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1.
Int J Pharm Compd ; 24(1): 77-82, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023219

RESUMO

This study reports on the stability of United States Pharmacopeia-grade metronidazole powder and commercially available metronidazole tablets in two dye-free oral suspending vehicles, namely Oral Mix and Oral Mix Sugar-Free. Metronidazole at 50 mg/mL was prepared individually in Oral Mix and Oral Mix Sugar-Free suspension vehicles and placed in 50-mL amber polyethyleneterephthalate bottles and 3-mL amber plastic syringes and stored at 4°C or 25°C/60% relative humidity for 90 days. The solutions were analyzed at the time of preparation and at 7 days, 14 days, 30 days, 45 days, 60 days, 75 days, and 90 days, with the concentration of metronidazole measured by high-performance liquid chromatography with photodiode array detection. The oral solutions were also monitored for pH, homogeneity, color, and odor. Except for the Oral Mix suspension of metronidazole prepared from the United States Pharmacopeia-grade powder and from the commercial tablet, when stored in pre-filled syringes, all the other preparations were stable at 4°C or 25°C/60% relative humidity for 90 days, with the metronidazole remaining within ± 10% of the initial concentration. The pH, color, odor, and resuspendability remained essentially unchanged. Metronidazole in Oral Mix and Oral Mix Sugar-Free oral suspensions, compounded from United States Pharmacopeia-grade powder or commercially available tablets, are a suitable alternative as an extemporaneously prepared medication.


Assuntos
Metronidazol , Administração Oral , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Suspensões , Comprimidos/administração & dosagem , Estados Unidos
2.
Rev. bras. cancerol ; 66(2): 1-9, 20200402.
Artigo em Português | LILACS | ID: biblio-1095547

RESUMO

Introdução: A manipulação de antineoplásicos para ajuste de dose, como partição de comprimidos, é comum no tratamento de leucemias agudas de crianças e adolescentes. Objetivo: Identificar a frequência e descrever a prática da partição domiciliar de comprimidos antineoplásicos utilizados no tratamento oral de crianças e adolescentes com leucemias agudas na fase de manutenção. Método: Trata-se de um estudo transversal descritivo, realizado em um hospital pertencente à rede de saúde pública do Distrito Federal com assistência especializada em pediatria. Foram incluídos no estudo crianças e adolescentes entre 1 e 18 anos, diagnosticados com leucemias agudas e em fase de manutenção do tratamento no período de estudo. Foi aplicado um questionário semiestruturado ao responsável principal pela administração dos medicamentos quimioterápicos via oral, podendo ser o cuidador ou a própria criança/adolescente. Foram coletadas variáveis sociodemográficas dos pacientes e cuidadores e variáveis sobre a prática de partição de medicamentos antineoplásicos no domicílio. Resultados: Todos os 48 entrevistados no período do estudo relataram ter partido comprimidos antineoplásicos ao longo do tratamento de leucemias agudas, sendo estes mercaptopurina (n=45 [93,75%]) e tioguanina (n=3 [6,25%]). Conclusão: A partição de comprimidos antineoplásicos foi uma prática unânime em virtude da necessidade referida de ajuste de dose individual para o tratamento de leucemias agudas de crianças e adolescentes, considerando a indisponibilidade de formulações adequadas. Os resultados reforçam a necessidade de a partição ser uniformizada e realizada de maneira a minimizar os riscos e a garantir a segurança para as crianças e adolescentes e seus cuidadores.


Introduction: Antineoplastic drug manipulation for dose adjustment, such as tablet splitting, is standard in acute leukemia treatment for children and adolescents. Objective: To identify the frequency and describe the practice of household splitting of antineoplastic tablet for oral treatment of children and adolescents with acute leukemias in the maintenance phase. Method: Cross-sectional descriptive study performed in a public health system hospital from Distrito Federal (Brazil) with specialized pediatric assistance. Children and teenagers between 1 and 18 years old, diagnosed with acute leukemia and in treatment maintenance phase during the study period were included. A semi-structured questionnaire was applied to the main responsible for administering oral chemotherapy drugs, which could be the caregiver or the child/adolescent themselves. Sociodemographic variables of patients and caregivers and variables on the practice of splitting antineoplastic drugs at home were collected. Results: All 48 interviewees in the study period reported having split antineoplastic tablets during the treatment for acute leukemias, such as mercaptopurine (n = 45 [93.75%]) and thioguanine (n = 3 [6.25%]). Conclusion: The splitting of antineoplastic tablets was a unanimous practice due to the reported need to adjust the individual dose for acute leukemia treatment in children and adolescents, considering the unavailability of adequate formulations. The results reinforce the need for splitting to be standardized and performed in a way that minimizes risks and ensures safety for patients and their caregivers


Introducción: La manipulación de fármacos antineoplásicos para el ajuste de dosis, como las particiones de comprimidos, es frecuente en el tratamiento de las leucemias agudas en niños y jóvenes. Objetivo: Identificar la frecuencia y describir la práctica de la división domiciliaria de medicamentos antineoplásicos utilizados en el tratamiento oral de niños y adolescentes con leucemias agudas en la fase de mantenimiento. Método: Se trata de un estudio transversal descriptivo realizado en un hospital de la red de salud pública del Distrito Federal (Brasil) con asistencia especializada en pediatría. El estudio incluyó a niños y jóvenes de entre 1 y 18 años de edad diagnosticados con leucemia aguda y en fase de mantenimiento del tratamiento en el período del estudio. Se aplicó un cuestionario semiestructurado a la persona principal responsable de la administración de fármacos quimioterapéuticos por vía oral, que puede ser el cuidador o el propio niño/joven. Fueron colectadas variables sociodemográficas de los pacientes y cuidadores y variables sobre la práctica de la división de los medicamentos antineoplásicos en domicílios. Resultados: Los 48 entrevistados en el período de estudio informaron haber roto las pastillas antineoplásicas durante el tratamiento de la leucemia aguda, siendo éstas mercaptopurina (n=45 [93,75%]) y tioguanina (n=3 [6,25%]). Conclusión: La partición de comprimidos antineoplásicos fue una práctica unánime debido a la necesidad mencionada de ajustar la dosis individual para el tratamiento de las leucemias agudas de niños y adolescentes, considerando la falta de formulaciones apropiadas. Los resultados refuerzan la necesidad de estandarizar y realizar la partición para minimizar los riesgos y garantizar la seguridad de los niños, jóvenes y sus cuidadores.


Assuntos
Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Comprimidos/administração & dosagem , Leucemia/tratamento farmacológico , Leucemia/terapia , Criança , Adolescente , Conduta do Tratamento Medicamentoso , Antineoplásicos/administração & dosagem
3.
Medicine (Baltimore) ; 98(42): e17189, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626083

RESUMO

BACKGROUND: Physical manipulation of the manufactured dose form is a common practice, with almost a quarter of all drugs administered in primary care having their dose altered. Splitting a tablet can be advantageous as it facilitates swallowing, allows for dose flexibility and provides cost reductions. However, there are concerns these physical changes can lead to inaccurate portions resulting in significant variations from the prescribed dose. Thus, the review described in this protocol aims to summarise the literature assessing the effect of tablet splitting on dose accuracy. METHODS: Relevant studies will be identified through electronic searches in databases including EMBASE, MEDLINE, CINAHL, and the Cochrane Library, from the beginning of databases until January 2020. Studies investigating any drug, where the tablet was split, will be potentially eligible. Two reviewers will independently screen studies and extract data using standardised forms. Data extracted will include general study information, characteristics of the study, intervention characteristics and outcomes. Primary outcome is to assess dose accuracy of a split tablet measured by drug content or weight variability. Assessment of risk of bias will be dependent upon study design. If deemed feasible, meta-analysis will be performed. RESULTS: The study described within this protocol will provide a synthesis of current evidence assessing the effect of tablet splitting on dose accuracy. CONCLUSION: The conclusion of our study will provide evidence to judge whether splitting a tablet results in an accurate half dose. ETHICS AND DISSEMINATION: Ethics approval was not required for this study. The results of the systematic review described will be published in a peer-reviewed journal. REGISTRATION DETAILS: PROSPERO CRD42018106252.


Assuntos
Comprimidos/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Revisões Sistemáticas como Assunto , Comprimidos/economia
4.
Chem Pharm Bull (Tokyo) ; 67(10): 1144-1151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582634

RESUMO

Definitive screening design (DSD) is a new class of small three-level experimental design that is attracting much attention as a technical tool of a quality by design (QbD) approach. The purpose of this study is to examine the usefulness of DSD for QbD through a pharmaceutical study on the preparation of ethenzamide-containing orally disintegrating tablet. Model tablets were prepared by directly compressing the mixture of the active pharmaceutical ingredient (API) and excipients. The five evaluated factors assigned to DSD were: the contents of API (X1) and lubricant (X2), and the compression force (X3) of the tableting process, the mixing time (X4), and the filling ratio of powder in the V-type mixer (X5). After tablet preparation, hardness and disintegration time were measured. The same experiments were performed by using the conventional design of experiments [i.e., L8 and L16 orthogonal array designs and central composite design (CCD)]. Results showed that DSD successfully clarified how various factors contribute to tablet properties. Moreover, the analysis result from DSD agreed well with those from the L8 and L16 experiments. In additional experiments, response surfaces for tablet properties were created by DSD. Compared with the response surfaces created by CCD, DSD could produce reliable response surfaces for its smaller number of experiments. We conclude that DSD is a powerful tool for implementing pharmaceutical studies including the QbD approach.


Assuntos
Desenho de Fármacos , Preparações Farmacêuticas/química , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Propriedades de Superfície , Comprimidos/administração & dosagem , Comprimidos/química
5.
Chem Pharm Bull (Tokyo) ; 67(10): 1152-1159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582635

RESUMO

Melt adsorption is a manufacturing method that offers precise control of particle size distribution of granules and circumvents the disadvantages of conventional melt granulation. However, drug release from particles adsorbed with hydrophobic materials has not been fully investigated, and there are missing details as to whether particles manufactured by this technique can be applied to orally disintegrating tablets (ODT). In this report, we aimed to optimize process parameters and formulation to manufacture ODT containing melt adsorption-particles with the specific characteristic of sustained release. Melt adsorption particles containing Neusilin US2 as the adsorbent were prepared by using various waxes to determine the most suitable material for controlled release formulation. Glycerol fatty acid ester (Poem TR-FB: TR-FB) was the optimal wax examined because of its drug release pattern and tabletability. We then optimized manufacturing conditions by examining granulation time, disintegrant amount per tablet and compression force on the tablet for ODT that meet the criteria of controlled drug release, tensile strength and disintegration of the tablet. Multiple regression analysis revealed the effect of process parameters on tablet properties and drug release with increasing the granulation time affording sustained release of the drug. The analysis also showed that a high compression force crushed the granules coated by TR-FB, which impaired sustained drug release. From the regression model the optimal manufacturing conditions were determined, and the tablet prepared under these conditions concurred with the predicted values and met all criteria. This new technique should contribute to the development of ODT to improve medication adherence.


Assuntos
Compostos de Alumínio/química , Compostos de Magnésio/química , Silicatos/química , Administração Oral , Adsorção , Ésteres/química , Ácidos Graxos/química , Glicerol/química , Interações Hidrofóbicas e Hidrofílicas , Tamanho da Partícula , Propriedades de Superfície , Comprimidos/administração & dosagem , Comprimidos/química
6.
Pharm Res ; 36(12): 167, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650274

RESUMO

PURPOSE: Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API's in which long term stability is not required. METHOD: Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP). RESULTS: This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2 weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen. CONCLUSIONS: On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.


Assuntos
Excipientes/química , Comprimidos/química , Ciprofloxacino/química , Diazepam/química , Difenidramina/química , Doxiciclina/química , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Ibuprofeno/química , Tamanho da Partícula , Pós/administração & dosagem , Pós/química , Solubilidade , Solventes/química , Comprimidos/administração & dosagem
7.
AAPS PharmSciTech ; 20(8): 321, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650430

RESUMO

Combined dissolution and permeation systems are designed to simultaneously assess the dissolution of a pharmaceutical dosage form and the permeation of dissolved drugs therefrom. However, there were still some limitations on predicting the possible absorption rate-limiting steps and improving the in vitro-in vivo correlation (IVIVC) of a complete dosage form. In this study, the modified biorelevant media with some solubilizers and pH modifiers were integrated into the drug dissolution/absorption simulating system (DDASS). Indapamide, a poorly soluble compound (pKa = 8.8), was selected to validate the applicability of the modified biorelevant media. The elution and permeation dynamics of indapamide were investigated by using appropriate solubilizing agents in the DDASS. The absorption behaviors were analyzed after oral administration of indapamide in beagle dogs. The absorption rate-limiting steps and IVIVCs were predicted from the dissolution-permeation-absorption dynamic parameters. As a result, the absorption fraction of indapamide in the FaSSIFmod of DDASS was estimated to be approximately 100%, in accordance with its high permeability. The ratios of permeation rate to elution rate were 2.55 and 3.34 for the immediate- and sustained-release tablets of indapamide, respectively, suggesting a dissolution rate-limiting absorption for indapamine. In addition, point-to-point correlations were established between in vitro elution and in vivo absorption by the nonlinear and linear regression analysis ways (r > 0.85). The findings indicate that DDASS is a promising technique to develop improved IVIVCs of a complete dosage form, and the FaSSIFmod is suitable to predict the possible absorption rate-limiting steps of poorly soluble drugs in DDASS.


Assuntos
Liberação Controlada de Fármacos , Indapamida/administração & dosagem , Indapamida/metabolismo , Absorção Intestinal/efeitos dos fármacos , Administração Oral , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/metabolismo , Cães , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos/métodos , Previsões , Absorção Intestinal/fisiologia , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Solubilidade , Comprimidos/administração & dosagem , Comprimidos/química , Comprimidos/farmacocinética
8.
J Agric Food Chem ; 67(43): 11911-11921, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31475818

RESUMO

Red algae sulfated polysaccharides (RASP) were extracted from Porphyra haitanensis and Gracilaria lemaneiformis. RASP were applied to effervescent tablets to develop a type of functional food, termed red algae sulfated polysaccharide effervescent tablets (RASPET), based on the antiallergic activities of RASP. The antiallergic activities and the mechanisms of RASPET were investigated in an ovalbumin (OVA)-induced mouse model of food allergy. The results revealed that RASPET alleviated intestinal villi injury by scanning electron microscopy and anaphylactic symptoms; reduced OVA-specific immunoglobulin E, histamine, and mast cell protease-1 levels in the serum; reduced the level of serum interleukin-4; increased serum interferon-γ level; and decreased B cell and mast cell populations. Remarkably, RASPET increased the levels of serum interleukin-10, transforming growth factor-ß, and upregulated splenic CD4+foxp3+ T cell populations (15.28, 16.82, and 17.58%, respectively) compared to the OVA group (13.17%). In conclusion, RASPET attenuated OVA-induced anaphylaxis via the upregulation of regulatory T cells.


Assuntos
Anafilaxia/tratamento farmacológico , Antialérgicos/administração & dosagem , Ovalbumina/efeitos adversos , Polissacarídeos/administração & dosagem , Rodófitas/química , Linfócitos T Reguladores/imunologia , Anafilaxia/etiologia , Anafilaxia/imunologia , Animais , Antialérgicos/química , Modelos Animais de Doenças , Feminino , Histamina/imunologia , Humanos , Imunoglobulina E/imunologia , Interferon gama/imunologia , Interleucina-4/imunologia , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos/química , Comprimidos/administração & dosagem , Comprimidos/química
9.
Lancet ; 394(10200): 737-745, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31311674

RESUMO

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. METHODS: In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. FINDINGS: Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6-14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3-13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3â€ˆ× the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2â€ˆ× the upper limit of normal were reported. Treated participants reported no serious adverse events. INTERPRETATION: In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. FUNDING: Biohaven Pharmaceuticals.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas/administração & dosagem , Piridinas/administração & dosagem , Administração Sublingual , Adulto , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Piridinas/efeitos adversos , Comprimidos/administração & dosagem
10.
Lipids Health Dis ; 18(1): 157, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31351498

RESUMO

BACKGROUND: The hypolipidemic effect of phytosterols has been wildely recognized, but its application is limited due to its insolubility in water and low solubility in oil. In this study, ß-sitosterol ester with linoleic acids and ß-sitosterol self-microemulsions were prepared and their hypolipidemic effects on hyperlipidemia mice were studied. METHODS: Firstly, the mice were randomly divided into normal group and model group,they were fed with basic diet and high-fat diet for 70 days respectively. After high-fat model mice was successfully established, the model group was further divided into eight groups: HFD (high-fat diet feeding), SELA-TSO(8 ml/kg, SELA:700 mg/kg), TSO (8 ml/kg), SSSM (8 ml/kg,SS:700 mg/kg), NLSM (8 ml/kg), SSHT-TSO (8 ml/kg, SS: 700 mg/kg) and SS-TSO (8 ml/kg, SS: 700 mg/kg) groups, and treated with ß-sitosterol ester with linoleic acid, ß-sitosterol self-microemulsion, commercial ß-sitosterol health tablets and ß-sitosterol powder for 35 days, respectively, and blank control groups were established. At the end of the treatment period, the blood lipid level, tissues, cholesterol and lipids in feces of mice in each group were investigated. Statistical and analytical data with SPSS 17.0 Software,statistical significance was set at p* < 0.05 and p** < 0.01 levels . RESULTS: The order of lowering blood lipid effect is listed as: SSSM> SELA-TSO > SSHT-TSO > SS-TSO, which shows that ß-sitosterolself-microemulsion have the highest treatment effect among the experimental groups. CONCLUSIONS: In this study, a new formulation of ß-sitosterol was developed, and its hypolipidemic effect was investigated. The results showed that ß-sitosterol self-microemulsion has a good blood lipid lowering effect.


Assuntos
Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Ácido Linoleico/farmacologia , Sitosteroides/farmacologia , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Emulsões/administração & dosagem , Emulsões/química , Emulsões/farmacologia , Fezes/química , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Ácido Linoleico/administração & dosagem , Ácido Linoleico/química , Lipídeos/sangue , Masculino , Camundongos , Microscopia Eletrônica de Transmissão , Tamanho do Órgão/efeitos dos fármacos , Sitosteroides/administração & dosagem , Sitosteroides/química , Comprimidos/administração & dosagem , Comprimidos/farmacologia
11.
Eur J Pharm Sci ; 138: 105016, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31356869

RESUMO

We aim to optimize the paediatric dosing regimen of isoniazid, rifampicin and pyrazinamide for the first-line treatment of tuberculosis, based on a fixed dose combination (FDC) mini-tablet using simulations. An optimization problem was set up to determine the 3 strengths of the drugs of the mini-tablet and 4 cutoff points that define the weight bands of a dosing chart, simultaneously. Using Monte Carlo simulations, first, exposure targets were determined for the 3 drugs, from published population pharmacokinetic models for adults, assuming that the approved doses for adults are de facto efficacious. Then optimal strengths and cutoff points were determined by matching children exposures generated from population pharmacokinetic models to the adults targets. The optimal dosing strengths of the FDC tablet were found to be 95 mg of rifampicin, 200 mg of pyrazinamide and 75 mg of isoniazid, and the 4 body weight bands for 1 to 4 mini-tablets, respectively were: 4 to 8 kg, 8 to 12 kg, 12 to 18 kg and 18 to 28 kg. Children with body weight ≥ 28 kg will be treated with adult dosages. The higher doses proposed were evaluated to be much closer to the adult targets compared to the existing recommended by WHO paediatric doses.


Assuntos
Antituberculosos/administração & dosagem , Comprimidos/administração & dosagem , Tuberculose/tratamento farmacológico , Adulto , Criança , Humanos , Isoniazida/administração & dosagem , Pirazinamida/administração & dosagem , Rifampina/administração & dosagem
12.
Drugs R D ; 19(3): 255-265, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31197606

RESUMO

BACKGROUND: Two phase I studies assessed the pharmacokinetics of buprenorphine, its metabolite norbuprenorphine, and naloxone following administration of buprenorphine/naloxone sublingual tablets in Chinese participants. METHODS: In the first phase I, open-label, single ascending-dose (SAD) study, 82 opioid-naïve volunteers received a single buprenorphine/naloxone dose ranging from 2 mg/0.5 mg to 24 mg/6 mg while under naltrexone block. In a second phase I, open-label, multiple ascending-dose (MAD) study, 27 patients with opioid dependence in withdrawal received buprenorphine/naloxone doses of either 16 mg/4 mg or 24 mg/6 mg for 9 consecutive days. Serial blood samples were collected after a single dose (SAD study) and at steady-state (MAD study). Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety assessments included adverse events monitoring and laboratory tests. RESULTS: The pharmacokinetic profiles of buprenorphine and naloxone were consistent between single- and multiple-dose studies. Peak plasma concentrations (Cmax) were reached early for buprenorphine (0.75-1.0 h) and naloxone (0.5 h), supporting rapid absorption. In the SAD study, increases in plasma exposures to buprenorphine and naloxone were less than dose proportional, in line with previous observations in Western populations. Buprenorphine-to-naloxone ratios for Cmax and area under the curve (AUC) were constant over the dose range investigated and also consistent with Western populations data. Steady state was reached within 7 days of daily dosing, with slight accumulation over repeated doses. No serious adverse events were observed. CONCLUSIONS: The present data suggest that buprenorphine/naloxone pharmacokinetic profiles in Chinese participants are consistent, overall, with those in Western populations, supporting no differences in dosing. CLINICAL TRIAL REGISTRATION: The protocols were registered on the official website of the China Food and Drug Administration (CFDA): http://www.chinadrugtrials.org.cn/ ; Registration numbers CTR20132963 (RB-CN-10-0012), CTR20140153 (RB-CN-10-0015).


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacocinética , Buprenorfina/administração & dosagem , Buprenorfina/farmacocinética , Comprimidos/administração & dosagem , Comprimidos/farmacocinética , Administração Sublingual , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Disponibilidade Biológica , Buprenorfina/análogos & derivados , Feminino , Humanos , Masculino , Naloxona/administração & dosagem , Naloxona/farmacocinética , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/metabolismo
13.
Chem Pharm Bull (Tokyo) ; 67(6): 540-545, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31155559

RESUMO

Fixed-dose combination (FDC) medicines containing two or more active pharmaceutical ingredients (APIs) in a single dosage form have been reported to improve patient adherence to a greater extent than single dosages of individual components (ICs). Orally disintegrating tablets (ODTs) are easier to swallow than conventional tablets. The aim of this study was to elucidate the clinical pharmaceutical characteristics of taking a FDC-ODT and two IC-ODTs. We prepared three ODTs containing mitiglinide, voglibose, and mitiglinide/voglibose and three corresponding placebo ODTs and performed 2 independent clinical trials with 13 healthy subjects (mean age, 23.4 ± 1.6 years). One trial evaluated the ease of taking tablets and the amount of water required for taking the tablets; placebo ODTs were used in order to avoid administering APIs. The other trial evaluated the bitterness, sweetness and overall palatability of ODTs containing APIs during disintegration and after spitting out. Ease and taste were evaluated using both a visual analog scale (VAS) and a verbal rating scale (VRS). The results of the VAS and VRS evaluation indicated that FDC-ODT could ease tablet intake unlike IC-ODTs. In addition, FDC-ODT reduced the amount of water required for tablet intake in contrast to IC-ODTs. Taste evaluation results did not reveal any difference between FDC-ODT and IC-ODTs, except for the sweetness score after spitting out. In conclusion, FDC-ODT is easy to take and can help improve patient adherence.


Assuntos
Inositol/análogos & derivados , Isoindóis/química , Comprimidos/administração & dosagem , Administração Oral , Adulto , Composição de Medicamentos , Feminino , Humanos , Inositol/química , Masculino , Efeito Placebo , Solubilidade , Paladar/fisiologia , Água/administração & dosagem , Adulto Jovem
14.
Drugs R D ; 19(3): 247-254, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177479

RESUMO

INTRODUCTION: Sublingual fentanyl tablets (SFTs) have been shown to be a safe and effective option in controlling breakthrough cancer pain (BTcP). However, further examination is required to investigate the use of SFTs among the elderly. The aim of this study was to examine the influence of age in BTcP management with SFTs in the elderly population. METHODS: We performed subgroup analyses of a recently completed trial in two subsets of individuals: patients aged 65-74 years (low age group) and patients ≥ 75 years (high age group). Pain intensity (PI), onset of pain relief, frequency and duration of BTcP episodes, and adverse events (AEs) were assessed at 3, 7, 15, and 30 days. Health status instruments used were the Hospital Anxiety and Depression Scale (HADS-A and HADS-D) and the Short Form 12, version 2 (SF-12v2) questionnaire. RESULTS: Levels of PI at the end of the study improved significantly as compared with baseline in both the low and the high age groups (30.0% and 27.7% reduction, respectively). The onset of analgesia at the end of the study began in < 10 min in 85.0% of young-old subjects and in 62.5% of patients ≥ 75 years, but no significant differences were found. BTcP episodes lasted < 15 min in 75.0% of patients in the low age group and 58.3% in the high age group (p = 0.24). Most of patients in both groups experienced one to five BTcP daily episodes, at all assessment points. HADS-D decreased from 10.78 (± 4.33) to 8.21 (± 3.57) in the low age group, and from 10.96 (± 4.26) to 9.36 (± 3.35) in the high age group (p = 0.02). Significant differences in HADS-A scores from baseline to the end of the study were also observed in both subgroups (p < 0.05). Patients in the low age group had less favorable mental component summary (MCS) and physical component summary (PCS) scores than patients in the high age group. At the end of the study, 10.0% of young-old patients and 29.2% of patients aged ≥ 75 years reported AEs related to their treatment. The most commonly reported AEs included nausea, vomiting, constipation, somnolence, and skin disorders and they were generally mild to moderate in severity. CONCLUSIONS: The results of this study showed that SFTs provided safe and clinically meaningful pain relief in both elderly subgroups. Clinical implications of these findings await validation in large, confirmatory studies to identify age subgroup divergences among elderly cancer patients treated with SFTs.


Assuntos
Analgésicos Opioides/administração & dosagem , Dor Irruptiva/tratamento farmacológico , Dor do Câncer/tratamento farmacológico , Fentanila/administração & dosagem , Neoplasias/complicações , Comprimidos/administração & dosagem , Administração Sublingual , Idoso , Feminino , Humanos , Masculino , Manejo da Dor/métodos
15.
Pharm Dev Technol ; 24(7): 902-914, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31215850

RESUMO

The oral administration route is considered to be the most widely used route because of its convenience of administration and manufacturing. Dosage forms, like orally disintegrating tablets (ODTs), mini tablets, and orally disintegrating mini tablets (ODMTs), are recognized as promising for use in pediatric patients. ODTs are known to be suitable drug delivery systems, especially for pediatric patients, because of their rapid disintegration properties, use without water, and no swallowing problems. In addition, in recent years, a new formulation approach has been developed. ODMTs, are the newest drug delivery systems. They combine the advantageous properties of ODTs and the small size of mini tablets, aimed for pediatric use. These tablets, which can be formulated as 2-4 mm in diameter, are known as drug delivery systems that have children acceptability age as low as 6-months old. The fact that the ODTs and the ODMTs can be formulated with acceptable flavors for children further increases the importance of these carrier systems in the treatment. The objective of this article is to highlight the development of ODTs and mini-ODTs, their significance, ideal characteristics, various techniques, and aspects related to design and formulation, marketed preparations, and future perspectives, especially for the pediatric patients.


Assuntos
Portadores de Fármacos/química , Composição de Medicamentos/métodos , Comprimidos/química , Administração Oral , Criança , Pré-Escolar , Portadores de Fármacos/administração & dosagem , Humanos , Lactente , Tamanho da Partícula , Solubilidade , Comprimidos/administração & dosagem
16.
AAPS PharmSciTech ; 20(6): 229, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227930

RESUMO

Atropine sulfate (AS) fast-disintegrating sublingual tablets (FDSTs) were tested for AS sublingual permeation's feasibility as a potential alternative dosage form to treat organophosphates (OP) toxicity. More than 12,000 OP pesticide toxicity cases were reported in the USA from 2011 to 2014. AS is the recommended antidote for OP toxicity; however, it is only available as an ATROPEN® auto-injector, an IM injection, for self-administration, which is associated with several drawbacks and limitations. Six AS FDST batches were formulated and characterized. Two tablet sizes, group A weighing 150 mg and group B weighing 50 mg, were formulated with three different AS doses: 2 mg (A1 and B1), 4 mg (A2 and B2), and 8 mg (A3 and B3). AS in vitro diffusion and sublingual permeation were investigated in Franz cells using a cellulose membrane and an excised porcine sublingual membrane. The effect of AS load and tablet size on sublingual permeation was also evaluated. All batches passed quality control tests. AS FDSTs' size and AS load had a significant effect on tablet disintegration time and drug dissolution, which significantly impacted AS concentration gradient across the diffusional membrane. Group B FDSTs (smaller tablets) resulted in a significantly higher initial permeation (JAUC0-15) compared to group A FDSTs. Also, the cumulative AS (JAUC0-90) and AS influx (J) increased linearly with increasing AS dose. These AS FDSTs have the potential to be explored in vivo to determine the required bioequivalent sublingual AS dose as an alternative dosage form for the treatment of OP toxicity.


Assuntos
Atropina/administração & dosagem , Atropina/uso terapêutico , Intoxicação por Organofosfatos/tratamento farmacológico , Comprimidos/administração & dosagem , Administração Sublingual , Animais , Difusão , Permeabilidade , Suínos
17.
AAPS PharmSciTech ; 20(6): 236, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236762

RESUMO

The objective of this study was to investigate the development of a novel puerarin gastric floating system with a concentric annular internal pattern by a 3D extrusion-based printing technique and to explore the flexibility of turning the release behavior through the design of the internal structure. The composition consisted of the conventional sustained-release pharmaceutical excipients without addition of foaming agent or light materials. First, the proper alcohol/water proportion was selected for the binding agent. The desired drug release behaviors and good floating properties were obtained either through modification of the formulation composition or adjustment of the internal structure. In vitro, the printed tablets were evaluated for drug release, mechanical properties, lag time, and floating duration time. The in vivo behaviors of the formulations were noted at certain time intervals through assessment of the radiographic pictures of healthy volunteers. The gastric retention time in the 3D-printed tablet was approximately 6 h in vivo. Results indicated these puerarin gastric floating 3D-printed tablets had great potential to achieve good gastric residence time and controlled release. Therefore, 3D extrusion-based printing appears to be appropriate for the production of oral administration systems, owing to its flexibility and the great floating ability and controlled-release capacity of its products.


Assuntos
Preparações de Ação Retardada/química , Isoflavonas/administração & dosagem , Impressão Tridimensional , Estômago , Comprimidos/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Excipientes/química , Humanos , Isoflavonas/farmacocinética
18.
Pak J Pharm Sci ; 32(2 (Supplementary)): 793-798, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31103974

RESUMO

Cinitapride has been widely given in gastro-esophageal reflux disease (GERD) and dysphagia due to irregularities of GI motilities. Mouth dissolving tablets were prepared for rapid availability and action of drug. Multi-point dissolution studies were conducted in 0.1 N HCl solution of pH 1.2 and phosphate buffer of pH 4.5 and 6.8. Drug release profile showed higher liberation of cinitapride at lower pH then basic medium (<80%). Formulation containing crospovidone (10%) was found to be optimized trial having excellent quality pharmaceutical attributes. The lowest AIC, highest MSC and regression (> 0.9) values were observed for Weibull kinetics in all dissolution medium reflecting the excellent model fitting for the present study. Accelerated stability testing data showed excellent results of drug assay (>99%) along with physical characteristics indicating the absence of drug degradation as well excipient interaction. The estimated shelf life period of various optimized trial formulations was found in between 33 to 41 months.


Assuntos
Benzamidas/química , Benzamidas/farmacocinética , Comprimidos/química , Comprimidos/farmacocinética , Administração Oral , Benzamidas/administração & dosagem , Tampões (Química) , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Cinética , Comprimidos/administração & dosagem
19.
Int J Infect Dis ; 83: 130-138, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30978465

RESUMO

OBJECTIVES: Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness. METHODS: We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively. RESULTS: Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 - 03/2016 were observed. Median age was 58 years (range: 19 - 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 µg/L (IQR 573-1,498 µg/L) and 904 µg/L (IQR 728-1,550 µg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 - 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD. CONCLUSIONS: Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species.


Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Centros de Atenção Terciária , Triazóis/uso terapêutico , Administração Intravenosa , Adulto , Idoso , Antifúngicos/administração & dosagem , Feminino , Humanos , Infecções Fúngicas Invasivas/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Comprimidos/administração & dosagem , Comprimidos/uso terapêutico , Resultado do Tratamento , Triazóis/administração & dosagem , Adulto Jovem
20.
Adv Parasitol ; 103: 75-89, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30878059

RESUMO

The importance of implementing paediatric clinical trials for neglected tropical diseases (NTDs) in compliance with the Good Clinical Practices of the International Conference of Harmonisation (ICH-GCP) and other applicable regulatory and ethics guidelines is increasingly being recognised as an essential pathway to provide safe and effective medicines for millions of untreated children living in sub-Saharan Africa (SSA). This paper describes the learnings and challenges faced by the Pediatric Praziquantel Consortium team during the implementation of an industry-sponsored Phase II clinical study in pre-school-aged children infected with schistosomiasis, conducted in remote rural settings in Côte d'Ivoire. The importance of close interactions with the ethics committee, the regulatory and administrative authorities and the rural communities are highlighted. The difficulties faced included obtaining a valid informed consent from the child's parent or guardian, the collection of blood samples from children during the study while respecting cultural beliefs as well as the weak medical research infrastructure. The paper illustrates how a public-private collaborative partnership can promote capacity-building and high-quality NTD paediatric clinical research in SSA.


Assuntos
Ensaios Clínicos Fase II como Assunto/normas , Praziquantel/administração & dosagem , Esquistossomose/tratamento farmacológico , Administração Oral , Anti-Helmínticos/administração & dosagem , Pré-Escolar , Ensaios Clínicos Fase II como Assunto/ética , Costa do Marfim , Humanos , Consentimento Livre e Esclarecido , População Rural , Comprimidos/administração & dosagem
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