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Nanoparticulate tablet dosage form of lisofylline-linoleic acid conjugate for type 1 diabetes: in situ single-pass intestinal perfusion (SPIP) studies and pharmacokinetics in rat

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Abstract

Lisofylline (LSF) is an anti-inflammatory molecule with high aqueous solubility and rapid metabolic interconversion to its parent drug, pentoxifylline (PTX) resulting in very poor pharmacokinetic (PK) parameters, necessitating high dose and dosing frequency. In the present study, we resolved the physicochemical and pharmacokinetic limitations associated with LSF and designed its oral dosage form as a tablet for effective treatment in type 1 diabetes (T1D). Self-assembling polymeric micelles of LSF (lisofylline-linoleic acid polymeric micelles (LSF-LA PLM)) were optimized for scale-up (6 g batch size) and lyophilized followed by compression into tablets. Powder blend and tablets were evaluated as per USP. LSF-LA PLM tablet so formed was evaluated for in vitro release in simulated biological fluids (with enzymes) and for cell viability in MIN-6 cells. LSF-LA PLM in tablet formulation was further evaluated for intestinal permeability (in situ) along with LSF and LSF-LA self-assembled micelles (SM) as controls in a rat model using single-pass intestinal perfusion (SPIP) study. SPIP studies revealed 1.8-fold higher oral absorption of LSF-LA from LSF-LA PLM as compared to LSF-LA SM and ~5.9-fold higher than LSF (alone) solution. Pharmacokinetic studies of LSF-LA PLM tablet showed greater Cmax than LSF, LSF-LA, and LSF-LA PLM. Designed facile LSF-LA PLM tablet dosage form has potential for an immediate decrease in the postprandial glucose levels in patients of T1D.

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Abbreviations

Ø :

Angle of repose

AUC:

Area under curve

AUMC:

Area under first moment curve

CAF:

Central animal facility

C max :

Maximum (or peak) concentration

GIT:

Gastrointestinal tract

HPLC:

High-performance liquid chromatography

IAEC:

Institutional Animal Ethics Committee

Ka :

Apparent first-order absorption rate constant

LA:

Linoleic acid

LSF:

Lisofylline

LSF-LA:

Lisofylline-linoleic acid

LSF-LA PLM:

Lisofylline-linoleic acid polymeric micelles

LSF-LA SM:

Lisofylline-linoleic acid self-assembled micelles

MCC:

Microcrystalline cellulose

MIN-6:

Mouse insulinoma 6

mPEG-b-P(CB-co-LA):

Methoxy-polyethylene-glycol-b-poly(carbonate-colactide)

MRT:

Mean residence time

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

PD:

Pharmacodynamics

PDA:

Photodiode array

PDE:

Phosphodiesterase

PDI:

Polydispersity index

PEG-2000:

Polyethylene glycol 2000

P eff :

Permeability coefficient

PK:

Pharmacokinetic

PLM:

Polymeric micelles

PTX:

Pentoxifylline

RPMI:

Roswell Park Memorial Institute Medium

SGF:

Simulated gastric fluid

SIF:

Simulated intestinal fluid

SPIP:

Single-pass intestinal perfusion

T1:

Tablets without LSF-LA PLM (blank tablets)

T2:

Tablets with LSF-LA PLM

t1/2 :

Half-life

T1D:

Type 1 diabetes

USP:

United States Pharmacopeia

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Acknowledgments

The authors acknowledge Gangwal Chemicals Pvt. Ltd. (Mumbai, INDIA) for providing Fujicalin SG® as a gift sample for this work.

Funding

The work elaborated in the study was funded by SERB-DST, Govt. of India research grant #YSS/2014/000551 and DST-INSPIRE, fellowship to K.S.I. [#IF160659].

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Authors and Affiliations

  1. Department of Pharmacy, Birla Institute of Technology and Science (BITS PILANI), Pilani Campus, Pilani, Rajasthan, 333031, India

    Kishan S. Italiya, Arihant K. Singh, Deepak Chitkara & Anupama Mittal

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  1. Kishan S. Italiya
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Correspondence to Anupama Mittal.

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Conflict of interest

The authors (DC and AM) are the founding directors of Nanobrid Innovations Private Limited that is involved in the development of nanotechnology-based products. They have business and/or financial interest in the operations of the company. The same could be disclosed on request. The authors declare that they have no conflict of interest pertaining to the work outlined in this study.

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Italiya, K.S., Singh, A.K., Chitkara, D. et al. Nanoparticulate tablet dosage form of lisofylline-linoleic acid conjugate for type 1 diabetes: in situ single-pass intestinal perfusion (SPIP) studies and pharmacokinetics in rat. AAPS PharmSciTech 22, 114 (2021). https://doi.org/10.1208/s12249-021-01980-5

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