Nanopartículas poliméricas com pregabalina para o tratamento de dor neuropática em ratos: obtenção, caracterização e avaliação in vivo do efeito antinociceptivo e da farmacocinética

Abstract

Neuropathic pain is a type of chronic pain, in which damage occurs to the somatosensory nervous system and is difficult to treat. A controlled release system can change the pharmacokinetic parameters of the substance, reducing side effects and increasing adherence to treatment. Thus, the aim of this work was to obtain and characterize polymeric nanoparticles with pregabalin (PG), and to verify its pharmacokinetics, nociception potential and side effect (drowsiness) of this formulation. For this, polymeric nanoparticles with PG were developed using the ionotropic gelling method, between chitosan and hydroxypropylmethylcellulose phthalate. The particles showed an average particle size of 432 nm, with good homogeneity in particle size spherical shape, the average zeta potential of +19.0 mV and the average pH of 5.7. The formulation showed an association rate of approximately 44%. X-ray diffraction, thermogravimetry and differential exploratory calorimetry tests suggested the formation of the polymeric nanoparticles with PG. The Fourier transform infrared spectroscopy test confirmed the interaction form of the nanoparticles. For the evaluation of pharmacokinetics, antinociceptive effect, motor coordination, locomotor behavior and side effect, male Wistar rats (220-250 g) were used and divided into 4 groups: polymeric nanoparticle with PG (NP PG), PG, empty nanoparticle (NP VAZ) and ultrapure water (WATER), and received the substances orally, in a single dose (10 mg/Kg). To calculate the pharmacokinetic parameters, plasma concentrations were determined by UPLC-MS/MS. PG NP showed increased volume of distribution and clearance compared to PG. To evaluate the antinociceptive effect, the animals underwent induction of neuropathic pain by chronic sciatic nerve constriction (CCI) in the right paw and received the substances on day 14 after CCI and mechanical allodynia was tested only in the right paw before CCI and on day 14: before administration of the substances, 1, 2:15, 4, 8, 24, 48 and 72 h after administration of the substances. When we compared the CCI-PG and CCI-NP PG groups with CCI-WATER, the CCI-PG group showed an antinociceptive effect at 1 to 8 h and the CCI-NP PG group at 1 to 48 h after the administration of the substances. When we compared CCI-NP PG with CCI-PG, the antinociceptive profile of the groups only differed at 48 h after the administration

of the substances, showing that NP PG still maintained the positive effect in reducing nociception. The results of the rota-rod showed that none of the substances caused motor deficit in any of the tested times. The results of the open field showed the same profile of reduced exploration over time with all substances administered. The drowsiness results showed that both the PG and NP PG groups showed sedative effects, when compared to the WATER and NP VAZ groups; with the duration of the sedative effect of NP PG significantly shorter than that of PG. Thus, the administration of PG through polymeric nanoparticles showed prolongation of the antinociceptive effect, longer duration of stay in the body and reduction of side effects.