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1.
AAPS PharmSciTech ; 20(6): 252, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300965

RESUMO

The objective of the present study was to investigate the effect of partially hydrolyzed ginsenoside on the physicochemical properties and in vitro release of curcumin from phospholipid-based nanostructured lipid carrier (NLC). NLC formulas modified with partially hydrolyzed ginsenoside (NLC-PG) were prepared with different amounts of ginsenoside using the conventional hot-melt method. The average particle size of curcumin-loaded NLC-PG ranged from 150 to 200 nm, and polydispersity index was in the range of 0.101-0.177, indicating monodispersed particle size distribution. Optical microscopy showed no sedimentation or recrystallization of curcumin even at 10,000 µg/ml concentration as NLC-PG in distilled water, indicating significantly enhanced solubility. TEM image showed that the nanoparticles were monodispersed with a multilayered core/shell structure. X-ray diffraction and FTIR spectroscopy showed that curcumin was amorphous in the NLC-PG, and there was no interaction between curcumin and the excipients. In vitro release study using simulated gastric/intestinal fluid media revealed that the release rate (Jss) of curcumin from the NLC-PG increased as a function of the ginsenoside content in the lipid carrier. Moreover, the Jss of curcumin kept gradually increasing in the presence of lipase, whereas in the presence of viscozyme, it sharply increased until the ginsenoside content reached 9.09% and subsequently plateaued. Partially hydrolyzed ginsenoside increased the Jss of curcumin from curcumin-loaded NLC-PG and therefore may be useful for improving the bioavailability of curcumin.


Assuntos
Curcumina/química , Portadores de Fármacos/química , Ginsenosídeos/química , Lipídeos/química , Nanoestruturas/química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Curcumina/farmacocinética , Portadores de Fármacos/farmacocinética , Excipientes/química , Excipientes/farmacocinética , Ginsenosídeos/farmacocinética , Hidrólise , Lipídeos/farmacocinética , Lisofosfatidilcolinas/química , Lisofosfatidilcolinas/farmacocinética , Tamanho da Partícula , Fosfatidilcolinas/química , Fosfatidilcolinas/farmacocinética , Óleo de Soja/química , Óleo de Soja/farmacocinética , Difração de Raios X/métodos
2.
Expert Opin Pharmacother ; 20(14): 1689-1702, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31339385

RESUMO

Introduction: The cyclooxygenase (COX)-2 inhibitor celecoxib is an approved compound for rheumatoid (RA) and osteoarthritis (OA), combining both anti-inflammatory and analgesic properties with a good gastrointestinal tolerability. Areas covered: This article covers the pharmacological properties and clinical efficacy as well as the latest safety data available for celecoxib with emphasis on the treatment of RA and OA. It is based primarily on a current literature search on PubMed and Web of Science, but also on the professional rheumatological expertise of the authors. Expert opinion: Celecoxib has been shown to be superior to placebo and equivalent to traditional non-steroidal anti-inflammatory drugs (tNSAIDs). Many studies have been published making celecoxib a good and safe treatment option in particular in moderate arthritis and patients without established cardiovascular (CV) disease. Moreover, older patients might gain significant benefits compared to tNSAIDs due to reduced gastrointestinal events even when having a history of ulcer bleedings. Nonetheless, there is still much to learn, especially regarding the prescription of celecoxib in patients with cardiovascular co-morbidities. While low doses seem to be safe according to present data, the knowledge on the more effective, higher doses >400 mg/day is still limited.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Celecoxib/uso terapêutico , Osteoartrite/tratamento farmacológico , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Artrite Reumatoide/patologia , Doenças Cardiovasculares/etiologia , Celecoxib/efeitos adversos , Celecoxib/farmacocinética , Ensaios Clínicos como Assunto , Meia-Vida , Humanos , Osteoartrite/patologia , Prostaglandina-Endoperóxido Sintases/química , Prostaglandina-Endoperóxido Sintases/metabolismo , Resultado do Tratamento
3.
J Zoo Wildl Med ; 50(2): 322-329, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260196

RESUMO

Flunixin meglumine, a nonsteroidal anti-inflammatory medication, has been used in rhinoceros species at doses extrapolated from domestic animals. There is increasing evidence to suggest significant variations exist in metabolism of drugs in exotic species. Due to the differences in drug metabolism, dose extrapolation from domestic animals may not be appropriate for exotic species. The objective of this study was to investigate the pharmacokinetics of flunixin meglumine in five white rhinoceroses (Ceratotherium simum) administered a single (1 mg/kg) oral dose of a commercial equine flunixin meglumine paste. Concentrations of flunixin and its metabolite 5-OH flunixin were analyzed, and pharmacokinetic parameters were estimated for each animal. Mean observed plasma concentrations peaked at 1,207 ± 601 ng/ml and occurred at 3 ± 1 hr. The geometric mean of the apparent elimination half-life after oral administration was 8.3 ± 1.2 hr. This data suggests that flunixin meglumine appears to be slowly metabolized or slowly absorbed in this species. No adverse clinical effects were observed during the study period. A single dose of 1 mg/kg appears safe for use in the white rhinoceros. Multidose studies are needed to determine if plasma accumulation of flunixin meglumine occurs and to evaluate safety.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Clonixina/análogos & derivados , Perissodáctilos/sangue , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Área Sob a Curva , Clonixina/administração & dosagem , Clonixina/sangue , Clonixina/farmacocinética , Feminino , Meia-Vida , Masculino
4.
Vet Anaesth Analg ; 46(4): 548-555, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31153785

RESUMO

OBJECTIVE: To investigate the pharmacokinetics and absolute oral bioavailability of meloxicam in guinea pigs. STUDY DESIGN: Prospective crossover study. ANIMALS: A group of six healthy male Dunkin Hartley guinea pigs. METHODS: A single dose of meloxicam (1.5 mg kg-1) was administered orally and intravenously (IV) to six healthy male guinea pigs. A wash-out period of 48 hours was taken into account between administrations (oral and IV) in the same animal. Blood was sampled through a central venous catheter before administration (t = 0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 and 28 hours post administration. After centrifugation, plasma concentrations of meloxicam were measured by high-performance liquid chromatography with UV detection, and pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS: Meloxicam in guinea pigs exhibited a moderate absorption rate after oral dosing (time to maximal plasma concentration 3.7 ± 1.7 hours) and maximal plasma concentration was 0.92 ± 0.30 µg mL-1. After IV administration, total body clearance and volume of distribution were 0.13 ± 0.04 and 0.72 ± 0.36 L kg-1, respectively. Terminal half-life was 3.7 ± 0.7 hours and 3.5 ± 1.1 hours after IV and oral administration, respectively. Body extraction ratio was 0.0087 and mean absorption time was 3.8 ± 1.7 hours. The absolute oral bioavailability was 0.54 ± 0.14 in unfasted guinea pigs. CONCLUSIONS AND CLINICAL RELEVANCE: This study reported the pharmacokinetics of meloxicam in guinea pigs. Studies concerning efficacy and safety are the next step towards a rational use of this drug in guinea pigs.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Meloxicam/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Disponibilidade Biológica , Cobaias , Meia-Vida , Injeções Intravenosas , Masculino , Meloxicam/administração & dosagem , Meloxicam/sangue
5.
J Microencapsul ; 36(2): 169-179, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31104531

RESUMO

Curcumin, a natural polyphenolic compound, has numerous pharmacological activities; while it faces several bioavailability problems, due to its poor solubility and stability. So, many nanostructures have been designed to overcome these drawbacks. The aim of this study was to prepare a polymeric niosomal structure by incorporating hyaluronan to improve curcumin efficiencies. Hyaluronan containing niosomes were prepared by thin film hydration medium with slight modifications. In the formulation of hyaluronan containing niosomes size and zeta potential studies, Atomic Force Microscopy (AFM), Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), in-vitro release test, DPPH antioxidant assay and in-vivo anti-inflammatory test were investigated. The results showed that hyaluronan containing niosomes were 249.83 ± 6.38 nm and the entrapment of curcumin was 98.28 ± 0.278% (w/w). In addition, the shape of the hyaluronan containing niosomes was spherical. 500 µl of the prepared formulation with 4.002 × 10-7 moles of curcumin showed 100% antioxidant effect. Moreover, the anti-inflammatory effect of the hyaluronan containing niosomes was higher than the anti-inflammatory effect of the simple suspension of curcumin.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Antioxidantes/administração & dosagem , Curcumina/administração & dosagem , Ácido Hialurônico/química , Nanocápsulas/química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Antioxidantes/farmacocinética , Antioxidantes/farmacologia , Curcumina/farmacocinética , Curcumina/farmacologia , Liberação Controlada de Fármacos , Feminino , Tamanho da Partícula , Ratos
6.
Artigo em Inglês | MEDLINE | ID: mdl-31046561

RESUMO

Acetaminophen, a popular NSAID (Non-steroidal anti-inflammatory drug), was studied for efficacy of removal from aqueous solutions. While Octolig® (a polyethylenediimine covalently attached to silica gel) is able to remove many simple anions and some acidic pharmaceuticals having a pKa value less than 4.5, it lacked efficacy with acetaminophen. Accordingly different transition- metal derivatives of Octolig® were tested by column chromatography using as substrates Octolig® derivatives of copper(II), cobalt(II), iron(III), manganese(II), nickel(II), and zinc(II).


Assuntos
Anti-Inflamatórios não Esteroides/isolamento & purificação , Sílica Gel/química , Poluentes Químicos da Água/isolamento & purificação , Purificação da Água/métodos , Água/química , Acetaminofen/isolamento & purificação , Acetaminofen/farmacocinética , Ânions , Anti-Inflamatórios não Esteroides/farmacocinética , Cromatografia/métodos , Cobalto/química , Cobre/química , Compostos Férricos/química , Humanos , Manganês/química , Níquel/química , Polietilenos/química , Sílica Gel/metabolismo , Soluções/química , Poluentes Químicos da Água/farmacocinética , Zinco/química
7.
AAPS PharmSciTech ; 20(5): 193, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31115746

RESUMO

Three polymers, polyvinylpyrrolidone (PVP K30), hydroxypropyl methyl cellulose (HPMC E5), and Kollidone VA64 (PVP-VA64), have been assessed for their impact on the nucleation and crystal growth of indomethacin (IND) from supersaturation solutions. PVP was the most effective inhibitor on IND nucleation among three polymers, but the effect of three polymers on inhibiting nucleation is quite limited when the degree of supersaturation S is higher than about 9. Analysis of the nucleation data by classical nucleation theory model generally afforded good data fitting with the model and showed that addition of polymers may affect the crystal/solution interfacial free energy γ and also the pre-exponential kinetic factor. PVP-VA showed better inhibitory effects on crystal growth of IND when the polymer concentration is high (0.1%, w/w) as reflected by the crystal growth inhibition factor R, and PVP exhibited relatively stronger effects on inhibiting crystal growth at low polymer concentrations (0.005%, w/w). The crystal growth inhibitory effect of polymers should be attributable to the retardation of the surface integration of the drug, and such effect should also be polymer and drug dependent. The enhancement of supersaturation level of IND should be attributable to both nucleation and crystal growth inhibition by polymers. The nucleation and crystal growth rate of α-polymorph IND is higher than that of γ-polymorph, and α-polymorph is the predominant form appeared in supersaturated solutions. A rational selection of the appropriate polymer for specific drug is critical for developing supersaturated drug delivery formulations.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Indometacina/síntese química , Polímeros/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Cristalização/métodos , Composição de Medicamentos , Derivados da Hipromelose/síntese química , Derivados da Hipromelose/farmacocinética , Indometacina/farmacocinética , Soluções Farmacêuticas/síntese química , Soluções Farmacêuticas/farmacocinética , Polímeros/farmacocinética , Povidona/síntese química , Povidona/farmacocinética , Solubilidade
8.
J Anim Sci ; 97(7): 2750-2768, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31100113

RESUMO

Painful processing procedures in piglets such as tail docking, castration, and teeth clipping are an emerging animal welfare concern. We hypothesized that transmammary delivery of a nonsteroidal anti-inflammatory drug, firocoxib, would reduce pain associated with processing in piglets. This study compared the pharmacokinetics, efficacy, safety, and tissue residue concentrations of 4 doses of firocoxib (0.5, 1.0, 1.5, or 2.0 mg/kg) administered to sows and delivered to nursing piglets prior to processing. Sixteen sows, 5 ± 2 d postpartum, were randomly assigned to 1 of 4 treatment groups. On day 0, sows received a single intramuscular dose of firocoxib at 7 ± 1 h before piglet surgical castration, tail docking, and teeth clipping (males) or sham handling (females). Firocoxib and cortisol concentrations were determined from selected samples collected from sows and 3 piglets per litter (2 barrows and 1 gilt) at 0, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after drug administration. On day 21, piglets were weighed and all animals were euthanized and necropsied. Tissues were collected from 3 piglets per litter for histological examination and drug residue analysis. Mean (±SEM) peak plasma firocoxib concentrations (Cmax) were 107.90 ± 15.18, 157.50 ± 24.91, 343.68 ± 78.89, and 452.83 ± 90.27 ng/mL in sows receiving 0.5, 1.0, 1.5, and 2.0 mg/kg firocoxib, respectively, and 9.53 ± 1.21, 31.04 ± 6.79, 53.30 ± 11.1, and 44.03 ± 7.47 ng/mL in their respective piglets. Mean plasma terminal half-life values ranged from 26 to 31 h in sows and 30 to 48 h in piglets. Barrows nursing sows that received 2.0 mg/kg firocoxib had a lower mean plasma cortisol concentration at 1 ± 1 h after processing compared with barrows nursing sows that received 1.0 mg/kg (P = 0.0416) and 0.5 mg/kg of firocoxib (P = 0.0397). From processing to weaning, litters of sows receiving 2.0 mg/kg firocoxib gained more weight than litters of sows that received 0.5 mg/kg (P = 0.008) or 1.0 mg/kg (P = 0.005). No signs of nonsteroidal anti-inflammatory drug toxicity were observed on examination of the kidney, liver, stomach, and small intestine, and concentrations of firocoxib and the descyclopropylmethyl metabolite were below the limit of detection (0.01 µg/g) in all tissues examined from sows and piglets. These findings indicate that maternal delivery of firocoxib to suckling piglets before tail docking and castration may safely reduce processing-induced stress and enhance production by increasing weaning weights.


Assuntos
4-Butirolactona/análogos & derivados , Bem-Estar do Animal , Anti-Inflamatórios não Esteroides/administração & dosagem , Sulfonas/administração & dosagem , Suínos/fisiologia , 4-Butirolactona/administração & dosagem , 4-Butirolactona/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Feminino , Hidrocortisona/sangue , Injeções Intramusculares/veterinária , Lactação , Masculino , Orquiectomia/veterinária , Dor/prevenção & controle , Dor/veterinária , Gravidez , Distribuição Aleatória , Sulfonas/farmacocinética , Suínos/cirurgia , Dente/cirurgia , Desmame
9.
AAPS PharmSciTech ; 20(5): 204, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31140011

RESUMO

Deep eutectic solvents (DESs) have recently been getting a great deal of attention in many fields of science and technology. The objective of this study was to peruse the solubility of indomethacin (IMC) as sparingly soluble drug in some tetrabutylammonium bromide (TBAB)-based DESs (TBAB/ethylene glycol and TBAB/glycerol). The shake flask method has been employed in this study at temperature ranges T = (298.15-313.15) K and atmospheric pressure (pP = 86.6 kPa). The results showed that the solubility of IMC in TBAB/ethylene glycol system was obtained approximately 17,000-fold more than its solubility in water. The solubility data were accurately correlated by the famous local composition activity coefficient models including e-NRTL and UNIQUAC. It was also our aim to evaluate Hansen solubility parameters in IMC solubility prediction. These parameters can help to predict the solvent performance during the manufacturing processes and will be useful in guessing solvent behavior in many other fields of effort. The experimental and the Hansen solubility parameters results are very well matched. In addition, the apparent thermodynamic properties of dissolution and mixing were studied in these solutions based on Van't Hoff and Gibbs equations.


Assuntos
Anti-Inflamatórios não Esteroides/química , Indometacina/química , Modelos Químicos , Compostos de Amônio Quaternário/química , Temperatura Ambiente , Água/química , Anti-Inflamatórios não Esteroides/farmacocinética , Previsões , Indometacina/farmacocinética , Compostos de Amônio Quaternário/farmacocinética , Solubilidade , Solventes , Termodinâmica
10.
Drug Deliv ; 26(1): 481-489, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30957571

RESUMO

OBJECTIVES: Ginsenosides Rb1 (Rb1) could form micelles in aqueous solutions. Self-assembled Rb1 micelles could potentially be utilized as ocular drug delivery system, and it was postulated that the encapsulation of a medicine within Rb1 micelles might strengthen the drug's therapeutic action and reduce side effects. METHODS: Diclofenac-loaded Rb1 micelles (Rb1-Dic micelles) were formulated, optimized, and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vivo corneal permeation, and in vivo anti-inflammatory efficacy. RESULTS: Rb1 self-assembled into micelles with ultra-small particle size (<8 nm) in a homogeneous distribution state (polydispersity index [PDI] < 0.3). Diclofenac was highly encapsulated into the micelles according to the weight ratios of Rb1 to diclofenac. The ophthalmic solution of Rb1-Dic micelle was simple to prepare. Rb1 had good cellular tolerance, and it also improved the cellular tolerance of the encapsulated diclofenac. Rb1-Dic micelles also showed non-irritants to the rabbit eyes. The use of Rb1 micelles significantly improved the in vivo corneal permeation as well as the anti-inflammatory efficacy of diclofenac when compared to commercial diclofenac eye drops. CONCLUSION: Rb1 micelle formulations have great potential as a novel ocular drug delivery system to improve the bioavailability of drugs such as diclofenac.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Córnea/metabolismo , Diclofenaco/administração & dosagem , Portadores de Fármacos/química , Ginsenosídeos/química , Nanopartículas/química , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/toxicidade , Disponibilidade Biológica , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diclofenaco/farmacocinética , Diclofenaco/toxicidade , Células Epiteliais/efeitos dos fármacos , Humanos , Micelas , Soluções Oftálmicas , Tamanho da Partícula , Coelhos , Solubilidade
11.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925715

RESUMO

Aquaporin-3 (AQP3) plays an important role in water transport in the gastrointestinal (GI) tract. In this study, we conducted a Caco-2 cell permeability assay to examine how changes in the expression and function of AQP3 affect the rate at which a drug is absorbed via passive transport in the GI tract. When the function of AQP3 was inhibited by mercuric chloride or phloretin, there was no change in warfarin permeability. In contrast, when the expression of AQP3 protein was decreased by prostaglandin E2 (PGE2) treatment, warfarin permeability increased to approximately twice the control level, and membrane fluidity increased by 15%. In addition, warfarin permeability increased to an extent comparable to that after PGE2 treatment when cell membrane fluidity was increased by 10% via boric acid/EDTA treatment. These findings suggest the possibility that the increased drug absorption under decreased AQP3 expression was attributable to increased membrane fluidity. The results of this study demonstrate that the rate of water transport has little effect on drug absorption. However, our findings also indicate that although AQP3 and other similar transmembrane proteins do not themselves transport drugs, changes in their expression levels can cause changes in cell membrane fluidity, thus affecting drug absorption rates.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Anticoagulantes/farmacocinética , Antipirina/farmacocinética , Aquaporina 3/metabolismo , Trato Gastrointestinal/metabolismo , Absorção Intestinal , Varfarina/farmacocinética , Células CACO-2 , Permeabilidade da Membrana Celular , Humanos , Fluidez de Membrana , Permeabilidade
12.
Skin Pharmacol Physiol ; 32(3): 132-141, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909278

RESUMO

BACKGROUND/AIMS: The mechanisms by which permeation enhancers increase human skin permeation of caffeine and naproxen were assessed in vitro. METHODS: Active compound solubility in the vehicles and in the stratum corneum (SC), active compound flux across epidermal membranes and uptake of active and vehicle components into the SC were measured. The effect of vehicle pH on the permeation of caffeine and naproxen was also determined. RESULTS: Oleic acid and eucalyptol significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous controls. Naproxen permeation was increased from vehicles with pH presenting more ionized naproxen. Caffeine maximum flux enhancement was associated with an increase in caffeine SC solubility and skin diffusivity, whereas for naproxen a penetration enhancer/vehicle-induced increase in solubility in the SC correlated with an increase in maximum flux. SC solubility was related to experimentally determined active uptake, which was in turn predicted by vehicle uptake and active compound solubility in the vehicle. CONCLUSION: A permeation enhancer-induced alteration in diffusivity, rather than effects on SC solubility, was the main driving force behind increases in permeation flux of the hydrophilic molecule caffeine. For the more the lipophilic molecule naproxen, increased SC solubility drove the increases in permeation flux.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Cafeína/farmacocinética , Epiderme/efeitos dos fármacos , Naproxeno/farmacocinética , Veículos Farmacêuticos/farmacologia , Absorção Cutânea/efeitos dos fármacos , Epiderme/metabolismo , Etanol/farmacologia , Eucaliptol/farmacologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Ácido Oleico/farmacologia , Permeabilidade , Polietilenoglicóis/farmacologia , Dodecilsulfato de Sódio/farmacologia
13.
Drug Dev Ind Pharm ; 45(6): 895-904, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30889990

RESUMO

In the present study, in order to improve the solubility and bioavailability of poorly water-soluble dexibuprofen, a novel dexibuprofen-loaded solid dispersion was developed using the spray-drying technique. The controlled-release dexibuprofen formulation was developed by combining the immediate-release dispersion powder and the sustained-release formula. The solid dispersion composed of dexibuprofen/poloxamer 407/hydroxypropyl methylcellulose (HPMC) 2910 (50 cps)/sodium lauryl sulfate (SLS) (10/1/4/0.1 mg) was selected as the immediate-release formulation due to its increased solubility and dissolution rate. This immediate-release formulation showed a significantly higher initial plasma concentration, AUC, and Cmax of dexibuprofen than those of dexibuprofen powder. Based on the prolonged effect of high plasma concentration, the formulation consisting of dexibuprofen/ethylcellulose/HPMC 2910 (4000 cps)/magnesium stearate (66/16.5/16.5/1 mg) was selected as the sustained-release formulation. Finally, the controlled-release (CR) formulation was prepared by encapsulating the immediate-release and sustained-release formulations in hard gelatin capsules. The proposed CR formulation showed enhanced AUC (5.5-fold) and Cmax (3.5-fold) compared to dexibuprofen powder. The results of the present study suggest that the CR formulation containing dexibuprofen may be a potential oral dosage form for a fast onset and a prolonged effect of poorly water-soluble dexibuprofen.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Composição de Medicamentos/métodos , Excipientes/química , Ibuprofeno/análogos & derivados , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Cápsulas , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Ibuprofeno/administração & dosagem , Ibuprofeno/farmacocinética , Masculino , Pós , Ratos , Ratos Sprague-Dawley , Solubilidade
14.
Eur J Pharm Biopharm ; 139: 132-141, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30910731

RESUMO

The current study proposes an original oral delivery system for the bioavailability enhancement of indomethacin (IND), a BCS class II drug, with the aim to overcome the common limitations of amorphous solid dispersion. In fact, the potential risk of drug re-crystallization is a serious concern for the stability of amorphous systems and represents, despite the great bioavailability, one of the primary causes of their limited clinical applications. IND-loaded microparticles (MPs) were prepared by spray congealing using oral-approved excipients (Gelucire 50/13 and the recently marketed Gelucire 48/16). MPs were characterized regarding particle size, morphology, drug content and IND solid state; moreover, they were tested in vitro for IND solubility and dissolution rate. Solid state characterization indicated that IND was present into the MPs in the amorphous form. The best formulation showed a considerable enhancement in drug dissolution rate and 31-fold higher drug solubility than pure γ-IND. The oral administration of MPs showed 2.5-times increased bioavailability in vivo compared to either pure γ-IND or its physical mixture with unloaded MPs. Notably, the formulation was stable after 18 months with no changes in IND solid state and dissolution performance. This study offers a valid approach to enhance IND oral bioavailability by conversion into the amorphous form by spray congealed MPs, which have great potential for industrial application due to their characteristics of high encapsulation efficiency, no-toxicity, low-cost, prolonged stability and the use of a simple and easily scaled-up manufacturing technology.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Composição de Medicamentos/métodos , Excipientes/química , Indometacina/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Disponibilidade Biológica , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Gorduras/química , Indometacina/administração & dosagem , Indometacina/química , Masculino , Modelos Animais , Óleos/química , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Difração de Raios X
15.
Analyst ; 144(6): 2062-2079, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30724915

RESUMO

trans-Resveratrol (RSV) is a plant-derived polyphenol endowed with a broad spectrum of promising therapeutic activities. The applicability of RSV in vivo has, however, had limited success so far, largely due to its inefficient systemic delivery resulting from its low water solubility. Layer-by-Layer (LbL) nanotechnology constitutes an innovative formulation strategy to address this concern, and is based on the design of tunable onion-like multilayered nanoarchitectures on the surface of low solubility drug nanocores, such as RSV. The purpose of this study was the investigation of the bioavailability of an LbL nanoformulation composed of 5.5 bilayers of polyallylamine hydrochloride (PAH) and dextran sulfate (DS) (LbL NPs) by pharmacokinetic studies following oral dosing to Wistar rats (20 mg kg-1). The systemic exposure of LbL NPs was compared to the respective nanoformulation without LbL coatings (RSV nanocores) and the free RSV suspension. The results demonstrated that both LbL NPs and RSV nanocores significantly enhanced, respectively, 1.76-fold and 2.74-fold the systemic exposure of RSV compared to the free RSV suspension, emphasizing their biopharmaceutical advantage. Surprisingly, besides the modified drug release potential of the LbL NPs, these exhibited a slightly lower systemic exposure (0.36-fold) in comparison with non-LbL modified RSV nanocores. These results were justified only by the electrostatic interactions composition of the LbL shell composition, requiring further research towards the application of stronger interactions. For this study, due to the key role of the bioanalytical method in the in vivo data acquisition, a rapid, selective, and sensitive HPLC-DAD method has been successfully optimized and fully validated to confidently quantify RSV levels in the rat plasma matrix, together with the optimization of the sample preparation procedure. Moreover, the chemical stability of RSV was evaluated for 24 h in simulated gastric and intestinal fluids with enzymes. Overall, our findings suggest that LbL NPs should be given great attention, representing a potential drug delivery system for RSV in view of the application of RSV not solely as a supplement but also as a therapeutic drug.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Sistemas de Liberação de Medicamentos , Nanopartículas/administração & dosagem , Nanopartículas/química , Resveratrol/administração & dosagem , Resveratrol/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
16.
J Vet Pharmacol Ther ; 42(3): 368-371, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30761557

RESUMO

This study describes the pharmacokinetics of vitacoxib in healthy rabbits following administration of 10 mg/kg intravenous (i.v.) and 10 mg/kg oral. Twelve New Zealand white rabbits were randomly allocated to two equally sized treatment groups. Blood samples were collected at predetermined times from 0 to 36 hr after treatment. Plasma drug concentrations were determined using UPLC-MS/MS. Pharmacokinetic analysis was completed using noncompartmental methods via WinNonlin™ 6.4 software. The mean concentration area under curve (AUClast ) for vitacoxib was determined to be 11.0 ± 4.37 µg hr/ml for i.v. administration and 2.82 ± 0.98 µg hr/ml for oral administration. The elimination half-life (T1/2λz ) was 6.30 ± 2.44 and 6.30 ± 1.19 hr for the i.v. and oral route, respectively. The Cmax (maximum plasma concentration) and Tmax (time to reach the observed maximum (peak) concentration at steady-state) following oral application were 189 ± 83.1 ng/ml and 6.58 ± 3.41 hr, respectively. Mean residence time (MRTlast ) following i.v. injection was 6.91 ± 3.22 and 11.7 ± 2.12 hr after oral administration. The mean bioavailability of oral administration was calculated to be 25.6%. No adverse effects were observed in any rabbit. Further studies characterizing the pharmacodynamics of vitacoxib are required to develop a formulation of vitacoxib for rabbits.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Imidazóis/farmacocinética , Sulfonas/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Disponibilidade Biológica , Imidazóis/administração & dosagem , Imidazóis/sangue , Injeções Intravenosas/veterinária , Coelhos , Sulfonas/administração & dosagem , Sulfonas/sangue
17.
J Vet Pharmacol Ther ; 42(3): 309-317, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30802981

RESUMO

The aim of this study was to determine the pharmacokinetics and prostaglandin E2 (PGE2 ) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight adult female Boer goats. A dose of 2.2 mg/kg was administered intravenously (IV) and 3.3 mg/kg administered TD using a cross-over design. Plasma flunixin concentrations were measured by LC-MS/MS. Prostaglandin E2 concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE2 concentrations decreased after flunixin meglumine for both routes of administration. Mean λz -HL after IV administration was 6.032 hr (range 4.735-9.244 hr) resulting from a mean Vz of 584.1 ml/kg (range, 357.1-1,092 ml/kg) and plasma clearance of 67.11 ml kg-1  hr-1 (range, 45.57-82.35 ml kg-1  hr-1 ). The mean Cmax , Tmax, and λz -HL for flunixin following TD administration was 0.134 µg/ml (range, 0.050-0.188 µg/ml), 11.41 hr (range, 6.00-36.00 hr), and 43.12 hr (15.98-62.49 hr), respectively. The mean bioavailability for TD flunixin was calculated as 24.76%. The mean 80% inhibitory concentration (IC80 ) of PGE2 by flunixin meglumine was 0.28 µg/ml (range, 0.08-0.69 µg/ml) and was only achieved with IV formulation of flunixin in this study. The PK results support clinical studies to examine the efficacy of TD flunixin in goats. Determining the systemic effects of flunixin-mediated PGE2 suppression in goats is also warranted.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Clonixina/análogos & derivados , Administração Cutânea , Animais , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacologia , Clonixina/sangue , Clonixina/farmacocinética , Clonixina/farmacologia , Estudos Cross-Over , Dinoprostona/sangue , Feminino , Cabras/sangue , Injeções Intravenosas/veterinária , Distribuição Aleatória
18.
J Vet Intern Med ; 33(2): 961-967, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30768821

RESUMO

BACKGROUND: Nonsteroidal anti-inflammatory drugs are administered in horses for several systemic diseases. Selective cyclooxygenase-2 inhibitors are preferred because of lower risk of adverse effects. Several meloxicam formulations have been tested in horses, but a recently marketed granule oral formulation has not been studied. OBJECTIVE: To characterize the pharmacokinetics of a novel granule meloxicam formulation in fasted and fed horses, and to compare pharmacokinetic features with oral suspension and tablets. ANIMALS: Seven healthy adult horses. METHODS: Meloxicam was administered at 0.6 mg/kg in fasted or fed horses. Blood samples were collected for pharmacokinetic analysis, and vital signs, hematology, and biochemistry variables were monitored for 72 hours. RESULTS: No adverse effects were detected. Volume of distribution and clearance after intravenous administration of meloxicam were 0.36 L/kg and 29.12 mL/h/kg, respectively, with a 12.39 hours of terminal half-life. Protein binding was of 97%. Bioavailability was high for every oral formulation, ranging 70%-110%, without feed effect. Because of a slower absorption, meloxicam after administration of granules had a longer half-life (24 and 34 hours, fasted and fed, respectively) and mean residence time (31 and 47 hours), than suspension and tablets (ranging 10-13 and 13-15 hours, respectively). In addition, the time above therapeutic concentration was higher for the granule formulation than other formulations. CONCLUSIONS AND CLINICAL IMPORTANCE: Granule formulation has different PK parameters compared to other oral formulations, which could enable this formulation to be used for different dosage regimens in order to reach a desired clinical effect or decrease the risk of adverse effects.


Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Cavalos/metabolismo , Meloxicam/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/sangue , Disponibilidade Biológica , Jejum , Feminino , Masculino , Meloxicam/administração & dosagem , Meloxicam/sangue , Comprimidos
19.
AAPS PharmSciTech ; 20(3): 112, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30761441

RESUMO

We have successfully conjugated mesalamine (5-aminosalicylic acid, 5-ASA) with xylan, a biopolymer isolated from pineapple stem waste, to form xylan-5-ASA conjugate. The biopolymer was used to provide colon-targeting properties for 5-ASA, a golden standard anti-inflammatory agent commonly used for ulcerative colitis treatment. A series of data from FTIR spectroscopy, UV-Vis spectrophotometry, and HPLC confirmed the xylan-5-ASA conjugate formation. To ensure successful colon targeting properties, in vitro and in vivo drug release studies after oral administration of xylan-5-ASA conjugate to Wistar rats were performed. Xylan-5-ASA conjugate was able to retain 5-ASA release in the upper gastrointestinal tract fluid simulation but rapidly released 5-ASA in the rat colon fluid simulation. In vivo release profile shows a very low peak plasma concentration, reached at 6 h after xylan-5-ASA conjugate administration. The delayed release and the lower bioavailability of 5-ASA from xylan-5-ASA conjugate administration compared to free 5-ASA administration confirmed the successful local colon delivery of 5-ASA using xylan-5-ASA conjugate. The administration of xylan-5-ASA conjugate also exhibited greater efficacy in recovering 2,4,6-trinitrobenzene sulfonic acid-induced colon ulcer compared to free 5-ASA administration. Taken together, xylan isolated from pineapple stem waste is promising to obtain colon targeting property for 5-ASA.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Biopolímeros/química , Colo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Mesalamina/administração & dosagem , Caules de Planta/química , Xilanos/química , Administração Oral , Ananas/química , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacocinética , Biopolímeros/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Colite Ulcerativa/metabolismo , Masculino , Mesalamina/efeitos adversos , Mesalamina/farmacocinética , Ratos , Ratos Wistar , Espectrofotometria Ultravioleta , Ácido Trinitrobenzenossulfônico/química , Xilanos/isolamento & purificação , Xilanos/farmacocinética
20.
Eur J Pharm Sci ; 130: 78-90, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684657

RESUMO

Many strategies have been employed to improve oral drug delivery. One such approach involves the use of supersaturable delivery systems such as amorphous self-micellizing solid dispersions (SmSDs). SmSDs have attracted more attention recently, but little is known regarding the impact of production methods on profiles and internal mechanisms of final SmSDs in spite of its importance. In this study, amorphous SmSDs containing self-micellizing Soluplus® and BCS II drug (either indomethacin (IND) or fenofibrate (FEN)) were generated using various methods: solvent evaporation (SOL), freeze-drying (FD), microwave radiation-quench cooling (MQC), and hot melt extrusion (HME). Microscopic morphology, amorphous state, thermal behavior, dissolution/solubility, and "spring-parachute" data were used to assemble physicochemical profiles for SmSD systems prepared using each method. Analysis of intermolecular interactions, solubilization, and crystallization inhibition further uncovered internal mechanisms explaining observed physicochemical properties. Generally, SmSD/IND and SmSD/FEN systems generated using HME exhibited superior dissolution, solubility, and spring-parachute profiles. The superior advantages of HME-generated SmSD/IND systems were attributed to relatively stronger intermolecular interactions than observed in SmSD/IND systems fabricated using other methods. Moreover, self-micellizing Soluplus® carrier was able to solubilize IND or FEN and suppress drug crystallization from a supersaturated state, which seemed to be an important mechanism for the properties enhancement caused by SmSD/FENHME. This knowledge should be useful for guiding further development of self-micellizing solid dispersions and for gaining deeper understanding of how HME technology can improve supersaturable drug delivery based on SmSDs strategy.


Assuntos
Química Farmacêutica/métodos , Fenofibrato/química , Temperatura Alta , Indometacina/química , Micelas , Polietilenoglicóis/química , Polivinil/química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Relação Dose-Resposta a Droga , Fenofibrato/farmacocinética , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Indometacina/farmacocinética , Polietilenoglicóis/farmacocinética , Polivinil/farmacocinética , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos
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