Chitosan nanoparticles as a promising approach for pulmonary delivery of bedaquiline.

The purpose of the present research work was to explore chitosan nanoparticles (NPs) of a novel anti-tubercular drug, bedaquiline (BDQ) in order to reduce dose and side effects associated with oral BDQ formulation. The NPs were fabricated using ionic gelation method and evaluated for particle size, zeta potential, entrapment efficiency and drug loading. Plackett Burman was used as screening design. Two level three-factor factorial design was applied for optimization. Following freeze drying of NPs, the powder obtained was mixed with lactose pre-blend to obtain a respirable powder. In vitro deposition studies were performed using non-viable cascade impactor. In vitro cytotoxicity and in vivo toxicity studies were performed. In vivo pharmacokinetics of NPs formulation was compared with conventional dry powder inhaler (DPI) formulation and oral drug solution. Polymer amount, TPP concentration and probe sonication time were the significant factors. Optimized batch showed particle size of 109.7 ±â€¯9.3 nm with a zeta potential of 36 ±â€¯2.1 mV. In vitro and in vivo toxicity studies unveiled better safety profile of NPs in comparison to conventional DPI and oral solution. Pharmacokinetic studies manifested higher concentration of BDQ in lungs via developed formulation. Therefore, the developed formulation could efficiently deliver BDQ into the lungs.

Chitosan Nanoparticles of Gamma-Oryzanol: Formulation, Optimization, and In vivo Evaluation of Anti-hyperlipidemic Activity.

The elevated blood levels of cholesterol and low-density lipoproteins result in hyperlipidemia. The available expensive prophylactic treatments are kindred with severe side effects. Therefore, we fabricated the polymeric nanoparticles of gamma-oryzanol to achieving the improved efficacy of drug. The nanoparticles were prepared by ionic gelation method and optimized using 23 full factorial design taking drug/polymer ratio (X1), polymer/cross linking agent ratio (X2), and stirring speed (X3) as independent variables. The average particle size, percentage entrapment efficiency, and in vitro drug release at 2, 12, and 24 h were selected as response parameters. The factorial batches were statistically analyzed and optimized. The optimized nanoparticles were characterized with respect to particle size (141 nm) and zeta potential (+ 6.45 mV). Results obtained with the prepared and characterized formulation showed 83% mucoadhesion towards the intestinal mucosa. The in vitro findings were complemented well by in vivo anti-hyperlipidemic activity of developed formulation carried out in Swiss albino mouse model. The in vivo studies showed improved atherogenic index, malondialdehyde, and superoxide dismutase levels in poloxamer-407-induced hyperlipidemic animals when treated with oryzanol and gamma-oryzanol nanoformulation. Based on our findings, we believe that chitosan-mediated delivery of gamma-oryzanol nanoparticles might prove better in terms of anti-hyperlipidemic therapeutics.

Dry-Powder Inhaler Formulation of Rifampicin: An Improved Targeted Delivery System for Alveolar Tuberculosis.

BACKGROUND: The delivery of antitubercular drugs through direct lung targeting can lead to reduction in the dose as well as side effects of the drug. In the present investigation, carrier (lactose)-based dry-powder inhaler of rifampicin was prepared to achieve direct targeting of the drug into the lungs. METHODS: The dry powder inhaler formulation was prepared by simply mixing micronized rifampicin with coarse and fine lactose preblend. Preliminary blends of the drug were prepared with various lactose grades (Inhalac®, Respitose,® and Lactohale®). Rotahaler® and Revolizer® were evaluated for the performance. The 32 factorial design was used to optimize the amount of drug (X1) and amount of fine lactose (X2). In vitro lung deposition was carried out using Andersen Cascade Impactor. The % cell viability studies of the formulation were carried out using murine macrophage J774 cell lines. The in vivo toxicity was determined using histopathology. Further in vivo pulmonary pharmacokinetics of the developed dry-powder inhaler (DPI) formulation was carried out in comparison to the marketed formulation in the rat lungs. RESULTS: Based on preliminary trials, Inhalac 230 and Inhalac 400 were selected as coarse and fine lactose grades, respectively. Rotahaler® exhibited better DPI performance with the evaluated drug blends. The mass median aerodynamic diameter (MMAD) was in the range of 4.3-5.8 µm with the maximum fine particle fraction of 28.9%. The formulation exhibited negligible cytotoxicity on macrophage J774 cell lines with about 75%-80% cell viability at 6- and 12-hour exposure. The histopathological examination revealed negligible toxicity of DPI in comparison to the marketed formulation. The in vivo pulmonary pharmacokinetic studies of the DPI formulation in rats showed higher drug concentration in lungs in comparison to the marketed formulation. CONCLUSION: The carrier-mediated dry-powder inhaler of rifampicin could serve as an improved and efficient system for local targeting of drugs into the lungs.

Rifampicin loaded chitosan nanoparticle dry powder presents an improved therapeutic approach for alveolar tuberculosis.

Current treatment therapeutic approach for tuberculosis is the administration of first line drugs in the form of tablets and capsules for 4-6 months. However, this approach leads to severe adverse effects. Therefore, present study was designed to achieving local and sustained targeting of anti-tubercular drugs in order to reduce dose and frequency. The nanoparticle based dry powder formulation of rifampicin was developed and analyzed with respect to its direct targeting potential of lungs. Rifampicin loaded nanoparticles were formulated by ionic gelation probe sonication method, and characterized with respect to particle size, zeta potential, entrapment and drug loading efficiency. The range of size and entrapment efficiency of prepared nanoparticles was estimated from 124.1±0.2 to 402.3±2.8nm and 72.00±0.1%, respectively. The freeze-dried powder of nanoparticle formulation was used to carry out in vitro lung deposition studies through Andersen cascade impactor. The cumulative in vitro drug release studies with developed nanoparticle formulation showed sustained release up to 24h. Our in vitro sustained drug release results were corroborated by the extended residence and slow clearance of rifampicin from the lungs. Furthermore, our results suggest the minimum lung distribution of drug in treated rats which confirms the negligible toxicity rendered by nanoparticle dry powder formulation. Moreover, pharmacokinetic and toxicity studies carried out with prepared NPs dry powder inhalation (DPI) formulations and compared with conventional DPI.

Combating Tuberculosis Infection: A Forbidding Challenge.

After 50 years drought, several drugs are looming from the pipeline to combat tuberculosis. They will serve as a boon to the field that has been burdened with primitive, inadequate treatments and drug-resistant bacterial strains. From the decades, due to lack of interest and resources, the field has suffered a lot. Learning from the flaws, scientists have renovated their approaches to the finding of new antitubercular drugs. The first line drugs take about six months or more for the entire treatment. The second line remedy for resistant-tuberculosis requires daily injections which carry severe side effects. Drug resistance remains a constant menace because patients stop the medication once they start feeling better. So new drugs are required to be explored which are effective against tuberculosis especially drug resistant tuberculosis. These drugs need to work well with other drugs as well as with antivirals used for the treatment of human immunodeficiency virus. It is also very important to be considered that the treatments need to be cheap, as tuberculosis primarily affects people more in the developing countries. Further, new drugs must cure the disease in short span of time than the current six to nine month regimen. Recently a few new and potent drugs such as bedaquiline, delamanid, teixobactin have been evolved which may serve as a nice step forward, with a better outcome. Teixobactin, a new antibiotic has been found to have promising action against resistant strains, is also under consideration.