spectroscopy.

Poly(lactic-co-glycolic acid) (PLGA) is among the most common of biodegradable polymers studied in various biomedical applications such as drug delivery and tissue engineering. To facilitate the understanding of the often overlooked impact of PLGA microstructure on important factors affecting PLGA performance, we measured four key parameters of 17 commonly used commercial PLGA polymers (Expansorb®, Resomer®, Purasorb®, Lactel®, and Wako®) by NMR spectroscopy. 1HNMR and 13CNMR spectra were used to determine lactic to glycolic ratio (L/G ratio), polymer end-capping, glycolic blockiness (Rc), and average glycolic and lactic block lengths (LG and LL). In PLGAs with a labeled L/G ratio of 50/50 and acid end-capping, the actual lactic content slightly decreased as molecular weight increased in both Expansorb® and Resomer®. Whether or not acid- or ester-, termination of these PLGAs was confirmed to be consistent with their brand labels. Moreover, in the ester end-capped 75/25 L/G ratio group, the blockiness value (Rc) of Resomer® RG 756S (Rc: 1.7) was highest in its group; whereas for the 50/50 acid end-capped group, Expansorb® DLG 50-2A (Rc: 1.9) displayed notably higher values than their counterparts. Expansorb® 50-2E (LL: 2.5, LG: 2.6) and Resomer® RG 502 (LL: 2.6, LG: 2.5) showed the lowest block lengths, suggesting they may undergo a steadier hydrolytic process compared to random, heterogeneously distributed PLGA.

Engineering large porous microparticles with tailored porosity and sustained drug release behavior for inhalation.

Sustained drug delivery is considered as an effective strategy to improve the treatment of local lung diseases. In this context, inhalation administration of large porous microparticles (LPPs) represents promising prospects. However, one major challenge with said delivery technology is to control the drug release pattern (especially to decrease the burst release) while maintaining a low mass density/high porosity, which is of high significance for the aerodynamic behavior of LPP systems. Here, we show how to engineer drug-loaded, biodegradable LPPs with varying microstructure by means of a premix membrane emulsification-solvent evaporation (PME-SE) method using poly(vinyl pyrrolidone) (PVP) as the pore former. The influence of PVP concentration on the physicochemical properties, in-vitro drug release behavior and in-vitro aerodynamic performance of the drug-loaded microparticles was tested. We demonstrated that the PME-SE technique led to LPPs with favorable pore distribution characteristics (i.e., low external but high internal porosity) as a function of the PVP concentration. In general, more PVP conditioned a larger discrepancy of the internal vs. external porosity. When the external porosity of the LPP formulation (15% of PVP during the manufacturing process) was less than 3%, the burst release of the embedded drug was significantly reduced compared to LPPs prepared by a "conventional" emulsification solvent evaporation method. All the formulations prepared by the PME-SE method had aerodynamic properties suitable for inhalation. This is the first report indicating that the microstructure of LPPs can be tailored using the PME-SE technology with PVP as a suitable pore former. Doing so, we designed LPP formulations having full control over the drug release kinetics and aerodynamic behavior.

Antioxidant-mediated control of degradation and drug release from surface-eroding poly(ethylene carbonate).

Surface-eroding polymers are of significant interest for various applications in the field of controlled drug delivery. Poly(ethylene carbonate), as an example, offers little control over the rate of degradation and, thus, drug release, which usually conflicts with the requirements for long-acting medications. Here, we challenged an option to decelerate the degradation of poly(ethylene carbonate) in vitro and in vivo. When polymer films loaded with distinct antioxidants (vitamins) along with the model drugs leuprorelin and risperidone were incubated in superoxide radical solution and phagocyte culture, the mass loss and drug release from the delivery vehicle was a function of the type and dose of the utilized antioxidant. Once the polymer surface was "attacked" by reactive oxygen species, the antioxidants were released on demand quenching the polymer-degrading radicals. Accordingly, specific combinations of polymer and radical scavengers resulted in controlled release medications with an extended "life-time" of one month or longer, which is difficult to achieve for poly(ethylene carbonate) in the absence of antioxidants. A comparable degradation and drug release behavior was observed when antioxidant-loaded poly(ethylene carbonate) films were implanted in rats. Furthermore, linear correlations were obtained between the mass loss of the polymer films and the released fraction of drug (with slopes close to 1), a clear indication for the surface erosion of poly(ethylene carbonate) in vitro and in vivo. Overall, an addition of antioxidants to poly(ethylene carbonate)-based controlled drug delivery vehicles represents a reasonable approach to modify the performance of long-acting medications, especially when a "life time" of weeks to months needs to be achieved. STATEMENT OF SIGNIFICANCE: Surface-eroding poly(ethylene carbonate) (PEC) is of significant interest for long-acting injectable formulations. However, PEC offers only little control over the rate of degradation and, thus, drug release kinetics. We describe an option to decelerate the degradation rate of PEC in vitro and in vivo. When polymer films loaded with distinct antioxidants along with model drugs were incubated in superoxide radical solution, phagocyte culture and implanted in rats, their mass loss and drug release was a function of the type and dose of the utilized antioxidant. Accordingly, specific combinations of polymer and radical scavengers resulted in controlled release medications with an extended "life-time" of one month or longer, which is difficult to achieve for PEC in the absence of antioxidants.

In Situ Gel Formation in Microporated Skin for Enhanced Topical Delivery of Niacinamide.

Although used widely in cosmetic formulations, topical delivery of niacinamide (LogP = -0.35) is unfavorable by conventional means. Poly(lactide-co-glycolide) (PLGA) formulations, can undergo a sol-gel transition triggered by solvent exchange, entrapping molecules and sustaining their release. The current study aims to exploit the ability of PLGA to gel in situ and enhance the topical delivery of niacinamide in microporated skin. In vitro drug permeation studies were performed using vertical Franz diffusion cells. Microporation was performed using Dr. PenTM Ultima A6, where pre-treatment with a 1 mm needle-length for 10 s and a 0.5 mm needle-length for 5 s, both at 13,000 insertions/min were compared. The effect of different grades of PLGA, EXPANSORB® DLG 50-2A ("low" molecular weight), and EXPANSORB® DLG 50-8A ("high" molecular weight) on topical delivery was also determined. Formulations containing PLGA resulted in successful gelation in situ on application over microporated skin. A significantly higher amount of drug was found in the skin with the 0.5 mm treatment for 5 s (892 ± 36 µg/cm2) than with 1 mm for 10 s (167 ± 16 µg/cm2). Hence, the different grades of PLGA were evaluated with 0.5 mm, 5 s treatment, and a significantly larger amount was seen in skin with the higher rather than the lower molecular weight polymer (172 ± 53 µg/cm2).

Polymer-coated aperture plates for tailored atomization processes.

There is a significant industrial demand for minimizing the size of droplets for various technical applications. Herein, conformal polymer coatings were used to decrease the orifice dimensions of aperture plates to almost any desired dimension. The generated droplet size revealed a relevant impact on the final dried particle size in a spray-drying process. Likewise, the smaller droplets generated resulted in an improved lung deposition following inhalation. Overall, the current results help increase the understanding on how to manipulate the size distribution of droplets produced by actuated aperture plates, especially in the sub-10 µm range.

Medication Tracking: Design and Fabrication of a Dry Powder Inhaler with Integrated Acoustic Element by 3D Printing.

PURPOSE: Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler. METHODS: The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression. RESULTS: Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking. CONCLUSIONS: This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

Risperidone-Loaded PLGA-Lipid Particles with Improved Release Kinetics: Manufacturing and Detailed Characterization by Electron Microscopy and Nano-CT.

For parenteral controlled drug release, the desired zero order release profile with no lag time is often difficult to achieve. To overcome the undesired lag time of the current commercial risperidone controlled release formulation, we developed PLGA-lipid microcapsules (MCs) and PLGA-lipid microgels (MGs). The lipid phase was composed of middle chain triglycerides (MCT) or isopropylmyristate (IPM). Hydroxystearic acid was used as an oleogelator. The three-dimensional inner structure of Risperidone-loaded MCs and MGs was assessed by using the invasive method of electron microscopy with focused ion beam cutting (FIB-SEM) and the noninvasive method of high-resolution nanoscale X-ray computed tomography (nano-CT). FIB-SEM and nano-CT measurements revealed the presence of highly dispersed spherical structures around two micrometres in size. Drug release kinetics did strongly depend on the used lipid phase and the presence or absence of hydroxystearic acid. We achieved a nearly zero order release without a lag time over 60 days with the MC-MCT formulation. In conclusion, the developed lipid-PLGA microparticles are attractive alternatives to pure PLGA-based particles. The advantages include improved release profiles, which can be easily tuned by the lipid composition.

Fabrication and characterization of hyaluronic acid microneedles to enhance delivery of magnesium ascorbyl phosphate into skin.

This study investigated the in vitro transdermal delivery of magnesium ascorbyl phosphate (MAP) through porcine ear skin treated with hyaluronic acid (HA) microneedles (MNs). In this study, the micro-molding method was used to fabricate HA MNs. HA solution (10% w/v) containing 3% of MAP was placed onto a poly(dimethyl siloxane) mold to fill the microchannels under vacuum followed by drying in a desiccator. Scanning electron microscopy was performed to record the dimensions of the MNs. Skin microporation was demonstrated by dye binding. Histological skin sections revealed the shape of microchannels under hematoxylin-eosin staining. The actual depth of the microchannels and drug distribution pathways were studied by confocal microscopy. In vitro permeation on Franz diffusion cells were performed to determine the rate and extent of drug delivery into and across the skin. SEM captured individual MNs from the array, and the length of each MN was found to be ~400 µm. The 10 × 10 MN array prepared, resulted in the formation of 95 to 100 microchannels after 2 mins of treatment. In addition, the histological evaluations showed the formation of microchannels in the skin, complementary in shape to the MNs. The depths of the formed microchannels amounted to ~125 µm as determined by confocal microscopy. The application of the current MN technology enhanced the delivery of MAP into skin (96.8 ± 3.9 µg/cm2) compared to the passive delivery strategy of MAP (44.9 ± 16.3 µg/cm2). HA MNs markedly enhanced the in vitro transdermal delivery of MAP into and across skin.

Stability of Polymer Coatings on Nebulizer Membranes During Aerosol Generation.

The dimensions of orifices found in aperture plates used for nebulization can be modified by thin polymer coatings with the aim to control the size distribution of the generated aerosol droplets. However, the stability of such polymer coatings on the surface of nebulizer membranes during aerosol generation has not been elucidated. Nebulizer membranes made of stainless steel were covered with a thin film of poly(chloro-p-xylylene) (~1 µm) in the presence or absence of a silane-based adhesion promoter. Thereby, the orifice cross-sections of the nebulizer membrane were reduced by ~50%, accompanied by a remarkable decline in droplet size. Upon continuous nebulization of aqueous test liquids, the droplet size generated by the nonconditioned (no silane), poly(chloro-p-xylylene)-coated membranes reverted to that of the uncoated nebulizer membrane within ~5 min. By contrast, no such rapid return of droplet size to "baseline" values was noticed for the silane-conditioned, poly(chloro-p-xylylene)-coated counterparts. Scanning electron microscopy exhibited significant polymer detachment from the orifices of the nonconditioned (no silane) membranes and thus confirmed the findings from laser diffraction. Overall, silane-based adhesion promoters can increase the persistence of poly(chloro-p-xylylene) coatings on nebulizer membranes during aerosol generation.

Design and Evaluation of a Poly(Lactide-co-Glycolide)-Based In Situ Film-Forming System for Topical Delivery of Trolamine Salicylate.

Trolamine salicylate (TS) is a topical anti-inflammatory analgesic used to treat small joint pain. The topical route is preferred over the oral one owing to gastrointestinal side effects. In this study, a poly(lactide-co-glycolide) (PLGA)-based in situ bio-adhesive film-forming system for the transdermal delivery of TS was designed and evaluated. Therefore, varying amounts (0%, 5%, 10%, 20%, and 25% (w/w)) of PLGA (EXPANSORB® DLG 50-2A, 50-5A, 50-8A, and 75-5A), ethyl 2-cyanoacrylate, poly (ethylene glycol) 400, and 1% of TS were dissolved together in acetone to form the bio-adhesive polymeric solution. In vitro drug permeation studies were performed on a vertical Franz diffusion cell and dermatomed porcine ear skin to evaluate the distinct formulations. The bio-adhesive polymeric solutions were prepared successfully and formed a thin film upon application in situ. A significantly higher amount of TS was delivered from a formulation containing 20% PLGA (45 ± 4 µg/cm2) and compared to PLGA-free counterpart (0.6 ± 0.2 µg/cm2). Furthermore, the addition of PLGA to the polymer film facilitated an early onset of TS delivery across dermatomed porcine skin. The optimized formulation also enhanced the delivery of TS into and across the skin.

Phospholipid-modified poly(lactide-co-glycolide) microparticles for tuning the interaction with alveolar macrophages: In vitro and in vivo assessment.

Controlled drug delivery to the lungs is promising with plentiful advantages over current rapid release products. However, alveolar macrophage clearance has severely hindered the application of inhaled controlled release preparations. The objective of our study was to explore the feasibility to decorate poly(lactide-co-glycolide) (PLGA) microparticles with endogenous phospholipids found in the deep lungs, thus, to regulate the interplay with alveolar macrophages. The influence of the phospholipid amount and type on macrophage uptake of PLGA microparticles was investigated systemically under both in vitro (RAW264.7 and NR8383) and in vivo conditions. The uptake rate (k) by macrophages, in vivo elimination rate from the bronchoalveolar lavage fluid (k') and elimination rate from the whole lung (k″) were used as parameters for evaluation. Our data showed that a modification with dipalmitoyl phosphatidylcholine (DPPC) enhanced the macrophage phagocytosis significantly over the unmodified counterparts. Thereafter, using the same modification ratio, remarkable enhancement of macrophage uptake was found in the presence of different types of other phospholipids, especially with distearoyl phosphatidylethanolamine (DSPE). When replaced by a poly(ethylene glycol)-conjugated version of DSPE the uptake of the modified PLGA microparticles was reduced by ~200%. Meanwhile, the drug content in the lung tissue was improved by 3-fold (area under the curve value). Finally, it was possible to establish a correlation between in vitro phagocytosis and in vivo lung elimination rate for the investigated formulations. Overall, our study demonstrated that phospholipids play an important role in modulating the clearance of microparticle-based drug delivery vehicles, which gives a meaningful insight into the development of prolonged drug release system for inhalation.

In vitro-in vivo correlation of inhalable budesonide-loaded large porous particles for sustained treatment regimen of asthma.

Large porous particles (LPPs) are well-known vehicles for drug delivery to the lungs. However, it remains uncertain whether or to which extent the in vitro drug release behavior of LPPs can be predictive of their in vivo performance (e.g., systemic exposure and therapeutic efficacy). With regard to this, three budesonide-loaded LPP formulations with identical composition but distinct in vitro drug release profiles were studied in vivo for their pharmacokinetic and pharmacodynamic behavior after delivery to rat lung, and finally, an in vitro/in vivo correlation (IVIVC) was established. All formulations reduced approximately 75% of the uptake by RAW264.7 macrophages compared with budesonide/lactose physical mixture and showed a drug release-dependent retention behavior in the lungs of rats. Likewise, the highest budesonide plasma concentration was measured for the formulation revealing the fastest in vitro drug release. After deconvolution of the plasma concentration/time profiles, the calculated in vivo drug release data were successfully utilized for a point-to-point IVIVC with the in vitro release profiles and the predictability of the developed IVIVC was acceptable. Finally, effective therapy was observed in an allergic asthma rat model for the sustained drug release formulations. Overall, the obtained in vitro results correlate well with the systemic drug exposure and the therapeutic performance of the investigated lung-delivered formulations, which can provide an experimental basis for IVIVC development in the pulmonary-controlled delivery system. STATEMENT OF SIGNIFICANCE: Large porous particles (LPPs) are well-known vehicles for drug delivery to the lungs. However, it remains uncertain whether or to which extent the in vitro drug release behavior of LPPs can be predicted by their in vivo performance (e.g., systemic exposure and therapeutic efficacy). With regard to this, three budesonide-loaded PLGA-based LPP formulations with identical composition but distinct in vitro drug release profiles were studied in vivo for their pharmacokinetic and pharmacodynamic behavior, and finally, an in vitro/in vivo correlation (IVIVC) was established. It was demonstrated that the influence of the in vitro drug release profile was obvious during lung retention, systemic exposure, and therapeutic efficacy measurements. An IVIVC (Level A) was successfully established for the budesonide-loaded LPPs delivered to the airspace of rats for the first time. Taken together, the present work will clearly support research and development activities in the field of controlled drug delivery to the lungs.

Bioinspired polymer nanoparticles omit biophysical interactions with natural lung surfactant.

Herein, we report the attenuated impact of bioinspired nanoparticles on the essential function of lung surfactant. Colloidal particles made from poly(lactide) caused a significant loss of surfactant protein B (and C) from a natural lung surfactant accompanied by a decline in surface activity under static conditions and surface area cycling. No such perturbation of lung surfactant composition and function was observed for polymer nanoparticles coated with bioinspired poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC). More specifically, increasing the PMPC-coating layer thickness (≥3 nm) and density (dense conformation, distance of individual polymer chains of ≤3 nm) on the polymer nanoparticle surface diminished bioadverse events. PMPC-coated poly(lactide) nanoparticles provoked a less severe perturbation of the utilized lung surfactant when compared to colloidal counterparts coated with poly(ethylene glycol). Overall, a steric shielding of colloidal drug delivery vehicles with bioinspired PMPC can be considered as a valuable approach for the rationale development of biocompatible nanomedicines intended for lung delivery.

Making Concentrated Antibody Formulations Accessible for Vibrating-Mesh Nebulization.

Despite the significant interest in therapeutic antibodies for the treatment of airway diseases, no study addressed the challenge, which can arise when such formulations need to be made accessible for nebulization in concentrated (viscous) form. By (1) determining the maximum viscosity, which can still be atomized by vibrating-mesh technology and (2) supplementing the antibody formulation under investigation with at least 1 excipient, which decreases the viscosity under that specific threshold value of the utilized inhaler (and maintains the stability of the formulation), it should be possible to nebulize concentrated antibody formulations. Using sucrose as a viscosity enhancer, the viscosity threshold value amounted to ∼6 mPa*s for the eFlow®rapid device (output rate of <0.1 g/min). When a supplementation of a concentrated model antibody formulation (125 mg/mL) with specific amounts of lysine (≥50 mM) and arginine (≥20 mM) led to the desired drop in viscosity (to <5.5 mPa*s), the previously non-nebulizable formulation (no measurable aerosol output) was made accessible for vibrating-mesh nebulization (output rate of up to ∼0.5 g/min, droplet diameter of <5 µm). The stability of the current antibody formulation was not adversely affected when nebulized in the presence of lysine and arginine. Overall, the presented results will help increase the understanding on how to aerosolize concentrated protein formulations by vibrating-mesh technology.