Stability and Release Kinetics of an Advanced Gliclazide-Cholic Acid Formulation: The Use of Artificial-Cell Microencapsulation in Slow Release Targeted Oral Delivery of Antidiabetics

Introduction: In previous studies carried out in our laboratory, a bile acid (BA) formulation exerted a hypoglycaemic effect in a rat model of type-1 diabetes (T1D). When the antidiabetic drug gliclazide (G) was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide-cholic acid (G-CA), with good structural properties, excipient compatibility and exhibits pseudoplastic-thixotropic characteristics. The aim of this study is to test the slow release and pH-controlled properties of this new formulation. The aim is also to examine the effect of CA on G release kinetics at various pH values and different temperatures. Method: Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) and G-CA-SA (test) at a constant ratio (1:3:30), respectively. Microcapsules were examined for efficiency, size, release kinetics, stability and swelling studies at pH 1.5, pH 3, pH 7.4 and pH 7.8 and temperatures of 20 and 30 °C. Results: The new formulation is further optimised by the addition of CA. CA reduced microcapsule swelling of the microcapsules at pH 7.8 and pH 3 at 30 °C and pH 3 at 20 °C, and, even though microcapsule size remains similar after CA addition, percent G release was enhanced at high pH values (pH 7.4 and pH 7.8, p < 0.01). Conclusion: The new formulation exhibits colon-targeted delivery and the addition of CA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and CA to the lower intestine

Development of a multi-unit floating drug delivery system by hot melt coating technique with drug-lipid dispersion

A multi-unit floating drug delivery system containing pellets with lipid coating were fabricated. Coated pellets were prepared by a fluid bed hot melt coating technique with drug-lipid dispersion. Metoprolol tartrate was used as a water soluble model drug and hydrogenated soybean oil (HSO) was used as a lipid carrier. The drug was dispersed in molten HSO and the mixture was directly sprayed on inert nonpareils in a fluid bed chamber. No major interaction between drug and HSO was observed, nevertheless, the drug could be partially dissolved in the molten HSO. Increasing coating amount or adding an inert substance, Aerosil R972, in the coating mixture reduced the initial burst release as well as the total drug release. Increasing drug particle size gave a variation in the drug release due to brittle fracture induced at the nozzle by pressurized atomization air. Coated pellets presented a good floating property in vitro regardless of the coating amount. The present study shows that a drug-lipid dispersion coating prepared by a hot melt coating technique is a promising means for the development of multi-unit floating drug delivery systems

Polymorphic change of a triglyceride base in hot melt coating process and stability acceleration by tempering process

In this study, the influence of hot melt coating condition on polymorphic change of a triglyceride base, hydrogenated soybean oil (HSO) was studied. Metoprolol tartrate was used as a water-soluble model drug. Coated pellets were prepared by spraying drug-lipid dispersion onto nonpareil seeds. A tempering process was employed in order to achieve the stable form of HSO. Differential scanning calorimetry was used to simulate the coating and tempering conditions prior to the processing and to characterize polymorphic change together with powder X-ray diffractometry and hot stage microscopy. Coated pellets possessed three polymorphic forms of HSO but only the stable form was dominant after tempering. Tempered pellets presented crystal growth of HSO with 1-2 mu m microstructure elements. This morphological change led to the reduced porosity and increased surface area of the pellets as well as the increased drug release. The release profile was attributable to the tempering temperature. In order to stabilize the drug release, the tempering process was suggested to perform at the temperature below the melting point of the unstable form

Experimental design and optimization of the hydrogenation process of soybean oil

The hydrogenated soybean oil was prepared by catalytic hydrogenation process in order to be used as a pharmaceutical excipient for hot melt applications. To optimize the hydrogenation process and produce a product whose quality conforms to the hydrogenated vegetable oil type I in the US Pharmacopoeia (USP 24), a central composite design was applied. The influence of three main process parameters, i.e. amount of catalyst, hydrogen pressure and temperature on the hydrogen consumption, the time required for the completion of the reaction and the reaction rate as well as the quality of final products was studied. The increase in the amount of catalyst and temperature significantly enhanced the reaction rate. However, at higher temperature, the acid values of the final products also increased. The thermal behavior of the product showed tolerance to high temperature exposure, i.e. 80-120 degrees C, where unchanged exothermic peaks were determined in the thermograms before and after exposure. This novel excipient is applied in a next step in the hot melt coating application for the preparation of modified release formulations

Development and Comparison of Different Nanoparticulate Polyelectrolyte Complexes as Insulin Carriers

The overall objective of our research is to produce polyanion/chitosan nanoparticulate oral delivery systems for insulin. Specific objectives of the present study were to study dextran sulfate or alginate complexation with chitosan on mean particle size, insulin association efficiency, loading capacity and release profile. Nanoparticles were formed by ionotropic complexation and coacervation between polyanions (dextran sulfate and alginate) and chitosan. Diameter was evaluated with photon correlation spectroscopy, polymer interaction was confirmed by DSC and FTIR and particle morphology was assessed by SEM and TEM. Mean nanoparticle diameter ranged from 423 to 850 nm, insulin association efficiency from 63 to 94% and loading capacity from 5 to 13%. Dextran sulfate provided highest insulin association efficiency and retention of insulin in gastric simulated conditions. These nanoparticle systems show promise as insulin and potentially other therapeutic polypeptides carriers

Effect of polysulfonate resins and direct compression fillers on multiple-unit sustained-release dextromethorphan resinate tablets

The purpose of this work was to investigate the effect of different polysulfonate resins and direct compression fillers on physical properties of multiple-unit sustained-release dextromethorphan (DMP) tablets. DMP resinates were formed by a complexation of DMP and strong cation exchange resins, Dowex 50 W and Amberlite IRP69. The tablets consisted of the DMP resinates and direct compression fillers, such as microcrystalline cellulose (MCC), dicalcium phosphate dihydrate (DCP), and spray-dried rice starch (SDRS). Physical properties of tablets, such as hardness, disintegration time, and in vitro release, were investigated. A good performance of the tablets was obtained when MCC or SDRS was used. The use of rod-like and plate-like particles of Amberlite IRP69 caused a statistical decrease in tablet hardness, whereas good tablet hardness was obtained when spherical particle of Dowex 50 W was used. The plastic deformation of the fillers, such as MCC and SDRS, caused a little change in the release of DMP. A higher release rate constant was found in the tablets containing DCP and Dowex 50 W, indicating the fracture of the resinates under compression, which was attributable to the fragmentation of DCP. However, the release of DMP from the tablets using Amberlite IRP69 was not significantly changed because of the higher degree of cross-linking of the resinates, which exhibited more resistance to deformation under compression. In conclusion, the properties of polysulfonate resin, such as particle shape and degree of cross-linking, and the deformation under compaction of fillers affect the physical properties and the drug release of the resinate tablets

The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets

The purpose of this study was to investigate the efficiency of superdisintegrants in promoting tablet disintegration and drug dissolution under varied media pH. Significant reductions in the rate and extent of water uptake and swelling were observed for both sodium starch glycolate (Primojel) and croscarmellose sodium (Ac-Di-Sol) in an acidic medium (0.1 N HCl) but not for crospovidone NF (Polyplasdone XL10), a nonionic polymer. When Primojel and Ac-Di-Sol were incorporated in model formulations, a significant increase in tablet disintegration time was observed for slowly disintegrating tablets (lactose-based tablets) but not for the rapidly disintegrating tablets (dicalcium phosphate-based tablets). The dissolution rate of the model drug, hydrochlorothiazide, was found highly dependent on both tablet disintegration efficiency and the solubility of base material(s) in the testing medium. A laser diffraction particle size analyzer proved to be an effective tool for determining the intrinsic swelling of disintegrant particles in different media. Water uptake and swelling were confirmed as 2 important functions of superdisintegrants. The reduced water uptake and swelling capacity of disintegrants containing ionizable substituents in an acidic medium can potentially jeopardize their efficiency in promoting tablet disintegration and the drug dissolution rate