Microparticle-based lung delivery of INH decreases INH metabolism and targets alveolar macrophages

Zhou, Huiyu; Zhang, Yanling; Biggs, D.; Manning, Mark C.; Randolph, Theodore W.; Christians, Uwe; Hybertson, Brooks M.; Ng, Ka‐Yun

doi:10.1016/j.jconrel.2005.06.009

Cited by 50 publications

(40 citation statements)

References 35 publications

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“…INH and RFB were associated with approximately equal efficiency, demonstrating that the process was independent of the aqueous solubility of the drugs (125 mg/mL for INH and 0.19 mg/mL for RFB). Owing to its hydrophilic nature, INH was easily dissolved in the LBG solution and, thus, the association efficiency of 89% was not surprising, being similar to that reported for other INH-loaded spray-dried microparticles [29,30]. Such association efficiency resulted in a loading capacity around 9%.…”

Section: Association Of Drugs and Characterisation Of Microparticlessupporting

confidence: 78%

“…INH-loaded microparticles have the fastest release (86% in 20 min), which was expected owing to the high solubility of INH. In general, this profile is identical to that obtained from INH-loaded polylactic acid microparticles in PBS pH 7.4 [29]. The release of RFB was somewhat slower at initial time points, particularly for microparticles with the highest amount of the drug (LBG:RFB 10:1, w/w), although it still corresponds to a rapid release profile.…”

Section: In Vitro Drug Releasesupporting

confidence: 73%

“…INH-loaded microparticles have the fastest release (86% in 20 min), which was expected owing to the high solubility of INH. In general, this profile is identical to that obtained from INH-loaded polylactic acid microparticles in PBS pH 7.4 [29]. The release profile of both INH and RFB from the respective microparticle formulations is plotted in Figure 4.…”

Section: In Vitro Drug Releasesupporting

confidence: 65%

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Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

et al. 2016

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Tuberculosis remains a major global health problem and alternative therapeutic approaches are needed. Considering the high prevalence of lung tuberculosis (80% of cases), the pulmonary delivery of antitubercular drugs in a carrier system capable of reaching the alveoli, being recognised and phagocytosed by alveolar macrophages (mycobacterium hosts), would be a significant improvement to current oral drug regimens. Locust bean gum (LBG) is a polysaccharide composed of galactose and mannose residues, which may favour specific recognition by macrophages and potentiate phagocytosis. LBG microparticles produced by spray-drying are reported herein for the first time, incorporating either isoniazid or rifabutin, first-line antitubercular drugs (association efficiencies >82%). Microparticles have adequate theoretical properties for deep lung delivery (aerodynamic diameters between 1.15 and 1.67 µm). The cytotoxic evaluation in lung epithelial cells (A549 cells) and macrophages (THP-1 cells) revealed a toxic effect from rifabutin-loaded microparticles at the highest concentrations, but we may consider that these were very high comparing with in vivo conditions. LBG microparticles further evidenced strong ability to be captured by macrophages (percentage of phagocytosis >94%). Overall, the obtained data indicated the potential of the proposed system for tuberculosis therapy.

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Section: Association Of Drugs and Characterisation Of Microparticlessupporting

confidence: 78%

Section: In Vitro Drug Releasesupporting

confidence: 73%

“…INH-loaded microparticles have the fastest release (86% in 20 min), which was expected owing to the high solubility of INH. In general, this profile is identical to that obtained from INH-loaded polylactic acid microparticles in PBS pH 7.4 [29]. The release profile of both INH and RFB from the respective microparticle formulations is plotted in Figure 4.…”

Section: In Vitro Drug Releasesupporting

confidence: 65%

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Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

et al. 2016

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“…Achieving an effective concentration of drug by oral administration and a complete cure is complicated by the difficulty of delivering drugs to the sites deep within the lungs where Mycobacterium tuberculosis resides. Several studies have attempted to improve the delivery of drugs into the lungs [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. Such targeted delivery of drugs is expected to improve the treatment of TB, decrease the necessary doses, and reduce systemic sideeffects.…”

Section: Introductionmentioning

confidence: 99%

Application of a Four-fluid Nozzle Spray Drier to Prepare Inhalable Rifampicin-containing Mannitol Microparticles

2008

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Abstract. The purpose of this study was to use a four-fluid nozzle spray drier as a new one-step method for preparing rifampicin (RFP)-containing mannitol microparticles. A RFP-acetone/methanol (2:1) solution and aqueous solutions of mannitol (MAN) were simultaneously supplied through different liquid passages of a four-fluid nozzle spray drier and then dried to obtain MAN microparticles containing RFP. Using a cascade impactor, the in vitro aerosol performance of RFP powder and RFP-MAN microparticles with 1:5, 1:10, and 1:20 ratios was compared. The in vivo retention of RFP in the lungs of rats after intratracheal administration of 1:20 RFP-MAN microparticles was also compared. The RFP-MAN microparticles had better aerosol performance than RFP powder and delivery to the lung stages improved as the fraction of MAN was increased. For the 1:20 RFP-MAN microparticles, deposition in stages 2-7 was approximately 43%, which is sufficient for treatment. Approximately 8% of the RFP-MAN microparticles were deposited in stages 6-7, which corresponds to alveoli containing alveolar macrophages. The initial retention of RFP in the lung following pulmonary delivery of 1:20 RFP-MAN microparticles was higher than following oral or intravenous administration of RFP, but the elimination was rapid, resulting in the disappearance of RFP from the lung within 4 h. The plasma concentrationtime profile of RFP after intratracheal administration of 1:20 RFP-MAN microparticles was consistent with the profile for RFP retention in the lung. Addition of cholesterol or phosphatidylcholine to RFP had little effect on its retention in the lung. The RFP-MAN microparticles were effective for delivery of RFP to the lung, but the RFP rapidly removed from the lung into the blood circulation. This study demonstrated that RFP-containing MAN microparticles prepared in one step using the four-fluid nozzle spray drier efficiently deliver RFP to the lung, although methods must be developed to prolong its retention and improve targeting to alveolar macrophages.

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“…Cells with seeding density of 1×10 6 cells/mL were plated in 12-well culture plates in RPMI 1640 supplemented with 10% fetal calf serum and 1% antibiotics. After overnight incubation at 37°C and 5% CO 2 , the cells were treated with free INH, GMs, and mGMs at the same dose level (21). In a parallel experiment, 0.05 M mannose, a corresponding sugar inhibitor, was added to observe its effect on the cell internalization behavior of mGMs.…”

Section: Ex Vivo Drug Accumulation Studies In Cultured Alveolar Macromentioning

confidence: 99%

Macrophage-Specific Targeting of Isoniazid Through Mannosylated Gelatin Microspheres

et al. 2011

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Abstract. Active targeting of drug molecules can be achieved by effective attachment of suitable ligands to the surface of carriers. The present work was attempted to prepare mannosylated gelatin microspheres (m-GMs) so as to achieve targeted delivery of isoniazid (INH) to alveolar macrophages (AMs) and maintain its therapeutic concentration for prolonged period of time. Microspheres were prepared by emulsification solvent extraction method and evaluated for physicochemical characteristics, drug release, ex vivo drug uptake by AMs and pharmacokinetic characteristics. Fourier transform infrared spectroscopy and nuclear magnetic resonance spectral analysis confirmed that mannosylation took place through Schiff base formation between aldehyde and amino groups of mannose and gelatin, respectively. Prepared microspheres offered suitable physicochemical characteristics for their delivery to AMs. Their average size was about 4 μm and drug entrapment efficiency of 56% was achieved with them. Ex vivo uptake results indicated that in comparison to plain microspheres, m-GMs were selectively uptaken and were found to be associated with phago-lysosomal vesicles of AMs. Pharmacokinetic studies showed the formulation could maintain the therapeutic concentration of INH for prolonged period of time even with a reduced clinical dose. m-GMs were found to be stable in broncheo-alveolar lavage fluid. The study concluded that ligand decorated carriers could be a potential strategy to improve the therapeutic properties of INH.

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Microparticle-based lung delivery of INH decreases INH metabolism and targets alveolar macrophages

Cited by 50 publications

References 35 publications

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

Inhalable Antitubercular Therapy Mediated by Locust Bean Gum Microparticles

Application of a Four-fluid Nozzle Spray Drier to Prepare Inhalable Rifampicin-containing Mannitol Microparticles

Macrophage-Specific Targeting of Isoniazid Through Mannosylated Gelatin Microspheres

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