title: Effect of the excipient concentration on the pharmacokinetics of PM181104, a novel antimicrobial thiazolyl cyclic peptide antibiotic, following intravenous administration to mice.
abstract: Thiazolyl cyclic peptide antibiotics are known for their poor aqueous solubility and unfavorable pharmacokinetics (PK) and hence pose challenging tasks in developing these antibiotics as clinical candidates. In the current paper, we report a possible way to address these challenges with exemplification of our antibiotic PM181104. The approach was to prepare formulations with known excipients, Polysorbate 80 (Tween 80, T-80) and PEG 400 through their varied stiochiometric combination in appropriate ratio to achieve acceptable osmolarity, pH and particle size of the formulation. Two different sets of formulations were prepared with two distinct average particle diameters ranging from 32.8 to 465.4 nm. First, semi-transparent solutions with a particle size of >100 nm were achieved by keeping concentration of PEG 400 constant at 8% (w/v) and decreasing the amounts of T-80. Second, clear colorless solutions with a particle size of <100 nm were achieved by keeping concentration of T-80 constant at 8% (w/v) and decreasing the amounts of PEG 400. In PK studies, intravenous administration of formulation with particle size <100 nm to mice resulted in a two-fold increase in area under the plasma concentration-time curve (AUClast) and concentration at time zero (C 0), there by facilitating the selection of suitable formulation for further efficacy studies.
authors.affiliation: Piramal Life Sciences, 1-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, India.
authors.forename: Vijayaphanikumar
authors.initials: V
authors.lastname: Yemparala
authors.affiliation: Piramal Life Sciences, 1-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, India.
authors.forename: Anagha A
authors.initials: AA
authors.lastname: Damre
authors.affiliation: Piramal Life Sciences, 1-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, India.
authors.forename: Venkat
authors.initials: V
authors.lastname: Manohar
authors.affiliation: Piramal Life Sciences, 1-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, India.
authors.forename: Kishori
authors.initials: K
authors.lastname: Sharan Singh
authors.affiliation: Piramal Life Sciences, 1-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, India.
authors.forename: Girish B
authors.initials: GB
authors.lastname: Mahajan
authors.affiliation: Piramal Life Sciences, 1-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, India.
authors.forename: Satish N
authors.initials: SN
authors.lastname: Sawant
authors.affiliation: Piramal Life Sciences, 1-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, India.
authors.forename: Tanaji
authors.initials: T
authors.lastname: Deokule
authors.affiliation: Piramal Life Sciences, 1-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, India.
authors.forename: H
authors.initials: H
authors.lastname: Sivaramakrishnan
keywords: Antisolvent precipitation; Nanoparticle size; PEG 400; PM181104; Pharmacokinetics; Tween 80