Inhaled dry powder of bedaquiline loaded nano-carrier for the treatment of multi-drug resistant tuberculosis

Year 2025, Volume: 29 Issue: 1, 445 - 468

Priyank Patel Rakeshkumar Parmar

Abstract

According to ICH Q8(R2) guideline, this research presents development of inhaled dry powder of
bedaquiline loaded nano-carrier for the treatment of MDR-tuberculosis to mitigate the side effects of marketed oral
dosage form. Circumscribed Central composite design was utilised to optimize the bedaquiline fumarate (BDQ)
loaded NLCs formulated by solvent injection technique and examine the impact of independent variables such as SP
Crodamol ML-MBAL-LQ-(RB), Lipoid S 100 and MyrjTM S 40 on dependent variables such as %drug loading, zeta
potential, vesicle size, %entrapment efficiency & %In-vitro drug release (Q12). The optimized formulation gave a
sustained drug release up to 12 hrs (97.12% ± 0.89%). It formed a stable emulsion with desired zeta potential (-34.98
mV), high entrapment efficiency (65.42% ± 0.49%), smaller vesicle size (175.51 nm) and sufficient drug loading
(18.01% ± 0.14%). Further the BDQ loaded NLCs emulsion was lyophilized using mannitol as lyoprotectant and
ethylene glycol as cryoprotectant. The lyophilized cake was sifted from #100 and then to #120 and filled in
Red/Transparent coloured size “3” hard gelatin capsule. It had good flow characteristics; maximum drug content &
the formulation provided no impedance to BDQ release. In-vitro lung deposition study showed that the inhaled dry
powder of BDQ loaded NLCs could be deposited in the deep lung tissue & GSD=1 showed that all the particles
were of same size. The minimum inhibitory concentration (MIC) of inhaled dry powder of BDQ loaded NLCs
capsule 50 mg was found to be 2 µg/ml which was less than the available marketed dosage form. According to ICH
Q1C guideline, the formulation was found stable for 6 month accelerated & long term stability conditions. The
inhaled dry powder of BDQ loaded NLCs reduced the peripheral tissue exposure and dosing frequency, gave a
target specific action, improved the bioavailability and patient compliance.

Keywords

Bedaquiline fumarate, NLCs, DPIs, ICH Q8(R2) guideline, ICH Q1C guideline

References

• [1] Rajiv M. Bedaquiline: First FDA-approved tuberculosis drug in 40 years. Int J Appl Basic Med Res 2013;3:1-2. https://doi.org/10.4103/2229-516X.112228
• [2] Ashish Kumar K, Neha D. Bedaquiline for the treatment of resistant tuberculosis: promises and pitfalls. Tuberculosis 2014;94:357-362. https://doi.org/10.1016/j.tube.2014.04.001
• [3] Pubchem. National Library of Medicine. Bedaquiline Fumarate. https://pubchem.ncbi.nlm.nih.gov/compound/Bedaquiline-fumarate (Accessed on 16 September 2023).
• [4] Centre for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Reviews. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/204384Orig1s000ClinPharmR.pdf (Accessed on 16 September 2023).
• [5] Fang CL, Al-Suwayeh SA, Fang JY. Nanostructured lipid carriers (NLCs) for drug delivery and targeting. Recent Pat Nanotechnol. 2013;7(1):41-55. https://doi.org/10.2174/18722105130105
• [6] Elmowafy M, Al-Sanea MM. Nanostructured lipid carriers (NLCs) as drug delivery platform: Advances in formulation and delivery strategies. Saudi Pharm J. 2021;29(9):999-1012. https://doi.org/10.1016/j.jsps.2021.07.015 for versatile
• [7] Van Hong N, Vy Nguyen T, Toi Vo V, Anh Hoang D, Beom-jin L. Nanostructured lipid carriers and their potential applications drug delivery via oral administration. OpenNano 2022;8:100064 https://doi.org/10.1016/j.onano.2022.100064
• [8] Ye Y, Ma Y, Zhu J. The future of dry powder inhaled therapy: Promising or discouraging for systemic disorders? Int J Pharm. 2022;614:121457. https://doi.org/10.1016%2Fj.ijpharm.2022.121457
• [9] Chaurasiya B, Zhao YY. Dry Powder for Pulmonary Delivery: A Comprehensive Review. Pharmaceutics. 2020;13(1):31. https://doi.org/10.3390%2Fpharmaceutics13010031
• [10] Ho Wan C, Stephanie C, Xinyue Z, Yayi Z, Henry Hoi Yee T, Shing Fung C. Inhalable nanoparticle based dry powder formulations for respiratory diseases: Challenges and strategies for translational research. AAPS PharmSciTech 2023;24(4):98. https://doi.org/10.1208/s12249-023-02559-y
• [11] Pharmaceutical Development Q8(R2). https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf (Accessed on 24 January 2024).
• [12] Min-Hwan K, Ki-Taek K, Seo-Yeon S, Jae-Young L, Chang Hyung L, Hee Y, Bo Kyung L, Ki Won L, Dae-Duk K. Formulation and evaluation of nanostructured lipid carriers (NLCs) of 20(S)-protopanaxadiol (PPD) by box behnken design. Int J Nanomed. 2019;14:8509-8520. https://doi.org/10.2147/IJN.S215835
• [13] Ortiz AC, Yañez O, Salas-Huenuleo E, Morales JO. Development of a Nanostructured Lipid Carrier (NLC) by a Low-Energy Method, Comparison of Release Kinetics and Molecular Dynamics Simulation. Pharmaceutics. 2021;13(4):531. https://doi.org/10.3390/pharmaceutics13040531
• [14] Pasero L, Susa F, Chiavarino R, Limongi T, Sulpizi A, Guidi T, Pisano R. Tailoring Dry Microparticles for Pulmonary Drug Delivery: Ultrasonic Spray Freeze-Drying with Mannitol and Salbutamol Sulphate. Processes. 2023; 11(11):3096. https://doi.org/10.3390/pr11113096
• [15] Chow MYT, Tai W, Chang RYK, Chan HK, Kwok PCL. In vitro-in vivo correlation of cascade impactor data for orally inhaled pharmaceutical aerosols. Adv Drug Deliv Rev. 2021;177:113952.https://doi.org/10.1016/j.addr.2021.113952
• [16] Labirish NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 2003;56:588-599. https://doi.org/10.1046%2Fj.1365 2125.2003.01892.x
• [17] Technical manual for drug susceptibility testing of medicines used in the treatment of tuberculosis. https://iris.who.int/bitstream/handle/10665/275469/9789241514842-eng.pdf?sequence=1 (Accessed on 24 January 2024).
• [18] Note for guidance on stability testing: requirements for new dosage forms Q1C. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-1-c-stability-testing-requirements-new dosage-forms-step-5_en.pdf (Accessed on 24 January 2024).