International Journal of Pharmaceutics (v.268, #1-2)

Pellets were coated with ethylcellulose powder to achieve extended release. The film forming ability of ethylcellulose powder and the effect of formulation factors (plasticizer type and concentration) and curing conditions (curing temperature and time) were investigated. The coating formulation was divided into two components consisting of a powder mixture (polymer plus talc) and a mixture of liquid materials (plasticizer plus binder solution), which were sprayed separately into the coating chamber of a fluidized bed coater (Glatt® GPCG-1, Wurster insert). The coated pellets were oven-cured under different conditions (60–80 °C, 2–24 h) without and with humidity (100% relative humidity). Propranolol hydrochloride was used as a model drug, and drug release was studied in 0.1N HCl at 37 °C (USP XXV paddle method). Despite the high glass transition temperature of ethylcellulose (133.4 °C), micronized ethylcellulose powder can be used for dry powder coating by adjusting the coating temperature, amount and type of plasticizer applied, and curing conditions. 40% plasticizer and a curing step (80 °C, 24 h) were required to achieve complete coalescence of the polymer particles and extended drug release of coated pellets. Although ethylcellulose-coated pellets had an uneven surface, extended drug release could be obtained with coating level of 15%. Because of its high glass transition temperature, ethylcellulose-coated pellets showed unchanged drug release profiles upon storage at room temperature for 3 years.
Keywords: Curing; Dry powder coating; Ethylcellulose; Film formation; Extended release;

Evaluation of oral formulations of gentamicin containing labrasol in beagle dogs by Y.V. Rama Prasad; Sudarat Eaimtrakarn; Makoto Ishida; Yoichi Kusawake; Riichi Tawa; Yukako Yoshikawa; Nobuhito Shibata; Kanji Takada (13-21).
Gentamicin (GM) is a polarized water-soluble compound having very poor intestinal membrane permeability resulting in low oral bioavailability. Labrasol was found to improve the intestinal absorption of GM in rats. In the present study, GM formulations containing labrasol were evaluated in beagle dogs after filling into hydroxypropylmethyl cellulose (HPMC) capsules wrapped with Eudragit L100 (Eud L) and Eudragit S100 (Eud S) films. The results of the in vitro drug release studies could not differentiate between two kinds of enteric capsules and among the three kinds of GM formulations. Oral administration of GM solution at a dose of 50.0 mg per dog of GM and 0.60 ml per dog of labrasol has resulted in C max values of 2.38±0.50 μg/ml and 2.30±0.42 μg/ml with Eud L and Eud S capsules, respectively. The AUC values obtained were also higher at 4.35±1.31 μg h/ml and 5.34±0.95 μg h/ml with Eud L and Eud S capsules, respectively. Formulation of GM as a suspension in labrasol has resulted in the decrease of C max values by two to four times and AUC values by >2.5 times compared to the solution formulation. The above results indicate that solution formulation was better over the suspension. An absorbent, synthetic sponge was used to absorb GM solution formulation and encapsulated with Eud L and Eud S capsules. The C max and AUC values obtained with sponge formulation were higher than those of suspension formulations but were lower than solution formulations. There was no significant difference in the extent of GM absorption between Eud L and Eud S capsules used for encapsulating GM formulations.
Keywords: Gentamicin sulfate; Labrasol; Enteric polymers; Oral delivery; Absorption enhancer;

Preparation and characterization of injectable microspheres of contraceptive hormones by Magharla Dasaratha Dhanaraju; Kiran Vema; Rajadas Jayakumar; Chandrasekar Vamsadhara (23-29).
Present study describes the development of a new formulation of levonorgestrel and ethinylestradiol based on double emulsion-solvent evaporation technique using poly(ε-caprolactone) (PCL) as biodegradable polymer. The effect of polymer concentration on microspheres and entrapment of drug into microspheres were studied. PCL was selected because of its hydrophobicity and advantages over other biodegradable polymers. Characterization of biodegradable polymer used for controlled drug delivery is essential to ensure reproducibility of in vitro and in vivo performances. The selected characterisation techniques established for PCL microspheres include its loading and entrapment efficiencies, DSC to analyse thermal behaviour, SEM to observe surface morphology, drug content of microspheres and in vitro release of drugs from microspheres. The SEM reports showed that microspheres were with smooth surface and DSC thermograms revealed no interaction between drug and polymer. The entrapment was found to be 58 and 47% for 1:10 and 1:5 batches and in vitro release studies showed that about 69.7% of LNG and 66.7% of EE from 1:10 batch and about 80% of LNG and 75.5% of EE from 1:5 batch for 150 days.
Keywords: Levonorgestrel; Ethinylestradiol; Microspheres; Biodegradable polymers; Poly(ε-caprolactone);

Therapeutic efficacy study of novel 5-FU-loaded PMM 2.1.2-based microspheres on C6 glioma by E. Fournier; C. Passirani; A. Vonarbourg; L. Lemaire; N. Colin; S. Sagodira; P. Menei; J.-P. Benoit (31-35).
The aim of this study was to evaluate the potential of poly(methylidene malonate 2.1.2) as a new drug delivery system to the central nervous system. 5-Fluorouracil microspheres were formulated by an emulsion–extraction method, and evaluated on a C6 glioma model. Twenty-seven Sprague–Dawley female rats underwent implantation of various C6 cell concentrations. Magnetic resonance imaging was performed at day 10 to control the setting of the tumor, by using a T2-weighted sequence. At day 12, 18 animals received blank or 5-FU-loaded microspheres, while 9 animals were not implanted and constituted the controls. Thereafter, MRI was performed twice a week to follow the tumor growth. In 12 animals, an alloimmune rejection of the tumor was observed, showing the limitations of the C6 glioma model. When tumor developed, no relationship was observed between the number of C6 cells injected and the tumor volume. 5-FU microsphere efficacy could statistically be demonstrated by significantly improving the median survival of C6 glioma-bearing animals and also by decreasing tumor burden.
Keywords: PMM 2.1.2; Microspheres; 5-Fluorouracil; C6 glioma; MRI;

The migration of ketoprofen through a series of simple gels that varied in solvent composition to simulate snapshots of a dynamically drying topical formulation was studied. Firstly, the release rate of ketoprofen was determined from formulations based on Cabosil® and PEG 400, the proportion of which was varied to mimic progressively dryer states. Secondly, the apparent permeability of ketoprofen across the corresponding blank Cabosil® gels was determined. Thirdly, the effect of macro viscosity on these data was probed by comparing permeation of ketoprofen across Cabosil® and hydroxypropyl cellulose (HPC) gels of equal viscosity. Linear release profiles were produced for all formulations suggesting first-order release and the rate of ketoprofen liberated was inversely to the proportion of Cabosil®, suggesting that the drier the film, the slower the rate of release. At the lowest level of thickener used (5%) the release rate was reduced to 45% of the control. At 25% the release rate was reduced to 24% of the control. The presence of the Cabosil® had an even more dramatic effect on the apparent permeability of ketoprofen across the gels. At 5% Cabosil® the apparent steady state flux was reduced to 4% of the control. At 25% the apparent steady state flux was reduced to <1% of the control. Although the 0.5% HPC gel and the 1% Cabosil® gel possessed identical macro viscosities, the permeation of ketoprofen through the HPC gel was almost double that of the Cabosil® gel. The data from these experiments demonstrated that migration of active molecules through a gel is significantly affected by the amount of solvent present in, or lost from, the system. It is proposed that increased adsorption of active to the thickener plays a more important role than increased macro viscosity for reduced active release as the formulation becomes increasingly dry. Furthermore, such affects are profoundly influenced by the chemical nature of the thickener.
Keywords: Ketoprofen; Gel; Cabosil®; PEG 400; Topical drug delivery; Release rate;

Encapsulation and release of the hypnotic agent zolpidem from biodegradable polymer microparticles containing hydroxypropyl-β-cyclodextrin by Giuseppe Trapani; Angela Lopedota; Giancarlo Boghetich; Andrea Latrofa; Massimo Franco; Enrico Sanna; Gaetano Liso (47-57).
The goal of this study was to design a prolonged release system of the hypnotic agent zolpidem (ZP) useful for the treatment of insomnia. In this work, ZP alone or in the presence of HP-β-CD was encapsulated in microparticles constituted by poly(dl-lactide) (PDLLA) and poly(dl-lactide-co-glycolide) (PLGA) and the drug release from these systems was evaluated. ZP alone-loaded microparticles were prepared by the classical O/W emulsion–solvent evaporation method. Conversely, ZP/HP-β-CD containing microparticles were prepared by the W/O/W emulsion–solvent evaporation method following two different procedures (i.e. A and B). Following procedure A, the previously produced ZP/HP-β-CD solid complex was added to the water phase of primary emulsion. In the procedure B, HP-β-CD was added to the aqueous phase and ZP to the organic phase. The resulting microparticles were characterized about morphology, size, encapsulation efficiency and release rates. FT-IR, X-ray, and DSC results suggest the drug is in an essentially amorphous state within the microparticles. The release profiles of ZP from microparticles were in general biphasic, being characterized by an initial burst effect and a subsequent slow ZP release. It resulted that co-encapsulating ZP with or without HP-β-CD in PDLLA and PLGA the drug release from the corresponding microparticles was protracted. Moreover, in a preliminary pharmacological screening, the ataxic activity in rats was investigated and it was found that intragastric administration of the ZP/HP-β-CD/PLGA microparticles prepared according to procedure B produced the same ataxic induction time as the one induced by the currently used formulation Stilnox®. Interestingly moreover, there was a longer ataxic lasting and a lower intensity of ataxia produced by the ZP/HP-β-CD/PLGA-B-formulation already after 60 min following the administration. However, a need for further pharmacokinetic and pharmacodynamic studies resulted to fully evaluate the utility of this last formulation for the sustained delivery of ZP.
Keywords: Zolpidem; Encapsulation; Microparticles; Biodegradable polymers;

The performance of five different compressors (CR60®, Porta-Neb®, Pulmo-Aide®, TurboBoy® and Freeway® Freedom) was studied in combination with the widely recommended PARI LC PLUS® nebuliser for the aerosolisation of a marketed tobramycin solution (TOBI®). The droplet size distribution of the generated aerosol was measured with laser diffraction technique at stationary inspiratory flow rates through the nebuliser cup of 20, 30 and 40 lN/min. The different compressors showed a distinct difference in droplet size distribution of the aerosol and nebulisation time till dry running. The finest droplets with a volume (equals mass) median diameter (mmd) of 1.84 μm (which was the same at all flow rates), as well as the narrowest size distribution were obtained with a CR60®. The Freeway® Freedom generated the largest droplets: mmd ranged between 2.63 and 3.72 μm depending on the inspiratory flow rate. The aerosol produced with this compressor also had the widest size distribution. The differences between the compressors could be explained with differences in the jet flow. A higher jet flow resulted in finer droplets, less dependence on the inspiratory flow rate and a shorter time till dry running. Thus, to obtain the required fineness of the aerosol for peripheral airway deposition of the tobramycin, independent of the inspiratory flow rate, the use of the CR60® compressor is preferred over the use of Porta-Neb®, Pulmo-Aide®, TurboBoy® and Freeway® Freedom (in order of decreasing preference). Finally, it was found that careful cleaning with warm water and liquid soap of the nebuliser cup is essential to obtain adequate performance of the LC PLUS®.
Keywords: Tobramycin; TOBI®; Nebulisation; PARI LC PLUS®; Compressor; Laser diffraction analysis;

The objective of the work was to investigate the effects of a range of poly-hydroxy aliphatic esters (poly-lactide (PLA) and poly-lactide-co-glycolide (PLGA)) of different molecular weight and composition on the release and stability of the amphoteric drug amoxycillin. The effect of this amphoteric drug on the extent and kinetics of polymer degradation was also investigated. The polymers were used to prepare drug-free and drug-loaded cylindrical discs. Drug release profiles were determined while changes in polymer composition were monitored by weight loss and molecular weight change. The extent of drug release was highly dependant on polymer molecular weight and composition, with earlier complete release occurring with the lower molecular weight and lower lactide containing polymers. A larger proportion of drug was released by polymer degradation control with the higher lactide containing polymer. The proportion of drug released intact was influenced by the polymer molecular weight, with a greater proportion of intact drug being released from the higher molecular weight systems. The inclusion of amoxycillin influenced polymer degradation and resulted in slower polymer hydrolysis. Model parameters obtained for polymer degradation indicated that this retardation effect increased with increasing lactide content of the polymer. The results suggest that small amounts of amoxycillin or its degradation products may bind or cross link with the polymers, thus retarding their degradation.
Keywords: Poly (d,l-lactide-co-glycolyde) (PLGA); Amoxycillin; Polymer degradation-controlled release; Amphoteric drugs; Drug degradation; Glass transition temperature;