Anthony J. Hickey

Pharmacokinetics of Inhaled Rifampicin Porous Particles for Tuberculosis Treatment: Insight into Rifampicin Absorption from the Lungs of Guinea Pigs

Tuberculosis (TB) is a life-threatening infection that requires a lengthy treatment process that is often associated with adverse effects. Pulmonary delivery of anti-TB drugs has the potential to increase efficacy of treatment by increasing drug concentrations at the lungs, the primary site of infection. The aim of the present study is to evaluate the disposition of rifampicin (RIF) after its pulmonary administration as porous particles (PPs) to guinea pigs and contrast it to that after oral administration. RIF microparticles were prepared by spray drying a solution of RIF and L-leucine (9:1), and the resulting particles were characterized for their physicochemical properties. Animals received RIF either as intravenous solution (iv), as oral suspension of micronized RIF (ORS) and RIF-PPs (ORPP), or by insufflation of the PPs (IRPP). Plasma samples were collected at preselected time points, and bronchoalveolar lavage (BAL) was performed at the end of the study. RIF concentrations in biological samples were analyzed by HPLC. Plasma concentration versus time data was analyzed by compartmental and noncompartmental methods. RIF PPs were thin walled porous particles with mass median aerodynamic diameter (MMAD) of 4.8±0.1 μm, GSD=1.29±0.03, and fine particle fraction below 5.8 μm of 52.9±2.0%. RIF content in the resulting particles was 91.8±0.1%. Plasma concentration vs time profiles revealed that the terminal slope of the iv group was different from that of the oral or pulmonary groups, indicating the possibility of flip-flop kinetics. RIF from IRPP appeared to be absorbed faster than that of ORPP or ORS as evidenced by higher RIF plasma concentrations up until 2 h. Notably, similar AUC (when corrected by dose), similar CL, λ, and half-life were obtained after oral administration of RIF at 40 mg/kg and pulmonary administration of RIF at 20 mg/kg. However, RIF in the IRPP group had a shorter Tmax and higher bioavailability than orally dosed groups. In addition, RIF concentrations in the BAL of animals in the IRPP group were 3-4-fold larger than those in the orally dosed groups. The disposition in ORS and ORPP were best described by a model with two sequential compartments, whereas the disposition of IRPP was best described by a two parallel compartment model. The advantages of delivering RIF by the pulmonary route are demonstrated in the present study. These include achieving higher RIF concentrations in the lungs and similar systemic levels after pulmonary delivery of one-half of the oral nominal dose. This is expected to result in a more effective treatment of pulmonary TB, as shown previously in published efficacy studies.

Bioequivalence of inhaled drugs: fundamentals, challenges and perspectives

Interest in bioequivalence (BE) of inhaled drugs derives largely from the desire to offer generic substitutes to successful drug products. The complexity of aerosol dosage forms renders them difficult to mimic and raises questions regarding definitions of similarities and those properties that must be controlled to guarantee both the quality and the efficacy of the product. Despite a high level of enthusiasm to identify and control desirable properties there is no clear guidance, regulatory or scientific, for the variety of aerosol dosage forms, on practical measures of BE from which products can be developed. As more data on the pharmaceutical and clinical relevance of various techniques, as described in this review, become available, it is likely that a path to the demonstration of BE will become evident. In the meantime, debate on this topic will continue.

Erratum to: Scope and relevance of a pulmonary biopharmaceutical classification system AAPS/FDA/USP Workshop March 16-17th, 2015 in Baltimore, MD

The Biopharmaceutics Classification System (BCS), developed in the 1990s for oral immediate release drugs, is utilized by R&D scientists and regulators to streamline product development and regulatory approval timelines. This elegant, science-based approach is based on three in vitro parameters representing a combination of drug substance physicochemical and physiological properties with respect to oral administration; specifically a dose number, dissolution number, and absorption number. Interest in applying similar principles to pulmonary drug products is increasing. To date the focus has been on dissolution of drugs in the lung. A workshop co-sponsored by the AAPS, FDA, and USP was held in March 2015 in Baltimore to evaluate if a systematic framework to classify pulmonary drugs could be established, and the scope and relevance of such a classification scheme. The focus of the workshop was to address factors influencing drug delivery and action in the lungs rather than the development of a specific model or system. Presentations included: the history and evolution of the oral BCS (described as the “giBCS” by Gordon Amidon), lung physiology and the fate of inhaled drugs, regional aerosol deposition and dose, macroscopic clearance mechanisms, particle dissolution, drug permeability, absorption and their interplay with pharmacokinetics and pharmacodynamics. Background discussions were followed by three separate breakout sessions each focused on the BCS concepts of dose, dissolution, and absorption numbers as they would apply to pulmonary drug delivery. The workshop concluded that a classification system, if fully developed, would be a useful tool for formulators and discovery chemists. The scope of such a system, at this point in time, would not include aspects relevant to regulatory relief. The goals of the workshop were met by identifying an opportunity to develop a model to classify pulmonary drugs based on physicochemical attributes specific to lung physiology and drug delivery.

Biopharmaceutical in vitro characterization of CPZEN-45, a drug candidate for inhalation therapy of tuberculosis

BACKGROUND The caprazamycin derivative, CPZEN-45 has previously demonstrated antitubercular activity against Mycobacterium tuberculosis H37Rv. Here, the authors report a basic biopharmaceutical characterization of the compound focusing on in vitro permeability and cytotoxicity, with respect to the suitability of CPZEN-45 hydrochloride for inhalation treatment of tuberculosis. RESULTS MTT assays confirmed that CPZEN-45 HCl had no acute cytotoxic effects up to 3 mg/ml. In transport studies, apparent permeability coefficients of CPZEN-45 HCl across Calu-3 monolayers in absorptive and secretive directions were 0.43 ± 0.20 × 10(-6) cm/s and 0.38 ± 0.12 × 10(-6) cm/s, respectively. Across ATI-like monolayers, apparent permeability values were 12.10 ± 4.31 × 10(-6) cm/s and 8.50 ± 1.83 × 10(-6) cm/s. CPZEN-45 HCl formed colloidal complexes at concentrations above 0.38 mg/ml; however, these complexes were not micelles, as assessed by Orange OT encapsulation assay. CONCLUSION CPZEN-45 is an interesting new drug candidate with potential to be used in aerosol therapy of tuberculosis.

Spray Dried Aerosol Particles of Pyrazinoic Acid Salts for Tuberculosis Therapy. [Corrected].

Tuberculosis is the most serious infectious disease caused by a single organism, Mycobacterium tuberculosis (Mtb). The standard of care is a protracted and complex drug treatment regimen made more complicated and of longer duration by the incidence of multiple and extensively drug resistant disease. Pulmonary delivery of aerosols as a supplement to the existing regimen offers the advantage of delivering high local drug doses to the initial site of infection and most prominent organ system involved in disease. Pyrazinamide is used in combination with other drugs to treat tuberculosis. It is postulated that the action of pyrazinoic acid (POA), the active moiety of pyrazinamide, may be enhanced by local pH adjustment, when presented as a salt form. POA was prepared as leucine (POA-leu) and ammonium salts (POA-NH4), spray dried, and characterized in terms of physicochemical properties (melting point, crystallinity, moisture content), aerodynamic performance (aerodynamic particle size distribution, emitted dose), and in vitro inhibitory effect on two mycobacteria (Mtb and Mycobacterium bovis). Particles were prepared in sizes suitable for inhalation (3.3 and 5.4 μm mass median aerodynamic diameter and 61 and 40% of the aerodynamic particle size distribution less than 4.46 μm, as measured by inertial impaction, for POA-leu and POA-NH4, respectively) and with properties (stoichiometric 1:1 ratio of salt to drug, melting points at ∼180 °C, with water content of <1%) that would support further development as an inhaled dosage form. In addition, POA salts demonstrated greater potency in inhibiting mycobacterial growth compared with POA alone, which is promising for therapy.

Spray dried aerosol particles of salts for tuberculosis therapy

Tuberculosis is the most serious infectious disease caused by a single organism, Mycobacterium tuberculosis (Mtb). The standard of care is a protracted and complex drug treatment regimen made more complicated and of longer duration by the incidence of multiple and extensively drug resistant disease. Pulmonary delivery of aerosols as a supplement to the existing regimen offers the advantage of delivering high local drug doses to the initial site of infection and most prominent organ system involved in disease. Pyrazinamide is used in combination with other drugs to treat tuberculosis. It is postulated that the action of pyrazinoic acid (POA), the active moiety of pyrazinamide, may be enhanced by local pH adjustment, when presented as a salt form. POA was prepared as leucine (POA-leu) and ammonium salts (POA-NH4), spray dried, and characterized in terms of physicochemical properties (melting point, crystallinity, moisture content), aerodynamic performance (aerodynamic particle size distribution, emitted dose), and in vitro inhibitory effect on two mycobacteria (Mtb and Mycobacterium bovis). Particles were prepared in sizes suitable for inhalation (3.3 and 5.4 μm mass median aerodynamic diameter and 61 and 40% of the aerodynamic particle size distribution less than 4.46 μm, as measured by inertial impaction, for POA-leu and POA-NH4, respectively) and with properties (stoichiometric 1:1 ratio of salt to drug, melting points at ∼180 °C, with water content of <1%) that would support further development as an inhaled dosage form. In addition, POA salts demonstrated greater potency in inhibiting mycobacterial growth compared with POA alone, which is promising for therapy.

Pharmacokinetics of Ethionamide Delivered in Spray-Dried Microparticles to the Lungs of Guinea Pigs

The use of ethionamide (ETH) in treating multidrug-resistant tuberculosis is limited by severe side effects. ETH disposition after pulmonary administration in spray-dried particles might minimize systemic exposure and side effects. To explore this hypothesis, spray-dried ETH particles were optimized for performance in a dry powder aerosol generator and exposure chamber. ETH particles were administered by the intravenous (IV), oral, or pulmonary routes to guinea pigs. ETH appearance in plasma, bronchoalveolar lavage, and lung tissues was measured and subjected to noncompartmental pharmacokinetic analysis. Dry powder aerosol generator dispersion of 20% ETH particles gave the highest dose at the exposure chamber ports and fine particle fraction of 72.3%. Pulmonary ETH was absorbed more rapidly and to a greater extent than orally administered drug. At Tmax, ETH concentrations were significantly higher in plasma than lungs from IV dosing, whereas insufflation lung concentrations were 5-fold higher than in plasma. AUC(0-t) (area under the curve) and apparent total body clearance (CL) were similar after IV administration and insufflation. AUC(0-t) after oral administration was 6- to 7-fold smaller and CL was 6-fold faster. Notably, ETH bioavailability after pulmonary administration was significantly higher (85%) than after oral administration (17%). These results suggest that pulmonary ETH delivery would potentially enhance efficacy for tuberculosis treatment given the high lung concentrations and bioavailability.

Disposable Dosators for Pulmonary Insufflation of Therapeutic Agents to Small Animals

Development of new therapeutic products requires efficacy testing in an animal model. The pulmonary route of administration can be utilized to deliver drugs locally and systemically. Evaluation of dry powder aerosols necessitates an efficient dispersion mechanism to maintain high concentrations in an exposure chamber or for direct endotracheal administration. While solutions exist to expose animals by passive inhalation to dry powder aerosols, most require masses of powder in large excess of the dose delivered. This precludes conducting early feasibility studies as insufficient drug is available at the research or early development stage to support the dose delivery requirements for conventional aerosol delivery systems. When designing an aerosol drug product, aerodynamic performance can relate directly to delivery efficiency and efficacy. Dispersion of powder into an aerosol requires energy input sufficient to overcome interparticulate forces, and particle engineering approaches can substantially improve aerosol performance. We have developed a dispersion system (dosator) which can aerosolize engineered dry powder aerosols efficiently for the purpose of direct pulmonary insufflation, dispersion into an exposure system or generation for analytical purposes.

Nanomaterial Drug Products: Manufacturing and Analytical Perspectives

ABSTRACTThe increasing use of nanotechnology, including nanoparticles, in the preparation of drug products requires both manufacturing and analytical considerations in order to establish the quality metrics suitable for performance and risk assessment. A range of different nanoparticle systems exists including (but not limited to) nano-drugs, nano-additives, and nano-carriers. These systems generally require more complex production and characterization strategies than conventional pharmaceutical dosage forms. The advantage of using nanoparticle systems in pharmaceutical science is that the effective and desired function of the material can be designed through modern manufacturing processes. This paper offers a systematic nomenclature which allows for greater understanding of the drug product under evaluation based on available data from other nanoparticle reports. Analytical considerations of nano-drugs, nano-additives, and nano-carriers and the way in which they are measured are directly connected to quality control. Ultimately, the objective is to consider the entire nano-drug, nano-additive, and nano-carrier product life cycle with respect to its manufacture, use, and eventual fate. The tools and approaches to address the needs of these products exist; it should be the task of the pharmaceutical scientists and those in related disciplines to increase their understanding of nanomedicine and its novel products.

Reproducibility, sharing and progress in nanomaterial databases

Publicly accessible databases are core resources for data-rich research, consolidating field-specific knowledge and highlighting best practices and challenges. Further effective growth of nanomaterial databases requires the concerted efforts of database stewards, researchers, funding agencies and publishers.