Influence of Hydrodynamics and Particle Size on the Absorption of Felodipine in Labradors

Purpose. To study the influence of GI hydrodynamics and drug particle size on felodipine absorption in the dog. Methods. Labradors fistulated at midjejunum were used to selectively study the influence of hydrodynamics and particle size on the in vivodissolution and absorption of the poorly soluble, lipophilic drug felodipine. A combination of infusion and oral administration of either normal saline or a 5% glucose solution was used to maintain fasted and establish fed state motility patterns, respectively. The absorption characteristics of both a micronized (8 m) and a coarse fraction (125 m) of felodipine were subsequently studied under these two motility patterns. Results. A reduction in particle size led up to an approximate 22-fold increase in maximum plasma concentration and up to an approximate 14-fold increase in area under the curve, with a commensurate decrease in the time at which the maximum plasma concentration occurred. Although the absorption of felodipine from the solution and micronized suspension was not influenced by a change in the hydrodynamics, felodipine was absorbed from the coarse suspension almost twice as well in the fed state as under fasted conditions. Conclusions. Absorption from coarse suspensions of felodipine was sensitive to luminal hydrodynamics, whereas micronized suspensions were not. However, the particle size seems to have a much more important influence on the bioavailability of felodipine than the hydrodynamics per se.     

Production and Characterization of a Budesonide Nanosuspension for Pulmonary Administration

Purpose. This study describes the production of a budesonide nanosuspension by high-pressure homogenization for pulmonary delivery from 40 mL up to 300 mL. The aim was to obtain a nanosuspension that can be nebulized and is also long-term stable. Methods. The nanosuspension was produced by high-pressure homogenization. Particle size analysis was performed by laser diffraction and photon correlation spectroscopy. For further particle characterization, zeta potential was determined. To investigate the aerosolization properties, the nanosuspension was nebulized and afterward analyzed on particle size. Results. It was possible to obtain a long-term stable budesonide nanosuspension. Mean particle size of this nanosuspension was about 500-600nm, analyzed by photon correlation spectroscopy. Analysis by laser diffraction showed that the diameters 95% and 99% were below 3 m. Budesonide nanosuspension showed a long-term stability; no aggregates and particle growth occurred over the examined period of 1 year. The PCS diameter before and after aerosolization did not change, and the LD diameters increased negligibly, showing the suitability for pulmonary delivery. The scale-up from 40 mL up to 300 mL was performed successfully. Conclusions. High-pressure homogenization is a production method to obtain nanosuspensions with budesonide for pulmonary application.     

Aerosol Electrostatics I: Properties of Fine Powders Before and After Aerosolization by Dry Powder Inhalers

Purpose. To evaluate the dependence of fine particle dose charge (FPD charge) generated from powder inhalers on physico-chemical properties of the inhalation powder, inhaler type, deaggregation mechanism, dose number and/or retained powder. Methods. Electrostatic charges were determined on micronized powders and aerosolized fine particle doses withdrawn from two, high efficiency, multidose powder inhalers, Turbohalerand prototype Dryhaler. The behavior of terbutaline sulfate, budesonide, albuterol (sulfate and base), beclomethasone dipropionate and lactose was assessed before and after aerosolization. Results. Both inhalers conferred triboelectric FPD charges during aerosolization in the range –400 pC through +200 pC. Specific charges (charge/unit mass) on the fine particle doses of budesonide from Dryhaler were significantly less than those from Turbohaler (p < 0.01). Electrostatic charges on the potentially respirable cloud of terbutaline sulfate generated by Bricanyl Turbohaler were positive and/or negative and unpredictable. With Pulmicort Turbohaler, FPD charges on budesonide were always positive. Dryhaler was used to determine the chemical dependence of fine particle triboelectrification during the aerosolization of pure materials. A triboelectric series was constructed from the Dryhaler results ranking the powders from positive to negative as budesonide > lactose > albuterol sulfate > terbutaline sulfate albuterol beclomethasone dipropionate. Conclusions. While there was no evidence of FPD charge dependence upon dose number with either inhaler, FPD charges were dependent upon the powder under investigation, as well as the construction and deaggregation mechanism of the inhaler. The specific charge on the fine particle dose of budesonide from Turbohaler corresponded to approximately 200 electronic charges per particle, a value which is known to affect both total and regional aerosol deposition in the human lung. Electrostatic charge effects may be important determinants of aerosol behavior and should not be neglected.     

Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder

Purpose. To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere® powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs). Methods. Budesonide PulmoSphere (PS_bud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 g budesonide PulmoSphere inhaled from Eclipse® DPI at target PIF of 25 L·min^-1 (PS_bud25), and 50 L·min^-1 (PS_bud50), and 800 g of pelletized budesonide from Pulmicort® Turbuhaler® at 60 L·min^-1(TH_bud60). PS_bud powder was radiolabeled with ^99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation. Results. Pulmonary deposition (mean ± sd) of PS_bud was 57 ± 7% and 58 ± 8% of the nominal dose at 25 and 50 L·min^-1, respectively. Mean peak plasma budesonide levels were 4.7 (PS_bud25), 4.0 (PS_bud50), and 2.2 ng·ml^-1 (TH_bud60). Median t_max was 5 min after both PS_bud inhalations compared to 20 min for Turbuhaler (P < 0.05). Mean AUCs were comparable after all inhalations, 5.1 (PS_bud25), 5.9 (PS_bud50), and 6.0 (TH_bud60) ng·h·ml^-1. The engineered PS_bud powder delivered at both flow rates from the Eclipse® DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L·min^-1 from the Turbuhaler. Intersubject variability was also dramatically decreased for PS_bud relative to TH_bud. Conclusion. Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.     

Disposition Kinetics of α-Tocopherol in Apolipoprotein B Knockout Mice

Purpose. We examined the effects of apolipoprotein B (apoB) on the disposition kinetics of -tocopherol by using apoB knockout mice. Methods. The concentrations of -tocopherol in plasma and tissues were measured by gas chromatography-mass spectrometry. Results. In apob (–/–) mice, the endogenous levels of -tocopherol in plasma and tissues (except liver) were significantly lower, and the liver concentration was significantly higher than those in wild-type mice. After single i.v. administration of -tocopherol (25 mg/kg), the area under the plasma concentration-time curve (AUC) and the distribution volume at steady state were significantly decreased, whereas the total clearance of -tocopherol was significantly increased in apob (–/–) vs. wild-type mice. -Tocopherol was highly distributed to the liver, compared with other tissues. After an oral administration of -tocopherol (100 mg/kg), the intestinal absorption of -tocopherol was very low in apoB knockout mice, as the value of AUC_0-32h for apob (–/–) mice (17.7 ± 8.3 g h/mL) was significantly less than that for apob (+/+) wild-type mice (96.5 ± 15.8 g h/mL, mean ± SD of five experiments, p < 0.01). The biliary excretion of -tocopherol was significantly greater in apob (+/–) mice than in apob (+/+) mice. Conclusions. These results show that apoB plays a role in hepatic secretion and intestinal absorption of -tocopherol.     

PLG Microsphere Size Controls Drug Release Rate Through Several Competing Factors

Purpose. Although the rate of drug release from poly(D,L-lactide-co-glycolide) (PLG) microspheres is often modulated by changing fabrication conditions or materials, the specific factors directly controlling the release profiles are often unclear. We have fabricated uniform rhodamine- and piroxicam-containing microspheres, 10 to 100 m in diameter, to better understand how microsphere size controls drug release. Methods. Drug distribution within the microspheres was examined using confocal fluorescence microscopy. The rate of polymer degradation was determined as the change in molecular weight, measured by gel permeation chromatography, during in vitro degradation experiments. Further, changes in the surface and interior morphology of the particles during in vitro degradation were investigated by scanning electron microscopy. Results. Microsphere size greatly affected drug distribution. Small (10-m) microspheres showed an essentially uniform drug distribution. Larger (100-m) microspheres showed redistribution of drug to specific regions of the microspheres. Rhodamine partitioned to the surface and piroxicam partitioned to the interior of large PLG microspheres. Further, the rate of polymer degradation increased with microsphere size, possibly the result of a more acidic interior caused by increased accumulation of hydrolyzed polymer products in larger particles. Finally, larger microspheres developed a more porous interior structure during the drug release. Conclusions. Microsphere size affects drug release not only through changes in diffusion rates but also through secondary effects including drug distribution in the particle, polymer degradation rate, and microsphere erosion rates.     

Influence of Morphometric Factors on Quantitation of Paracellular Permeability of Intestinal Epithelia In Vitro

Purpose. The relative contribution of the small and large intestine to paracellular absorption is a subject of some controversy. Direct comparison of paracellular permeability in different epithelia is complicated by variations in junctional density and/or the absorptive surface area. Methods. This study used a combination of morphometric analyses and in vitro absorption studies to define permeability characteristics in relation to the amount of paracellular pathway present in rat ileum, colon and the model epithelium, Caco-2. Results. Mucosal to serosal amplification was higher in ileum (3.9) than colon (1.9) or Caco-2 (1). Tight junctional density (1p) of ileal crypts was 3 fold greater (91 m/cm²) than that measured in ileal villi, colonic surface and crypt cells or Caco-2 monolayers (34–37 m/ cm²). However, when the relative contributions of the crypts and villi was taken into account there was no significant difference in the mean 1p per mucosal area for the three epithelia studied. Using these data to correct for morphometric differences the permeabilities of a range of small hydrophilic molecules (atenolol, D-PheAsp and PEG oligomers MW 282-634) was measured. Permeability of rat ileum and colon were virtually identical for all compounds studied. In contrast, Caco-2 monolayers showed a significantly lower permeability than intestinal tissues with the difference increasing markedly with molecular size. Conclusions. These studies suggest the importance of accounting for morphological variation when comparing the permeability characteristics of different epithelial systems.     

Use of Solid Corrugated Particles to Enhance Powder Aerosol Performance

Purpose. To study the dispersion performance of non-porous corrugated particles, with a focus on the effect of particle surface morphology on aerosolization of bovine serum albumin (BSA) powders. Methods. The solid-state characteristics of the spray-dried BSA powders, one consisting of smooth spherical particles and another corrugated particles, were characterized by laser diffraction, X-ray powder diffraction, scanning electron microscopy, confocal microscopy, thermogravimetric analysis, surface area analyzer, and buoyancy method. The powders were dispersed using the Rotahaler® and the Dinkihaler® coupled to a four-stage liquid impinger operating at 30 to 120 L/min. Fine particle fraction (FPF) was expressed as the wt. % of BSA particles of size 5 m collected from the liquid impinger. Results. Apart from the morphology and morphology-related properties (specific surface area, envelope density), the corrugated particles and spherical particles of BSA had very similar solid-state characteristics (particle size distribution, water content, true density, amorphous nature). Using the Dinkihaler®, the FPFs of the corrugated particles were 10-20 wt. % higher than those of the smooth particles. Similar FPF differences were found for the powders dispersed by the Rotahaler®, but the relative changes were larger. In addition, the differences were inversely proportional to the air flows (17.3% at 30 L/min, 25.2% at 60 L/min, 13.8% at 90, 8.5% at 120 L/min). Depending on the inhaler, capsule and device retention and impaction loss at the impinger throat were lower for the corrugated particles. Conclusions. Enhanced aerosol performance of powders can be obtained by surface modification of the particles. The surface asperities of the corrugated particles could lower the true area of contact between the particles, and thus reduce the powder cohesiveness. A distinct advantage of using corrugated particles is that the inhaler choice and air flow become less critical for these particles.     

Characterization of Two Polymorphs of Salmeterol Xinafoate Crystallized From Supercritical Fluids

Purpose. To characterize two polymorphs of salmeterol xinafoate (SX-I and SX-II) produced by supercritical fluid crystallization. Methods. SX-I and SX-II were crystallized as fine powders using Solution Enhanced Dispersion by Supercritical Fluids (SEDS). The two polymorphs and a reference micronized SX sample (MSX) were characterized using powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), aqueous solubility (and dissolution) determination at 5-40°C, BET adsorption analysis, and inverse gas chromatography (IGC). Results. Compared with SX-I, SX-II exhibited a lower enthalpy of fusion, a higher equilibrium solubility, a higher intrinsic dissolution rate, a lower enthalpy of solution (based on van't Hoff solubility plots), and a different FTIR spectrum (reflecting differences in intermolecular hydrogen bonding). Solubility ratio plot yielded a transition temperature (99°C) below the melting points of both polymorphs. MSX showed essentially the same crystal form as SX-I (confirmed by PXRD and FTIR), but a distinctly different thermal behaviour. Mild trituration of SX-I afforded a similar DSC profile to MSX while prolonged grinding of SX-I gave rise to an endotherm at 109°C, corresponding to solid-solid transition of SX-I to SX-II. Surface analysis of MSX, SX-I, and SX-II by IGC revealed significant differences in surface free energy in terms of both dispersive (non-polar) interactions and specific (polar) acid-base properties. Conclusions. The SEDS-processed SX-I and SX-II display high polymorphic purity and distinctly different physical and surface properties. The polymorphs are related enantiotropically with SX-I being the thermodynamically stable form at room temperature.     

Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans

Purpose. A theoretical method has been devised for prediction of drug absorption after oral administration to humans. Methods. Twenty structurally diverse model drugs, ranging from 0.3 to 100% absorbed, were investigated. The compounds also displayed diversity in physicochemical properties such as lipophilicity, hydrogen bonding potential and molecular size. The dynamic molecular surface properties of the compounds were calculated, taking into account their three-dimensional shape and flexibility. Results. An excellent sigmoidal relationship was established between the absorbed fraction after oral administration to humans (FA) and the dynamic polar molecular surface area (PSA_d) (r² = 0.94). The relationship was stronger than those obtained for more established predictors of drug absorption. Drugs that are completely absorbed (FA > 90%) had a PSA_d 60 ² while drugs that are < 10% absorbed had a PSA_d > 140 ². Conclusions. The results indicate that PS Ad can be used to differentiate poorly absorbed drugs at an early stage of the drug discovery process.     

NanoClusters Surface Area Allows Nanoparticle Dissolution with Microparticle Properties

Poorly water-soluble drugs comprise the majority of new drug molecules. Nanoparticle agglomerates, called NanoClusters, can increase the dissolution rate of poorly soluble compounds by increasing particle surface area. Budesonide and danazol, two poorly soluble steroids, were studied as model compounds. NanoCluster suspensions were made using a Netzsch MiniCer media mill with samples collected between 5 and 15 h and lyophilized. Differential scanning calorimetry (DSC) and powder X-ray Diffraction were used to evaluate the physicochemical properties of the powders, and Brunauer, Emmett and Teller (BET) analysis was used to determine surface area. Scanning electron microscopy confirmed NanoClusters were between 1 and 5 μm. NanoCluster samples showed an increase in dissolution rate compared with the micronized stock and similar to a dried nanoparticle suspension. BET analysis determined an increase in surface area of eight times for budesonide NanoClusters and 10–15 times for danazol NanoClusters compared with the micronized stock. Melting temperatures decreased with increased mill time of NanoClusters by DSC. The increased surface area of NanoClusters provides a potential micron-sized alternative to nanoparticles to increase dissolution rate of poorly water-soluble drugs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1787–1798, 2014     

Excipient-free nanoporous microparticles of budesonide for pulmonary delivery

The aim of this study was to investigate the application of a spray-drying process for the production of nanoporous microparticles (NPMPs) to budesonide, and to characterise the particles produced in terms of their suitability for pulmonary delivery.Budesonide was spray dried with and without ammonium carbonate from ethanol/water or methanol/water solutions. The solid-state characteristics and micromeritic (particle size, density, surface area) properties of spray dried powders were assessed. In vitro deposition studies were performed to assess aerosol performance.The densities of the NPMPs were significantly lower and the surface areas significantly higher than for non-porous spray dried or micronised material. NPMPs of budesonide demonstrated improved aerosolisation properties compared to spray dried non-porous, micronised material and two budesonide commercial products. All spray dried materials were amorphous in nature. The glass transition temperature (90 °C) was sufficiently high to suggest good physical stability at room temperature. When stored at 25 °C/60% RH NPMPs showed a reduced tendency to recrystallise compared to the equivalent non-porous spray dried powder. The physical stability and amorphous nature of NPMPs was retained, under these storage conditions for at least one year and the in vitro aerosolisation properties were not affected by the storage conditions.Excipient-free porous microparticles, prepared by the novel process described, show good potential for drug delivery by oral inhalation with improved in vitro deposition properties compared to non-porous particles.     

Role of Brain Tissue Localized Purine Metabolizing Enzymes in the Central Nervous System Delivery of Anti-HIV Agents 2′-β-Fluoro-2,3′-Dideoxyinosine and 2′-β-Fluoro-2′,3′-Dideoxyadenosine in Rats

Purpose. This study examines the central nervous system (CNS) delivery of 2--fluoro-2,3-dideoxyadenosine (F-ddA) and 2--fluoro-2,3-dideoxyinosine (F-ddl), acid stable analogues of dideoxyadenosine (ddA) and dideoxyinosine (ddI) having reduced susceptibility to purine salvage pathway enzymes important in the metabolism of ddA and ddI, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), respectively. Their CNS delivery compared to that for ddI provides insight into the role of brain tissue ADA and PNP in these processes. Methods. Brain and cerebrospinal fluid (CSF) concentration-time profiles were obtained for F-ddI during and after intravenous infusions of F-ddl, and for both F-ddA and F-ddI after F-ddA infusions in normal rats or rats pre-treated with the ADA inhibitor 2-deoxycoformycin (DCF). Rate constants for CNS entry, efflux and metabolism were estimated by computer fits using plasma concentration-time profiles as the driving force functions. Results. The CNS delivery of F-ddI did not differ significantly from that for ddI. F-ddA, which is more lipophilic than F-ddI, provided higher brain ( 8×) and CSF ( 11×) concentrations of total dideoxynucleoside (F-ddA and F-ddI) compared to F-ddI. Deamination by brain tissue ADA to form F-ddI reduced CNS levels of intact F-ddA but provided higher brain parenchyma (5×) and CSF/plasma (3×) ratios of F-ddI relative to F-ddI controls. Thus, F-ddA functions in part as a CNS-activated prodrug of F-ddI. DCF pre-treatment inhibited brain tissue ADA, abolishing the prodrug effect, and enhancing F-ddA concentrations in both brain parenchyma (5×) and CSF (6×). Conclusions. PNP metabolism does not appear to play a role in the low CNS delivery of ddI. On the other hand, deamination of F-ddA by brain tissue ADA is an important process, such that F-ddA functions in part as a CNS-activated prodrug of F-ddI. Enhanced CNS uptake of intact F-ddA can be achieved with ADA inhibition.     

Influence of cooling on the responsiveness of rat isolated anococcygeus muscle to noradrenaline

Summary The isolated anococcygeus muscle of the rat was used to study the effect of temperature on noradrenaline-induced contraction. The preparation was suspended in an organ bath containing Krebs bicarbonate solution for isometric tension recording. A decrease of the bath temperature from 37°C to 20°C (cooling) produced an increase in tissue sensitivity to noradrenaline, as reflected in a 5.37-fold leftward shift in the concentration-response curve, and increased the maximum contractile response to this agonist (14.3%). Cooling had no effect on tissue sensitivity to a selective ₁-adrenoceptor agonist, methoxamine, but increased (12.4%) the maximum contraction to a similar extent to that to noradrenaline. 6-Hydroxydopamine pretreatment or nortriptyline (1 mol/l) induced a leftward shift of the noradrenaline concentration-response curve at 37°C, and profoundly inhibited the potentiating effect of cooling on tissue sensitivity to the catecholamine; the effect of cooling on the maximum response was unaffected. The affinity of noradrenaline or methoxamine for ₁-adrenoceptors at 37°C, determined from its dissociation constant (K _A), was not significantly different from that at 20°C. K _A values were determined by use of irreversible antagonism with phenoxybenzamine. On the other hand, diltiazem at concentration of 3 mol/1, which almost completely abolished the calcium ion-induced contraction of the potassium ion-depolarized muscle, caused only slight inhibition in the concentration-response curve for noradrenaline. The contractile responses to Ca²⁺ of the K⁺-depolarized muscle and of the tissue incubated in Ca²⁺-free (EGTA 0.1 mmol/1) Krebs solution containing diltiazem and noradrenaline were both depressed by cooling. However, the contractile response of the anococcygeus muscle caused by noradrenaline or methoxamine in Ca²⁺-free Krebs solution was augmented at 20°C. At 37°C, vanadate (1 mol/1) also augmented the methoxamine-induced contraction of the tissue incubated in Ca²⁺-free solution. This potentiating effect of vanadate was not observed at 20°C. From these observations, it is concluded that increased responsiveness of the rat anococcygeus muscle to noradrenaline with lowered temperature may involve the inhibition of neuronal uptake mechanism of the catecholamine and the inhibition of removal mechanism of Ca²⁺ which is released from intracellular stores associated with the postsynaptic ₁-adrenoceptors. Send offprint requests to T. Ishii at the above address     

Assessing Tablet Bond Types from Structural Features that Affect Tablet Tensile Strength

Purpose. The aim of this article was to study the possibility of assessing the structural features affecting tablet tensile strength to obtain information on the dominating bond types, i.e. interparticulate attractions, in tablets. Methods. The features of the internal tablet structure considered to be important for tablet tensile strength were assessed using a simple tablet model for tablets made from seven materials: potassium chloride, sodium chloride, sodium bicarbonate, lactose, sucrose, microcrystalline cellulose, and ascorbic acid. Results. Tablet porosity and particle size (measured as external specific surface area by permeametry) were the structural features that best correlated with tablet tensile strength. These features were described by a structural factor, which was combined with tablet tensile strength, as an interaction factor, to reflect the dominating bond types in tablets. Conclusion. The qualitative results gave dominating bond types in the tablets studied that matched the results of earlier studies, thus supporting the applicability of the method.     

Characterization of Particle-Interactions by Atomic Force Microscopy: Effect of Contact Area

Purpose. The purpose of this work was to compare adhesion forces, contact area, and work of adhesion of salbutamol sulphate particles produced using micronization and a supercritical fluid technique (solution-enhanced dispersion by supercritical fluids - SEDS) using atomic force microscopy (AFM). Methods. Adhesion forces of individual particles of micronized and SEDS salbutamol against a highly orientated pyrolytic graphite surface were acquired in a liquid environment consistent with that of a pressurized metered dose inhaler. The forces were then related to contact area and work of adhesion. Results. The raw adhesion force data for the micronized and SEDS material were 14.1 nN (SD 2.5 nN) and 4.2 nN (SD 0.8 nN), respectively. After correction for contact area, the forces per unit area were 13 mN/m² (SD 2.3 mN/m²) and 3 mN/m² (SD 0.6 mN/m²). The average work of adhesion was calculated using the Johnson-Kendall-Roberts theory and was found to be 19 mJm^–2 (SD 3.4 mJm^–2) for the micronized particle and 4 mJm^–2 (SD 0.8 mJm^–2) for the SEDS particle. Conclusions. It is possible to produce a three-dimensional representation of the contact area involved in the interaction and make quantitative comparisons between different particles. There was a lower force per unit area and work of adhesion observed for the SEDS material, possibly because of its lower surface free energy.     

Interaction Between Superoxide Dismutase and Dipalmitoylphosphotidylglycerol Bilayers: A Fourier Transform Infrared (FT-IR) Spectroscopic Study

Purpose. Superoxide dismutase (SOD), an antioxidant enzyme, converts peroxide radicals into hydrogen peroxide. Liposomes have been used as carriers for SOD to enhance its antioxidant effect. Our previous DSC study has suggested that SOD binding to dipalmitoylphosphatidylglycerol (DPPG) may protect lipid membranes against oxygen-mediated injury. We now present FT-IR studies on the effect of DPPG binding on the temperature-induced SOD folding-unfolding process. Methods. The FT-IR spectra of SOD in D₂O or DPPG membranes are measured as temperatures increase from 28° to 121°C at a rate of 0.5°C/ min. From the quantitative determination of the changes in the amide I band components of the Fourier self-deconvoluted spectra, the DPPG-induced changes of SOD secondary structure could be detected as a function of temperature. Results. We observe that the relative intensity of the SOD bands from 28°C to 77°C show graduate loss of -sheet distorted structure, loss of turns, and existence of an intermediate state around 50°C. Beginning at 80°C, changes are obtained in three temperature regions: (i) 80°C, (ii) 92°C, (iii) 109°C. The result suggests that SOD folding/unfolding transition involves mostly the relative changes within the regions of helix-like hydrogen bonding pattern, turn, twisted -bend and irregular structures. When SOD is bound to DPPG, the conformational changes shift to lower temperatures, indicating a reduction of SOD thermal stability. In addition, the gel to liquid crystalline phase transition temperature of DPPG increases from 42°C to 43.5°C. Conclusions. These results suggest that the thermal stability of SOD is reduced by DPPG binding. However, DPPG bilayer is stabilized by the presence of SOD.     

Respirable PLGA Microspheres Containing Rifampicin for the Treatment of Tuberculosis: Manufacture and Characterization

Purpose. Particles with aerodynamic diameters of 1–5m deposit in the periphery of the lungs and are phagocytized by alveolarmacrophages, the primary site of Mycobacterium tuberculosisinfection. Aerosols of biodegradable polymeric microspheres containingantitubercular agents may be delivered to the lungs to improve the treatmentof tuberculosis. Methods. Poly(lactide-co-glycolide) (PLGA) microspherescontaining rifampicin were prepared using solvent evaporation and spraydrying methods. The solvent evaporation process was optimized usingfactorial experimental design and surface response methodology. Themorphology, particle size, drug loading, and dissolution of microspheres wasevaluated. Results. The spray dried rifampicin loaded PLGAmicroparticles were shriveled, unlike the spherical particles produced bysolvent evaporation. Drug loadings of 20;pc and 30;pc were achieved forsolvent evaporation and spray dried products, respectively. The particlesprepared by solvent evaporation and spray drying had 3.45 m and 2.76m median diameters by volume, respectively. Conclusions. Respirable rifampicin loaded PLGAmicrospheres were produced by both solvent evaporation and spray dryingmethods. These particles are being evaluated in an animal model oftuberculosis.     

Pharmacokinetic drug evaluation of budesonide in the treatment of Crohn’s disease

Introduction: Crohn’s disease (CD) is a chronic inflammatory disorder that commonly affects the terminal ileum and proximal colon. Although systemic corticosteroids such as prednisone and methylprednisolone are widely used for treatment of CD, these agents have a high incidence of adverse drug reactions due to off-target effects. Budesonide is a locally acting corticosteroid with enhanced formulation properties that offer a superior therapeutic index in comparison to conventional members of the class.

Areas covered: This review focuses on budesonide for the treatment of CD. The pharmacological and pharmacokinetics of the drug are summarized, along with clinical efficacy and safety data. We also indicate the role of budesonide in therapeutic algorithms.

Expert opinion: Budesonide has an important role as an induction therapy in patients with mild to moderately active CD of the ileum and proximal colon. The most distinctive advantage of budesonide over conventional corticosteroids is a substantially reduced risk of corticosteroid-related side effects.     

Supercritical fluids crystallization of budesonide and flunisolide

Purpose: Budesonide and flunisolide anhydrate were crystallized using the solution enhanced dispersion by supercritical fluids (SEDS) technique. The aim was to investigate the possibility of preparing different pure polymorphs. Methods: 0.25% w/v solutions of each drug were prepared from acetone and methanol. Operating conditions were 40-80°C and 80-200 bars. The flow rate of drug solution was 0.3 mL/min and that of CO₂ was 9-25 mL/min. Sample characterizations included differential scanning calorimetry, X-ray powder diffraction, variable temperature X-ray diffraction, scanning electron microscopy, and solubility studies. Results: The particle morphology of budesonide was dependent on the nature of the solvent. SEDS processing of flunisolide with acetone at 100 bars resulted in the formation of polymorphic mixtures at 80°C and a new polymorph III at 60 C and 40°C. With methanol at 100 bars another new polymorph IV was formed with different particle morphology at 80°C and a polymorphic mixture at 60°C. Conclusion: Using the SEDS, microparticles of crystalline budesonide were prepared and new polymorphs of flunisolide were produced. Particle characteristics were controlled by the temperature, pressure and relative flow rates of drug solution and CO₂.