Abstract
BackgroundMetformin hydrochloride is a biguanide derivative that has been widely used to treat type 2 diabetes in humans. In veterinary medicine, metformin has shown increasing potential for diabetes treatment in different species, such as equids, dogs, cats and rabbits. It is highly hydrophilic, with incomplete gastrointestinal absorption and very large variability in absolute bioavailability between species, ranging from 4% in equids to 60% in humans. Metformin also shows a short half-life of approximately 2 h in dogs, cats, horses and humans. The objectives of this study were to evaluate a poly (lactic acid) (PLA) metformin microparticle formulation to test in rabbits and conduct a pharmacokinetics study of intravenous (SIV) and oral solution (SPO) metformin administration and oral PLA microparticle (SPLA) administration to rabbits to evaluate the improvement in the metformin pharmacokinetics profile.ResultsMetformin-loaded PLA microparticles were characterized by a spherical shape and high encapsulation efficiency. The results from Fourier transform infrared (FTIR) spectroscopy suggested the presence of interactions between metformin and PLA. X-Ray diffraction (XRD) analysis corroborated the results from the differential scanning calorimetry (DSC) studies, showing that metformin is present in an amorphous state within the microparticles. Physicochemical characterization suggested that PLA and metformin hydrochloride interacted within the microparticles via hydrogen bonding interactions. The pharmacokinetic study in rabbits showed sustained-release characteristics from the prepared microparticles with a delay in the time needed to reach the maximum concentration (Tmax), decreased Cmax and bioavailability, and increased mean residence time (MRT) and half-life compared to the pure drug solution.ConclusionsMetformin-loaded PLA microparticles showed optimal and beneficial properties in terms of their physicochemical characteristics, making them suitable for use in an in vivo pharmacokinetic study. The pharmacokinetic parameters of the metformin microparticles from the in vivo study showed a shorter Tmax, longer MRT and half-life, decreased Cmax and the prolonged/sustained release expected for metformin. However, the unexpected decrease in bioavailability of metformin from the microparticles with respect to the oral solution should be evaluated for microparticle and dose design in future works, especially before being tested in other animal species in veterinary medicine.
Highlights
Metformin hydrochloride is a biguanide derivative that has been widely used to treat type 2 diabetes in humans
Encapsulation efficiency and characterization of PLA microparticles Metformin HCl was encapsulated within PLA microparticles by the double emulsion solvent evaporation method
The high observed encapsulation efficiency may be due to hydrogen bonding between PLA and metformin that may occur during the microparticle formation process, which allows high entrapment of the drug in the polymer matrix
Summary
Metformin hydrochloride is a biguanide derivative that has been widely used to treat type 2 diabetes in humans. Metformin has shown increasing potential for diabetes treatment in different species, such as equids, dogs, cats and rabbits It is highly hydrophilic, with incomplete gastrointestinal absorption and very large variability in absolute bioavailability between species, ranging from 4% in equids to 60% in humans. In the case of animal species, when it is necessary to use the prescribing cascade principle, extrapolation from human doses is used due to the lack of knowledge of the pharmacokinetic parameters and, the most appropriate dosing regimens, which may cause problems in treated animals In this context, in veterinary medicine, the special conditions for the treatment of animals make long-acting formulations powerful tools for use in animals affected by diabetes (and other medical conditions) [10,11,12]
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