Seema Upadhyay1, Iliyas Khan1, Avinash Gothwal1, Praveen K Pachouri2, N Bhaskar2, Umesh D Gupta2, Devendra S Chauhan2, Umesh Gupta3. 1. Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan, 305817, India. 2. National JALMA Institute for Leprosy and other Mycobacterial Diseases, Tajganj, Agra, Uttar Pradesh, 282001, India. 3. Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan, 305817, India. umeshgupta175@gmail.com.
Abstract
PURPOSE: First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF. METHODS: HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and 1H-NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC's interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis. RESULTS: Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p < 0.01, INH Vs PMRI; p < 0.0001, RIF Vs PMRI), respectively. MABA assay (cytotoxicity) based MIC values of PMRI formulation was observed as ≥0.0625 and ≥0.50 μg/mL (for sensitive and resistant strain). The microscopic analysis further confirmed that the delivery approach was effective than pure drugs. CONCLUSIONS: RIF loaded and INH conjugated HPMA-PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.
PURPOSE: First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF. METHODS: HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and 1H-NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC's interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis. RESULTS: Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p < 0.01, INH Vs PMRI; p < 0.0001, RIF Vs PMRI), respectively. MABA assay (cytotoxicity) based MIC values of PMRI formulation was observed as ≥0.0625 and ≥0.50 μg/mL (for sensitive and resistant strain). The microscopic analysis further confirmed that the delivery approach was effective than pure drugs. CONCLUSIONS:RIF loaded and INH conjugated HPMA-PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.
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