Modulating drug release profiles by lipid semi solid matrix formulations for BCS class II drug--an in vitro and an in vivo study.

The main objective of the study was to alter the dissolution profile of a practically insoluble Biopharmaceutics Classification System class II drug, aceclofenac, by formulating into lipid semisolid matrix (SSM) formulations using liquid filling technology in hard gelatin capsules, for both immediate and sustained release. SSM formulations of aceclofenac were prepared by melt fusion technique, using Gelucires (44/14, 50/13, 33/01 and 43/01), polyethylene glycols (4000 and 6000) and Poloxamer 188 at different levels. Role of additives like docusate sodium, Tween 80, Aerosil 200 and polyvinylpyrrolidone K-30 in enhancement of drug release was investigated. The optimized immediate and sustained SSM capsules were characterized in terms of assay, in vitro drug release, moisture uptake and differential scanning calorimetry. More than 80% of the drug was released within 15 min in various dissolution media studied, from Gelucire 44/14-based immediate release formulations. Incorporation of docusate sodium and Tween 80 provided further enhancement in drug dissolution when compared to plain drug and marketed tablet. SSM formulations based on Gelucire blends of 50/13 and 43/01 and 44/14 and 43/01 sustained the release of the drug for a period of 24 h following zero-order kinetics. The in vivo study of the optimized immediate release and sustained release formulations revealed significant enhancement in anti inflammatory activity (p < 0.01) in rats. From these findings, liquid fill technique in hard gelatin capsules using Gelucire and their blends might be an efficacious approach for designing immediate or sustained drug release profiles for poorly soluble drugs like aceclofenac.

Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin.

PURPOSE: The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone. METHODS: Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship. RESULTS: The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement. CONCLUSION: The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.

Development and validation of a dissolution method using HPLC for diclofenac potassium in oral suspension

The present study describes the development and validation of an in vitro dissolution method for evaluation to release diclofenac potassium in oral suspension. The dissolution test was developed and validated according to international guidelines. Parameters like linearity, specificity, precision and accuracy were evaluated, as well as the influence of rotation speed and surfactant concentration on the medium. After selecting the best conditions, the method was validated using apparatus 2 (paddle), 50-rpm rotation speed, 900 mL of water with 0.3% sodium lauryl sulfate (SLS) as dissolution medium at 37.0 ± 0.5°C. Samples were analyzed using the HPLC-UV (PDA) method. The results obtained were satisfactory for the parameters evaluated. The method developed may be useful in routine quality control for pharmaceutical industries that produce oral suspensions containing diclofenac potassium.

O presente estudo descreve o desenvolvimento e validação de um método de dissolução in vitro para avaliação da liberação de diclofenaco potássico suspensão oral. O teste de dissolução foi desenvolvido e validado de acordo com as diretrizes internacionais. Parâmetros como linearidade, especificidade, precisão e exatidão foram avaliados, bem como a influência da velocidade de rotação e a concentração de tensoativono meio. Depois de selecionar as melhores condições, o método foi validado usando o aparato 2 (pás), velocidade de rotação de 50 rpm, 900 mL de água com 0,3% de lauril sulfato de sódio (LSS) como meio de dissolução a 37,0 ± 0,5 ºC. As amostras foram analisadas pelo método de CLAE-UV (PDA). Os resultados obtidos foram satisfatórios para os parâmetros avaliados. O método desenvolvido pode ser útil na rotina de controle de qualidade para as indústrias farmacêuticas que produzem suspensões orais contendo diclofenaco potássico.

An intravenous exposure mouse model for prediction of potential drug-sensitization using reporter antigens popliteal lymph node assay.

Immune-mediated drug hypersensitivity is a particularly concerning health-safety issue among clinicians given its unpredictability and potentially life-threatening effects, especially with exposure to intravenous drugs. Therefore, the development of intravenous drug-exposure models for drug-hazard assessments has garnered increasing interest in recent years. In this study, we used reporter antigens popliteal lymph node assay to investigate the potential value of intravenous exposure to a selected variety of allergenic compounds, including ovalbumin (OVA), concanavalin A (ConA) and diclofenac. The trinitrophenyl (TNP)-specific antibody-forming cells were used to assess the systemic immune responses to a bystander antigen. Mice were subsequently sensitized by TNP-OVA, and then intravenous exposure to one of the selective compounds. As expected, all positive compounds induced significant popliteal lymph node (PLN) proliferation compared with the control. OVA significantly increased Cluster of Differentiation 4 receptors (CD4)⁺ interleukin-4 (IL-4)⁺ T-helper 2 (Th2) cells and, consequently, increased the ratios of IL-4/interferon-γ (IFN-γ) antibody-forming cells (AFCs) in PLNs, while bringing about a dose-dependent increase in immunoglobulin G1 (IgG1) AFCs; these findings indicate that a Th2 hypersensitivity response was induced. A Th2 response was also observed in diclofenac sodium-treated groups, and for ConA, a more mixed Th1/Th2 immune response appeared to be induced. In addition, there was no marked reaction with the negative compound. Together, it seems likely that the intravenous exposure model may be useful for drug-induced systemic hypersensitivity assessments.