Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 291
Filtrar
1.
J Pharm Pharm Sci ; 24: 563-570, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34826378

RESUMO

PURPOSE: The aim of this study was to evaluate the intraluminal behavior of various transporter substrates in different regions of the gastrointestinal (GI) tract. METHODS: Drug solutions containing non-absorbable FITC-dextran 4000 (FD-4), were orally administered to rats. Residual water was sampled from the GI regions to measure the luminal drug concentration. RESULTS: Cephalexin (CEX), a substrate of the proton-coupled oligopeptide transporter, was absorbed rapidly, and no drug was detected in the lower small intestine. Saquinavir (SQV) was primarily absorbed in the upper region. However, unlike CEX, SQV was detected even in the lower segment probably due to the efflux of SQV via P-glycoprotein (P-gp). The concentration of methotrexate (MTX) showed a similar pattern to that of non-absorbable FD-4. The low absorption of MTX was probably due to efflux via several efflux transporters, and the limited expression of proton-coupled folate transporter, an absorptive transporter for MTX, in the upper region. CONCLUSION: This study revealed that the luminal concentration pattern of each drug differed considerably depending on the site because of the different absorption properties and luminal volumes. Although further investigation using a specific transporter inhibitor or transporter-knockout animals are necessary to clarify the actual contribution of each transporter to the drug absorption, this information will be valuable in evaluating transporter-mediated drug absorption in in vitro transport studies for ensuring optimal drug concentrations.


Assuntos
Proteínas de Transporte/metabolismo , Absorção Intestinal/fisiologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico/fisiologia , Cefalexina/farmacocinética , Dextranos/farmacocinética , Fluoresceína-5-Isotiocianato , Masculino , Metotrexato/farmacocinética , Ratos , Ratos Sprague-Dawley , Saquinavir/farmacocinética
2.
Mol Pharm ; 18(4): 1768-1778, 2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33729806

RESUMO

The aim of this study was to evaluate the effect of lipid digestion on the permeability and absorption of orally administered saquinavir (SQV), a biopharmaceutics classification system (BCS) class IV drug, in different lipid-based formulations. Three LBFs were prepared: a mixed short- and medium-chain lipid-based formulation (SMCF), a medium-chain lipid-based formulation (MCF), and a long-chain lipid-based formulation (LCF). SQV was loaded into these LBFs at 26.7 mg/g. To evaluate the pharmacokinetics of SQV in vivo, drug-loaded formulations were predispersed in purified water at 3% w/w and orally administered to rats. A low dose (0.8 mg/rat) was employed to limit confounding effects on drug solubilization, and consistent with this design, presolubilization of SQV in the LBFs did not increase in vivo exposure compared to a control suspension formulation. The areas under the plasma concentration-time curve were, however, significantly lower after administration of SQV as MCF and LCF compared to SMCF. To evaluate the key mechanisms underpinning absorption, each LBF containing SQV was digested, and the flux of SQV from the digests across a dialysis membrane was evaluated in in vitro permeation experiments. This study revealed that the absorption profiles were driven by the free concentration of SQV and that this varied due to differences in SQV solubilization in the digestion products generated by LBF digestion. The apparent first-order permeation rate constants of SQV (kapp,total) were estimated by dividing the flux of SQV in the dialysis membrane experiments by the concentration of total SQV on the donor side. kapp,total values strongly correlated with in vivo AUC. The data provide one of the first studies of the effect of digestion products on the free concentration of a drug in the GI fluid and oral absorption. This simple permeation model may be a useful tool for the evaluation of the impact of lipid digestion on apparent drug permeability from lipid-based formulations. These effects should be assessed alongside, and in addition to, the more well-known effects of lipids on enhancing intestinal solubilization of poorly water-soluble drugs.


Assuntos
Excipientes/química , Lipídeos/química , Saquinavir/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Líquidos Corporais/química , Química Farmacêutica , Absorção Gastrointestinal , Absorção Intestinal , Masculino , Modelos Animais , Permeabilidade , Ratos , Saquinavir/administração & dosagem , Saquinavir/química , Solubilidade
3.
Int J Nanomedicine ; 14: 8589-8601, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31802871

RESUMO

BACKGROUND: Saquinavir mesylate (SQR) tablets are widely used against human immunodeficiency virus. SQR has bioavailability issues owing to its poor aqueous solubility, extensive first-pass metabolism, and even low gastrointestinal tract permeability and absorption. OBJECTIVE: An in-depth optimization process was carried out using factorial design to improve the permeation parameters and thereby the bioavailability of SQR by formulating self-nanoemulsifying drug delivery system (SNEDDS)-loaded polymeric transdermal films. METHODS: The solubility of SQR in different nanoemulsion components was examined. Various combinations of selected components were prepared in an extreme vertices mixture design to identify the useful nanoemulsion zone and to develop SNEDDS with minimum globule size. The optimized SQR-SNEDDS was loaded in polyvinyl alcohol (PVA)-based transdermal films. The Box-Behnken design was used to optimize and evaluate SQR permeability. The prepared films were characterized for thickness, tensile strength, elongation, folding endurance, and accelerated stability studies. The optimized film was examined for ex vivo skin permeation and in vivo pharmacokinetic parameters. RESULTS: The optimized SQR-SNEDDS was prepared in proportions of 0.1, 0.55, and 0.35 of clove oil, labrasol, and Transcutol, respectively. The implemented Box-Behnken design indicated the optimized film consisted of 1.0% PVA, 0.25% propylene glycol, and clove oil as the oil phase. The tensile strength, thickness, percent elongation, and folding endurance of the optimized SQR-SNEDDS film were 0.93 ± 0.013 kg/cm2, 0.22 ± 0.006 mm, 43.1 ± 0.022%, and >200 times, respectively. A higher Cmax and double the AUC were observed for SQR-SNEDDS-loaded film in comparison to pure SQR-loaded films. CONCLUSION: Implementation of a two-step design to optimize and control experimental factors in the preparation of SQR-SNEDDS and its loading onto PVA-based transdermal films was achieved. The films indicated improved ex vivo skin permeation, enhanced bioavailability, and overcame the limitations of the oral dosage form.


Assuntos
Emulsões/química , Nanopartículas/química , Saquinavir/farmacologia , Administração Cutânea , Administração Oral , Animais , Sistemas de Liberação de Medicamentos , Humanos , Masculino , Permeabilidade , Transição de Fase , Ratos Wistar , Saquinavir/sangue , Saquinavir/farmacocinética , Pele/efeitos dos fármacos , Solubilidade , Tensoativos/química , Comprimidos
4.
Arch Virol ; 164(4): 949-960, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30680529

RESUMO

HIV is one of the most lethal viral diseases in the human population. Patients often suffer from drug resistance, which hampers HIV therapy. Eleven different structural analogues of saquinavir (SQV), designed using ChemSketch™ and named S1 through S11, were compared with SQV with respect to their pharmacodynamic and pharmacokinetic properties. Pharmacokinetic predictions were carried out using AutoDock, and molecular docking between macromolecule HIV protease (PDB ID: 3IXO) and analogues S1 - S11 as ligands was performed. Analogues S1, S3, S4, S9 and S11 had lower binding scores when compared with saquinavir, whereas that of analogue S5 was similar. Pharmacokinetic predictions made using ACDilab2, including the Lipinski profile, general physical features, absorption, distribution, metabolism and excretion parameters, and toxicity values, for the eleven analogues and SQV suggested that S1 and S5 are pharmacodynamically and pharmacokinetically robust molecules that could be developed and established as lead molecules after in vitro and in vivo studies.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacocinética , HIV-1/enzimologia , Saquinavir/análogos & derivados , Saquinavir/farmacocinética , Animais , Infecções por HIV/virologia , Protease de HIV/química , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Saquinavir/administração & dosagem
5.
J Control Release ; 269: 159-170, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29129657

RESUMO

Pure drug nanoparticles (NPs) represent a promising formulation for improved drug solubility and controlled dissolution velocity. However, limited absorption by the intestinal epithelium remains challenge to their clinical application, and little is known about how these NPs within the cells are transported. To improve cellular uptake and transport of pure nanodrug in cells, here, a lipid covered saquinavir (SQV) pure drug NP (Lipo@nanodrug) was designed by modifying a pure SQV NP (nanodrug) with a phospholipid bilayer. We studied their endocytosis, intracellular trafficking mechanism using Caco-2 cell model. Uptake of Lipo@nanodrug by Caco-2 cells was 1.91-fold greater than that of pure nanodrug via processes involving cell lipid raft. The transcellular transport of Lipo@nanodrug across Caco-2 monolayers was 3.75-fold and 1.92-fold higher than that of coarse crystals and pure nanodrug, respectively. Within cells, Lipo@nanodrug was mainly localized in the endoplasmic reticulum and Golgi apparatus, leading to transcytosis of Lipo@nanodrug across intestinal epithelial cells, whereas pure nanodrug tended to be retained and to dissolve in cell and removed by P-gp-mediated efflux. In rats, the oral bioavailability of the model drug SQV after Lipo@nanodrug administration was 4.29-fold and 1.77-fold greater than after coarse crystal and pure nanodrug administration, respectively. In conclusion, addition of a phospholipid bilayer to pure drug NP increased their cellular uptake and altered their intracellular processing, helping to improve drug transport across intestinal epithelium. To our knowledge, this is the first presentation of the novel phospholipid bilayer covered SQV pure drug NP design, and a mechanistic study on intracellular trafficking in in vitro cell models has been described. The findings provide a new platform for oral delivery of poorly water-soluble drugs.


Assuntos
Inibidores da Protease de HIV/administração & dosagem , Mucosa Intestinal/metabolismo , Nanopartículas/administração & dosagem , Fosfolipídeos/administração & dosagem , Saquinavir/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Células CACO-2 , Inibidores da Protease de HIV/farmacocinética , Humanos , Masculino , Fosfolipídeos/farmacocinética , Ratos Sprague-Dawley , Saquinavir/farmacocinética
6.
Eur J Drug Metab Pharmacokinet ; 42(1): 135-141, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26846485

RESUMO

BACKGROUND AND OBJECTIVES: Although lipid-based drug delivery systems have gained much importance in recent years due to their ability to improve the solubility and bioavailability of poorly soluble drugs, compartmental pharmacokinetic analyses have not been extensively explored. The oral pharmacokinetics of commercial liquid formulation and a developed semisolid system containing saquinavir mesylate (SQVM) were compared in Beagle dogs. A compartmental analysis after intravenous bolus administration of this drug (1 mg/kg) was also performed. METHOD: Pharmacokinetic profiles were analyzed using both non-compartmental and compartmental approaches. Plasma concentration of the drug was determined by high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS). RESULTS: The disposition curve of SQVM given intravenously was better described by a three-compartment model. In contrast, plasma profiles obtained following the oral administration were fitted to a two-compartment model with lag time due to the fact that the distribution phase was masked by the absorption phase in these formulations. CONCLUSION: The proposed semisolid lipid system was found to be a promising formulation for commercial purposes given the similarity of SQVM absorption rate to that from the commercial liquid formulation.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Saquinavir/administração & dosagem , Saquinavir/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Cães , Emulsões , Lipídeos/química , Lipídeos/farmacocinética , Masculino , Modelos Biológicos , Saquinavir/sangue , Saquinavir/química
7.
Drug Des Devel Ther ; 10: 3699-3706, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27895462

RESUMO

BACKGROUND: The intestinal cytochrome P450 3A (CYP 3A) and P-glycoprotein (P-gp) present a barrier to the oral absorption of saquinavir (SQV). Resveratrol (RESV) has been indicated to have modulatory effects on P-gp and CYP 3A. Therefore, this study was to investigate the effects of RESV on P-gp and CYP 3A activities in vitro and in vivo on oral SQV pharmacokinetics in rats. METHODS: In vitro, intestinal microsomes were used to evaluate RESV effect on CYP 3A-mediated metabolism of SQV; MDR1-expressing Madin-Darby canine kidney (MDCKII-MDR1) cells were employed to assess the impact of RESV on P-gp-mediated efflux of SQV. In vivo effects were studied using 10 rats randomly assigned to receive oral SQV (30 mg/kg) with or without RESV (20 mg/kg). Serial blood samples were obtained over the following 24 h. Concentrations of SQV in samples were ascertained using high-performance liquid chromatography-tandem mass spectrometry analysis. RESULTS: RESV (1-100 µM) enhanced residual SQV (% of control) in a dose-dependent manner after incubation with intestinal microsomes. RESV (1-100 µM) reduced the accumulation of SQV in MDCKII-MDR1 cells in a concentration-dependent manner. A double peaking phenomenon was observed in the plasma SQV profiles in rats. The first peak of plasma SQV concentration was increased, but the second peak was reduced by coadministration with RESV. The mean AUC0-∞ of SQV was slightly decreased, with no statistical significance probably due to the high individual variation. CONCLUSION: RESV can alter the plasma SQV concentration profiles, shorten the Tmax of SQV. RESV might also cause a slight decrease tendency in the SQV bioavailability in rats.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores Enzimáticos/farmacologia , Saquinavir/metabolismo , Saquinavir/farmacocinética , Estilbenos/farmacologia , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cães , Interações Medicamentosas , Inibidores Enzimáticos/farmacocinética , Absorção Intestinal , Masculino , Microssomos , Ratos , Ratos Sprague-Dawley , Resveratrol , Saquinavir/administração & dosagem , Estilbenos/farmacocinética , Espectrometria de Massas em Tandem
8.
Drug Res (Stuttg) ; 66(9): 484-488, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27409329

RESUMO

The study was aim to assess the impact of biochanin A on the oral bioavailability and pharmacokinetics (PK) of saquinavir (SQV), a substrate of P-glycoprotein (P-gp), in rats. 10 male rats were randomized into 2 groups of equal size, and administered orally 30 mg/kg SQV with or without 20 mg/kg biochanin A. The PK of SQV was assessed using non-compartmental analysis. Results revealed that the area under the plasma concentration-time curve of SQV from time zero to time infinity (AUC0-∞) was reduced by 51.39% by biochanin A (P=0.038); while the apparent systemic clearance (CL/F) was increased by 87.62% (P=0.028). Double peak phenomenon was observed in the plasma SQV profiles. Biochanin A increased the first peak, yet decreased the second peak of plasma SQV levels. Our study demonstrates that biochanin A can significantly reduce SQV oral bioavailability and alter SQV PK profiles in rats. Findings in this study suggest a precaution in the clinic when SQV is administered with dietary/herbal supplements that contain biochanin A.


Assuntos
Disponibilidade Biológica , Genisteína/farmacologia , Saquinavir/farmacocinética , Administração Oral , Animais , Interações Medicamentosas , Masculino , Ratos , Saquinavir/administração & dosagem , Saquinavir/sangue
10.
Acta Pharmacol Sin ; 36(9): 1151-60, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26256404

RESUMO

AIM: Saquinavir (SQV) is the first protease inhibitor for the treatment of HIV infection, but with poor solubility. The aim of this study was to prepare a colloidal nanocrystal suspension for improving the oral absorption of SQV. METHODS: SQV nanocrystals were prepared using anti-solvent precipitation-high pressure homogenization method. The nanocrystals were characterized by a Zetasizer and transmission electron microscopy (TEM). Their dissolution, cellular uptake and transport across the human colorectal adenocarcinoma cell line (Caco-2) monolayer were investigated. Bioimaging of ex vivo intestinal sections of rats was conducted with confocal laser scanning microscopy. Pharmacokinetic analysis was performed in rats administered nanocrystal SQV suspension (50 mg/kg, ig), and the plasma SQV concentrations were measured with HPLC. RESULTS: The SQV nanocrystals were approximately 200 nm in diameter, with a uniform size distribution. The nanocrystals had a rod-like shape under TEM. The dissolution, cellular uptake, and transport across a Caco-2 monolayer of the nanocrystal formulation were significantly improved compared to those of the coarse crystals. The ex vivo intestinal section study revealed that the fluorescently labeled nanocrystals were located in the lamina propria and the epithelium of the duodenum and jejunum. Pharmacokinetic study showed that the maximal plasma concentration (Cmax) was 2.16-fold of that for coarse crystalline SQV suspension, whereas the area under the curve (AUC) of nanocrystal SQV suspension was 1.95-fold of that for coarse crystalline SQV suspension. CONCLUSION: The nanocrystal drug delivery system significantly improves the oral absorption of saquinavir.


Assuntos
Inibidores da Protease de HIV/farmacocinética , Saquinavir/farmacocinética , Administração Oral , Animais , Células CACO-2 , Cristalização/métodos , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/química , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Masculino , Nanopartículas/administração & dosagem , Nanopartículas/química , Ratos , Ratos Sprague-Dawley , Saquinavir/administração & dosagem , Saquinavir/sangue , Saquinavir/química , Solubilidade
11.
Drugs R D ; 15(1): 141-53, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25742730

RESUMO

BACKGROUND: Saquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose lead-in phase may reduce potential saquinavir-/ritonavir-induced QT prolongations. OBJECTIVE: To explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naïve HIV-1-infected patients. METHODS: Twenty-three HIV-1-infected treatment-naïve patients received saquinavir/ritonavir 500/100 mg BID on days 1-7 and 1000/100 mg BID on days 8-14 in combination with two nucleoside reverse transcriptase inhibitors. The primary endpoint was mean maximum change from dense predose baseline in QT values corrected using Fridericia's formula (∆QTcFdense) across study days. Secondary endpoints included maximum change from time-matched baseline in QTcF, antiviral activity, pharmacokinetics, and safety over the 14 days. RESULTS: The mean maximum ∆QTcFdense was 3, 1, 7, 12, and 7 ms on days 3, 4, 7, 10, and 14, respectively. Across all study days, 2/21 patients had a maximum ∆QTcFdense ≥30 ms (on day 10); the highest mean ∆QTcFdense was <10 ms. During week 1, saquinavir exposure was highest on day 3 and lowest on day 7. All patients showed continuous declines in HIV-RNA; none experienced virologic breakthrough/rebound. The modified regimen was generally well tolerated. CONCLUSION: Treatment initiation with the modified saquinavir/ritonavir regimen in treatment-naïve HIV-1-infected patients reduced saquinavir exposure during week 1, potentially mitigating/reducing QT liability while suppressing HIV-RNA during the course of treatment.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Ritonavir/administração & dosagem , Saquinavir/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , HIV-1 , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/epidemiologia , Masculino , RNA Viral/sangue , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Saquinavir/efeitos adversos , Saquinavir/farmacocinética , Resultado do Tratamento , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-26736983

RESUMO

The mechanism of drug-drug interaction between saquinavir, a protease inhibitor used effectively for HIV/AIDS treatment, and itraconazole, an azole antifungal agent, is hypothesized to involve competitive inhibition at CYP3A4 enzyme, an important drug metabolizing enzyme in humans. The resulting interaction between these CYP3A4 substrates can be utilized clinically as a pharmacokinetic booster for prolonging saquinavir dosing regimen and/or decreasing saquinavir dose requirement in HIV/AIDS patients. To quantitatively describe this specific drug-drug interaction, based on the existing data, we aimed to develop a mathematical model incorporated with the competitive inhibition phenomena. PlotDigitizer was used to extract data from literature. Advance Continuous Simulating Language Extreme (ACSLX), a FORTRAN-based computer program, was employed as our developing tool. Our computer model simulations could successfully describe concentration-time course of saquinavir from selected pharmacokinetic studies in HIV-1-positive patients. To extend the model's utility as an aid in saquinavir dosage regimens, the developed model may be applied to other HIV/AIDS patients in genuine clinical settings.


Assuntos
Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Itraconazol/farmacocinética , Modelos Teóricos , Saquinavir/farmacocinética , Disponibilidade Biológica , Relação Dose-Resposta a Droga , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Humanos , Itraconazol/administração & dosagem , Saquinavir/administração & dosagem
13.
Pharm Res ; 32(5): 1817-29, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25428258

RESUMO

PURPOSE: Intestinal lymphatic transport of specific lipophilic drugs offers therapeutic advantages and maximises oral bioavailability. The aims of this study were; to compare intestinal lymphatic transport of a range of drugs and to investigate the influence of cyclosporine A on the mechanism/extent of lymphatic transport. METHODS: Caco2 cells and an anaesthetised mesenteric lymphatic cannulated rat model were used for in vitro and in vivo studies. Lymphatic transport of three lipophilic drugs was directly compared in a long chain fatty acid formulation. In addition, the impact of cyclosporine A on triglyceride turnover was evaluated in vivo and in vitro. RESULTS: The extent of intestinal lymphatic transport in rats was positively correlated with drug solubility in triglyceride and negatively correlated with drug aqueous solubility. Cyclosporine A displayed non-linear lymphatic transport kinetics and reduced intestinal lymph triglyceride. In vitro experiments indicated that the cellular processes affected were intracellular lipid processing and/or lipid secretion. CONCLUSIONS: The linear correlations obtained using a range of lipophilic drugs confirm that the simplified approach of determining aqueous or triglyceride drug solubility is useful in predicting the extent of lymphatic transport. In vitro experiments correlated with in vivo observations, demonstrating the usefulness of the Caco-2 model for mechanistic investigations.


Assuntos
Absorção Intestinal , Mucosa Intestinal/metabolismo , Linfa/metabolismo , Animais , Células CACO-2 , Ciclosporina/química , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/farmacocinética , DDT/química , DDT/farmacocinética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Intestinos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Linfa/efeitos dos fármacos , Ratos , Saquinavir/química , Saquinavir/farmacocinética , Solubilidade , Triglicerídeos/metabolismo
14.
Int J Pharm ; 475(1-2): 191-7, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25178831

RESUMO

Saquinavir mesylate (SM) is a protease inhibitor with activity against human immunodeficiency virus type 1 (HIV-1) and is available in tablet form, which has three major problems. First, the drug undergoes extensive first pass metabolism. Second, the drug has a poor aqueous solubility. And third, it has low GIT permeability and absorption. These constrains lead to decrease oral bioavailability (4% only) and administration of large doses which increase the incidence of occurrence of the side effects. The aim of this research was to utilize nanotechnology to formulate (SM) into a nasal in situ nanosized microemulsion gel (NEG) to provide a solution for the previously mentioned problems. The solubility of (SM) in various oils, surfactants, and cosurfactants was estimated. Pseudo-ternary phase diagrams were developed and various nanosized microemulsion (NE) were prepared, and subjected to characterization, stability study, and droplet size measurements. Gellan gum was used as an in situ gelling agent. The gel strength, critical ionic concentration, gelation characteristics, in vitro release, and ex vivo nasal permeation were determined. The pharmacokinetic study was carried out in rabbits. Stable NEs were successfully developed with a droplet size range of 25-61 nm. A NEG composed of 17.5% Labrafac PG, 33% Labrasol, and 11% Transcutol HP successfully provided the maximum in vitro and ex vivo permeation, and enhanced the bioavailability in the rabbits by 12-fold when compared with the marketed tablets. It can be concluded that the nasal NEG is a promising novel formula for (SM) that has higher nasal tissue permeability and enhanced systemic bioavailability.


Assuntos
Portadores de Fármacos/administração & dosagem , Excipientes/química , Inibidores da Protease de HIV/administração & dosagem , Nanoestruturas/química , Absorção Nasal , Saquinavir/administração & dosagem , Administração Intranasal , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacocinética , Composição de Medicamentos , Estabilidade de Medicamentos , Emulsões , Etilenoglicóis/química , Géis , Glicerídeos/química , Protease de HIV/química , Protease de HIV/metabolismo , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Masculino , Polietilenoglicóis/química , Polissacarídeos Bacterianos/química , Coelhos , Saquinavir/química , Saquinavir/metabolismo , Saquinavir/farmacocinética , Solubilidade , Tensoativos/química
15.
Biomed Chromatogr ; 28(12): 1874-80, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24944096

RESUMO

An ionic liquid-based dispersive liquid-liquid microextraction followed by RP-HPLC determination of the most commonly prescribed protease inhibitor, saquinavir, in rat plasma was developed and validated. The effects of different ionic liquids, dispersive solvents, extractant/disperser ratio and salt concentration on sample recovery and enrichment were studied. Among the ionic liquids investigated, 1-butyl-3-methylimidazolium hexafluorophosphate was found to be most effective for extraction of saquinavir from rat serum. The recovery was found to be 95% at an extractant/disperser ratio of 0.43 using 1-butyl-3-methylimidazolium hexafluorophosphate and methanol as extraction and dispersive solvents. The recovery was further enhanced to 99.5% by addition of 5.0% NaCl. A threefold enhancement in detection and quantification limits was achieved, at 0.01 and 0.03 µg/mL, compared with the conventional protein precipitation method. A linear relationship was observed in the range of 0.035-10.0 µg/mL with a correlation coefficient (r(2) ) of 0.9996. The method was validated and applied to study pharmacokinetics of saquinavir in rat serum.


Assuntos
Cromatografia de Fase Reversa/métodos , Microextração em Fase Líquida/métodos , Saquinavir/sangue , Saquinavir/isolamento & purificação , Animais , Cromatografia Líquida de Alta Pressão/métodos , Imidazóis/química , Líquidos Iônicos/química , Limite de Detecção , Modelos Lineares , Masculino , Metanol/química , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Saquinavir/química , Saquinavir/farmacocinética , Cloreto de Sódio
16.
Drug Dev Ind Pharm ; 40(5): 639-48, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24499179

RESUMO

Saquinavir (SQV), a candidate for buccal drug delivery, is limited by poor solubility. This study identified the effects of high-energy ball milling on the buccal permeability of SQV and compared it to the effects of chemical enhancers, i.e. ethylenediaminetetraacetic acid (EDTA), sodium lauryl sulfate (SLS), polyethylene glycol (PEG) and beta cyclodextrin (ß-cyclodextrin). SQV was ball milled using a high energy planetary mill (1, 3, 15 and 30 h) and permeation studies across porcine buccal mucosa were performed using franz diffusion cells. Drug was quantified by UV spectrophotometry. Both unmilled and milled SQV samples were able to permeate the buccal mucosa. Milled samples of 15 h displayed the greatest flux of 10.40 ± 1.24 µg/cm(2 )h and an enhancement ratio of 2.61. All enhancers were able to increase the buccal permeability of unmilled SQV, with SLS achieving the greatest flux (6.99 ± 0.7 µg/cm(2)) and an enhancement ratio of 1.75. However, all the milled SQV samples displayed greater permeability than SLS, the best chemical enhancer for unmilled SQV. Enhanced permeability by ball milling was attributed to reduction in particle size, formation of solid dispersions and an increase in solubility of milled samples. Microscopical evaluation revealed no significant loss in mucosal cellular integrity treated with either unmilled or milled SQV. Histological studies suggest that SQV uses both the paracellular and transcellular route of transport across the mucosa, with drug treatment having no permanent affects. High-energy ball milling was superior to the chemical enhancers studied for enhancement of SQV buccal permeation.


Assuntos
Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/farmacocinética , Saquinavir/administração & dosagem , Saquinavir/farmacocinética , Administração Bucal , Animais , Química Farmacêutica , Formas de Dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Microscopia Eletrônica de Transmissão , Mucosa Bucal/anatomia & histologia , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/metabolismo , Absorção pela Mucosa Oral , Permeabilidade , Dodecilsulfato de Sódio , Solubilidade , Tensoativos , Sus scrofa
17.
Biotechnol Prog ; 30(1): 198-206, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24167123

RESUMO

Cholesterol-mediated cationic solid lipid nanoparticles (CSLNs) were formulated with esterquat 1 (EQ 1) and stearylamine as positively charged external layers on hydrophobic internal cores of cacao butter. These CSLNs were employed to deliver saquinavir (SQV) to the brain. The permeability of SQV across the blood-brain barrier (BBB) using SQV-loaded CSLNs (SQV-CSLNs) was estimated with an in vitro model of a monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes. The results revealed that the average diameter of SQV-CSLNs diminished when the weight percentage of cholesterol and EQ 1 increased. The morphological images indicated a uniform size of SQV-CSLNs with compact lipid structure. In addition, an increasing weight percentage of cholesterol and EQ 1 enhanced the zeta potential of SQV-CSLNs. The fluorescent staining demonstrated that HBMECs could internalize SQV-CSLNs. An increase in the weight percentage of cholesterol and EQ 1 also promoted the uptake of SQV-CSLNs by HBMECs. Moreover, a high content of cholesterol and EQ 1 in SQV-CSLNs increased the BBB permeability of SQV. The cholesterol-mediated SQV-CSLNs can be an efficacious drug delivery system for brain-targeting delivery of antiviral agents.


Assuntos
Barreira Hematoencefálica/metabolismo , Colesterol/química , Modelos Biológicos , Nanopartículas/química , Saquinavir/química , Saquinavir/farmacocinética , Astrócitos/metabolismo , Cátions/química , Permeabilidade da Membrana Celular , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Células Endoteliais/metabolismo , Corantes Fluorescentes , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacocinética , Humanos , Lipídeos/química , Tamanho da Partícula
18.
Pharmazie ; 69(10): 745-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25985563

RESUMO

This study was performed to investigate the impact of pharmaceutical excipients commonly used for lymphatic transport on in vitro drug association with chylomicrons (CM). A CM association study was conducted using saquinavir solubilized in four different pharmaceutical excipients. We observed a linear relationship between saquinavir solubility and drug association, suggesting that the solubility of saquinavir in excipients is a key determinant for successful lymphatic delivery. Broadly, these results suggest that excipients with good solubilization properties may be advantageous for enhancing lymphatic drug delivery.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/química , Quilomícrons/química , Saquinavir/administração & dosagem , Saquinavir/química , Animais , Fármacos Anti-HIV/farmacocinética , Química Farmacêutica , Excipientes , Masculino , Tamanho da Partícula , Ratos , Ratos Wistar , Saquinavir/farmacocinética , Solubilidade
19.
Int J Nanomedicine ; 8: 2847-58, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23966779

RESUMO

The goal of this study was to develop and characterize an intravaginal nanomedicine for the active targeted delivery of saquinavir (SQV) to CD4(+) immune cells as a potential strategy to prevent or reduce HIV infection. The nanomedicine was formulated into a vaginal gel to provide ease in self-administration and to enhance retention within the vaginal tract. SQV-encapsulated nanoparticles (SQV-NPs) were prepared from poly(lactic-co-glycolic acid) (PLGA) and conjugated to antihuman anti-CD4 antibody. Antibody-conjugated SQV-NPs (Ab-SQV-NPs) had an encapsulation efficiency (EE%) of 74.4% + 3.7% and an antibody conjugation efficiency (ACE%) of 80.95% + 1.10%. Over 50% of total loaded SQV was released from NPs over 3 days. NPs were rapidly taken up by Sup-T1 cells, with more than a twofold increase in the intracellular levels of SQV when delivered by Ab-SQV-NPs in comparison to controls 1 hour post-treatment. No cytotoxicity was observed when vaginal epithelial cells were treated for 24 hours with drug-free Ab-NPs (1,000 µg/mL), 1% HEC placebo gel (200 mg/mL), or 1% HEC gel loaded with drug-free Ab-NPs (5 mg NPs/g gel, 200 mg/mL of gel mixture). Overall, we described an intravaginal nanomedicine that is nontoxic and can specifically deliver SQV into CD4(+) immune cells. This platform may demonstrate potential utility in its application as postexposure prophylaxis for the treatment or reduction of HIV infection, but further studies are required.


Assuntos
Inibidores da Protease de HIV/farmacocinética , Nanocápsulas/química , Saquinavir/farmacocinética , Cremes, Espumas e Géis Vaginais/química , Anticorpos/química , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Celulose/análogos & derivados , Feminino , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/toxicidade , Humanos , Saquinavir/química , Saquinavir/toxicidade , Viscosidade
20.
Eur J Pharm Sci ; 49(5): 800-4, 2013 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-23748001

RESUMO

The present study aimed to evaluate the effect of curcumin-loaded solid dispersion on the pharmacokinetics of saquinavir in rats. Solid dispersion (SD) formulation was prepared with Solutol® HS15 to improve the solubility and bioavailability of curcumin. Subsequently, its inhibition effect on P-gp mediated cellular efflux was examined by using NCI/ADR-RES cells overexpressing P-gp. Compared to the untreated curcumin, SD formulation enhanced the cellular uptake of rhodamine-123, a P-gp substrate by approximately 3 folds in NCI/ADR-RES cells. The oral and intravenous pharmacokinetics of saquinavir were also determined in rats with/without curcumin in the different formulations. Compared to the control given saquinavir alone, curcumin-loaded solid dispersion significantly (p<0.05) increased the oral exposure of saquinavir in rats, while it did not affect the intravenous pharmacokinetics of saquinavir. The AUC and Cmax of oral saquinavir increased by 3.8- and 2.7-folds, respectively in the presence of curcumin-loaded solid dispersion. In contrast, the untreated curcumin did not affect the oral pharmacokinetics of saquinavir. These results suggest that SD formulation of curcumin should be effective to improve the in vivo effectiveness of curcumin as an absorption enhancer, leading to the improved oral exposure of saquinavir.


Assuntos
Curcumina/administração & dosagem , Inibidores da Protease de HIV/farmacocinética , Saquinavir/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Curcumina/química , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/sangue , Humanos , Masculino , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Saquinavir/administração & dosagem , Saquinavir/sangue , Ácidos Esteáricos/química , Suspensões
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...