Drug Deposition Research Articles

Formulation and Assessment of Tolnaftate Microsponges for Topical Medication Deliverance

Objective: This study aimed to develop and evaluate the sustained delivery of Tolnaftate using topical polymeric microsponges. Materials and Methods: Tolnaftate-loaded microsponges made of ethyl cellulose were prepared via quasi-emulsion solvent diffusion. The effects of the drug-to-polymer ratio on active drug content, particle size, and entrapment efficiency were examined. The optimized formulation was incorporated into a Carbopol gel and evaluated for drug content, pH, viscosity, and in vitro drug release. The study considered internal phase volume, stirring rate, and emulsifier concentration as variables and analyzed their impact on entrapment efficiency and particle size. Results: Increasing stirring speed reduced particle size and improved entrapment efficiency, while a higher volume of dichloromethane decreased particle size. Scanning electron microscopy revealed porous and spherical microsponges. The 1.5:1 drug-to-polymer ratio yielded the highest active drug content, optimal entrapment efficiency, and smallest particle size, making it the preferred ratio for further studies. Conclusions: The drug release from the microsponge gel was more sustained compared to both the marketed product and pure drug gel. An ex vivo drug deposition study using rat abdominal skin showed satisfactory drug deposition. These polymeric microsponges show potential as a topical drug delivery system for antifungal therapy.

The efficacy and safety of aerosol therapy in rhinology

Abstract Aerosol drug administration has a long history as an important part of the treatment for different respiratory disorders in both adult and paediatric patients. The nebulization process permits the drug delivery directly to the upper and lower airways tracts, allowing increased local effectiveness, and avoids systemic side effects. The aerosol therapy is mainly used in pneumology for lower respiratory tract disorders, a series of drugs having a proven efficacy. Few publications present the efficacy and safety of ENT nebulization, despite its worldwide utilization. Topical drug delivery to the nasal cavities and paranasal sinuses via aerosols appears to be an interesting, but also a challenging alternative. The transport and deposition of drugs and aerosol particles into the sinuses is debatable due to several factors: sinuses are poorly perfused and virtually non-ventilated cavities; they are protected by the efficient particle filtration function of the nasal cavities. The review evaluates the efficacy and safety of aerosol therapy in rhinologic pathology.

Evaluation of the interactions between human stratum corneum and liposome formulations using QCM-D

The interactions between human stratum corneum (SC) and two liposomal formulations, azithromycin (AZM)- and nisin-loaded liposomal formulations designed for topical/intradermal application, were investigated using quartz crystal microbalance with dissipation (QCM-D) using. SC isolated from cadaver skin was affixed onto the QCM sensor’s surface. The liposome formulations were prepared using the thin film rehydration method. The particle sizes of the blank liposome, nisin-loaded, AZM-loaded, and combined-loaded liposomes were measured as 90.7 ± 0.58 nm, 100.8 ± 2.5 nm, 136.9 ± 6.5 nm, and 174.3 ± 9.8 nm, respectively. The frequency shifts when blank and drug-loaded liposomes were passed over the gold surface were ∼20 and ∼25 Hz, respectively as a result of the formation of bilayers in a two-step process, adsorption of intact vesicles followed by the formation of the bilayer upon rinsing with water. The frequency shifts for blank and drug-loaded liposomes on SC were ∼8 and ∼15 Hz, respectively. These results show that the liposomes are deposited as bilayers on SC with both the blank and drug-loaded liposomes. The increase in frequency shifts with drug-loaded liposomes indicate the deposition of drug along with lipids onto both the gold and SC surfaces. More significantly, the data showed much slower kinetics of liposome component spreading onto the SC than on gold. The changes in dissipation that accompanies these differences in frequency shifts show transformation of vesicle onto rigid bilayer on gold upon rinsing with water, but direct formation of lipid bilayers on SC. The findings of this study contribute to a better understanding of the interaction between SC and liposomes, such as adsorption, deformation, and rupture of liposomes on different substrates, paving the way for investigating topical and intradermal mechanisms of drug delivery and cosmetic products developed based on liposome formulations.

Effect of lubricants type and particle size on the rheological properties and aerosolization behavior of dry powder inhalers

A commonly used strategy to improve aerosolization behavior of carrier-based dry powder inhalers (DPIs) is the addition of magnesium stearate as a lubricant, yet it may also negatively affect properties of DPIs. Thus, the aim of this study was to find lubricants that could be used as alternatives of magnesium stearate and meanwhile verify the applicability of using powder rheological properties to predict the performance of different lubricants in DPIs. Here, using fluticasone propionate as a model drug, LH200 as the carrier, influence of lubricants type and particle size, including magnesium stearate, sodium stearate, Leucine, sodium stearate fumarate, Compritol® 888 ATO, and Compritol® HD5 ATO, on the physicochemical properties, powder rheology and aerosolization behavior of the DPI formulations was characterized. Further, the relationship between powder rheological parameters and in-vitro drug deposition parameter, fine particle fraction (FPF), were explored, and the contribution of powder flowability and adhesion was evaluated using principal component analysis (PCA). The results showed that magnesium stearate, sodium stearate and smaller sized leucine significantly reduced the basic flowability energy, aeration energy and Permeability of the DPI formulations, leading to improved aerosolization behavior. A robust linear correlation was established between rheological parameters and FPF. PCA showed that in lubricants containing formulations, the contribution of flowability (74.69%) was greater than that of adhesion (25.31%). In conclusion, sodium stearate and smaller particle size Leucine can be considered as substitutes of magnesium stearate in DPI formulations.

Non-local impact of distal airway constrictions on patterns of inhaled particle deposition.

Airway constriction and blockage in obstructive lung diseases cause ventilation heterogeneity and create barriers to effective drug deposition. Established computational particle-deposition models have not accounted for these impacts of disease. We present a new particle-deposition model that calculates ventilation based on the resistance of each airway, such that ventilation responds to airway constriction. The model incorporates distal airway constrictions representative of cystic fibrosis, allowing us to investigate the resulting impact on patterns of deposition. Unlike previous models, our model predicts how constrictions affect deposition in airways throughout the lungs, not just in the constricted airways. Deposition is reduced in airways directly distal and proximal to constrictions. When constrictions are clustered together, central-airways deposition can increase significantly in regions away from constrictions, but distal-airways deposition in those regions remains largely unchanged. We use our model to calculate lung clearance index (LCI), a clinical measure of ventilation heterogeneity, after applying constrictions of varying severities in one lobe. We find an increase in LCI coinciding with significantly reduced deposition in the affected lobe. Our results show how the model provides a framework for development of computational tools that capture the impacts of airway disease, which could significantly affect predictions of regional dosing.

Rational development of fingolimod nano-embedded microparticles as nose-to-brain neuroprotective therapy for ischemic stroke.

Ischemic stroke is one of the major diseases causing varying degrees of dysfunction and disability worldwide. The current management of ischemic stroke poses significant challenges due to short therapeutic windows and limited efficacy, highlighting the pressing need for novel neuroprotective treatment strategies. Previous studies have shown that fingolimod (FIN) is a promising neuroprotective drug. Here, we report the rational development of FIN nano-embedded nasal powders using full factorial design experiments, aiming to provide rapid neuroprotection after ischemic stroke. Flash nanoprecipitation was employed to produce FIN nanosuspensions with the aid of polyvinylpyrrolidone and cholesterol as stabilizers. The optimized nanosuspension (particle size = 134.0 ± 0.6nm, PDI = 0.179 ± 0.021, physical stability = 72 ± 0h, and encapsulation efficiency of FIN = 90.67 ± 0.08%) was subsequently spray-dried into a dry powder, which exhibited excellent redispersibility (RdI = 1.09 ± 0.04) and satisfactory drug deposition in the olfactory region using a customized 3D-printed nasal cast (45.4%) and an Alberta Idealized Nasal Inlet model (8.6%) at 15L/min. The safety of the optimized FIN nano-embedded dry powder was confirmed in cytotoxicity studies with nasal (RPMI 2650 and Calu-3 cells) and brain related cells (SH-SY5Y and PC 12 cells), while the neuroprotective effects were demonstrated by observed behavioral improvements and reduced cerebral infarct size in a middle cerebral artery occlusion mouse stroke model. The neuroprotective effect was further evidenced by increased expression of anti-apoptotic protein BCL-2 and decreased expression of pro-apoptotic proteins CC3 and BAX in brain peri-infarct tissues. Our findings highlight the potential of nasal delivery of FIN nano-embedded dry powder as a rapid neuroprotective treatment strategy for acute ischemic stroke.

Fast simulation of coronary in‐stent restenosis: A non‐intrusive data‐driven reduced order surrogate model

AbstractModeling and simulation of coronary artery disease (CAD) is of great importance for supporting and predicting the outcome of percutaneous coronary intervention (PCI). However, an in silico model generally requires heavy computational resources. An effective reduced order surrogate model is indispensable in this context. This study aims to develop a non‐intrusive data‐driven reduced order surrogate model for coronary in‐stent restenosis (ISR) incorporating anti‐inflammatory drugs embedded in the drug‐eluting stents. The constitutive model includes a detailed multiphysics approach based on partial differential equations (PDEs), which include descriptions of platelet aggregation, growth‐factor release, cellular motility and drug deposition. Dimensionality reduction is carried out based on a 3D convolutional autoencoder, which comprises an encoder and decoder. The former condenses the full‐order solution into a lower‐dimensional latent space, while the latter recovers the full solution from the latent space. Special attention is paid to handle the multidimensional outputs and network architecture.

Delivery Efficiency of Albuterol Pressurized Metered Dose Inhaler Through Small Size Laryngeal Mask Airways in an Infant and Child Model.

Intraoperative bronchospasm in pediatric patients supported through laryngeal mask airways (LMAs) is commonly treated with pressurized metered-dose inhaler (pMDI) albuterol. The aim of the study was to evaluate delivery of pMDI albuterol through LMAs under different conditions in a model of infant/child supported with a ventilator. We compared drug delivery efficiency of 4 actuations of albuterol pMDI (captured on a filter placed between the LMA and a test lung), drug deposition in the circuit (elbow) and in the LMA under different experimental conditions. Outcomes were expressed of percentage of nominal dose. We compared devices (valved holding chamber [VHC] and adapter), timing of administration (inspiration and expiration), tidal volumes (50 mL and 100 mL), mode of actuation (single and multiple), and LMA sizes (1, 1.5, and 2). Multiple regression analysis was used to evaluate the contribution of each to these components to the outcomes. P < .05 was considered statistically significant. Results are expressed as median (interquartile range) of pooled data. Drug delivery efficiency was 0% (0-1.1) and 6.3% (3.2-14.7) for adapter and VHC, respectively. Elbow deposition was 25.8% (19.2-63.3) and 2.9% (1.4-6.4) for adapter and VHC, respectively. LMA deposition was 2.6% (1.3-4.6) and 4.6% (2.9-6.1) for adapter and VHC, respectively. Multiple regression analysis showed that device, timing of actuation, and LMA size explained 33%, 17%, and 8% of the observed variation in delivery efficiency (R2 0.63), respectively. Multiple regression analysis showed that device and timing of actuation explained 52% and 16% of the observed variation, respectively (R2 0.70). Multiple regression analysis poorly explained factors associated with LMA deposition (R2 0.22). Using a VHC, actuating the pMDI during exhalation, and using a small LMA size increased drug delivery efficiency. The adapter was an inefficient add-on device for aerosol delivery with a pMDI through an LMA that caused significant circuit deposition.

In Vitro Analysis of Aerodynamic Properties and Co-Deposition of a Fixed-Dose Combination of Fluticasone Furoate, Umeclidinium Bromide, and Vilanterol Trifenatate.

Effective airway delivery of a fixed-dose combination of triple-aerosolized inhaled corticosteroid (ICS)/long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) is likely to positively affect therapeutic responses predicted in patients with asthma and chronic obstructive pulmonary disease. This study aimed to conduct in vitro fluticasone furoate, vilanterol trifenatate, and umeclidinium bromide depositions in a Next Generation Impactor. The aerodynamic properties of these inhaled medications influence the spatial distribution and drug abundance, particularly in the smaller airways, to reverse or alleviate disease pathology. The Next Generation Impactor was used to demonstrate the aerodynamic particle size distributions of fluticasone furoate, vilanterol trifenatate, and umeclidinium bromide delivered from a dry powder inhaler at different flow rates across all stages of the impactors. This in vitro study analyzed the distribution pattern of individual drug components to simulate mono-component deposition and co-deposition in the official model in the United States Pharmacopeia. An Andersen cascade impactor together with scanning electron microscope-energy-dispersive X-ray was employed to observe the drug deposition on each stage of the impactor. We found that the distribution pattern of each component at the same cascade level was comparable, and the aerosol particles of the three drugs reached the in vitro representation of the lower airway compartment. The specified flow rates generated the desired fine particle fraction, fine particle dose, and mass median aerodynamic diameter. Our results also demonstrated visualized deposition patterns of the delivered drugs from different stages of the cascade impactor that may predict deposition as it occurs in vivo. Spatial distribution and abundance of ICS/LABA/LAMA in the same cascade levels were closely comparable, and the aerosol particles were able to reach the small aerosol-sized cascades at the lower levels to some extent.

Amikacin Liposomal Inhalation Suspension for Non-Tuberculous Mycobacteria Lung Infection: A Greek Observational Study.

Background and Objectives: Intravenous amikacin, recommended for severe or recurrent M. avium complex (MAC) infections and as initial treatment for M. abscessus lung disease, is often limited by serious adverse effects such as renal and auditory toxicities. Inhaled Amikacin Liposome Inhalation Suspension (ALIS) enhances pulmonary drug deposition while minimizing systemic adverse effects, and it has recently been introduced as an add-on therapy for refractory MAC infections or when other standard treatments are inadequate. This study aims to retrospectively describe the outcomes of Greek patients with difficult-to-treat non-tuberculous mycobacterial (NTM) lung disease following the addition of ALIS to guideline-based therapy. Materials and Methods: Seventeen consecutive patients (median age: 66 years) treated with ALIS as an add-on therapy to a standard regimen at "Sotiria" General Hospital of Chest Diseases (Athens, Greece) from 2020 to 2023 were enrolled in this study. These patients had recurrent or refractory NTM lung disease and/or limited treatment options due to prior treatment-related adverse effects. Clinical, radiological, and microbiological data on treatment response and overall outcomes after ALIS initiation were recorded for each patient. Results: By the end of 2023, 14 out of 17 patients had either successfully completed or were continuing their ALIS therapy. At 6 months, 85.7% (12/14) showed clinical, microbiological, and radiological improvement. However, 25% (3/12) of treated patients, primarily those with monomicrobial or combined M. abscessus lung disease, experienced disease relapse after therapy completion. The most frequent adverse effects related to ALIS were mild and localized to the respiratory tract, with only one patient discontinuing therapy due to hypersensitivity pneumonitis. Conclusions: Adding ALIS to standard regimens was effective and safe in a small group of Greek patients with refractory or recurrent NTM lung disease, particularly those who had discontinued intravenous aminoglycosides due to significant adverse effects, with notable responses observed in MAC lung disease. Further research is needed to validate these findings in clinical practice and to investigate ALIS's role in NTM lung disease caused by other species.

Barriers that Inhaled Particles Encounter.

Inhalable particulate drug carriers-nano- and micro-particles, liposomes, and micelles-should be designed to promote drug deposition in the lung and engineered to exhibit the desired drug release property. To deposit at the desired site of action, inhaled particles must evade various lines of lung defense, including mucociliary clearance, entrapment by mucus layer, and phagocytosis by alveolar macrophages. Various physiological, mechanical, and chemical barriers of the respiratory system reduce particle residence time in the lungs, prevent particle deposition in the deep lung, remove drug-filled particles from the lung, and thus diminish the therapeutic efficacy of inhaled drugs. To develop inhalable drug carriers with efficient deposition properties and optimal retention in the lungs, particle engineers should have a thorough understanding of the barriers that particles confront and appreciate the lung defenses that remove the particles from the respiratory system. Thus, this section summarizes the mechanical, chemical, and immunological barriers of the lungs that inhaled particles must overcome and discusses the influence of these barriers on the fate of inhaled particles.

Anatomically-detailed segmented representative adult and pediatric nasal models for assessing regional drug delivery and bioequivalence with suspension nasal sprays

In vitro nasal models can potentially facilitate development and approval of nasal drug products. This study aims to evaluate the potential for using regional deposition measurements from in vitro nasal models to evaluate nasal spray performance across several products. To accomplish this, the posterior regions of six anatomically realistic nasal airway models of adult and pediatric subjects, representing Low (L), Mean (M) and High (H) posterior drug deposition (PD) for each of the two age groups, were segmented with high anatomical precision into five regions of interest. These models were previously developed with the goal of quantifying the range of intersubject variability of PD following administration of inhaled corticosteroids. The in vitro regional drug deposition values were measured for the reference listed drug (RLD) product for triamcinolone acetonide and two corresponding generic (test) nasal spray products, as well as an RLD product for fluticasone furoate nasal spray. In general, the pediatric models mostly demonstrated higher PD compared to the adult models. The majority (>85 %) of PD was confined to the front and the inferior meatus regions. Subsequent population bioequivalence (PBE) analyses of the regional nasal deposition suggested that the anatomical differences among subjects may impact the nasal spray performance across different nasal products.

Coupled Discrete Phase and Eulerian Wall Film Models for Drug Deposition Efficacy Analysis in Human Respiratory Airways.

The current study explores the effectiveness of drug particle deposition into human respiratory airways to cure various pulmonary-bound ailments. It has been assumed that drug solutions are inhaled in the form of tiny droplets or mist, which after striking create a thin layer along the inner surface of airways where the virus initially resides to infect the human body. A coupled Eulerian wall film (EWF) and discrete phase model (DPM) based simulation approach is used to capture these dynamics. Here, the Lagrangian DPM technique tracks the dynamics of tiny droplets, while the liquid layer formation after striking is captured using the Eulerian thin film approximations or the EWF model. Previous studies in this field primarily employed only the DPM method, which is inadequate to predict the poststriking dynamics of drug layer deposition and their spread to neutralize the respiratory virus. The drug delivery effectiveness is characterized by three different particle sizes, 1, 5, and 10 μm at the inhalation rates of 15, 30, and 60 L per minute (LPM). It has been found that the size of the drug particles significantly influences drug delivery effectiveness. The film thickness increases monotonically with particle sizes and inhalation rates. However, this increase in averaged film thickness is prominent in the range 5 to 10 μm (≈60%) compared to 1 to 5 μm (≈10%) droplet sizes at generation level 4 (G4). The other deposition parameters, e.g., deposition fraction, deposition density, and area coverage) roughly show similar behavior with the increase in droplet sizes. Therefore, it is recommended to vary the droplet sizes between 5 and 10 μm for better deposition effectiveness. The sizes of more than 10 μm mostly stuck into the oral cavity and cannot reach the targeted generations. In contrast, less than 5 μm may reach much deeper generations than the targeted one.

Cyanocobalamin-loaded dissolving microneedles diminish skin inflammation in vivo

Inflammatory diseases of the skin have a considerable high prevalence worldwide and negatively impact the patients' quality of life. First-line standard therapies for these conditions inherently entail important side effects when used long-term, particularly complicating the management of chronic cases. Therefore, there is a need to develop novel therapeutic strategies to offer reliable alternative treatments. Abnormally high reactive oxygen species (ROS) levels are characteristic of this kind of illnesses, and therefore a reasonable therapeutic goal. Cyanocobalamin, also known as Vitamin B12, possesses notable antioxidant and ROS-scavenging properties which could make it a possible therapeutic alternative. However, its considerable molecular weight restricts passive diffusion through the skin and forces the use of an advanced transdermal delivery system. Here, we present several prototypes of Cyanocobalamin-loaded Dissolving Microarray Patches (B12@DMAPs) with adequate mechanical properties to effectively penetrate the stratum corneum barrier, allowing drug deposition into the skin structure. Ex vivo penetration and permeability studies noted an effective drug presence within the dermal skin layers; in vitro compatibility studies in representative cell skin cell lines such as L929 fibroblasts and HaCaT keratinocytes ensured their safe use. The in vivo efficacy of the selected prototype was tested in a delayed-type hypersensitivity murine model that mimics an inflammatory skin process. Several findings such as a reduction of MPO-related photon emission in a bioluminescence study, protection against histological damage, and decrease of inflammatory cytokines levels point out the effectivity of B12@DMAPs to downregulate the skin inflammatory environment. Overall, B12@DMAPs offer a cost-effective translational alternative for improving patients' skin healthcare.

In vitro assessment of skin permeation properties of enzymatically derived oil-based fatty acid esters of vitamin C.

Current topical formulations containing vitamin C face limitations in therapeutic effectiveness due to the skin's selective properties that impede drug deposition. Consequently, the widespread use of toxic and irritating chemical permeation enhancers is common. Hereby, we investigated enzymatically derived fatty acid ascorbyl esters (FAAEs) obtained using natural oils for their skin permeation properties using the Strat-M® skin model in a Franz cell diffusion study. By evaluating various cosmetic formulations without added enhancers, we found that emulgel is most suitable for enhancing the cutaneous and transdermal delivery of FAAEs. Furthermore, medium-chain coconut oil-derived FAAEs exhibited faster diffusion rates compared to sunflower oil-based FAAEs with long-side acyl residues, including the commonly applied ascorbyl palmitate. Experimental data were successfully fitted using the Peppas and Sahlin model, which accounted for a lag phase and the combined effect of Fickian diffusion and polymer relaxation. In the case of long-chain esters, the lag phase was prolonged, and the calculated effective diffusion coefficients (Deff) were lower compared to medium-chain FAAEs. Accordingly, the highest Deff value was observed for ascorbyl caprylate, being even 60 times higher than for ascorbyl palmitate. These results suggest the emerging potential of emulgel with incorporated coconut oil-derived FAAEs for efficiently delivering vitamin C into the skin.

Novel embelin-loaded transniosomes for topical delivery: comprehensive exploration of in vitro, ex vivo and dermatokinetic assessment for anti-cancer activity.

This study systematically designed and optimised a transniosomal formulation containing embelin for skin cancer management. The transniosomes were developed using a rotary evaporation method and then optimised using a Box-Behnken design. The optimized embelin-loaded transniosomes (Opt-EMB-TNs) exhibited a vesicle size of 149.01 nm, polydispersity index of 0.184, a zeta potential of -21.14 mV, an entrapment efficiency of 75.6 ± 0.65%, drug loading of 3.36 ± 0.03% and drug release of 80.88 ± 2.55%. The antioxidant potential of Opt-EMB-TNs was found to be 88.54% when compared to standard ascorbic acid. Dermatokinetic studies showed a greater drug deposition in targeted skin areas with Opt-EMB-TN gel compared to the embelin conventional gel (EMB-CF gel). In addition, the penetration depth study of the skin sample revealed that the transniosomal gel containing rhodamine B dye exhibited higher penetration than that of the rhodamine B dye containing hydroalcoholic solution. The efficacy of Opt-EMB-TNs for skin cancer was confirmed by cytotoxicity assay against the B16F10 melanoma cell line. The study concluded that the Opt-EMB-TN gel formulation is a promising and effective topical treatment for skin cancer, demonstrating significant potential for further development and clinical application. © 2024 Society of Chemical Industry.

Enhancing capture efficiency of drug-carrier particles in the carotid sinus by utilizing a combination of magnetic fields: A numerical approach

Magnetic drug targeting is a relatively new method to treat vascular occlusion in different body parts. However, the effectiveness of this method can be affected due to the severity and location of the occlusion. This can lead to the injection of high dosages of drugs, which can cause serious side effects due to the deposition of drugs in unwanted parts. To mitigate these effects, this study investigates the potential of a guiding magnetic field in enhancing drug absorption for vascular occlusion treatment. The method relies on guiding magnetic nanoparticles (NPs) loaded with drugs toward the occlusion site using two external magnetic fields. Blood flow was modeled as non-Newtonian, considering shear-rate-dependent viscosity and unsteady at the inlet. To test this idea, a computational fluid dynamic (CFD) coupled with a discrete phase model (DPM) approach has been employed to simulate drug delivery in three-vessel structures with varying degrees of occlusion (45 %, 60 %, and 90 %). To avoid the escape of drug carriers, a secondary magnetic field was applied at the bifurcation point to direct the NPs to the site of blockage where the primary magnetic field acts. Then, the states with or without a guiding source at the bifurcation site are compared based on the capture efficiency of each structure. The simulation demonstrated a significant increase in NP capture at the target site, ranging from 2 % to 15 %, depending on the NP size. However, the severity of occlusion substantially impacted the secondary magnetic field's effectiveness. In the 90 % occlusion scenario, the method's efficiency decreased significantly from 26 % to 16 % for NP sizes exceeding 1.5μm. This study highlights the potential of guiding magnetic fields in improving drug delivery to target sites in vascular occlusion.

HSPiP and QbD oriented optimized stearylamine-elastic liposomes for topical delivery of ketoconazole to treat deep seated fungal infections: In vitro and ex vivo evaluations

The study explored stearylamine containing cationic elastic liposomes to improve topical delivery and efficacy of ketoconazole (KETO) to treat deeply seated fungal infections. Stearylamine was used for dual functionalities (electrostatic interaction and flexibility in lipid bilayer). Hansen solubility program (HSPiP) estimated Hansen solubility parameters (HSP) based on the SMILE file and structural properties followed by experimental solubility study to validate the predicted values. Various formulations were developed by varying phosphatidylcholine and surfactants (tween 80 and span 80) concentration. To impart cationic properties, stearylamine (1.0 %) was added into the organic phase. Using quality by design (QbD) method, we optimized the formulations and evaluated for vesicle size, polydispersity index, zeta potential, morphology (scanning electron microscopy), in vitro drug release (%), and ex vivo permeation profiles. Result showed that there is a good correlation (0.65) between HSPiP predicted and actual experimental solubility of KETO in water, chloroform, S80, and tween 80. Spherical OKEL1 showed an established correlation between the predicted and the actual formulation parameters (size, zeta potential, and polydispersity index) (259 nm vs 270 nm, +2.4 vs 0.21 mV, and 0.24 vs 0.27). OKEL1 was associated with the highest value of %EE (83.1 %) as compared to liposomes. Finally, OKEL1 exhibited the highest % cumulative permeation (49.9 %) as compared to DS (13 %) and liposomes (25 %). Moreover, OKEL1 resulted in 4-fold increase in permeation flux as compared to DS which may be attributed to vesicular mediated improved permeation and gel based compensated trans epidermal water loss in the skin. The drug deposition elicited OKEL1 and OKEL1-gel as suitable carriers for maximum therapeutic benefit to treat deeply seated fungal infections.

The effect of decoupling humidity control on aerosol drug delivery during HFNC for infants.

Aerosol therapy is commonly used during treatment with high-flow nasal cannula (HFNC) in the intensive care unit (ICU). Heated humidification inside the HFNC tubing circuit leads to unwanted condensation, which may greatly limit the efficiency of drug delivery. In this study, we aimed to investigate whether a novel humidification system, which decouples temperature and humidity control, can improve the delivered dose. In a bench study setup, fluorescein sodium solution was nebulized using a vibrating-mesh nebulizer in an infant HFNC circuit to measure the delivered dose, with a conventional versus a novel decoupled humidifier. The deposition of fluorescein inside each breathing circuit component and a final collection filter at the end of the nasal cannula was collected and quantified with a UV-vis spectrometer. Droplet sizes at different sections of the breathing circuit were measured by laser diffraction. Three air flow rates: 5, 10 and 15 L/min, and two nebulizer positions: (1) at the humidifier and (2) after the inspiratory tube, were tested. The delivered dose decreased with increasing flow rate for the conventional setup and was higher when the nebulizer was placed after the inspiratory tube. Turning off the conventional humidifier 10 minutes before and during nebulization did not improve the delivered dose. The decoupled humidifier achieved a significantly higher (p = .002) delivered dose than the conventional setup. The highest delivered dose obtained by the decoupled humidifier was 62.4% when the nebulizer was placed after the humidifier, while the highest dose obtained for the conventional humidifier was 36.3% by placing the nebulizer after the inspiratory tube. In this bench study, we found that the delivered dose for an infant HFNC nebulization setup could be improved significantly by decoupling temperature and humidity control inside the HFNC circuit, as it reduced drug deposition inside the breathing circuit.

Ex-vivo skin retention of crisaborole from microemulsion and micellar formulations

The aim of the present work was to optimize the delivery of crisaborole to the skin, incorporating the drug in topical formulations with a texture suitable also for application to the hairy skin. In particular we focused on microemulsions and micelles. As reference, the concentration of crisaborole in skin layers obtained with the commercial ointment Eucrisa®, was considered. Two microemulsions, one w/o and one o/w, were tested ex-vivo and both produced drug deposition into the skin comparable to the commercial formulation, but with higher delivery efficiency and with a non measurable permeation across the skin. Solutol®, TPGS and Soluplus® at different concentration were used for the preparation of crisaborole micellar solutions. Compared to the commercial formulation, all the micellar systems produced lower drug concentration in the skin layers, with the only exception of Soluplus® 6 %. However, due to differences in drug loading and thus in the applied dose, the delivery efficiency of all the formulation tested was higher compared to the commercial ointment. Moreover with Soluplus® 6 % formulation, a 5-fold increase in the retained/permeated ratio compared to the ointment was obtained. Two-photon microscopy studies showed that Soluplus® 6 % micelles do not permeate intact across the skin but disassemble in correspondence of the tissue surface.