Pulmonary Drug Delivery

The applications of the crystallization technique in the pharmaceutical industry as a purification and separation process for the isolation and synthesis of pure active pharmaceutical ingredients (API), co-crystals, controlled release pulmonary drug delivery, and separation of chiral isomers are briefly discussed using a few case studies. The effect of process variables and solvent on the polymorphism and morphology of stavudine

The pulmonary route is one of the most attractive routes for local and systematic drug delivery owing to the large surface area of lungs, abundant blood supply, and thin alveolar epithelial lining. Despite these advantages, pulmonary disorders are still the third leading cause of premature death globally. The off-target deposition, mucociliary clearance, and phagocytosis of drug particles are major challenges in the effective delivery of the drugs to the lungs. To circumvent these challenges, various drug delivery carriers such as liposomes, micelles, polymeric microparticles, solid lipid nanoparticles, and hydrogels have been investigated. The wide size range, stimuli-responsive swelling behavior, mucoadhesiveness, and biocompatibility render hydrogels as versatile biomaterials for pulmonary drug delivery. This chapter provides a detailed insight into hydrogels and their role in pulmonary drug delivery and the diagnosis of lung diseases. In addition, the pharmacokinetics, toxicity, and future prospects of the hydrogel-based pulmonary delivery systems are also discussed.

PURPOSE:

The aim of this work was to optimize biodegradable polyester poly(glycerol adipate-co-ω-pentadecalactone), PGA-co-PDL, microparticles as sustained release (SR) carriers for pulmonary drug delivery.

METHODS:

Microparticles were produced by spray drying directly from double emulsion with and without dispersibility enhancers ((L)-arginine and (L)-leucine) (0.5-1.5%w/w) using sodium fluorescein (SF) as a model hydrophilic drug.

RESULTS:

Spray-dried microparticles without dispersibility enhancers exhibited aggregated powders leading to low fine particle fraction (%FPF) (28.79 ± 3.24), fine particle dose (FPD) (14.42 ± 1.57 μg), with a mass median aerodynamic diameter (MMAD) 2.86 ± 0.24 μm. However, (L)-leucine was significantly superior in enhancing the aerosolization performance ((L-)arginine:%FPF 27.61 ± 4.49-26.57 ± 1.85; FPD 12.40 ± 0.99-19.54 ± 0.16 μg and MMAD 2.18 ± 0.35-2.98 ± 0.25 μm, (L)-leucine:%FPF 36.90 ± 3.6-43.38 ± 5.6; FPD 18.66 ± 2.90-21.58 ± 2.46 μg and MMAD 2.55 ± 0.03-3.68 ± 0.12 μm). Incorporating (L)-leucine (1.5%w/w) reduced the burst release (24.04 ± 3.87%) of SF compared to unmodified formulations (41.87 ± 2.46%), with both undergoing a square root of time (Higuchi's pattern) dependent release. Comparing the toxicity profiles of PGA-co-PDL with (L)-leucine (1.5%w/w) (5 mg/ml) and poly(lactide-co-glycolide), (5 mg/ml) spray-dried microparticles in human bronchial epithelial 16HBE14o- cell lines, resulted in cell viability of 85.57 ± 5.44 and 60.66 ± 6.75%, respectively, after 72 h treatment.

CONCLUSION:

The above data suggest that PGA-co-PDL may be a useful polymer for preparing SR microparticle carriers, together with dispersibility enhancers, for pulmonary delivery.

Aerosol administration of peptide-based drugs plays an important role in the treatment of pulmonary and systemic diseases and the unique cellular properties of airway epithelium offers a great potential to deliver new compounds. As the relative contributions from the large airways to the alveolar space are important to the local and systemic availability, the sites and mechanism of uptake and transport of different target compounds have to be characterized. Among the different respiratory cells, the ciliated epithelial cells of the larger and smaller airways and the type I and type II pneumocytes are the key players in pulmonary drug transport. With their diverse cellular characteristics, each of these cell types displays a unique uptake possibility. Next to the knowledge of these cellular aspects, the nature of aerosolized drugs, characteristics of delivery systems and the depositional and pulmonary clearance mechanisms display major targets to optimize pulmonary drug delivery. Bas...

Modern local therapy for lung diseases is now largely based on pressurized metered-dose inhalers (MDIs). The research of alternatives to MDIs has recently accelerated, primarily due to environmental concerns related to the use of chlorofluorocarbon (CFC) propellants. The most recent and attractive solution to this problem is represented by the development of dry powder inhalers (DPIs), particularly designed to avoid the use of propellants. DPIs have been developed for specific products, therefore they possess a reduced versatility in term of application of the same device to different drugs. However, they did introduce new concepts in pulmonary drug delivery, solving some disadvantages of the pressurized devices. They are in their infancy and the efforts of researchers are now impressive. The future will certainly see many other devices containing additional innovative features for the effective respiratory delivery of drug. The goals still remain the delivery of precise and uniform...

Background: The amount of drug aerosol from an inhaler that can pass through an in vitro model of the mouth and throat (MT) during a realistic breath or inhalation flow rate vs time profile (IP) is designated the total lung dose in vitro, or TLDin vitro. This paper describes a clinical study that enabled us to recommend a general method of selecting IPs for use with powder inhalers of known airflow resistance, R, provided subjects followed written instructions either alone or in combination with formal training.
Methods: In a drug-free clinical trial, inhaler-naïve, non-smoking healthy adult human volunteers were screened for normal pulmonary function. IPs were collected from each volunteer inhaling through different air flow resistances after different levels of training. IPs were analyzed to determine the distribution of inhalation variables across the population and their dependence on training and airflow resistance.
Results: Equations for IP simulation are presented that describe the data including confidence limits at each resistance and training condition. Realistic IPs at upper (90%), median (50%) and lower (10%) confidence limits were functions of R and training. Peak inspiratory flow rates, PIFR, were inversely proportional to R so that if R was assigned, values for PIFR could be calculated. The time of PIFR, TPIFR and the total inhaled volume, V were unrelated to R, but dependent on training. Once R was assigned for a powder inhaler to be tested, a range of simulated IPs could be generated for the different training scenarios. Values for flow rate acceleration and depth of inspiration could also be varied within the population limits of TPIFR and V.
Conclusions: The use of simulated IPs, in concert with realistic in vitro testing, should improve the DPI design process and the confidence with which clinical testing may be initiated for a chosen device.

The development and performance of a novel nanoparticle-based formulation for pulmonary delivery has been characterized chronologically through the particle preparation process, in vitro testing of drug release, biocompatibility, degradation, drug transport in cell culture, and in vivo bronchoprotection studies in anaesthetised guinea pigs. This study demonstrates excellent agreement of the in vitro and in vivo experiments undertaken to prove the feasibility of the design, thereby serving as an example highlighting the importance of in vitro test methods that predict in vivo performance. Nanoparticles were prepared from the newly designed negatively-charged polymer poly(vinyl sulfonate-co-vinyl alcohol)-g-poly(d,l-lactic-co-glycolic acid) loaded with salbutamol free base. Average particle sizes of blank and drug-loaded nanoparticles prepared at the various stages of the investigations were between 91 and 204nm; average zeta potential values were between -50.1 and -25.6mV. Blank nanoparticles showed no significant toxicity, and no inflammatory activity was detected in Calu-3 cells. Sustained release of salbutamol from the nanoparticles was observed for 2.5h in vitro, and a prolonged effect was observed for 120min in vivo. These results demonstrate good agreement between in vitro and in vivo tests and also present a promising foundation for future advancement in nanomedicine strategies for pulmonary drug delivery.

The applications of the crystallization technique in the pharmaceutical industry as a purification and separation process for the isolation and synthesis of pure active pharmaceutical ingredients (API), co-crystals, controlled release pulmonary drug delivery, and separation of chiral isomers are briefly discussed using a few case studies. The effect of process variables and solvent on the polymorphism and morphology of stavudine

This study aimed to prepare and evaluate rifampicin microparticles for the lung delivery of rifampicin as respirable powder. The microparticles were prepared using chitosan by the spray-drying method and evaluated for aerodynamic properties and pulmonary drug absorption. To control the drug release, tripoly-phosphate in different concentrations 0.6, 0.9, 1.2, and 1.5 was employed to get a sustained drug release profile. The microparticles were evaluated for drug loading, % entrapment efficiency, tapped density, morphological characteristics, and in vitro drug release studies. Aerosol properties were determined using the Andersen cascade impactor. Porous microparticles with particle sizes (d 0.5) less than 10 μm were obtained. The entrapment of rifampicin in microparticles was up to 72%. In vitro drug release suggested that the crosslinked microparticles showed sustained release for more than 12 hrs. The drug release rate was found to be decreased as the TPP concentration was increased. The microparticles showed a fine particle fraction in the range of 55–63% with mass median aerodynamic diameter (MMAD) values below 3 μm. The in vivo pulmonary absorption of the chitosan microparticles suggested a sustained drug release profile up to 72 hrs with an elimination rate of 0.010 per hr. The studies revealed that the spray-dried porous microparticles have suitable properties to be used as respirable powder in rifampicin delivery to the lungs.