Evaluation and comparison of dissolution data derived from different modified release dosage forms: an alternative method.
ABSTRACT Dissolution testing is an essential requirement for the development, establishment of in vitro dissolution and in vivo performance (IVIVR), registration and quality control of solid oral dosage forms. The objective of the present study was to investigate the effect of delivery system positioning in accordance with the USP 23-recommended dissolution methods and the proposed modification on drug release from controlled release systems having different operating release mechanisms, namely, swellable floatable, swellable sticking and osmotic pump. The delivery systems were evaluated by placing each dosage form either in the dissolution vessel in accordance with the USP 23 methods or over/below a designed ring/mesh device for achieving full surface exposure to the dissolution medium for sticking or floatable systems respectively. Results indicate that the overall release profiles from the sticking and floatable systems of theophylline are sensitive to their positioning in the dissolution vessel (P<0.05). Furthermore, release of diltiazem hydrochloride from the sticking system also demonstrated sensitivity (P<0.05). In contrast, the floatable dosage form of this latter drug with the application of a helical wire sinker, or when it was placed below the ring/mesh assembly, or by allowing the dosage form to float, did not show sensitivity (P>0.05) for the overall release behavior. This was attributed to the greater solubility of diltiazem hydrochloride (50% solubility in water at 25 degreesC) in comparison to theophylline which is a sparingly soluble drug (0.85% solubility in water at 25 degreesC). Drug release from the osmotic pump appeared to be identical under the given experimental conditions (P>0.05). Statistical analysis of data was performed by comparing the t50%, t70%, t90%; mean dissolution times (MDT50%, MDT70%, MDT90%); the "difference factor, f1" and "similarity factor, f2". It is concluded that the results derived from the application of the "similarity factor, f2" are superior to the individual time points (e.g. tx%) and MDTx% values in differentiating between overall release patterns or the border line release profile differences. It also became apparent that in the case of the swellable sticking systems full surface exposure to the dissolution medium results in greater release rate. For the osmotic pump the required osmotic pressure threshold necessary for constant rate drug delivery appears to have reached independent of the hydrodynamic conditions. A successful and more accurate evaluation of dissolution data can be derived when full surface exposure is considered and this can be accomplished by dissolution method modification with the aid of the designed ring/mesh assembly.
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ABSTRACT: Progering® is the only intravaginal ring intended for contraception therapies during lactation. It is made of silicone and releases progesterone through the vaginal walls. However, some drawbacks have been reported in the use of silicone. Therefore, ethylene vinyl acetate copolymer (EVA) was tested in order to replace it. EVA rings were produced by a hot-melt extrusion procedure. Swelling and degradation assays of these matrices were conducted in different mixtures of ethanol/water. Solubility and partition coefficient of progesterone were measured, together with the initial hormone load and characteristic dimensions. A mathematical model was used to design an EVA ring that releases the hormone at specific rate. An EVA ring releasing progesterone in vitro at about 12.05 ± 8.91 mg day(-1) was successfully designed. This rate of release is similar to that observed for Progering®. In addition, it was observed that as the initial hormone load or ring dimension increases, the rate of release also increases. Also, the device lifetime was extended with a rise in the initial amount of hormone load. EVA rings could be designed to release progesterone in vitro at a rate of 12.05 ± 8.91 mg day(-1). This ring would be used in contraception therapies during lactation. The use of EVA in this field could have initially several advantages: less initial and residual hormone content in rings, no need for additional steps of curing or crosslinking, less manufacturing time and costs, and the possibility to recycle the used rings.Pharmaceutical Research 10/2013; · 4.74 Impact Factor
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ABSTRACT: The study was aimed to develop a novel gastro-floating multiparticulate system based on a porous and low-density matrix core with excellent floatability. The gastro-floating pellets (GFP) were composed of a porous matrix core, a drug loaded layer (DIP and HPMC), a sub-coating layer (HPMC) and a retarding layer (Eudragit® NE 30D). The porous matrix cores were evaluated in specific. EC was chosen as the matrix membrane for its rigidity and minimal expansion to large extent. The porous matrix core was achieved by the complete release of the bulk water soluble excipient from the EC coated beads, and Mannitol was selected as the optimal water soluble excipient. SEM photomicrographs confirmed the structure of porous matrix cores.The compositions of GFP were investigated and optimized by orthogonal array design. The optimized formulation could sustain the drug release for 12h and float on the dissolution medium for at least 12h without lag time to float. The pharmacokinetic study was conducted in beagle dogs, and the relative bioavailability of the test preparation was 193.11±3.43%. In conclusion, the novel gastro-floating pellets can be developed as a promising approach for the gastro-retentive drug delivery systems.International Journal of Pharmaceutics 12/2013; · 3.99 Impact Factor
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ABSTRACT: The aim of this study was to produce microparticles with optimal aerodynamic diameter for deep lung delivery (i.e., 1-3μm) of a protein drug intended for systemic absorption, using a combination of generally regarded as safe (GRAS) excipients. Based on the preliminary experiments, mannitol, l-alanine, sodium alginate, chitosan and dipalmitoylphosphatidilcholine (DPPC) were chosen as excipients and human insulin as a model protein drug. Dry powders were prepared by spray-drying. Powders with varying yields (29-80%) and low tapped densities (0.22-0.38g/cm(3)) were obtained. Scanning electron microscopy (SEM) revealed distinctive particle morphologies among formulations from isolated spherical to highly folded particles. Aerodynamic properties were assessed by next generation impactor (NGI). Mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) ranged between 2.1 and 4.6μm and 46 and 81%, respectively. A comparative study of protein release from microparticles was conducted in vitro using an open membrane system with more than 50% cumulative release in all formulations which followed different kinetic models. Insulin's integrity was investigated by spectrofluorimetry and electrophoresis, and no tangible changes were observed in the structure of insulin. Of the formulations studied, the third, containing mannitol/sodium alginate/insulin/sodium citrate showed promising characteristics, optimal for systemic delivery of proteins via deep lung deposition.International Journal of Pharmaceutics 02/2014; · 3.99 Impact Factor