Intranasal Eutectic Powder of Zolmitriptan with Enhanced Bioavailability in the Rat Brain.

Intranasal administration can potentially deliver drugs to the brain because of the proximity of the delivery site to the olfactory lobe. We prepared triturates of micronized or crystalline zolmitriptan with a GRAS substance, nicotinamide, to form a eutectic. We characterized the formulation using differential scanning calorimetry, powder X-ray diffraction, and FTIR spectroscopy to confirm its eutectic nature and generated a phase diagram. The eutectic formulation was aerosolized using an in-house insufflator into the nares of rats. Groups of rats received zolmitriptan intravenously or intranasally, or intranasal eutectic formulation. Zolmitriptan was estimated in the olfactory lobe, cerebral cortex, cerebellum, and blood plasma at different time-points by LC-MS. Pharmacokinetics in these tissues indicated the superiority of the intranasal eutectic formulation for brain targeting when compared with results of IV solution and intranasal pure zolmitriptan powder. Enhancement of nose-to-brain transport is likely to have resulted from more rapid dissolution of the eutectic as compared to pure drug.

Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B.

We investigated efficacy of nitric oxide (NO) against Leishmania donovani. NO is a mediator of host response to infection, with direct parasiticidal activity in addition to its role in signalling to evoke innate macrophage responses. However, it is short-lived and volatile, and is therefore difficult to introduce into infected cells and maintain inracellular concentrations for meaningful periods of time. We incorporated diethylenetriamine NO adduct (DETA/NO), a prodrug, into poly(lactide-co-glycolide) particles of ∼200 nm, with or without amphotericin B (AMB). These particles sustained NO levels in mouse macrophage culture supernatants, generating an area under curve (AUC0.08-24h) of 591.2 ± 95.1 mM × h. Free DETA/NO resulted in NO peaking at 3 h and declining rapidly to yield an AUC of 462.5 ± 193.4. Particles containing AMB and DETA/NO were able to kill ∼98% of promastigotes and ∼76% of amastigotes in 12 h when tested in vitro. Promastigotes and amastigotes were killed less efficiently by particles containing a single drug- either DETA/NO (∼42%, 35%) or AMB (∼90%, 50%) alone, or by equivalent concentrations of drugs in solution. In a pre-clinical efficacy study of power >0.95 in the hamster model, DETA/NO particles were non-inferior to Fungizone® but not Ambisome®, resulting in significant (∼73%) reduction in spleen parasites in 7 days. Particles containing both DETA/NO and AMB were superior (∼93% reduction) to Ambisome®. We conclude that NO delivered to the cytosol of macrophages infected with Leishmania possesses intrinsic activity and adds significantly to the efficacy of AMB.

Preparation and Preclinical Evaluation of Inhalable Particles Containing Rapamycin and Anti-Tuberculosis Agents for Induction of Autophagy.

PURPOSE: Mycobacterium tuberculosis (Mtb) inhibits host defense mechanisms, including autophagy. We investigated particles containing rapamycin (RAP) alone or in combination with isoniazid (INH) and rifabutin (RFB) for: targeting lung macrophages on inhalation; inducing autophagy; and killing macrophage-resident Mtb and/or augmenting anti-tuberculosis (TB) drugs. METHODS: PLGA and drugs were spray-dried. Pharmacokinetics, partial biodistribution (LC-MS/MS) and efficacy (colony forming units, qPCR, acid fast staining, histopathology) in mice following dry powder inhalation were evaluated. RESULTS: Aerodynamic diameters of formulations were 0.7-4.7 µm. Inhaled particles reached deep lungs and were phagocytosed by alveolar macrophages, yielding AUC0-48 of 102 compared to 0.1 µg/ml × h obtained with equivalent intravenous dose. RAP particles induced more autophagy in Mtb-infected macrophages than solutions. Inhaled particles containing RAP alone in daily, alternate-day and weekly dosing regimens reduced bacterial burden in lungs and spleens, inducing autophagy and phagosome-lysosome fusion. Inhalation of particles containing RAP with INH and RFB cleared the lungs and spleens of culturable bacteria. CONCLUSIONS: Targeting a potent autophagy-inducing agent to airway and lung macrophages alone is feasible, but not sufficient to eliminate Mtb. Combination of macrophage-targeted inhaled RAP with classical anti-TB drugs contributes to restoring tissue architecture and killing Mtb.

Opportunities and Challenges for Host-Directed Therapies in Tuberculosis.

BACKGROUND: Tuberculosis (TB) ranks alongside the human immunodeficiency virus (HIV) as cause of death due to an infectious disease. Recently, host-targeted therapies (HDT) have gained attention as a means to shorten the course of treatment of drug-sensitive TB, improve treatment outcomes of drug-resistant TB and generally improve the efficacy and preserve or restore lung architecture of TB patients. It has been suggested that supplementing anti-TB therapy with host response modulators will augment standard TB treatment by overcoming antibiotic resistance in pathogenic strains of Mycobacterium tuberculosis (Mtb) and related species, thus aiding in killing non-replicating bacilli. METHODS: The aim of this review is to examine pulmonary delivery strategies that can enhance the safety as well as efficacy of HDT against pulmonary TB. We reviewed literature in the public domain and revisited our own results on inhaled HDT to arrive at broad conclusions. RESULTS: HDT can be viewed as a strategy to evoke one or more of the following macrophage responses: (i) soluble, intracellular factors such as free radicals and antimicrobial peptides; (ii) soluble extracellular signals like cytokines, chemokines, prostaglandins, lipids, etc.; (iii) organelles and assemblies such as phagolysosomes or the inflammasome; (iv) Autophagy, via mTOR/S6 Kinase; and (v) apoptosis via caspases, bcr/abl products, etc. All of these may be optimally addressed using drugs approved for other uses. CONCLUSION: Deployment of HDT in TB may be optimally achieved through macrophage-targeted inhaled delivery systems.

Particulate pulmonary delivery systems containing anti-tuberculosis agents.

There is renewed interest in delivering anti-tuberculosis (TB) drugs to the lungs by inhalation. Several groups have investigated particulate pulmonary drug delivery formulations containing anti-TB agents, prepared using a variety of design approaches and processes. This review summarizes trends that indicate feasibility and translation of research efforts aimed at developing inhaled therapies for TB. Whereas formulations intended for reconstitution as solutions prior to nebulization can be produced with relative ease, particle engineering for powder formulations is more specialized. Spray drying and emulsion methods used to prepare particulate pulmonary delivery systems of anti-TB agents are compared. Pharmaceutical characterization is outlined. Administration of repeated inhalations to laboratory animals, especially under Animal Biosafety Level-3 (ABSL-3) containment as required for TB research, is another major challenge. Techniques employed by different groups are reviewed in the context of suitability for drug delivery and amenability towards use in ABSL-3 settings. It is concluded that spray drying is suitable for production of inhalable particles, rigorous physicochemical characterization is necessary for developing inhaled therapies as drug products, and pulmonary delivery of formulations containing anti-TB drugs to animals infected with Mycobacterium tuberculosis can best be carried out using handheld devices.