[Effect of the microencapsulation process parameters piroxicam by complex coacervation]. / Effet des paramètres du procédé de microencapsulation du piroxicam par coacervation complexe.

INTRODUCTION: The gelatin-acacia system is used for the microencapsulation of piroxicam by complex coacervation. MATERIALS AND METHODS: The effect of some formulation parameters and process, namely the ratio of gelatin/gum acacia, core/wall ratio, concentration of crosslinking agent and crosslinking time are studied. The microcapsules properties are evaluated. RESULTS: The results showed that the microcapsules have a spherical shape, a coacervation efficiency greater than 70%, an average diameter less than 250 microns, a good stability and finally, the better values are obtained for gelatin/acacia ratio (5/3), ratio core/wall (1/4), an amount of 2 mL of crosslinking agent and a crosslinking time of 60 minutes.

[Fecal microbiota transplantation in recurrent Clostridium difficile infections. Framework and pharmaceutical preparation aspects]. / Le transfert de microbiote fécal lors d'infections récidivantes à Clostridium difficile. Cadre et aspects pharmacotechniques.

The fecal microbiota transplantation consists in introducing a preparation constituted by a dilution of stools of a healthy donor in the digestive tract of a patient recipient, to restore his intestinal physiological balance. This therapeutic approach was the subject of numerous studies showing its efficiency in the treatment of the recurrent infections with Clostridium difficile. The fecal microbiota transplantation has now a high level of clinical evidence, which explains that it appears in various international recommendations. In France, the fecal microbiota transplantation responds to the definition of a medication and can be executed as a pharmaceutical preparation or as an experimental drug for clinical trials under the responsibility of a hospital pharmacy. The objective of this paper is to propose a definition of a framework and to describe the methods of preparation of the fecal microbiota transplantation in the treatment of the recurrent infections with C. difficile and the interactions to consider for hospital pharmacies that do not have technical means to operate this technique.

[Preparation of citrulline microspheres by spray drying technique for colonic targeting]. / Préparation des microsphères de citrulline à ciblage colique par la technique de spray drying.

INTRODUCTION: Citrulline is an amino acid that becomes essential in situations of intestinal insufficiency such as short bowel syndrome. It is therefore interesting to provide the patients with dosage forms for routing citrulline to the colon. The aim of this work is to formulate microspheres of citrulline for colonic targeting by the technique of spray drying. MATERIAL AND METHODS: Eudragit(®) FS 30D was selected as polymer to encapsulate citrulline using the spray drying technique. Citrulline and Eudragit(®) FS 30D were dissolved in water and ethanol, respectively. The aqueous and the ethanolic solutions were then mixed in 1:2 (v/v) ratio. Microspheres were obtained by nebulizing the citrulline-Eudragit(®) FS 30D solution using a Mini spray dryer equipped with a 0.7mm nozzle. The microspheres have been formulated using citrulline and Eudragit(®) FS 30D. The size distribution of microspheres was determined by light diffraction. The morphology of the microspheres was studied by electron microscopy. Manufacturing yields, encapsulation rate and dissolution profiles were also studied. RESULTS AND DISCUSSION: The microspheres obtained had a spherical shape with a smooth surface and a homogeneous size except for the microspheres containing the highest concentration of polymer (90 %). The formulation showed that the size and morphology of the microspheres are influenced by the polymer concentration. Manufacturing yields were about 51 % but encapsulation rate were always very high (above 90 %). The in vitro dissolution study showed that the use of the Eudragit(®) FS 30D under these conditions is not appropriate to change the dissolution profile of the citrulline. CONCLUSION: This technique has led to the formulation of microspheres with good physical properties in terms of morphology and size. The compression of the microspheres should help to control citrulline release for colonic targeting.

[Solutions for organ preservation and other cardioplegic liquid formulations. Role of the hospital pharmacist]. / Solutions pour conservation d'organes et pour cardioplégie. Le rôle du pharmacien hospitalier.

Solid organ transplantation is an increasing need and a well-established activity which requires maintaining the quality of the transplant from procurement through the entire, storage, transport and graft procedure. Solutions for organ preservation play a key role in this procedure, by minimizing the deleterious effects of both ischemia and reperfusion. As such, their qualitative and quantitative compositions have to be optimized and validated. The development strategy and formulations proposed for these solutions are analyzed in this review as well as the results of the clinical studies which have set up the relevant pharmacological and physicochemical criteria. The French regulatory status of these products is also discussed. A clear distinction has to be made between solutions for organ preservation which are classified as produits thérapeutiques annexes (therapeutic ancillary products) and cardioplegic liquid formulations which are considered as medicinal products and are subject to marketing approval. Finally, the roles of the hospital pharmacist in the evaluation, selection, purchase and proper use of these products are described.

Release of a macromolecular drug from alginate-impregnated microspheres.

Macroporous microspheres were impregnated with calcium alginate to encapsulate fluorescein isothiocyanate-labeled dextran (FITC-dextran) and control its release. The detailed study of the impregnation process lead to its optimization: the quantity of alginate in the impregnated microspheres and the FITC-dextran encapsulation efficiency were increased. FITC-dextran diffused out of the impregnated microspheres in a slow rate in deionised water, while in presence of sodium ions, its release rate was increased as a consequence of the progressive swelling and erosion of calcium alginate. Release studies from different formulations of impregnated microspheres were performed in a continuous flow apparatus. The release profiles were composed of a slow release phase explained by the progressive erosion of calcium alginate and a faster release phase related to eroded impregnated microspheres. Therefore, the delayed release by microspheres induced by impregnation would permit the delivery of their payload at the vascular occlusion site, limit the amount of drug lost in the systemic circulation and improve the therapy.

Cefazolin serum protein binding and its inhibition by bilirubin, fatty acids and other drugs.

This paper describes the protein binding of cefazolin to human serum and to human serum albumin (HSA) using equilibrium dialysis. The drug is exclusively bound to HSA with a moderate affinity, Ka = 16,600 +/- 1600 M-1, and one saturable binding site, n = 0.73 +/- 0.02. Moreover cefazolin shows a dose-dependent binding leading a possible increase of the free fraction (when its total concentration increases). This antibiotic is displaced by free fatty acids (FFA) and bilirubin. Cefazolin binding to human serum and human serum albumin (HSA) was studied in presence of acidic drugs. At low concentrations clofibric acid and phenylbutazone both exhibiting high affinity for HSA displace strongly cefazolin. Valproic and salicylic acids, sulfamethoxazole, cefoperazone which have approximately the same affinity as cefazolin, must be used at higher concentrations to displace this antibiotic. A particular phenomenon was observed with cefazolin on HSA when associated with furosemide. A low concentration (5-25 microM) of this drug induces a positive cooperativity of binding between cefazolin and HSA. But at a molar ratio of furosemide to albumin greater than one, such cooperative interaction disappears and a competitive inhibition of cefazolin binding occurs. For all drugs studied, a competitive inhibition was found except for tryptophan. Finally, it is concluded that cefazolin shares the warfarin binding site on HSA.

Could oral erythromycin optimize high energy continuous enteral nutrition?

BACKGROUND: Intravenous erythromycin has previously been reported to stimulate gastric emptying, to inhibit gastric acid secretion and to stimulate pancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers. AIM: The aim of this study was to evaluate the effects of oral erythromycin (160 mg/h) on gastrointestinal function under these conditions in seven healthy subjects. METHOD: This randomized double-blind cross-over study measured the gastric emptying rate of nutrients, gastric acid secretion, gastric pH, jejunal flow rate as well as biliopancreatic secretion and duodeno-caecal transit time during a 19.9 kJ/min continuous infusion of a nutrient solution (4.18 kJ/mL) in the antrum over a 6-h period by a perfusion method. RESULTS: The nutrition was well tolerated except by one subject with placebo perfusion. During the 6-period, total gastric volume and gastric volume of nutrient decreased during erythromycin administration by 22 +/- 8 and 22 +/- 6%, respectively. Gastric acid secretion was not modified by erythromycin. Lipase and bile salt outputs were significantly higher with erythromycin. The duodeno-caecal transit time was not statistically different with drug and placebo (169 +/- 15 and 146 +/- 19 min, respectively). CONCLUSION: During continuous gastric infusion of a liquid diet, the effect of oral erythromycin on gastric emptying could be useful to optimize cyclic enteral nutrition or to enhance the tolerance of enteral nutrition.

Indomethacin release from ion-exchange microspheres: impregnation with alginate reduces release rate.

Ion-exchange microspheres (MS) designed as a drug delivery system for embolization coupling ability to occlude vessels and chemotherapy were used to evaluate a manufacturing process allowing to control the drug release rate through reduction of diffusion rate of the drug within the particle by impregnation of calcium alginate inside the porous MS. Impregnation was performed by diffusion of sodium alginate inside DEAE-Trisacryl(R) MS, dispersion of the MS in deionised water and gelling alginate by adding CaCl(2) to the dispersed MS. Studied parameters were alginate concentration, alginate diffusion time and calcium concentration. Indomethacin was loaded into the MS by eluting an aqueous indomethacin solution through a chromatographic column packed with impregnated MS. Indomethacin loading was reduced by alginate. Swelling studies showed indomethacin loading enhanced the hydrophobicity of MS while impregnation had no effect. This had an incidence on indomethacin release rate, which was assessed using the rapid elution of PBS through loaded impregnated MS packed in a column. Indomethacin loading reduced its own rate of release. MS impregnated with 2% w/v alginate gelled with a 40 mM calcium solution presented the lower release rate. This work indicated the manufacturing conditions to display a calcium alginate matrix effect on indomethacin release from DEAE-Trisacryl MS.

Effects of erythromycin on gastric emptying, duodeno-caecal transit time, gastric and biliopancreatic secretion during continuous gastric infusion of a liquid diet in healthy volunteers.

OBJECTIVE: Erythromycin, a macrolide antibiotic, has been reported to increase gastric emptying. The aim of this study was to evaluate the effects of intravenous erythromycin (150 mg/h) on gastric emptying, small intestinal transit time, gastric and biliopancreatic secretions during gastric infusion of a liquid diet in healthy volunteers. DESIGN: A randomized double-blind crossover study (erythromycin versus placebo). METHODS: Gastric emptying rates of nutrients, gastric acid secretion, gastric pH, jejunal flow rates, as well as biliopancreatic secretions and duodeno-caecal transit time, were evaluated during a continuous infusion at 4.5 kcal/min of a nutrient solution (1 kcal/ml) in the antrum, over a 6 h period, by a perfusion method. RESULTS: During the 6 h period, total gastric volume and gastric acid secretion decreased during erythromycin administration of 37 and 22%, respectively (area under the curves). Lipase outputs were significantly higher with erythromycin than placebo. Bile salt output was not significantly different between erythromycin and placebo. Duodeno-caecal transit time increased significantly during erythromycin infusion compared with placebo (191 +/- 12 versus 159 +/- 17 min; P < 0.05). CONCLUSION: During continuous gastric infusion of a liquid diet, intravenous erythromycin has a powerful effect on gastrointestinal function. The motor and secretory effects may enhance the tolerance and the efficiency of enteral nutrition in humans.

Systemic morphine pharmacokinetics after ocular administration.

Pharmacokinetics of a single dose of morphine ocularly applied is reported in rabbits before and after lacrimal canaliculi ligature. Our investigations are based on a sensitive reversed-phase ion-pair chromatographic determination of morphine. This study describes the various resorption sites of morphine when administered through the conjunctiva. After ocular administration, morphine rapidly reaches high blood levels compatible with pharmacological activity. Ocular bioavailability of morphine is higher than after non-parenteral routes. Canaliculi ligature modifies the morphine pharmacokinetic profile without significant modification of drug bioavailability. Our results suggest a great capacity of drug resorption for the conjunctiva, and indicate the major role of nasal mucosa in physiological conditions.

Microencapsulation of lipophilic drugs in chitosan-coated alginate microspheres.

Chitosan-coated alginate microspheres containing a lipophilic marker dissolved in an edible oil, were prepared by emulsification/internal gelation and the potential use as an oral controlled release system investigated. Microsphere formation involved dispersing a lipophilic marker dissolved in soybean oil into an alginate solution containing insoluble calcium carbonate microcrystals. The dispersion was then emulsified in silicone oil to form an O/W/O multiple phase emulsion. Addition of an oil soluble acid released calcium from carbonate complex for gelation of the alginate. Chitosan was then applied as a membrane coat to increase the mechanical strength and stabilize the microspheres in simulated intestinal media. Parameters studied included encapsulation yield, alginate concentration, chitosan molecular weight and membrane formation time. Mean diameters ranging from 500 to 800 micron and encapsulation yields ranging from 60 to 80% were obtained. Minimal marker release was observed under simulated gastric conditions, and rapid release was triggered by transfer into simulated intestinal fluid. Higher overall levels of release were obtained with uncoated microspheres, possibly due to binding of marker to the chitosan membrane coat. However the slower rate of release from coated microspheres was felt better suited as a delivery vehicle for oil soluble drugs.

Gastrointestinal transit of pellets in rats: effect of size and density.

Gastrointestinal distribution kinetics of a large amount (0.5-1 g) of three types of non-disintegrating pellets which had the same size (S1, 710-1000 micrometers) but different densities (D1, 0.9 and D2, 1.5 g cm-3), or which had the same density (D1) but different diameters (S1 and S2, 1250-1600 micrometers) were examined in fed rats. The percentage of pellets remaining in the stomach, small gut, caecum and colon was measured at suitable intervals. Whatever the size of the pellets, the heavier the density, the longer the gastric emptying (2.1 h for D2-S1 instead of 1.3 h for D1-S1 and 0.7 h for D1-S2). The small gut transit time was not influenced by density but was slightly prolonged by size: 3.3 h for D1-S2 instead of 2.6 h for D1-S1 and D2-S1. Conversely, the gastrocolonic transit time was widely influenced by density (13.5 h for D2-S1) and somewhat by size (8.2 h for D1-S2 and 4.5 h for D1-S1). This delays were proportional to caecal residence time in the large, sacculated and derivated caecum of rats. In order to use the rat as an experimental model for pharmaceutical pellets, those results should have implication for the design of dosage forms, particularly those for controlled or timed release or those for targeted release at specific positions in the gastrointestinal tract.

Micronization: a method of improving the bioavailability of poorly soluble drugs.

For poorly soluble drugs, the digestive absorption depends on their rate of dissolution. Decreasing the particle size of these drugs improves their rate of dissolution. Fine grinding mills are use to micronize powders: either jar mills or fluid energy mills. Theses processes were applied to griseofulvin, progesterone, spironolactone and diosmin. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy.

Colonic delivery of sodium butyrate via oral route: acrylic coating design of pellets and in vivo evaluation in rats.

Few pharmaceutical studies, with the exception of those on rectal solutions, are described on short chain fatty acid (SCFA) formulations-especially for sodium butyrate, which is a colonocyte preferential substrate. Highly dosed butyrate pellets (90%) were prepared and their coating was designed for colonic delivery. In vivo determination (pH and transit time of pellets in rats) allowed to respectively choose the grade and thickness (resistance of 6 h) of the pH-dependent coating (Eudragi L+S, 1:1). The coated pellets were administered to naturally butyrate-deprived rats. The rats' colonic mucosa had the particularity to weakly express mitochondrial HMG-CoA synthase, an enzyme that responds to luminal butyrate. The results did not show early absorption of butyrate, but a probable cecal loss in the rat cecum as cecal residence time of the pellets was important and as pH was propitious for the coating hydrolysis. It seemed that butyrate, given daily for 7 days without the other main SCFA. was unable to induce the enzyme and/or that the dose (0.32 mmol/day) was insufficient.

Study of the gastrointestinal diffusion system (GDS): influence of acacia gum on mechanical and chemical properties in free cellulose acetate films.

In this work a study of free cellulose acetate films was carried out in the presence and absence of acacia gum at high concentrations (50 and 75%). The mechanical toughness and the aspect were influenced by operatory conditions and by the relative air humidity. The increase of relative humidity from about 0% to 75% decreased the mechanical toughness and the color film changed from a clear to opaque white. The presence of acacia gum decreased the mechanical toughness and the water vapour transmission rate and increased the film water solubility.

[Rheology and extensiometry of ophthalmic preparations with a vegetable oil base]. / Rhéologie et extensométrie de préparations ophthalmiques à base d'huiles végétales.

The physical characteristics of ophthalmic preparations based on vegetable oils destined for hot climates was studied in part by determining their rheological properties and also by measuring their extensibility. The results obtained showed that the thixotropy of the formulations studied was a favorable property which would permit their uniform application to the surface of the eye.

Binding of cefalotin to human serum albumin.

Binding of cefalotin to human serum albumin was studied in vitro by equilibrium dialysis and the quantitative measurement of cefalotin was made by fluorimetric assay. The binding rate of cefalotin to human serum albumin found to be 61,1%. The determination of drug binding parameters showed a large number of binding sites (n = 9.36) and a moderate affinity (K = 3898 M-1).

[Resumption of function of the liver graft. Controlled comparative study of UW solution and SLF Cochin]. / Reprise de fonction du greffon hépatique. Etude contrôlée comparant la solution UW et le SLF Cochin.

Nowadays the UW solution is usually used in liver transplantation for graft preservation. The importance of each of its components has not been fully resolved. The omission of some of the components does not result in poor hepatic function. The aim of this controlled study was to assess the early graft function (ALAT, factor V and total bilirubin at days 1, 2, 3 and 6) after use of the UW solution and SLF Cochin. SLF Cochin is a modified UW solution without hydroxyethyl starch, adenosine, penicillin, dexamethazone and allopurinol. No significant difference was observed in the early graft function between the two solutions for a cold ischemia time below 15 hours. Considering the qualities of the SLF Cochin and its three fold lower cost, it is concluded that the use of the SLF Cochin solution is justified for liver transplantation in which foreseeable cold ischemia time is less than 15 hours.

[Correction of selenium deficiency in patients with renal failure undergoing hemodialysis]. / Correction du déficit en sélénium chez des insuffisants rénaux hémodialysés.

Plasma selenium levels (p Se) as well as glutathione peroxidase activity in plasma (p GPx) and in erythrocytes (e GPx) were measured in 39 haemodialysis patients. Glutathione peroxidase is a selenium-dependent enzyme which protects cells against oxidation. The mean level values obtained were significantly lower in patients than in controls: p Se: 38 +/- 14 versus 88 +/- 17 micrograms/l; p GPx: 15 +/- 32 versus 334 +/- 41 IU/l; e GPx: 19 +/- 4 versus 26 +/- 4 IU/g Hb. These values were found to correlate significantly with the duration of dialysis and with the type of membrane utilized. The total muscular mass was significantly smaller in patients with the lowest p Se or p GPx values. At echocardiography, septal hypertrophy correlated with both p Se and p GPx. Twenty patients were supplemented with sodium selenite administered orally at the end of each haemodialysis session during 6 months. After this period, muscular mass and septal hypertrophy were decreased and the echocardiographic contractility parameters were improved, albeit not significantly.

[Packaging: the guarantee of medicinal quality]. / Le conditionnement garant de la qualité du médicament.

Primary packaging guarantees the pharmaceutical quality of the medicinal preparation received by the patient. Glass bottles containing parenteral solutions for example ensure that sterility, quality and optimal stability are preserved until administration. Recent innovations in materials research has lead to improvements in parenteral infusions. Multicompartmental bags, allowing extemporaneous mixtures without opening the container, constitute an extremely beneficial advance for the patient, allowing administration of mixtures with solutions and emulsions which would be unstable if stored. Metered dose pressurized inhalers are an excellent example of drug administration devices designed specifically to ensure quality and bioavailability. These examples illustrate the important role of primary packaging and demonstrate the usefulness of research and development in this area.