Microemulsion composed of combination of skin beneficial oils as vehicle: Development of resveratrol-loaded microemulsion based formulations for skin care applications.

Microemulsion can be a potential delivery vehicle to deliver skin care actives to deep skin layer for chronic skin care benefits. On top of skin care active, microemulsion vehicle composed of multiple skin beneficial oils can deliver additional skin care efficacies. In this study, microemulsions were developed using combinations of two skin beneficial oils, tea tree oil and medium chain triglyceride instead of single oil. For that, pseudo ternary phase diagrams were constructed on these oil combinations at different ratios of surfactant/co-surfactants. Ratio of oils and surfactant/co-surfactant combinations exhibited significant impact on the microemulsion region. A few compositions were selected from the single phase microemulsion regions of these phase diagrams for the preparation of resveratrol-loaded microemulsion and microemulsion gel formulations. The particle size of the resveratrol-loaded microemulsions were <50 nm. Cryogenic scanning electron microscope image clearly showed nano-droplets dispersed in continuous phase. Both physical and chemical stability of the formulations varied depending on their compositions, such as surfactant/co-surfactant combination and % total oil. The presence of chelating agent and anti-oxidant was also crucial to stabilize the formulations. The selected formulations demonstrated good physicochemical stability at 5 °C, 25 °C, and 40 °C/75 % RH (relative humidity) stability conditions. The results further showed that the % total oil and surfactant phase composition had huge influence on resveratrol release and skin permeation patterns from the microemulsion gels. In vitro skin permeation result indicated that the microemulsion gels can help resveratrol penetration into deep skin layer. Therefore, the developed resveratrol-loaded microemulsion gels can be utilized as skin care product with multiple skin care benefits.

Development of microemulsion based topical ivermectin formulations: Pre-formulation and formulation studies.

The aim of this work was to develop microemulsions and microemulsion gels which can be used as vehicles for the topical delivery of ivermectin. Tea tree oil and ethyl butanoate were found to be suitable for ivermectin-loaded microemulsion formulations due to the higher solubility of ivermectin in these two oils than other tested oils. The pseudo-ternary phase diagrams were constructed based on these selected oils and combination of different surfactant/co-surfactant at different ratios. Ivermectin-loaded stable microemulsions and microemulsion gels were successfully formulated based on the selected compositions from the phase diagrams. Ivermectin-loaded microemulsions showed spherical nano-droplets dispersed in the continuous phase (via cryogenic field emission scanning electron microscope image) and the particle size was less than 100 nm (via dynamic light scattering measurement). Ethyl butanoate based microemulsion appeared to be the best microemulsion formulation considering the stability and permeation profiles while tea tree oil based microemulsion showed the best stability profile. Overall, microemulsion gel formulations exhibited better stability profiles than their microemulsion counterparts. All microemulsion gel formulations demonstrated significantly faster in vitro membrane permeation (release) rate of ivermectin than Soolantra cream (reference marketed product by Galderma, USA).The developed microemulsion and microemulsion gel formulations appear to be promising vehicles for topical delivery of ivermectin.

Inhaled mucoactive particles with tailored architecture for enhanced aerodynamicity, stability and efficacy.

In respiratory and genetic disorders such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis and cystic fibrosis (CF), the lungs produce excess mucus, resulting in a thickened mass, which clogs up the airways and reduces airflow. Consequently, breathing becomes more difficult. Medications that break down the structure of mucus will be especially useful in managing the early symptoms of these diseases and preventing their progression into the more severe forms. This work therefore seeks to develop an inhaled mucoactive dry powder formulation that is efficacious on multiple fronts. As an innovative step, sodium chloride was used to tailor the surface architecture of ambroxol hydrochloride particles, such that the resulting angular features on the surfaces contributed to the creation of corrugated particles with enhanced aerodynamicity. The optimized spray-dried powder particles were of respirable-size (d50 of 2.85 ±â€¯0.15 µm) and moderately corrugated. When the crystalline powder was dispersed via an Aerolizer® inhaler at 60 L/min, it gave a fine particle fraction (FPF) of ~31%, which was a ten-fold improvement over the unmodified species (i.e. ambroxol hydrochloride alone). Tests on artificial sputum medium (ASM) showed that the optimized formulation was potentially useful in liquefying the mucus, which favorably pointed towards the effectiveness of the formulation. In addition, the formulation was also stable to moisture ingress (up to ~60% RH) and had good flowability. Hence, the advent of angular adjuvant sodium chloride particles in a mucoactive formulation conferred a three-fold benefit to the product: (1) Improved aerodynamicity and flowability, (2) Enhanced moisture stability and (3) Synergistic mucolytic properties.

Tailored Antibiotic Combination Powders for Inhaled Rotational Antibiotic Therapy.

Respiratory lung infections due to multidrug-resistant (MDR) superbugs are on a global upsurge and have very grim clinical outcomes. Their MDR profile makes therapeutic options extremely limited. Although a highly toxic antibiotic, colistin, is favored today as a "last-line" therapeutic against these hard-to-treat MDR pathogens, it is fast losing its effectiveness. This work therefore seeks to identify and tailor-make useful combination regimens (that are potentially rotatable and synergistic) as attractive alternative strategies to address the rising rates of drug resistance. Three potentially rotatable ternary dry powder inhaler constructs (each involving colistin and 2 other different-classed antibiotics chosen from rifampicin, meropenem, and tigecycline) were identified (with distinct complementary killing mechanisms), coformulated via spray drying, evaluated on their aerosol performance using a Next-Generation Impactor and tested for their efficacies against a number of MDR pathogens. The powder particles were of respirable size (d50, 3.1 ± 0.3 µm-3.4 ± 0.1 µm) and predominantly crumpled in morphology. When dispersed via a model dry powder inhaler (Aerolizer(®)) at 60 L/min, the powders showed concomitant in vitro deposition with fine particle fractions of ∼53%-70%. All formulations were successfully tested in the laboratory to be highly effective against the MDR pathogens. In addition, a favorable synergistic interaction was detected across all 3 formulations when tested against MDR Pseudomonas aeruginosa.

A novel inhaled multi-pronged attack against respiratory bacteria.

Airway mucus hypersecretion is a common clinical feature of many severe respiratory diseases, and when complicated by a recalcitrant bacterial infection, the whole treatment regimen thereby becomes more challenging and protracted. The accumulation of thickened mucus secretions in the lower airways provides a nutrient-rich breeding ground for bacteria that promotes their growth and limits the ease of effective eradication. Unfortunately, no direct-inhaled dry powder formulation to treat these respiratory mucoid infections more effectively is available commercially. This work therefore seeks to develop a highly-efficacious ternary dry powder inhaler (DPI) formulation (ciprofloxacin hydrochloride (CIP), gatifloxacin hydrochloride (GAT) and ambroxol hydrochloride (AMB)) capable of delivering a novel multi-pronged attack (synergy, quorum quenching and mucociliary clearance) on Pseudomonas aeruginosa, a common respiratory bacteria found in mucoid infections. The powders were prepared via spray drying, evaluated on their aerosol performance via a multi-stage liquid impinger (MSLI) and tested for their efficacies in bacteria-spiked artificial sputum medium (ASM). The optimized particles were of respirable-size (d50 of ∼1.61±0.03µm) and slightly corrugated. When dispersed via an Aerolizer® inhaler at 60L/min, the powder showed concomitant in vitro deposition, minimal capsule, device and throat retention, and highly promising and uniform fine particle fractions (of the loaded dose) of ∼64-69%, which was a vast improvement over the singly-delivered actives. Favourably, when tested on bacteria-spiked ASM, the optimized ternary formulation (with AMB) was more effective at killing bacteria (i.e. faster rate of killing) than just the synergistic antibiotics alone (binary formulation; without AMB). In conclusion, a ternary antibiotic-(non-antibiotic) DPI formulation involving a unique multi-pronged attack mechanism was successfully pioneered and optimized for mucoid infections.

Steroid-decorated antibiotic microparticles for inhaled anti-infective therapy.

Despite advances in vaccination and antimicrobial therapy, community-acquired pneumonia (CAP) remains as a leading cause of morbidity and mortality worldwide. As the severity of CAP has been linked to the extent of inflammation in the body, adjunctive therapeutic measures aimed at modulating the immune response have therefore become increasingly attractive in recent years. In particular, for CAP patients with underlying medical conditions such as chronic obstructive pulmonary disease (COPD), a steroid-antibiotic combination will no doubt be a useful and timely therapeutic intervention. Unfortunately, no combined steroid-antibiotic dry powder formulation is available commercially or has been reported in the academic literature. The aim of this work was hence to develop a novel steroid-antibiotic dry powder inhaler formulation [ciprofloxacin hydrochloride (CIP) and beclomethasone dipropionate (BP)] for inhaled anti-infective therapy. The spray-dried powder was of respirable size (d50 of ∼2.3 µm), partially crystalline and had BP preferentially deposited on the particle surface. Favorably, when formulated as a binary mix, both CIP and BP showed much higher drug release and fine particle fractions (of the loaded dose) over their singly delivered counterparts, and had robust activity against the respiratory tract infection-causing bacteria Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus.

Novel alternatives to reduce powder retention in the dry powder inhaler during aerosolization.

Dry powder inhalers (DPIs) are used predominantly for the treatment of pulmonary diseases by delivering drugs directly into the lungs. The drug delivery efficiency is typically low and there is significant drug retention inside the DPI. An innovative 'green' initiative aimed at minimizing drug wastage via channeling the residual drug into the useful inhaled therapeutic fraction was pioneered. Drug retention could be minimized via coating the drug capsule and delivery device with pharmaceutically acceptable force-control agents. This coating reduces the adhesion between the drug particles and the internal surfaces of the DPI, which in turn increases the fine particle dose by as much as 300%.

Synergistic combination dry powders for inhaled antimicrobial therapy: formulation, characterization and in vitro evaluation.

In combination antimicrobial therapy, the desired outcome is to broaden the antimicrobial spectrum and to achieve a possible synergistic effect. However, adverse antagonistic species may also emerge from such combinations, leading to treatment failure with serious consequences. It is therefore imperative to screen the drug candidates for compatibility and possible antagonistic interactions. The aim of this work was to develop a novel synergistic dry powder inhaler (DPI) formulation for antimicrobial combination therapy via the pulmonary route. Binary (ciprofloxacin hydrochloride and gatifloxacin hydrochloride, SD-CIP/GAT) and ternary (ciprofloxacin hydrochloride, gatifloxacin hydrochloride, and lysozyme, SD-CIP/GAT/LYS) combinations were prepared via spray-drying on a BUCHI® Nano Spray Dryer B-90. The powder morphologies were spherical with a slightly corrugated surface and all within the respirable size range. The powders yielded fine particle fractions (of the loaded dose) of over 40% when dispersed using an Aerolizer® at 60 L/min. Time-kill studies carried out against the respiratory tract infection-causing bacteria Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumonia, and Acinetobacter baumannii at 1 × the minimum inhibitory concentration (MIC) over 24h revealed no antagonistic behavior for both the binary and ternary combinations. While the interactions were generally found to be indifferent, a favorable synergistic effect was detected in the dual combination (SD-CIP/GAT) when it was tested against P. aeruginosa bacteria.

The nano spray dryer B-90.

INTRODUCTION: Spray drying is an extremely well-established technology for the production of micro-particulate powders suited for a variety of drug delivery applications. In recent years, the rise in nanomedicine has placed increased pressure on the existing systems to produce nanoparticles in good yield and with a narrow size distribution. However, the separation and collection of nanoparticles with conventional spray dryer set ups is extremely challenging due to their typical low collection efficiency for fine particles < 2 µm. Currently, nanoparticles have to be agglomerated into larger microparticles, via a two-step approach, in order to collect them in a sizeable amount. However, this method has to contend with the issue of adequate redispersibility of the primary particles to reap the full benefits of nanosizing. AREAS COVERED: An overview on the advances in spray drying technology is provided in this review with particular emphasis on the novel Buchi® Nano Spray Dryer B-90. Readers will appreciate the limitations of conventional spray drying technology, understand the mechanisms of the Buchi® Nano Spray Dryer B-90, and also learn about the strengths and shortcomings of the system. EXPERT OPINION: The Buchi® Nano Spray Dryer B-90 offers a new, simple and alternative approach for the production of nanoparticles suited for a variety of drug delivery applications.

Nano spray drying: a novel method for preparing protein nanoparticles for protein therapy.

There has been an increasing interest in the development of protein nanotherapeutics for diseases such as cancer, diabetes and asthma. Spray drying with prior micro mixing is commonly used to obtain these powders. However, the separation and collection of protein nanoparticles with conventional spray dryer setups has been known to be extremely challenging due to its typical low collection efficiency for fine particles less than 2µm. To date, there has been no feasible approach to produce these protein nanoparticles in a single step and with high yield (>70%). In this study, we explored the feasibility of the novel Nano Spray Dryer B-90 (equipped with a vibrating mesh spray technology and an electrostatic particle collector) for the production of bovine serum albumin (BSA) nanoparticles. A statistical experimental design method (Taguchi method based on three levels, five variables L(18) orthogonal array robust design) was implemented to study the effect of and optimize the experimental conditions of: (1) spray mesh size, (2) BSA solution concentration, (3) surfactant concentration, (4) drying air flow rate and (5) inlet temperature on: (1) size and (2) morphology (axial ratio). Particle size and morphology were predominantly influenced by the spray mesh size and surfactant concentration, respectively. The drying air flow rate and inlet temperature had minimal impact. Optimized production of smooth spherical nanoparticles (median size: 460±10nm, axial ratio: 1.03±0.00, span 1.03±0.03, yield: 72±4%) was achieved using the 4µm spray mesh at BSA concentration of 0.1% (w/v), surfactant concentration of 0.05% (w/v), drying flow rate of 150L/min and inlet temperature of 120°C. The Nano Spray Dryer B-90 thus offers a new, simple and alternative approach for the production of protein nanoparticles suited for a variety of drug delivery applications.

In vitro and in vivo investigation on PLA-TPGS nanoparticles for controlled and sustained small molecule chemotherapy.

PURPOSE: The aim of this work was to evaluate in vivo poly(lactide)-D: -alpha-tocopheryl polyethylene glycol 1,000 succinate nanoparticles (PLA-TPGS NPs) for controlled and sustained small molecule drug chemotherapy. METHODS: The drug-loaded PLA-TPGS NPs were prepared by the dialysis method. Particle size, surface morphology and surface chemistry, in vitro drug release and cellular uptake of NPs were characterized. In vitro and in vivo therapeutic effects of the nanoparticle formulation were evaluated in comparison with Taxol. RESULTS: The PLA-TPGS NP formulation exhibited significant advantages in in vivo pharmacokinetics and xenograft tumor model versus the PLGA NP formulation and the pristine drug. Compared with Taxol, the PLA-TPGS NP formulation achieved 27.4-fold longer half-life in circulation, 1.6-fold larger area-under-the-curve (AUC) with no portion located above the maximum tolerance concentration level. For the first time in the literature, one shot for 240 h chemotherapy was achieved in comparison with only 22 h chemotherapy for Taxol at the same 10 mg/kg paclitaxel dose. Xenograft tumor model further confirmed the advantages of the NP formulation versus Taxol. CONCLUSIONS: The PLA-TPGS NP formulation can realize a way of controlled and sustained drug release for more than 10 days, which relieves one of the two major concerns on cancer nanotechnology, i.e. feasibility.

Nanoparticles of poly(lactide)-tocopheryl polyethylene glycol succinate (PLA-TPGS) copolymers for protein drug delivery.

Nanoparticles (NPs) of poly(lactide)-tocopheryl polyethylene glycol succinate (PLA-TPGS) copolymers with various PLA:TPGS component ratios were prepared by the double emulsion technique for protein drug formulation with bovine serum albumin (BSA) as a model protein. Influence of the PLA:TPGS component ratio and the BSA loading level on the drug encapsulation efficiency (EE) and in vitro drug release behavior was investigated. The PLA-TPGS NPs achieved 16.7% protein drug loading and 75.6% EE, which exhibited a biphasic pattern of controlled protein release with higher initial burst for those NPs of more TPGS content. Furthermore, the released proteins retained good structural integrity for at least 35 days at 37 degrees C as indicated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and circular dichroism (CD) spectroscopy. Compared with other biodegradable polymeric NPs such as poly(D,L-lactide-co-glycolide) (PLGA) NPs, PLA-TPGS NPs could provide the encapsulated proteins a milder environment. Confocal laser scanning microscopy (CLSM) observation demonstrated the intracellular uptake of the PLA-TPGS NPs by NIH-3T3 fibroblast cells and Caco-2 cancer cells. This research suggests that PLA-TPGS NPs could be of great potential for clinical formulation of proteins and peptides.

A simple way to prepare PbS nanocrystals with morphology tuning at room temperature.

A simple way to synthesize PbS nanocrystals with the ability to tune their morphology at room temperature is reported. The preparation utilizes an amine-catalyzed decomposition of a precursor and the amine was found to play dual roles as both the catalyst and the capping agent. Spherical PbS nanocrystals of diameters 5 to 10 nm were obtained when long chain alkylamines were used in the pot. When difunctional ethylenediamine was used instead, exclusively PbS dendrites can be isolated from the same precursor at room temperature. Uniform six- and four-armed dendrites are observed, with regular branches of approximately 20 nm in diameter growing in a parallel order. In a further step, morphology tuning of the dendrites to induce 1D growth into nanorods is achievable through the addition of a trace amount of stronger capping dodecanethiol molecules. Thus, PbS nanorods with aspect ratios of approximately 20 to 30 could be successfully obtained and illustrated. A possible formation mechanism is discussed and the initial step of the reaction mechanism was modeled with DFT calculations as a nucleophilic attack.