RESUMO
OBJECTIVES: Loratadine is a selective H1 receptor inhibitor that has been widely used in the clinical treatment of allergic diseases. Here we aimed to develop a novel solid loratadine nanocrystal to increase the low and pH-dependent water solubility for bioavailability enhancement. METHODS: Loratadine solid nanocrystal was developed through high-speed shear-high pressure homogenization followed by freeze-drying, which was further prepared into tablets through direct compression. The formulation and process parameter were screened. Furthermore, the characterization and oral bioavailability of loratadine nanocrystal were studied. KEY FINDINGS: The loratadine nanocrystal had the satisfactory particle size of 425.9 nm and great redispersibility, which was mainly attributed to the addition of Pluronic F127 and polyvinylpyrrolidone K17 as the stabilizer. The saturation solubility of the loratadine nanocrystal was increased to 3.81, 3.22 and 2.57-fold that of the crude drug in water, pH 6.8 and pH 4.5 buffer respectively. Furthermore, the pharmacokinetic studies in rats revealed that the AUC (0-∞) of the nanocrystal tablets was 2.38-fold that of raw tablets and 1.94-fold that of commercial tablets, respectively. CONCLUSIONS: The nanocrystal tablets could significantly improve the oral bioavailability of loratadine, which would also be a promising approach to enhance the solubility of insoluble drugs.
Assuntos
Composição de Medicamentos/métodos , Hipersensibilidade/tratamento farmacológico , Loratadina , Nanopartículas/química , Solubilidade , Disponibilidade Biológica , Excipientes/farmacologia , Liofilização , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Loratadina/química , Loratadina/farmacocinética , ComprimidosRESUMO
BACKGROUND: Loratadine (LTD) is a Biopharmaceutical Classification System II basic drug with pH-sensitive aqueous solubility and dissolution is a speed-limiting step of its absorption. The drug dissolution and the gastrointestinal tract pH conditions are likely to influence the in vivo pharmacokinetic behavior of LTD tablets. MATERIALS AND METHOD: A rapid, sensitive, and reliable bioanalytical method for simultaneous quantitation of LTD and its active metabolite desloratadine (DL) in beagle plasma was developed and validated based on liquid chromatography tandem mass spectrometry (LC-MS/MS). Sample preparation in low plasma consumption was accomplished by liquid-liquid extraction. The chromatographic separation was achieved on a Phenomenex Kinetex C8 column using acetonitrile and 5 mM ammonium formate as the mobile phase. A comparative pharmacokinetics study of three LTD tablets with different dissolution rates was conducted in male beagles in fasting state and an omeprazole-induced drug-drug interaction (DDI) study was subsequently performed under pretreatment of omeprazole. RESULTS AND CONCLUSION: The method showed a good linear correlation over the concentration ranges of 0.008-24 ng/mL for LTD and 0.8-800 ng/mL for DL, and was successfully applied to analyze the two compounds in beagle plasma. Pharmacokinetic results showed in the fasting state the three LTD tablets were equivalent in beagles in terms of effective components. DL of the three tablets were equivalent, indicating metabolite was less susceptible to pharmaceutic preparation factors for LTD tablets in beagles. Moreover, significant changes in LTD and DL pharmacokinetics parameters were observed under the effect of omeprazole-induced pH increase in gastrointestinal tract, suggesting that DDI effects are of concern for the curative effect of LTD when combined with omeprazole. The findings will contribute to the future pharmaceutical preparations research as well as the clinical application of LTD.
Assuntos
Interações Medicamentosas , Loratadina/farmacocinética , Omeprazol/farmacocinética , Administração Oral , Animais , Cromatografia Líquida , Cães , Loratadina/administração & dosagem , Loratadina/análogos & derivados , Masculino , Omeprazol/administração & dosagem , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Desloratadine is a drug with a phenotypic polymorphism in metabolism and has been approved for use in many countries to treat allergic diseases. CYP2C8 and UGT2B10 are metabolic enzymes, which may be involved in the metabolism of desloratadine. OBJECTIVE: This study aimed to demonstrate bioequivalence between the test product (desloratadine tablet) and the reference product AERIUS (5mg), both orally administered. And the role of UGT2B10 and CYP2C8 genotypes in healthy Chinese subjects with different Desloratadine metabolic phenotypes was examined. METHODS: It was a randomized, open-label, and four-sequence, single-dose crossover study conducted on 56 healthy Chinese subjects. The pharmacokinetics (PK) and safety of the test and reference Desloratadine products were compared. UGT2B10 and CYP2C8 genotypes were determined by the TaqMan assay using genomic DNA. Multiple linear regression was applied to analyze the correlation between genotypes and the metabolic ratio. RESULTS: The mean serum concentration-time curves of desloratadine and 3-OH-desloratadine were similar between the test product and the reference product. For the PK similarity comparison, the 90% CIs for the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ of desloratadine and 3-OH-desloratadine of test and reference product were completely within 80-125%. None of all 56 subjects had serious adverse events. Only 2 subjects were poor-metabolizers in 56 healthy subjects. There was no significant correlation between investigated genotypes of CYP2C8 and UGT2B10 and the metabolic ratio. CONCLUSION: The test desloratadine tablet was bioequivalent to the reference product. No direct relationship between CYP2C8 and UGT2B10 genotypes and desloratadine metabolic ratio was identified.
Assuntos
Citocromo P-450 CYP2C8/genética , Glucuronosiltransferase/genética , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Loratadina/análogos & derivados , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP2C8/metabolismo , Feminino , Glucuronosiltransferase/metabolismo , Voluntários Saudáveis , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Humanos , Loratadina/administração & dosagem , Loratadina/farmacocinética , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Comprimidos , Equivalência Terapêutica , Adulto JovemRESUMO
Loratadine (LOR) and its major metabolite, desloratadine (DL) are new-generation antihistamines. The hydroxylated metabolites of them, 6-OH-DL, 5-OH-DL and 3-OH-DL are also active because of their ability to inhibit binding of pyrilamine to brain H1 receptors and a tendency for distributing to specific immune-regulatory tissues. In this study, a new validated LC-MS/MS method to simultaneously quantify LOR, DL, 6-OH-DL, 5-OH-DL and 3-OH-DL in plasma and tissues was established and applied to an investigation of their pharmacokinetics and target-tissue distribution tendency for the first time. Pharmacokinetics parameters in rat were measured and the results suggest that the body's exposure to active metabolites were much higher than to the prodrug with LOR, but much lower with DL. The tissue distribution study shows that LOR, DL and their active metabolites were widely distributed in the liver, spleen, thymus, heart, adrenal glands and pituitary gland. For immune-regulatory tissues, the concentrations of LOR, DL and their active metabolites in the spleen were much higher than in the thymus, which is related to the spleen, one of the sites where immune responses occur. LOR and its metabolites might inhibit immune-mediated allergic inflammation through the hypothalamic-pituitary-adrenal (HPA) axis. It was also found that the concentration of LOR in the heart was highest after liver and adrenal glands while those of DL, 6-OH-DL and 5-OH-DL in the liver, adrenal glands and spleen were all higher than those in the heart, which suggests that LOR may have a greater tendency to distribute in the heart than its metabolites.
Assuntos
Monitoramento de Medicamentos/métodos , Antagonistas dos Receptores Histamínicos/farmacocinética , Loratadina/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Administração Oral , Glândulas Suprarrenais/química , Glândulas Suprarrenais/metabolismo , Animais , Cromatografia Líquida de Alta Pressão/métodos , Antagonistas dos Receptores Histamínicos/administração & dosagem , Fígado/química , Fígado/metabolismo , Loratadina/administração & dosagem , Loratadina/isolamento & purificação , Loratadina/farmacocinética , Masculino , Modelos Animais , Miocárdio/química , Miocárdio/metabolismo , Hipófise/química , Hipófise/metabolismo , Ratos , Baço/química , Baço/metabolismo , Equivalência Terapêutica , Timo/química , Timo/metabolismo , Distribuição TecidualRESUMO
The PXB-mouse is potentially a useful in vivo model to predict human hepatic metabolism and clearance. Four model compounds, [14C]desloratadine, [3H]mianserin, cyproheptadine, and [3H]carbazeran, all reported with disproportionate human metabolites, were orally administered to PXB- or control SCID mice to elucidate the biotransformation of each of them. For [14C]desloratadine in PXB-mice, O-glucuronide of 3-hydroxydesloratadine was observed as the predominant metabolite in both the plasma and urine. Both 3-hydroxydesloratadine and its O-glucuronide were detected as major drug-related materials in the bile, whereas only 3-hydroxydesloratadine was detected in the feces, suggesting that a fraction of 3-hydroxydesloratadine in feces was derived from deconjugation of its O-glucuronide by gut microflora. This information can help understand the biliary clearance mechanism of a drug and may fill the gap in a human absorption, distribution, metabolism, and excretion study, in which the bile samples are typically not available. The metabolic profiles in PXB-mice were qualitatively similar to those reported in humans in a clinical study in which 3-hydroxydesloratadine and its O-glucuronide were major and disproportionate metabolites compared with rat, mouse, and monkey. In the control SCID mice, neither of the metabolites was detected in any matrix. Similarly, for the other three compounds, all human specific or disproportionate metabolites were detected at a high level in PXB-mice, but they were either minimally observed or not observed in the control mice. Data from these four compounds indicate that studies in PXB-mice can help predict the potential for the presence of human disproportionate metabolites (relative to preclinical species) prior to conducting clinical studies and understand the biliary clearance mechanism of a drug. SIGNIFICANCE STATEMENT: Studies in PXB-mice have successfully predicted the human major and disproportionate metabolites compared with preclinical safety species for desloratadine, mianserin, cyproheptadine, and carbazeran. In addition, biliary excretion data from PXB-mice can help illustrate the human biliary clearance mechanism of a drug.
Assuntos
Eliminação Hepatobiliar , Fígado/metabolismo , Animais , Bile/metabolismo , Biotransformação , Carbamatos/administração & dosagem , Carbamatos/farmacocinética , Ciproeptadina/administração & dosagem , Ciproeptadina/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Hepatócitos/metabolismo , Hepatócitos/transplante , Humanos , Fígado/citologia , Loratadina/administração & dosagem , Loratadina/análogos & derivados , Loratadina/farmacocinética , Masculino , Mianserina/administração & dosagem , Mianserina/farmacocinética , Camundongos , Quimeras de Transplante/metabolismoRESUMO
An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts of lead compounds for structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming candidates into newly functionalized leads. A key to success is the utilization of microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits the use of low amounts of lead compounds (1-5 µmol). The approach delivers multiple analogues from a single lead at nanomole-scale amounts as DMSO-d6 stock solutions with a known structure and concentration for in vitro pharmacology and absorption, distribution, metabolism, and excretion testing. To demonstrate the feasibility of this approach, we have used the antihistamine agent loratadine (1). Twenty-six analogues of loratadine were isolated and fully characterized by NMR. Informative SAR analogues were identified, which display potent affinity for the human histamine H1 receptor and improved metabolic stability.
Assuntos
Loratadina/análogos & derivados , Loratadina/farmacocinética , Relação Estrutura-Atividade , Animais , Cromatografia Líquida de Alta Pressão , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Dimetil Sulfóxido/química , Cães , Descoberta de Drogas/métodos , Antagonistas não Sedativos dos Receptores H1 da Histamina/química , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Humanos , Ligação de Hidrogênio , Inativação Metabólica , Loratadina/química , Espectroscopia de Ressonância Magnética , Metaloporfirinas/química , Metaloporfirinas/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Coelhos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
The unique requirements of poorly water-soluble drug delivery have driven a great deal of research into new formulations and routes of administration. This study investigates the use of nanosuspensions for solubility enhancement and drug delivery. Simple methods were used to prepare nasal formulations of loratadine based on nanosuspension pre-dispersion with sodium hyaluronate as a mucoadhesive agent. The nanosuspension was prepared by antisolvent precipitation method followed by ultrasonication and characterized for particle size, polydispersity index, zeta potential, morphology, and structure. Moreover, the nasal formulations were characterized for drug loading, pH, particle size, viscosity, bioadhesive viscosity parameter, and were evaluated for in vitro dissolution and diffusion, in addition to in vivo studies in a rat model. Loratadine nanosuspension displayed a particle size of 311 nm, a polydispersity index of 0.16, and zeta potential of -22.05 mV. The nanosuspension preserved the crystalline status of the raw drug. The addition of sodium hyaluronate exhibited an increase in the mean particle size and zeta potential of the nanoparticles. The nasal formulations showed enhanced bioadhesive properties compared to the unprocessed loratadine in the reference samples. The nanosuspension based-formulation that contained 5 mg mL-1 sodium hyaluronate and 2.5 mg mL-1 loratadine (NF4) showed a significant enhancement of flux and permeability coefficient through a synthetic membrane. NF4 exhibited 24.73 µg cm-2 h-1 and 0.082 cm h-1, while the reference sample showed 1.49 µg cm-2 h-1 and 0.017 cm h-1, for the flux and the permeability coefficient, respectively. Nasal administration of NF4 showed a bioavailability of 5.54-fold relative to the oral administration. The results obtained in this study indicate the potential of the nasal route and the nanosuspension for loratadine delivery. The relative bioavailability of NF4 was 1.84-fold compared to unprocessed loratadine in the reference sample. Therefore, the nanosized loratadine could be suggested as a practical and simple nanosystem for the intranasal delivery with improved bioavailability.
Assuntos
Adesivos/química , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Ácido Hialurônico/química , Loratadina/química , Loratadina/farmacocinética , Nanoestruturas/química , Suspensões/química , Adesivos/administração & dosagem , Administração Intranasal , Administração Oral , Animais , Disponibilidade Biológica , Liberação Controlada de Fármacos , Ácido Hialurônico/administração & dosagem , Masculino , Nanoestruturas/administração & dosagem , Nanoestruturas/ultraestrutura , Tamanho da Partícula , Ratos , Propriedades de Superfície , Suspensões/administração & dosagem , ViscosidadeRESUMO
PURPOSE: Pancreatic cancer (PC) is predicted to become the second leading cause of cancer associated deaths by 2020. Earlier, we confirmed the development and efficacy of our novel Loratadine Self-Microemulsifying-Drug-Delivery-System - Sulforaphane (LOR SMEDDS -SFN) nanoformulation in PC chemoprevention. In this report, we extend our studies to evaluate the PC chemoprevention efficacy of LOR SMEDDS - SFN. METHODS: The nanoformulation was subjected to in vitro colony formation assays, in vivo oral pharmacokinetics and stability studies. RESULTS: The colony formation assay using Panc-1 PC cells demonstrated a survival fraction of 0.74 with LOR-SFN (p < 0.001) which further reduced to 0.35 with LOR SMEDDS-SFN treatment (p < 0.0001) confirming the synergistic chemoprevention efficacy of the nanoformulation. Further, the oral pharmacokinetic studies of LOR SMEDDS-SFN showed 4-fold and 9-fold increase in Cmax (503.2 ± 5.8 ng/mL) and oral bioavailability (20,274.8 ± 3711.0 ng·h/mL) for LOR compared to LOR-SFN combination respectively assuring the enhanced performance by the SMEDDS. Additionally, the formulation exhibited statistically non-significant alteration in globule size, zeta potential, drug content and in vitro drug release during stability studies confirming its stability and pharmaceutical acceptability. CONCLUSION: Our studies have demonstrated a potential of LOR SMEDDS-SFN nanoformulation as an effective PC chemoprevention strategy.
Assuntos
Loratadina/farmacologia , Loratadina/farmacocinética , Pâncreas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/prevenção & controle , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioprevenção/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Emulsões/farmacocinética , Emulsões/farmacologia , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Solubilidade/efeitos dos fármacosRESUMO
The effervescent method, as a simple and effective technology to prepare nanosuspensions, has gained great attention. In this present research, loratadine (LTD) nanosuspensions were successfully prepared by the effervescent method using Soluplus as stabilizer to improve the bioavailability of LTD in vivo. The mean particle size was about 100 nm. And the LTD nanosuspensions were lyophilized for further study. The freeze-dried powders could be dissolved quickly, and the mean particle size remained almost unchanged after powders were re-dissolved. By transmission electron microscope (TEM), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (X-RD), the characterizations of LTD nanosuspensions and freeze-dried powders were studied. Commercial tablets were used as the reference to investigate the dissolution behaviors in different release media and of bioavailability in vivo of LTD freeze-dried powders. The cumulative dissolution of the LTD freeze-dried powders was superior in different release media compared with commercial tables. In addition, for the evaluation of the bioavailability of LTD nanosuspensions, the LTD concentration in rat plasma was determined using LC-MS/MS method. The results showed that the AUC0-24 and Cmax of LTD freeze-dried powders were about 2.14- and 2.01-fold higher than those of commercial tablets. In short, the effervescent method has been successfully applied to the preparation of LTD nanosuspensions to improve the bioavailability of LTD in vivo with the advantage of low energy consumption. This simple technology also provides an idea for the preparation of the other nanosuspensions.
Assuntos
Loratadina/administração & dosagem , Plasma/química , Polietilenoglicóis/química , Polivinil/química , Administração Oral , Animais , Disponibilidade Biológica , Composição de Medicamentos , Liofilização , Loratadina/química , Loratadina/farmacocinética , Masculino , Nanopartículas , Tamanho da Partícula , Ratos , Suspensões , ComprimidosRESUMO
Some histamine H1 receptor (H1R) antagonists induce adverse sedative reactions caused by blockade of histamine transmission in the brain. Desloratadine is a second-generation antihistamine for treatment of allergic disorders. Its binding to brain H1Rs, which is the basis of sedative property of antihistamines, has not been examined previously in the human brain by positron emission tomography (PET). We examined brain H1R binding potential ratio (BPR), H1R occupancy (H1RO), and subjective sleepiness after oral desloratadine administration in comparison to loratadine. Eight healthy male volunteers underwent PET imaging with [11C]-doxepin, a PET tracer for H1Rs, after a single oral administration of desloratadine (5 mg), loratadine (10 mg), or placebo in a double-blind crossover study. BPR and H1RO in the cerebral cortex were calculated, and plasma concentrations of loratadine and desloratadine were measured. Subjective sleepiness was quantified by the Line Analogue Rating Scale (LARS) and the Stanford Sleepiness Scale (SSS). BPR was significantly lower after loratadine administration than after placebo (0.504 ± 0.074 vs 0.584 ± 0.059 [mean ± SD], P < 0.05), but BPR after desloratadine administration was not significantly different from BPR after placebo (0.546 ± 0.084 vs 0.584 ± 0.059, P = 0.250). The plasma concentration of loratadine was negatively correlated with BPR in subjects receiving loratadine, but that of desloratadine was not correlated with BPR. Brain H1ROs after desloratadine and loratadine administration were 6.47 ± 10.5% and 13.8 ± 7.00%, respectively (P = 0.103). Subjective sleepiness did not significantly differ among subjects receiving the two antihistamines and placebo. At therapeutic doses, desloratadine did not bind significantly to brain H1Rs and did not induce any significant sedation.
Assuntos
Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Loratadina/análogos & derivados , Loratadina/administração & dosagem , Receptores Histamínicos H1/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Voluntários Saudáveis , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Humanos , Loratadina/farmacocinética , Masculino , Tomografia por Emissão de Pósitrons/métodos , Sonolência , Adulto JovemRESUMO
BACKGROUND: The purpose of this study was to develop an innovative surfactant-free lipidbased formulation (LF) for improving oral bioavailability of loratadine based on using solid particles colloidal silicon dioxide (CSD) as emulsifier and solid carrier. METHODS: Loratadine was dissolved in oil solution with the aid of co-solvent and LF formulations were prepared by a simple adsorption and milling technique. The LF Powder was evaluated in terms of angle of repose and X-ray powder diffraction. After dispersing and emulsifying in water, the particle size and morphology were also characterized. In vitro dissolution and pharmacokinetic behavior in vivo were also studied. RESULTS: Orthogonal design indicated that the amount of CSD in formulations had a major and significant influence on emulsification. The optimal formulation showed LF with good flowability and without crystallization or deposition of loratadine in it. CONCLUSION: After dispersing in water, an emulsion with the mean droplet size of 1.2µm was obtained. Although the dissolution of drug from LF was slower in vitro in acidic aqueous solution, pharmacokinetic studies in vivo showed that the bioavailability of loratadine increased 2.49-fold by CF compared to a commercial tablet.
Assuntos
Portadores de Fármacos , Antagonistas não Sedativos dos Receptores H1 da Histamina , Loratadina , Administração Oral , Animais , Disponibilidade Biológica , Cães , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Emulsões , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/química , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Lipídeos/administração & dosagem , Lipídeos/química , Lipídeos/farmacocinética , Loratadina/administração & dosagem , Loratadina/química , Loratadina/farmacocinética , Masculino , Tamanho da Partícula , Difração de Pó , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Solubilidade , Tensoativos , Difração de Raios XRESUMO
Fast dissolving oral film is a stamp-style, drug-loaded polymer film with rapid disintegration and dissolution. This new kind of drug delivery system requires effective taste masking technology. Suspension intermediate and liposome intermediate were prepared, respectively, for the formulation of two kinds of fast dissolving oral films with the aim of studying the effect of taste masking technology on the bioavailability of oral films. Loratadine was selected as the model drug. The surface pH of the films was close to neutral, avoiding oral mucosal irritation or side effects. The thickness of a 2 cm × 2 cm suspension oral film containing 10 mg of loratadine was 100 µm. Electron microscope analysis showed that liposomes were spherical before and after re-dissolution, and drugs with obvious bitterness could be masked by the encapsulation of liposomes. Dissolution of the two films was superior to that of the commercial tablets. Rat pharmacokinetic experiments showed that the oral bioavailability of the suspension film was significantly higher than that of the commercial tablets, and the relative bioavailability of the suspension film was 175%. Liposomal film produced a certain amount of improvement in bioavailability, but lower than that of the suspension film.
Assuntos
Polímeros/química , Paladar/fisiologia , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Concentração de Íons de Hidrogênio , Lipossomos , Loratadina/administração & dosagem , Loratadina/sangue , Loratadina/farmacocinética , Loratadina/farmacologia , Tamanho da Partícula , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Suspensões , Fatores de Tempo , Difração de Raios XRESUMO
The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Acetatos/metabolismo , Acetatos/farmacocinética , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacocinética , Antiasmáticos/metabolismo , Antiasmáticos/farmacocinética , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacocinética , Antifúngicos/metabolismo , Antifúngicos/farmacocinética , Broncodilatadores/metabolismo , Broncodilatadores/farmacocinética , Criança , Pré-Escolar , Ciclopropanos , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Diclofenaco/metabolismo , Diclofenaco/farmacocinética , Esomeprazol/metabolismo , Esomeprazol/farmacocinética , Antagonistas não Sedativos dos Receptores H1 da Histamina/metabolismo , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Humanos , Lactente , Recém-Nascido , Itraconazol/metabolismo , Itraconazol/farmacocinética , Lansoprazol/metabolismo , Lansoprazol/farmacocinética , Loratadina/análogos & derivados , Loratadina/metabolismo , Loratadina/farmacocinética , Ondansetron/metabolismo , Ondansetron/farmacocinética , Inibidores da Bomba de Prótons/metabolismo , Inibidores da Bomba de Prótons/farmacocinética , Quinolinas/metabolismo , Quinolinas/farmacocinética , Antagonistas da Serotonina/metabolismo , Antagonistas da Serotonina/farmacocinética , Sufentanil/metabolismo , Sufentanil/farmacocinética , Sulfetos , Teofilina/metabolismo , Teofilina/farmacocinéticaRESUMO
Loratadine (LTD) is an antihistaminic drug that suffers limited solubility, poor oral bioavailability (owing to extensive first-pass metabolism), and highly variable oral absorption. This study was undertaken to develop and statistically optimize transfersomal gel for transbuccal delivery of LTD. Transfersomes bearing LTD were prepared by conventional thin film hydration method and optimized using sequential Quality-by-Design approach that involved Placket-Burman design for screening followed by constrained simplex-centroid design for optimization of a Tween-80/Span-60/Span-80 mixture. The transferosomes were characterized for entrapment efficiency, particle size, and shape. Optimized transferosomes were incorporated in a mucoadhesive gel. The gel was characterized for rheology, ex vivo permeation across chicken pouch buccal mucosa, in vitro release, and mucoadhesion. Pharmacokinetic behavior of LTD formulations was investigated in healthy volunteers following administration of a single 10-mg dose. Optimal transferosomes characterized by submicron size (380 nm), spherical shape and adequate loading capacity (60%) were obtained by using quasi-equal ratio surfactant mixture. In terms of amount permeated, percentage released, and mucoadhesion time, the transferosomal gel proved superior to control, transferosome-free gel. Bioavailability of the transferosomal gel was comparable to Claritin® oral tablets. However, inter-individual variability in Cmax and AUC was reduced by 76 and 90%, respectively, when the buccal gel was used. Linear Correlation of in vitro release with in vivo buccal absorption fractions was established with excellent correlation coefficient (R2>0.97). In summary, a novel buccal delivery system for LTD was developed. However, further clinical investigation is warranted to evaluate its therapeutic effectiveness and utility.
Assuntos
Loratadina/farmacocinética , Administração Bucal , Disponibilidade Biológica , Química Farmacêutica , Voluntários Saudáveis , HumanosRESUMO
Coamorphous systems using citric acid as a small molecular excipient were studied for improving physical stability and bioavailability of loratadine, a BCS class II drug with low water solubility and high permeability. Coamorphous loratadine-citric acid systems were prepared by solvent evaporation technique and characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. Solid-state analysis proofed that coamorphous loratadine-citric acid system (1:1) was amorphous and homogeneous, had a higher T g over amorphous loratadine, and the intermolecular hydrogen bond interactions between loratadine and citric acid exist. The solubility and dissolution of coamorphous loratadine-citric acid system (1:1) were found to be significantly greater than those of crystalline and amorphous form. The pharmacokinetic study in rats proved that coamorphous loratadine-citric acid system (1:1) could significantly improve absorption and bioavailability of loratadine. Coamorphous loratadine-citric acid system (1:1) showed excellently physical stability over a period of 3 months at 25°C under 0% RH and 25°C under 60% RH conditions. The improved stability of coamorphous loratadine-citric acid system (1:1) could be related to an elevated T g over amorphous form and the intermolecular hydrogen bond interactions between loratadine and citric acid. These studies demonstrate that the developed coamorphous loratadine-citric acid system might be a promising oral formulation for improving solubility and bioavailability of loratadine.
Assuntos
Ácido Cítrico/química , Loratadina/química , Animais , Disponibilidade Biológica , Estabilidade de Medicamentos , Excipientes/química , Loratadina/farmacocinética , Masculino , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
BACKGROUND: Intractable bone pain is a notorious adverse effect of granulocyte-colony stimulating factors (G-CSFs), such as pegfilgrastim and filgrastim, which are given to help prevent neutropenia in patients who are undergoing chemotherapy. G-CSF-induced bone pain is surprisingly common and often refractory to treatment with conventional analgesics. CASE REPORT: This article describes an emergency department case of opiate and nonsteroidal anti-inflammatory drug-resistant pegfilgrastim-induced bone pain that was successfully alleviated with 10 mg of oral loratadine, allowing for discharge home. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case suggests that loratadine may be an easy to implement, safe, and effective therapy in the emergency department management of intractable bone pain caused by G-CSF use. Emergency physicians should be aware that loratadine may successfully relieve otherwise intractable G-CSF-induced bone pain and allow for discharge home.
Assuntos
Osso e Ossos/fisiopatologia , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Hidromorfona/farmacologia , Loratadina/farmacocinética , Manejo da Dor/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Serviço Hospitalar de Emergência/organização & administração , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Hidromorfona/farmacocinética , Hidromorfona/uso terapêutico , Loratadina/farmacologia , Loratadina/uso terapêutico , Pessoa de Meia-Idade , Neoplasias/complicações , Neutropenia/tratamento farmacológico , Manejo da Dor/métodos , Dor Intratável/tratamento farmacológico , Dor Intratável/etiologia , Polietilenoglicóis , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêuticoRESUMO
A rapid, sensitive, and accurate bioanalytical method was established for the quantitation and pharmacokinetic investigation of loratadine (LTD) in rat plasma by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS/MS) using loratadine-d5 as internal standard (ISTD). The analyte and ISTD were extracted by solid-phase extraction and chromatographic separation was achieved on Gemini NX- Reverse Phase C18 (50 × 4.6mm; 5 µ) using mobile phase mixture of 5mM ammonium formate buffer in water (pH 3.5 ± 0.1 with formic acid), and acetonitrile (20:80 v/v), at a flow rate of 0.400 mL/min with injection volume of 10 µL. LTD and ISTD were detected at m/z 383.3 â 337.4 and 388.4 â 337.3 with retention time of 2.62 and 2.59 min, respectively. High sensitivity (1.0 ng/mL) was achieved using small volume of rat plasma (20 µL) and the method was validated over a linearity range of 1.05-405.41 ng/mL with high correlation coefficient (r = 0.9998). The extraction method displayed a mean process efficiency of 63.25 and 65.47% for LTD and ISTD, respectively. The validated method when successfully applied for quantification of LTD in rat plasma revealed enhanced bioavailability of orally administered LTD-loaded self-nanoemulsifying drug delivery system (SNEDDS) (Cmax, 466.65 ± 18.94 ng/mL and AUC0-t 633.00 ± 12.44 ng-h/mL) over LTD-suspension (Cmax, 104.75 ± 2.87 ng/mL and AUC0-t 287.00 ± 9.11 ng-h/mL). The in vivo-in silico prediction by the GastroPlus™ software showed good prediction accuracy for LTD-SNEDDS (fold error < 2). The Loo-Reigelman method (2-compartment) presented best model-fitting indicating adequate in vitro-in vivo correlations. Conclusively, the developed sensitive analytical method displayed enhanced systemic availability of LTD-SNEDDS, and the in vivo in silico approach revealed sufficiently good GI simulation.
Assuntos
Cromatografia Líquida/métodos , Simulação por Computador , Sistemas de Liberação de Medicamentos , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Loratadina/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Animais , Emulsões , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/sangue , Loratadina/administração & dosagem , Loratadina/sangue , Ratos , Sensibilidade e EspecificidadeRESUMO
In this investigation, multivariate design approach was employed to develop self-nanoemulsifying drug delivery system (SNEDDS) of loratadine and to exploit its potential for intestinal permeability. Drug solubility was determined in various vehicles and existence of self-nanoemulsifying region was evaluated by phase diagram studies. The influence of formulation variables X1 (Capmul MCM C8) and X2 (Solutol HS15) on SNEDDS was assessed for mean globule sizes in different media (Y1-Y3), emulsification time (Y4) and drug-release parameters (Y5-Y6), to improve quality attributes of SNEDDS. Significant models were generated, statistically analyzed by analysis of variance and validated using the residual and leverage plots. The interaction, contour and response plots explicitly demonstrated the influence of one factor on the other and displayed trend of factor-effect on responses. The pH-independent optimized formulation was obtained with appreciable global desirability (0.9266). The strenuous act of determining emulsification time is innovatively replaced by the use of oil-soluble dye to produce visibly distinct globules that otherwise may be deceiving. TEM images displayed non-aggregated state of spherical globules (size < 25 nm) and also revealed the structural transitions occurring during emulsification. Optimized formulation exhibited non-Newtonian flow justified by the model-fit and also presented the stability to dilution effects and thermodynamic stress testing. The ex vivo permeation study using confocal laser scanning microscopy indicate strong potential of rhodamine 123-loaded loratadine-SNEDDS to inhibit P-gp efflux and facilitate intestinal permeation. To conclude, the effectiveness of design yields a stable optimized SNEDDS with enhanced permeation potential, which is expected to improve oral bioavailability of loratadine.
Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Lipídeos/química , Loratadina/administração & dosagem , Animais , Antialérgicos/administração & dosagem , Antialérgicos/farmacocinética , Disponibilidade Biológica , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Emulsões , Concentração de Íons de Hidrogênio , Absorção Intestinal , Loratadina/farmacocinética , Masculino , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , TermodinâmicaRESUMO
OBJECTIVE: Buccoadhesive wafer dosage form containing Loratadine is formulated utilizing Formulation by Design (FbD) approach incorporating sodium alginate and lactose monohydrate as independent variable employing solvent casting method. METHODS: The wafers were statistically optimized using Response Surface Methodology (RSM) and Artificial Neural Network algorithm (ANN) for predicting physicochemical and physico-mechanical properties of the wafers as responses. Morphologically wafers were tested using SEM. Quick disintegration of the samples was examined employing Optical Contact Angle (OCA). RESULTS: The comparison of the predictability of RSM and ANN showed a high prognostic capacity of RSM model over ANN model in forecasting mechanical and physicochemical properties of the wafers. The in vivo assessment of the optimized buccoadhesive wafer exhibits marked increase in bioavailability justifying the administration of Loratadine through buccal route, bypassing hepatic first pass metabolism.
Assuntos
Adesivos/administração & dosagem , Adesivos/química , Loratadina/administração & dosagem , Loratadina/química , Modelos Estatísticos , Mucosa Bucal/metabolismo , Adesivos/farmacocinética , Administração Bucal , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Formas de Dosagem , Loratadina/farmacocinética , Masculino , Redes Neurais de Computação , CoelhosRESUMO
OBJECTIVE: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of desloratadine and its metabolite 3-OH desloratadine in human plasma. METHODS: 24 healthy male volunteers received a single oral dose of 5 mg desloratadine tablets in a randomized crossover bioequivalence study with two preparations of tablets. Serial plasma samples were taken and analyzed by the LC-MS/MS method. The pharmacokinetic parameters of the two preparations were calculated and compared statistically to evaluate their bioequivalence using Winnonlin 6. 3. RESULTS: The calibration curves of desloratadine and 3-OH desloratadine were both linear over the concentration range of 0. 050-6. 0 ng/mL, with intra-batch and inter-batch relative standard deviations less than 15%. The 90% confidence intervals (CIs) of peak concentration (Cmax) area under the curve (AUC)0t and AUC0-∞ of desloratadine and 3-OH desloratadine all resided within the bioequivalence limit 80%-125%. No significant difference in peak time (Tmax) was demonstrated between the two preparations. CONCLUSION: The LC-MS/MS method can be used for simultaneous determination of desloratadine and 3-OH desloratadine in human plasma, which has been successfully applied-to a bioequivalence study.