iBCS: 3. A Biopharmaceutics Classification System for Orally Inhaled Drug Products.

In this article, we specify for the first time a quantitative biopharmaceutics classification system for orally inhaled drugs. To date, orally inhaled drug product developers have lacked a biopharmaceutics classification system like the one developed to navigate the development of immediate release of oral medicines. Guideposts for respiratory drug discovery chemists and inhalation product formulators have been elusive and difficult to identify due to the complexity of pulmonary physiology, the intricacies of drug deposition and disposition in the lungs, and the influence of the inhalation delivery device used to deliver the drug as a respirable aerosol. The development of an inhalation biopharmaceutics classification system (iBCS) was an initiative supported by the Product Quality Research Institute (PQRI). The goal of the PQRI iBCS working group was to generate a qualitative biopharmaceutics classification system that can be utilized by inhalation scientists as a "rule of thumb" to identify desirable molecular properties and recognize and manage CMC product development risks based on physicochemical properties of the drug and the deposited lung dose. Herein, we define the iBCS classes quantitatively according to the dose number and permeability. The proposed iBCS was evaluated for its ability to categorize marketed inhaled drugs using data from the literature. The appropriateness of the classification of each drug was assessed based on published development, clinical and nonclinical data, and mechanistic physiologically based biopharmaceutics modeling. The inhaled drug product development challenges for each iBCS classification are discussed and illustrated for different classes of marketed inhaled drugs. Finally, it is recognized that discriminatory laboratory methods to characterize regional lung deposition, dissolution, and permeability will be key to fully realizing the benefits of an iBCS to streamline and derisk inhaled drug development.

iBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System.

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.

iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes.

This work is the second in a series of publications outlining the fundamental principles and proposed design of a biopharmaceutics classifications system for inhaled drugs and drug products (the iBCS). Here, a mechanistic computer-based model has been used to explore the sensitivity of the primary biopharmaceutics functional output parameters: (i) pulmonary fraction dose absorbed (Fabs) and (ii) drug half-life in lumen (t1/2) to biopharmaceutics-relevant input attributes including dose number (Do) and effective permeability (Peff). Results show the nonlinear sensitivity of primary functional outputs to variations in these attributes. Drugs with Do < 1 and Peff > 1 × 10-6 cm/s show rapid (t1/2 < 20 min) and complete (Fabs > 85%) absorption from lung lumen into lung tissue. At Do > 1, dissolution becomes a critical drug product attribute and Fabs becomes dependent on regional lung deposition. The input attributes used here, Do and Peff, thus enabled the classification of inhaled drugs into parameter spaces with distinctly different biopharmaceutic risks. The implications of these findings with respect to the design of an inhalation-based biopharmaceutics classification system (iBCS) and to the need for experimental methodologies to classify drugs need to be further explored.

Aerodynamic factors responsible for the deaggregation of carrier-free drug powders to form micrometer and submicrometer aerosols.

PURPOSE: To employ in vitro experiments combined with computational fluid dynamics (CFD) analysis to determine which aerodynamic factors were most responsible for deaggregating carrier-free powders to form micrometer and submicrometer aerosols from a capsule-based platform. METHODS: Eight airflow passages were evaluated for deaggregation of the aerosol including a standard constricted tube, impaction surface, 2D mesh, inward radial jets, and newly proposed 3D grids and rod arrays. CFD simulations were implemented to evaluate existing and new aerodynamic factors for deaggregation and in vitro experiments were used to evaluate performance of each inhaler. RESULTS: For the carrier-free formulation considered, turbulence was determined to be the primary deaggregation mechanism. A strong quantitative correlation was established between the mass median diameter (MMD) and newly proposed non-dimensional specific dissipation (NDSD) factor, which accounts for turbulent energy, inverse of the turbulent length scale, and exposure time. A 3D rod array design with unidirectional elements maximized NDSD and produced the best deaggregation with MMD<1 µm. CONCLUSIONS: The new NDSD parameter can be used to develop highly effective dry powder inhalers like the 3D rod array that can efficiently produce submicrometer aerosols for next-generation respiratory drug delivery applications.

The use of condensational growth methods for efficient drug delivery to the lungs during noninvasive ventilation high flow therapy.

PURPOSE: The objective of this study was to evaluate the delivery of nasally administered aerosols to the lungs during noninvasive ventilation using controlled condensational growth techniques. METHODS: An optimized mixer, combined with a mesh nebulizer, was used to generate submicrometer aerosol particles using drug alone (albuterol sulfate) and with mannitol or sodium chloride added as hygroscopic excipients. The deposition and growth of these particles were evaluated in an adult nose-mouth-throat (NMT) model using in vitro experimental methods and computational fluid dynamics simulations. RESULTS: Significant improvement in the lung dose (3-4× increase) was observed using excipient enhanced growth (EEG) and enhanced condensational growth (ECG) delivery modes compared to control studies performed with a conventional size aerosol (~5 µm). This was due to reduced device retention and minimal deposition in the NMT airways. Increased condensational growth of the initially submicrometer particles was observed using the ECG mode and in the presence of hygroscopic excipients. CFD predictions for regional drug deposition and aerosol size increase were in good agreement with the observed experimental results. CONCLUSIONS: These controlled condensational growth techniques for the delivery of submicrometer aerosols were found to be highly efficient methods for delivering nasally-administered drugs to the lungs.

Production of Inhalable Submicrometer Aerosols from Conventional Mesh Nebulizers for Improved Respiratory Drug Delivery.

Submicrometer and nanoparticle aerosols may significantly improve the delivery efficiency, dissolution characteristics, and bioavailability of inhaled pharmaceuticals. The objective of this study was to explore the formation of submicrometer and nanometer aerosols from mesh nebulizers suitable for respiratory drug delivery using experiments and computational fluid dynamics (CFD) modeling. Mesh nebulizers were coupled with add-on devices to promote aerosol drying and the formation of submicrometer particles, as well as to control the inhaled aerosol temperature and relative humidity. Cascade impaction experiments were used to determine the initial mass median aerodynamic diameters of 0.1% albuterol aerosols produced by the AeroNeb commercial (4.69 µm) and lab (3.90 µm) nebulizers and to validate the CFD model in terms of droplet evaporation. Through an appropriate selection of flow rates, nebulizers, and model drug concentrations, submicrometer and nanometer aerosols could be formed with the three devices considered. Based on CFD simulations, a wire heated design was shown to overheat the airstream producing unsafe conditions for inhalation if the aerosol was not uniformly distributed in the tube cross-section or if the nebulizer stopped producing droplets. In comparison, a counter-flow heated design provided sufficient thermal energy to produce submicrometer particles, but also automatically limited the maximum aerosol outlet temperature based on the physics of heat transfer. With the counter-flow design, submicrometer aerosols were produced at flow rates of 5, 15, and 30 LPM, which may be suitable for various forms of oral and nasal aerosol delivery. Thermodynamic conditions of the aerosol stream exiting the counter-flow design were found be in a range of 21-45 °C with relative humidity greater than 40% in some cases, which was considered safe for direct inhalation and advantageous for condensational growth delivery.

Optimizing Spray-Dried Porous Particles for High Dose Delivery with a Portable Dry Powder Inhaler.

This manuscript critically reviews the design and delivery of spray-dried particles for the achievement of high total lung doses (TLD) with a portable dry powder inhaler. We introduce a new metric termed the product density, which is simply the TLD of a drug divided by the volume of the receptacle it is contained within. The product density is given by the product of three terms: the packing density (the mass of powder divided by the volume of the receptacle), the drug loading (the mass of drug divided by the mass of powder), and the aerosol performance (the TLD divided by the mass of drug). This manuscript discusses strategies for maximizing each of these terms. Spray drying at low drying rates with small amounts of a shell-forming excipient (low Peclet number) leads to the formation of higher density particles with high packing densities. This enables ultrahigh TLD (>100 mg of drug) to be achieved from a single receptacle. The emptying of powder from capsules is directly proportional to the mass of powder in the receptacle, requiring an inhaled volume of about 1 L for fill masses between 40 and 50 mg and up to 3.2 L for a fill mass of 150 mg.

Idealhalers Versus Realhalers: Is It Possible to Bypass Deposition in the Upper Respiratory Tract?

This review discusses how advances in formulation and device design can be utilized to dramatically improve lung targeting and dose consistency relative to current marketed dry powder inhalers (DPIs). Central to the review is the development of engineered particles that effectively bypass deposition in the upper respiratory tract (URT). This not only reduces the potential for off-target effects but it also reduces variability in dose delivery to the lungs resulting from anatomical differences in the soft tissue in the mouth and throat. Low-density porous particles are able to largely bypass URT deposition due to the fact that both the primary particles and their agglomerates are respirable. The low-density particles also exhibit dose delivery to the lungs that is largely independent of inspiratory flow rate across a range of flow rates that most subjects achieve with portable DPIs. Coupling this with delivery devices that are breath actuated, simple to operate (open-inhale-close), and have adherence-tracking capability enables drug delivery that is largely independent of how a subject inhales, with a user experience that is close to that of an "idealhaler."

Advancements in dry powder delivery to the lung.

The dry powder inhaler (DPI) has become widely known as a very attractive platform for drug delivery. Many patients have traditionally used DPIs to treat asthma and chronic obstructive pulmonary disease. Recently, the development of new DPIs for delivering therapeutic proteins such as insulin has been accelerated by patient demands, and innovative research. The current market for DPIs has over 20 devices presently in use, and many devices under development for delivering a variety of therapeutic agents. DPIs are recognized as suitable alternatives to pressurized metered dose inhalers for some patients, but the performance of DPI devices may vary according to a given patient's physiological condition. This variation can be associated with the necessary powder dispersion mechanism of each device. As such, much interest has focused on the development of efficient powder dispersion mechanisms, as this effectively minimizes the influence of interpatient variability. This article reviews DPI devices currently available, advantages of newly developed devices, outlines some requirements for future device design.

Biodistribution and anti-tumor efficacy of doxorubicin loaded glycol-chitosan nanoaggregates by EPR effect.

An in vivo tumor targeting test of glycol-chitosan nanoaggregates was carried out with FITC-conjugated glycol-chitosan nanoaggregates (FTC-GC) and the doxorubicin conjugated glycol-chitosan (GC-DOX). To investigate its biodistribution in tumor-bearing rats, glycol-chitosan was labeled with fluorescein isothiocyanate (FITC), which formed nanoaggregates with a diameter of about 250 nm in aqueous media. GC-DOX nanoaggregates containing acid-sensitive spacers were prepared. The GC-DOX formed micelle-like nanoaggregates spontaneously in aqueous media. GC-DOX nanoaggregates had a narrow and unimodal size distribution, and its hydrodynamic diameter measured by dynamic light scattering ranged from 250 to 300 nm. A loading content of doxorubicin into GC-DOX nanoaggregates as high as 38%, with 97% loading efficiency, could be obtained using a physical entrapment method. A tumor-bearing animal model was developed by inoculating tumor cells into the back of a rat. The FTC-GC nanoaggregates were injected into the tail vein of tumor-bearing rats and their tissue distribution was examined. The FTC-GC nanoaggregates were distributed mainly in kidney, tumor and the liver and were scarcely observed in other tissues. They were maintained at a high level for 8 days and their distribution in tumor tissues increased gradually. This suggests that chitosan nanoaggregates accumulate passively in the tumor tissue due to the enhanced permeability and retention (EPR) effect. Doxorubicin loaded GC-DOX nanoaggregates (DOX/GC-DOX) were injected into the tail vein of tumor-bearing rats and their anti-tumor effect was examined. Tumor growth was suppressed over 10 days.

Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: effect of spray drying process conditions on aerosol performance.

The aim of this study was to develop a spray dried submicrometer powder formulation suitable for the excipient enhanced growth (EEG) application. Combination particles were prepared using the Buchi Nano spray dryer B-90. A number of spray drying and formulation variables were investigated with the aims of producing dry powder formulations that were readily dispersed upon aerosolization and maximizing the fraction of submicrometer particles. Albuterol sulfate, mannitol, L-leucine, and poloxamer 188 were selected as a model drug, hygroscopic excipient, dispersibility enhancer and surfactant, respectively. Formulations were assessed by scanning electron microscopy and aerosol performance following aerosolization using an Aerolizer dry powder inhaler (DPI). In vitro drug deposition was studied using a realistic mouth-throat (MT) model. Based on the in vitro aerosolization results, the best performing submicrometer powder formulation consisted of albuterol sulfate, mannitol, L-leucine and poloxamer 188 in a ratio of 30:48:20:2, containing 0.5% solids in a water:ethanol (80:20%, v/v) solution which was spray dried at 70 °C. The submicrometer particle fraction (FPF(1 µm/ED)) of this final formulation was 28.3% with more than 80% of the capsule contents being emitted during aerosolization. This formulation also showed 4.1% MT deposition. The developed combination formulation delivered a powder aerosol developed for the EEG application with high dispersion efficiency and low MT deposition from a convenient DPI device platform.

Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation.

The aim of this study was to evaluate and modify commercial dry powder inhalers (DPIs) for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. The optimized device and formulation combination was then tested in a realistic in vitro mouth-throat - tracheobronchial (MT-TB) model. An optimized EEG submicrometer powder formulation, consisting of albuterol sulfate (drug), mannitol (hygroscopic excipient), l-leucine (dispersion enhancer) and poloxamer 188 (surfactant) in a ratio of 30:48:20:2 was prepared using a Büchi Nano spray dryer. The aerosolization performance of the EEG formulation was evaluated with five conventional DPIs: Aerolizer, Novolizer, HandiHaler, Exubera and Spiros. To improve powder dispersion, the HandiHaler was modified with novel mouth piece (MP) designs. The aerosol performance of each device was assessed using a next generation impactor (NGI) at airflow rates generating a pressure drop of 4 kPa across the DPI. In silico and in vitro deposition and hygroscopic growth of formulations was studied using a MT-TB airway geometry model. Both HandiHaler and Aerolizer produced high emitted doses (EDs) together with a significant submicrometer aerosol fraction. A modified HandiHaler with a MP including a three-dimensional (3D) array of rods (HH-3D) produced a submicrometer particle fraction of 38.8% with a conventional fine particle fraction (%<5 µm) of 97.3%. The mass median diameter (MMD) of the aerosol was reduced below 1 µm using this HH-3D DPI. The aerosol generated from the modified HandiHaler increased to micrometer size (2.8 µm) suitable for pulmonary deposition, when exposed to simulated respiratory conditions, with negligible mouth-throat (MT) deposition (2.6%).

High-efficiency generation and delivery of aerosols through nasal cannula during noninvasive ventilation.

BACKGROUND: Previous studies have demonstrated the delivery of pharmaceutical aerosols through nasal cannula and the feasibility of enhanced condensational growth (ECG) with a nasal interface. The objectives of this study were to develop a device for generating submicrometer aerosols with minimal depositional loss in the formation process and to improve aerosol delivery efficiencies through nasal cannulas. METHODS: A combination of in vitro experiments and computational fluid dynamics (CFD) simulations that used the strengths of each method was applied. Aerosols were formed using a conventional mesh nebulizer, mixed with ventilation gas, and heated to produce submicrometer sizes. An improved version of the mixer and heater unit was developed based on CFD simulations, and performance was verified with experiments. Aerosol delivery was considered through a commercial large-bore adult cannula, a divided (D) design for use with ECG, and a divided and streamlined (DS) design. RESULTS: The improved mixer design reduced the total deposition fraction (DF) of drug within the mixer by a factor of 3 compared with an initial version, had a total DF of approximately 10%, and produced submicrometer aerosols at flow rates of 10 and 15 L/min. Compared with the commercial and D designs for submicrometer aerosols, the DS cannula reduced depositional losses by a factor of 2-3 and retained only approximately 5% or less of the nebulized dose at all flow rates considered. For conventional-sized aerosols (3.9 and 4.7 µm), the DS device provided delivery efficiencies of approximately 80% and above at flow rates of 2-15 L/min. CONCLUSIONS: Submicrometer aerosols can be formed using a conventional mesh nebulizer and delivered through a nasal cannula with total delivery efficiencies of 80-90%. Streamlining the nasal cannula significantly improved the delivery efficiency of both submicrometer and micrometer aerosols; however, use of submicrometer particles with ECG delivery resulted in overall lower depositional losses.

Preparation of sustained release rifampicin microparticles for inhalation.

OBJECTIVES: The aim of this research was to develop a novel carrier-free dry powder formulation of rifampicin for inhalation with controlled-release properties. METHODS: Rifampicin dihydrate (RFDH) microcrystals were prepared by a polymorphic transformation of rifampicin. The prepared RFDH microcrystals were coated with poly (DL-lactide-co-glycolide) or poly (DL-lactide), using a spray-dryer equipped with two different types of three-fluid (3F) spray nozzles. The physicochemical and aerodynamic properties of the coated RFDH microcrystals were compared with those of conventional matrix microparticles. KEY FINDINGS: The coated RFDH powder, encapsulating 50% of rifampicin, was successfully prepared by simple in-situ coating methods using two different types of 3F nozzles and had mass median aerodynamic diameter values of 3.5-4.5 µM. The thin flaky morphology of RFDH powders, providing good aerosolization properties, was maintained after coating. The coated RFDH formulations showed relatively low initial rifampicin release, compared with the uncoated RFDH crystals, followed by slow rifampicin release (about 70%) over 8 h in phosphate-buffered saline media (pH 7.4). Significant chemical degradations were not observed from the crystalline-structured RFDH formulations, while the amorphous-structured matrix formulations showed chemical degradation in six months. CONCLUSIONS: These polymer coated RFDH formulations may be a valuable alternative in the treatment of tuberculosis since the carrier-free formulation offers the benefit of delivering a maximum-potency formulation of the antibiotic directly to the site of infection, and long drug residence times may be achieved by the controlled release of the drug.

Performance of combination drug and hygroscopic excipient submicrometer particles from a softmist inhaler in a characteristic model of the airways.

Excipient enhanced growth (EEG) of inhaled submicrometer pharmaceutical aerosols is a recently proposed method intended to significantly reduce extrathoracic deposition and improve lung delivery. The objective of this study was to evaluate the size increase of combination drug and hygroscopic excipient particles in a characteristic model of the airways during inhalation using both in vitro experiments and computational fluid dynamic (CFD) simulations. The airway model included a characteristic mouth-throat (MT) and upper tracheobronchial (TB) region through the third bifurcation and was enclosed in a chamber geometry used to simulate the thermodynamic conditions of the lungs. Both in vitro results and CFD simulations were in close agreement and indicated that EEG delivery of combination submicrometer particles could nearly eliminate MT deposition for inhaled pharmaceutical aerosols. Compared with current inhalers, the proposed delivery approach represents a 1-2 order of magnitude reduction in MT deposition. Transient inhalation was found to influence the final size of the aerosol based on changes in residence times and relative humidity values. Aerosol sizes following EEG when exiting the chamber (2.75-4.61 µm) for all cases of initial submicrometer combination particles were equivalent to or larger than many conventional pharmaceutical aerosols that frequently have MMADs in the range of 2-3 µm.

A new respirable form of rifampicin.

The aim of this research was to investigate a novel dry powder formulation of rifampicin (RF) that presents an improved lung deposition profile by means of a polymorphic transformation into a flake-like crystal hydrate. Rifampicin dihydrate (RFDH) was prepared by recrystallization of RF in anhydrous ethanol. A control formulation, amorphous RF (RFAM) was prepared by spray drying. The physicochemical properties of the RFDH and the RFAM were characterized. Aerosol performances of RFDH and RFAM were studied with two dry powder inhalers (DPIs), an Aerolizer and a Handihaler, using a Next Generation Impactor (NGI). The RFDH powder was successfully prepared using simple recrystallization process and had a MMAD of 2.2 µm. The RFDH powders were characterized as having a very thin flaky structure; this unique morphology provided improved aerosolization properties with a decreased device dependency upon aerosolization. The flaky morphology of RFDH resulted in a reduced agglomeration tendency than that of spherical RFAM particles. The maximum fine particle fraction (FPF(TD)) of 68% for the RFDH was achieved with the Aerolizer device. Significant chemical degradation was not observed from the RFDH, while the RFAM showed significant chemical degradation at 9 months. The excipient-free formulation of the RFDH offers the benefit of delivering a maximum potency formulation, of the antibiotic, directly to the site of infection, the lung.

Development of a standardized dissolution test method for inhaled pharmaceutical formulations.

The aim of this research was to investigate a potential standardized test method to characterize the dissolution properties of formulations intended for pulmonary delivery. A commercially available dissolution tester was adapted to be used as a testing apparatus by incorporation of a membrane containing cassette. The cassette was designed to enclose previously air-classified formulations, so that they could be uniformly tested in the dissolution apparatus. The influence of particle size, amount of drug loading, and the composition of a simulated lung fluid (SLF) dissolution media on the dissolution rate were studied. Dissolution rate was significantly affected by the uniformity of drug loading, and particle size. Diffusion coefficients, estimated using the Higuchi model, showed an increase from 2.28 to 9.60x10(-7) cm(2)/h as the particle size decreased. Addition of DPPC (0.02%, w/v) to the SLF dissolution media resulted also resulted in an increase in the diffusion coefficient value. This study demonstrated that the developed method was reproducible and may be used to evaluate the dissolution properties of pharmaceutical inhalation products following their aerodynamic particle classification.

Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution.

Invasive fungal infections in immunocompromised patients have high mortality rates despite current treatment modalities. This study was designed to evaluate the suitability of an aqueous solution of voriconazole solubilized with sulfobutyl ether-beta-cyclodextrin for targeted drug delivery to the lungs via nebulization. A solution was prepared such that the inspired aerosol dose was isotonic with an acceptable mass median aerodynamic diameter of 2.98 microm and a fine particle fraction of 71.7%. Following single and multiple inhaled doses, high voriconazole concentrations were observed within 30 min in the lung tissue and plasma. Drug solubilization with sulfobutyl ether-beta-cyclodextrin contributed to the rapid and high drug concentrations in plasma following inhalation. Maximal concentrations in the lung and plasma were 11.0 +/- 1.6 microg/g wet lung weight and 7.9 +/- 0.68 microg/mL, respectively, following a single inhaled dose with a corresponding tissue/plasma concentration ratio of 1.4 to 1. Following multiple inhaled doses, peak concentrations in lung tissue and plasma were 6.73 +/- 3.64 microg/g wet lung weight and 2.32 +/- 1.52 microg/mL, respectively. AUC values in lung tissue and plasma were also high. The clinically relevant observed pharmacokinetic parameters of inhaled aqueous solutions of voriconazole suggest that therapeutic outcomes could be benefitted through the use of inhaled voriconazole.