In vivo efficacy of a dry powder formulation of ciprofloxacin-copper complex in a chronic lung infection model of bioluminescent Pseudomonas aeruginosa.

A significant limitation of locally delivered treatments for chronic pulmonary infections is often the short residence time within the airways. Ciprofloxacin (CIP), for example, undergoes rapid absorption from the airway lumen. Previously, we demonstrated that the complexation of CIP with copper (CIP-Cu) reduces its apparent epithelial permeability and pulmonary absorption rate without affecting antimicrobial activity against Pseudomonas aeruginosa grown planktonically or as biofilms.

Oxaliplatin Pt(IV) prodrugs conjugated to gadolinium-texaphyrin as potential antitumor agents.

Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines.

Caveolin-1-derived peptide limits development of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median 5-year survival of ~20%. Current U.S.

Enhanced Aerosolization of High Potency Nanoaggregates of Voriconazole by Dry Powder Inhalation.

Invasive pulmonary aspergillosis is a deadly fungal infection with a high mortality rate, particularly in patients having undergone transplant surgery. Voriconazole, a triazole antifungal pharmaceutical product, is considered as a first-line therapy for invasive pulmonary aspergillosis, and exhibits efficacy even for patients who have failed other antifungal drug therapies. The objective of this study is to develop high potency nanoaggregates of crystalline voriconazole composition for dry powder inhalation using the particle engineering process, thin film freezing.

Delivery Technologies for Orally Inhaled Products: an Update.

Orally inhaled products have well-known benefits. They allow for effective local administration of many drugs for the treatment of pulmonary disease, and they allow for rapid absorption and avoidance of first-pass metabolism of several systemically acting drugs. Several challenges remain, however, such as dosing limitations, low and variable deposition of the drug in the lungs, and high drug deposition in the oropharynx region.

Manufacturing and ambient stability of shelf freeze dried bacteriophage powder formulations.

The severity of multidrug resistance to antibiotics has urged development of alternative treatment approaches, including bacteriophage therapy. Given the complexity of the bacteriophage structure, formulation and stability are primary concerns. Our present work optimized process and formulations of phage powder manufacturing and investigated the stability of lyophilized bacteriophage powders under ambient storage.

An update on coating/manufacturing techniques of microneedles.

Recently, results have been published for the first successful phase I human clinical trial investigating the use of dissolving polymeric microneedles… Even so, further clinical development represents an important hurdle that remains in the translation of microneedle technology to approved products. Specifically, the potential for accumulation of polymer within the skin upon repeated application of dissolving and coated microneedles, combined with a lack of safety data in humans, predicates a need for further clinical investigation. Polymers are an important consideration for microneedle technology-from both manufacturing and drug delivery perspectives.

Formulation of a novel fixed dose combination of salmeterol xinafoate and mometasone furoate for inhaled drug delivery.

Co-administration of an inhaled corticosteroid and long acting beta agonist for chronic obstructive pulmonary disease has reduced mortality compared to either drug alone. This combination reduces exacerbations, hospitalization, emergency department visits and health care costs. A novel fixed-dose combination of the long acting beta-2 agonist salmeterol xinafoate (SX) and the corticosteroid mometasone furoate (MF) were prepared in a composite particle formulation as brittle matrix powder (BMP) and investigated for suitability as an inhaled combination product.

Characterization and pharmacokinetic analysis of crystalline versus amorphous rapamycin dry powder via pulmonary administration in rats.

The pharmacokinetics of inhaled rapamycin (RAPA) is compared for amorphous versus crystalline dry powder formulations. The amorphous formulation of RAPA and lactose (RapaLac) was prepared by thin film freezing (TFF) using lactose as the stabilizing agent in the weight ratio 1:1. The crystalline formulation was prepared by wet ball milling RAPA and lactose and posteriorly blending the mixture with coarse lactose (micronized RAPA/micronized lactose/coarse lactose=0.

In vitro and in vivo performance of dry powder inhalation formulations: comparison of particles prepared by thin film freezing and micronization.

Recently, inhaled immunosuppressive agents have attracted increasing attention for maintenance therapy following lung transplantation. The rationale for this delivery approach includes a more targeted and localized delivery to the diseased site with reduced systemic exposure, potentially leading to decreased adverse side effects. In this study, the in vitro and in vivo performance of an amorphous formulation prepared by thin film freezing (TFF) and a crystalline micronized formulation produced by milling was compared for tacrolimus (TAC).

The impact of pulmonary diseases on the fate of inhaled medicines--a review.

The portfolio of compounds approved for inhalation therapy has expanded rapidly for treatment of lung diseases. To assess the efficacy and safety of inhaled medicines, a better understanding of their fate in the lungs is essential; especially in diseased lungs where changes in anatomical structure, ventilation parameters and breathing pattern may occur. In this article, the impact of lung pathophysiology factors on the fate of inhaled medicines is reviewed, and discussed in the context of aerosol deposition, dissolution, absorption and clearance.

Respirable low-density microparticles formed in situ from aerosolized brittle matrices.

Purpose: Inhalation of low-density porous particles enables deep lung delivery with less dependence on device design and patient inspiration. The purpose of this study was to implement Thin Film Freezing (TFF) to investigate a novel approach to dry powder inhalation.

Methods: Powders produced by TFF were evaluated for aerodynamic and geometric particle size by cascade impaction and laser light scattering, respectively.

Preclinical evaluation of tacrolimus colloidal dispersion for inhalation.

Substantial improvements in transplant therapy have been made in the past four decades resulting in the acceptance of organ transplantation as a viable treatment for late-stage disease and organ failure. More recently, lung transplantation has gained acceptance; however, high incidence of chronic rejection and opportunistic infections has limited success rates in comparison with other transplant procedures. To achieve more targeted therapy, pulmonary administration of nebulized tacrolimus (TAC) colloidal dispersion once daily for 28 consecutive days in Sprague Dawley (SD) rats has been investigated for safety and systemic elimination.

Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model.

Lung transplantation animal models have been well established and enabled the investigation of a variety of new pharmacotherapeutic strategies for prevention of lung allograft rejection. Direct administration of immunosuppressive agents to the lung is a commonly investigated approach; however, can prove challenging due to the poor solubility of the drug molecule, the tortuous pathways of the lung periphery, and the limited number of excipients approved for inhalation. In this study, we aimed to evaluate a solubility enhancing formulation of tacrolimus for localized therapy in a lung transplanted rat model and determine the extent of drug absorption into systemic circulation.

Influence of polymeric subcoats on the drug release properties of tablets powder-coated with pre-plasticized Eudragit L 100-55.

The aim of the study was to investigate the properties of sodium valproate tablets that were dry powder-coated with pre-plasticized Eudragit L 100-55. Polyethylene glycol 3350 (PEG 3350) was used as primer to facilitate initial coating powder adhesion. Solubility parameters were employed to determine the wetting properties of the PEG 3350 primer.

Recent developments in drug delivery to prolong allograft survival in lung transplant patients.

Since the discovery of cyclosporine in 1971, calcineurin inhibitors have played a critical role in the therapeutic suppression of the immune response. Patients receiving solid organ transplants rely heavily on these medications to prevent the acute and chronic rejection of allografted tissue. These therapies can prove difficult because of potential toxicity, heightened risk of invasive infection, and erratic oral bioavailability, requiring frequent blood samples for monitoring of systemic levels.

Current therapies and technological advances in aqueous aerosol drug delivery.

Recent advances in aerosolization technology have led to renewed interest in pulmonary delivery of a variety of drugs. Pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) have experienced success in recent years; however, many limitations are presented by formulation difficulties, inefficient delivery, and complex device designs. Simplification of the formulation process as well as adaptability of new devices has led many in the pharmaceutical industry to reconsider aerosolization in an aqueous carrier.

The manufacture and characterisation of hot-melt extruded enteric tablets.

The aim of this highly novel study was to use hot-melt extrusion technology as an alternative process to enteric coating. In so doing, oral dosage forms displaying enteric properties may be produced in a continuous, rapid process, providing significant advantages over traditional pharmaceutical coating technology. Eudragit L100-55, an enteric polymer, was pre-plasticized with triethyl citrate (TEC) and citric acid and subsequently dry-mixed with 5-aminosalicylic acid, a model active pharmaceutical ingredient (API), and an optional gelling agent (PVP K30 or Carbopol 971P).