Search

After the pH dependency of novel pH-dependent ileocolonic drug delivery systems is confirmed in vitro, their performance should be evaluated in human volunteers.

Delivering drugs to the ileo-colonic region of the intestinal tract might improve therapy for patients with diseases within their large intestines. The pH variations in the gastrointestinal tract can be used to achieve the targeted delivery. The pH rises from the stomach to the end of the small intestine, where the highest value is found. An example of a system that uses this pH profile is the ColoPulse coating. In this thesis, research is described in which the ColoPulse coating was applied to develop several novel ileo-colonic targeting formulations.Celecoxib, which has a poor water solubility, is a drug of interest for the treatment and prevention of colon cancer. We were able to create a celecoxib formulation that improves its solubility as well as targets the ileo-colonic region. When a single unit dosage form is damaged, then there is a risk that the entire dose is released in higher regions of the intestinal tract instead of the ileo-colonic region. Therefore, a multi-particulate formulation is preferred. To that end, we developed a pellet formulation that releases its contents in the ileo-colonic region. Sulfasalazine and caffeine were incorporated in these pellets, since these compounds can be used to verify ileo-colonic drug delivery. Since the colon has a low free water content, we also developed a formulation that was able to deliver an aqueous drug solution to the ileo-colonic region. With this work, we hope that in the future, therapy of patients can be improved.

The ColoPulse coating is a pH-dependent coating that can be used to target drug release to the ileo-colonic region. ColoPulse coated tablets and capsules have demonstrated their targeting capabilities in vivo in more than 100 volunteers and patients. However, so far the ColoPulse coating has not been used for multi-particulate pellet formulations. The sulfasalazine–caffeine method can be used to confirm ileo-colonic drug delivery in vivo. Caffeine serves as a release marker in this method, while sulfasalazine serves as a marker for colonic arrival. In this study, extrusion–spheronization was used to produce microcrystalline cellulose based pellets containing both caffeine and sulfasalazine. Dissolution tests revealed that a superdisintegrant, i.e., croscarmellose sodium or sodium starch glycolate, should be incorporated in the formulation to achieve acceptable release profiles for both sulfasalazine and caffeine. However, acceptable release profiles were only obtained when the pelletizing liquid consisted of ethanol/water 1/1 (v/v) but not with pure water. This phenomenon was ascribed to the differences in the degree of swelling of the superdisintegrant in the pelletizing liquid during the granulation process. The pellets were coated with the ColoPulse coating and showed the desired pH-dependent pulsatile release profile in vitro. In future clinical studies, ileo-colonic targeting should be verified.

Targeting celecoxib to the ileo-colonic region could be beneficial for the treatment and prevention of colon cancer. Ileo-colonic targeting can be achieved by using pH-dependent coating systems such as ColoPulse. Celecoxib has poor aqueous solubility, which may jeopardize optimal treatment. Therefore, we combined a pH-dependent coating with self-emulsifying drug delivery systems (SEDDS) or with solid dispersion systems (SD), two approaches that are often used to improve the dissolution behavior of lipophilic drugs. The dissolution behavior of various formulations of both systems was investigated. Optimized formulations with and without precipitation inhibitors were coated with the ColoPulse and the release of celecoxib was tested under non-sink conditions using an in vitro dissolution system, simulating the pH gradient of the gastrointestinal tract. The dissolution behavior of SDs with and without precipitation inhibitor (sodium dodecyl sulfate) and the SEDDS without precipitation inhibitor was negatively impacted by the coating. Control experiments indicated that components of the coating released in the dissolution medium acted as precipitation mediators. However, the SEDDS formulation with HPMC 4000 cps as a precipitation inhibitor showed excellent dissolution behavior. We hypothesize that HPMC accumulates at the oil/water interface of the emulsion thereby stabilizing the emulsion resulting in maintenance of the supersaturated state.

Injectable sustained release drug delivery systems are an attractive alternative for the intravenous delivery of therapeutic proteins. In particular, for chronic diseases such as fibrosis, this approach could improve therapy by reducing the administration frequency while avoiding large variations in plasma levels. In fibrotic tissues the platelet-derived growth factor receptor beta (PDGFβR) is highly upregulated, which provides a target for site-specific delivery of drugs. Our aim was to develop an injectable sustained release formulation for the subcutaneous delivery of the PDGFβR-targeted drug carrier protein pPB-HSA, which is composed of multiple PDGFβR-recognizing moieties (pPB) attached to human serum albumin (HSA). We used blends of biodegradable multi-block copolymers with different swelling degree to optimize the release rate using the model protein HSA from microspheres produced via a water-in-oil-in-water double emulsion evaporation process. The optimized formulation containing pPB-HSA, showed complete release in vitro within 14 days. After subcutaneous administration to mice suffering from renal fibrosis pPB-HSA was released from the microspheres and distributed into plasma for at least 7days after administration. Furthermore, we demonstrated an enhanced accumulation of pPB-HSA in the fibrotic kidney. Altogether, we show that subcutaneously administered polymeric microspheres present a suitable sustained release drug delivery system for the controlled systemic delivery for proteins such as pPB-HSA.