Stability analysis and quantitative evaluation of metronidazole suspension.

Suspension is a heterogeneous mixture including solid particles that are satisfactorily bulky for sedimentation. Generally they must be larger than one micrometer. It is when particles are left floating around freely in a solvent. The inner phase (solid) is discrete all through the external phase (fluid) during mechanical stir, with utilizing of certain excipients or suspending agents. Metronidazole or 2-(2 methyl-5 nitro-1 H –imidazol-1 yl) ethanol belongs to the nitro imidazole group of antibiotics whose antimicrobial property through derive from the formation of toxic free radicals by intracellular reduction. The objective of present study was to prepare suspension of Metronidazole by using different suspending agents and stability testing was to provide evidence on how the quality of suspensions varies with the time under of influence of environmental factors such as temperature, light, oxygen, moisture, other ingredient or excipients in the dosage form, particle size of drug, microbial contamination etc. and to establish a recommended storage condition. The FTIR and DSC techniques are use for characterization of active ingredient MBZ. This suspension was evaluated for appearance, pH, sedimentation volume and dissolution study for in vitro drug release. Result of evaluation indicates 1% w/v xanthan gum give optimal characteristic suspension. Suspension containing 1% w/v was exposed for the stability studies as per ICH guidelines. The suspensions were evaluated for their physicochemical parameter, particle size, drug release, drug content and microbiological assessment. The suspension shows good stability at 25ºC ± 2 ºC /60%± 5% RH, 30 ºC ± 2 ºC /65%± 5% RH and good quantitative analysis result throughout the period of study. Suspension stored at 40 ºC ± 2 ºC /75%± 5% RH shows noncompliance with the analysis parameter after 4 week of storage. This indicate high temperature storage was shows degradation of the suspension which results in crystal growth in formulation and affect the physicochemical parameter as Appearance, pH, viscosity, specific gravity, drug dissolution profile and drug content.

Comparative Evaluation of semisolid bases for transdermal use of Ketorolac tromethamine.

Ketorolac tromethamine (KT) is a non-steroidal anti-inflammatory drug that belongs to class of heteroacetyl derivatives. An attempt has been made to make use of ointments, creams and gels as suitable vehicles for KT, which will released the drug effectively on surface when applied topically. Formulations belongs to ointment, cream and gel bases containing 1% KT were prepared and were evaluated for physiochemical parameters like physical appearance, pH, viscosity, spreadability, drug content. Drug release was also studied by in-vitro techniques. Viscosity was found highest in ointment formulation F3 Gel formulation showed better extrudability and spreadability as compared to ointment and creams. Gel formulation showed better release as compared to ointment and creams.

Preparation of naproxen microemulsion-gel with high drug content and investigation of its in vitro transdermal delivery ability / 中国药学杂志

OBJECTIVE: To prepare naproxen microemulsion-gel with high drug content and adhesiveness, and investigate its in vitro transdermal delivery ability. METHODS: The ranges of microemulsion with the mixture of Tween 80 and Tween 20 as surfactant, carbitol as cosurfactant, peponida as oil, were defined through construction of the pseudo-ternary phase diagrams. Drug-loaded microemulsions were prepared by phase transfer temperature method. Naproxen microemulsion-gel was prepared by directly adding carbomer 980 into its microemulsion. The diffusion studies of all formulations were performed using a drug diffusion apparatus. The mean droplet sizes of naproxen microemulsion were measured via dynamic light scattering(DLS) on a Zetasizer, their microstructures were observed by transmission electron microscope(TEM). RESULTS: Microemulsion range was largest when the mass ratio of Tween 80 and Tween 20 was 3:1, surfactant and cosurfactant was 2:1. While the microemulsion composed of 5% peponida, 35% emulsifier and 60% water, drug loaded in microemulsion can attain 4%, which was accorded with the characterization of microemulsion. Adding 2.5% carbomer 980 into optimization microemulsion, even and transparence microemulsion-gel was obtained, which has the combination of o/w microstructure of microemulsion and the three-dimensional gel network of hydrogel. The viscosity of microemulsion-gel was increased from 104.5 mPa · s to 18.9 Pa · s, the steady-state permeation rates through excised cavia skin increased from(531.912±1.3) to(640.327±0.7) μg · cm-2 · h-1. CONCLUSION Naproxen microemulsion-gels prepared by selected carbitol as cosurfactant can obtain high drug content and percutaneous absorbtion, exhibit favourable adhesiveness, which may be a promising new dosage form for transdermal delivery of naproxen.

Avaliação de diferentes cronogramas de coletas de amostras biológicas em estudos de bioequivalência e análise da influência de teor de fármaco sobre os resultados destes estudos / Evaluation of the effects on different doses and sampling schedules on the assessment of bioequivalence

Os estudos de bioequivalência são realizados em humanos, por meio da administração dos medicamentos em estudo pela mesma via extravascular, sob condições experimentais padronizadas, seguida pela determinação das concentrações plasmáticas do fármaco em função do tempo. Nestes estudos considera-se que curvas estatisticamente semelhantes de decaimento sanguíneo de fármacos produzem o mesmo resultado em termos de eficácia e segurança. A partir das curvas de concentração em função do tempo obtidas, determinam-se os parâmetros farmacocinéticos Cmax, tmax e ASC. A bioequivalência entre dois produtos é estabelecida por meio do IC 90%, que deve estar entre 80 a 125% para os parâmetros farmacocinéticos Cmax e ASC. O cronograma de coleta de amostras biológicas é um dos aspectos mais críticos no planejamento de estudos de bioequivalência, pois este afeta diretamente a determinação dos parâmetros farmacocinéticos utilizados na avaliação da bioequivalência. Outro aspecto importante relacionado a este tipo de estudo é a diferença de teor entre os produtos a serem submetidos ao estudo de bioequivalência, que segundo a legislação brasileira vigente, deve ser menor ou igual a 5%. Neste trabalho foram avaliados diferentes cronogramas de coleta de amostras sangue, avaliando-se o impacto destes no resultado final de um estudo de bioequivalência e, além disso, a influência da diferença de teor de fármaco entre dois produtos que levaria à bioinequivalência também foi investigada. Para tanto simulações matemáticas e um estudo in vivo foram conduzidos. O fármaco modelo escolhido foi a cefadroxila, por apresentar características farmacocinéticas e farmacodinâmicas ideais. O programa Microsoft Office Excel 2003 foi utilizado para simular as concentrações plasmáticas e determinar o IC 90%. As simulações foram feitas por meio de dois modelos: modelo baseado em máximos e mínimos de parâmetros farmacocinéticos, e modelo baseado em coeficientes de variação intra e inter-individuais do fármaco. Dez diferentes doses, entre -10% a 20% da dose referência, e 6 cronogramas de coleta foram avaliados. O estudo in vivo foi realizado com quatro doses diferentes de cefadroxila. A bioequivalência entre as doses e em diferentes cronogramas de coleta foi avaliada em 24 voluntários sadios do sexo masculino. Os voluntários receberam as quatro doses do estudo em desenho cruzado, em quatro períodos e quatro seqüências, com washout de 7 dias entre as doses. As concentrações plasmáticas de cefadroxila, até 8 horas após a administração, foram determinadas por cromatografia líquida de alta eficiência com detecção DAD. Os parâmetros farmacocinéticos tmax, Cmax e AUC0-t foram determinados nas diferentes doses e cronogramas de coleta, sendo que o critério para estabelecer-se a bioequivalência foi baseada nos resultados do IC 90% dos parâmetros farmacocinéticos Cmax e AUC0-t. Os resultados obtidos nas simulações mostraram boa correlação com os dados reais obtidos a partir de estudos in vivo. As simulações baseadas em coeficientes de variação intra e inter-individuais descreveram melhor os resultados observados no estudo in vivo. De acordo com os resultados obtidos no estudo in vivo pode-se concluir que cronogramas de coletas com menos amostras são tão eficientes quanto cronogramas de coletas com mais amostras, desde que o tempo de tmax esteja incluído. Em relação ao teor de fármaco, concluiu-se que dois produtos com diferença de teor menor ou igual a 11% ainda são bioequivalentes e que diferença maior ou igual a 14% resultam em bioinequivalência. Observou-se ainda que o parâmetro farmacocinético ASC0-t é mais sensível que Cmax para detectar diferenças

Bioequivalence studies are designed to compare the in vivo performance of different formulations of the same drug or different drug products by a randomized crossover study. Pharmacokinetic parameters are obtained from the drug concentration-time profile in blood, serum, or plasma. The most frequently used pharmacokinetic parameters are area under the plasma or blood concentration-time curve (AUC), maximum concentration (Cmax) and time to achieve maximum concentration (tmax). Bioequivalence is concluded if the average bioavailability of the test formulation is within (80%, 125%) that of the reference formulation, with a certain assurance, that is, an equivalence criterion of 80% to 125% for assessment of bioequivalence based on the ratio of average bioavailability is employed. The logarithmic transformation is used for AUC and Cmax. Accuracy in measuring pharmacokinetics parameters directly affects accuracy of bioequivalence tests. Since the number of blood samples per patient is limited, sampling points should be chosen such that the time concentration profile is adequately defined so as to allow the calculation of relevant parameters. According to guidelines proposed by the National Agency of Sanitary Vigilance of Brazil (ANVISA), bioequivalence studies can be conducted only if the difference in drug content between the reference and test product is less than or equal to 5%. The goals of this study are to evaluate the influence of differences in amount of active moiety present in the formulation and possibility of reducing the number of sampling points in bioequivalence studies and to discuss the impact of these parameters in bioequivalence conclusions. For these approaches, simulations and an in vivo study were done. The drug selected was cefadroxil. Cefadroxil presents ideal pharmacokinetics and pharmacodynamics characteristics for this kind of study, such as high bioavailability, low intra and intersubject variability, short elimination rate and wide therapeutic range. Microsoft Office Excel 2003 software was used to simulate drug concentration-time profiles for different doses and several sampling schedules, and to determine 90% confidence interval. Simulations were done by two models: a) based on assumed maximum and minimum pharmacokinetic parameters values; b) based on assumed intra and intersubject variability. Ten different doses, ranging from -10% to 20% of the reference dose, and six sampling schedules were evaluated. The in vivo study was performed with four different cefadroxil doses. Their relative bioavailability were evaluated in 24 healthy volunteers who received a single oral dose of each preparation. An open, randomized clinical trial designed as four-periods and four sequences crossover with 7-days washout between doses was employed. Plasma samples for assessments of their cefadroxil concentration by HPLC-DAD were obtained over 8 h after administration. Pharmacokinetics parameters tmax, Cmax and AUC0-t were evaluated using different doses and sampling schedules. For the purpose of bioequivalence analysis Cmax and AUC0-t were considered. For each schedule, to claim bioequivalence in average bioavailability, a 90% confidence interval was constructed for ratio of average between test and reference products and compared with (80%, 125%) limits. If the constructed confidence interval falls within the limits, then the two formulations are considered bioequivalent. The results obtained by simulate time-concentration profiles, showed good correlation with real data. Comparing the results obtained through in vivo study and the two simulations models, the simulations based in intra and intersubject variability was more predictive. In conclusion, no significant differences were found between sampling schedules evaluated, since the sampling time around tmax were maintained in sampling schedules. Bioinequivalence was observed when the difference between cefadroxil doses was higher than 14%. The parameter AUC0-t was more sensitive than Cmax to detect differences

Research on drug content and encapsulated efficency of Ophiopogon saponin enteric microphase / 中成药

AIM: To explore the effect of drug content and encapsulated efficency of microsphere ophiopogon saponin preparation, providing more precise computational method. METHODS: Ophiopogon saponin enteric microsphere was prepared by spray drying technique, and the sum of saponin was determined by colorimetric analysis to evaluate the drug content and encapsulated efficency. RESULTS: The encapsulated efficency (%) was 94.75? 2.68. The drug content (mg/g) was 54.81? 2.12. CONCLUSION: The drug content the encapsulated efficency can affect the clinical dosage and the encapsulated efficency stands for the preparation process and the quality. So we should detect both drug content and the encapsulated efficency to evaluate preparation quality evaluation.