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1.
Int J Pharm ; 575: 118875, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31765781

RESUMO

Drug administration failure has been often witnessed in pediatric due to children's resistance to take medicines with bitter taste. Taste-masking is the key requirement among the scanty drugs available for children. Solid taste-masking systems, such as tablets and capsules, are difficult to swallow for children. Therefore, a liquid taste-masking system based on lyotropic liquid crystalline nanoparticles (LLCNs) was developed in this study. Cefpodoxime proxetil (CFP), a typically bitter drug used as antibiotic in pediatric, was selected as the model drug, and the encapsulation of CFP into the LLCNs was envisaged to improve their taste. Pluronic F127 was added to improve the colloidal stability of CFP-LLCNs. The optimized CFP-LLCNs showed the particle size of 187.29 ± 4.12 nm and the encapsulation efficiency of 85.80%. The mesophase analysis by polarized light microscopy and small angle X-ray scattering confirmed the cubic phase of CFP-LLCNs. It showed a sustained-release profile well fitted to Higuchi model, indicating that diffusion and erosion were both responsible for the CFP release. The taste-masking ability of CFP-LLCNs was confirmed by electronic tongue, compared to CFP and commercial product. The colloidal stability was verified after 3 months storage in room condition (25 ± 2 °C, 70 ± 2%RH). To sum up, the taste-masking and colloidal-stable CFP-LLCNs showed great potential for pediatric oral delivery.


Assuntos
Antibacterianos/administração & dosagem , Ceftizoxima/análogos & derivados , Sistemas de Liberação de Medicamentos , Cristais Líquidos , Nanopartículas/administração & dosagem , Paladar , Administração Oral , Antibacterianos/química , Ceftizoxima/administração & dosagem , Ceftizoxima/química , Criança , Coloides , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Nariz Eletrônico , Suco Gástrico/química , Humanos , Secreções Intestinais/química , Nanopartículas/química
2.
Int J Pharm ; 575: 118892, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31786354

RESUMO

Solubilizing adjuvants are commonly used to dissolve insoluble drugs by simply adding in a formulation. In this study, gelatin and oleic acid sodium salt (OAS), a generally recognized as safe-listed material were chosen and conjugated to develop a natural solubilizing adjuvant using the fattigation platform technology to enhance solubility and dissolution rate of poorly water-soluble drugs according to self-assembly and nanonization principle when simply mixed with poorly water-soluble drugs. We synthesized the gelatin and OAS conjugates (GOC) at three different ratios (1:1, 1:3, 1:5; GOC 1, GOC 2, and GOC 3, respectively) via the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide reaction using a spray dryer. This amphiphilic micronized GOC was self-assembled into nanoparticles. The synthesis of new amphiphilic conjugates was identified through Fourier transform-infrared (FT-IR) spectroscopy. The powder properties of the GOCs, such as angle of repose, bulk density, and tapped density were varied with the oleic acid bonding ratio. Then, GOCs were utilized to investigate the enhanced solubility and release rate of various poorly water-soluble drugs such as cilostazol (CSZ), coenzyme Q10, ticagrelor, telmisartan, aprepitant and itraconazole as model drugs. Based on the solubility studies by concentration and type of GOCs, 3% GOC 2 was selected. When this GOC was mixed with these model drugs by the physical mixing, wetting and hot melting methoods, the solubility was highly enhanced compared to the pure control drug, ranging from 20 to 150,000 times. In case of CSZ, all formulations were significantly improved release rate compared to the of CSZ alone and the reference tablet, cilostan® (Korea United Pharm) in simulated intestinal fluid containing 0.2% sodium lauryl sulfate. Differential scanning calorimetry and powder X-ray diffraction were conducted to confirm the crystal polymorphic structure of CSZ, and as a result they changed to diminutive peak intensity compared to CSZ alone. Field-emission scanning electron microscopy indicated that GOC was round with a reduced size of about 100 nm. The reduction of drug particles via nanonization and self-assembly of amphiphilic GOC in an aqueous media could be a key factor to improve poor water solubility by providing a favorable dispersion of drug molecules in an amphiphilic network.


Assuntos
Adjuvantes Farmacêuticos/química , Gelatina/química , Nanopartículas/química , Ácido Oleico/química , Aprepitanto/química , Cilostazol/química , Liberação Controlada de Fármacos , Secreções Intestinais/química , Itraconazol/química , Solubilidade , Telmisartan/química , Ticagrelor/química , Água/química
3.
Allergol Immunopathol (Madr) ; 48(1): 26-33, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31623945

RESUMO

INTRODUCTION AND OBJECTIVES: The production and consumption of oysters is increasing annually because it can provide essential nutrients and benefit for human health, leading to frequent occurrence of severe allergic reactions observed in sensitized individuals. The aim of the present study was to investigate the effects of acid and protease treatment on the conformation and IgE-binding capacity of recombinant Crassostrea gigas tropomyosin (Cra g 1). RESULTS: Under acidic conditions, Cra g 1 did not undergo degradation, however, the changes obvious in the intensity of CD signal and ANS-binding fluorescence were observed, which was associated with a decrease in antibody reactivity. In simulated gastrointestinal fluid (SGF) and simulated intestinal fluid (SIF) digestion system, acid-treated Cra g 1 was relatively resistant to digestion, but the degradative patterns were very different. Moreover, owing to alterations of secondary structure and hydrophobic surface of the protein during digestive processing, antigenicity of acid-induced Cra g 1 reduced in SGF while it increased significantly in SIF. CONCLUSION: To our knowledge, this is the first study reporting that antigenicity of acid-treated oyster tropomyosin increased after SIF digestion. These results revealed that treatment with acid and pepsin, rather than trypsin, was an effective way of reducing IgE-binding capacity of tropomyosin from oyster.


Assuntos
Ácidos/metabolismo , Alérgenos/imunologia , Imunoglobulina E/imunologia , Tropomiosina/imunologia , Ácidos/análise , Alérgenos/química , Alérgenos/metabolismo , Afinidade de Anticorpos , Suco Gástrico/química , Suco Gástrico/metabolismo , Humanos , Secreções Intestinais/química , Secreções Intestinais/metabolismo , Pepsina A/análise , Pepsina A/metabolismo , Conformação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Tropomiosina/química , Tropomiosina/metabolismo , Tripsina/análise , Tripsina/metabolismo
4.
Vet Microbiol ; 239: 108462, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31767100

RESUMO

In contrast to human influenza viruses that replicate in the respiratory tract and are airborne transmitted, avian viruses also replicate in gut epithelial cells and are transmitted via the fecal-oral route. On this route, the virus is exposed to destructive fluids of the digestive tract, which are acidic and contain the proteases pepsin (gizzard) or chymotrypsin and trypsin (intestine). Only the latter enzyme activates virus by cleaving hemagglutinin (HA) into HA1 and HA2 subunits. We mimicked the passage of viruses through the gastrointestinal tract by treating them with digestive fluids from chicken and determined titers and integrity of HA by western-blot. Gizzard fluid completely inactivated virions and degrades HA even at a high dilution, but only if the pH was kept acidic. If the fluid is diluted with neutral buffer (mimicking virus uptake with seawater) particles were more resistant. Virions containing an uncleaved HA were even activated suggesting that gastric juice contains a trypsin-like protease. Undiluted intestinal fluid inactivated particles and destroyed HA, but diluted fluid activated virions. A virus isolated from the duck´s intestine is more tolerant against intestinal fluid compared to fowl plague virus suggesting that the former is better adapted to grow in the intestine. We also demonstrate that influenza viruses replicate to high titers in a novel chicken epithelial gut cell line. While viruses with a monobasic HA cleavage site require addition of trypsin, these cells effectively process HA with a polybasic cleavage site, which could be blocked with an inhibitor of the cellular furin protease.


Assuntos
Trato Gastrointestinal/virologia , Hemaglutininas/metabolismo , Influenza Aviária/virologia , Animais , Galinhas , Células Epiteliais/citologia , Células Epiteliais/virologia , Suco Gástrico/química , Suco Gástrico/enzimologia , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Secreções Intestinais/química , Secreções Intestinais/enzimologia , Inativação de Vírus , Replicação Viral/fisiologia
5.
Int J Pharm ; 572: 118801, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678529

RESUMO

This study was aimed to monitor the transit through the intestine by X-ray imaging using barium sulfate (BS) as tracer. The in vitro features of monolithic tablets were correlated with their in vivo behavior in order to provide a tool for the development of targeted formulations containing macromolecular bioactive agents. The impact of BS on various matrices (neutral, ionic) was studied in simulated fluids using the disintegration time (DT) as main parameter. Dry tablets were characterized by spectroscopic methods (X-ray diffraction and Infra-Red) and scanning electron microscopy (SEM). The selected formulations were followed in a beagle dog model. The in vivo and in vitro DT of tablets formulated with BS were compared. Results: anionic excipients carboxymethylcellulose (CMC) and carboxymethylstarch (CMS) protected the active ingredient from the gastric acidity, ensuring its targeted delivery in the intestine. The SEM analysis, before and after transit in simulated fluids, showed that BS remained in the tablets allowing their good follow-up in vivo. The incorporation of 30% protein in tablets with 40% BS had no impact on their behavior. In conclusion, BS and X-ray imagery could be a good alternative to scintigraphy for development of targeted formulations containing high molecular weight bioactive agents.


Assuntos
Sulfato de Bário/administração & dosagem , Carboximetilcelulose Sódica/química , Meios de Contraste/administração & dosagem , Excipientes/química , Intestinos/diagnóstico por imagem , Soroalbumina Bovina/administração & dosagem , Amido/análogos & derivados , Animais , Sulfato de Bário/química , Meios de Contraste/química , Cães , Composição de Medicamentos , Liberação Controlada de Fármacos , Suco Gástrico/química , Trânsito Gastrointestinal , Concentração de Íons de Hidrogênio , Secreções Intestinais/química , Soroalbumina Bovina/química , Amido/química , Comprimidos , Fatores de Tempo
6.
J Control Release ; 311-312: 74-84, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31487499

RESUMO

This research aimed to develop a pH-responsive organic-inorganic hybrid nanocomposite as an effective oral delivery system for protein drugs. Three different nanocomposites were prepared by using bovine serum albumin (BSA) as a model protein. A nanocomplex of BSA with 3-aminopropyl functionalized magnesium phyllosilicate (AC-BSA) was obtained via the spontaneous co-assembly and then sequentially coated with glycol-chitosan (GAC-BSA) and the pH sensitive polymer, Eudragit®L100-55 (EGAC-BSA). These organic-inorganic hybrid nanocomposites exhibited high entrapment efficiency (86-99%) and their structural characteristics were confirmed by using energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and circular dichroism analysis, indicating that the secondary structure of BSA was well retained in the nanocomposites. At pH 1.2, AC-BSA achieved rapid drug release of about 80% within 2 h, while GAC-BSA and EGAC-BSA exhibited slow drug release of 30% and 15%, respectively, indicating that the surface-coated nanocomposites were more stable in the gastric condition. Furthermore, the conformational stability of BSA entrapped in EGAC-BSA was well retained in the presence of proteolytic enzymes, suggesting that EGAC-BSA should be effective in protecting the protein against gastrointestinal harsh environment. Compared to free BSA, all of tested nanocomposites demonstrated 2.1-3.8-fold higher cellular uptake in Caco-2 cells. Furthermore, energy-dependent endocytosis and paracellular pathway contributed to the cellular transport of nanoparticles. After oral administration in rats, EGAC-BSA significantly enhanced the intestinal permeation of BSA compared to free BSA. In conclusion, EGAC-BSA appears to be promising as an effective oral delivery system for proteins with enhanced intestinal absorption.


Assuntos
Quitosana/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanocompostos/administração & dosagem , Ácidos Polimetacrílicos/administração & dosagem , Soroalbumina Bovina/administração & dosagem , Administração Oral , Animais , Células CACO-2 , Quitosana/química , Liberação Controlada de Fármacos , Suco Gástrico/química , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal , Secreções Intestinais/química , Masculino , Nanocompostos/química , Ácidos Polimetacrílicos/química , Ratos Sprague-Dawley , Soroalbumina Bovina/química , Silicatos/administração & dosagem , Silicatos/química
7.
Food Chem Toxicol ; 133: 110778, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31472224

RESUMO

This study was to investigate the structure of a polysaccharide fraction from the Fortunella margarita and the relationship between its digestibility and structure. A novel polysaccharide fraction extracted by graded precipitation at ethanol concentrations of 20% from F. margarita (named FP20) comprised mainly glucose, galactose, and mannose. The unit composition was →4)-ß-Glcp-(1 → 2)-α-Glcp-(1 → 2)-α-Galp-(1 → 4)-α-Galp-(1→ bone, and in →2)-α-Galp-(1→) with a branching point at C6 of ß-Manp. FP20 was identified as a mannogalactoglucan with a different monosaccharide composition ratio and side-chain sugar residues compared with other plant polysaccharides. Moreover, FP20 had a spherical aggregations by atomic force microscope test. FP20 had an island-shaped structures with a smooth surface revealed by field emission scanning electron microscopy. Furthermore, in vitro digestive test, FP20 was resistance to a digestion system of saliva-gastric-small intestinal. The digestibility of FP20 was related to its backbone unit, structure and tight, uniform, and spherical chain conformation in aqueous.


Assuntos
Digestão , Galactanos/química , Glucanos/química , Rutaceae/química , Sequência de Carboidratos , Suco Gástrico/química , Hidrólise , Secreções Intestinais/química , Manose/química , Peso Molecular , Saliva/química
8.
Int J Pharm ; 569: 118602, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31394182

RESUMO

An innovative abuse-deterrent composition was developed to deter the most dangerous route of drug abuse, the intravenous route. The composition is based on a crosslinked sodium starch glycolate (X-SSG) that can effectively complex with cationic drugs in aqueous solutions and minimize the amount of the free drug available for extraction. Furthermore, the crosslinked polymer swells in and entraps a portion of the drug solution by which it reduces the available volume for syringing and subsequent injection. Two deterrent compositions were prepared, a drug-polymer physical blend and a drug-polymer chemical complex. The composition in its complexed form showed greater deterrence capacity than the physical blend except in solvents with ionic moieties, where the deterrence remained almost the same. The studies revealed that the complexation with the drug played a major role in total drug entrapment. Tablets prepared from the drug-polymer complex showed a complete and immediate drug release in 0.1 N HCl within the first 15 min. Moreover, the dissolution studies in the simulated intestinal media ruled out the re-complexation potential between the drug and the polymer. The proposed X-SSG composition provides a desirable drug release in the gastric and intestinal media under the legitimate use while deterring an intravenous abuse.


Assuntos
Formulações de Dissuasão de Abuso , Amido/análogos & derivados , Liberação Controlada de Fármacos , Suco Gástrico/química , Secreções Intestinais/química , Amido/química , Comprimidos
9.
J Control Release ; 311-312: 1-15, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31465825

RESUMO

Silica nanoparticles (SiO2 NPs) have potential utility in controlled release. Despite significant research in this area, there is a gap in the understanding of the correlation between SiO2 NP physicochemical properties on the one hand and their degradation in solutions, in cells, and in vivo on the other. Here, we fabricated SiO2 NPs with variations in size, porosity, density, and composition: 100 nm Stöber, 100 and 500 nm mesoporous, 100 nm disulfide-based mesoporous, and 100 nm disulfide-based hollow mesoporous. Degradation profiles over 28 days were investigated in simulated biological fluids and deionized water. Results show Meso 100, and 500 nanoparticles degraded faster at higher pH values. Results from macrophages indicate Meso 100 nanoparticles showed the highest degradation amount (~3.8%). Cytotoxicity evaluation of the particles in Human Aortal Endothelial Cells (HAECs) shows concentration-dependent toxicity for the particles. Results from CD-1 mice show ~53% of Meso 100 nanoparticles (25 mg kg-1) degraded and were detected in urine after seven days. It was shown nanoparticle porosity and composition as well as pH and ionic strength of the medium play the predominant roles for degradation of SiO2 NPs. Based on histological evaluations, at the injected doses investigated, the particles did not show toxicity.


Assuntos
Nanopartículas/administração & dosagem , Dióxido de Silício/administração & dosagem , Animais , Aorta/citologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fezes/química , Feminino , Suco Gástrico/química , Humanos , Concentração de Íons de Hidrogênio , Secreções Intestinais/química , Lisossomos/química , Camundongos , Nanopartículas/química , Nanopartículas/toxicidade , Concentração Osmolar , Tamanho da Partícula , Porosidade , Dióxido de Silício/química , Dióxido de Silício/toxicidade , Dióxido de Silício/urina , Distribuição Tecidual
10.
Int J Pharm ; 568: 118527, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319145

RESUMO

This study aims at identifying the more suitable polysaccharide in a composite film based on Eudragit RS for 5-ASA delivery to the colon. Different polysaccharides (pectin, chitosan, guar, inulin, and dextran) were examined. The mechanical properties, swelling index, loss of film mass and permeability of films to 5-ASA were recorded at simulating gastric (SGF), intestinal (SIF) and colonic fluids (SCF). Films containing inulin or dextran were more flexible and showed better mechanical properties. Films containing chitosan, pectin or guar exhibited extensive swelling in SGF and SIF. Loss of film mass and drug permeation was more pronounced in SCF than SIF for all samples indicating their sensitivity to colonic bacteria. However, films containing inulin or dextran showed minimum swelling index in SGF and SIF and the highest ratio of permeability in SCF to SIF. Accordingly, inulin and dextran are suggested as appropriate polysaccharides in a film based on Eudragit RS for colon delivery of 5-ASA.


Assuntos
Resinas Acrílicas/química , Anti-Inflamatórios não Esteroides/química , Sistemas de Liberação de Medicamentos , Mesalamina/química , Polissacarídeos/química , Animais , Colo/metabolismo , Suco Gástrico/química , Secreções Intestinais/química , Masculino , Ratos Wistar , Resistência à Tração
11.
Mater Sci Eng C Mater Biol Appl ; 103: 109737, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349514

RESUMO

In this study, twisted rod-like chiral mesoporous silicas (CMSs) with discriminating chiral characteristics (D/L) were designed and biomimetic synthesized by using L- and d-alanine derivatives as templates, and employed as poorly water-soluble chiral drug ibuprofen (IBU) carriers. The morphology and mesoscopic characteristics of CMSs were determined by transmission electron microscope (TEM) and small-angle X-ray scattering (SAXS). Meanwhile, the physicochemical properties of CMSs before and after drug loading were systematically characterized by infrared spectroscopy (IR), nitrogen adsorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and induced circular dichroism (ICD). The results suggested that, the CMSs exhibited local chiral characteristics, which were successfully endowed by the alanine-derivative surfactants templates with a reversal of chirality. The crystalline state of IBU was effectively converted to amorphous state after being incorporated into CMSs, and the drug delivery systems shared the chiral characteristic of carriers. Besides, in vitro drug release experiments were respectively performed in simulated gastric fluid (SGF, pH 1) and simulated intestinal fluid (SIF, pH 6.8) medium, and the results demonstrated that both l-CMS and d-CMS could improve the dissolution of IBU in SGF medium, which could be explained by the amorphization of IBU. Particularly, due to the different pore geometry of these two materials, CMSs with different chirality (D/L) could be applied as carriers to accomplish drug release differentiation.


Assuntos
Materiais Biomiméticos , Portadores de Fármacos , Ibuprofeno , Dióxido de Silício , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Materiais Biomiméticos/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Suco Gástrico/química , Humanos , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/farmacologia , Secreções Intestinais/química , Tamanho da Partícula , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/farmacologia
12.
J Pharm Pharm Sci ; 22(1): 221-246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31219781

RESUMO

This study investigates the influence of surfactant sodium lauryl sulfate (SLS) on the solubility of poorly-water soluble drug substances, model Compound X and Compound Y, used in a fixed dose combination oral solid dosage form. To determine the impact of SLS concentration on the solubility of compounds X and Y, we experimentally determined the critical micelle concentration (CMC) of SLS in water, simulated gastric fluid (SGF), and fed state simulated intestinal fluid (FeSSIF) in the presence of Compound X and Compound Y using UV/Visible spectrophotometry at 25°C. The aggregation of SLS was characterized by calculating the standard Gibbs free energy of micellization in all the media investigated.  To enhance the understanding of SLS aggregation, high throughput experiments and in-vivo mechanistic modelling were used to determine the effect of increasing levels of SLS on the solubility of compounds X and Y as both single agent and combination products to be formulated into a suitable oral solid dosage form. Micellar formation of SLS is a spontaneous process as shown by the negative values of the standard free energy of micellization. The CMC of SLS in the various media investigated in the presence of compounds X and Y decreases in the following order: water> FeSSIF> SGF. However, the aggregation of SLS in the various media is overall more spontaneous in the following order: SGF>FeSSIF>water. Using high throughput experimentation and in-vivo mechanistic modelling, it was determined that a combination oral solid product of compounds X and Y will have optimum solubility and in-vivo absorption if 2 mg of SLS was used in the oral solid dosage form.  The results obtained from this study will help broaden the understanding of the micellization process involving SLS and poorly-water soluble drugs used in combination oral solid dosage forms.


Assuntos
Absorção Intestinal , Modelos Biológicos , Dodecilsulfato de Sódio/química , Dodecilsulfato de Sódio/farmacocinética , Tensoativos/química , Tensoativos/farmacocinética , Células CACO-2 , Humanos , Secreções Intestinais/química , Micelas , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Solubilidade , Água/química
13.
Curr Drug Deliv ; 16(7): 672-686, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31250754

RESUMO

BACKGROUND: In this study, four nanoparticle formulations (F1 to F4) comprising varying ratios of alginate, Pluronic F-68 and calcium chloride with a constant amount of insulin and chitosan as a coating material were prepared using polyelectrolyte complexation and ionotropic gelation methods to protect insulin against enzymatic degradation. METHODS: This study describes the formulation design, optimisation, characterisation and evaluation of insulin concentration via oral delivery in rats. A reversed-phase high-performance liquid chromatography (HPLC) method was developed and validated to quantify insulin concentration in rat plasma. The proposed method produced a linear response over the concentration range of 0.39 to 50 µg/ml. RESULTS: In vitro release study showed that dissolution of insulin in simulated gastric juice of pH 1.2 was prevented by alginate core and chitosan coating but rapidly released in simulated intestinal fluid (pH 6.8). Additionally, Formulation 3 (F3) has a particle size of 340.40 ± 2.39 nm with narrow uniformity exhibiting encapsulation efficiency (EE) of 72.78 ± 1.25 % produced highest absorption profile of insulin with a bioavailability of 40.23 ±1.29% and reduced blood glucose after its oral administration in rats. CONCLUSION: In conclusion, insulin oral delivery system containing alginate and chitosan as a coating material has the ability to protect the insulin from enzymatic degradation thus enhance its absorption in the intestine. However, more work should be done for instance to involve human study to materialise this delivery system for human use.


Assuntos
Alginatos/administração & dosagem , Quitosana/administração & dosagem , Portadores de Fármacos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Alginatos/química , Alginatos/farmacocinética , Animais , Glicemia/efeitos dos fármacos , Quitosana/química , Quitosana/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Suco Gástrico/química , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Insulina/sangue , Insulina/química , Insulina/farmacocinética , Absorção Intestinal , Secreções Intestinais/química , Masculino , Nanopartículas/química , Ratos Sprague-Dawley
14.
J Hazard Mater ; 375: 130-137, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31054530

RESUMO

Mercury (Hg) is readily bioaccumulated in seafood, a common ingredient in indigenous cuisines throughout the world. This study investigates Hg speciation in cooked seafood after gastric and intestinal digestion. The results showed that the removal of Hg by washing was negligible. Additionally, the results of our calculations regarding the mass balance of Hg concentration indicated that cooking reduced Hg mainly by means of volatilization and that Hg2+ was more readily reduced than MeHg. Moreover, cooking lowered the bioaccessibility of Hg in seafood: the reduced percent of bioaccessible Hg2+ after cooking ranged from 2 to 35% (on average, 16%). The corresponding numbers were slightly lower compared with those for MeHg (on average, 19%). Furthermore, there might be a chemical transformation of Hg during in vitro gastrointestinal digestion. The results of in vivo tests in laboratory mice suggested that methylation of Hg mainly took place in the gastric tract, whereas demethylation of Hg occurred primarily during intestinal digestion. These findings indicate that the bioaccessibility of Hg2+ and MeHg was not only related to their initial concentrations in the food samples, but also that further studies on the mechanisms of Hg demethylation and methylation during gastrointestinal digestion are essential for more realistic risk assessments.


Assuntos
Culinária , Contaminação de Alimentos/análise , Mercúrio/análise , Alimentos Marinhos/análise , Animais , Bivalves , Desmetilação , Digestão , Peixes , Mucosa Gástrica/metabolismo , Mucosa Intestinal/metabolismo , Secreções Intestinais/química , Mercúrio/química , Mercúrio/farmacocinética , Metilação , Compostos de Metilmercúrio/análise , Compostos de Metilmercúrio/química , Compostos de Metilmercúrio/farmacocinética , Volatilização
15.
Biopharm Drug Dispos ; 40(3-4): 151-161, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30931529

RESUMO

GL-V9, a derivative of wogonin, has potent anti-cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL-V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL-V9, an in situ single-pass perfusion model and a Caco-2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (Fa × Fg ) was 21.28 ± 5.38%. The unmetabolized fraction in the gut wall (Fgut wall ) was 98.59 ± 9.74%, while the hepatic bioavailability (Fh ) was 29.11 ± 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL-V9. The effective permeability (Peff ) in the duodenum and jejunum was 1.34 ± 0.50 × 10-4 and 0.90 ± 0.27 × 10-4  cm/s, respectively. The high permeability of GL-V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Clint, CYP450s and UGT of GL-V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL-V9 possesses higher permeability than wogonin and the metabolism of GL-V9 is related to its disposition in rat intestine and liver.


Assuntos
Antineoplásicos/farmacocinética , Flavonoides/farmacocinética , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Disponibilidade Biológica , Células CACO-2 , Flavonoides/sangue , Flavonoides/química , Suco Gástrico/química , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Secreções Intestinais/química , Fígado/metabolismo , Masculino , Microssomos/metabolismo , Ratos Sprague-Dawley
16.
Biopharm Drug Dispos ; 40(3-4): 121-134, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30891805

RESUMO

BACKGROUND: Food may affect the oral absorption of drugs. PURPOSE: The aim of the present study was to investigate the influence of food on the oral absorption of clarithromycin by evaluating the effect of media parameters, such as pH, bile secretions and food composition, on the release of the drug from immediate release tablets, using in vitro and in silico assessments. METHOD: The solubility, disintegration and dissolution profiles of clarithromycin 500 mg immediate release tablets in compendial media with/without the addition of a homogenized FDA meal as well as in biorelevant simulated intestinal media mimicking fasting and fed conditions were determined. These in vitro data were input to GastroPlus™, which was used for developing a physiological absorption model capable of anticipating the effect of food on clarithromycin absorption. Level A in vitro-in vivo linear correlations were established using a mechanistic absorption modelling based deconvolution approach. RESULTS: The pH of the media has a profound effect on clarithromycin solubility, tablet disintegration and drug release. Clarithromycin has lower solubility in biorelevant media compared with other media, due to complex formation with bile salts. Clarithromycin tablets exhibited prolonged disintegration times and reduced dissolution rates in the presence of the standard FDA meal. The simulation model predicted no significant food effect on the oral bioavailability of clarithromycin. The developed IVIVC model considered SIF, acetate buffer and FaSSIF media to be the most relevant from the physiological standpoint. CONCLUSION: The intake of a standard FDA meal may have no significant effect on the oral bioavailability of clarithromycin immediate release tablet.


Assuntos
Antibacterianos/farmacocinética , Claritromicina/farmacocinética , Interações Alimento-Droga , Modelos Biológicos , Administração Oral , Antibacterianos/administração & dosagem , Antibacterianos/química , Claritromicina/administração & dosagem , Claritromicina/química , Simulação por Computador , Liberação Controlada de Fármacos , Jejum/metabolismo , Suco Gástrico/química , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal , Secreções Intestinais/química , Solubilidade , Comprimidos
17.
Eur J Pharm Sci ; 133: 167-182, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30902654

RESUMO

Thymoquinone is an effective phytochemical compound in the treatment of various diseases. However, its practical administration has been limited due to poor aqueous solubility and bioavailability. In this work, we developed a novel inclusion complex of thymoquinone and hydroxypropyl-ß-cyclodextrin that features improved solubility and bioactivity. The drug solubility was markedly accelerated in the increasing ratio of hydroxypropyl-ß-cyclodextrin to thymoquinone amount. The formation of the thymoquinone/hydroxypropyl-ß-cyclodextrin inclusion complex was evidenced using X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, Fourier transform infrared, scanning electron microscopy and nuclear magnetic resonance. The release behavior of the complex, as well as of their mixtures, was examined in artificial gastric (pH 1.2) and intestinal (pH 6.8) dissolution media. The formulated complex released the drug rapidly at the initial stage, followed by a slow release. Thermodynamic parameters ΔH, ΔS and ΔG were calculated with temperatures ranging from 20 to 45 °C to evaluate the complexation process. The activity of the inclusion complex was evaluated on IgE-mediated allergic response in rat basophilic leukemia (RBL-2H3) cells by monitoring key allergic mediators. The results revealed that compared with free thymoquinone, the inclusion complex more strongly inhibited the release of histamine, tumor necrosis factor-α, and interleukin-4, and was not cytotoxic at the tested thymoquinone concentrations (0.125-4 µg/mL) indicating the inclusion complex possibly had better antiallergic effects. Our finding suggested that the inclusion complex achieved prolonged action and reduced side-effect of thymoquinone.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , Antialérgicos/administração & dosagem , Benzoquinonas/administração & dosagem , Sistemas de Liberação de Medicamentos , Animais , Antialérgicos/química , Benzoquinonas/química , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Suco Gástrico/química , Histamina/metabolismo , Interleucina-4/metabolismo , Secreções Intestinais/química , Ratos , Fator de Necrose Tumoral alfa/metabolismo
18.
Mol Pharm ; 16(5): 1890-1905, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-30848917

RESUMO

Oral administration of a solid dosage form requires drug dissolution in the gastrointestinal tract before absorption. Solubility is a key factor controlling dissolution, and it is recognized that, within the intestinal tract, this is influenced by the luminal fluid pH, amphiphile content, and composition. Various simulated intestinal fluid recipes have been introduced to mimic this behavior and studied using a range of different experimental techniques. In this article, we have measured equilibrium solubility utilizing a novel four component mixture design (4CMD) with biorelevant amphiphiles (bile salt, phospholipid, oleate, and monoglyceride) within a matrix of three pH values (5, 6, and 7) and total amphiphile concentrations (11.7, 30.6, and 77.5 mM) to provide a topographical and statistical overview. Three poorly soluble drugs representing acidic (indomethacin), basic (carvedilol), and neutral (fenofibrate) categories have been studied. The macroscopic solubility behavior agrees with literature and exhibits an overall increasing solubility from low pH and total amphiphile concentration to high pH and total amphiphile concentration. Within the matrix, all three drugs display different topographies, which can be related to the statistical effect levels of the individual amphiphiles or amphiphile interactions on solubility. The study also identifies previously unreported three and four way factor interactions notably between bile salt, phospholipid, pH, and total amphiphile concentration. In addition, the results also reveal that solubility variability is linked to the number of amphiphiles and the respective ratios in the measurement fluid, with the minimum variation present in systems containing all four amphiphiles. The individual 4CMD experiments within the matrix can be linked to provide a possible intestinal solubility window for each drug that could be applied in PBPK modeling systems. Overall the approach provides a novel overview of intestinal solubility topography along with greater detail on the impact of the various factors studied; however, each matrix requires 351 individual solubility measurements. Further studies will be required to refine the experimental protocol in order the maximize information garnered while minimizing the number of measurements required.


Assuntos
Equilíbrio Ácido-Base/fisiologia , Líquidos Corporais/química , Química Farmacêutica/métodos , Liberação Controlada de Fármacos/fisiologia , Secreções Intestinais/química , Modelos Biológicos , Administração Oral , Ácidos e Sais Biliares/química , Carvedilol/química , Formas de Dosagem , Fenofibrato/química , Humanos , Concentração de Íons de Hidrogênio , Indometacina/química , Absorção Intestinal/fisiologia , Monoglicerídeos/química , Concentração Osmolar , Fosfolipídeos/química , Solubilidade , Tensoativos/química
19.
Food Res Int ; 116: 676-686, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30716995

RESUMO

Different oregano species have been traditionally used as infusions in folk medicine. Oregano medicinal properties, such as antioxidant and anti-inflammatory, have been partially attributed to its polyphenolic content. However, information regarding bioaccessibility of oregano polyphenols is limited. Cell-based antioxidant activity, and in vitro hypoglycemic, and hypolipidemic properties of polyphenolic extracts from three species of oregano species, namely, Hedeoma patens (HP), Lippia graveolens (LG) and Lippia palmeri (LP), subjected to simulated gastrointestinal digestion were evaluated. LC-TOF-MS analysis of HP, LG and LP allowed the identification of 9 flavonoids and 6 hydroxycinnamic acid derivatives with nutraceutical significance. Oregano polyphenolic extracts and digests from HP, LG, and LP exhibited cellular antioxidant capacity, hypoglycemic and hypolipidemic properties. Altogether, our results suggest that HP, LG and LP polyphenols exhibit potential for use as hypoglycemic, hypolipidemic, and antioxidant agents.


Assuntos
Antioxidantes/farmacologia , Digestão , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipolipemiantes/farmacologia , Lipase/antagonistas & inibidores , Origanum/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Antioxidantes/isolamento & purificação , Células CACO-2 , Cromatografia Líquida de Alta Pressão , Ácido Gástrico/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Humanos , Hipolipemiantes/isolamento & purificação , Secreções Intestinais/química , Lipase/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Polifenóis/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray
20.
J Microbiol Biotechnol ; 29(2): 200-208, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691251

RESUMO

Probiotics show low cell viability after oral administration because they have difficulty surviving in the stomach due to low pH and enzymes. For the oral delivery of probiotics, developing a formula that protects the probiotic bacteria from gastric acidity while providing living cells is mandatory. In this study, we developed tablets using a new pH-sensitive phthalyl inulin (PI) to protect probiotics from gastric conditions and investigated the effects of different compression forces on cell survival. We made three different tablets under different compression forces and measured survivability, disintegration time, and kinetics in simulated gastric-intestinal fluid. During tableting, there were no significant differences in probiotic viability among the different compression forces although disintegration time was affected by the compression force. A higher compression force resulted in higher viability in simulated gastric fluid. The swelling degree of the PI tablets in simulated intestinal fluid was higher than that of the tablets in simulated gastric fluid due to the pH sensitivity of the PI. The probiotic viability formulated in the tablets was also higher in acidic gastric conditions than that for probiotics in solution. Rapid release of the probiotics from the tablet occurred in the simulated intestinal fluid due to the pH sensitivity. After 6 months of refrigeration, the viability of the PI probiotics was kept. Overall, this is the first study to show the pH-sensitive properties of PI and one that may be useful for oral delivery of the probiotics.


Assuntos
Inulina/administração & dosagem , Inulina/química , Probióticos/administração & dosagem , Probióticos/química , Administração Oral , Força Compressiva , Composição de Medicamentos , Estabilidade de Medicamentos , Armazenamento de Medicamentos , Suco Gástrico/química , Concentração de Íons de Hidrogênio , Secreções Intestinais/química , Inulina/farmacocinética , Viabilidade Microbiana , Probióticos/farmacocinética , Comprimidos/administração & dosagem , Comprimidos/química , Comprimidos/farmacocinética
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