International Journal of Pharmaceutics (v.258, #1-2)
TITLE PAGE (EDI BOARD) (iii).
Terbutaline microparticles suitable for aerosol delivery produced by supercritical assisted atomization by E Reverchon; G Della Porta (1-9).
A new micronization technique called supercritical assisted atomization has been used to produce terbutaline microparticles with controlled particle size distribution in the range of drug particles deliverable by aerosol. The process is based on the solubilization of a fixed amount of supercritical carbon dioxide in a liquid solution; then, the ternary mixture is sprayed through a nozzle and atomized in order to produce microparticles. Water has been used as the liquid solvent; heated nitrogen has also been delivered into the precipitator to evaporate the liquid droplets. The process has been first optimized with respect to pressure and temperature (mixing temperature and pressure, precipitation temperature) and very mild operation conditions have been selected; then, the influence of the solute concentration in the liquid solution on particle size has been studied. The terbutaline produced powders were characterized with respect to morphologies and particle size. Spherical particles with very narrow volumetric particle size distributions were produced. Particularly, operating at 30 and 50 mg of terbutaline per ml of water, more than 90% of the two distributions ranged between 1 and 3 μm; at 80 mg/ml more than 99% of the distribution ranged between 1 and 4 μm. HPLC analysis confirmed that no chemical degradation occurred in the drug as a consequence of the supercritical processing.
Keywords: Terbutaline; Supercritical fluids; Micronization;
Polyethylene glycol-coated liposomes for oral delivery of recombinant human epidermal growth factor by Hong Li; Jong-Hwa Song; Jeong-Sook Park; Kun Han (11-19).
The present study was to investigate the feasibility of oral delivery of recombinant human epidermal growth factor (rhEGF). Polyethylene glycol (PEG)-coated liposomes containing rhEGF was prepared and evaluated for their stability and permeability in Caco-2 cells. In the animal study, we also determined plasma concentration and gastric ulcer healing effect after oral administration of rhEGF liposomes or the solution. Encapsulation of rhEGF into liposomes, suppressed the degradation in Caco-2 cell homogenate compared with the solution. The flux of rhEGF from dipalmitoylphosphatidylcholine (DPPC) liposome across Caco-2 cell monolayer from the apical to basolateral side was three times greater than that from phosphatidylcholine (PC) liposome or the solution. After oral administration of rhEGF liposomes or the solution in rats, the area under the concentration–time curve (AUC) of rhEGF increased 1.7- and 2.5-fold for PC and DPPC liposomes, respectively. The gastric ulcer healing effect was significantly increased in DPPC liposome compared with PC liposome and the solution. The enhanced curative ratio of rhEGF encapsulated into DPPC liposome may be due to the resistance to enzyme degradation, higher permeability and increased plasma AUC. Therefore, PEG-coated liposomes containing rhEGF could be used as an oral delivery formulation with enhanced encapsulation efficiency.
Keywords: rhEGF; Liposome; DPPC; PEG-coated; Caco-2; Oral delivery;
In vitro and in vivo evaluation of mucoadhesive microspheres consisting of dextran derivatives and cellulose acetate butyrate by Yasunori Miyazaki; Kanako Ogihara; Shigeru Yakou; Tsuneji Nagai; Kozo Takayama (21-29).
The objective of this study was to evaluate mucoadhesive properties and gastrointestinal transit of microspheres made of oppositely charged dextran derivatives and cellulose acetate butyrate (CAB). The microspheres were prepared by emulsion solvent evaporation method. A reference microsphere was made of lactose instead of dextran derivatives. Microspheres with a diameter of 425–710 μm were examined for in vitro mucoadhesion by the everted sac method. The results indicated that the percentage of adherence to the rat small intestine was affected by the amount of dextran derivatives in the microspheres. After 1.5 h, the adhering percent of the reference microspheres and the microspheres containing 50% of dextran derivatives were 34 and 74%, respectively. Then gastrointestinal transit after oral administration to rats was evaluated by counting the microspheres remaining in the stomach and small intestine. The microspheres containing 40% of dextran derivatives adhered to the stomach rather than the small intestine. Mathematical analysis revealed that the time required for 50% of microspheres to leave the stomach was 1.42 h, three times longer than the reference. These findings suggest that the microsphere is a promising device as a multiple-unit mucoadhesive system.
Keywords: Dextran derivatives; Mucoadhesion; Microspheres; Gastrointestinal transit; Polyion complex; Cellulose acetate butyrate;
Prediction of in vivo drug release behavior of controlled-release multiple-unit dosage forms in dogs using a flow-through type dissolution test method by Kengo Ikegami; Kozo Tagawa; Masao Kobayashi; Takashi Osawa (31-43).
A newly designed flow-through type dissolution test method (FT method) was applied to predict in vivo drug release behaviors in dogs of controlled-release multiple unit dosage forms. The in vivo drug release behaviors were directly observed by measuring the residual amount of drugs in preparations recovered from the gastrointestinal (GI) tract after oral administration. Theophylline (TP), acetaminophen (AA), and phenylpropanolamine hydrochloride (PPA), which have different solubility, were used as model drugs. In vivo drug release behaviors in the gastrointestinal (GI) tract of dogs were similar to the results of the Wagner–Nelson method. In vivo release behaviors of TP and AA, until 2 h after administration, were well correlated to in vitro behaviors obtained by the paddle method at 100 rpm. However, the in vivo release rates of TP and AA were gradually decreased because of a lack of fluid in the lower region of the GI tract, their poor solubility, the difference of the release rates, and so on. Non-sink conditions, which would reflect TP and AA release in the lower region of the GI tract, were obtained by the FT method at a cell volume of 0.5 ml and a flow rate of 0.37 ml/h (TP), 0.48 ml/h (AA), respectively. The in vitro release profiles obtained by the FT method combining sink and non-sink conditions were similar to their in vivo profiles. On the other hand, in the case of PPA, the in vivo release profiles were considerably similar to the in vitro ones obtained by both the paddle method and the FT method. In conclusion, the FT method combining sink and non-sink conditions will give a good in vitro/in vivo correlation regarding release behavior for controlled-release multiple unit dosage forms.
Keywords: Controlled-release; Flow-through method; Theophylline; Non-sink condition; In vitro/in vivo correlation;
Stability and antitumor effects of all-trans retinoic acid-loaded liposomes contained sterylglucoside mixture by Kazuyuki Shimizu; Kayoko Tamagawa; Noriko Takahashi; Kozo Takayama; Yoshie Maitani (45-53).
The aim of this study was to develop an intravenous delivery of all-trans retinoic acid (ATRA) for the treatment of cancer. Two kinds of liposomes composed of dipalmitoylphosphatidylcholine and cholesterol with sterylglucoside (SG) mixture (SG liposomes) or without SG (non-SG liposomes) were prepared. A limited amount of ATRA was incorporated into liposomes approximately 3 mol%. ATRA-loaded SG liposomes were more stable at 4 °C with light protection for 24 days than non-SG liposomes; maintaining 83.1% ATRA and the average diameter 198.5 nm (36 days), and in 80% rat serum for 120 min. SG seems to increase the ATRA-loaded efficiency in liposomes and stability of liposomes compared with cholesterol. The mean survival time of mice given SG liposomes (18.2 days) indicated a greater antitumor activity than saline (14.1 days) (P<0.001) without change of mean body weight. It is concluded that the current ATRA-loaded SG liposomes are potentially applicable for hepatic metastasis of M5076 tumor.
Keywords: All-trans retinoic acid; Liposomes; M5076; Sterylglucoside; Stability; Antitumor effect;
Oral sustained delivery of paracetamol from in situ-gelling gellan and sodium alginate formulations by Wataru Kubo; Shozo Miyazaki; David Attwood (55-64).
The purpose of this study was to evaluate the potential for the oral sustained delivery of paracetamol of two formulations with in situ gelling properties. Oral administration of aqueous solutions of either gellan gum (1.0%, w/v) or sodium alginate (1.5%, w/v) containing calcium ions in complexed form resulted in the formation of gel depots in rabbit and rat stomachs as a consequence of the release of the calcium ions in the acidic environment. In vitro studies demonstrated diffusion-controlled release of paracetamol from the gels over a period of 6 h. The bioavailability of paracetamol from the gels formed in situ in the stomachs of rabbits following oral administration of the liquid formulations was similar to that of a commercially available suspension containing an identical dose of paracetamol.
Keywords: In situ gelation; Paracetamol; Oral drug delivery; Sustained release; Gellan gels; Alginate gels;
In vitro characterization of jet-milled and in-situ-micronized fluticasone-17-propionate by Hartwig Steckel; Norbert Rasenack; Peter Villax; Bernd W Müller (65-75).
Particle properties are decisive for therapeutic efficiency of an inhaled pulmonary drug. Jet-milling as the common way for micronization of inhaled powder drugs shows several disadvantages such as a non-homogeneous particle size distribution and unnatural, thermodynamically-activated particle surfaces causing a high agglomeration behavior. For pulmonary use in a dry powder inhaler (DPI) beside a small particle size, a good de-agglomeration activity is required. In this study, fluticasone-17-propionate (FP) is in-situ prepared in a respirable particle size by a controlled crystallization technique. First, the drug is dissolved in acetone and precipitated by a solvent change method in the presence of a cellulose ether (HPMC) as stabilizing hydrocolloid. By rapidly pouring the drug solution into the polymer-rich water phase, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth simultaneously by the presence of the hydrophilic polymer. This dispersion was then spray-dried. The mean particle size of the drug was around 2 μm and consequently in the respirable range. The physico-chemical properties of the in-situ-micronized drug were compared to those of an unmilled and a jet-milled quality. Differences in the X-ray patterns and amorphous parts could be detected for the jet-milled but not for the in-situ-micronized drug. In addition, the aerodynamic behavior of the engineered and the jet-milled FP was analyzed using the FlowCaps® inhaler as delivery device and compared to the commercial product Flutide® Diskus®. The fine particle fraction (FPF) (<5 μm) was increased four-fold from approximately 9% for the jet-milled drug to approximately 40% for the in-situ-micronized drug when the pure drug powder was dispersed with the FlowCaps® device.
Keywords: In-situ-micronization; Pulmonary drug delivery; Dry powder inhaler; Controlled crystallization; Fluticasone-17-propionate; FlowCaps®;
The determination of equilibrium constants, ΔG, ΔH and ΔS for vapour interaction with a pharmaceutical drug, using gravimetric vapour sorption by Richard J Willson; Anthony E Beezer (77-83).
The application of gravimetric vapour sorption (GVS) to the characterisation of pharmaceutical drugs is often restricted to the study of gross behaviour such as a measure of hygroscopicity. Although useful in early development of a drug substance, for example, in salt selection screening exercises, such types of analysis may not contribute to a fundamental understanding of the properties of the material. This paper reports a new methodology for GVS experimentation that will allow specific sorption parameters to be calculated; equilibrium constant (K), van’t Hoff enthalpy change (ΔH v), Gibbs free energy for sorption (ΔG) and the entropy change for sorption (ΔS). Unlike other reports of such type of analysis that require the application of a specific model, this method is model free. The analysis does require that over the narrow temperature range of the study ΔH v is constant and there is no change in interaction mechanism.
Keywords: Gravimetric vapour sorption; Equilibrium constants; Vapour–drug interaction;
Using deepest regression method for optimization of fluidized bed granulation on semi-full scale by B Rambali; S Van Aelst; L Baert; D.L Massart (85-94).
This study applied the deepest regression method to estimate the granule size of unsuccessful fluidized bed granulation runs. This study uses data from a previous study [Int. J. Pharm. 220 (2001) 149] on optimization of fluidized granulation process, wherein 8 of the 30 runs did not succeeded due to overwetting of the powder bed. The “complete data” (the observed and the estimated granule size by the depth regression method) were used to develop two regression models for the granule size: an empirical model based on the process variables (inlet air temperature, inlet airflow rate, spray rate, and inlet air humidity) and a fundamental model based on the powder bed moisture content and the relative droplet size. The regression models based on the incomplete data from the previous study and the regression models of the “complete data” were comparable in the sense that the contour plots based on the respective models and the predicted granule size were comparable.
Keywords: Fluidized bed granulation; Granule size; Deepest regression; Experimental design;
Structural modeling of drug release from biodegradable porous matrices based on a combined diffusion/erosion process by V. Lemaire; J. Bélair; P. Hildgen (95-107).
Biodegradable, porous microspheres exhibit a wide range of release profiles. We propose in this paper a unifying approach based on the dual action of diffusion and erosion to establish which mechanisms are responsible for the variety of release kinetics observed during in vitro experiments. Our modeling procedure leads to the partitioning of the matrix into multiple, identical elements, thus simplifying significantly the mathematical and numerical treatment of the problem. The model equations cannot be solved analytically, since the domain contains a moving interface, and must therefore be solved numerically, using specific methods designed for that purpose. Our model confirms the major role that the relative dominance between diffusion and erosion plays in the release kinetics. In particular, the velocity of erosion, the effective diffusion coefficient of the drug molecule in the wetted polymer, the average pore length, and the initial pore diameter are sensitive parameters, whereas the porosity and the effective diffusion coefficient of the drug in the solvent-filled pores is seen to have little influence, if any, on the release kinetics. The model is confirmed by using release data from biodegradable microspheres with different ratios of low and high molecular weight PLA. Excellent goodness of fit is achieved by varying two parameters for all types of experimental kinetics: from the typical square root of time profile to zero-order kinetics to concave release curves. We are also able to predict, by interpolation, release curves from microspheres made of intermediate, untested ratios of PLA by using a relation between two model parameters.
Keywords: Mathematical modeling; Release kinetics; Diffusion; Erosion; Biodegradable porous matrices; Microspheres;
Crystallisation of amorphous mannitol is retarded using boric acid by Tomohiro Yoshinari; Robert T Forbes; Peter York; Yoshiaki Kawashima (109-120).
An approach to inhibit the crystallisation of amorphous mannitol was investigated. Boric acid was selected as a model additive for a fundamental study of its ability to retard crystallisation and to facilitate characterisation of the properties of the amorphous solid. At concentrations above 5% (w/w) of boric acid, the DSC scans indicated that a totally amorphous solid could be prepared by cooling the melted pre-mixture under ambient conditions. An increase in the glass transition temperature (T g) was observed with a corresponding increase in boric acid content, and their relationship was well fitted by the Gordon–Taylor equation. This result suggested that mannitol and boric acid mixed homogeneously.The crystallisation profiles of the resultant amorphous compositions were best described by the Avrami–Eroféev equation (n=1/3), which indicated that random nucleation and three-dimensional crystal growth was the best-fitting mechanism of this crystallisation. The activation energy of crystallisation decreased with increasing boric acid content, indicating that the temperature dependency for crystallisation decreased with increasing boric acid content. Furthermore, the rate of crystallisation at 30 °C for mannitol alone was 7000 times higher than that of mannitol containing 7.5% (w/w) of boric acid.
Keywords: Mannitol; Boric acid; Amorphous state; Crystallisation; Anti-nucleant; Crystallisation inhibitor;
The improved compaction properties of mannitol after a moisture-induced polymorphic transition by Tomohiro Yoshinari; Robert T. Forbes; Peter York; Yoshiaki Kawashima (121-131).
We have previously shown that by exposing one form of mannitol to high relative humidity, a moisture-induced polymorphic transition of mannitol with a concurrent change in particle morphology occurs [Int. J. Pharm. 247 (2002) 69]. In this paper, we propose that if these changes occur during a wet-granulation procedure, it may be possible to make bring about an in situ size-reduction of mannitol with compaction property enhancement. Powder X-ray diffraction and scanning electron microscopy confirmed that a polymorphic transition (the δ form forming the β form) had occurred on wet-granulation, and that a concomitant morphology change resulted in an agglomerate consisting of filament-like fine primary crystals (δ-granule). The aim of present study was to evaluate the compression properties of this agglomerate. The compact compressed with δ-granules possessed a tensile strength 1.5 times higher than other mannitol samples. Heckel analysis indicated that the mannitol compression process proceeded by deformation without fragmentation and was thus particle size dependent. The δ-granule showed enhanced plastic deformability, due to its unique particle structure. Because the intrinsic compression properties of the polymorphs were similar, the primary particle size and specific surface area of mannitol were indicated to be the major contributing factors for the improved compaction behaviour, rather than the polymorphic transition. When using the δ-granule as an excipient for a tablet formulation containing a high amount of phenylpropanolamine hydrochloride (PPA) as a poorly compactable model drug, excellent tablets could be prepared without capping, whereas conventional mannitol produced capped tablets.
Keywords: Mannitol polymorphs; Polymorphic transition; Compaction; Compression; Plastic deformation; Polymorphism;
Permeation of cyproterone acetate through pig skin from different vehicles with phospholipids by Claudia Valenta; Michaela Janisch (133-139).
The permeation of cyproterone acetate (CPA) from Derma Membrane Structure (DMS) creams and liposomal formulations was investigated. Standard diffusion experiments with dermatomed porcine skin were performed. The cumulative CPA amount permeated of the DMS creams was between 2.9 and 6.8 μg/cm2 within 48 h. By addition of a phospholipid concentrate, the CPA permeation could be 2.6-fold further increased compared to the control DMS. A working temperature of 60 °C resulted in a change of the preparation and a higher permeation which could be confirmed by additional differential scanning calorimetry studies. In case of the liposomal formulations, the CPA permeation was strongly dependent on the lipid content. The higher the lipid content, the higher was the CPA permeation. Extruding procedures for decreasing the particle size of the liposomes resulted in a two-fold increase in CPA permeation compared to the unextruded liposomes.It is possible to control the CPA permeation by combining various formulations containing different phospholipids with saturated and unsaturated fatty acids.
Keywords: Cyproterone acetate; Phospholipids; Dermatomed pig skin; Differential scanning calorimetry;
Particle size of liposomes influences dermal delivery of substances into skin by D.D. Verma; S. Verma; G. Blume; A. Fahr (141-151).
In the present study, the influence of vesicle size on the penetration of two fluorescently labeled substances into the human skin was investigated. For the measurements either a hydrophilic fluorescent compound [carboxyfluorescein (CF)] or a lipophilic one [1,1′-dioctadecyl-3,3,3′,3′-tertramethylindocarbo-cyanine perchlorate (DiI)] were encapsulated into vesicles. Liposomal formulations were prepared by extruding the vesicles through polycarbonate membrane filters with pores of different sizes. In vitro penetration studies into human abdominal skin were performed by using the Franz diffusion cell and a standardized skin stripping technique in attempt to find an optimum size for topical drug delivery by liposomes. Confocal laser scanning microscopy (CLSM) was used to visualize the effect of penetration ability of liposomal DiI. The maximum DiI fluorescence in the skin was observed with smaller liposomes of 71 nm diameter. The liposomes with a size of 120 nm diameter showed statistically enhanced penetration of CF into the skin as compared to larger ones. The results indicated that the CF penetration was inversely related to the size of the liposomes, which was confirmed by the data of the confocal laser scanning microscopy studies.
Keywords: Topical delivery; Liposomes; Particle size; Carboxyfluorescein; Skin penetration;
Compactibility of agglomerated mixtures of calcium carbonate and microcrystalline cellulose by Marı́a de Lourdes Garzón Serra; Leopoldo Villafuerte Robles (153-163).
The tablet tensile strength (T) of agglomerated mixtures of microcrystalline cellulose—Avicel PH 102 (MC), calcium carbonate (CC) and polyvinylpyrrolidone (Povidone, PVP), lubricated with magnesium stearate (MS), and formed under a compaction pressure (P c) ranging up to 618 MPa has been determined. The compactibility was defined through: ln(−ln(1−T/T max ))=Slope×ln P c +Intercept . MC/CC mixtures added of an agglutinant, before and after lubrication, show an important positive effect on their tablet tensile strength compared to a lineal relationship. This positive effect becomes smaller with decreasing compaction pressures. By different mixing methods, the higher the mixing efficiency the higher the compactibility, following the order: spray-dried>wet massing>tumble mixing. The compactibility of MC/CC/PVP spray-dried mixtures with calcium carbonate content from 20 to 60% was equal to or greater than that of pure microcrystalline cellulose. After lubrication with 2% MS the compactibility decreased, only the mixture with the maximal tablet tensile strength attained the tensile strength of pure microcrystalline cellulose. The presence of the binder, the lubricant and higher compaction pressures allow the accommodation of higher calcium carbonate proportions in the mixtures, at the maximal tablet tensile strength of the series. The lubricant decreases in a greater extent the compactibility of mixtures with a continuous phase of MC/PVP than that of CC/PVP. This is attributed to the plastic behavior of the MC/PVP continuous phase compared to a calcium carbonate continuous phase able to disrupt the Povidone and the possible lubricant coatings allowing a stronger interparticle interaction.
Keywords: Calcium carbonate; Microcrystalline cellulose; Compactibility; Agglomerated mixtures; Tablet tensile strength; Lubricants; Agglutinants;
Poly(acrylic acid) microgels (carbopol® 934)/surfactant interactions in aqueous media by R Barreiro-Iglesias; C Alvarez-Lorenzo; A Concheiro (165-177).
The interaction between Tween 80 and Pluronic F-127 with carbopol in water was studied as a function of surfactant concentration. 0.25% carbopol microgels dispersions showed a continuous decrease in transmittance, viscosity and conductivity when surfactant concentration ranged from 0.01–0.02% to 0.50% Tween 80 or from 0.03–0.06% to 0.30% Pluronic F-127. These limit values can be considered as the critical association concentration and the saturation binding concentration, respectively. In this concentration range, a strong rise in pH (from 3.18 to 3.50) suggested that surfactant–polymer binding occurred mainly through a stoichiometric hydrogen-bonding interaction between the oxyethylene and carboxylic groups. In the presence of carbopol, the concentration of Tween 80 at the air/water interface decreases as the surfactant is adsorbed onto the polymer and drawn into the bulk solution. In contrast, the interaction with the polymer seems to change the conformation of the expanded chains of Pluronic F-127, making it easier for more molecules of surfactant to be at the interface and increasing the thickness of the interfacial surfactant layer. Fluorescence probes indicated that the carbopol network presents a more apolar medium than pure water, and the differences in the hydrophile–lipophile balance (HLB) of each surfactant were responsible for the lower I I/I III values obtained with Tween 80/carbopol systems. Microcalorimetry titration data made it possible to conclude that Tween 80/carbopol interaction, at 298 K, is an enthalpy-driven process due to stabilization of Tween 80 units inside the polymer network. In contrast, Pluronic F-127/carbopol association (endothermic process) occurs owing to a gain in entropy when polymer–surfactant interaction allows the restoration of free water hydrogen-bonding structure, resembling the micellization process.
Keywords: Carbopol; Tween 80; Pluronic F-127; Poly(acrylic acid)/surfactant interactions; Microcalorimetry;
Poly(acrylic acid) microgels (carbopol® 934)/surfactant interactions in aqueous media by R. Barreiro-Iglesias; C. Alvarez-Lorenzo; A. Concheiro (179-191).
The interaction of sodium dodecylsulfate (SDS) or benzalkonium chloride (BkCl) with carbopol microgels (0.25% (w/w)) in water was studied through pH, trasmittance, viscosity, surface tension, conductivity, fluorescence, oil solubilization, and microcalorimetry measurements. In the case of the anionic surfactant, enthalpy-driven hydrophobic absorption of SDS into carbopol microgels began when SDS concentration reached 0.05–0.08% and ended around 0.6%. These concentrations were estimated as the critical aggregation (cac) and saturation binding concentration, respectively. The hydrophobic absorption of the surfactant accompanied by its counter-ion caused carbopol microgels to swell and promoted the occurrence of bridges among several carbopol microgels. As a consequence, the consistency of the dispersions increased significantly. Above binding saturation, further addition of SDS produced a shielding effect among the anionic charges of carbopol and its dehydration, which was shown as a decrease in the viscosity of the dispersions. At low shear rates, the dispersions behaved as pseudoplastic owing to orientation of carbopol/SDS aggregates in the flow direction. Increasing shear rates caused the inter-microgel bridges to break, the water layer surrounding them to diminish, and the system to show a shear-thickening behavior. In contrast, carbopol/BkCl aggregates showed shear-thickening flow in the whole range of shear rates analyzed. Electrostatic interactions between BkCl and carbopol carboxylic groups release protons to the medium and decrease the internal osmotic pressure of the microgels. This may favor the establishment of hydrophobic interactions among surfactant tails, and induces carbopol microgels to collapse. The cac was approximately 0.01% BkCl. Saturation binding occurred at 0.3–0.5%, indicating that only 25–40 mol% carboxylic groups were neutralized with BkCl. The shrinking of carbopol microgels as BkCl is absorbed prevents additional surfactant molecules from interacting with the remaining carboxylic groups. Microcalorimetry assays revealed that the aggregation process occurred with a strong gain in enthalpy.
Keywords: Carbopol; SDS; Benzalkonium chloride; Poly(acrylic acid)/surfactant interactions; Microcalorimetry;
Solubility of drugs in aqueous solutions by E Ruckenstein; I Shulgin (193-201).
The present paper deals with the application of the fluctuation theory of solutions to the solubility of poorly soluble drugs in aqueous mixed solvents. The fluctuation theory of ternary solutions is first used to derive an expression for the activity coefficient of a solute at infinite dilution in an ideal mixed solvent and, further, to obtain an equation for the solubility of a poorly soluble solid in an ideal mixed solvent. Finally, this equation is adapted to the solubility of poorly soluble drugs in aqueous mixed solvents by treating the molar volume of the mixed solvent as nonideal and including one adjustable parameter in its expression. The obtained expression was applied to 32 experimental data sets and the results were compared with the three parameter equations available in the literature.
Keywords: Drug solubility; Fluctuation theory; Aqueous mixed solvents;
Importance of using solid lipid microspheres as carriers for UV filters on the example octyl methoxy cinnamate by Gülgün Yener; Tuba Incegül; Namýk Yener (203-207).
The aim of this study was to prepare solid lipid microspheres (SLM) of octyl methoxy cinnamate (2-ethylhexyl-p-methoxy cinnamate; OMC) to achieve controlled release, decrease penetration of this UV absorber from skin and improve its photostability. The influence of the carrier on the rate of release was studied in vitro with a cellulose acetate membrane and in vivo from excised rat skin with Franz diffusion cells. The release rate was decreased by up to 13–80% with the SLM formulation. In vivo, penetration of OMC into skin was investigated by HPLC method. It was found out that the rate of penetration is significantly dependent upon the formulation and could be decreased by up to 77% in SLM formulations. When different topical vehicles were compared, OMC was released and penetrated into rat skin more quickly and in greater amount from vehicles containing free OMC than in SLM form. Additionally, photostability was shown to be improved in SLM form.
Keywords: Octyl methoxy cinnamate; Solid lipid microspheres; Penetration from skin; Photostability;
Effect of chitosan on progesterone release from hydroxypropyl-β-cyclodextrin complexes by T Cerchiara; B Luppi; F Bigucci; V Zecchi (209-215).
An inclusion complex composed of progesterone (Prog) and hydroxypropyl-β-cyclodextrin (HPβCD) was prepared by the spray-drying and freeze-drying methods. Prog alone and its inclusion complex with HPβCD were incorporated into chitosan by spray-drying and freeze-drying. The inclusion complex was characterized by IR and DSC. The inclusion complex was investigated in solution by phase solubility diagrams and stability constant was determined at pH 7.4 and at different temperatures (10, 25 and 37 °C) to obtain the thermodynamic parameters of inclusion. The results indicate that the Prog–HPβCD inclusion complex is more water soluble than Prog alone. Release data from all samples showed significant improvement of the dissolution rate of Prog and a controlled release is obtained in the presence of chitosan.
Keywords: Progesterone; Spray-drying; Freeze-drying; Chitosan; Hydroxypropyl-β-cyclodextrin;
Comparison of skin permeation enhancement by 3-l-menthoxypropane-1,2-diol and l-menthol: the permeation of indomethacin and antipyrine through Yucatan micropig skin and changes in infrared spectra and X-ray diffraction patterns of stratum corneum by Makiko Fujii; Yasuhiro Takeda; Minako Yoshida; Naoki Utoguchi; Mitsuo Matsumoto; Yoshiteru Watanabe (217-223).
3-l-Menthoxypropane-1,2-diol (MPD) is a derivative of l-menthol, which has an enhancement effect on drug permeation through skin. In this study, the effect of MPD on drug permeation through skin was compared with that of l-menthol. MPD or l-menthol at final concentrations of 3% in 40% ethanol was added to the drugs indomethacin or antipyrine and each mix then applied to Yucatan micropig skin in vitro. Drug concentrations in the skin were higher in the presence of either MPD or l-menthol, however, only l-menthol shortened the lag time of permeation. MPD enhanced the skin permeation of the drugs only by increasing the skin concentration of the drugs. In contrast, l-menthol enhanced the skin permeation of the drugs by increasing both the skin concentration and the diffusion rate in skin. The infrared (IR) spectra and X-ray diffraction patterns of stratum corneum after treatment with MPD did not differ from those of intact stratum corneum. A change in the IR spectra of stratum corneum after treatment with l-menthol was observed at the CH band, and the peaks representative of the lipid structure in the X-ray diffraction patterns decreased in intensity. These results suggest that l-menthol, but not MPD, disrupts the intercellular lipid structure of stratum corneum. Thus, MPD is expected to be a moderate skin permeation enhancer.
Keywords: 3-l-Menthoxypropane-1,2-diol (cooling agent 10); Skin permeation; Enhancer; l-Menthol; Indomethacin; Antipyrine; Yucatan micropig skin;
Erratum to “Planar gamma scintigraphy—points to consider when quantifying pulmonary dry powder aerosol deposition” (225).
Planar gamma scintigraphy—points to consider when quantifying pulmonary dry powder aerosol deposition by Eva Bondesson; Thomas Bengtsson; Lars Borgström; Lars-Erik Nilsson; Kristina Norrgren; Eva Trofast; Per Wollmer (227-240).
Methodological aspects of planar gamma scintigraphy used to quantify pulmonary aerosol deposition were investigated using an experimental dry powder formulation. Particles of micronized salbutamol sulphate were labelled with technetium-99m and admixed to an ordered mixture of unlabelled micronized salbutamol sulphate and larger carrier particles of lactose. The radioaerosol was administered to 24 healthy subjects, 12 in each of two consecutive, similarly designed studies. Pulmonary deposition was determined using two methods: repeated planar imaging, and pharmacokinetic assessments following charcoal co-administration to prevent gastrointestinal salbutamol absorption. After due consideration had been taken to ensure appropriate radiolabelling, image acquisition and processing procedures, a scintigraphic estimate of 26.2% (with 95% confidence interval of 24.2–28.4%) was obtained, which did not significantly differ from the pharmacokinetic estimate of 26.4% (24.4–28.7%). In summary, pre-study validation of the radiolabelling technique, quality control of radioaerosols produced during the study, correction for re-distribution of radiolabel from the lungs, selection of regions of interest, assessment of lung contours, correction for tissue attenuation of gamma rays and establishment of the actual recovery of radioactivity in the scintigraphic measurements could potentially affect the accuracy of the scintigraphic estimate of pulmonary deposition and, thus, should be carefully considered in the design or evaluation of any such study.
Keywords: Radionuclide imaging; Radioactive aerosol; Administration; Inhalation; Technetium-99m; Powder inhaler;