Polymeric nanoparticle aqueous suspensions have been proposed as drug carriers to improve the eff... more Polymeric nanoparticle aqueous suspensions have been proposed as drug carriers to improve the efficacy of medicines. Considering those nanocarriers, nanocapsules are vesicular structures containing an oil core surrounded by a polymeric wall. Recently, we proposed the supramolecular model for a new kind of nanocapsule prepared with triacylglycerol, sorbitan monostearate (SM), polyester and polysorbate 80. Varying the proportions of the raw
International journal of pharmaceutics, Jan 9, 2008
The encapsulation of lipophilic drugs in polymeric nanoparticles can form simultaneously both pol... more The encapsulation of lipophilic drugs in polymeric nanoparticles can form simultaneously both polymeric nanoparticles and drug nanocrystals. The objective was to detect the presence of nanocrystals in the nanoparticle suspensions using a simple methodology, and to determine if the nanocrystals are formed during preparation or by drug leakage from the particles during storage. Indomethacin was chosen as drug model. Unloaded and drug-loaded (1mg/mL) nanocapsules showed diameters close to 280nm and polydispersity lower than 0.20, remaining constant after 120 days. Comparing indomethacin loaded (3mg/mL) and unloaded formulations, variations in the scattered light depolarization degree indicated the simultaneous presence of nanocrystals and nanocapsules in the suspensions. A relation between the scattered light intensities and the drug precipitation was established. As a function of time, when the decrease in the Rayleigh ratios occurred, the drug contents decreased due to precipitation....
In this work, we aimed to evaluate the influence of the proportions of poly(epsilon-caprolactone)... more In this work, we aimed to evaluate the influence of the proportions of poly(epsilon-caprolactone) (PCL) in the poly(hydroxybutyrate-co-hydroxyvalerate) (PHBHV) blended microparticles on the drug release profiles of drug models and to determine the drug release mechanism. Diclofenac and indomethacin used as drug models showed encapsulation efficiencies close to 85%. The average diameters (122-273microm) and the specific surface areas (26-120m(2)g(-1)) of the microparticles were dependent on the PCL concentration in the blends. Differential scanning calorimetry (DSC) analyses showed that the microparticle preparation process influenced the thermal behavior of PHBHV, as well as the glass transition temperature of PHBHV increased with the presence of indomethacin. The release profiles, described by a biexponential equation, showed sustained phase half-lives varying from 131 to 912min (diclofenac) and from 502 to 6300min (indomethacin) depending on the decrease of the PCL concentration. The product between the diffusion coefficient and the drug solubility in the matrix (DC(s,m)), which was proportional to the PCL concentration, was calculated by fitting the release data to the Baker-Lonsdale equation. The mechanism of release was mainly controlled by the drug diffusion and the drug release profiles were controlled by varying the PCL concentration systematically in the blended PHBHV/PCL microparticles.
The aim of this work was to establish a quantitative correlation between the drug permeability an... more The aim of this work was to establish a quantitative correlation between the drug permeability and the polymer concentration in the nanocapsules. Indomethacin ethyl ester-loaded nanoemulsion and nanocapsules containing poly (epsilon-caprolactone) at ...
Based on the structure of polymeric nanocapsules containing a lipid-dispersed core composed of ca... more Based on the structure of polymeric nanocapsules containing a lipid-dispersed core composed of caprylic/capric trygliceride (CCT) and sorbitan monostearate (SM), we hypothesized that varying the core component concentrations the drug release kinetic could be modulated. Our objective was also to determine the parameters which were responsible for controlling the drug release kinetics. The nanocapsules were prepared by interfacial deposition of poly(epsilon-caprolactone). Interfacial hydrolysis of indomethacin ester (IndOEt) was used to simulate a sink condition of release. Mathematical modeling showed that the IndOEt half-lives increased (198 to 378 and 263 to 508 min) with the increase in the core lipid concentrations, and that the release mechanism was the anomalous transport. By increasing the SM concentration, the diameters were constant (around 250 nm) and the surface areas increased (from 1.06 x 10(4) to 1.51 x 10(4) cm2 x ml(-1)), while by increasing the CCT concentration, the diameters increased (215 to 391 nm) and the surface areas reduced (1.46 x 10(4) to 1.06 x 10(4) cm2 x ml(-1)). The presence of SM increased the viscosity of CCT and the IndOEt apparent permeability decreased from 4.26 x 10(-7) to 2.54 x 10(-7) cm x s(-1), while for CCT series, the apparent permeability was constant around 3.0 x 10(-7) cm x s(-1). A mathematical correlation was established and the IndOEt apparent permeability can be estimated by the SM concentration. In conclusion, varying the CCT and SM concentrations the IndOEt release was controlled by the nanocapsule surface area and by the viscosity of the core, respectively.
The aim of this work was to investigate if the indomethacin ethyl ester (IndOEt) released from li... more The aim of this work was to investigate if the indomethacin ethyl ester (IndOEt) released from lipid-core nanocapsules (NC) is converted into indomethacin (IndOH) in the intestine lumen, intestine wall or after the particles reach the blood stream. NC-IndOEt had monomodal size distribution (242 nm; PDI 0.2) and zeta potential of -11 mV. The everted rat gut sac model showed IndOEt passage of 0.16 micromol m(-2) through the serosal fluid (30 min). From 15 to 120 min, the IndOEt concentrations in the tissue increased from 6.13 to 27.47 micromol m(-2). No IndOH was formed ex vivo. A fluorescent-NC formulation was used to determine the copolymer bioadhesion (0.012 micromol m(-2)). After NC-IndOEt oral administration to rats, IndOEt and IndOH were detected in the gastrointestinal tract (contents and tissues). In the tissues, the IndOEt concentrations decreased from 459 to 5 microg g(-1) after scrapping, demonstrating the NC mucoadhesion. In plasma (peripheric and portal vein), in spleen and liver, exclusively IndOH was detected. In conclusion, after oral dosing of NC-IndOEt, IndOEt is converted into IndOH in the intestinal lumen and wall before reaching the blood stream. The complexity of a living system was not predicted by the ex vivo gut sac model.
Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2011
Polymeric nanoparticle aqueous suspensions have been proposed as drug carriers to improve the eff... more Polymeric nanoparticle aqueous suspensions have been proposed as drug carriers to improve the efficacy of medicines. Considering those nanocarriers, nanocapsules are vesicular structures containing an oil core surrounded by a polymeric wall. Recently, we proposed the supramolecular model for a new kind of nanocapsule prepared with triacylglycerol, sorbitan monostearate (SM), polyester and polysorbate 80. Varying the proportions of the raw
Multimodal combinations of target agents with radiation and chemotherapy may enhance cancer treat... more Multimodal combinations of target agents with radiation and chemotherapy may enhance cancer treatment efficacy; however, despite these treatments, gliomas recur early due to their highly proliferative, infiltrative and invasive behaviors. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intensive interest in recent years since they may provide a sustained, controlled and targeted delivery. In the present study, we investigated the effect of indomethacin-loaded nanocapsules in an experimental glioma model. The rats treated with indomethacin-loaded nanocapsules demonstrated a significant reduction in tumor size and half of these animals presented just cells with characteristics of a residual tumor, as shown by immunostaining for nestin. Pathological analyses showed that the treated gliomas presented a significant reduction in the mitotic index and other histological characteristics that indicate a less invasive/proliferative tumor. An important finding of the present study is that indomethacin carried by polymeric nanocapsules achieved higher intracerebral drug concentrations than those of indomethacin in solution. Furthermore, indomethacin achieved a greater concentration in the hemisphere where the glioma was implanted, compared with the contralateral healthy hemisphere. Indomethacin-loaded nanocapsule treatment did not cause characteristics of toxicity and increased the survival of animals. Thus, our results show that polymeric nanocapsules are able to increase the intratumoral bioavailability of indomethacin and reduce the growth of implanted gliomas. Data suggest that indomethacin-loaded nanocapsules could offer new and potentially highly effective strategies for the treatment of malignant gliomas.
Polymeric nanoparticle aqueous suspensions have been proposed as drug carriers to improve the eff... more Polymeric nanoparticle aqueous suspensions have been proposed as drug carriers to improve the efficacy of medicines. Considering those nanocarriers, nanocapsules are vesicular structures containing an oil core surrounded by a polymeric wall. Recently, we proposed the supramolecular model for a new kind of nanocapsule prepared with triacylglycerol, sorbitan monostearate (SM), polyester and polysorbate 80. Varying the proportions of the raw
International journal of pharmaceutics, Jan 9, 2008
The encapsulation of lipophilic drugs in polymeric nanoparticles can form simultaneously both pol... more The encapsulation of lipophilic drugs in polymeric nanoparticles can form simultaneously both polymeric nanoparticles and drug nanocrystals. The objective was to detect the presence of nanocrystals in the nanoparticle suspensions using a simple methodology, and to determine if the nanocrystals are formed during preparation or by drug leakage from the particles during storage. Indomethacin was chosen as drug model. Unloaded and drug-loaded (1mg/mL) nanocapsules showed diameters close to 280nm and polydispersity lower than 0.20, remaining constant after 120 days. Comparing indomethacin loaded (3mg/mL) and unloaded formulations, variations in the scattered light depolarization degree indicated the simultaneous presence of nanocrystals and nanocapsules in the suspensions. A relation between the scattered light intensities and the drug precipitation was established. As a function of time, when the decrease in the Rayleigh ratios occurred, the drug contents decreased due to precipitation....
In this work, we aimed to evaluate the influence of the proportions of poly(epsilon-caprolactone)... more In this work, we aimed to evaluate the influence of the proportions of poly(epsilon-caprolactone) (PCL) in the poly(hydroxybutyrate-co-hydroxyvalerate) (PHBHV) blended microparticles on the drug release profiles of drug models and to determine the drug release mechanism. Diclofenac and indomethacin used as drug models showed encapsulation efficiencies close to 85%. The average diameters (122-273microm) and the specific surface areas (26-120m(2)g(-1)) of the microparticles were dependent on the PCL concentration in the blends. Differential scanning calorimetry (DSC) analyses showed that the microparticle preparation process influenced the thermal behavior of PHBHV, as well as the glass transition temperature of PHBHV increased with the presence of indomethacin. The release profiles, described by a biexponential equation, showed sustained phase half-lives varying from 131 to 912min (diclofenac) and from 502 to 6300min (indomethacin) depending on the decrease of the PCL concentration. The product between the diffusion coefficient and the drug solubility in the matrix (DC(s,m)), which was proportional to the PCL concentration, was calculated by fitting the release data to the Baker-Lonsdale equation. The mechanism of release was mainly controlled by the drug diffusion and the drug release profiles were controlled by varying the PCL concentration systematically in the blended PHBHV/PCL microparticles.
The aim of this work was to establish a quantitative correlation between the drug permeability an... more The aim of this work was to establish a quantitative correlation between the drug permeability and the polymer concentration in the nanocapsules. Indomethacin ethyl ester-loaded nanoemulsion and nanocapsules containing poly (epsilon-caprolactone) at ...
Based on the structure of polymeric nanocapsules containing a lipid-dispersed core composed of ca... more Based on the structure of polymeric nanocapsules containing a lipid-dispersed core composed of caprylic/capric trygliceride (CCT) and sorbitan monostearate (SM), we hypothesized that varying the core component concentrations the drug release kinetic could be modulated. Our objective was also to determine the parameters which were responsible for controlling the drug release kinetics. The nanocapsules were prepared by interfacial deposition of poly(epsilon-caprolactone). Interfacial hydrolysis of indomethacin ester (IndOEt) was used to simulate a sink condition of release. Mathematical modeling showed that the IndOEt half-lives increased (198 to 378 and 263 to 508 min) with the increase in the core lipid concentrations, and that the release mechanism was the anomalous transport. By increasing the SM concentration, the diameters were constant (around 250 nm) and the surface areas increased (from 1.06 x 10(4) to 1.51 x 10(4) cm2 x ml(-1)), while by increasing the CCT concentration, the diameters increased (215 to 391 nm) and the surface areas reduced (1.46 x 10(4) to 1.06 x 10(4) cm2 x ml(-1)). The presence of SM increased the viscosity of CCT and the IndOEt apparent permeability decreased from 4.26 x 10(-7) to 2.54 x 10(-7) cm x s(-1), while for CCT series, the apparent permeability was constant around 3.0 x 10(-7) cm x s(-1). A mathematical correlation was established and the IndOEt apparent permeability can be estimated by the SM concentration. In conclusion, varying the CCT and SM concentrations the IndOEt release was controlled by the nanocapsule surface area and by the viscosity of the core, respectively.
The aim of this work was to investigate if the indomethacin ethyl ester (IndOEt) released from li... more The aim of this work was to investigate if the indomethacin ethyl ester (IndOEt) released from lipid-core nanocapsules (NC) is converted into indomethacin (IndOH) in the intestine lumen, intestine wall or after the particles reach the blood stream. NC-IndOEt had monomodal size distribution (242 nm; PDI 0.2) and zeta potential of -11 mV. The everted rat gut sac model showed IndOEt passage of 0.16 micromol m(-2) through the serosal fluid (30 min). From 15 to 120 min, the IndOEt concentrations in the tissue increased from 6.13 to 27.47 micromol m(-2). No IndOH was formed ex vivo. A fluorescent-NC formulation was used to determine the copolymer bioadhesion (0.012 micromol m(-2)). After NC-IndOEt oral administration to rats, IndOEt and IndOH were detected in the gastrointestinal tract (contents and tissues). In the tissues, the IndOEt concentrations decreased from 459 to 5 microg g(-1) after scrapping, demonstrating the NC mucoadhesion. In plasma (peripheric and portal vein), in spleen and liver, exclusively IndOH was detected. In conclusion, after oral dosing of NC-IndOEt, IndOEt is converted into IndOH in the intestinal lumen and wall before reaching the blood stream. The complexity of a living system was not predicted by the ex vivo gut sac model.
Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2011
Polymeric nanoparticle aqueous suspensions have been proposed as drug carriers to improve the eff... more Polymeric nanoparticle aqueous suspensions have been proposed as drug carriers to improve the efficacy of medicines. Considering those nanocarriers, nanocapsules are vesicular structures containing an oil core surrounded by a polymeric wall. Recently, we proposed the supramolecular model for a new kind of nanocapsule prepared with triacylglycerol, sorbitan monostearate (SM), polyester and polysorbate 80. Varying the proportions of the raw
Multimodal combinations of target agents with radiation and chemotherapy may enhance cancer treat... more Multimodal combinations of target agents with radiation and chemotherapy may enhance cancer treatment efficacy; however, despite these treatments, gliomas recur early due to their highly proliferative, infiltrative and invasive behaviors. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intensive interest in recent years since they may provide a sustained, controlled and targeted delivery. In the present study, we investigated the effect of indomethacin-loaded nanocapsules in an experimental glioma model. The rats treated with indomethacin-loaded nanocapsules demonstrated a significant reduction in tumor size and half of these animals presented just cells with characteristics of a residual tumor, as shown by immunostaining for nestin. Pathological analyses showed that the treated gliomas presented a significant reduction in the mitotic index and other histological characteristics that indicate a less invasive/proliferative tumor. An important finding of the present study is that indomethacin carried by polymeric nanocapsules achieved higher intracerebral drug concentrations than those of indomethacin in solution. Furthermore, indomethacin achieved a greater concentration in the hemisphere where the glioma was implanted, compared with the contralateral healthy hemisphere. Indomethacin-loaded nanocapsule treatment did not cause characteristics of toxicity and increased the survival of animals. Thus, our results show that polymeric nanocapsules are able to increase the intratumoral bioavailability of indomethacin and reduce the growth of implanted gliomas. Data suggest that indomethacin-loaded nanocapsules could offer new and potentially highly effective strategies for the treatment of malignant gliomas.
Uploads
Papers by Eliézer Jäger