Effects of physicochemical properties of salting-out layer components on drug release.

A "Salting-out Taste-masking System" generates a long lag time for numbness and bitterness masking, with subsequent immediate drug release to exert pharmacological effects. In this study, the effects of physicochemical properties of salting-out agents and water-soluble polymers in the salting-out layer on the dissolution behaviors of acetaminophen were investigated and predominant factors for lag time generation (Lag time index, hereafter LI) and subsequent drug release (Rapid release index, hereafter RI) were discussed. Each prepared formulation showed a different dissolution profile of acetaminophen with a lag time and subsequent immediate release. Significant correlations between both LI and RI and DeltaCST (the salting-out power of salting-out agents) (r(2)=0.90, 0.67, respectively) and between both LI and RI and CST(1) (the sensitivity of water-soluble polymers to a salting-out effect) (r(2)=0.98, 0.71, respectively) were shown. These results suggest that the components showing a strong salting-out effect inside the beads lead to extended lag times and slow drug releases after the lag times. Results further suggest the use of CST(1) to evaluate suitable combinations of salting-out agents and water-soluble polymers in this system.

Optimization of salting-out taste-masking system for micro-beads containing drugs with high solubility.

The salting-out taste-masking system is a multiparticulate system consisting of a drug core, a salting-out layer containing salts and water-soluble polymers, and a water-penetration control layer containing water-insoluble materials. The system generates a long lag time (time when released drug is less than 1%) for numbness masking, and a subsequent immediate drug release for high bioavailability. Aiming to contain the system and drugs that cause numbness in oral disintegrating tablets, the system was optimized to reduce the particle size and contain drugs with high water solubility in this study. The amount of coating on the layers, the coating solvent, and the positioning of the components were also optimized. The findings in this study will lead to the provision of numbness-masked oral disintegrating tablets to patients.

Mechanism of controlled drug release from a salting-out taste-masking system.

A "salting-out taste-masking system" is a multiparticulate system consisting of a drug core, a salting-out layer containing salts and water-soluble polymers, and a water-penetration control layer containing water-insoluble materials. The system generates a long lag time for numbness masking, with subsequent immediate drug release for high bioavailability. In this study, sodium carbonate (Na2CO3) and hydroxypropylmethylcellulose (HPMC) were used as the salt and water-soluble polymer in the salting-out layer, respectively. The drug release rate from the formulation containing the HPMC layer was affected by the Na2CO3 concentrations in the media used in the drug dissolution tests. The HPMC layer suppressed drug release in a medium with a high Na2CO3 concentration, and subsequently increased the drug release rate in a medium with a low Na2CO3 concentration. Drug release from the system was suppressed while Na2CO3 remained in the formulations. Microscopic changes in HPMC in the salting-out layers correlated well with changes in the drug release rate. These results indicate that, in the salting-out taste-masking system, the drug release suppression and the immediate release are caused by insolubilization and dissolution of the water-soluble polymer respectively. These findings will allow for smarter formulation design.

Effects of absorption promoters on insulin absorption through colon-targeted delivery.

The aim of this study were to investigate the effect of sodium glycocholate (GC-Na) as an absorption promoter and the effects of the co-administration of GC-Na and various absorption promoters on orally administered insulin absorption utilizing a colon-targeted delivery system. The system containing insulin and GC-Na (CDS) was administered to dogs, and plasma glucose and insulin levels were then measured at 24h after administration. For CDS, the C(max) in plasma glucose level was significantly higher than a reference formulation without GC-Na. The pharmacological availability for CDS was not significantly higher than the reference formulation. In contrast, CDS with poly(ethylene oxide) as a gelling agent (CDSP) showed prolonged hypoglycemia effects. The pharmacological availability was 5.5% and significantly different from the reference formulation. The absolute bioavailability for CDS was 0.25%, and for CDSP it was 0.42%. Consequently, the results of this study demonstrated that colon-specific delivery of insulin with GC-Na was more effective in increasing hypoglycemic effects after oral administration, and the combination of GC-Na and poly(ethylene oxide) tended to prolong the colonic absorption of insulin and might be more effective for improvement of orally administered insulin absorption utilizing the colon-targeted delivery system.

Scintigraphic evaluation of a novel colon-targeted delivery system (CODES) in healthy volunteers.

The purposes of this study are to investigate the gastrointestinal transit and release properties of a novel, colon-targeted delivery system (CODES) administered to healthy volunteers using gamma scintigraphy and to confirm that lactulose functions to promote disintegration in the colon. Two placebo formulations were studied: one was CODES, which consisted of a lactulose containing core overcoated with both Eudragit E and Eudragit L designed to rapidly disintegrate in the colon, the other was lactulose-free reference formulation (LFRF) that consisted of lactulose-free tablet core overcoated with the same materials. Transit and disintegration of the radiolabeled formulations were followed by gamma scintigraphy. In the fasted state, scintigraphic images indicated that CODES started to disintegrate in the ascending colon in the majority of subjects at 7.11 +/- 2.01 h post-dose. Disintegration was complete within 1 h following commencement of in vivo release. In contrast, LFRF presented with prolonged in vivo disintegration properties. In the fed state, the disintegration period of CODES was almost comparable to that observed in the fasted state. Gamma scintigraphic studies clearly showed that CODES provides for rapid target site release in the colon regardless of the ingestion of food.

A new stressed test to predict the foreign matter formation of minodronic acid in solution.

A formulation containing 0.5 mg/ml minodronic acid, 40 mM citrate, pH 4.5, and sodium chloride, stored in regular flint glass ampoules, was stable without particulate increase under high temperature conditions, such as 40 degrees C for 6 months, or 50 or 60 degrees C for 3 months. However, when stored at 25 degrees C, there was an increase in >or=2 microm particles at the 5-month timepoint. This demonstrated that long-term stability cannot simply be predicted by the evaluation of samples just stored at higher temperatures. Therefore, a new stressed test was designed which is useful in the rapid selection of formulations that are stable and without particulate increase. Since the particulate matter is apparently a complex of minodronic acid and aluminum ions leaching from ampoules, samples were placed at 80 degrees C for up to 4 weeks to accelerate aluminum leaching. Although no particulate increase was observed directly after storage at 80 degrees C, 4 freeze-thaw cycles following the storage caused a drastic particulate increase. The evaluation of samples subjected to the freeze-thaw cycles indicated that the following formulation modifications have inhibitory effects on particulate generation: (1). addition of meglumine, diethanolamine, mannitol, or glycerol to the formulation; (2). increase of citric acid concentration; (3). decrease of minodronic acid concentration. These modifications also worked well for samples stored at 25 degrees C for 6 months, and particulate increase did not occur. This method is a powerful tool for predicting the stability of minodronic acid in solution.

Studies on lactulose formulations for colon-specific drug delivery.

A novel, colon-targeted delivery system (CODES), which uses lactulose, was investigated in this study. Lactulose is not absorbed in the upper GI tract, but degraded to organic acids by enterobacteria in the lower gastrointestinal tract, especially the colon. A CODES consists of three components: a core containing lactulose and the drug, an inner acid-soluble material layer, and an outer layer of an enterosoluble material. When a CODES containing a pigment was introduced into the rat cecum directly after shaking in JP 2nd fluid for 3 h, pigment release was observed 1 h after introduction. A CODES containing 5-aminosalicylic acid (5-ASA) was orally administered to fasting and fed dogs to evaluate its pharmacokinetic profiles. 5-ASA was first detected in plasma after 3 h, which is the reported colon arrival time for indigestible solids, after dosing to fasting dogs. The T(max) in fed dogs was delayed by 9 h when compared to fasting dogs. This corresponds to the gastric emptying time. However, the C(max) and AUC under fed conditions were almost as same as those under fasting conditions. The results of this study show that lactulose can act as a trigger for drug release in the colon, utilizing the action of enterobacteria.

In vitro evaluation of dissolution behavior for a colon-specific drug delivery system (CODES) in multi-pH media using United States Pharmacopeia apparatus II and III.

United States Pharmacopeia dissolution apparatus II (paddle) and III (reciprocating cylinder) coupled with automatic sampling devices and software were used to develop a testing procedure for acquiring release profiles of colon-specific drug delivery system (CODES) drug formulations in multi-pH media using acetaminophen (APAP) as a model drug. System suitability was examined. Several important instrument parameters and formulation variables were evaluated. Release profiles in artificial gastric fluid (pH 1.2), intestinal fluid (pH 6.8), and pH 5.0 buffer were determined. As expected, the percent release of APAP from coated core tablets was highly pH dependent. A release profile exhibiting a negligible release in pH 1.2 and 6.8 buffers followed by a rapid release in pH 5.0 buffer was established. The drug release in pH 5.0 buffer increased significantly with the increase in the dip or paddle speed but was inversely related to the screen mesh observed at lower dip speeds. It was interesting to note that there was a close similarity (f2 = 80.6) between the release profiles at dip speed 5 dpm and paddle speed 100 rpm. In addition, the release rate was reduced significantly with the increase in acid-soluble Eudragit E coating levels, but lactulose loading showed only a negligible effect. In conclusion, the established reciprocating cylinder method at lower agitation rates can give release profiles equivalent to those for the paddle procedure for CODES drug pH-gradient release testing. Apparatus III was demonstrated to be more convenient and efficient than apparatus II by providing various programmable options in sampling times, agitation rates, and medium changes, which suggested that the apparatus III approach has better potential for in vitro evaluation of colon-specific drug delivery systems.