International Journal of Pharmaceutics (v.269, #2)

SolEmuls®—novel technology for the formulation of i.v. emulsions with poorly soluble drugs by R.H Müller; S Schmidt; I Buttle; A Akkar; J Schmitt; S Brömer (293-302).
Intravenously injectable o/w emulsions of drugs being poorly soluble in water and simultaneously in oils need to be produced by locating the drug in the interfacial lecithin layer, e.g. amphotericin B. For achieving this, up to now organic solvents were required. The objective was to develop a solvent-free production method for such emulsions. Drug and the pre-formed parenteral emulsion Lipofundin® were mixed and subjected to high pressure homogenisation. Drug powder and emulsions were characterised regarding size and physical stability by photon correlation spectroscopy (PCS), laser diffractometry (LD) and zeta potential measurements. Drug incorporation was studied using light microscopy, electron microscopy (EM) and a centrifugation test to separate non-dissolved drug. Amphotericin B and carbamazepine were used as model drugs. The high streaming velocities lead to accelerated drug dissolution and partitioning into the interfacial layer (so-called “solubilisation by emulsification”, SolEmuls® Technology). The interfacial layer could incorporate (solubilise) a certain amount of drug, revealed by EM pictures. Exceeding this concentration, hybrid dispersions were formed consisting of drug-loaded oil droplets and drug nanocrystals of similar size (approximately 200 nm).Both dispersion types are i.v. injectable opening the opportunity to deliver the drug in a concentrated form at desired low injection volume, e.g. 10 mg/ml.
Keywords: Amphotericin B; Carbamazepine; Emulsion; High pressure homogenisation; SolEmuls®;

In vitro evaluation of intestinal absorption of desmopressin using drug-delivery systems based on superporous hydrogels by Assadang Polnok; J.Coos Verhoef; Gerrit Borchard; Narong Sarisuta; Hans E. Junginger (303-310).
The aim of this study was to investigate and modify the potential of drug-delivery systems based on superporous hydrogel (SPH) for improving the intestinal transport of the peptide drug desmopressin in vitro. The swelling properties and mechanical strength of SPHs were studied. The release profile of desmopressin was investigated by changing the composition of excipients in the formulations. Subsequently, the ability of the SPH-based drug-delivery systems to enhance the transport of desmopressin across porcine intestine was performed in vitro. The swelling properties and mechanical strength of SPHs were affected by the addition of the disintregrant AcDiSol®. This disintregrant reduced the swelling ratio to 10% and the time to 80% swelling was retarded by 3–5 min in comparison to the negative control. AcDiSol® increased the mechanical strength, according to the increasing of penetration pressure value, the pressure that the punch can penetrate the gel, of the SPHs. The transport of desmopressin across the intestinal mucosa in vitro was enhanced four- and six-fold by applying SPH, with AcDiSol®, in the absence and presence of the additional absorption enhancer trimethyl chitosan chloride, respectively, in comparison to the negative control. It is concluded that drug-delivery systems based on SPHs are promising for enhancing the intestinal absorption of desmopressin.
Keywords: Desmopressin; Superporous hydrogels; Trimethyl chitosan chloride; Intestinal absorption in vitro; Absorption enhancers;

Targeting of the central nervous system by direct drug transport from the nose to the brain has gained increased attention through the last decade. In the present study, a model for olfactory drug absorption has been investigated using intravenous and unilateral nasal administration of lidocaine hydrochloride in rats. To investigate the possible drug delivery aspects of this route of transport to a central part of the brain a microdialysis model using in vivo recovery by calibrator was applied to the systemic blood and to right and left striatum. The integrity of the blood–brain barrier was evaluated following microdialysis probe implantation. The in vivo experiments were carried out as a cross-over study in rats. The drainage from the nasal cavity was not restricted by occlusion. It was found that true unbound lidocaine concentrations could be calculated from in vivo recovery measurements of retrodialysis of prilocaine hydrochloride. The relative in vivo recoveries in striatum (11.3%) and blood (24.0%) were significantly lower than in vitro (31.3 and 44.9%). The blood–brain barrier was found to retain its physical integrity when evaluated one hour after probe implantation. From pharmacokinetic modelling of the time–concentration curves it was found that the absorption rates and area under the curve (AUC) values of lidocaine in left and right striatum were not statistically different following nasal and intravenous administration, respectively. The average nasal bioavailabilities of lidocaine in blood, left and right striatum were 85, 103 and 129%, respectively. It was concluded that no significant olfactory absorption to striatum was evident in the present study. However, the method should be applicable to studies of drug delivery to blood and brain following nasal administration of other drugs.
Keywords: Olfactory pathway; Nasal drug delivery; Microdialysis; Pharmacokinetics; Blood–brain barrier integrity; Lidocaine; Rats;

The purpose of the present study was to compare Franz cells (FC) and microdialysis (MD) for monitoring the skin absorption of salicylic acid (SA). The influence of pH on SA flux was also assessed by these two techniques.Excised abdominal human skin was used in the experiments. SA was dissolved in phosphate buffer solutions of pH 2, 5 and 7 (2 mg/ml). SA concentrations in the receptor FC solutions and in MD samples were assessed by high performance liquid chromatography (HPLC).The results demonstrate that the flux of SA decreased with increased pH. The profiles permeation determined by Franz cells and microdialysis were similar. However, whatever the pH, the SA flux was higher with microdialysis than with Franz cells.The results showed that SA percutaneous permeation conformed to the pH partition hypothesis. The flux of SA was different when it was determined by the two techniques. The collect of SA, by these two techniques is different. The results of the two techniques are compared and discussed.
Keywords: Skin permeation; Franz cells; Microdialysis; Salicylic acid; Human skin; pH partition;

Pellets of a wide range of mechanical properties were produced by the process of extrusion and spheronisation using various formulation factors. A range of mechanical properties from a simple fracture load to detailed load/displacement curves obtained when pellets were subjected to diametral compression test and a bed of pellets was compacted, were used to provide measure of tensile strength, deformability, linear strain, elastic modulus, yield and shear strength. Such conventional techniques resulted in irreversible damage to the structure of the pellets and were unable to establish the viscoelastic properties of the pellets. The application of the dynamic mechanical analysis (DMA), however, allowed the determination of (1) an accurate Young’s modulus of elasticity, which was found to be between 8.4 and 24-fold higher than that determined from the diametral compression test, (2) the presence of a reversible elastic deformation even after the yield point in terms of storage modulus and (3) a change in the values of the phase angle, which illustrates the increase in viscoelasticity of the pellets formed with ethanol, glyceryl monostearate (GMS) or glycerol, while a decrease in viscoelasticity with the incorporation of lactose into the microcrystalline cellulose (MCC) pellets. This work further demonstrated that the only feasible technique for determining the elastic and plastic deformability of the pellets is the one which subjects the specimen to stress/relaxation cycles and can determine the dissipated energy in terms of loss modulus or phase angle, and that is DMA.
Keywords: Dynamic mechanical analysis (DMA); Extrusion and spheronisation; Mechanical properties; Pellets;

Polymers–gamma ray interaction. Effects of gamma irradiation on modified release drug delivery systems for oral administration by L Maggi; L Segale; E Ochoa Machiste; A Faucitano; A Buttafava; U Conte (343-351).
The aim of this work is to verify the efficiency of two kinds of matrix tablets formulations containing PEO or PVA as retarding polymer. Moreover, since in the last years the exposure to ionizing radiation is a more and more used method to reduce bacterial charge in pharmaceutical products, the effects of gamma irradiation on these two kinds of polymers has been evaluated. The study is performed on matrix tablets containing diltiazem HCl, as model drug, and polyethylene oxides (PEO) of two different molecular weights or polyvinylalchool (PVA) of medium degree of hydrolysis, as drug release modulators. Dissolution of the matrices, release of diltiazem and morphological behaviour of the samples, before and after exposure to increasing doses of gamma irradiation, are investigated in order to verify their stability.The results show that the ionizing radiation does not modify significantly the dissolution trend of the PVA samples; on the contrary, the dissolution and the morphological behaviour of the PEO matrices is strongly affected by the radiation dose received. In particular, the dissolution rate of the irradiated PEO tablets dramatically increases as a function of the irradiation dose and the swelling process, which characterised the non-irradiated PEO samples, was replaced by a rapid erosion process responsible for the quickly dissolution of the matrices. The changes of the dissolution and morphological PEO tablets performances could be explained by a breaking of the polymeric chains (shown by EPR studies) as a consequence of the exposure to gamma rays. These chemical–structural modifications of the polymers are responsible for the reduced efficacy of the PEO systems in controlling the drug release rate.
Keywords: Polyethylene oxide; Polyvinylalcohol; Controlled drug release; Matrix tablets; Gamma irradiation;

A simple computational method for calculating dielectric constants of solvent mixtures based on Redlich-Kister extension was proposed. The model was applied to the experimental dielectric constant of binary and ternary solvent mixtures at fixed and/or various temperatures and showed accurate results. Overall average percentage deviation (OAPD) between calculated and experimental dielectric constants was calculated as an accuracy criterion. The OAPDs for correlative and predictive analyses of dielectric constants in binary solvents at a fixed temperature were 0.56 and 1.42%, respectively. The corresponding values for binary solvents at different temperatures were 1.29 and 1.92%, respectively. The OAPDs for correlative and predictive analyses of dielectric constants of a nonaqueous ternary solvent mixture at various temperatures were 1.61 and 3.05%. The accuracy of the proposed models has also been compared with those of previously published models and results showed that the proposed models were superior and capable of providing more accurate results.
Keywords: Dielectric constants; Mixed solvents; Mathematical model; Prediction;

An investigation of calibration methods for solution calorimetry by Barbara T.S. Yff; Paul G. Royall; Marc B. Brown; Gary P. Martin (361-372).
Solution calorimetry has been used in a number of varying applications within pharmaceutical research as a technique for the physical characterisation of pharmaceutical materials, such as quantifying small degrees of amorphous content, identifying polymorphs and investigating interactions between drugs and carbohydrates or proteins and carbohydrates. A calibration test procedure is necessary to validate the instrumentation; a few of the suggested calibration reactions are the enthalpies of solution associated with dissolving Tris in 0.1 M HCl or NaCl, KCl or propan-1-ol in water. In addition, there are a number of different methods available to determine enthalpies of solution from the experimental data provided by the calorimeter, for example, the Regnault–Pfaundler’s method, a graphical extrapolation based on the Dickinson method, or a manual integration-based method. Thus, the aim of the study was to investigate how each of these methods influences the values for the enthalpy of solution. Experiments were performed according to the method outlined by Hogan and Buckton [Int. J. Pharm. 207 (2000) 57] using KCl (samples of 50, 100 and 200 mg), Tris and sucrose as calibrants. For all three materials the manual integration method was found to be the most consistent with the KCl in water (sample mass of 200 mg) being the most precise. Thus, this method is recommended for the validation of solution calorimeters.
Keywords: Solution calorimetry; Calibrations; Potassium chloride; Sucrose;

Development of a perillyl alcohol topical cream formulation by Abhishek Gupta; Paul B. Myrdal (373-383).
Perillyl alcohol (POH) is a relatively non-toxic agent that has been shown to be a promising anticancer monoterpene in preclinical models. Studies have indicated that topical application of POH may prove to be effective as a skin cancer chemoprevention therapy. The main aim of this study was to determine the influence of several factors on the stability of POH in solution and develop a topical formulation of POH. During preformulation, the influence of pH, temperature, ionic strength, and organic solvents, on the stability of POH was evaluated at four different temperatures: 4, 25, 37, and 48 °C. POH was found to degrade under acidic conditions with degradation following apparent first-order kinetics. A hydrophilic topical cream formulation of POH was developed and prepared for toxicology and clinical studies. A reverse phase gradient HPLC method was developed to quantitate POH in the complex formulation. Stability studies of the formulation and a placebo were performed and the formulation was found to be physically and chemically stable over a period of 1 year at 4 and 25 °C.
Keywords: Perillyl alcohol; Stability; Topical cream formulation; Reverse phase HPLC assay;

Evaluation of the vibratory feeder method for assessment of powder flow properties by Shobha N. Bhattachar; David B. Hedden; Angela M. Olsofsky; Xianggui Qu; Wen-Yaw Hsieh; Kelly G. Canter (385-392).
The flow properties of pharmaceutical powders and blends used in solid oral dosage forms are an important consideration during dosage form development. The vibratory feeder method, a flow measurement technique that quantifies avalanche flow, has been adapted for measurement of the flow properties of common pharmaceutical powders used in solid oral dosage forms. The flow properties of 17 different powders were measured with the instrument, and the results are reported as a powder flow index (PFI). The PFI trends of the powders correlate well with flow properties reported in the literature. The flow properties of the powders were also measured with a commercially available avalanche instrument, the Aero-Flow™, and the results were reported as the mean time to avalanche (MTA). Since the two instruments analyze the avalanche by different algorithms, the results were compared with nonparametric statistical evaluation of ranked data, and they were found to be in excellent agreement. A recommended procedure for measurement of powder flow with the vibratory feeder is presented.
Keywords: Powder flow; Powder avalanche; Vibratory feeder;

Film coating as a method to enhance the preparation of tablets from dimenhydrinate crystals by János Bajdik; Klára Pintye-Hódi; Odon Planinšek; Géza Regdon; Rok Dreu; Stane Srčič; István Erős (393-401).
Crystals of dimenhydrinate as a model drug were used for crystal coating, a method that can be applied to increase the flowability of a material and facilitate the tablet making. An increase in particle size was observed during the film coating. The change in shape of the coated particles was also examined. Some physicochemical parameters changed during coating, e.g. the surface free energy parameters and the wetting of the samples. The amount of coating material (and therefore the coating time) influenced several parameters (the shape of the particles, the flow properties and surface free energy parameters, compressibility and compactibility). Several parameters of prepared tablet (porosity, breaking hardness) were examined. Accordingly, coating of the crystals can be performed in order to enhance the handling of a material with insufficient properties for tablet making.
Keywords: Crystal coating; Dimenhydrinate; Flowability; HPMC; Surface free energy; Tablet making;

Simulation of roller compaction using a laboratory scale compaction simulator by Andrey V. Zinchuk; Matthew P. Mullarney; Bruno C. Hancock (403-415).
A method for simulation of the roller compaction process using a laboratory scale compaction simulator was developed. The simulation was evaluated using microcrystalline cellulose as model material and ribbon solid fraction and tensile strength as key ribbon properties. When compacted to the same solid fractions, real and simulated ribbons exhibited similar compression behavior and equivalent mechanical properties (tensile strengths). Thus, simulated and real ribbons are expected to result in equivalent granulations. Although the simulation cannot account for some roller compaction aspects (non-homogeneous ribbon density and material bypass) it enables prediction of the effects that critical parameters such as roll speed, pressure and radius have on the properties of ribbons using a fraction of material required by conventional roller compaction equipment. Furthermore, constant ribbon solid fraction and/or tensile strength may be utilized as scale up and transfer factors for the roller compaction process. The improved material efficiency and product transfer methods could enable formulation of tablet dosage forms earlier in drug product development.
Keywords: Roller compaction; Simulation; Microcrystalline cellulose; Solid fraction; Tensile strength;

Preparation and physicochemical properties of niclosamide anhydrate and two monohydrates by Elsa C. van Tonder; Tshoane S.P. Maleka; Wilna Liebenberg; Mingna Song; Dale Eric Wurster; Melgardt M. de Villiers (417-432).
The intent of the study was to prepare and characterize three crystal forms of niclosamide namely the anhydrate and the two monohydrates and to investigate the moisture adsorption and desorption behavior of these crystal forms. The crystal forms were prepared by recrystallization and were characterized by differential scanning calorimetry, thermogravimetric analysis, isoperibol solution calorimetry, Karl Fischer titration, and X-ray powder diffractometry. Moisture adsorption by the anhydrate at increased relative humidities and two temperatures, 30 and 40 °C, was measured while the desorption from the monohydrates was determined at 45, 55, and 65 °C for monohydrate HA and 75, 90, and 100 °C for monohydrate HB. Thermal analysis and solution calorimetry showed that monohydrate HB is more stable than monohydrate HA and solubility measurements showed the solubility of the crystal forms decreased in the order: anhydrate⪢monohydrate HA>monohydrate HB. With an increase in temperature and relative humidity niclosamide anhydrate adsorbed moisture to form monohydrate HA by a random nucleation process. Dehydration of monohydrate HA at increased temperatures followed zero order kinetics and resulted in a change to the anhydrate. Monohydrate HB was transformed to the anhydrate at higher temperatures by a three-dimensional diffusion mechanism.
Keywords: Niclosamide; Hydrates; Solubility; Moisture adsorption; Transformation; Stability;

Moisture sorption by cellulose powders of varying crystallinity by Albert Mihranyan; Assumpcio Piñas Llagostera; Richard Karmhag; Maria Strømme; Ragnar Ek (433-442).
Moisture in microcrystalline cellulose may cause stability problems for moisture sensitive drugs. The aim of this study was to investigate the influence of crystallinity and surface area on the uptake of moisture in cellulose powders. Powders of varying crystallinity were manufactured, and the uptake of moisture was investigated at different relative humidities. The structure of the cellulose powders was characterized by X-ray diffraction, BET surface area analysis, and scanning electron microscopy. Moisture uptake was directly related to the cellulose crystallinity and pore volume: Cellulose powders with higher crystallinity showed lower moisture uptake at relative humidities below 75%, while at higher humidities the moisture uptake could be associated with filling of the large pore volume of the cellulose powder of highest crystallinity. In conclusion, the structure of cellulose should be thoroughly considered when manufacturing low moisture grades of MCC.
Keywords: Microcrystalline cellulose; Algae cellulose; Moisture sorption; Cellulose structure;

Effects of plasma irradiation on the wettability and dissolution of compacts of griseofulvin by A. Naseem; C.J. Olliff; L.G. Martini; A.W. Lloyd (443-450).
In this study, the use of plasma irradiation was investigated as a possible technique for increasing the dissolution rate of the poorly soluble drug griseofulvin. Plasma is a partially ionised gas consisting of ions, electrons and neutral species. Oxygen plasma was used to treat griseofulvin compacts as this would lead to the formation of oxygen containing functional groups on the surface of the compact thus increasing the wettability. Compacts containing 300 mg of the drug were prepared using a stainless steel punch and die assembly and plasma treated. The effect of the length and power of the plasma treatment upon the dissolution rate of griseofulvin was investigated. Dissolution experiments of griseofulvin were carried out using the paddle method using 0.1 M HCl and 0.1 M HCl with 2% sodium dodecyl sulphate (SDS) as the dissolution media. The wettability was assessed by contact angle measurements using the sessile drop technique with the contact angle being measured every second for a period of ten seconds using pure water (to European Pharmacopoeia standards). Plasma treated and untreated samples were also analysed by scanning electron microscopy. Although plasma treatment was found to increase the wettability of griseofulvin it was not found to increase the dissolution rate as the treatment caused surface fusion of the material.
Keywords: Poorly soluble drugs; Dissolution; Wettability; Plasma irradiation;

An in vitro cultured monolayer system of alveolar epithelial cells was used as a model to investigate the transport pathway of the peptides and proteins, salmon calcitonin (sCT), insulin (INS), recombinant hirudin (rHAV2), and recombinant human growth hormone (rhGH), in pulmonary epithelium. Human lung adenocarcinoma A549 cells formed continuous monolayers when grown on the polycarbonate filters of Transwell plates. The transport of the peptides and proteins having MW of 3400–22,000 Da was studied under different conditions. The results showed that the apparent permeability coefficients (P app) of these macromolecules across A549 cell monolayers ranged from 2×10−6 to 5×10−6  cm s−1 and exhibited a good inverse correlation with molecular weight. No concentration, direction, or temperature dependence was observed in the permeation of sCT, INS, and rHAV2. While the P app of rhGH in the BA direction (2.25×10−6  cm s−1) was less than that in the AB direction at both concentrations (3.20×10−6 and 3.29×10−6  cm s−1). The P app values of rhGH were concentration and temperature independent in the AB direction. These findings suggest that the hydrophilic peptides and proteins used in this study, sCT, INS, rHAV2, and rhGH, appear to cross the A549 cell monolayers via a paracellular pathway by a passive diffusion mechanism.
Keywords: Pulmonary absorption; Proteins and peptides; A549;

Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung by Jeffrey O.-H Sham; Yu Zhang; Warren H Finlay; Wilson H Roa; Raimar Löbenberg (457-467).
Spray-drying is a common practice of powder preparation for a wide range of drugs. Spray-dried powders can be used to deliver particles to the lungs via a dry powder inhaler (DPI). The present study investigated the feasibility of developing a platform for aerosol delivery of nanoparticles. Lactose was used as the excipient and spray-dried with two different types of nanoparticles: gelatin and polybutylcyanoacrylate nanoparticles. Results showed that some carrier particles were hollow while others had a continuous matrix. Gelatin nanoparticles were incorporated throughout the matrix and sometimes accumulated at one end of the lactose. Polycyanoacrylate nanoparticles mostly clustered in different spots within the lactose carriers. The mean sizes of both nanoparticle types were characterized at two different times: before they were spray-dried and after they were redissolved from the spray-dried powders. Both nanoparticle types remained in the nano-range size after spray-drying. The mean nanoparticle sizes were increased by approximately 30% after spray-drying, though this increase was statistically significant only for the gelatin nanoparticles. Dispersion of the powder with an in-house passive dry powder inhaler and subsequent cascade impaction measurements showed that incorporation of the nanoparticles did not affect the fine particle fraction (FPF) or mass median aerodynamic diameter (MMAD) of the powders. FPF was approximately 40% while MMAD was 3.0±0.2 μm, indicating the present formulations yield aerosols of a suitable particle size for efficient lung delivery of nanoparticles.The present work demonstrates that nanoparticles can be delivered to the lungs via carrier particles that dissolve after coming in contact with the aqueous environment of the lung epithelium. This opens the way for new drug-targeting strategies using nanoparticles for pulmonary delivery of drugs and diagnostics.
Keywords: Nanoparticle; Pulmonary delivery; Powder inhalation; Spray-drying;

The intercalation of amino acids and some peptides into Mg–Al layered double hydroxide known as hydrotalcite was examined. Although the intercalation by ion-exchange method was unsuccessful, all the amino acids except for Lys and Arg, and peptides examined could be intercalated into the layered double hydroxide by reconstruction method using Mg–Al oxide precursor. The uptake amounts of amino acids and peptides were 0.9–2.7 mmol per 1 g of LDH. Intercalation compounds were examined by using XRD and solid-state NMR. For Gly, Ala, Ser, Thr, Pro, Asn, Gln, Asp, Glu, and aspartame the intercalation accompanied the expansion of interlayer distance of the solid products, whereas the other amino acids and oligoglycine showed no expansion. The intercalation mechanism and release profile in K2CO3 aqueous solution were also investigated. And the cointercalation of amino acids and peptides into Mg–Al LDH and easy release of amino acids from the LDH layer were found.
Keywords: Intercalation; Amino acid; Layered double hydroxide; Hydrotalcite; Solid-state NMR;

Serum aminotransferase activity as a predictor of clearance of drugs metabolized by CYP isoforms in rats with acute hepatic failure induced by carbon tetrachloride by Koichi Yokogawa; Mao Watanabe; Harunori Takeshita; Masaaki Nomura; Yasunari Mano; Ken-ichi Miyamoto (479-489).
The values of serum aminotransferase activity (AST) in untreated rats and rats with acute hepatic failure at 24 h after an oral administration of CCl4 (0.5 ml/kg) were 85±9 IU/l and 4260±620 IU/l (mean±S.D., n=6), respectively. The values of total clearance (CLtot) after intravenous administration of caffeine, tolbutamide, chlorzoxazone or lidocaine (as probe drugs for various CYP isoforms) to CCl4-treated rats were decreased to about 1/8, 1/3, 1/3 or 1/2 compared with those in untreated rats. Good correlations were observed between mRNA expression and enzyme activity of CYP2C11, CYP2E1, CYP3A2 and CYP1A2 in livers of rats given various doses of CCl4. There was also a good negative correlation between serum AST activity and hepatic enzyme activity of each CYP. The serum AST activities corresponding to a 50% decrease of CYP2C 11, CYP2E1, CYP3A2 and CYP1A2 activities were about 710, 780, 1030 and 1300 IU/l, respectively. In conclusion, when the serum AST value in CCl4-treated rats reached about 4000 IU/l, the hepatic CYP activities were one-tenth or less of the control, although the degree of decrease of the CLtot values varied markedly. Nevertheless, the AST value appears to be a promising candidate for an indicator to predict appropriate dose modification of drugs for patients with acute hepatic failure.
Keywords: Cytochrome P450; Metabolic activity; Liver function; Acute hepatic failure; Disposition kinetics;

Poly(ε-caprolactone) and Eudragit® microparticles containing fludrocortisone acetate by Stéphane Gibaud; Najim Jabir Al Awwadi; Camille Ducki; Alain Astier (491-508).
Substitutive hormonal therapies have to be administered for long periods. Thus, the development of sustained-release forms, as microparticle suspensions, is interesting in order to improve patient compliance by reducing dosing frequencies and side effects. The aim of this work was to compare different formulations of fludrocortisone microparticles for the treatment of mineralocorticoid insufficiency. The study was done with different polymers (poly(ε-caprolactone), Eudragit® RS and Eudragit® RL) and different processes (O/W solvent evaporation methods and S/O/W evaporation methods). The use of a suspension of micronized drug in dichloromethane as dispersed phase (S/O/W method) significantly improved the process. Whereas low concentrations of FLU dissolved in the dispersed phase led to smooth-surface homogeneous microparticles and poor incorporation efficiency (5.8–7.3%); suspensions of FLU led to microparticles with numerous crystals on their surfaces (S/O/W microparticles) and high incorporation efficiency (about 79%). However, the best release profiles were obtained with microparticles prepared with 7.5 mg/ml of dichloromethane, near saturation. Moreover, the use of mixtures of poly(ε-caprolactone), Eudragit® RS and RL did not improve the release profiles.
Keywords: Fludrocortisone; Microparticles; Polymer; Sustained release; Polycaprolactone;

Physicochemical properties and mechanism of drug release from ethyl cellulose matrix tablets prepared by direct compression and hot-melt extrusion by Michael M. Crowley; Britta Schroeder; Anke Fredersdorf; Sakae Obara; Mark Talarico; Shawn Kucera; James W. McGinity (509-522).
The objective of this research project was to determine the physicochemical properties and investigate the drug release mechanism from ethyl cellulose (EC) matrix tablets prepared by either direct compression or hot-melt extrusion (HME) of binary mixtures of water soluble drug (guaifenesin) and the polymer. Ethyl cellulose was separated into “fine” or “coarse” particle size fractions corresponding to 325–80 and 80–30 mesh particles, respectively. Tablets containing 30% guaifenesin were prepared at 10, 30, or 50 kN compaction forces and extruded at processing temperatures of 80–90 and 90–110 °C. The drug dissolution and release kinetics were determined and the tablet pore characteristics, tortuosity, thermal properties and surface morphologies were studied using helium pycnometry, mercury porosimetry, differential scanning calorimetry and scanning electron microscopy. The tortuosity was measured directly by a novel technique that allows for the calculation of diffusion coefficients in three experiments. The Higuchi diffusion model, Percolation Theory and Polymer Free Volume Theory were applied to the dissolution data to explain the release properties of drug from the matrix systems. The release rate was shown to be dependent on the ethyl cellulose particle size, compaction force and extrusion temperature.
Keywords: Hot-melt extrusion; Guaifenesin; Ethyl cellulose; Matrix tablets; Higuchi diffusion model; Porosity; Tortuosity; Percolation; Free volume; Sustained release; Mercury porosimetry;

Administration of an insulin powder to the lungs of cynomolgus monkeys using a Penn Century insufflator by C.I. Grainger; R. Alcock; T.G. Gard; A.V. Quirk; G. van Amerongen; R.L. de Swart; J.G. Hardy (523-527).
A powder formulation of live-attenuated measles vaccine is being developed for administration to the lungs. The safety and efficacy of the powder will be assessed by insufflation into cynomolgus monkeys. A Penn Century insufflator has been evaluated for powder dosing to the monkeys using an insulin formulation having similar physicochemical characteristics to the vaccine powder. Insulin pharmacokinetics were compared following dosing by powder insufflation, solution instillation into the trachea and subcutaneous injection. The insulin dosed to the lungs and trachea was more rapidly absorbed than that administered subcutaneously. Insulin bioavailability was greater from the inhaled powder than from the instilled solution. The findings confirm that the Penn Century device is suitable for vaccine powder dosing to the deep lung.
Keywords: Pulmonary administration; Insulin; Monkey; Measles vaccine; Powder insufflation;

NOTICEBOARD (529-531).