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 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.

Bacteriophage endolysin powders for inhaled delivery against pulmonary infections.

Endolysins are bacteriophage-encoded enzymatic proteins that have great potential to treat multidrug-resistant bacterial infections. Bacteriophage endolysins Cpl-1 and ClyJ-3 have shown promising antimicrobial activity against Streptococcus pneumoniae, which causes pneumonia in humans. This is the first study to investigate the feasibility of spray-dried endolysins Cpl-1 and ClyJ-3 with excipients to produce inhalable powders. The two endolysins were individually tested with leucine and sugar (lactose or trehalose) for spray drying method followed by characterization of biological and physico-chemical properties. A complete loss of ClyJ-3 bioactivity was observed after atomization of the liquid feed solution（before the drying process）, while Cpl-1 maintained its bioactivity in the spray-dried powders. Cpl-1 formulations containing leucine with lactose or trehalose showed promising physico-chemical properties (particle size, crystallinity, hygroscopicity, etc.) and aerosol performances (fine particle fraction values above 65%). The results indicated that endolysin Cpl-1 can be formulated as spray dried powders suitable for inhaled delivery to the lungs for the potential treatment of pulmonary infections.

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.

A dual action of D-amino acids on anti-biofilm activity and moisture-protection of inhalable ciprofloxacin powders.

Although inhalation powder aerosols of antibiotics have been used to treat respiratory infections caused by Pseudomonas aeruginosa, biofilms are difficult to clear. Ciprofloxacin and D-amino acids (D-Met, D-Trp and D-Phe) were shown to facilitate P. aeruginosa biofilm removal. Spray dried powders for inhalation tend to be amorphous, hence unstable to moisture which causes deterioration in the aerosol performance. Hydrophobic L-amino acids such as leucine can impart moisture protection. In this study, we hypothesized that co-spray dried formulations of ciprofloxacin and hydrophobic D-amino acids will offer the combined benefits of both anti-biofilm and moisture protection properties. Of the three D-amino acids tested, D-Met and D-Trp (at 5 mM) but not D-Phe reduced clinical isolate P. aeruginosa biofilm loads and the extent of biofilm clearance was further enhanced in the presence of ciprofloxacin. Subsequently, ciprofloxacin was spray dried alone or in combination with 30% (w/w) D-Met or D-Trp. The biological and physicochemical properties of the powders were assessed, including the minimum inhibitory concentration, anti-biofilm activity, particle size distribution and morphology, solid-state properties, water sorption, and aerosol performance. The spray dried combination powders were physically stable and inhalable with fine particle fraction (<5 µm) values of 50-57% when aerosolized. The powders exhibited enhanced anti-biofilm activity compared with ciprofloxacin alone. The presence of D-amino acids provided moisture protection, with the recrystallization event shifting from 50% RH to 80% RH in powders containing D-Trp. In conclusion, the use of D-amino acids (D-Met or D-Trp) is an attractive formulation strategy which offers dual benefits of anti-biofilm effect and moisture protection.

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.

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.

Nebulised Isotonic Hydroxychloroquine Aerosols for Potential Treatment of COVID-19.

The coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has severely impacted global public health and the economy. Hydroxychloroquine administered orally to COVID-19 patients was ineffective, but its antiviral and anti-inflammatory actions were observed in vitro. The lack of efficacy in vivo could be due to the inefficiency of the oral route in attaining high drug concentration in the lungs. Delivering hydroxychloroquine by inhalation may be a promising alternative for direct targeting with minimal systemic exposure. This paper reports on the characterisation of isotonic, pH-neutral hydroxychloroquine sulphate (HCQS) solutions for nebulisation for COVID-19. They can be prepared, sterilised, and nebulised for testing as an investigational new drug for treating this infection. The 20, 50, and 100 mg/mL HCQS solutions were stable for at least 15 days without refrigeration when stored in darkness. They were atomised from Aerogen Solo Ultra vibrating mesh nebulisers (1 mL of each of the three concentrations and, in addition, 1.5 mL of 100 mg/mL) to form droplets having a median volumetric diameter of 4.3-5.2 µm, with about 50-60% of the aerosol by volume < 5 µm. The aerosol droplet size decreased (from 4.95 to 4.34 µm) with increasing drug concentration (from 20 to 100 mg/mL). As the drug concentration and liquid volume increased, the nebulisation duration increased from 3 to 11 min. The emitted doses ranged from 9.1 to 75.9 mg, depending on the concentration and volume nebulised. The HCQS solutions appear suitable for preclinical and clinical studies for potential COVID-19 treatment.

Spray-Dried Powder Formulation of Capreomycin Designed for Inhaled Tuberculosis Therapy.

Multi-drug-resistant tuberculosis (MDR-TB) is a huge public health problem. The treatment regimen of MDR-TB requires prolonged chemotherapy with multiple drugs including second-line anti-TB agents associated with severe adverse effects. Capreomycin, a polypeptide antibiotic, is the first choice of second-line anti-TB drugs in MDR-TB therapy. It requires repeated intramuscular or intravenous administration five times per week. Pulmonary drug delivery is non-invasive with the advantages of local targeting and reduced risk of systemic toxicity. In this study, inhaled dry powder formulation of capreomycin targeting the lung was developed using spray drying technique. Among the 16 formulations designed, the one containing 25% capreomycin (w/w) and spray-dried at an inlet temperature of 90 °C showed the best overall performance with the mass median aerodynamic diameter (MMAD) of 3.38 µm and a fine particle fraction (FPF) of around 65%. In the pharmacokinetic study in mice, drug concentration in the lungs was approximately 8-fold higher than the minimum inhibitory concentration (MIC) (1.25 to 2.5 µg/mL) for at least 24 h following intratracheal administration (20 mg/kg). Compared to intravenous injection, inhaled capreomycin showed significantly higher area under the curve, slower clearance and longer mean residence time in both the lungs and plasma.

Inhalable Hydroxychloroquine Powders for Potential Treatment of COVID-19.

Background: Hydroxychloroquine (HCQ) is one of the repurposed drugs proposed for the treatment of coronavirus disease 2019 (COVID-19). However, all the published clinical trials involve oral administration of the drug, although the disease is primarily a respiratory one. Direct inhaled delivery could reduce the side effects associated with oral use and ensure a high concentration of the drug in the lungs. In this study, inhalable HCQ powders were prepared and characterized for potential COVID-19 therapy. Methods: Hydroxychloroquine sulfate (HCQ-sul) was jet milled (JM) followed by conditioning by storage at different relative humidities (43%, 53%, 58%, and 75% RHs) for 7 days. The solid-state properties, including particle morphology and size distribution, crystallinity, and vapor moisture profiles of HCQ-sul samples, were characterized by scanning electron microscopy, laser diffraction, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and dynamic water vapor sorption. The aerosol performance of the HCQ-sul powders was assessed using a medium-high resistance Osmohaler coupling to a next-generation impactor (NGI) at a flow rate of 60 L/min. Results: The jet-milled powder showed a volume median diameter of 1.7 µm (span 1.5) and retained the same crystalline form as the raw HCQ-sul. A small amount of amorphous materials was present in the jet-milled HCQ-sul, which was convertible to the stable, crystalline state after conditioning at 53%, 58%, and 75% RH. The recovered fine particle fraction (FPF)recovered and the emitted fine particle fraction (FPFemitted) of the HCQ-sul sample immediately after jet milling and the samples after conditioning at 43%, 53%, and 58% RH were similar at ∼43% and 61%, respectively. In contrast, the sample having conditioned at 75%RH showed lower corresponding values at 33% and 26% respectively, due to the formation of solid bridges caused by excessive moisture. Conclusion: Inhalable crystalline powders of HCQ-sul were successfully prepared, which can be used for clinical testing as a potential inhaled COVID-19 treatment.

Effect of formulation and inhaler parameters on the dispersion of spray freeze dried voriconazole particles.

Spray freeze drying is a particle engineering technique that allows the production of porous particles of low density with excellent aerosol performance for inhalation. There are a number of operating parameters that can be manipulated in order to optimise the powder properties. In this study, a two-fluid nozzle was used to prepare spray freeze dried formulation of voriconazole, a triazole antifungal agent for the treatment of pulmonary aspergillosis. A full factorial design approach was adopted to explore the effects of drug concentration, atomisation gas flow rate and primary drying temperature. The aerosol performance of the spray freeze dried powder was evaluated using the next generation impactor (NGI) operated with different inhaler devices and flow rates. The results showed that the primary drying temperature played an important role in determining the aerosol properties of the powder. In general, the higher the primary drying temperature, the lower the emitted fraction (EF) and the higher the fine particle fraction (FPF). Formulations that contained the highest voriconazole concentration (80% w/w) and prepared at a high primary drying temperature (-10 °C) exhibited the best aerosol performance under different experimental conditions. The high concentration of the hydrophobic voriconazole reduced surface energy and cohesion, hence better powder dispersibility. The powders produced with higher primary drying temperature had a smaller particle size after dispersion and improved aerosol property, possibly due to the faster sublimation rate in the freeze-drying step that led to the formation of less aggregating or more fragile particles. Moreover, Breezhaler®, which has a low intrinsic resistance, was able to generate the best aerosol performance of the spray freeze dried voriconazole powders in terms of FPF.