Preparation of Solifenacin Succinate Functional Particles Embedded in a Gelling-Swelling Layer (PEGS) and Their Formulation in Orally Disintegrating Tablets.

The purpose of this research was firstly to prepare solifenacin succinate functional particles embedded in a gelling-swelling layer (PEGS) so as to achieve both taste-masking of the unpleasant taste of the drug and rapid drug elution, and secondly to incorporate these PEGS into orally disintegrating tablets (ODTs). In in vitro dissolution tests, initial drug release from the prepared PEGS could be suppressed to less than 1% after 2 min and increased to more than 85% after 30 min by adjusting the composition of the PEGS, in particular the thickness of the outer water-penetration control layer which contains a water-insoluble polymer. For the preparation of ODTs containing PEGS, a semi-direct compression method was adopted in order to prevent damage to the PEGS by processes such as granulation or compaction. The use of a fibre-shaped microcrystalline cellulose with poor fluidity improved the content uniformity of the ODTs, as the crystal fibres became entangled with the PEGS and other additives. The use of spherical mannitol with a hollow structure produced by spray drying imparted relatively high hardness and rapid disintegration properties to the final ODTs containing PEGS, which were tableted using a low compression force. There was no significant difference in the drug-release profiles of the optimally formulated ODTs containing PEGS tableted at different compression forces. The ODTs containing PEGS maintained a drug-release lag time sufficient for taste-masking of solifenacin succinate.

Preparation of Novel Functional Drug Particles Embedded in a Gelling-Swelling Layer (PEGS) for Taste Masking and Subsequent Rapid Drug Release.

The purpose of this research was to develop novel functional drug particles embedded in a gelling-swelling layer (PEGS) which are capable of achieving both taste-masking of unpalatable drugs and rapid drug elution. The functional particles had a three-layer structure consisting of a core drug layer, a gelling-swelling layer and an outer water-penetration control layer containing a water-insoluble polymer. The concept of formulation design was as follows: when water reaches the gelling-swelling layer, pulverized fine gelling-swelling particles gellate and swell from water absorption to form a rigid layer, thereby preventing drug release. After a defined lag time, the increased volume of the gelling-swelling layer breaks down the outer water-penetration control layer, leading to rapid drug release. In order to adapt this system for use in orally disintegrating tablets, PEGS were prepared at a size of about 250 µm using a fine particle-coating method. Ambroxol hydrochloride was used as a model drug for bitterness and the effects of different gelling-swelling agents and water-insoluble polymers on drug release characteristics from PEGS were examined. In in vitro dissolution tests, it was shown that the drug dissolution rate from PEGS could be suppressed to about 5% after 2 min and increased to more than 85% after 30 min by adjusting the composition and thickness of the outer layer. The PEGS expanded about 1.5-fold and the outer layer was ruptured after 5 min in water.

Development of a novel and simple method to evaluate disintegration of rapidly disintegrating tablets.

The purpose of this study was to develop and test a novel and simple method for evaluating the disintegration time of rapidly disintegrating tablets (RDTs) in vitro, since the conventional disintegration test described in the pharmacopoeia produces poor results due to the difference of its environmental conditions from those of an actual oral cavity. Six RDTs prepared in our laboratory and 5 types of commercial RDTs were used as model formulations. Using our original apparatus, a good correlation was observed between in vivo and in vitro disintegration times by adjusting the height from which the solution was dropped to 8 cm and the weight of the load to 10 or 20 g. Properties of RDTs, such as the pattern of their disintegrating process, can be assessed by verifying the load. These findings confirmed that our proposed method for an in vitro disintegration test apparatus is an excellent one for estimating disintegration time and the disintegration profile of RDTs.

Solventless dry powder coating for sustained drug release using mechanochemical treatment based on the tri-component system of acetaminophen, carnauba wax and glidant.

OBJECTIVE: Solventless dry powder coating methods have many advantages compared to solvent-based methods: they are more economical, simpler, safer, more environmentally friendly and easier to scale up. The purpose of this study was to investigate a highly effective dry powder coating method using the mechanofusion system, a mechanochemical treatment equipped with high compressive and shearing force. MATERIALS AND METHODS: Acetaminophen (AAP) and carnauba wax (CW) were selected as core particles of the model drug and coating material, respectively. Mixtures of AAP and CW with and without talc were processed using the mechanofusion system. RESULTS: Sustained AAP release was observed by selecting appropriate processing conditions for the rotation speed and the slit size. The dissolution rate of AAP processed with CW substantially decreased with an increase in talc content up to 40% of the amount of CW loaded. Increasing the coating amount by two-step addition of CW led to more effective coating and extended drug release. Scanning electron micrographs indicated that CW adhered and showed satisfactory coverage of the surface of AAP particles. CONCLUSION: Effective CW coating onto the AAP surface was successfully achieved by strictly controlling the processing conditions and the composition of core particles, coating material and glidant. Our mechanochemical dry powder coating method using the mechanofusion system is a simple and promising means of solventless pharmaceutical coating.

A completely solvent-free process for the improvement of erythritol compactibility.

OBJECTIVE: We obtained improvement of erythritol compactibility by formulating composite particles composed of erythritol and porous silica using a twin-screw kneader. METHODS: Erythritol-based tablets formulated with composite particles were directly compacted, and we estimated their hardness and the friability. The compression properties of the erythritol powder bed including composite particles were estimated using a Heckel analysis and force-displacement profiles, and we investigated the physical states of the composite particles by powder X-ray diffractometry, a thermal analysis and a nitrogen gas adsorption study. RESULTS: A direct-compacted erythritol tablet formulated with composite particles, prepared at the melting temperature of erythritol (120 °C), exhibited high hardness and low friability. A pressure transmission study revealed the higher plasticity and lower elasticity of an erythritol powder bed formulated with composite particles prepared at 120 °C. Physical states of the composite particles indicated that erythritol in the composite particles was adsorbed onto porous silica with a subsequent decrease in the erythritol crystallinity as a result of high mechanical force at the melting temperature of erythritol. CONCLUSION: The improvement of the erythritol compactibility formulated with composite particles through processing with a twin-screw kneader at 120 °C. This was affected by the reduction of the erythritol crystallinity in the composite particles.

Roles of heme axial ligands in the regulation of CO binding to CooA.

CooA is a CO-dependent transcription factor of the bacterium Rhodospirillum rubrum that contains a six-coordinate heme. It has as its heme axial ligands Pro(2) and Cys(75) in the ferric state and Pro(2) and His(77) in the ferrous state. To probe the regulation of CO binding and the ligand switching mechanism in CooA, we have prepared site-directed mutants in which the residues contributing the axial ligands are substituted. The properties of these mutants were investigated by resonance Raman and CO titration methods. Wild-type CooA binds CO with a modest dissociation constant (K(d)) of 11 microm, this value being typical for gas-sensing heme proteins. The K(d) value was greatly decreased in the P2H mutant, indicating that Pro(2) coordination fine tunes CO sensing in CooA. The bound CO in P2H gives rise to a nu(Fe-CO) stretching Raman line at 490 cm(-1), which is similar to that in wild-type CooA. Thus, Pro(2) is the ligand that is replaced by exogenous CO. In the H77A mutant, equilibrium CO binding is biphasic, and at high CO pressures two CO molecules occupy both axial sites. The nu(Fe-CO) stretching Raman line for the first CO molecule was observed at 497 cm(-1). Some of the His(77) mutants showed an additional nu(Fe-CO) line at 525 cm(-1). The binding affinity of the second CO molecule correlates with the five-coordinate component in the ferrous His(77) mutants and also with the acidity of the side chain at position 77. Thus, we propose the Cys(75)-His(77) ligand switch is controlled by His(77) acting as a proton reservoir.

The C-helix in CooA rolls upon CO binding to ferrous heme.

CooA is a homodimeric transcriptional activator from Rhodospirillum rubrum containing one heme in each subunit. CO binding to the heme in its sensor domain activates CooA, facilitating the binding to DNA by its DNA-binding domain. The C-helix links the two domains and shapes an interface between the subunits. To probe the nature of CO activation, residues at positions 112-121 on the C-helix were replaced by Asn or Gln and their effects were evaluated by resonance Raman spectroscopy and by the measurements of CO binding affinity. The nu(Fe-CO) stretching Raman line in CO-bound wild-type CooA was up-shifted by 6 cm(-1) in the L116Q, G117N, and L120Q mutants, indicating unequivocally that these residues are close to the bound CO. Residues Leu116 and Leu120 from each subunit form contacts with the corresponding residues in the opposite subunit, enabling hydrophobic interactions in the inactive ferrous form. Thus, in the CO-bound activated form, both C-helices appear to roll to direct these residues toward the heme, forming a hydrophobic pocket for the bound CO. The CO affinity is approximately one order of magnitude higher in the L112Q, I115Q, L116Q, G117N, L120Q, and T121N mutants but reduced in A114N mutant. The variation indicates that these residues are close to the heme in the ferrous and/or CO-bound forms and are responsible for CooA activation. A roll-and-slide mechanism is proposed for CO activation of CooA.