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Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycobacterium Tuberculosis

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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.

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Abbreviations

Ar:

Aromatic

CMC:

Critical micelle concentration

DCC:

N,N′-dicyclohexylcarbodiimide

DCM:

Dichloromethane

EDC:

N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide

ETH:

Ethambutol

HPI:

HPMA-PLA-INH conjugates

HPMA:

N(2-hydroxypropyl) methacrylamide

INH:

Isoniazid

MDR-TB:

Multidrug-resistant TB

PLA:

Poly lactic acid

PMRI:

RIF loading in HPMA-PLA-INH conjugates

PYZ:

Pyrazinamide

RIF:

Rifampicin

SEM:

Scanning electron microscopy and

TB:

Tuberculosis

TEM:

Transmission electron microscopy

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Authors and Affiliations

  1. Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan, 305817, India

    Seema Upadhyay, Iliyas Khan, Avinash Gothwal & Umesh Gupta

  2. National JALMA Institute for Leprosy and other Mycobacterial Diseases, Tajganj, Agra, Uttar Pradesh, 282001, India

    Praveen K. Pachouri, N. Bhaskar, Umesh D. Gupta & Devendra S. Chauhan

Authors
  1. Seema Upadhyay
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  2. Iliyas Khan
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  3. Avinash Gothwal
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  4. Praveen K. Pachouri
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  5. N. Bhaskar
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  6. Umesh D. Gupta
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  7. Devendra S. Chauhan
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  8. Umesh Gupta
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Correspondence to Umesh Gupta.

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The authors declare no competing financial interest.

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Upadhyay, S., Khan, I., Gothwal, A. et al. Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycobacterium Tuberculosis . Pharm Res 34, 1944–1955 (2017). https://doi.org/10.1007/s11095-017-2206-3

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  • DOI: https://doi.org/10.1007/s11095-017-2206-3

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