In vivo evaluation of a novel pH- and time-based multiunit colonic drug delivery system.

BACKGROUND: Targeted drug delivery to the colon is important for topical treatment of inflammatory bowel diseases. Established targeting systems predominantly focus on either pH- or time-dependent release, or bacterial degradation. AIM: To perform a three-phase, crossover design trial evaluating a novel combined pH- and time-based multiunit delivery system. METHODS: Twelve healthy male volunteers each received 200 mg of caffeine as either uncoated immediate release tablets, coated pellets with pH-dependent rapid release (EUDRAGIT FS 30D), and pellets with pH- and time-based release (inner layer EUDRAGIT RL/RS 30D; outer layer EUDRAGIT FS 30D). Orocecal transit time was measured using lactose-[13C]ureide. Serum concentrations of caffeine were measured by high-performance liquid chromatography. RESULTS: In contrast to the uncoated tablet, both coated systems reached the ileocecal region almost at the same time (3.19 +/- 0.71 and 3.33 +/- 0.81 h). Serum caffeine profiles were significantly prolonged for the pH and time delivery system compared with the pH-only based system (median tmax 12.0 vs. 5.5 h; P < 0.001). This was further reflected by a lower Cmax value and a lower area under the curve within 24 h after application. CONCLUSION: Compared with the conventional delivery systems, drug release from the new dosage form may offer a new dimension for the oral treatment of mid to distal ulcerative colitis.

Formulation and process considerations affecting the stability of solid dosage forms formulated with methacrylate copolymers.

General considerations concerning the stability of coated dosage forms are discussed, in order to avoid predictable interactions which may cause long-term stability problems. As polymers themselves maintain a high chemical stability and a low reactivity, instability phenomena mainly have to be explained by interactions of low molecular weight substances or physical changes. Possible interactions of functional groups can be predicted easily and insulating subcoates are proper countermeasures. Impurities, remaining in the polymeric material from the manufacturing process, may accelerate the hydrolysis of sensitive drugs. Instabilities of coated dosage forms are mainly based on physical interactions, caused by improper formulations of coating suspensions (i.e. plasticizers or pigments) or the film coating process. Residual moisture or solvents, probably enclosed in the core and migrating over time, may increase the permeability of coatings, due to plasticizing effects. The functionality of coatings from aqueous dispersions is linked to coalescence of latex particles. Thus any incomplete film formation, caused by too high or too low coating temperatures, may result in high permeable coatings. During storage, preferably under stress conditions this process will continue and thus change the release profile. Therefore bed temperatures of 10-20 degrees C above MFT must ensure the formation of homogeneous polymer layers during the coating process. Stability test procedures and packaging materials also need to be adapted to the physicochemical properties of the dosage form, in order to get meaningful results in stability tests.

Film coatings for taste masking and moisture protection.

Taste masking and moisture protection of oral dosage forms contribute significantly to the therapeutic effect of pharmaceutical and nutraceutical formulations either by ensuring patient compliance or by providing stability through shelf life of the dosage form. Among different types of taste, bitter taste is the most relevant for patient acceptance because of the extremely high sensitivity. As hydrolysis is the most common mode of degradation of an active ingredient, moisture protection plays a vital role in the stability of the active during manufacturing and storage. Optimized oral dosage forms need to reliably hinder the release of bitter drug molecules in the mouth or ensure stability of the active compound, while also ensuring fast drug release in the stomach to enable early therapeutic onset. Besides different formulation concepts, film coating is found to be the most effective and commonly used approach for taste masking and moisture protection. Film coating can be achieved through the use of water-soluble, cationic, anionic or neutral insoluble polymers from different chemical structures. Cationic polymers provide efficient moisture protection as well as taste masking without influencing the release of the drug in the gastric fluids. Polymers may be sprayed onto various types of cores from dispersions or solutions in organic, solvents or water in drum or fluidzed bed coaters. Applied quantities need insuring complete coating thickness ranging from 0.5 to 50 µm or more finally. Insulating excipients, such as hydrophobic plasticizers, lipids, pigments or other insoluble substances will influence the functionality of films. Organoleptic tests are still common in testing the quality of taste-masked formulations. Recently, multi-channel taste sensors have been developed to quantify different types of taste. Dynamic vapor sorption technique and studies at elevated temperature provide effective concepts study the efficacy of the formulations. Efficient taste masking and reliable moisture protection of solid oral dosage forms can be achieved by film coating implementing the options of pharmaceutical polymers and processes.

Controlled release by permeability alteration of cationic ammonio methacrylate copolymers using ionic interactions.

A multiparticulate drug delivery system was studied in which the drug release of a model drug theophylline could be modulated by interactions of ammonio methacrylate polymer and anions. The system consisted of a EUDRAGIT NE coated anionic core, layered with drug and further layered with EUDRAGIT RS. The effects of different anions like chloride, succinate, citrate, and acetate as well as the thickness of the polymer layers on the in vitro drug release were studied. It was seen that succinate and acetate anions had permeability enhancing effects and citrate and chloride anions had permeability retarding effects on the polymer. The results indicate that changing these variables would enable us to get a desired release profile and hence the proposed system could be a viable alternative to existing technologies for the development of a controlled drug delivery system.