An in vivo pharmacokinetic study of metformin microparticles as an oral sustained release formulation in rabbits

Abstract

Background Metformin 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. Results Metformin-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. Conclusions Metformin-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.

Fabrication of Ropivacaine/Dexamethasone-Eluting Poly(D, L-lactide-co-glycolide) Microparticles via Electrospraying Technique for Postoperational Pain Control

“…The potential burst effect may also lead to overdose and toxicity of the drug. Bouriche et al [39] showed an unexpected decrease in bioavailability of the drug from the microparticles compared with the oral dosage form of the same drug. Additionally, local anesthetics can not only reduce the pain but may also lead to some side effects, such as nerve injury or local anesthetic systemic toxicity [40].…”

Formulation and Characterization of Metformin-Loaded Ethosomes for Topical Application to Experimentally Induced Skin Cancer in Mice

“…Metformin in the optimal metformin-loaded ethosome formula (formula #13) did not show a characteristic peak. These findings highlight that metformin was dissolved within the ethosomes during the formulation process (Figure 6) [27].…”

“…The pure metformin curve revealed a sharp endothermic peak at 242 • C, while the optimal metformin-loaded ethosome formula (#13) showed a peak appearing at 135 • C, but the thermogram of the empty formula (excipient) revealed two endothermic peaks at 103 • C and 148 • C. Metformin in the optimal metformin-loaded ethosome formula (formula #13) did not show a characteristic peak. These findings highlight that metformin was dissolved within the ethosomes during the formulation process (Figure 6) [27].…”

“…DSC has been used to show the physical state of metformin within the ethosomes, as well as the intermolecular interactions between metformin and ethosomes [27]. There was a lack for the characteristic metformin peaks, showing that metformin was fully solubilized in the ethosome system.…”

“…Each group contained 6 animals, and the selected optimal formula was applied topically on the dorsal region of the skin (10 mg/cm 2 of the affected area) per week for a total of 4 weeks [27,48]. The experimental groups are shown in Table 4.…”