Carolina Morales Moraes

Benzocaine-Loaded Polymeric Nanocapsules: Study of the Anesthetic Activities

This paper describes a comparison of different polymeric nanocapsules (NCs) prepared with the polymers poly(D,L-lactide-co-glycolide), poly(L-lactide) (PLA), and poly(ε-caprolactone) and used as carrier systems for the local anesthetic (LA) benzocaine (BZC). The systems were characterized and their anesthetic activities investigated. The results showed particle size distributions with polydispersity indices below 0.135, average diameters up to 120 nm, zeta potentials up to -30 mV, and entrapment efficiencies around 70%. Formulations of BZC using the polymeric NCs presented slower release profiles, compared with that of free BZC. Slowest release (release constant, k = 0.0016 min(-1)) was obtained using the PLA NC system. Pharmacological evaluation showed that encapsulation of BZC in PLA NCs prolonged its anesthetic action. This new formulation could potentially be used in future applications involving the gradual release of local anesthetics (LAs).

Physicochemical Stability of Poly(lactide-co-glycolide) Nanocapsules Containing the Local Anesthetic Bupivacaine

This paper describes the preparation of poly(DL-lactide-co-glicolide) (PLGA) nanocapsules as a drug carrier system for the local anesthetic bupivacaine. The system was characterized and its stability investigated. The results showed a size distribution with a polydispersity index of 0.12, an average diameter of 148 nm, a zeta potential of –43.5 mV and an entrapment efficiency of 75.8%. The physicochemical properties of polymeric nanocapsule suspensions (average diameter, polydispersity, zeta potential and drug association efficiency) were evaluated as a function of time to determine the formulation stability. The formulation did not display major changes in these properties over the time, and it was considered stable up to 120 days of storage at room temperature. The results reported here which refer to the initial characterization of these new formulations for the local anesthetic bupivacaine show a promising potential for future in vivo studies.

Preparação e caracterização físico-química de complexos de inclusão entre anestésicos locais e hidroxipropil-beta-ciclodextrina

S(-) Bupivacaine (S(-)BVC) and Lidocaine (LDC) are widely used local anesthetics (LA). Hydroxypropyl b-cyclodextrin (HP-b-CD) is used as a drug-carrier system. The aim of this work was to characterize inclusion complexes between LA and HP-b-CD. The affinity constants determined at different pHs show favourable complexation. The release kinetics experiments showed that S(-)BVC and LDC changed the released profiles in the presence of HP-b-CD. Nuclear magnetic resonance experiments gave information about the interaction between LA and the cyclodextrin cavity. This study focused on the physicochemical characterization of drug-delivery formulations that come out as potentially new therapeutic options for pain treatment.

Caracterização do complexo de inclusão ropivacaína: β-ciclodextrina

Characteriza of the inclusion complex ropivacaine: b-cyclodextrin. Ropivacaine (RVC) is a widely used local anesthetic. The complexation of RVC with b-cyclodextrin (b-CD) is of great interest for the development of more efficient local anesthetic formulations. The present work focuses on the characterization of the RVC:b-CD complex by nuclear magnetic resonance (NMR). The stoichiometry of the complex is 1:2 RVC:b-CD. DOSY-NMR shows that the association constant is 55.5 M-1. Longitudinal relaxation time results show that RVC changes its mobility in the presence of b-CD. This study is focused on the physicochemical characterization of inclusion complexes that are potentials options for pain treatment.

Caracterização físico-química de complexo de inclusão entre hidroximetilnitrofurazona e hidroxipropil-beta-ciclodextrina

Hydroxymethylnitrofurazone (NFOH) is a prodrug that is active against Trypanosoma cruzi. It however presents low solubility and high toxicity. Hydroxypropyl-b-cyclodextrin (HP-b-CD) can be used as a drug-delivery system for NFOH modifying its physico-chemical properties. The aim of this work is to characterize the inclusion complex between NFOH and HP-b-CD. The rate of NFOH release decreases after complexation and thermodynamic parameters from the solubility isotherm studies revealed that a stable complex is formed (DGo= 1.7 kJ/mol). This study focuses on the physico-chemical characterization of a drug-delivery formulation that comes out as a potentially new therapeutic option for Chagas disease treatment.

Mistura com excesso enantiomérico de 50% (S75-R25) de bupivacaína complexada com ciclodextrinas e anestesia por via subaracnóidea em ratos

JUSTIFICATIVA Y OBJETIVOS: Con la finalidad de prolongar la duracion de la accion y reducir la toxicidad sistemica, se han desarrollado formulaciones de AL con complejo de ciclodextrinas (CD). Ese estudio realizo la caracterizacion fisico-quimica y evaluo en ratones, los efectos de los complejos de inclusion de bupivacaina racemica (S50-R50) y de la mezcla con exceso enantiomerico de 50% (S75-R25) de bupivacaina con hidroxipropil-betaciclodextrina (HP-b-CD), comparandolos con las soluciones actualmente utilizadas en la clinica. METODO: Los complejos de inclusion de S75-R25 en HP-b-CD (razon molar 1:1) fueron caracterizados por estudios de solubilidad de fases variando las concentraciones de HP-b-CD y la temperatura. Fueron determinadas las constantes de afinidad (K) por la HP-b-CD y los parametros termodinamicos para los complejos. Los bloqueos motor y sensitivo fueron evaluados en ratones, a traves de la administracion subaracnoidea de las formulaciones en la concentracion clinica de 0,5%. RESULTADOS: La formacion de complejos de inclusion se observo a traves del aumento de la solubilidad acuosa del AL bajo diferentes temperaturas y concentraciones de HP-b-CD. Las pruebas in vivo mostraron que S50-R50HP-b-CD y S75-R25HP-b-CD redujeron la latencia (p < 0,001) sin alterar el tiempo de recuperacion del bloqueo motor, tiempo para efecto maximo y efecto total de los farmacos. Ademas, ambas formulaciones aumentaron la intensidad (1,5 veces, p < 0,001) y prolongaron la duracion de la analgesia, con relacion a los farmacos libres. CONCLUSIONES: Los complejos, S50-R50HP-b-CD y S75-R25HP-b-CD, potenciaron el bloqueo nervioso diferencial, pudiendo ser utilizados para reducir la frecuencia de administraciones o la dosis de AL para induccion de un mismo efecto. La formulacion conteniendo la mezcla con exceso enantiomerico de 50% (S75-R25) de bupivacaina fue interesante en el desarrollo de formulaciones seguras y utiles para el tratamiento del dolor agudo en el periodo postoperatorio.BACKGROUND AND OBJECTIVES In order to prolong the action and reduce systemic toxicity, formulations of local anesthetic (LA) complexed with cyclodextrins (CD) have been developed. This study determined the physical-chemical characterization and evaluated the effects of inclusion complexes of racemic bupivacaine (S50-R50) and 50% enantiomeric excess (S75-R25) bupivacaine with hydroxypropil-beta-cyclodextrin (HP-beta-CD) in rats, and comparing them with the solutions currently used in the clinical practice. METHODS Inclusion complexation of S75-R25 with HP-beta-CD (equimolar ratio 1:1) was characterized by phase-solubility studies varying the concentrations of HP-beta-CD and the temperature. Affinity constants (K) for HP-beta-CD and the thermodynamic parameters for complexation were determined. Motor and sensitive anesthesias were evaluated through the subarachnoid administration of the formulations in the concentration of 0.5%. RESULTS Inclusion complexation was observed through the increase in aqueous solubility of LA in different temperatures and concentrations of HP-beta-CD. The in vivo tests demonstrated that S50-R50HP-beta-CD and S75-R25HP-beta-CD reduced latency (p < 0.001) without changing the recovery time of the motor block, time for maximal effect, and total effect of the drugs. Besides, both formulations increased the intensity (1.5 times, p < 0.001) and prolonged the duration of analgesia compared to the free drugs. CONCLUSIONS The complexes S50-R50HP-beta-CD and S75-R25HP-beta-CD potentiated the differential nervous block, and can be used to reduce the frequency of administration or the dose of the LA to induce the same effect. The formulation containing enantiomeric excess (S75-R25) bupivacaine showed to be interesting in the development of safer formulations, and useful for the treatment of acute pain in the postoperative period.

Complexation of 50% enantiomeric excess (S75-R25) bupivacaine with cyclodextrins and spinal block anesthesia in rats

JUSTIFICATIVA Y OBJETIVOS: Con la finalidad de prolongar la duracion de la accion y reducir la toxicidad sistemica, se han desarrollado formulaciones de AL con complejo de ciclodextrinas (CD). Ese estudio realizo la caracterizacion fisico-quimica y evaluo en ratones, los efectos de los complejos de inclusion de bupivacaina racemica (S50-R50) y de la mezcla con exceso enantiomerico de 50% (S75-R25) de bupivacaina con hidroxipropil-betaciclodextrina (HP-b-CD), comparandolos con las soluciones actualmente utilizadas en la clinica. METODO: Los complejos de inclusion de S75-R25 en HP-b-CD (razon molar 1:1) fueron caracterizados por estudios de solubilidad de fases variando las concentraciones de HP-b-CD y la temperatura. Fueron determinadas las constantes de afinidad (K) por la HP-b-CD y los parametros termodinamicos para los complejos. Los bloqueos motor y sensitivo fueron evaluados en ratones, a traves de la administracion subaracnoidea de las formulaciones en la concentracion clinica de 0,5%. RESULTADOS: La formacion de complejos de inclusion se observo a traves del aumento de la solubilidad acuosa del AL bajo diferentes temperaturas y concentraciones de HP-b-CD. Las pruebas in vivo mostraron que S50-R50HP-b-CD y S75-R25HP-b-CD redujeron la latencia (p < 0,001) sin alterar el tiempo de recuperacion del bloqueo motor, tiempo para efecto maximo y efecto total de los farmacos. Ademas, ambas formulaciones aumentaron la intensidad (1,5 veces, p < 0,001) y prolongaron la duracion de la analgesia, con relacion a los farmacos libres. CONCLUSIONES: Los complejos, S50-R50HP-b-CD y S75-R25HP-b-CD, potenciaron el bloqueo nervioso diferencial, pudiendo ser utilizados para reducir la frecuencia de administraciones o la dosis de AL para induccion de un mismo efecto. La formulacion conteniendo la mezcla con exceso enantiomerico de 50% (S75-R25) de bupivacaina fue interesante en el desarrollo de formulaciones seguras y utiles para el tratamiento del dolor agudo en el periodo postoperatorio.BACKGROUND AND OBJECTIVES In order to prolong the action and reduce systemic toxicity, formulations of local anesthetic (LA) complexed with cyclodextrins (CD) have been developed. This study determined the physical-chemical characterization and evaluated the effects of inclusion complexes of racemic bupivacaine (S50-R50) and 50% enantiomeric excess (S75-R25) bupivacaine with hydroxypropil-beta-cyclodextrin (HP-beta-CD) in rats, and comparing them with the solutions currently used in the clinical practice. METHODS Inclusion complexation of S75-R25 with HP-beta-CD (equimolar ratio 1:1) was characterized by phase-solubility studies varying the concentrations of HP-beta-CD and the temperature. Affinity constants (K) for HP-beta-CD and the thermodynamic parameters for complexation were determined. Motor and sensitive anesthesias were evaluated through the subarachnoid administration of the formulations in the concentration of 0.5%. RESULTS Inclusion complexation was observed through the increase in aqueous solubility of LA in different temperatures and concentrations of HP-beta-CD. The in vivo tests demonstrated that S50-R50HP-beta-CD and S75-R25HP-beta-CD reduced latency (p < 0.001) without changing the recovery time of the motor block, time for maximal effect, and total effect of the drugs. Besides, both formulations increased the intensity (1.5 times, p < 0.001) and prolonged the duration of analgesia compared to the free drugs. CONCLUSIONS The complexes S50-R50HP-beta-CD and S75-R25HP-beta-CD potentiated the differential nervous block, and can be used to reduce the frequency of administration or the dose of the LA to induce the same effect. The formulation containing enantiomeric excess (S75-R25) bupivacaine showed to be interesting in the development of safer formulations, and useful for the treatment of acute pain in the postoperative period.

Sufentanil–2‐Hydroxypropyl‐β‐Cyclodextrin Inclusion Complex for pain Treatment: Physicochemical, Cytotoxicity, and Pharmacological Evaluation

Sufentanil (SUF) is a synthetic analgesic opioid widely used for the management of acute and chronic pain. This drug was complexed with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and the physicochemical characterization, in vitro/ex vivo toxicity assays, and pharmacological evaluation were performed. Differential scanning calorimetry, Fourier transform infrared spectroscopy (FTIR) analysis, and X-ray powder diffraction showed the formation and the morphology of the complex. Nuclear magnetic resonance afforded data regarding inclusion complex stoichiometry (1:1) with an association binding constant (K(a)) value of 515.2 ± 1.2 M(-1) between SUF and HP-β-CD. Complexation with HP-β-CD protected SUF from light exposure and increased its photostability. Release kinetics revealed a decrease in SUF release rate (K(rel) = 7.05 ± 0.52 and 5.61 ± 0.39 min(-1/2) for SUF-HP-β-CD and SUF, respectively) and reduced hemolytic or myotoxic effects after complexation. Time course of tail-flick test showed that the duration of analgesia induced by SUF (150.0 ± 34.6 min) was significantly increased (p < 0.001) after complexation with HP-β-CD (355.7 ± 47.2 min) when injected at the same dose (1 μg kg(-1)), prolonging the duration of analgesia after intramuscular administration and representing an alternative on the development of effective and safe drug-delivery system for opioid analgesics.

Validação de metodologia analítica por cromatografia líquida de alta eficiência para quantificação de bupivacaína (S75-R25) em nanoesferas de poli(lactídeo-co-glicolídeo)

Bupivacaine (S75-R25, NovaBupi®) is an amide type local anesthetic widely used. The present work consists of the development and validation of analytical methodology for evaluation of NovaBupi® content in the poly-lactide-co-glycolide nanospheres (PLGA-NS) by high performance liquid chromatography. The separation was made using the reversed-phase column LC-18, acetonitrile/phosphate buffer 85:15 v/v as mobile phase and detection at 220 nm. The results obtained show that the analytical methodology is accurate, reproducible, robust and linear over the concentration range 10-220.0 g/mL of NovaBupi®. The method was applied to determine the encapsulation efficiency and evaluate the release profile of NovaBupi®, showing good results.

Mezcla con exceso enantiomérico de 50% (S75-R25) de bupivacaina con complejo de ciclodextrinas y anestesia por vía subaracnoidea en ratones

JUSTIFICATIVA Y OBJETIVOS: Con la finalidad de prolongar la duracion de la accion y reducir la toxicidad sistemica, se han desarrollado formulaciones de AL con complejo de ciclodextrinas (CD). Ese estudio realizo la caracterizacion fisico-quimica y evaluo en ratones, los efectos de los complejos de inclusion de bupivacaina racemica (S50-R50) y de la mezcla con exceso enantiomerico de 50% (S75-R25) de bupivacaina con hidroxipropil-betaciclodextrina (HP-b-CD), comparandolos con las soluciones actualmente utilizadas en la clinica. METODO: Los complejos de inclusion de S75-R25 en HP-b-CD (razon molar 1:1) fueron caracterizados por estudios de solubilidad de fases variando las concentraciones de HP-b-CD y la temperatura. Fueron determinadas las constantes de afinidad (K) por la HP-b-CD y los parametros termodinamicos para los complejos. Los bloqueos motor y sensitivo fueron evaluados en ratones, a traves de la administracion subaracnoidea de las formulaciones en la concentracion clinica de 0,5%. RESULTADOS: La formacion de complejos de inclusion se observo a traves del aumento de la solubilidad acuosa del AL bajo diferentes temperaturas y concentraciones de HP-b-CD. Las pruebas in vivo mostraron que S50-R50HP-b-CD y S75-R25HP-b-CD redujeron la latencia (p < 0,001) sin alterar el tiempo de recuperacion del bloqueo motor, tiempo para efecto maximo y efecto total de los farmacos. Ademas, ambas formulaciones aumentaron la intensidad (1,5 veces, p < 0,001) y prolongaron la duracion de la analgesia, con relacion a los farmacos libres. CONCLUSIONES: Los complejos, S50-R50HP-b-CD y S75-R25HP-b-CD, potenciaron el bloqueo nervioso diferencial, pudiendo ser utilizados para reducir la frecuencia de administraciones o la dosis de AL para induccion de un mismo efecto. La formulacion conteniendo la mezcla con exceso enantiomerico de 50% (S75-R25) de bupivacaina fue interesante en el desarrollo de formulaciones seguras y utiles para el tratamiento del dolor agudo en el periodo postoperatorio.BACKGROUND AND OBJECTIVES In order to prolong the action and reduce systemic toxicity, formulations of local anesthetic (LA) complexed with cyclodextrins (CD) have been developed. This study determined the physical-chemical characterization and evaluated the effects of inclusion complexes of racemic bupivacaine (S50-R50) and 50% enantiomeric excess (S75-R25) bupivacaine with hydroxypropil-beta-cyclodextrin (HP-beta-CD) in rats, and comparing them with the solutions currently used in the clinical practice. METHODS Inclusion complexation of S75-R25 with HP-beta-CD (equimolar ratio 1:1) was characterized by phase-solubility studies varying the concentrations of HP-beta-CD and the temperature. Affinity constants (K) for HP-beta-CD and the thermodynamic parameters for complexation were determined. Motor and sensitive anesthesias were evaluated through the subarachnoid administration of the formulations in the concentration of 0.5%. RESULTS Inclusion complexation was observed through the increase in aqueous solubility of LA in different temperatures and concentrations of HP-beta-CD. The in vivo tests demonstrated that S50-R50HP-beta-CD and S75-R25HP-beta-CD reduced latency (p < 0.001) without changing the recovery time of the motor block, time for maximal effect, and total effect of the drugs. Besides, both formulations increased the intensity (1.5 times, p < 0.001) and prolonged the duration of analgesia compared to the free drugs. CONCLUSIONS The complexes S50-R50HP-beta-CD and S75-R25HP-beta-CD potentiated the differential nervous block, and can be used to reduce the frequency of administration or the dose of the LA to induce the same effect. The formulation containing enantiomeric excess (S75-R25) bupivacaine showed to be interesting in the development of safer formulations, and useful for the treatment of acute pain in the postoperative period.