In vitro and in vivo evaluation of floating riboflavin pellets developed using the melt pelletization process.

Floating pellets were prepared using the melt pelletization process in a Mi-Pro high shear mixer (Pro-C-epT, Belgium). Formulations were based on a mixture of Compritol and Precirol as meltable binders and on the use of sodium bicarbonate and tartaric acid as gas-generating agents. Good floating abilities were obtained by using the gas-generating agents in both the inner matrix and the outer coating layer of the pellets. In vitro evaluation of floating capability was performed both by using the resultant weight apparatus and by counting floating pellets at the surface of beakers containing 0.1N HCl solution, in vivo evaluation of floating pellets capabilities was also performed. Riboflavin-containing floating pellets (FRF) were administered orally to nine healthy volunteers versus non-floating pellets (NFRF). Volunteers were divided in two groups, fasted group (n=4) 729 kcal and fed group (n=5) 1634 kcal as the total calorie intake on the testing day. An increase of urinary excretion of riboflavin was observed when the volunteers were dosed with the floating pellets, especially after feeding. As riboflavin has a narrow window of absorption in the upper part of small intestine, this phenomenon could be attributable to the gastric retention of floating pellets.

Poly(N-isopropylacrylamide) copolymers for constant temperature controlled drug delivery.

In the course of the development of a new drug delivery concept, four thermosensitive copolymers of poly(N-isopropylacrylamide) (PNIPAAm), with phase transition temperature slightly higher than 37 degrees C, were synthesised and used as time-controlled drug delivery agents. For this purpose, compression-coated tablets coated with the thermosensitive copolymers and containing Na2SO4 were prepared and in vitro dissolution tests were performed at constant physiological temperature, the lag time before drug release being controlled by the amount of Na2SO4 incorporated into the form. Due to the salting out effect, the lag time was increased by up to 80-90% for PNIPAAm-co-NVA and PNIPAAm-co-MVA coated tablets.

Surfactant induced drug delivery based on the use of thermosensitive polymers.

A novel approach of controlled drug delivery using thermosensitive polymers is developed in this paper. The drug release occurs at physiological temperature, at which the polymer is normally not soluble, and no medium temperature changes are required to bring about the delivery. For this purpose benefit is taken from the specific binding properties of some anionic surfactants and poly(N-isopropylacrylamide) (PNIPAAm) in order to modify the dissolution properties of PNIPAAm and of a copolymer with N-vinyl-acetamide (NVA), and so to induce the release of a drug contained in compression coated tablets. The influence of surfactant type and amount on the drug release rates and lag times from tablets coated with PNIPAAm or with the copolymer are discussed. It was found that the lag time is influenced by the surfactant species and amount. When use is made of a copolymer as coating agent, it is possible to bring about the release of the drug by incorporating only a very small amount (as low as 2%) of sodium dodecyl sulfate (SDS) in the coating.

Effect of some physiological and non-physiological compounds on the phase transition temperature of thermoresponsive polymers intended for oral controlled-drug delivery.

Poly-N-isopropylacrylamide (PNIPAAm) thermosensibility makes this polymer a very attractive candidate for controlled drug delivery systems. The polymer possesses a lower critical solution temperature (LCST) which was found to be around 32 degrees C in pure water, but which can be affected by the medium composition, i.e. presence of salts or surfactants. The knowledge of the effects of such substances on the LCST is very important while using PNIPAAm as a controlled drug delivery agent. The influence of a number of physiological and non-physiological salts and surfactants has been studied. The results obtained show that the addition of salts provokes an important decrease of the LCST of the polymer (salting out effect). A strong influence of the valence and of the size of the anions of the halide group was found. As to the surfactants, according to their type and concentration, a decrease or an increase of the LCST or even no effect at all were found. The effect of the GI secretions on the PNIPAAm phase separation temperature is also discussed.

Deposition of nacystelyn from a dry powder inhaler in healthy volunteers and cystic fibrosis patients.

The aim of this study was to compare, using gamma scintigraphy, the lung deposition of a novel mucoactive agent, Nacystelyn (NAL), administered as a dry powder inhaler (DPI) in six healthy volunteers, six adult patients with cystic fibrosis (CF), and six children and adolescents patients with CF. The correlation between in vitro and in vivo results was also tested. It was first demonstrated that the method of labeling of NAL with 99mTc was reliable as tested by three in vitro methods (multistage liquid impinger, multistage cascade impactor, and 2-stage glass impinger). The deposition of unlabeled NAL, labeled NAL, and the radiolabel was similar in all stages of each device. Furthermore, the fine particle fraction (FPF) was the same on all apparatuses. The mean lung deposition obtained in volunteers was 27.5 +/- 13.5%. The results are approximately three times higher than the results obtained previously in healthy volunteers with NAL metered-dose inhalers (MDIs). As expected, the lung deposition observed in patients with CF was lower, e.g., 23.5 +/- 7.0% for adults and 16.5 +/- 5.9% for children and adolescents. A significant correlation was found between lung deposition and both the patient weight (p < 0.02) and height (p < 0.04). Surprisingly, the peripheral:central (P:C) ratio was similar for the three populations, indicating that the presence of mucus in moderately ill patients with CF does not modify the lung distribution of NAL. The FPF measured in vitro was similar to that obtained in volunteers but higher than that found in both patient populations. The DPI formulation of NAL developed will probably improve patient compliance and comfort in future clinical trials and postmarketing use of the drug.

Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate.

Theophylline pellets were coated with cellulosic (Aquacoat ECD 30, Surelease clear) or acrylic (Eudragit NE30D, RS30D) polymer aqueous dispersions, containing 10% (related to the insoluble polymer content) of pectin HM or calcium pectinate, using a Uni-Glatt fluidized-bed coating apparatus. When commercial pectinolytic enzymes were added to the dissolution media (0.05 M acetate - phosphate buffer, pH 6.0), the release of theophylline from the coated pellets was generally slower than that observed in the media without enzymes. The enzymatic slowing down of the drug release, depending on the type of the aqueous polymer dispersion used, is more important with mixed Eudragit NE/calcium pectinate coated pellets. The results obtained have been examined with regard to the validity of the approach based on the combination of pectins and the insoluble polymer aqueous dispersions intended for specific-delivery of drugs to the colon. The mechanism of the hydrophilic drug release from pellets coated with insoluble polymer aqueous dispersions containing an aqueous gel-forming polymer has been also discussed.

Studies of pectin HM/Eudragit RL/Eudragit NE film-coating formulations intended for colonic drug delivery.

Theophylline pellets were coated with Eudragit NE30D aqueous dispersions, containing various pectin HM/Eudragit RL30D ionic complexes, using an Uni-Glatt fluidized-bed apparatus. Dissolution studies were then carried out on the coated pellets at pH 6.0, in absence and in presence of commercial pectinolytic enzymes. The theophylline release from the coated pellets, after an initial latency phase, occurred linearly as a function of time. The theophylline release rate was dependent on the pectin HM content of the complexes incorporated in the coatings. The lowest theophylline release from the coated pellets was obtained when the pectin HM content of the complexes was 20.0% w/w (related to Eudragit RL), i.e. when the complexation between pectin HM and Eudragit RL is optimal. The theophylline release from the coated pellets was slower in presence of the pectinolytic enzymes when the pectin content of complexes is higher than 20% w/w. On the other hand, the effect of the enzymes induced an increase of the theophylline release when the pectin HM content of the coatings ranged between 10.0 and 15.0% w/w (related to Eudragit RL).

Influence of melting and rheological properties of fatty binders on the melt granulation process in a high-shear mixer.

The preparation of granules by melt granulation was investigated using a laboratory-scale high-shear mixer (Pellmix PL 1/8) and binary mixtures containing lactose and different lipidic binders, namely, Compritol 888, Cutina HR, or Precirol ATO5. During the process, the product temperature and the impeller motor power consumption were monitored. On the other hand, the melting behavior (thermal analysis) and the rheological properties (controlled stress capillary rheometer) of the different lipophilic binders were also determined. The granule formation was shown to be quite effective at product temperatures even below the melting point of the lipidic binder, that is, when the binder is sufficiently softened to be deformed by the very high shearing forces developed in the high-shear mixer. On the other hand, the performance of lipidic binders during the melt granulation process was shown to be closely dependent on their melting and rheological properties. The granule growth rate was shown to be higher when the binder melting range is narrow and the influence of temperature on the viscosity of the unmelted product is high.

Optimization of a dry powder inhaler formulation of nacystelyn, a new mucoactive agent.

The aim of this study was to optimize a dry powder inhaler formulation containing a new mucoactive drug, nacystelyn. Formulations were made using three types of lactose, crystalline alpha-lactose, spray-dried lactose and a roller-dried anhydrous beta-lactose. The roller-dried anhydrous beta-lactose possessed the most adequate surface properties, resulting in a significantly higher (P < 0.05) in-vitro lung deposition of nacystelyn than the conventional crystalline alpha-lactose and spray-dried lactose. The particle size distribution of roller-dried beta-lactose was optimized also. Within the size ranges tested (63-100, 90-125 and 100-160 microm), the coarser the lactose, the higher the in-vitro deposition of the drug (up to 40%). In contrast, the in-vitro lung deposition of 100-160 microm roller-dried beta-lactose was very low (< 0.5%), so limiting the potential risk of lung irritation due to the carrier. The influence of the ratio of active ingredient/excipient (w/w) was also investigated. No difference was observed for mixtures from 1:2 to 1:4 while higher dilutions (1:5 and 1:6) showed significantly (P < 0.005) lower deposition results. Finally, the influence of the airflow rate was assessed. No dependence of the fine particle dose was observed between 40 and 80 L min(-1) while significantly higher results were obtained at 100 L min(-1). The dry powder inhaler formulation of nacystelyn using the unusual roller-dried anhydrous beta-lactose resulted in very high and reproducible in-vitro deposition results. However, the latter needs to be confirmed by in-vivo studies.

Influence of additives on the release profile of nifedipine from poly(DL-lactide-co-glycolide) microspheres.

Nifedipine-containing poly(DL-lactide-co-glycolide) (PLGA) microspheres of various sizes and drug contents were prepared by the solvent evaporation method. The in vitro release profiles of nifedipine from PLGA microspheres and the degradation pattern of the polymer were evaluated. Four additives were incorporated in the microspheres: two non-fatty plasticizers: diethylphthalate and triacetin, and two fatty substances: isopropyl myristate and Myvacet. Diethylphthalate and Myvacet increased the nifedipine release rate while isopropyl myristate and triacetin had no influence on it. Triacetin seems to be very poorly incorporated into the microspheres. These additives did not modify the degradation rate of the polymer. Differential scanning calorimetry detected a decrease of the glass transition temperature of diethylphthalate-containing microspheres, a small variation with Myvacet, and very little change when triacetin or isopropyl myristate were incorporated. This variation of the glass transition temperature (Tg) tends to imply that nifedipine is released by a diffusion process through the polymer matrix which is enhanced when additives decrease the Tg. Scanning electron microscopy allowed the vizualization of the highly porous structure of microspheres containing the oily substances, and the unchanged smooth surface of diethylphthalate-containing microspheres.

Peroral sustained-release film-coated pellets as a means to overcome physicochemical and biological drug-related problems. I. In vitro development and evaluation.

In vitro preformulation testing has shown that the solubility and dissolution rate of the model drug compound ucb 11056 are highly pH dependent. Considering this, different sustained-release (SR) oral dosage forms of ucb 11056 were developed aiming to obtain the most constant and complete release of the drug during transit in the gastrointestinal (GI) tract. Classical approaches based on the use of SR formulations such as hydrophilic matrix tablets or pellets coated with one film-forming polymer (Eudragit NE30D or L30D-55) did not fulfill all expectations on the basis of their in vitro evaluation, i.e., the drug release and pattern remained highly dependent on the pH of the dissolution medium. Therefore, taking advantage of the flexibility of release adjustment obtainable from coating of pellets with different kinds of pH-sensitive film layers, a quite satisfactory pH independence of the release characteristics was obtained using formulation blends of neutral and anionic acrylic polymers. For the selected SR pellets batch 15 coated with NE30D/L30D-55 (7:3), the tridimensional topographic representation of the drug release versus time and pH showed that, notwithstanding the pH-dependent aqueous solubility of the drug, the release profiles were relatively homogeneous for any pH value ranging between 1 and 7.

Peroral sustained-release film-coated pellets as a means to overcome physicochemical and biological drug-related problems. II. Bioavailability and tolerance assessment in dogs.

Sustained-release (SR) dosage forms consisting of pellets coated with different pH-sensitive film layers, previously optimized in vitro with regard to pH independence of their drug release characteristics, were evaluated in vivo after single administration to Beagle dogs. In vivo performances were compared to those of a nonoptimized SR matrix tablet and a reference instant release (IR) capsule, in terms of the observed plasma pharmacokinetic profiles for the parent drug (ucb 11056) and its primary metabolite (ucb 26201), the bioavailability results, and the drug tolerance data. All SR dosage forms were seen to be effective in prolonging the relatively short biological half-life of the compound and in reducing the incidence of concentration-related side-effects, e.g., emesis, and of behavioral symptoms, e.g., restlessness, discomfort, and indisposition. The film-coated SR pellets offer a number of advantages over the monolithic SR matrix system in terms of a drug delivery pattern less dependent on pH changes in the gastrointestinal (GI) tract, a higher flexibility for adjusting and controlling the pharmacokinetic profiles, and a consequently more efficient approach for keeping all concentration-related side-effects under control.

Preparation of controlled-release coevaporates of dipyridamole by loading neutral pellets in a fluidized-bed coating system.

PURPOSE: The purpose of this study was to demonstrate that it is possible to prepare controlled-release drug-polymer coevaporates on an industrial scale, omitting the recovery problems and the milling and sieving processes encountered when coevaporates are prepared by the conventional solvent-evaporation technique. METHODS: Controlled-release coevaporates were prepared by spraying organic solutions of dipyridamole-Eudragit blends onto neutral pellets using the fluidized-bed coating method. Enteric acrylic polymers Eudragit L100-55, L, and S were used as dispersing agents and drug/polymer ratio 2:8 was selected for all formulations. Polarized light microscopy, X-ray diffraction spectroscopy, and differential scanning calorimetry were used to determine whether the drug was amorphous or crystalline in the coating films. Moreover, in vitro dissolution tests were performed on the dipyridamole coated pellets in test media simulating the pH variations in the GI tract and the results were compared to the release data obtained from coevaporates prepared by the conventional solvent-evaporation method. RESULTS: All the results clearly indicate that dipyridamole is amorphous in the coating films deposited on neutral pellets as well as in coevaporate particles obtained by the conventional solvent-evaporation method. When the release patterns of the dipyridamole coated pellets are compared to those of the drug coevaporate particles prepared with the same enteric acrylic polymers, the results show similar dissolution trends. CONCLUSIONS: The results obtained indicate that pelletization can be considered as a method of choice for pilot plant and/or full-scale production of controlled-release dosage forms based on the formation of amorphous solid dispersions.

Factors controlling the buoyancy and gastric retention capabilities of floating matrix capsules: new data for reconsidering the controversy.

Optimized floating (F) and non-floating (NF) hydrophilic matrix capsules have been characterized in vitro with regard to their buoyancy or non-buoyancy capabilities and their diametral size evolution with time. The gastric residence times (GRTs) and transit behaviors of these F and NF forms prepared in small, medium, and large sizes were then comparatively examined in fed volunteers remaining either upright or supine. The results show that all the optimized F forms do lastingly float upon the gastric contents, whereas the NF forms sink rapidly after ingestion. In upright subjects, the F forms are consequently protected against postprandial emptying. The GRTs of the NF forms are much more variable and highly dependent on their size (mean GRT small < medium < large units, p < 0.05). The GRT prolongation obtained with the F forms when compared with the NF ones is hence significantly marked for the small and medium size dosage forms (p < 0.05) but not for the large ones (p > or = 0.05). In supine subjects, a size effect influences the GRT of both the F and NF forms (p < 0.05). The F forms are more often emptied before the NF ones but, size for size, the mean GRTs do not differ in the aggregate. These findings, together with literature data, are used to explain why a number of former investigations have come to contradictory conclusions about the effect of density of an undigestible form on GRT. Uncontrolled factors are hiding from disclosure the GRT enhancement that should be observed when optimized F forms are used within defined conditions.

Gastroretentive dosage forms.

This article begins with a review of gastric emptying, small intestine transit, and colonic transit of drug delivery systems with special attention paid to the different physiological processes involved in stomach emptying and to the cut-off size of nondigestible solids for passage through the gastroduodenal junction during the digestive phase. Then, the proposed means for prolonging the gastric residence time (GRT) of drug delivery systems are reviewed and analyzed with special emphasis on floating (F) dosage forms. The following means are discussed: the use of passage-delaying agents, large single-unit dosage forms, bioadhesive drug delivery systems, "heavy" pellets, and buoyant forms. In the section devoted to bioadhesive forms, the influence of the turnover time of the intestinal mucus gel layer on the performance of mucoadhesive preparations is pointed out to explain the poor results obtained in humans with such peroral products. The use of a specifically designed apparatus for measuring the total force acting vertically on an object immersed in a liquid is presented as a methodology for selecting optimized buoyant formations in vitro. Scintigraphic studies are described in nonfasting human volunteers either in upright or in supine posture, who concurrently were given one optimized F and one nonfloating (NF) hydrophilic matrix capsules of the same size, for three different sizes (small, medium, and large). In upright subjects, the F forms stayed continuously above the gastric contents irrespective of their size, whereas the NF ones sank rapidly after administration and never rose back to the surface thereafter. Consequently, the F forms show prolonged and more reproducible GRTs compared to the NF ones. The significance and extent of this prolongation are the most marked for the small size units (p < 0.001) but gradually lessen as the dosage form size increases (p < 0.05 for the medium size units), to become insignificant for the large size units (p > 0.05). Moreover, there is no significant difference between the mean GRTs of the small, medium, and large F units (p > 0.05). This indirectly confirms that the intragastric buoyancy of the F forms is the main process determining their prolonged GRT and protecting them from random gastric emptying related to antral peristaltism. Thus, their GRT depends mainly on the occurrence of the end point of digestion. To the contrary, the lasting retention of the NF forms in the stomach is only size dependent.(ABSTRACT TRUNCATED AT 400 WORDS)

Intragastric positioning of two concurrently ingested pharmaceutical matrix dosage forms.

A triple nuclide scintigraphic technique is presented for the precise and lasting intragastric monitoring in man of two concurrently ingested hydrophilic matrix pharmaceutical forms. After in vitro testing of various labels, ion exchange resin-coupled 201T1- and 111In-oxinate were selected for their release characteristics. 99mTc-pertechnetate oral solution was used to selectively delineate the stomach. This technique was validated on healthy volunteers. It allowed measurement of the effects on gastric residence time of galenic parameters (size, density of matrices), as well as of physiological parameters such as subject posture.

Suppositories formulation and drug release.

This paper is concentrated on those suppositories where the drug substance is in suspension in a fatty vehicle. The drug release from such a dosage form can be divided in five stages, namely: melting of the suppository; spreading of the melted mass; sedimentation of the drug particles; passage of the solid particles through the oil/water interface; dissolution of the drug particles in the rectal aqueous fluid. The different factors involved in each stage are briefly reviewed for a better understanding of the influence of the formulation parameters on the drug release from fatty suppositories. A special attention is paid on the possible use of drug-PVP coevaporates to facilitate the passage through the oil/water interface and/or the dissolution in the rectal aqueous fluid when one or both of these processes have been identified as being the limiting steps of the drug release. Finally, the most recent works on the rectal absorption promoter such as enamines, sodium salicylate and related compounds, surfactants and mixed micelles are summarized.

[Research and development of oral controlled-release dosage forms]. / Recherche et développement de formes orales à libération contrôlée.

Important data concerning the gastrointestinal transit of oral solid dosage forms have been obtained recently by using the technique of gamma scintigraphy. It is now possible to put forward the principal limitations of the oral sustained release dosage forms actually available. The research and development of new controlled release products such as buoyant dosage forms and coevaporates with polymers should permit to decrease the large inter and intrasubject variations of drug plasma levels observed when the actual sustained release dosage forms are administered.