RESUMEN

About 90% of active pharmaceutical ingredients (APIs) in the oral drug delivery system pipeline have poor aqueous solubility and low bioavailability. To address this problem, amorphous solid dispersions (ASDs) embed hydrophobic APIs within polymer excipients to prevent drug crystallization, improve solubility, and increase bioavailability. There are a limited number of commercial polymer excipients, and the structure-function relationships which lead to successful ASD formulations are not well-documented. There are, however, certain solid-state ASD characteristics that inform ASD performance. One characteristic shared by successful ASDs is a high glass transition temperature (Tg), which correlates with higher shelf stability and decreased drug crystallization. We aim to identify how polymer features such as side chain geometry, backbone methylation, and hydrophilic-lipophilic balance impact Tg to design copolymers capable of forming high-Tg ASDs. We tested a library of 50 ASD formulations (18 previously studied and 32 newly synthesized) of the model drug probucol with copolymers synthesized through automated photoinduced electron/energy transfer-reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization. A machine learning (ML) algorithm was trained on the Tg data to identify the major factors influencing Tg, including backbone methylation and nonlinear side chain geometry. In both polymer alone and probucol-loaded ASDs, a Random Forest Regressor captured structure-function trends in the data set and accurately predicted Tg with an average R2 > 0.83 across a 10-fold cross validation. This ML model will be used to predict novel copolymers to design ASDs with high Tg, a crucial factor in predicting ASD success.

Asunto(s)

Excipientes , Polímeros , Excipientes/química , Polímeros/química , Solubilidad , Interacciones Hidrofóbicas e Hidrofílicas , Cristalización , Diseño de Fármacos , Probucol/química , Temperatura de Transición

RESUMEN

Oxidative stress is pivotal in retinal disease progression, causing dysfunction in various retinal components. An effective antioxidant, such as probucol (PB), is vital to counteract oxidative stress and emerges as a potential candidate for treating retinal degeneration. However, the challenges associated with delivering lipophilic drugs such as PB to the posterior segment of the eye, specifically targeting photoreceptor cells, necessitate innovative solutions. This study uses formulation-based spray dry encapsulation technology to develop polymer-based PB-lithocholic acid (LCA) nanoparticles and assesses their efficacy in the 661W photoreceptor-like cell line. Incorporating LCA enhances nanoparticles' biological efficacy without compromising PB stability. In vitro studies demonstrate that PB-LCA nanoparticles prevent reactive oxygen species (ROS)-induced oxidative stress by improving cellular viability through the nuclear erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. These findings propose PB-LCA nanoparticles as a promising therapeutic strategy for oxidative stress-induced retinopathies.

Asunto(s)

Antioxidantes , Ácido Litocólico , Nanopartículas , Estrés Oxidativo , Polímeros , Probucol , Especies Reactivas de Oxígeno , Probucol/farmacología , Probucol/administración & dosificación , Probucol/química , Estrés Oxidativo/efectos de los fármacos , Nanopartículas/química , Especies Reactivas de Oxígeno/metabolismo , Ácido Litocólico/química , Ácido Litocólico/farmacología , Animales , Polímeros/química , Línea Celular , Antioxidantes/farmacología , Antioxidantes/química , Factor 2 Relacionado con NF-E2/metabolismo , Supervivencia Celular/efectos de los fármacos , Ratones , Hemo-Oxigenasa 1/metabolismo , Humanos

RESUMEN

The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.

Asunto(s)

Felodipino , Simulación de Dinámica Molecular , Solubilidad , Perros , Animales , Felodipino/administración & dosificación , Felodipino/farmacocinética , Felodipino/química , Probucol/administración & dosificación , Probucol/farmacocinética , Probucol/química , Carvedilol/administración & dosificación , Carvedilol/farmacocinética , Carvedilol/química , Lípidos/química , Líquidos Corporales/química , Líquidos Corporales/metabolismo , Ácidos y Sales Biliares/química , Masculino , Secreciones Intestinales/química

RESUMEN

Targeted drug delivery is an ongoing aspect of scientific research that is expanding through the design of micro- and nanoparticles. In this paper, we focus on spray dried microparticles as carriers for a repurposed lipophilic antioxidant (probucol). We characterise the microparticles and quantify probucol prior to assessing cytotoxicity on both control and cisplatin treated hair cells (known as House Ear Institute-Organ of Corti 1; HEI-OC1). The addition of water-soluble polymers to 2% ß-cyclodextrin resulted in a stable probucol formulation. Ursodeoxycholic acid (UDCA) used as formulation excipient increases probucol miscibility and microparticle drug content. Formulation characterisations reveals spray drying results in spherical UDCA-drug microparticles with a mean size distribution of ∼5-12 µm. Probucol microparticles show stable short-term storage conditions accounting for only ∼10% loss over seven days. By mimicking cell culture conditions, both UDCA-probucol (67%) and probucol only (82%) microparticles show drug release in the initial two hours. Furthermore, probucol formulations with or without UDCA preserve cell viability and reduce cisplatin-induced oxidative stress. Mitochondrial bioenergetics results in lower basal respiration and non-mitochondrial respiration, with higher maximal respiration, spare capacity, ATP production and proton leak within cisplatin challenged UDCA-probucol groups. Overall, we present a facile method for incorporating lipophilic antioxidant carriers in polymer-based particles that are tolerated by HEI-OC1 cells and show stable drug release, sufficient in reducing cisplatin-induced reactive oxygen species accumulation.

Asunto(s)

Antioxidantes , Estabilidad de Medicamentos , Probucol , Ácido Ursodesoxicólico , Probucol/administración & dosificación , Probucol/química , Probucol/farmacocinética , Probucol/farmacología , Ácido Ursodesoxicólico/química , Ácido Ursodesoxicólico/farmacología , Ácido Ursodesoxicólico/administración & dosificación , Animales , Antioxidantes/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/química , Pérdida Auditiva/tratamiento farmacológico , Pérdida Auditiva/inducido químicamente , Supervivencia Celular/efectos de los fármacos , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/metabolismo , Línea Celular , Liberación de Fármacos , Ratones , Cisplatino/administración & dosificación , Cisplatino/farmacología , Tamaño de la Partícula , Composición de Medicamentos/métodos , Portadores de Fármacos/química , Excipientes/química

RESUMEN

A co-amorphous model drug was prepared by the spray-drying (SD) of probucol (PC) and atorvastatin calcium trihydrate salt (ATO) as low water solubility and co-former components, respectively. The physicochemical properties of the prepared samples were characterized by powder X-ray diffraction (PXRD) analysis, thermal analysis, Fourier transform infrared spectroscopy (FTIR), and dissolution tests. Stability tests were also conducted under a stress environment of 40 °C and 75% relative humidity. The results of PXRD measurements and thermal analysis suggested that PC and ATO form a co-amorphous system by SD. Thermal analysis also indicated an endothermic peak that followed an exotherm in amorphous PC and a physical mixture (PM) of amorphous PC and ATO; however, no endothermic peak was detected in the co-amorphous system. The dissolution profiles for PC in the co-amorphous sample composed of PC and ATO were improved compared to those for raw PC crystals or the PM. Stability tests indicated that the co-amorphous material formed by PC and ATO can be stored for 35 d without crystallization, whereas amorphous PC became crystallized within a day. Therefore, co-amorphization of PC and ATO prepared by SD is considered to be a useful method to improve the solubility of PC in water.

Asunto(s)

Probucol , Agua , Atorvastatina , Probucol/química , Estabilidad de Medicamentos , Cristalografía por Rayos X , Difracción de Rayos X , Agua/química , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Rastreo Diferencial de Calorimetría

RESUMEN

Atherosclerosis (AS) is a major cause of cardiovascular diseases, but its effective theranostic measure remains challenging thus far. Macrophages contribute to AS progress in diverse ways such as producing cytokines and reactive oxygen species (ROS), foaming macrophages, and differentiating into pro-inflammatory macrophages. With the aim of constructing a facile and efficacious theranostic system for diagnosis and treatment of AS, a templated self-assembly approach was developed. This strategy involves using indole molecule (indocyanine green (ICG) or IR783) as a template to assemble with probucol (PB) to gain multifunctional nanoparticles (IPNPs or IRPNPs). IPNPs and IRPNPs both showed excellent physicochemical properties, which testified the generality of the indole molecular self-assembly strategy for PB delivery. Besides, the nanoparticles have superior pharmaceutical characteristics including preventing macrophages from differentiating, more efficiently internalizing in inflammatory macrophages, eliminating overproduced ROS, lowering the level of inflammation cytokines, and inhibiting foaming. More importantly, IPNPs displayed effective therapeutic effects in AS model mice when administered via intravenous (i.v.) route. In addition, IPNPs and IRPNPs accumulated more effectively than ICG and IR783 via i.v. injection in the lesion area, and the blood circulation time was extended beyond 24 h. More interestingly, we discovered that the fluorescence imaging ability of IR783 and IRPNPs was more excellent than ICG and IPNPs, respectively. Moreover, a long-term treatment with IPNPs or IRPNPs revealed an excellent safety profile in mice. Accordingly, this self-assembly strategy developed herein is a universal and promising way for the delivery of lipophilic drugs. This study also provides new insights into developing effective theranostic agents for AS.

Asunto(s)

Antiinflamatorios no Esteroideos/farmacología , Aterosclerosis/tratamiento farmacológico , Verde de Indocianina/farmacología , Nanopartículas/química , Probucol/química , Nanomedicina Teranóstica , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Aterosclerosis/metabolismo , Células Cultivadas , Humanos , Verde de Indocianina/síntesis química , Verde de Indocianina/química , Masculino , Ratones , Ratones Endogámicos C57BL , Imagen Óptica , Células RAW 264.7 , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

The development of high-end targeted drugs and vaccines against modern pandemic infections, such as COVID-19, can take a too long time that lets the epidemic spin up and harms society. However, the countermeasures must be applied against the infection in this period until the targeted drugs became available. In this regard, the non-specific, broad-spectrum anti-viral means could be considered as a compromise allowing overcoming the period of trial. One way to enhance the ability to resist the infection is to activate the nonspecific immunity using a suitable driving-up agent, such as plant polysaccharides, particularly our drug Panavir isolated from the potato shoots. Earlier, we have shown the noticeable anti-viral and anti-bacterial activity of Panavir. Here we demonstrate the pro-inflammation activity of Panavir, which four-to-eight times intensified the ATP and MIF secretion by HL-60 cells. This effect was mediated by the active phagocytosis of the Panavir particles by the cells. We hypothesized the physiological basis of the Panavir proinflammatory activity is mediated by the indol-containing compounds (auxins) present in Panavir and acting as a plant analog of serotonin.

Asunto(s)

Antivirales , Tratamiento Farmacológico de COVID-19 , Portadores de Fármacos , Nanopartículas , Plantas/química , Polisacáridos , Probucol , Adolescente , Adulto , Antivirales/química , Antivirales/farmacocinética , Antivirales/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Células HL-60 , Humanos , Masculino , Nanopartículas/química , Nanopartículas/uso terapéutico , Fagocitosis/efectos de los fármacos , Polisacáridos/química , Polisacáridos/farmacología , Probucol/química , Probucol/farmacocinética , Probucol/farmacología

RESUMEN

Probucol (PB) is a drug that exhibits significant hydrophobicity and substantial intra and inter individual variability in oral absorption, with a miniature bioavailability and complex three compartmental pharmacokinetic modelling due to its high lipid affinity, low stability and high octanol to water partition coefficient. Multiple attempts to formulate PB have not produced satisfactory stable matrices, drug-release profile or rheological flow properties for optimum manufacturing conditions, and with positive and none toxic biological effects. Lithocholic acid (LCA) has recently shown to optimise formulation and cell uptake of drugs. Hence, the aim of this study was to design new PB delivery system, using LCA, and examine its morphology, rheology, stability, and cellular effects. PB was formulated with LCA and sodium alginate (PB-LCA-SA) using various microencapsulation methodologies, and best formulation was investigated in vitro and ex vivo. Using our Ionic Gelation Vibrational Jet flow technology, PB-LCA-SA microcapsules showed good stability and significantly enhanced cell viability, cellular respiration, and reduced inflammation suggesting potential LCA applications in PB delivery and biological effects.

Asunto(s)

Alginatos/química , Sistemas de Liberación de Medicamentos , Ácido Litocólico/química , Probucol/química , Alginatos/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Composición de Medicamentos/métodos , Estabilidad de Medicamentos , Microbioma Gastrointestinal/efectos de los fármacos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Ácido Litocólico/farmacología , Ratones , Probucol/farmacología , Reología , Agua/química

RESUMEN

Oral administration of nanoparticles is extremely limited due to the two processes of mucus permeation and epithelial absorption, which requires completely opposite surface properties of the nanocarriers. To tackle the contradiction, we developed a rational strategy to modify the surface of mesoporous carbon nanoparticles with chitosan concealed by a hydrophilic N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) layer. Probucol (PB) with the low poor permeability and solubility was loaded in optimal nanocarriers to realize the high loading efficacy and controlled release. The pHPMA polymer is a hydrophilic "mucus-inert" material, which could be dissociable from the surface of nanoparticles in the mucus, thus promoting their mucus permeation and causing exposure of chitosan in transepithelial transport. The swelling effect of chitosan under acidic conditions allowed regulation of PB release behavior. In conclusion, the mucus-permeable nanocarrier could effectively overcome multiple gastrointestinal absorption barriers and the oral bioavailability of PB-loaded HCMCN was 2.76-fold that of commercial preparation.

Asunto(s)

Carbono/química , Portadores de Fármacos/química , Nanopartículas/química , Polímeros/química , Probucol/química , Probucol/farmacocinética , Adhesividad , Administración Oral , Animales , Disponibilidad Biológica , Portadores de Fármacos/toxicidad , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ensayo de Materiales , Ratones , Membrana Mucosa/química , Porosidad , Probucol/administración & dosificación

RESUMEN

Antioxidants play a vital role in scavenging reactive oxygen species (ROS) produced by the reduction of molecular oxygen from various cellular mechanisms. Under oxidative stress, an increase in the levels of ROS overwhelms the antioxidant response, causing oxidative damage to biological molecules, and leading to the development of various diseases. Drug compounds with potent antioxidant properties are typically poorly water soluble and highly hydrophobic. An extreme case is Probucol (PB), a potent antioxidant with reported water solubility of 5 ng/ml, and oral bioavailiability of <10%. In this study, PB was loaded in mesoporous silica at various drug loadings to understand the changes to the physical properties of the loaded drug, and it's in vitro drug release. Further in vitro studies were conducted in endothelial and microglia cell models to compare the free radical scavening efficiency of ascorbic acid, PB, and PB release from mesoporous silica particles. Out of the three different mesostructured particles studied, the maximum loading of PB was achieved for large pore mesoporous particles (SBA-15) at 50 wt% drug loading, before complete pore filling was observed. For all materials, loadings above complete pore filling resulted in the recrystallization of PB on the external surface. In vitro drug release measurements showed a rapid dissolution rate at low drug loadings compared to a bimodal release profile of amorphous and crystalline drug at higher drug loadings. PB loaded in mesoporous particle was shown to enhance the antioxidant response to extracellular ROS in the endothelial cell line model, and to intracellular ROS in the microglia cell model. Our results indicate that the antioxidant properties of PB can be significantly improved by using mesoporous silica as a delivery vehicle.

Asunto(s)

Antioxidantes/fisiología , Probucol/farmacología , Dióxido de Silicio/farmacología , Animales , Antioxidantes/química , Línea Celular , Química Farmacéutica/métodos , Portadores de Fármacos/química , Composición de Medicamentos/métodos , Liberación de Fármacos/fisiología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Tamaño de la Partícula , Porosidad , Probucol/química , Especies Reactivas de Oxígeno/metabolismo , Dióxido de Silicio/química , Solubilidad/efectos de los fármacos , Agua/química

RESUMEN

In this study, the time-dependent evolution of amorphous probucol nanoparticles was characterized by cryogenic transmission electron microscopy (cryo-TEM) and atomic force microscopy (AFM). The nanoparticles were formed by dispersing ternary solid dispersions of probucol in water. Spray drying and cogrinding were used to prepare a spray-dried sample (SPD) and two ground-mixture samples (GM(I) and GM(II)) of probucol (PBC) form I and form II/hypromellose/sodium dodecyl sulfate ternary solid dispersions. The amorphization of PBC in the SPDs and GMs was confirmed using powder X-ray diffraction (PXRD) and solid-state 13C nuclear magnetic resonance (NMR) spectroscopy. Additionally, differential scanning calorimetry showed that relatively small amounts of PBC nuclei or PBC-rich domains remained in both GMs. Then, the physical stability of drug nanoparticles formed after aqueous dispersion in the SPD and GM suspensions during storage at 40 °C was characterized. Cryogenic transmission electron microscopy was used to monitor the evolution of the amorphous PBC nanoparticles in the SPD and GM suspensions during storage. Spherical nanoparticles smaller than 30 nm were observed in all of the suspensions just after dispersion. The size of the particles in the SPD suspension gradually increased but remained on the order of nanometers and retained their spherical shape during storage. In contrast, both GM suspensions evolved through three morphologies, spherical nanoparticles that gradually increased in size, needle-like nanocrystals, and micrometer-sized crystals with various shapes. The evolution of the nanoparticles suggested that their stability in the GM suspension was lower than in the SPD suspension. PXRD analysis of the freeze-dried suspensions of the particles showed that the PBC in the nanoparticles of the SPD suspension was in the amorphous state just after dispersion, while a small fraction of the PBC in the nanoparticles of the GM suspension exhibited a crystal phase and selectively crystallized to its initial crystal form during storage. AFM force-distance curves also demonstrated the existence of crystal phase PBC in the spherical nanoparticles in the GM suspension just after dispersion. The molecular state of PBC in the ternary solid dispersion was dependent on the preparation method (either completely amorphized or incompletely amorphized with residual nuclei or drug-rich domains) and determined the potential mechanisms of PBC nanoparticle evolution after aqueous dispersion. These findings confirm the importance of the molecular state on the particle evolution and the physical stability of the drug nanoparticles in the suspension. Cryo-TEM and AFM measurements provide more direct insight for designing solid dispersion formulations to produce stable amorphous drug nanosuspensions that efficiently improve the solubility and bioavailability of poorly water-soluble drugs.

Asunto(s)

Diseño de Fármacos , Microscopía de Fuerza Atómica/métodos , Microscopía Electrónica de Transmisión/métodos , Nanopartículas/química , Probucol/química , Agua/química , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Cristalización , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Liofilización , Espectroscopía de Resonancia Magnética , Tamaño de la Partícula , Solubilidad , Suspensiones , Difracción de Rayos X

RESUMEN

AIM: Taurine-conjugated bile acids possess positive formulation-stabilization effects, which are desirable in diabetes treatments. The taurine-conjugated bile acid, taurocholic acid (TCA), has shown promising formulation-stabilizing effects on the delivery of the antioxidant drug, probucol (PB), but success is limited due to its poor release profile. This study aimed to design new PB-TCA formulations using new polymers, and examine antioxidant and antidiabetic effects using ß-cells for PB with or without TCA. MATERIALS AND METHODS: Different formulations using alginate-insoluble esters of polymethylacrylate polymers encapsulating PB and TCA were developed, microencapsulated and examined for stability and biological activity. RESULTS: TCA addition to new PB matrices improved osmotic and mechanical properties, and this effect was dependent on polymethylacrylate composition and concentration. CONCLUSION: TCA can optimize the oral delivery of anti-diabetic compounds.

Asunto(s)

Antioxidantes/química , Ácidos y Sales Biliares/química , Cápsulas/química , Probucol/química , Taurina/química , Alginatos/química , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Línea Celular , Diabetes Mellitus/tratamiento farmacológico , Composición de Medicamentos , Estabilidad de Medicamentos , Humanos , Ratones , Estrés Oxidativo/efectos de los fármacos , Probucol/metabolismo , Probucol/farmacología , Probucol/uso terapéutico

RESUMEN

BACKGROUND: Self-Emulsifying Drug Delivery System (SEDDS), if taken orally, is expected to self-emulsify in GIT and improve the absorption and bioavailability. Probucol (PB) is a highly lipophilic compound with very low and variable bioavailability. OBJECTIVE: The objectives of this study were to examine the stability and conduct bioavailability of the prepared Probucol Self-Emulsified Drug Delivery System (PBSEDDS) in human volunteers. METHODS: The methods included preparation of different PBSEDDS using soybean oil (solvent), Labrafil M1944CS (surfactant) and Capmul MCM-C8 (co-surfactant). The formulations were characterized in vitro for spontaneity of emulsification, droplet size, turbidity and dissolution in water after packing in HPMC capsules. The optimized formulations were evaluated for stability at different storage temperatures and human bioavailability compared with the drug dissolved in soybean oil (reference). RESULTS: The results showed that formulations (F1-F4) were stable if stored at 20 °C. The mean (n=3) pharmacokinetic parameters for stable formulations were: The Cmax, 1070.76, 883.16, 2876.43, 3513.46 and 1047.37 ng/ml; the Tmax, 7.93, 7.33, 3.96, 3.67 and 4.67 hr.; the AUC (0-t), 41043.41, 37763.23, 75006.26, 46731.36 and 26966.43 ng.hr/ml for F1, F2, F3, F4 and reference, respectively. The percentage relative bioavailability was in this order: F3> F4> F1> F2>. CONCLUSION: In conclusion, the PBSEDDS formulations were stable at room temperature. F4 showed the highest Cmax and the shortest Tmax. All the formulations showed significant enhancement of bioavailability compared with the reference. The results illustrated the potential use of SEDDS for the delivery of probucol hydrophobic compound.

Asunto(s)

Sistemas de Liberación de Medicamentos , Emulsionantes/química , Emulsionantes/farmacocinética , Probucol/química , Probucol/farmacocinética , Adulto , Disponibilidad Biológica , Composición de Medicamentos , Estabilidad de Medicamentos , Emulsionantes/administración & dosificación , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Probucol/administración & dosificación , Propiedades de Superficie , Adulto Joven

RESUMEN

INTRODUCTION: The ratio of secondary to primary bile acids changes during Type 1 Diabetes (T1D) development and these effects might be ameliorated by using cholesterol lowering drugs or hydrophilic bile acids. Probucol is a cholesterol-lowering drug, while ursodeoxycholic acid is a hydrophilic bile acid. This study investigated whether nanoencapsulated probucol with ursodeoxycholic acid altered bile acid ratios and the development of diabetes. METHODS: Balb/c mice were divided into three groups and gavaged daily with either free probucol, nanoencapsulated probucol or nanoencapsulated probucol with ursodeoxycholic acid for seven days. Alloxan was injected and once T1D was confirmed the mice continued to receive daily gavages until euthanasia. Blood, tissues, faeces and urine were collected for analysis of insulin and bile acids. RESULTS AND CONCLUSIONS: Nanoencapsulated probucol-ursodeoxycholic acid resulted in significant levels of insulin in the blood, lower levels of secondary bile acids in liver and lower levels of primary bile acids in brain, while ratio of secondary to primary bile acids remains similar among all groups, except in the faeces. Findings suggests that nanoencapsulated probucol-ursodeoxycholic acid may exert a protective effect on pancreatic ß-cells and reserve systemic insulin load via modulation of bile acid concentrations in the liver and brain.

Asunto(s)

Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Mucosa Intestinal , Nanocápsulas , Probucol , Ácido Ursodesoxicólico , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos BALB C , Nanocápsulas/química , Nanocápsulas/uso terapéutico , Probucol/química , Probucol/farmacocinética , Probucol/farmacología , Ácido Ursodesoxicólico/química , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/farmacología

RESUMEN

To enhance the oral bioavailability and eliminate the food effect of probucol. Probucol-phospholipid complex was prepared using solvent-evaporation method in this research. Several methods were used to validate the formation of complexes, such as FT-IR, SEM, DSC and PXRD, and the solubility of PRO and PRO-PLC was detected by HPLC. Pharmacokinetic testing was conducted in the fasted and fed state. FTIR, SEM, DSC and PXRD validated the existence of PRO-PLC. The solubility of PRO in complexes was 15.05 µg/mL, which was 215-fold of the PRO-API. The dissolution rate was increased by preparing PRO-PLC. Compared with commercial tablets, the PRO-PLC complexes exhibited higher peak plasma concentration (1.69 ± 0.44 µg/mL), increased AUC0-24 h (6.8 ± 1.3 µg/mL h), which mean the bioavailability of PRO was increased. In addition, the absorption of PRO was not interfered with food. In conclusion, an improved solubility and bioavailability was achieved with the preparation of PRO-PLC. Additionally, the dissolution behaviour was good and the food effect was eliminated.

Asunto(s)

Fosfolípidos/química , Probucol/química , Animales , Disponibilidad Biológica , Perros , Interacciones Alimento-Droga , Fosfolípidos/farmacocinética , Probucol/farmacocinética , Solubilidad

RESUMEN

Smart polymers such as Eudragit (ED) have shown potential applications in oral drug delivery and targeted release. Probucol (PB) is a lipophilic drug used for hypercholesterolemia and possesses desirable antidiabetic effects such as antioxidant and cell protective effects. PB is highly hydrophobic and has poor bioavailability with significant inter- and intra-patient absorption, limiting its clinical applications in diabetes. This study aimed to design and analyse new PB-ED formulations with or without the absorption-enhancer chenodeoxycholic acid (CDCA). Sodium alginate-based microcapsules containing three different ED polymers (NM30D, RL30D and RS30D) were investigated with or without CDCA via scanning electron microscopy, energy dispersive X-ray spectroscopy (EDXR), confocal microscopy, osmotic stability, mechanical properties, buoyancy, release profiles (pH: 7.4), thermal stability and antioxidant effects. The effects of microcapsules on pancreatic ß-cell survival, function, inflammatory profile and PB cellular uptake were analysed. All microcapsules showed uniform morphology and surface topography with CDCA being distributed evenly throughout the microcapsules. Osmotic stability was significantly improved in PB-NM30D and PB-RL30D microcapsules (p < .01 and p < .05, respectively), and PB-NM30D microcapsules displayed low buoyancy (p < .01). CDCA improved PB-NM30D effects on pancreatic ß-cell function and bioenergetics, which suggests potential application of PB-NM30D-CDCA in PB delivery and diabetes treatment.

Asunto(s)

Antioxidantes , Portadores de Fármacos , Células Secretoras de Insulina/metabolismo , Probucol , Alginatos/química , Alginatos/farmacocinética , Alginatos/farmacología , Animales , Antioxidantes/química , Antioxidantes/farmacocinética , Antioxidantes/farmacología , Cápsulas , Supervivencia Celular/efectos de los fármacos , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Humanos , Células Secretoras de Insulina/ultraestructura , Ratones , Microscopía Electrónica de Rastreo , Probucol/química , Probucol/farmacocinética , Probucol/farmacología

RESUMEN

Oxidised low density lipoprotein (LDL) was considered to be important in the pathogenesis of atherosclerosis, but the large clinical trials of antioxidants, including the first one using probucol (the PQRST Trial), failed to show benefit and have cast doubt on the importance of oxidised LDL. We have shown previously that LDL oxidation can be catalysed by iron in the lysosomes of macrophages. The aim of this study was therefore to investigate the effectiveness of antioxidants in preventing LDL oxidation at lysosomal pH and also establish the possible mechanism of oxidation. Probucol did not effectively inhibit the oxidation of LDL at lysosomal pH, as measured by conjugated dienes or oxidised cholesteryl esters or tryptophan residues in isolated LDL or by ceroid formation in the lysosomes of macrophage-like cells, in marked contrast to its highly effective inhibition of LDL oxidation at pH 7.4. LDL oxidation at lysosomal pH was inhibited very effectively for long periods by N,N'-diphenyl-1,4-phenylenediamine, which is more hydrophobic than probucol and has been shown by others to inhibit atherosclerosis in rabbits, and by cysteamine, which is a hydrophilic antioxidant that accumulates in lysosomes. Iron-induced LDL oxidation might be due to the formation of the superoxide radical, which protonates at lysosomal pH to form the much more reactive, hydrophobic hydroperoxyl radical, which can enter LDL and reach its core. Probucol resides mainly in the surface monolayer of LDL and would not effectively scavenge hydroperoxyl radicals in the core of LDL. This might explain why probucol failed to protect against atherosclerosis in various clinical trials. The oxidised LDL hypothesis of atherosclerosis now needs to be re-evaluated using different and more effective antioxidants that protect against the lysosomal oxidation of LDL.

Asunto(s)

Antioxidantes/química , Lipoproteínas LDL/química , Lisosomas/química , Animales , Antioxidantes/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Línea Celular , Ceroide/química , Cromatografía Líquida de Alta Presión , Cisteamina/química , Compuestos Ferrosos/química , Humanos , Peróxido de Hidrógeno/química , Concentración de Iones de Hidrógeno , Lipoproteínas LDL/análisis , Oxidación-Reducción , Probucol/química , Probucol/uso terapéutico , Conejos

RESUMEN

The primary objective of this study was to develop lipid-based self-microemulsifying drug delivery systems (SMEDDS) without using any organic cosolvents that would spontaneously form microemulsions upon dilution with water. Cosolvents were avoided to prevent possible precipitation of drug upon dilution and other stability issues. Different polysorbates, namely, Tween 20, Tween 40, Tween 60, and Tween 80, were used as surfactants, and Captex 355 EP/NF (glycerol tricaprylate/caprate) or its 1:1 mixture with Capmul MCM NF (glycerol monocaprylocaprate) were used as lipids. Captex 355-Tween-water ternary phase diagrams showed that oil-in-water microemulsions were formed only when the surfactant content was high (80-90%) and the lipid content low (10-20%). Thus, mixtures of Tweens with Captex 355 alone were not suitable to prepare SMEDDS with substantial lipid contents. However, when Captex 355 was replaced with the 1:1 mixture of Captex 355 and Capmul MCM, clear isotropic microemulsion regions in phase diagrams with sizes in the increasing order of Tween 20 < Tween 40 < Tween 60 < Tween 80 were obtained. Tween 80 had the most profound effect among all surfactants as microemulsions were formed with lipid to surfactant ratios as high as 7:3, which may be attributed to the presence of double bond in its side chain that increased the curvature of surfactant layer. Thus, lipid-surfactant mixtures containing 1:1 mixture of medium chain triglyceride (Captex 355) and monoglyceride (Capmul MCM) and as low as 30% Tween 80 were identified as organic cosolvent-free systems for the preparation of SMEDDS. Formulations with a model drug, probucol, dispersed spontaneously and rapidly upon dilution with water to form microemulsions without any drug precipitation.

Asunto(s)

Sistemas de Liberación de Medicamentos/métodos , Emulsiones/química , Polisorbatos/química , Probucol/administración & dosificación , Caprilatos/química , Química Farmacéutica , Cromatografía Líquida de Alta Presión , Diglicéridos/química , Liberación de Fármacos , Monoglicéridos/química , Tamaño de la Partícula , Probucol/química , Tensoactivos/química , Triglicéridos/química

RESUMEN

The aim of this article was to check the physical stability of the amorphous form of probucol at both standard storage and manufacturing conditions. Our studies clearly show that disordered form of the examined, cholesterol lowering, agent stored at ambient pressure does not reveal any tendency toward recrystallization. The physical stability of neat probucol stored at ambient pressure has been investigated (i) at room temperature by means of X-ray diffraction technique (XRD) as well as (ii) at T = 333 K by means of broadband dielectric spectroscopy (BDS). Due to the fact that compression is an important stage of drugs manufacturing we additionally performed physical stability tests of amorphous probucol at elevated pressure. The recrystallization tendency of the examined pharmaceutical has been tracked online from the initial and further up to a few hours after compression by means of the high pressure BDS technique. These experiments indicate that even very small pressure applied during the sample compression immediately induce its recrystallization. Since, the sensitivity on pressure eliminates probucol from the group of physically stable amorphous APIs, its stabilization is required. Taking into account that there are many scientific reports describing the positive effect of coadministration of probucol with the drug atorvastatin, we used the latter as probucol's crystallization inhibitor.

Asunto(s)

Atorvastatina/química , Presión , Probucol/química , Espectroscopía Dieléctrica , Simulación de Dinámica Molecular , Temperatura , Difracción de Rayos X

RESUMEN

The polymer/probucol co-milled mixtures were prepared to improve drug dissolution rate and oral bioavailability. Probucol, a BCS II drug, was co-milled together with Copovidone (Kollidon VA64, VA64), Soluplus, or MCC using the dry media-milling process with planetary ball-milling equipment. The properties of the milled mixtures including morphology, crystal form, vitro drug dissolution and in vivo oral bioavailability in rats were evaluated. Probucol existed as an amorphous in the matrix of the co-milled mixtures containing VA64, which helped to enhance drug dissolution. The ternary mixture composed of VA64, RH40, and probucol showed increased dissolution rates in both sink and non-sink conditions. It also had a higher oral bioavailability compared to the reference formulation. Dry-media milling of binary or ternary mixtures composed of drug, polymer and surfactant possibly have wide applications to improve dissolution rate and oral bioavailability of water-insoluble drugs.

Asunto(s)

Probucol/química , Animales , Disponibilidad Biológica , Composición de Medicamentos , Liberación de Fármacos , Ratas , Solubilidad