Development and in vitro evaluation of a novel floating multiple unit dosage form obtained by melt pelletization.

The feasibility of preparing floating pellets by melt pelletization was investigated. The pellets were prepared in a high shear mixer. Formulations were based on a mixture of Compritol and Precirol as lipidic binders and on sodium bicarbonate as a gas-generating agent. The floating ability of the pellets was evaluated in vitro. Good floating capabilities were obtained for formulations containing the gas-generating agent in both the inner matrix and the outer coating layer of the pellets. As an example, a placebo formulation containing 50% lactose 450 Me, 22% Compritol, 15% Precirol, 8% sodium bicarbonate and 5% Methocel K100 (w/w) in the inner matrix, and 66% Precirol and 34% sodium bicarbonate (w/w) as a coating effervescent layer, showed very good floating capabilities. The percentage of floating placebo pellets was around 80% after 1 h and still above 75% for 23 h. Floating pellet formulations with high drug content, based on the use of tetracycline hydrochloride and theophylline were also evaluated. They showed a comparable floating ability to placebo formulations, combined with sustained release properties thanks to the lipophilic character of the binders used.

Preparation of poly(N-isopropylacrylamide) copolymers and preliminary assessment of their acute and subacute toxicity in mice.

A subacute toxicity study was conducted to evaluate the oral toxicity profile of poly(N-isopropylacrylamide) (PNIPAAm) derivatives. These thermoresponsive polymers may have several potential pharmaceutical applications such as ingredient for oral solid dosage form. A preliminary acute oral toxicity study was performed with one of the polymer (PNIPAAm-co-NVA) at a unique dose of 4000 mg/kg body weight administered to six male and six female mice, to determine the dosage for further evaluation. No treatment-related effect was observed on behavior and health condition of the experimental animals during the 14 days observational period. The autopsy of the treated animals did not revealed any macroscopic changes in major organ aspects. Based on these preliminary results we selected a 2000 mg/kg body weight/day dose for the 28 days long subacute study. Three polymers were tested, namely PNIPAAm, PNIPAAm-co-NVA and PNIPAAm-co-AAc and compared to a saline control. No significant changes in clinical signs, body weight and food consumption, hematology, clinical chemistry or absolute organ weight were observed. Histological examination of excised major organs showed no marked differences between treated and control mice. In conclusion, PNIPAAm-co-NVA is well tolerated up to 4000 mg/kg body weight when administered orally. In addition, the subacute study indicated the absence of cumulative toxicity and a no-observed-adverse-effect level (NOAEL) of 2000 mg/kg was identified for PNIPAAm and its two copolymers. Further studies are mandatory.

Physical and thermal characterisation of Precirol and Compritol as lipophilic glycerides used for the preparation of controlled-release matrix pellets.

Physical and thermal properties of Compritol and Precirol as potential lipophilic binders in melt pelletisation process for the preparation of sustained-release matrix pellets were evaluated in this study. Experimental measurements were carried out using X-ray diffractometry, differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and rheological measurements. These studies have shown that the lipophilic binders may present a relatively complex behaviour depending on the sample treatment (untreated, freshly solidified, aged samples). DSC and HSM methods have shown the presence of polymorphism for Precirol. Moreover, both untreated and fresh solidified Precirol and Compritol samples present partially amorphous layered structure which slowly crystallise in time. The rate of crystallisation was found to be more rapid for Precirol, and highly dependent on the ageing conditions (storage temperature). Finally, the evaluation of the thermal and rheological properties of Precirol and Compritol mixtures have shown that the use of such mixtures, presenting well distinct melting properties, could be a very interesting tool for the preparation of high fatty binder content prolonged-release pellets in high shear mixers if the product temperature is carefully controlled (between 45 and 50 degrees C) during the pelletisation process.

Synthesis and enzymatic degradation of epichlorohydrin cross-linked pectins.

The water solubility of pectin was successfully decreased by cross-linking with increasing amounts of epichlorohydrin in the reaction media. The initial molar ratios of epichlorohydrin/ galacturonic acid monomer in the reaction mixtures were 0, 0.37, 0.56, 0.74, 1.00, 1.47, and 2.44. The resulting epichlorohydrin cross-linked pectins were thus referred to as C-LP0, C-LP37, C-LP56, C-LP75, C-LP100, C-LP150, and C-LP250, respectively. Methoxylation degrees ranged from 60.5 +/- 0.9% to 68.0 +/- 0.6%, and the effective cross-linking degrees, determined by quantification of the hydroxyl anions consumed during the reaction, were 0, 17.8, 26.0, 38.3, 46.5, 53.5, and 58.7%. respectively. After incubating the different cross-linked pectins (0.5% w/v) in 25 mL of 0.05 M acetate-phosphate buffer (pH 4.5), containing 50 microL of Pectinex Ultra SP-L (pectinolytic enzymes), between 60 and 80% of the pectin osidic bounds were broken in less than 1 hr. Moreover, increasing the cross-linking degree only resulted in a weak slowing on the enzymatic degradation velocity.

Development and evaluation of prolonged release pellets obtained by the melt pelletization process.

This study was performed in order to evaluate the possibility of obtaining prolonged release matrix pellets by a melt pelletization process in a laboratory high shear mixer (Mi-Pro, Pro-C-epT). Phenylephrine hydrochloride pellet formulations based on lactose 450 mesh and a mixture of Compritol 888 and Precirol ATO 5 as melting binders were evaluated. The fatty binder content of pellets was substantially increased (from 18 to 80% w/w). The effects of jacket temperature, massing time (MT) and impeller speed (IS) on the pellet characteristics were investigated. It was shown that pellets of narrow size distribution can be produced by using an IS of 800 rpm, a chopper speed of 4000 rpm and a MT of 8 min. On the other hand, the applicability of this technique for the production of sustained-release pellets using ciprofloxacin hydrochloride, ketoprofen and theophylline as less water soluble model drugs than phenylephrine hydrochloride was also studied. This study demonstrated that formulations based on an appropriate mixture of Precirol and Compritol can be used to produce in a short time prolonged release pellets for very hydrosoluble drugs like phenylephrine hydrochloride as well as for the other drugs tested.

Evaluation of a new controlled-drug delivery concept based on the use of thermoresponsive polymers.

The purpose of this work is to develop a new delivery concept making a thermosensitive polymer based on poly(N-isopropylacrylamide) (PNIPAAm) useful as a time-controlled drug release device, without any temperature changes of the dissolution medium. It was previously found that some salts induce a decrease of the polymer lower critical solution temperature (LCST). Use is here made of that property to show that salt concentration variations can be used as a substitute for temperature changes to make the polymer coating of compression-coated tablets soluble or insoluble, consequently creating a possible new concept of drug delivery control from delivery systems containing thermoresponsive polymers. The obtained results show the influence of the type and amount of salts incorporated into compression-coated tablets on the release lag time of a model drug.