Deep Lung Delivery Research Articles

Comparison of bioavailability of amorphous versus crystalline itraconazole nanoparticles via pulmonary administration in rats

The effect of supersaturation on bioavailability of inhaled nebulized aerosols is compared for amorphous versus crystalline nanoparticulate dispersions. The nanocrystalline formulations of itraconazole (ITZ) were made by wet milling (i.e. Wet-milled ITZ), whereas amorphous nanostructured aggregates (ITZ/mannitol/lecithin=1:0.5:0.2, weight ratio) were made by an ultra-rapid freezing process (i.e. URF-ITZ). Dissolution tests revealed the extent of supersaturation was 4.7-times higher for URF-ITZ versus Wet-milled ITZ, though their dissolution rates were similar. The aerodynamic performances of both aqueous colloidal dispersions were comparable and suitable for deep lung delivery. Single-dose 24-h pharmacokinetic studies were conducted in Sprague-Dawley rats following inhalation of the nebulized colloidal dispersions (equivalent to 20mgITZ/mL dispersion in 5mL) in a nose-only dosing apparatus. Lung depositions following inhalation were similar for both compositions. In systemic circulation, Wet-milled ITZ and URF-ITZ achieved C(max) of 50 and 180ng/mL at 2.7 and 4.0h, and AUC(0-24) of 662 and 2543ngh/mL, respectively, based on a one-compartmental analysis. Pulmonary delivery of the nanoparticulate amorphous ITZ composition resulted in significantly higher systemic bioavailability than for the nanocrystalline ITZ composition, as a result of the higher supersaturation that increased the permeation.

In vitro characterization and pharmacokinetics in mice following pulmonary delivery of itraconazole as cyclodextrin solubilized solution

This study aims to make a 2-hydroxypropyl-β-cyclodextrin (HPβCD) solubilized itraconazole (ITZ) solution (i.e., HPβCD-ITZ) suitable for pulmonary delivery by nebulization, and compare pharmacokinetics of inhaled nebulized aerosols of HPβCD-ITZ versus a colloidal dispersion of ITZ nanoparticulate formulation (i.e., URF-ITZ). Solid state characterizations of lyophilized HPβCD-ITZ by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) indicated the formation of dynamic inclusion complexes between ITZ and HPβCD. Nebulized aerosols of both HPβCD-ITZ and colloidal dispersion of URF-ITZ were confirmed suitable for deep lung delivery. Single doses of the nebulized aerosols (equivalent to 5.3 mg ITZ/mL in 5 mL) in mice produced similar ITZ lung depositions and pharmacokinetic profiles, with ITZ lung levels of approximately 4 μg/g wet lung weight upon completion of nebulization and remained above 0.5 μg/g at 24 h. HPβCD-ITZ demonstrated faster systemic absorption of ITZ across lung epithelium than URF-ITZ, with t max values of 1.5 and 3.0 h, and AUC 0–∞ of 2513 and 3717 ng h/mL, respectively. The fast absorption of solubilized ITZ across lung mucosal surface may be due in part to the elimination of the phase-to-phase transition.

Inspiratory Efforts Achieved in Use of the Technosphere® Insulin Inhalation System

The Technosphere Insulin (TI) inhalation system comprises TI powder premetered into unit dose cartridges and the patient-friendly, reusable, breath-powered MedTone inhaler. This high-resistance system uses a patient's inspiratory effort to effect TI powder de-agglomeration and promote subsequent deep-lung delivery. This study reports on flow and pressure data achieved by patients with diabetes using the MedTone system. MedTone inhalers containing empty cartridges were adapted with pneumotach measuring devices to capture inhalation profiles. The measuring apparatuses had negligible impact on the nominal MedTone system resistance level of 0.117 kPa(0.5)/liters/min. Each of 56 subjects inhaled twice to mimic TI clinical study dosing instructions. Achieved inhalation profiles were characterized by peak inspiratory flow (PIF), peak inspiratory pressure (PIP), and average pressure drop from the time of PIP to 4 s (P(avg)). The achieved mean PIF (+/- standard deviation [SD]) in all subjects was 26.74 (+/-6.06) liters/min after the first inhalation and was similar to the mean PIF of 26.25 (+/-6.23) liters/min achieved after the second inhalation. Mean PIP (+/-SD) achieved by subjects was 8.49 (+/-2.86) and 8.1 (+/-2.99) kPa, and mean P(avg) drop (+/-SD) in all subjects was 6.53 (+/-2.24) and 6.09 (+/-2.08) kPa after the respective inhalations. Patients with diabetes demonstrated consistent inhalation efforts over two inhalations using the MedTone system. The achieved PIFs and PIPs demonstrate the capacity of this population to obtain sufficient inspiratory effort necessary for delivery of TI using the MedTone inhaler. Adequate postpeak pressures were also revealed, further supporting reliable and sustained inhalation efforts.

Nanomedicine for the management of lung and blood diseases.

Nanotechnology provides a broad range of opportunities to develop new solutions for clinical problems. For the pulmonary field, nanotechnology promises better delivery of drugs and nucleic acid-based therapeutics to disease sites. Administration of therapeutics via inhalation provides the opportunity for direct delivery to the lung epithelium, the lining of the respiratory tract. By appropriate selection of particle size, deep lung delivery can be obtained with control of phagocytic uptake, the removal of particles by resident macrophages. Nanotechnology can also help in pulmonary therapies administered by intravenous and oral routes through targeting specific cell types and controlling bioavailability and release kinetics. In the hematology field, nanotechnology can counter multiple drug resistance in leukemia by blocking drug efflux from cancer cells, and provide effective delivery of siRNA into lymphocytes to block apoptosis in sepsis. Controlling the surface properties of materials on devices such as valves and stents promises improved biocompatibility by inhibition of thrombosis, the formation of blood clots, and regulating cell adhesion and activation. Nanoparticle-based thrombolytic agents have the potential to improve the effectiveness of clot removal. Treatment of both lung and blood diseases is also likely to benefit from nano-scaffold-based methods for controlling the differentiation and proliferation of stem and progenitor cells.

Pulmonary delivery of ISCOMATRIX influenza vaccine induces both systemic and mucosal immunity with antigen dose sparing

Using a large animal model, we evaluated whether delivery of influenza vaccine via its mucosal site of infection could improve vaccine effectiveness. Unexpectedly, pulmonary immunization with extremely low antigen doses (0.04 μg influenza) induced serum antibody levels equivalent to those resulting from a current human vaccine equivalent (15 μg unadjuvanted influenza, subcutaneously) and vastly superior lung mucosal antibodies. Induction of this potent response following lung vaccination was dependent on addition of ISCOMATRIX adjuvant and deep lung delivery. Functional antibody activity, marked by hemagglutination inhibition, was only present in the lungs of animals that received adjuvanted vaccine via the lungs, suggesting this approach could potentially translate to improved protection. The 375-fold reduction in antigen dose and improved mucosal antibody responses, compared to the current vaccine, suggests that mucosal delivery via the pulmonary route may be particularly relevant in the event of an influenza pandemic, when vaccine supplies are unlikely to meet demand.

Templated Open Flocs of Nanorods for Enhanced Pulmonary Delivery with Pressurized Metered Dose Inhalers

A novel concept is presented for the formation of stable suspensions composed of low density flocs of high aspect ratio drug particles in hydrofluoroalkane (HFA) propellants, and for subdividing (templating) the flocs with aerosolized HFA droplets to achieve high fine particle fractions with a pressurized metered dose inhaler. Bovine serum albumin (BSA) nanorods, produced by thin film freezing (TFF), were added to HFA to form a suspension. Particle properties were analyzed with an Anderson cascade impactor (ACI), static and dynamic light scattering and optical microscopy. The space filling flocs in HFA were stable against settling for one year. The pMDI produced high fine particle fractions (38-47%) with an emitted dose of 0.7 mg/actuation. The atomized HFA droplets break apart, that is template, the highly open flocs. Upon evaporation of HFA, capillary forces shrink the templated flocs to produce porous particles with optimal aerodynamic diameters for deep lung delivery. Open flocs composed of nanorods, stable against settling, may be templated during actuation with a pMDI to produce optimal aerodynamic diameters and high fine particle fractions. This concept is applicable to a wide variety of drugs without the need for surfactants or cosolvents to stabilize the primary particles.

High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers

A nebulized dispersion of amorphous, high surface area, nanostructured aggregates of itraconazole (ITZ):mannitol:lecithin (1:0.5:0.2, w/w) yielded improved bioavailability in mice. The ultra-rapid freezing (URF) technique used to produce the nanoparticles was found to molecularly disperse the ITZ with the excipients as a solid solution. Upon addition to water, ITZ formed a colloidal dispersion suitable for nebulization, which demonstrated optimal aerodynamic properties for deep lung delivery and high lung and systemic levels when dosed to mice. The ITZ nanoparticles produced supersaturation levels 27 times the crystalline solubility upon dissolution in simulated lung fluid. A dissolution/permeation model indicated that the absorption of 3 μm ITZ particles is limited by the dissolution rate (BCS Class II behavior), while absorption is permeation-limited for more rapidly dissolving 230 nm particles. The predicted absorption half-life for 230 nm amorphous ITZ particles was only 15 min, as a result of the small particle size and high supersaturation, in general agreement with the in vivo results. Thus, bioavailability may be enhanced, by decreasing the particle size to accelerate dissolution and increasing permeation with (1) an amorphous morphology to raise the drug solubility, and (2) permeability enhancers.

New Approaches to Diabetes Disease Control, Insulin Delivery, and Monitoring

Some of the most dangerous outcomes of either form of diabetes are those related to long-term complications, including kidney damage, or diabetic nephropathy. Over time, small blood vessels inside the kidneys can become damaged and reduce the body’s ability to filter toxins from the blood. Damaged kidneys leak a protein, albumin, into the urine. Detection of even small albumin levels, microalbuminuria, is one of the earliest signs of kidney problems, and also one that is not always noticeable in the earliest stages of the disease. Left untreated, the damage worsens until the kidneys fail, a condition called end-stage renal disease (ESRD). Because of the serious long-term consequences of kidney damage, in mid-November, 2004 the International Society of Nephrology urged national health bodies around the world to proactively implement albuminuria screening with the goal of preventing further kidney function deterioration in diabetics and others with kidney disease. Currently, the American Diabetes Association recommends that people diagnosed with type 2 diabetes be tested for microalbuminuria at the time they are diagnosed and every year thereafter. Those with type 1 diabetes should be tested 5 years after diagnosis and every year thereafter. About 21% and 28% of people with type 1 and 2 diabetes, respectively, have detectable levels of microalbuminaria by age 15.New York, NY-based AusAm Biotechnologies, founded in 2000, has developed a new type of diagnostic test to better detect extremely low levels of albuminuria. The FDA approved the company’s Accumin diagnostic test in August 2003 as the first test to measure total intact urinary albumin. The technology is based on the work of Wayne Comper, Ph.D., DSc, of Monash University, Australia. “The problem with conventional tests for urine albumin is that they can miss intact albumin that does not react with the antibodies used in making these tests. As a result, conventional urine testing is subject to a potentially large false negative rate for microalbuminuria,” says Mr. James McCullough, AusAm’s CEO. “It was derived from raising antibodies to serum albumin. Dr. Comper recognized that as the serum albumin passes through the kidney and out through the urine, it can undergo a slight conformational change rendering it unreactive to conventional serum-derived albumin antibodies. In other words, intact albumin that is invisible to conventional antibodies—which is in all the major manufacturers’ platforms and dipsticks—ends up unrecognized in the urine.” In the clinical tests that Dr. Comper and colleagues performed, conventional tests generated a 33% false negative rate for microalbuminuria when they were compared with Accumin.“In May 2004, we published that we can detect microalbuminuria up to 12 years earlier than radioimmunoassay, which is the most sensitive of the conventional urine tests,” says McCullough, “But on average, it is really about 3 years earlier.” The key, claims McCullough, is that the antibody used in the test was raised to urine albumin. “After doing 2D electrophoresis and HPLC, we discovered this whole population of intact albumin which was unrecognizable by the conventional antibodies in all the major immunoassays around the world,” says McCullough.The test is done in combination with a test for creatinine, a protein excreted by the muscles. The results are reported as a ratio of microalbumin/creatinine. “If you are above 30 mg of albumin per gram of creatinine, you are said to be microalbuminuria positive,” explains McCullough. “We can pick up as low as 3–4 mg albumin per gram of creatinine.”“We are platform agnostic,” says McCullough. “The FDA-approved Accumin quantitative test is currently done with chromatography. But we are in the process now of working with several analyzer companies to place the technology in high-throughput immunochemical devices.” In 2005, AusAm hopes to roll out a dipstick version of the technology to bring it even closer to the point of care.

New polymeric carriers for controlled drug delivery following inhalation or injection

Inhalation is gaining increasing acceptance as a convenient, reproducible, and non-invasive method of drug delivery to the lung tissue and/or the systemic circulation. However, sustained drug release following inhalation remains elusive, due in part to the lack of appropriate materials designed specifically for use in the lungs to control the release of bioactive compounds. To address this problem, we have synthesized a new family of ether-anhydride copolymers composed entirely of FDA-approved monomers, including polyethylene glycol (PEG). Sebacic acid, a hydrophobic monomer, was copolymerized with PEG in order to produce water-insoluble polymers capable of providing continuous drug release kinetics following immersion in an aqueous environment. Various amounts of PEG (5−50% by mass) were incorporated into the backbone of the new polymers to allow tuning of particle surface properties for potentially enhanced aerosolization efficiency and to decrease particle clearance rates by phagocytosis in the deep lung. The preparation of large porous particles with these new polymers was systematically approached, utilizing central composite design, to develop improved particle physical properties for deep lung delivery. Microparticles containing model drugs were made with sizes suitable for deposition in various regions of the lung following inhalation as a dry powder. Due to such properties as surface erosion (leading to continuous drug release profiles), erosion times ranging from hours to days (allowing control over drug delivery duration), and ability to incorporate up to 50% PEG in their backbone, these new systems may also find application as “stealth” carriers for therapeutic compounds following intravenous injection.