Vildagliptina e associação com metformina : desenvolvimento de metodologia analítica, ensaio de dissolução e estudo da estabilidade

A vildagliptina (VLG) e o cloridrato de metformina (MET) são fármacos utilizados no tratamento da diabetes mellitus tipo 2. Esses fármacos podem ser utilizados como monoterapia ou em associação como terapia complementar. A análise de fármacos dentro da área do controle de qualidade é essencial para averiguar se os medicamentos comercializados são seguros e confiáveis do ponto de vista terapêutico e farmacológico. Existem poucos relatos de determinação quantitativa e de estudo de estabilidade encontrados na literatura para a VLG em comprimidos e também para a VLG em associação com metformina em comprimidos revestidos. Desse modo, o objetivo desse trabalho foi desenvolver e validar métodos analíticos qualitativos e quantitativos, tanto para a VLG quanto para a determinação dos fármacos em associação, realizar o estudo da estabilidade e ensaios de dissolução (utilizando os métodos de CLAE e UV derivada para avaliação). Métodos analíticos por cromatografia líquida de alta eficiência (CLAE) e eletroforese capilar (EC) foram desenvolvidos e validados para a determinação de VLG em comprimidos e de VLG em associação com MET em comprimidos revestidos. Os resultados encontrados foram adequados, de acordo com o preconizado pelos guias oficiais nacionais e internacionais, e os métodos foram considerados validados. Esse trabalho ainda, apresenta o desenvolvimento e validação de método analítico por cromatografia líquida acoplada à espectrometria de massas (CLAE-EM/EM) para análise dos referidos fármacos em associação e identificação dos produtos de degradação formados a partir das principais condições de degradação às quais os fármacos foram suscetíveis. Ainda, avaliou-se a citotoxicidade em células mononucleares humanas desses produtos de degradação os quais não demonstraram potencial citotóxico. Além disso, foram desenvolvidos e validados dois métodos de dissolução (um para VLG em comprimidos e outro para VLG em associação com MET) pelos quais foi possível realizar o controle de qualidade das formas farmacêuticas a partir dos perfis de dissolução dos fármacos nos meios selecionados. Os resultados obtidos pelos métodos foram comparados estatisticamente por ANOVA, que indicou não haver diferenças estatísticas significativas entre os métodos propostos.Vildagliptin (VLG) and metformin hydrochloride (MET) are drugs used in the treatment of type 2 diabetes mellitus. These drugs may be used as monotherapy or as adjunctive therapy. The analysis of drugs in the area of quality control is essential to establish whether the marketed drugs are safe and reliable in terms of therapeutic and pharmacological aspects. Few reports were found for quantitative determination and stability study in the literature for VLG in tablets and also to VLG in association with metformin in coated tablets. Thus, the aim of this study was to develop and validate qualitative and quantitative analytical methods for both VLG and for the determination of drugs in association, to perform study of stability and dissolution tests (using HPLC and derivative UV spectrophotometric methods for this evaluation). Analytical methods by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE) were developed and validated for the determination of VLG tablet and VLG in association with MET in coated tablets. The results found were adequate, according to nacional and international official guides, and the methods were considered validated. This work also performed the development and validation of an analytical method by liquid chromatography coupled to mass spectrometry (HPLC-MS/MS) for pharmaceutical analysis for both studied drugs and identification of degradation products formed in the main degradation condition which both drugs are susceptible. Moreover, it was performed the cytotoxicity evaluation for degradation products against human mononuclear cells and these products did not demonstrate potential cytotoxicity. Furthermore, were developed and validated two dissolution methods (one for VLG in tablet formulation and another for VLG in association with MET) which was possible to perform the quality control for the pharmaceutical dosage forms as from dissolution patterns of theses drugs in the selected dissolution medium. The results of the methods were statistically compared using ANOVA that showed no statistically significant differences between the proposed methods

SECOND-ORDER DERIVATIVE UV SPECTROPHOTOMETRIC AND RP-HPLC METHODS FOR THE ANALYSIS OF VILDAGLIPTIN AND APPLICATION FOR DISSOLUTION STUDY

This study describes two analytical methods, by second-order derivative UV spectrophotometric by HPLC, for determination of vildagliptin, a drug used for treatment of type 2 Diabetes Mellitus that belongs to a therapeutic class called inhibitors of dipeptidyl peptidase 4. The methods were validated in accordance with ICH and USP requirements. Analyses by UV derivative method were performed at 220 nm, which was the zero crossing point of excipient solutions. HPLC was optimized and the analysis was carried out using a Zorbax Eclipse Plus RP-C8 column (150 mm × 4.6 mm, 5 μm), detection at 207 nm, and potassium phosphate buffer solution pH 7.0 : acetonitrile (85:15, v/v) as mobile phase. In dissolution test, the conditions used were 0.01 mol L-1 hydrochloric acid in 900 mL of dissolution medium, USP apparatus 2 (paddle) and 50 rpm stirring speed. Both methods were successfully applied for analysis of dissolution samples from marketed vildagliptin tablets

CHARACTERIZATION OF LINAGLIPTIN USING ANALYTICAL TECHNIQUES

Linagliptin (LGT) is a member of the class of gliptins that inhibit the enzyme dipeptidyl-peptidase-4. They are used to reduce glucose blood levels in patients with type 2 Diabetes mellitus. Due to its recent development and launching on the market, LGT has no official compendium monograph, national or international, or available registries for the qualitative determination of this drug. The objective of this work was to characterize LGT by using thermal techniques, nuclear magnetic resonance, mass and infrared spectrometry, liquid chromatography and ultraviolet spectrophotometry to be used as a chemical reference substance. The range and melting point obtained are in accordance with that described in the literature. The main groups of LGT molecule were observed in infrared spectroscopy and the molecular ion m/z 473.25 ratio was found in mass spectroscopy analysis. In UV spectroscopy, the maximum wavelength absorption of the substance in different solvents can be observed. The chromatographic methods provide selectivity for LGT and can be used to analyze it qualitatively. The proposed conditions have been successfully applied for identification and qualitative analysis of LGT as a chemical reference substance, contributing to studies of this gliptin, and to the quality control of medicines that contain it.Linagliptin (LGT) is a member of the class of gliptins that inhibit the enzyme dipeptidyl-peptidase-4. They are used to reduce glucose blood levels in patients with type 2 Diabetes mellitus. Due to its recent development and launching on the market, LGT has no official compendium monograph, national or international, or available registries for the qualitative determination of this drug. The objective of this work was to characterize LGT by using thermal techniques, nuclear magnetic resonance, mass and infrared spectrometry, liquid chromatography and ultraviolet spectrophotometry to be used as a chemical reference substance. The range and melting point obtained are in accordance with that described in the literature. The main groups of LGT molecule were observed in infrared spectroscopy and the molecular ion m/z 473.25 ratio was found in mass spectroscopy analysis. In UV spectroscopy, the maximum wavelength absorption of the substance in different solvents can be observed. The chromatographic methods provide selectivity for LGT and can be used to analyze it qualitatively. The proposed conditions have been successfully applied for identification and qualitative analysis of LGT as a chemical reference substance, contributing to studies of this gliptin, and to the quality control of medicines that contain it

Abstracts from the NIHR INVOLVE Conference 2017

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Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Development and validation of analytical methods for determination of vildagliptin in tablets

Objetivos: os objetivos gerais deste trabalho foram desenvolver, validar e comparar métodos analíticos para caracterização e determinação quantitativa de vildagliptina (VLG) na forma farmacêutica comprimidos, assim como determinar a cinética de degradação do fármaco em condição de estresse. Métodos: método indicativo de estabilidade por cromatografia líquida de alta eficiência com detecção ultravioleta (CLAE-UV) foi desenvolvido e validado, conforme as normas da International Conference on Harmonisation (ICH). A cinética de degradação do fármaco foi determinada frente à hidrólise alcalina. A possível estrutura do produto de degradação majoritário, formado sob condições básicas, oxidativas e térmicas foi proposta de acordo com análises realizadas por espectrometria de massas (EM). Foi desenvolvido e validado, também, método por espectrofotometria ultravioleta derivada para quantificação do fármaco na forma farmacêutica. Resultados e Conclusões: o método de CLAE indicativo de estabilidade desenvolvido e validado demonstrou ser adequado para a quantificação da substância ativa na forma farmacêutica sem sofrer a interferência dos excipientes presentes na formulação e também na presença dos produtos de degradação. Os principais fatores extrínsecos que promoveram a degradação do fármaco foram: oxidação, hidrólise alcalina e temperatura. Determinou-se a cinética de degradação, sob condições alcalinas, como sendo de primeira ordem indicando, assim, que o processo de degradação é dependente da concentração de fármaco. O método por espectrofotometria UV derivada também se mostrou adequado para a quantificação de vildagliptina nos comprimidos. A comparação entre os métodos desenvolvidos não mostrou diferença estatística significativa demonstrando que ambos os métodos podem ser utilizados para determinação de vildagliptina no controle de qualidade dos comprimidos.Objectives: the aim of the present work was to develop, validate and compare analytical methods to characterization and quantitative determination of vildagliptin (VLG) in tablet dosage form, as well as to determinate the degradation kinetics of the drug in a stress condition. Methods: stability-indicating method for the analysis of VLG by high performance liquid chromatography (HPLC) with ultraviolet detection was developed and validated according to the International Conference on Harmonisation (ICH) guidelines. The degradation kinetics of the drug under the alkaline hydrolysis was determined. The possible molecular structure of the major degradation product obtained under the stress studies by alkaline hydrolysis, oxidation and thermal degradation was predicted by mass spectrometry (MS) Results and Conclusions: The developed stability-indicating method was adequate to determine the active substance in the formulation even in the presence of the excipient ingredients in the formulation and, also, in the presence of the degradation products. The main extrinsic factors which promoted the drug degradation were: oxidation, alkaline hydrolysis and thermal degradation. The degradation kinetics was determined, under alkaline conditions, as first order showing that the process is dependent on the drug concentration. The derivative spectrophotometric method also was adequate to the quantification of vildagliptin in tablets. There was no statistical significant difference between the methods demonstrating that both methods can be used for the determination of vildagliptin in quality control of pharmaceutical tablets

Evaluation of linagliptin dissolution from tablets using HPLC and UV methods

Linagliptin (LGT) is used to reduce glucose blood levels in patients with type 2 Diabetes mellitus. The proposed conditions for a biowaiver guide can be applied due to high solubility of linagliptin in aqueous media. The aim of the present study was to develop and validate a dissolution test for 5 mg linagliptin coated tablets. After diverse dissolution procedure evaluation, the selected method was achieved using USP apparatus 1 (basket) at 75 rpm and 900 mL of citrate buffer pH 3.5 as dissolution medium. The conditions proposed by biowaiver guide were also applied to this drug, using USP apparatus 2 (paddle) and 900 mL of 0.1 M HCl, pH 4.5 acetate buffer and pH 6.8 phosphate buffer as dissolution medium. HPLC and UV spectrophotometry were used to LGT quantitation and validated for this purpose. The chromatographic and spectrophotometric methods in the dissolution context proved to be linear in 0.5 – 20.0 μg.mL-1 range, precise with RSD values less than 1.0 % and 2.0%, respectively, and accurate (mean recovery 100.29 % and 100.59%). The parameters such as specificity, linearity, accuracy, precision and robustness were according to international guidelines for both methods HPLC and UV. Dissolved linagliptin results were compared using the Student’s t-test and the data found were not significant different (P=0.068). In most dissolution conditions evaluated, LGT presented more than 85% drug dissolved from the tablets in fifteen minutes. The proposed methods can be applied for quality control of this gliptin. According to the results, linagliptin may be a biowaiver candidate

Perfil bioquímico e de estresse oxidativo em pacientes fenilcetonúricos tratados

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Perfil bioquímico e de estresse oxidativo em pacientes fenilcetonúricos tratados

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