Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration.

The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.

Spray-Dried Particles of Nitric Oxide-Modified Glutathione for the Treatment of Chronic Lung Infection.

Antibiotic resistance in pathogenic bacteria has emerged as a big challenge to human and animal health and significant economy loss worldwide. Development of novel strategies to tackle antibiotic resistance is of the utmost priority. In this study, we combined glutathione (GSH), a master antioxidant in all mammalian cells, and nitric oxide, a proven biofilm-dispersing agent, to produce GSNO. The resazurin biofilm viability assay, crystal violet biofilm assay, and confocal microscopy techniques showed that GSNO disrupted biofilms of both P. aeruginosa PAO1 and multidrug resistant A. baumaunii (MRAB 015069) more efficiently than GSH alone. In addition, GSNO showed a higher reduction in biofilm viability and biomass when combined with antibiotics. This combination treatment also inhibited A. baumaunii (MRAB 015069) growth and facilitated human foreskin fibroblast (HFF-1) confluence and growth simultaneously. A potentially inhalable GSNO powder with reasonable aerosol performance and antibiofilm activity was produced by spray drying. This combination shows promise as a novel formulation for treating pulmonary bacterial infections.

Pharmacokinetics and pharmacodynamics of dexmedetomidine.

Dexmedetomidine is an alpha-2 adrenoceptor agonist and has been used as a general anesthetic, sedative and analgesic for about 30 years. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine, evaluate physiological factors that may affect the pharmacokinetics of dexmedetomidine, and summarize the pharmacodynamics of dexmedetomidine at different plasma levels. The pharmacokinetic parameters reported in previous studies according to noncompartmental analyses or population modeling results are compared. We concluded that the pharmacokinetic profile can be adequately described by a two-compartment model in population pharmacokinetic modeling. Body weight, height, albumin level, cardiac output, disease condition and other factors were considered to have significant influence on the clearance and/or distribution volume in different population pharmacokinetic models. The pharmacological effects of dexmedetomidine, such as sedation, heart rate reduction and biphasic change of blood pressure, vary at different plasma levels. These findings provide a reference for individualizing the dose of dexmedetomidine and achieving the desired pharmacological effects in clinical applications.

Measuring Bipolar Charge and Mass Distributions of Powder Aerosols by a Novel Tool (BOLAR).

The Bipolar Charge Analyzer (BOLAR) was evaluated for measuring bipolar electrostatic charge and mass distributions of powder aerosols generated from a dry powder inhaler. Mannitol powder (5, 10, and 20 mg) was dispersed using an Osmohaler inhaler into the BOLAR at air flow rates of 30 or 60 L/min. As the aerosol sample was drawn through the BOLAR, the air flow was divided into six equal fractions. Five of them entered individual detection tubes with a defined cutoff diameter in the range of 0.95 to 16.36 µm (depending on the flow rate) and the remaining (i.e., the sixth) fraction passed through a reference chamber. The aerosols that entered the detection tubes were separated according to the particle charge polarity (positive, negative, or neutral) and charge was measured by separate electrometers. The deposited powder of a single actuation from the inhaler was chemically assayed using high performance liquid chromatography. Additionally, the aerosol measurements were conducted on a modified Classic Electrical Low Pressure Impactor (ELPI) for comparison of the net specific charge per size fraction. Spray-dried mannitol carried significantly different positively and negatively charged particles in each of the five defined particle size fractions. The charge-to-mass ratio (q/m) of positively charged particles ranged from +1.11 to +32.57 pC/µg and negatively charged particles ranged from -1.39 to -9.25 pC/µg, resulting in a net q/m of -3.08 to +13.34 pC/µg. The net q/m values obtained on the modified ELPI ranged from -5.18 to +4.81 pC/µg, which were comparable to the BOLAR measurements. This is the first full report to utilize the BOLAR to measure bipolar charge and mass distributions of a powder aerosol. Positively and negatively charged particles were observed within each size fraction, and their corresponding q/m profiles were successfully characterized. Despite some potential drawbacks, the BOLAR has provided a new platform for investigating bipolar charge in powder aerosols for inhalation.

Effect of crystallinity on electrostatic charging in dry powder inhaler formulations.

PURPOSE: This study aimed to characterize inherent charge generated by micron-sized drug-only formulations of amorphous and crystalline salbutamol sulfate (SS). METHODS: Amorphous SS was produced by spray-drying whilst crystalline SS was produced by conditioning spray-dried SS with supercritical CO2 and menthol. Electrostatic charge of the powders was characterized in two ways. Firstly, the charge profile of the aerosols dispersed from an Aerolizer® was measured using a modified Electrostatic Low Pressure Impactor (ELPI™). Secondly, the net charge of the bulk powders generated from tumbling in containers composed of different materials (polyethylene, polyvinyl chloride, Teflon, nylon and stainless steel) was measured by a Faraday pail. RESULTS: Following aerosolization, crystalline SS appeared to show more consistent charging and mass deposition than amorphous SS. In the tumbling experiment crystalline SS had a significant correlation between net charge and work function, which was absent in amorphous SS. This may be due to the long-range crystal packing which was reflected as more predictable charging. In addition, the polarity of charging was attributed to the arrangement of SS molecules in the crystal lattice. CONCLUSIONS: The effect of crystallinity on the electrostatic charge behavior of inhalable micron-sized spherical drug particles with well-defined particle size distribution was investigated for the first time. The knowledge gained may assist in the development of optimized inhaled pharmaceutical products.

Spray freeze dried cannabidiol with dipalmitoylphosphatidylcholine (DPPC) for inhalation and solubility enhancement.

Pulmonary delivery is an efficient route of administration to deliver cannabidiol (CBD) due to the high bioavailability and fast onset of action. The major formulation challenge is the poor aqueous solubility of CBD. This study aimed to produce inhalable CBD powders with enhanced solubility and characterise their solid-state properties. CBD was spray freeze dried with mannitol or trehalose dihydrate with and without dipalmitoylphosphatidylcholine (DPPC). All four powders had acceptable yields at > 70 % with porous and spherical particles. The two crystalline mannitol powders contained less residual solvent than both amorphous trehalose ones. The addition of DPPC did not affect the crystallinity and residual solvent level of the powders. Instead, DPPC made the particles more porous, decreased the particle size from 19-23 µm to 11-13 µm, and increased CBD solubility from 0.36 µg/mL to over 2 µg/mL. The two DPPC powders were dispersed from a low resistance RS01 inhaler, showing acceptable aerosol performance with emitted fractions at 91-93 % and fine particle fractions < 5 µm at 34-43 %. These formulations can be used as a platform to deliver CBD and other cannabinoids by inhalation.

High-loading cannabidiol powders for inhalation.

Limited attempts have been made previously to develop high-loading CBD inhalable powders, which are essential for high dose delivery. Therefore, this study aimed to develop and characterise inhalable powders with ≥ 95 % w/w CBD by wet ball milling. The effects of magnesium stearate (2 % and 5 %) and inhaler resistance (low-resistance and high-resistance RS01 inhalers) on aerosol performance were also compared. Wet ball milling produced CBD powders with > 50 % production yield. The milled particles showed irregular shapes. The powders were crystalline with minimal amorphous content, low residual solvent level (<1%), and low moisture sorption (<4%). Magnesium stearate improved both the emitted and fine particle fractions. The aerodynamic particle size distribution of the formulations differed between the low-resistance and high-resistance RS01 inhalers. The latter decreased throat deposition but increased inhaler retention. The dissolution profiles showed that all three formulations released CBD steadily and plateaued at 30 min. The best scenario was CBD with 5 % magnesium stearate dispersed from the high resistance RS01 inhaler, showing the highest FPF with the lowest throat deposition. This combination may be tested in vivo in the future to investigate its pharmacokinetic profile.

Aerosol delivery of nanoparticles in uniform mannitol carriers formulated by ultrasonic spray freeze drying.

PURPOSE: While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization properties, high loadings of nanoparticles, and limited irreversible aggregation. METHODS: Aerosolizable mannitol carrier particles that encapsulate nanoparticles with dense PEG coatings were prepared by a combination of ultrasonic atomization and spray freeze drying. This process was contrasted to particle formation by conventional spray drying. RESULTS: Spray freeze drying a solution of nanoparticles and mannitol (2 wt% solids) resulted in particles with an average diameter of 21 ± 1.7 µm, regardless of the fraction of nanoparticles loaded (0-50% of total solids). Spray freeze dried (SFD) powders with a 50% nanoparticle loading had a fine particle fraction (FPF) of 60%. After formulation in a mannitol matrix, nanoparticles redispersed in water to < 1 µm with hand agitation and to < 250 nm with the aid of sonication. Powder production by spray drying was less successful, with low powder yields and extensive, irreversible aggregation of nanoparticles evident upon rehydration. CONCLUSIONS: This study reveals the unique advantages of processing by ultrasonic spray freeze drying to produce aerosol dry powders with controlled properties for the delivery of therapeutic nanoparticles to the lungs.

Role of Particle Size in Translational Research of Nanomedicines for Successful Drug Delivery: Discrepancies and Inadequacies.

Despite significant research progress in substantiating the therapeutic merits of nanomedicines and the emergence of sophisticated nanotechnologies, the translation of this knowledge into new therapeutic modalities has been sluggish, indicating the need for a more comprehensive understanding of how the unique physicochemical properties of nanoparticles affect their clinical applications. Particle size is a critical quality attribute that impacts the bio-fate of nanoparticles, yet precise knowledge of its effect remains elusive with discrepancies among literature reports. This review aims to address this scientific knowledge gap from a drug development perspective by highlighting potential inadequacies during the evaluation of particle size effects. We begin with a discussion on the major issues in particle size characterization along with the corresponding remedies. The influence of confounding factors on biological effects of particle size, including colloidal stability, polydispersity, and in vitro drug release, are addressed for establishing stronger in vitro-in vivo correlation. Particle size design and tailoring approaches for successful nanoparticulate drug delivery beyond parenteral administration are also illustrated. We believe a holistic understanding of the effect of particle size on bio-fate, combined with consistent nanoparticle manufacturing platforms and tailored characterization techniques, would expedite the translation of nanomedicines into clinical practice.

Does the United States Pharmacopeia throat introduce de-agglomeration of carrier-free powder from inhalers?

PURPOSE: We hypothesize that the USP induction port may de-agglomerate carrier-free powder emitting from dry powder inhalers (DPIs). METHODS: Aerosols emitting from a range of DPIs (Spinhaler®, Turbuhaler® and Osmohaler™) and induction ports (USP throat, straight tube, Alberta idealized mouth-throat geometry (AG)) were sized by laser diffraction. Total drug recovery was obtained by HPLC and fine particle fraction computed. Air flow patterns were simulated using Computational Fluid Dynamics (CFD). RESULTS: The straight tube did not de-agglomerate emitted powder. However, the USP throat and AG further de-agglomerated powders from the Spinhaler, but not the Turbuhaler and Osmohaler. While budesonide powder deposited similarly in all induction ports, deposition was significantly higher in the AG for both DSCG and mannitol. CFD revealed agglomerates impacting on the USP throat with higher localized velocity compared with the straight tube. CFD further showed a more complex flow pattern with high-velocity air jets in the AG, which explains the higher FPF for DSCG and the lower FPF for mannitol using the AG. CONCLUSION: The USP throat further de-agglomerated the emitted powder from the DPI when it did not sufficiently disperse the powder. Other tools such as laser diffraction may be used for cross-examining to avoid artifacts in the results.

Evaluation of the correlation between focal adhesion kinase phosphorylation and cell adhesion force using "DEP" technology.

Dielectrophoresis (DEP) is the phenomenon in which a particle, such as a living cell, is polarized and moved by electrical gravity in a non-uniform electric field. In the present study, the DEP force is utilized to act on the cells to induce spatial movement for investigating the correlation between the cell adhesion force and activation level of focal adhesion kinase (FAK). The DEP force produced by the non-uniform electric field was used to measure the cell adhesion force of ECV304 cells, on type 1 collagen (COL1)- and fibronectin (FN)-coated polydimethylsiloxane (PDMS) membranes. For COL1-coating, ECV304 cells revealed weak and variable adhesion force (0.343-0.760 nN) in the first eight hours of incubation. Interestingly, the cell adhesion force of ECV304 at two and five hours of cultivation was significantly high and matched their FAK activation level. In comparison, ECV304 on FN-coated membrane had higher and more stable cell adhesion force (0.577-2.053 nN). FN coating intensified the cell adhesion force of ECV304 with culture time and similar outcome was present on the activation level of FAK. Therefore, this study demonstrated a relationship between cell adhesion force and FAK activation level that was dependent on the choice of the extracellular matrix (ECM) component. Subsequently, two tyrosine kinase inhibitors (AG18 and genistein) and one PI3K inhibitor (LY294002) were applied to study the influence of protein phosphorylation on the cell adhesion force. FAK plays an important role on cell attachment and DEP force measurement is a useful technique for studying cell adhesion.

Recent advances in drug delivery to the central nervous system by inhalation.

INTRODUCTION: Drugs need to enter the systemic circulation efficiently before they can cross the blood-brain barrier and reach the central nervous system. Although the respiratory tract is not a common route of administration for delivering drugs to the central nervous system, it has attracted increasing interest in recent years for this purpose. AREAS COVERED: In this article, we compare pulmonary delivery to three other common routes (parenteral, oral, and intranasal) for delivering drugs to the central nervous system. Recent studies delivering drugs for different neurological disorders via inhalation are then discussed to illustrate the strengths of pulmonary delivery. EXPERT OPINION: Recent studies provide strong evidence and rationale to support inhaling neurological drugs. Since inhalation can achieve improved pharmacokinetics and rapid onset of action for multiple drugs, it is a noninvasive and efficient method to deliver drugs to the central nervous system. Future research should focus on delivering other small and macro-molecules via the lungs for different neurological conditions.

Phage-Antibiotic Therapy as a Promising Strategy to Combat Multidrug-Resistant Infections and to Enhance Antimicrobial Efficiency.

Infections caused by multidrug-resistant (MDR) bacteria have highlighted the importance of the development of new antimicrobial agents. While bacteriophages (phages) are widely studied as alternative agents to antibiotics, combined treatments using phages and antibiotics have exhibited Phage-Antibiotic Synergy (PAS), in which antibiotics promote phage replication and extraordinary antimicrobial efficacy with reduced development of bacterial resistance. This review paper on the current progress of phage-antibiotic therapy includes aspects of the mechanisms of PAS and the therapeutic performance of PAS in combating multidrug-resistant bacterial infections. The choice of phages and antibiotics, the administration time and sequence, and the concentrations of the two agents impact the bacterial inhibitory effects to different extents.

Advances and future perspectives in epithelial drug delivery.

Epithelial surfaces protect exposed tissues in the body against intrusion of foreign materials, including xenobiotics, pollen and microbiota. The relative permeability of the various epithelia reflects their extent of exposure to the external environment and is in the ranking: intestinal≈ nasal ≥ bronchial ≥ tracheal > vaginal ≥ rectal > blood-perilymph barrier (otic), corneal > buccal > skin. Each epithelium also varies in their morphology, biochemistry, physiology, immunology and external fluid in line with their function. Each epithelium is also used as drug delivery sites to treat local conditions and, in some cases, for systemic delivery. The associated delivery systems have had to evolve to enable the delivery of larger drugs and biologicals, such as peptides, proteins, antibodies and biologicals and now include a range of physical, chemical, electrical, light, sound and other enhancement technologies. In addition, the quality-by-design approach to product regulation and the growth of generic products have also fostered advancement in epithelial drug delivery systems.

Formation of protein nano-matrix particles with controlled surface architecture for respiratory drug delivery.

PURPOSE: To produce and examine the aerosol performance of protein nano-matrix particles with different surface roughness. METHODS: Aqueous lysozyme solutions were poured into isopropanol during high-shear mixing to produce nanoparticles by precipitation. The size of the nanoparticles was varied by adjusting the precipitation conditions. The resultant suspensions were spray-dried to obtain micron-sized aggregates (nano-matrices). Smooth particles were made by spray-drying a lysozyme solution. The aggregate size distribution, surface roughness, and cohesion were evaluated. The aerosol performance was assessed by dispersing 10 mg of powder from a Rotahaler(®) at 60 L/min or an Aerolizer® at 100 L/min into a Next Generation Impactor, followed by chemical assay (n=3). RESULTS: The median volume diameter and span of the nano-matrix particles were 1.0-1.2 µm and 1.5-1.6, respectively, which were comparable to those of the smooth particles. Surface roughness increased with the size of the primary nanoparticles. The nano-matrix particles were significantly less cohesive than the smooth particles. The fine particle fraction increased linearly with increasing surface roughness and decreasing cohesion. CONCLUSIONS: Nano-matrix particles with controlled surface architecture were successfully produced by spray-drying nanosuspensions. Aerosol performance was enhanced with increasing surface roughness due to the reduction in cohesion forces.

A 3D printed human upper respiratory tract model for particulate deposition profiling.

Pulmonary route is the main route of drug delivery for patients with asthma and chronic obstructive pulmonary diseases, offering several advantages over the oral route. Determining the amount of drug deposited onto various parts of the respiratory tract allows for a good correlation to clinical efficacy of inhalation drug devices. However, current in vitro cascade impactors measure only the aerodynamic particle size distribution, which does not truly represent the in vivo deposition pattern in human respiratory tract. In this study, a human upper respiratory tract model was fabricated using a 3D printer and subsequently characterized for its dimensional accuracy, surface finishing and air leaking. The effects of using a spacer and/or various airflow rates were also investigated. To assess this in vitro model, the deposition pattern of a model drug, namely, salbutamol sulphate, was tested. The resultant deposition pattern of salbutamol sulphate from a metered dose inhaler at 15 L per minute with the spacer, showed no significant difference from that of a published radiological in vivo study performed in adult humans. In addition, it was also found that the deposition pattern of salbutamol at 35 L per minute was comparable to the results of another published study in human. This in vitro model, showing reasonable in vitro-in vivo correlation, may provide opportunities for personalized medicine in special populations or disease states.

In vitro-in vivo correlation of cascade impactor data for orally inhaled pharmaceutical aerosols.

In vitro-in vivo correlation is the establishment of a predictive relationship between in vitro and in vivo data. In the context of cascade impactor results of orally inhaled pharmaceutical aerosols, this involves the linking of parameters such as the emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter to in vivo lung deposition from scintigraphy data. If the dissolution and absorption processes after deposition are adequately understood, the correlation may be extended to the pharmacokinetics and pharmacodynamics of the delivered drugs. Correlation of impactor data to lung deposition is a relatively new research area that has been gaining recent interest. Although few in number, experiments and meta-analyses have been conducted to examine such correlations. An artificial neural network approach has also been employed to analyse the complex relationships between multiple factors and responses. However, much research is needed to generate more data to obtain robust correlations. These predictive models will be useful in improving the efficiency in product development by reducing the need of expensive and lengthy clinical trials.

Co-spray dried hydrophobic drug formulations with crystalline lactose for inhalation aerosol delivery.

Spray drying is a rapid method for converting a liquid feed into dried particles for inhalation aerosols. Lactose is a major inhalation excipient used in spray-dried (SD) formulations. However, SD powders produced from solutions are usually amorphous hence unstable to moisture. This problem can potentially be minimized by spray drying a suspension (instead of solution) containing crystalline lactose particles and dissolved drugs. In the present study, the suspension formulation containing dissolved budesonide (BUD) or rifampicin (RIF) and suspended lactose crystals in isopropanol alcohol (IPA) were produced. For comparison, powders were also produced from solution formulations containing the same proportions of drug and lactose dissolved in 50:50 IPA/water as controls. These SD powders were stored at 25 °C/60% RH and 40 °C/75% RH for six months. The particulate properties and in vitro dispersion performance were examined at various storage time points. All powders obtained from spray drying of solutions recrystallized after one week of storage at 25 °C/60% RH. In contrast, SD BUD-lactose obtained from suspension did not change until after three-months of storage when the particle size increased gradually with morphology change and yet the crystallinity remained the same as determined by X-ray powder diffraction. For the SD RIF-lactose obtained from suspension, both particulate properties and in vitro powder dispersion performance showed no significant difference before and after storage at both storage conditions. To conclude, this is the first study to show that SD powder formulations obtained from suspensions containing lactose crystals demonstrated superior storage stability performance, which is desirable for inhaled powders.

Administration of dry powders during respiratory supports.

Inhaled drugs are routinely used for the treatment of respiratory-supported patients. To date, pressurized metered dose inhalers and nebulizers are the two platforms routinely employed in the clinical setting. The scarce utilization of the dry powder inhaler (DPI) platform is partly due to the lack of in vivo data that proves optimal delivery and drug efficacy are achievable. Additionally, fitting a DPI in-line to the respiratory circuit is not as straightforward as with the other aerosol delivery platforms. Importantly, there is a common misconception that the warm and humidified inspiratory air in respiratory supports, even for a short exposure, will deteriorate powder formulation compromising its delivery and efficacy. However, some recent studies have dispelled this myth, showing successful delivery of dry powders through the humidified circuit of respiratory supports. Compared with other aerosol delivery devices, the use of DPIs during respiratory supports possesses unique advantages such as rapid delivery and high dose. In this review, we presented in vitro studies showing various setups employing commercial DPIs and effects of ventilator parameters on the aerosol delivery. Inclusion of novel DPIs was also made to illustrate characteristics of an ideal inhaler that would give high lung dose with low powder deposition loss in tracheal tubes and respiratory circuits. Clinical trials are urgently needed to confirm the benefits of administration of dry powders in ventilated patients, thus enabling translation of powder delivery into practice.