Inhalable microparticles containing large payload of anti-tuberculosis drugs

Muttil, Pavan; Kaur, Jatinder; Kumar, Kaushlendra; Yadav, Awadh Bihari; Sharma, Rolee; Misra, Amit

doi:10.1016/j.ejps.2007.06.006

Cited by 160 publications

(100 citation statements)

References 34 publications

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“…It is worth mentioning that free drug would be more prone to metabolism as compared to the drug entrapped within the delivery system. Our observations corroborated to the findings of Muttil et al (28). Another study which, though is not specific to INH, also provided the evidence of metabolic activity of cultured macrophage cells (29).…”

Section: Ex Vivo Drug Uptake Studiessupporting

confidence: 82%

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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Section: Ex Vivo Drug Uptake Studiessupporting

confidence: 82%

Macrophage-Specific Targeting of Isoniazid Through Mannosylated Gelatin Microspheres

et al. 2011

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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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“…For TB, respirable insoluble micro-and nanoparticles of rifampin and isoniazid have received the most research attention but have been limited to animal studies thus far (49,50). Liposomal forms of antitubercular medications such as amikacin and capreomycin are also undergoing development (51,52).…”

Section: Mycobacterial Infectionsmentioning

confidence: 99%

Inhaled Antibiotics for Lower Airway Infections

2014

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Inhaled antibiotics have been used to treat chronic airway infections since the 1940s. The earliest experience with inhaled antibiotics involved aerosolizing antibiotics designed for parenteral administration. These formulations caused significant bronchial irritation due to added preservatives and nonphysiologic chemical composition. A major therapeutic advance took place in 1997, when tobramycin designed for inhalation was approved by the U.S. Food and Drug Administration (FDA) for use in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa infection. Attracted by the clinical benefits observed in CF and the availability of dry powder antibiotic formulations, there has been a growing interest in the use of inhaled antibiotics in other lower respiratory tract infections, such as non-CF bronchiectasis, ventilator-associated pneumonia, chronic obstructive pulmonary disease, mycobacterial disease, and in the post-lung transplant setting over the past decade.Antibiotics currently marketed for inhalation include nebulized and dry powder forms of tobramycin and colistin and nebulized aztreonam. Although both the U.S. Food and Drug Administration and European Medicines Agency have approved their use in CF, they have not been approved in other disease areas due to lack of supportive clinical trial evidence. Injectable formulations of gentamicin, tobramycin, amikacin, ceftazidime, and amphotericin are currently nebulized "off-label" to manage non-CF bronchiectasis, drug-resistant nontuberculous mycobacterial infections, ventilatorassociated pneumonia, and post-transplant airway infections. Future inhaled antibiotic trials must focus on disease areas outside of CF with sample sizes large enough to evaluate clinically important endpoints such as exacerbations. Extrapolating from CF, the impact of eradicating organisms such as P. aeruginosa in non-CF bronchiectasis should also be evaluated.

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Inhalable microparticles containing large payload of anti-tuberculosis drugs

Cited by 160 publications

References 34 publications

Macrophage-Specific Targeting of Isoniazid Through Mannosylated Gelatin Microspheres

Macrophage-Specific Targeting of Isoniazid Through Mannosylated Gelatin Microspheres

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

Inhaled Antibiotics for Lower Airway Infections

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