RESUMO
Oral drug administration, especially when composed of mucoadhesive delivery systems, has been a research trend due to increased residence time and contact with the mucosa, potentially increasing drug bioavailability and stability. In this context, this study aimed to develop self-assembly mucoadhesive beads composed of blends of κ-carrageenan and sericin (κ-Car/Ser) loaded with the anti-inflammatory drug indomethacin (IND). We investigated the swelling, adhesion behaviour, and mechanical/physical properties of the beads, assessing their effects on cell viability, safety and permeation characteristics in both 2D and triple-culture model. The swelling ratio of the beads indicated pH-responsiveness, with maximum water absorption at pH 6.8, and strong mucoadhesion, increasing primarily with higher polymer concentrations. The beads exhibited thermal stability and no chemical interaction with IND, showing improved mechanical properties. Furthermore, the beads remained stable during accelerated and long-term storage studies. The beads were found to be biocompatible, and IND encapsulation improved cell viability (>70 % in both models, 79 % in VN) and modified IND permeation through the models (6.3 % for F5 formulation (κ-Car 0.90 % w/v | Ser 1.2 % w/v| IND 3.0 g); 10.9 % for free IND, p < 0.05). Accordingly, κ-Car/Ser/IND beads were demonstrated to be a promising IND drug carrier to improve oral administration while mitigating the side effects of non-steroidal anti-inflammatories.
Assuntos
Carragenina , Preparações de Ação Retardada , Indometacina , Sericinas , Indometacina/química , Indometacina/administração & dosagem , Indometacina/farmacocinética , Carragenina/química , Administração Oral , Humanos , Sericinas/química , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Sobrevivência Celular/efeitos dos fármacos , Microesferas , Animais , Células CACO-2 , Concentração de Íons de HidrogênioRESUMO
The present studies were designed to evaluate inhalatory microparticles carrying indomethacin (IN) for potential local (specific and non-specific bronchial inflammatory asthma responses) and systemic treatments (joint inflammation, rheumatoid arthritis and osteoarthritis pain) by optimizing microparticle properties, characterizing their lung deposition, drug release, evaluating cytotoxicity and also pharmacological effect in vitro. The acidic groups of IN were complexed with the cationic groups of the polyelectrolyte polylysine in order to increase the drug water compatibility. The polylysine/indomethacin ratio was fixed and the pH was adjusted in different formulations. Microparticles were obtained by spray drying using a relatively high atomization air flowrate (742â¯L/min) and a high-performance cyclone in order to optimize the production of microparticles with adequate attributes for inhalatory delivery. The produced microparticles exhibited high process yield and IN loading, volumetric mean diameters smaller than 5⯵m and narrow particle size distributions. According to demonstrated aerosolization performance, the powders were suitable for inhalatory indomethacin local and systemic treatments. Emitted fraction was higher than 90%, the MMAD was around 3⯵m and the GSD lower than 3. The respirable fraction for particles with aerodynamic diameters smaller than 5⯵m was around 29% while for particles with aerodynamic diameters smaller than 3⯵m the value was around 17%. The addition of lactose as carrier worsened the aerodynamic performance of the microparticles. The developed powdered systems got wet and dissolved quickly and presented higher release rates respect to pure IN in simulated lung physiological conditions. Furthermore, the assays performed in RAW 264.7 cell line showed that the microparticles exhibited the same anti-inflammatory capability as the pure drug. The developed particles did not affect the RAW 264.7 cell viability. In conclusion, a promising powder formulation for DPIs has been developed to treat, locally and systemically, inflammatory diseases.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Sistemas de Liberação de Medicamentos , Indometacina/administração & dosagem , Inflamação/tratamento farmacológico , Administração por Inalação , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Inaladores de Pó Seco , Concentração de Íons de Hidrogênio , Indometacina/farmacocinética , Indometacina/farmacologia , Inflamação/patologia , Lactose/química , Pulmão/metabolismo , Camundongos , Microesferas , Tamanho da Partícula , Polilisina/química , Células RAW 264.7RESUMO
The aim of this work was to predict the permeability of two model drugs, sulfamerazine (SMR) and indomethacin (INM), and to determine the effect on their apparent permeabilities by complexation with cyclodextrins and/or meglumine or incorporation in microemulsions. Permeation experiments were performed using two-chamber diffusion cells with a new composition of bio-mimetic membrane composed of 80% of Lipoid® S100 and 20% of cholesterol in n-octanol 10% w/w solution, at 37 ± 0.5°C and 14,000 rpm. The predictive capacity of the permeability of passive diffusion absorbed compounds was evaluated using 20 drug standards and showed an exponential correlation between the apparent permeability coefficients (Papp) and the fraction absorbed percentages in humans (Fa%), with an R2 value of 0.67942 and a constant value of - 4.1 ± 0.8. SMR and INM were classified as Class II and I, respectively, according to the Biopharmaceutical Classification System. These drugs were complexed and incorporated in microemulsions. The Fa% from all the drug products was higher than 90%. SMR in the complexes and both drugs in microemulsions were classified as highly soluble. Thus, SMR and INM incorporated in these pharmaceutical products could be classified as Class I.
Assuntos
Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Emulsões/química , Emulsões/farmacocinética , Membranas Artificiais , Biomimética/métodos , Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Difusão , Indometacina/química , Indometacina/farmacocinética , Permeabilidade/efeitos dos fármacos , SolubilidadeRESUMO
OBJECTIVE: To determine the role of a pharmacokinetic interaction in the protective effect of curcumin against the gastric damage induced by indomethacin administration as such or as its prodrug acemetacin. METHODS: Wistar rats orally received single dose of indomethacin (30 mg/kg) with and without curcumin (30 mg/kg); gastric injury was evaluated by determining the total damaged area. Additional groups of rats received an oral single dose of indomethacin (30 mg/kg) or its prodrug acemetacin (34.86 mg/kg) in the presence or absence of curcumin (30 mg/kg). Indomethacin and acemetacin concentrations in plasma from blood draws were determined by high-performance liquid chromatography.Plasma concentration-against-time curves were constructed, and bioavailability parameters, maximal concentration (Cmax) and area under the curve to the last sampling time (AUC0-t) were estimated. RESULTS: Concomitant administration of indomethacin and curcumin resulted in a significantly reduced gastric damage compared to indomethacin alone. However, co-administration of curcumin did not produce any significant alteration in the bioavailability parameters of indomethacin and acemetacin after administration of either the active compound or the prodrug. CONCLUSION: Curcumin exhibits a protective effect against indomethacin-induced gastric damage, but does not produce a reduction of the bioavailability of this nonsteroidal anti-inflammatory drug, indomethacin. Data thus suggest that a pharmacokinetic mechanism of action is not involved in curcumin gastroprotection.
Assuntos
Curcumina/farmacologia , Indometacina/toxicidade , Animais , Disponibilidade Biológica , Interações Medicamentosas , Indometacina/análogos & derivados , Indometacina/farmacocinética , Masculino , Ratos , Ratos WistarRESUMO
AIM: The intent of this study is to examine whether intrauterine malnutrition provokes alterations in the progression of the acute and subchronic inflammatory response, and its influence on the pharmacological effect of indomethacin. METHODS DESIGN: Rat offspring of dams which were fed from the first day of their gestation to term receiving a balanced diet (Labina) or a basic regional diet (BRD) from northeastern Brazil. According to their dams, the offspring were divided in two groups: Control-N (nourished) and BRD-g (undernourished during gestation). At 2 months of age, the animals were divided into groups (n=06): (1) Animals that were subjected to carrageenan or (2) zymosan-induce paw edema (acute inflammation models) and (3) Animals that were subjected to cotton pellet-induced granuloma (subchronic inflammation model). All animals received (saline 0.9%; p.o.). Another set of adult offspring was submitted to the same procedure as above, but instead of saline they received (via gavage) a single oral dose of indomethacin (10mg/kg) for the animals subjected to acute inflammation models or 2mg/kg for seven consecutive days for the animals subjected to subchronic inflammation model. The animals were further divided in two groups: Control-NI (Control-N treated with indomethacin), and BRDI-g (BRD-g treated with indomethacin). The volume of hind paw swelling (mL) was measured at time zero (before), 30, 60, 120, 180 and 240 min after carrageenan or zymosan injection. In the subchronic model of inflammation, the pellets were removed and dried to a constant weight. Hind paw swelling, weight of granuloma, blood albumin and C-reactive protein (CRP) levels, leukocyte count and cytokine levels were evaluated as indicators of inflammation. RESULTS: Undernutrition during pregnancy caused fetal growth retardation which was shown in terms of low birth weight (5.38±0.28), when compared to the Control-N (7.26±0.64) group. The volume of paw edema, the serum levels of CRP and albumin and cytokine levels were lower than those in the BRD-g group when compared to those in the Control-N groups, in both models of acute inflammation studied. However, no difference was found in the total leukocyte count. When compared to the respective groups treated with saline (Control-N and BRD-g), the antiinflammatory effect of indomethacin in the animals of BRDI-g groups was lower than in the Control-NI groups, in the model of acute inflammation. In the model of subchronic inflammation, the pharmacological effect of indomethacin was effective only in nourished animals. CONCLUSION: Malnutrition in the early stages of development attenuated the severity of the acute inflammatory response, but there was no statistically significant change in subchronic inflammation induced by granulomatous lesion. Our findings provide impetus for larger trials to assess the influence of undernutrition on the pharmacokinetics/pharmacodynamics of indomethacin.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Transtornos da Nutrição Fetal/metabolismo , Indometacina/farmacocinética , Inflamação/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Análise de Variância , Ração Animal , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Peso ao Nascer , Proteína C-Reativa/análise , Carragenina/efeitos adversos , Edema/induzido quimicamente , Feminino , Retardo do Crescimento Fetal , Granuloma/induzido quimicamente , Indometacina/administração & dosagem , Inflamação/induzido quimicamente , Interleucina-6/análise , Contagem de Leucócitos , Masculino , Gravidez , Ratos , Ratos Wistar , Albumina Sérica/análise , Fatores de Tempo , Fator de Necrose Tumoral alfa/análise , Zimosan/efeitos adversosRESUMO
The aim of this work was to investigate if the indomethacin ethyl ester (IndOEt) released from lipid-core nanocapsules (NC) is converted into indomethacin (IndOH) in the intestine lumen, intestine wall or after the particles reach the blood stream. NC-IndOEt had monomodal size distribution (242 nm; PDI 0.2) and zeta potential of -11 mV. The everted rat gut sac model showed IndOEt passage of 0.16 micromol m(-2) through the serosal fluid (30 min). From 15 to 120 min, the IndOEt concentrations in the tissue increased from 6.13 to 27.47 micromol m(-2). No IndOH was formed ex vivo. A fluorescent-NC formulation was used to determine the copolymer bioadhesion (0.012 micromol m(-2)). After NC-IndOEt oral administration to rats, IndOEt and IndOH were detected in the gastrointestinal tract (contents and tissues). In the tissues, the IndOEt concentrations decreased from 459 to 5 microg g(-1) after scrapping, demonstrating the NC mucoadhesion. In plasma (peripheric and portal vein), in spleen and liver, exclusively IndOH was detected. In conclusion, after oral dosing of NC-IndOEt, IndOEt is converted into IndOH in the intestinal lumen and wall before reaching the blood stream. The complexity of a living system was not predicted by the ex vivo gut sac model.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Portadores de Fármacos/farmacocinética , Indometacina/análogos & derivados , Indometacina/farmacocinética , Mucosa Intestinal/metabolismo , Nanocápsulas/química , Administração Oral , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Corantes Fluorescentes/farmacocinética , Hidrólise , Indometacina/administração & dosagem , Indometacina/síntese química , Absorção Intestinal , Masculino , Modelos Animais , Nanocápsulas/administração & dosagem , Ratos , Ratos Wistar , Adesivos Teciduais/farmacocinética , Distribuição TecidualRESUMO
BACKGROUND AND AIM: The pharmacokinetics of acemetacin, a non-steroidal anti-inflammatory drug which is biotransformed to indomethacin by hepatic first-pass effect, was examined during the necrotic and regeneration phases resulting from acute hepatitis induced by carbon tetrachloride (CCl4). MATERIAL AND METHODS: Acute hepatitis was induced by oral CCl4 administration to male Wistar rats. On days 0, 1 and 3 after the insult, liver histological analysis was performed, biochemical markers of liver damage and regeneration were measured, and the pharmacokinetics of oral acemetacin and of its active metabolite, indomethacin, were determined. RESULTS: One day after CCl4 administration, liver necrosis was apparent and there was an increase in the circulating levels of indicators of liver damage and regeneration with regard to control conditions. Acemetacin bioavailability was increased, although not in a statistically significant manner. On the other hand, indomethacin bioavailability was significantly reduced. By day 3, histological analysis revealed liver recovery, although not complete, while biochemical indicators of hepatic damage had reverted either totally or partially. Markers of liver regeneration were still increased. Bioavailability acemetacin and indomethacin was comparable to control values. IN CONCLUSION: Indomethacin bioavailability after oral administration of its precursor, acemetacin, is significantly reduced by acute hepatitis produced by CCl4. Pharmacokinetic alterations, as liver damage, are reversible, but do not require complete liver regeneration to return to basal conditions.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Indometacina/análogos & derivados , Regeneração Hepática , Fígado/metabolismo , Doença Aguda , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Disponibilidade Biológica , Biotransformação , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Hepatectomia , Indometacina/administração & dosagem , Indometacina/farmacocinética , Fígado/patologia , Fígado/cirurgia , Masculino , Necrose , Ratos , Ratos WistarRESUMO
Goals were to evaluate indomethacin ethyl ester-nanoencapsules (IndOEt-NC) pharmacokinetics in rats and the in vivo ester conversion to indomethacin (IndOH). After i.v. and oral administration exclusively IndOH was detected in plasma. The AUC(IndOEt-NC)/AUC(IndOH) ratio after i.v. dosing was 0.68, accounting for dose and molecular weight differences, probably due to increased IndOH clearance after IndOEt-NC administration (alpha=0.05). The results confirm that antiedematogenic activity reported for IndOEt-NC is due to IndOH. Encapsulation did not protect the ester which in vivo is rapidly released and converted to IndOH, acting as a pro-drug.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Indometacina/análogos & derivados , Nanocápsulas , Pró-Fármacos/farmacocinética , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Biotransformação , Composição de Medicamentos , Indometacina/administração & dosagem , Indometacina/química , Indometacina/farmacocinética , Injeções Intravenosas , Masculino , Modelos Biológicos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Ratos , Ratos WistarRESUMO
BACKGROUND AND PURPOSE: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. EXPERIMENTAL APPROACH: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7-83.8 micromol kg(-1)) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E(2) and leukotriene (LT) B(4) levels in exudates, and whole blood thromboxane (TX) B(2) synthesis were measured. KEY RESULTS: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE(2) and TXB(2) synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB(4) production in the airpouch. CONCLUSIONS AND IMPLICATIONS: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB(4) production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Indometacina/análogos & derivados , Úlcera Gástrica/induzido quimicamente , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Área Sob a Curva , Biotransformação , Cromatografia Líquida de Alta Pressão , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Dinoprostona/genética , Exsudatos e Transudatos/metabolismo , Indometacina/efeitos adversos , Indometacina/metabolismo , Indometacina/farmacocinética , Indometacina/farmacologia , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Injeções Subcutâneas , Leucotrieno B4/metabolismo , Masculino , Prostaglandinas/biossíntese , Ratos , Ratos Wistar , Tromboxanos/biossíntese , Tromboxanos/sangue , ZimosanRESUMO
A two-phase study to investigate the influence of administration time on pharmacokinetics of indomethacin in sheep was performed. In phase I, 12 animals were allocated to four groups, each corresponding to a different time: 08:00, 14:00, 20:00, 02:00 h. Sheep received an intravenous administration of 1 mg/kg indomethacin. In phase II, each group was administered indomethacin with a 12-h difference compared to Phase I. The trial was performed in autumn, and animals were subjected to a natural light:dark cycle of 10:14 h. Blood samples were taken and processed by high performance liquid chromatography (HPLC) with ultraviolet detection. For each pharmacokinetic parameter, an analysis of variance was performed to outline the existence of chronobiological variations. Concentration at zero time (C0), hybrid constant for distribution and its half life, hybrid constant for elimination and its half-life, volume of distribution (V(d)), area under the curve (AUC(infinity)) and clearance rate (Cl), presented chronobiological variations (P < 0.05) and were fitted to a cosine equation. The following parameters adjusted to circadian rhythms: C(0) (acrophase: 13.9788 h); AUC(infinity) (acrophase: 13.4377 h); V(d) (acrophase: 0.8245 h) and Cl (acrophase: 1.4965 h). It was concluded that pharmacokinetic parameters of intravenously injected indomethacin in sheep would behave in a different, though predictable, manner according to the animal's biological clock.