Takashi Ishibashi

Design and evaluation of a new capsule-type dosage form for colon-targeted delivery of drugs

A new capsule-type dosage form was investigated to approximate the chronobiology of rheumatoid arthritis for colonic targeting. The system was designed by imparting a timed-release function and a pH-sensing function to a hard gelatin capsule. The technical characteristics of the system are to contain Succinic acid together with physical mixture of Etoricoxib (1:6ratio) in a capsule coated with a three-layered film consisting of an acid-soluble polymer, a watersoluble polymer, and an enteric polymer. In order to find the suitable formulation, various formulation factors were investigated through a series of in-vitro dissolution studies. The ability of colon targeted drug capsule to provide colon specific drug delivery was assessed by in vitro drug release studies in buffer solution at pH 1.2 for 2 h, and at pH 6.8(Simulated colonic fluid) for remaining hour. The results indicated that all the formulations shown no drug release in the stomach but the major portion of the drug was released in the colon and the drug release pattern was found to be F4>F3>F2>F1. From the analysis, it was found that, a predictable timed-release mechanism of a drug can be attained by adjusting the loading amount of Succinic acid. The outer enteric coating with cellulose acetate phthalate provided acceptable acid-resistibility. All these results suggested that this approach can provide a useful and practical means for colon-targeted delivery of drugs.

Evaluation of colonic absorbability of drugs in dogs using a novel colon-targeted delivery capsule (CTDC).

A series of dog studies were performed to examine the in vitro/in vivo relationship of drug release behavior of the newly developed colon-targeted delivery capsule (CTDC). The four kinds of CTDCs containing theophylline, each of which has a different in vitro dissolution lag time, were orally administered to four beagle dogs under fasted condition, and the onset times of drug absorption were compared. The CTDC with longer in vitro lag time had a later onset of drug absorption. It was also found that the time difference between the gastric emptying and the onset of drug absorption was almost equal to the in vitro dissolution lag time of the capsule, suggesting a similar performance of CTDC in the gastrointestinal tract. From the comparison to the absorption behavior of the colon arrival marker, i.e. sulfasalazine, it was proved that the CTDC with the lag time of 3 h can deliver the drug directly to the colon. This result implied that the CTDC can be used as a non-invasive means for assessing the regional absorbability of drugs in the gastrointestinal tract. To evaluate the absorbability of drugs in the colon, three model drugs, theophylline (THEO), acetaminophen (ACET), and phenylpropanolamine hydrochloride (PPA) were directly delivered to the colons of beagle dogs using the CTDC with the lag time of about 3 h. The obtained relative bioavailabilities to the solution form were as high as 94.2%, 71.0%, and 91.5% for THEO, ACET and PPA, respectively, suggesting that the colonic absorbability of those drugs is essentially good.

In vivo drug release behavior in dogs from a new colon-targeted delivery system

The colon-targeted delivery capsule (CTDC), a new capsule-type dosage form for colonic delivery of drugs, was investigated for the in vivo drug release behavior in dogs. A CTDC formulation with prednisolone as a model drug and theophylline as a marker substance for gastric emptying was prepared for this study. The enteric-coated capsule (ECC) formulation with a similar composition was also prepared as the reference. Both formulations were administered to four beagle dogs, and the drug release behavior thereof was compared. Under fasted condition, ECC released prednisolone and theophylline at the same time within 1 h after the gastric emptying. On the other hand the CTDC released prednisolone at 3.2 h after the gastric emptying. Such release behavior of CTDC was approximately consistent with the results obtained from the in vitro dissolution study, suggesting that the pH-sensing and timed-release functions imparted to the CTDC can work in the gastrointestinal tract of dogs as programmed. Under non-fasted condition, however, the gastric emptying of CTDC was found to be considerably delayed, up to about 14 h, and in this case the in vivo dissolution lag time of prednisolone at the small intestine was shortened to about 1.5 h.