International Journal of Pharmaceutics (v.251, #1-2)

BCNU-loaded poly(d, l-lactide-co-glycolide) wafer and antitumor activity against XF-498 human CNS tumor cells in vitro by Hasoo Seong; Tae Kun An; Gilson Khang; Sang-Un Choi; Chong Ock Lee; Hai Bang Lee (1-12).
Implantable polymeric device that can release chemotherapeutic agent directly into central nervous system (CNS) has had an impact on malignant glioma therapy. The purpose of our study was to develop an implantable polymeric device, which can release intact 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for long-term period over 1 month, and to evaluate its cytotoxicity against XF 498 human CNS tumor cells in vitro. BCNU was incorporated into biodegradable poly(d,l-lactide-co-glycolide) (PLGA), by using spray-drying method. BCNU-loaded PLGA microparticles were characterized by scanning electron microscopy (SEM), powder X-ray diffraction, and differential scanning calorimetry. SEM observation of the microparticles showed that the microparticles were spherical, i.e. microspheres. Homogeneous distribution of BCNU in PLGA microsphere was confirmed by significant reduction of crystallinity of BCNU. Microspheres were fabricated into wafers with flat and smooth surface by direct compression method. In vitro release of BCNU in pH 7.4 phosphate buffered saline was prolonged up to 8 weeks after short initial burst period. Antitumor activity of BCNU-loaded PLGA wafer against XF 498 human CNS tumor cells continued over 1 month and, PLGA only did not affect the growth of the cells. Meanwhile, the cytotoxic activity of BCNU powder disappeared within 12 h. These results strongly suggest that the BCNU/PLGA formulations increase release period of carmustine in vivo and also be useful in the development of implantable polymeric device for malignant glioma.
Keywords: Malignant glioma; 1,3-Bis(2-chloroethyl)-1-nitrosourea; Poly(d,l-lactide-co-glycolide) microparticle; Human tumor cell line;

In this study, injectable microemulsions of vincristine (M-VCR) were prepared and its pharmacokinetics, acute toxicity and antitumor effects were evaluated. In M-VCR, the surfactants were PEG-lipid and cholesterol, the oil phase was a vitamin E solution of oleic acid and VCR. The particle size distribution and zeta potential of M-VCR were measured by the laser light dynamic scattering method. The VCR-loading efficiency was measured by Sephadex G50 column chromatography. The stability of M-VCR was monitored by particle size, VCR-loading efficiency and VCR content changes of M-VCR stored at 7 °C. The pharmacokinetics, acute toxicity and antitumor effects of M-VCR were studied in C57BL/6 mice bearing mouse murine histocytoma M5076 tumors. When stored at 7 °C in the dark for 1 year, the average diameter and VCR-loading efficiency of M-VCR changed from 138.1±1.2 nm and 94.6±4.7% to 127.1±2.4 nm and 91.3±4.8% (n=3), respectively, while 7.4±0.3% VCR decomposition was observed (n=3). The plasma AUC of M-VCR was significantly greater than that of free VCR (F-VCR). The heart, spleen and liver AUC0.08–12 h of M-VCR were significantly smaller than those of F-VCR while the kidney AUC0.08–12 h of M-VCR was significantly greater than that of F-VCR. The tumor AUC0.08–12 h of M-VCR was significantly greater than that of F-VCR. M-VCR had lower acute toxicity and greater potential antitumor effects than F-VCR in M5076 tumor-bearing C57BL/6 mice. M-VCR is a useful tumor-targeting microemulsion drug delivery system.
Keywords: Micromulsions; Vincristine; Pharmacokinetics; Stability; Acute toxicity; Antitumor effects;

Polymeric nanoparticle composed of fatty acids and poly(ethylene glycol) as a drug carrier by Jong-Hoon Lee; Sun-Woong Jung; In-Sook Kim; Young-Il Jeong; Young-Hoon Kim; Sung-Ho Kim (23-32).
Diamine-terminated poly(ethylene glycol) (ATPEG) was hydrophobically modified with long-chain fatty acids (FAs) through a coupling reaction using N,N′-dicyclohexyl carbodiimide (DCC). FA–PEG–FA conjugates have different physico-chemical properties according to the chain length of the fatty acid (FA). Synthesized FA–PEG–FA conjugate was confirmed by Fourier transform-infrared (FT-IR). Since FA–PEG–FA conjugates have the amphiphilic characteristics in aqueous solution, polymeric nanoparticles of FA–PEG–FA conjugates were prepared using a simple dialysis method in water. The results of 1H nuclear magnetic resonance (NMR) spectroscopy and fluorescent spectroscopy suggest that the FA–PEG–FA conjugate has a typical core–shell type nanoparticle structure made by a self-assembling process. From the analysis of fluorescence excitation spectra, especially, the critical micelles concentration (CMC) of this conjugate was changed unpredictably, i.e. the critical association concentration (CAC) value was decreased below a FA carbon number of 16 but, above increased a FA carbon number of 16. Transmission electron micrograph readings showed the spherical morphologies of the polymeric nanoparticles. The particle size was continuously decreased until below a FA carbon number of 20, but it was increased above a FA carbon number of 20. Clonazepam (CNZ), as a model drug, was easy to entrap into polymeric nanoparticles of the FA–PEG–FA conjugates. The drug release behavior was changed according to the FA chain length and was mainly diffusion controlled from the core portion.
Keywords: Poly(ethylene glycol); Fatty acid; Core–shell type; Polymeric nanoparticles;

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 (33-47).
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% (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;

Sodium cromoglicate (SCG) is given by inhalation in prophylactic control of asthma. It was encapsulated in liposomes with a view to improve utilization of the drug when given via pulmonary route. The liposomes were characterized for encapsulation efficiency, shape, size and release rate. Liposomal dispersions were freeze-dried using a cryoprotectant. Freeze-dried liposomal dispersion retained 60% of drug upon reconstitution but increase in size of liposomes was noted. Liposomes exhibited good keeping properties when stored at 4 °C. In vivo performance of liposomal SCG was evaluated in sensitized guinea pigs. In one of the studies, differential leukocyte count and total leukocyte count in bronchoalveolar lavage fluid was measured. Liposomal dispersion showed significant inhibition of influx of neutrophils as compared with drug solution at 24 h. However, in the second study, when recovery period required by animal to revert back to normal respiratory pattern from the onset or preconvulsion time was measured, no significant difference was found between drug solution and liposomal dispersion when administered 2 h before allergen challenge.
Keywords: Sodium cromoglicate; Liposomes; Characterization; Inhibition of neutrophil influx;

Release of recombinant human bone morphogenetic protein 2 from a newly developed carrier by S Yokota; T Uchida; S Kokubo; K Aoyama; S Fukushima; K Nozaki; T Takahashi; R Fujimoto; R Sonohara; M Yoshida; S Higuchi; S Yokohama; T Sonobe (57-66).
After implantation of a polymer-coated gelatin sponge (PGS) containing either 0.4 or 1.0 mg of 125I-rhBMP-2 for each 1 cm3 of PGS into the right ulnar of rabbits, changes in the level of radioactivity at the implant site and in the blood were measured for 21 days after implantation, and the cumulative excretion ratio of radioactivity in the urine and feces was calculated. For both doses, radioactivity at the implant site was eliminated biphasically. The concentration of trichloroacetic acid (TCA)-precipitable radioactivity in the blood reached a maximum 6 h after implantation, at which time it was equivalent to 1.41% of the administered dose (0.4 mg/cm3). The remaining radioactivity was eliminated rapidly thereafter, falling below the detection limit within 48 h. The t 1/2α was about 0.1 days, the t 1/2β was about 3 days, and the mean resident time (MRT) value was about 4 days. By 17 days after implantation, 88.1% of the administered radioactivity had been excreted in the urine, and 1.7% had been excreted in the feces. TCA precipitation test results indicated that most of the radioactivity excreted in urine was a low-molecular weight decomposition product. At 21 days after implantation, the radioactivity of the PGS implant site had declined to 0.5% of the administered amount. Autoradiographs of the implant site taken 28 days after implantation revealed that, at both doses, the residual radioactivity was confined to the area of the implanted PGS. These results indicate that PGS retains an appropriate amount of recombinant human bone morphogenetic protein 2 (rhBMP-2) at the orthotopically implanted site for at least 21 days enough to induce bone regeneration. Thus, PGS shows great clinical potential as a carrier for rhBMP-2.
Keywords: Gelatin; Bone morphogenetic protein; Pharmacokinetics; Controlled release;

Conditions under which poly(ethyl acrylate, methyl methacrylate) 2:1 (poly(EA-MMA), Eudragit NE) forms a stable matrix were investigated in tablets with diclofenac sodium (DS) as an active substance. DS was granulated with the aqueous polymer dispersion. Granules and/or tablets were cured under various temperature and humidity conditions. A six position rotating disk (200 rpm) apparatus was used for the release studies conducted in 37 °C acid then phosphate buffer (0.4 M) pH 6.8 or buffer only as the dissolution media. Morphological characteristics of the tablet surface were observed under SEM. Changes in tablet structure upon curing were evaluated through changes in tablet mechanical characteristics. Modulus of rupture, Young's modulus, AUC, AUC<max, AUC>max, where AUC=AUC<max+AUC>max, were determined by the three-point bending test. Some poorly cured tablets dose-dumped when placed directly into buffer but not if first placed in acid and then buffer. A higher content of polymer in the matrix, led to formation of a stronger polymer network upon higher curing temperature and/or longer curing duration, whereas relative humidity had a minor effect.
Keywords: Dissolution; Dose dumping; Granulation; Matrix; Sustained release; Tensile strength;

The d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was used to increase the aqueous solubility and dissolution rate of furosemide. The solid dispersion of furosemide with TPGS was prepared by solvent method using methanol. The aqueous solubility and the dissolution rate of furosemide were rapid and markedly enhanced from the 1:2 furosemide–TPGS solid dispersion. The X-ray diffractometry showed that pure furosemide and furosemide contained within the physical mixture were crystalline in nature, whereas furosemide in the solid dispersion was not in crystalline form. The infrared spectroscopic analysis showed that an interaction, in the solid dispersion, such as an association between the functional groups of furosemide and TPGS might occur in the molecular level. The infrared spectroscopy and differential thermal analysis showed the physicochemical modifications of the furosemide from the solid dispersion. The solid dispersion technique with TPGS provides a promising way to increase the solubility and dissolution rate of poorly soluble drugs.
Keywords: Furosemide; Solid dispersion; TPGS; Dissolution rate; Spectroscopic characterization;

Emulsifying wax and polyoxyl 2 stearyl ether (Brij 72) nanoparticles (2 mg/ml) containing high concentrations of gadolinium hexanedione (GdH) (0–3 mg) have been engineered from oil-in-water microemulsion templates. Solid nanoparticles were cured by cooling warm microemulsion templates (prepared at 55 °C) to room temperature in one vessel. Nanoparticles were characterized by transmission electron microscopy (TEM), photon correlation spectroscopy (PCS) and gel permeation chromatography (GPC). To obtain folate-coated nanoparticles, a folate ligand was added to either the microemulsion templates or nanoparticle suspensions at 25 °C. Since the concentration of Gd in the tumor is critical to the success of Gd-neutron capture therapy (NCT), the effects of various formulation factors on GdH entrapment in nanoparticles as well as tumor-targeting were studied. GdH entrapment in nanoparticles was affected mostly by the method of GdH incorporation and surfactant concentration used in preparing the microemulsion templates. Cell uptake studies were carried out in KB cells (human nasopharyngeal epidermal carcinoma cell line). The method of adding folate ligand to the formulations did not significantly affect nanoparticle cell uptake (P>0.11; t-test). However, the concentration of folate ligand added to nanoparticles had the greatest influence on nanoparticle uptake (P<0.01; t-test). The results showed that GdH entrapment and cell uptake were optimized and suggested that engineered folate-coated nanoparticles may serve as effective carrier systems for Gd-NCT of tumors.
Keywords: KB cells; Emulsifying wax; Brij 72; Surfactant; Microemulsion;

A new stressed test to predict the foreign matter formation of minodronic acid in solution by Katsutoshi Nakamura; Shigeharu Yokohama; Masataka Katsuma; Toyohiro Sawada; Takashi Sonobe (99-106).
A formulation containing 0.5 mg/ml minodronic acid, 40 mM citrate, pH 4.5, and sodium chloride, stored in regular flint glass ampoules, was stable without particulate increase under high temperature conditions, such as 40 °C for 6 months, or 50 or 60 °C for 3 months. However, when stored at 25 °C, there was an increase in ≥2 μm particles at the 5-month timepoint. This demonstrated that long-term stability cannot simply be predicted by the evaluation of samples just stored at higher temperatures. Therefore, a new stressed test was designed which is useful in the rapid selection of formulations that are stable and without particulate increase. Since the particulate matter is apparently a complex of minodronic acid and aluminum ions leaching from ampoules, samples were placed at 80 °C for up to 4 weeks to accelerate aluminum leaching. Although no particulate increase was observed directly after storage at 80 °C, 4 freeze–thaw cycles following the storage caused a drastic particulate increase. The evaluation of samples subjected to the freeze–thaw cycles indicated that the following formulation modifications have inhibitory effects on particulate generation: (1) addition of meglumine, diethanolamine, mannitol, or glycerol to the formulation; (2) increase of citric acid concentration; (3) decrease of minodronic acid concentration. These modifications also worked well for samples stored at 25 °C for 6 months, and particulate increase did not occur. This method is a powerful tool for predicting the stability of minodronic acid in solution.
Keywords: Minodronic acid; Parenteral formulation; New stressed test; Particle; Complex; Aluminum ion;

The objective of this study was to determine, using a Caco-2 cell monolayer model, the extent to which the paracellular and transcellular routes are altered by citicholine (CDP-Ch) and DMSO in the presence of human serum albumin (HSA). The apparent permeability (Papp) of mannitol in the presence of 4% (w/v) HSA was investigated using 0, 0.5, 1.0, 2.5, 5.0, and 10.0% (v/v)) of DMSO. The Papp for mannitol ranged from 0.56×10−6 to 0.89×10−6 cm/s (mean 0.77×10−6). Increasing the concentration of DMSO does not appear to have an effect on the paracellular transport of mannitol and on the transepithelial resistance (TEER) of the monolayer, (P>0.05). The effect of citicholine (CDP-Ch) was investigated in confluent Caco-2 cell monolayers incubated in the presence of 2, 4, 10, 40, 60, 100 and 200 mM CDP-Ch at 37 °C in an atmosphere of 7% CO2 and 95% relative humidity. Papp of mannitol and diltiazem in the presence of CDP-Ch ranged from 0.53×10−6 to 8.52×10−6 cm/s and from 1.30×10−5 to 2.71×10−5 cm/s, respectively. CDP-Ch may have an effect on the stability of the tight junction complex resulting in an increase in the apparent permeability of mannitol.
Keywords: Caco-2 cells; DMSO; Citicholine; Paracellular; Transcellular; Albumin;

Objective: Many therapeutically active agents experience low bioavailability upon oral administration due to low permeability, low solubility, interaction with efflux transporters or first pass metabolism. In general, absorption enhancers are agents that can modulate the paracellular permeability of drugs, thus, potentially increasing oral bioavailability. The objective of this study was to examine the effect of the active fragment of Zonula occludens toxin (Zot), ΔG, on the transport of a paracellular marker, mannitol, using in vitro (Caco-2 cell monolayers) and in vivo (intraduodenal administration in rats) experimental methods. Methods: The transport of [14C]mannitol with ΔG (0, 50, 80, or 100 μg/ml) was determined across Caco-2 cells. Male Sprague–Dawley rats were assigned to receive one of the following treatments: [14C] mannitol (40 μCi/kg), [14C]mannitol/ΔG (417 μg/kg), or [14C] mannitol/ΔG/Protease inhibitors (PI). Results: The mean (±S.E.M.) apparent mannitol permeability coefficients (P app) observed after incubation with 0, 50, 80, and 100 μg/ml ΔG were 3.5 (±0.4), 4.17 (±0.27), 4.33 (±0.61), and 9.94 (±0.24)×10−6 cm/s. After oral administration, C max (3.8×10−4 vs. 4.4×10−4 mM) and AUC0–6 h (0.096 vs. 0.088 mM min), obtained for [14C]mannitol and [14C]mannitol/ΔG, respectively, were not statistically different. However, both C max (7.6×10−4 mM) and AUC0–6 h (0.25 mM min) were significantly higher for the [14C]mannitol/ΔG/PI treatment. Conclusions: The 12 kDa fragment of Zot, ΔG, enhanced the in vitro transport and oral absorption of the paracellular marker, mannitol, in the presence of protease inhibitors (PI).
Keywords: Permeability; ΔG; Zot; Mannitol; Bioavailability; Absorption enhancer;

Development of oral acetaminophen chewable tablets with inhibited bitter taste by Hiroyuki Suzuki; Hiraku Onishi; Yuri Takahashi; Masanori Iwata; Yoshiharu Machida (123-132).
Various formulations with some matrix bases and corrigents were examined for development of oral chewable tablets which suppressed the bitter taste of acetaminophen, often used as an antipyretic for infants. Corn starch/lactose, cacao butter and hard fat (Witepsol H-15) were used for matrix bases, and sucrose, cocoa powder and commercial bitter-masking powder mixture made from lecithin (Benecoat BMI-40) were used for corrigents against bitter taste. The bitter taste intensity was evaluated using volunteers by comparison of test samples with standard solutions containing quinine at various concentrations. For the tablets made of matrix base and drug, Witepsol H-15 best inhibited the bitter taste of the drug, and the bitter strength tended to be suppressed with increase in the Witepsol H-15 amount. When the inhibitory effect on the bitter taste of acetaminophen solution was compared among the corrigents, each tended to suppress the bitter taste; especially, Benecoat BMI-40 exhibited a more inhibitory effect. Further, chewable tablets were made of one matrix base and one corrigent, and of one matrix base and two kinds of corrigents, their bitter taste intensities after chewing were compared. As a result, the tablets made of Witepsol H-15/Benecoat BMI-40/sucrose, of Witepsol H-15/cocoa powder/sucrose and of Witepsol H-15/sucrose best masked the bitter taste so that they were tolerable enough to chew and swallow. The dosage forms best masking bitter taste showed good release of the drug, indicating little change in bioavailability by masking.
Keywords: Oral acetaminophen chewable tablet; Bitter taste intensity; Masking; Matrix base; Corrigent;

A procedure to prepare a complex of copoly (dl-lactic/glycolic acid) and zinc oxide (PLGA-zinc oxide complex) was developed. Out of sparingly water-soluble zinc compounds, zinc oxide was most remarkably soluble in a PLGA/dichloromethane solution and the dissolution rates became faster as the water contents in the PLGA/dichloromethane solutions increased. Since the solubility of zinc oxide was saturated at approximately 0.5-fold molar ratio to PLGA and water was generated with dissolution of zinc oxide in the PLGA/dichloromethane solutions, it is suggested that zinc oxide interacts with the terminal carboxyl group of PLGA. In addition, the glass-transition temperature of a solid material obtained by vacuum-drying the PLGA/dichloromethane solution dissolving zinc oxide became higher as the zinc content increased, suggesting that the formation of a PLGA-zinc oxide complex. Microcapsules were prepared with the PLGA-zinc oxide complex using recombinant human growth hormone (rhGH) in order to evaluate an effect of the complex on protein release and stability of protein in the microcapsules. Released rhGH amount from the microcapsules prepared with the PLGA-zinc oxide complex after subcutaneous administration in rats was significantly larger than that from microcapsules prepared with PLGA alone, indicating that rhGH molecules in the microcapsules was stabilized by the PLGA-zinc oxide complex.
Keywords: Copoly (dl-lactic/glycolic acid) (PLGA); Zinc oxide; Complex; Water content; Recombinant human growth hormone (rhGH); Stabilization in microcapsules;

Non-surfactant nanospheres of progesterone inclusion complexes with amphiphilic β-cyclodextrins by Erem Memişoğlu; Amélie Bochot; Murat Şen; Dominique Duchêne; A.Atilla Hıncal (143-153).
Amphiphilic β-cyclodextrins were formulated as nanospheres and characterised by particle size, zeta potential and TEM following freeze-fracture. The nanospheres were loaded with progesterone with different loading techniques involving the spontaneous formation of nanospheres from pre-formed inclusion complexes of amphiphilic β-cyclodextrins modified on the primary or secondary face with progesterone. Inclusion complexes were characterised with various techniques including Differential Scanning Calorimetry (DSC), Fast Atom Bombardment Mass Spectrometry (FAB MS) and 1H NMR spectroscopy; and progesterone was believed to be partially included in the CD cavity. Loading properties of conventionally-loaded nanospheres were compared with those prepared directly from pre-formed inclusion complexes and loading technique was found to enhance associated drug percentage significantly (P<0.05). Although both amphiphilic β-cyclodextrins (6-N-CAPRO-β-CD and β-CDC6) were capable of high progesterone loading, β-CDC6 displayed slightly higher entrapment efficiency due to the possible higher affinity of progesterone to the 14 alkyl chains surrounding this molecule resulting in higher drug adsorption to particle surface. Progesterone was released within a period of 1 h from all formulations. Progesterone-loaded amphiphilic β-CD nanospheres were proved to be a promising non-surfactant injectable delivery system providing high-quantity of water-insoluble progesterone rapidly within 1 h.
Keywords: Amphiphilic β-cyclodextrin; Nanosphere; Inclusion complex; Progesterone; Loading capacity; Drug release;

Adsorbed pluronics on the skin of human volunteers: effects on bacterial adhesion by Lorraine H Marsh; Cameron Alexander; Mark Coke; Peter W Dettmar; Michael Havler; Thomas G Nevell; John D Smart; Barry Timmins; John Tsibouklis (155-163).
An amphiphilic copolymer, Pluronic F127, has been deposited, by adsorption, to the skin of human volunteers and the ability of the coated skin to resist bacterial colonisation has been evaluated. In parallel, the ability of the same copolymer to act as a bacterial release agent has been evaluated. In both cases, F127 proved to be of little added value in formulations designed to suppress the bacterial colonisation of human skin.
Keywords: Bacterial-release coatings; Pluronic F127; In vivo evaluation;

Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion—part I by Geert Verreck; Karel Six; Guy Van den Mooter; Lieven Baert; Jef Peeters; Marcus E. Brewster (165-174).
Solid dispersions containing different ratios of itraconazole and hydroxypropylmethylcellulose (HPMC) were prepared by solvent casting. Based on dose, differential scanning calorimetry and dissolution results, a drug/polymer ratio of 40/60 w/w was selected in order to prepare dispersions by melt extrusion. The melt extrusion process was characterized using a design of experiments (DOE) approach. All parameter settings resulted in the formation of an amorphous solid dispersion whereby HPMC 2910 5 mPa s prevents re-crystallization of the drug during cooling. Dissolution measurements demonstrated that a significantly increased dissolution rate was obtained with the amorphous solid dispersion compared to the physical mixture. The outcome of DOE further indicated that melt extrusion is very robust with regard to the itraconazole/HPMC melt extrudate characteristics. Stability studies demonstrated that the itraconazole/HPMC 40/60 w/w milled melt extrudate formulation is chemically and physically stable for periods in excess of 6 months as indicated by the absence of degradation products or re-crystallization of the drug.
Keywords: Solid dispersion; Itraconazole; Melt extrusion;

The preparation and characterisation of drug-loaded alginate and chitosan sponges by Hui Ling Lai; Asad Abu'Khalil; Duncan Q.M. Craig (175-181).
Sponges composed of sodium alginate and chitosan were prepared via a freeze drying process in order to assess the utility of mixed sponges as potential wound dressings or matrices for tissue engineering. Sponge preparation involved dissolving both polymers (either individually or mixed) in 1% acetic acid and freeze-drying the corresponding solutions. The mechanical properties of the sponges were assessed using texture analysis and the microstructure examined using scanning electron microscopy. The dissolution of a model drug (paracetamol) from the sponges was assessed as a function of polysaccharide composition. It was noted that the sponges had a flexible yet strong texture, as assessed macroscopically. Measurement of the resistance to compression (‘hardness’) indicated that the chitosan sponges were the ‘hardest’ while the alginate sponges showed the least resistance to compression, with all sponges showing a high degree of recovery. In contrast, the breaking force (tensile force) of the sponges were greatest for the single component systems, while the elongation prior to breaking was similar for each material. SEM studies indicated that the mixed systems had a less well-defined microstructure than the single component sponges. This was ascribed to the two polysaccharides interacting in aqueous solution via coulombic forces, leading to a more randomly ordered network being formed on freezing. Dissolution studies indicated that systems containing chitosan alone showed the slowest release profile, with the mixed systems showing a relatively rapid dissolution profile. The use of chitosan and alginates together, therefore, appears to allow the formulator to manipulate both the mechanical properties and the drug release properties of the sponges.
Keywords: Alginate; Chitosan; Paracetamol; Sponge; Texture analysis;

Influence of enteric citric acid on the release profile of 4-aminopyridine from HPMC matrix tablets by Ilona Martı́nez González; Leopoldo Villafuerte Robles (183-193).
A weakly basic experimental drug, 4-aminopyridine (4-AP), was taken as a model to study the influence of enteric citric acid (ECA) on the release profile from hydroxypropyl methylcellulose (HPMC) matrices, to set up a system bringing about gradual release of the drug. For this purpose, powder mixtures were wet granulated with water and compressed with a hydraulic press at 55 MPa. Dissolution studies were made using first 900 ml HCl 0.1 N, and then phosphate buffer pH 7.4. Dissolution curves were described by M t /M inf =kt n . As physically expected, increasing proportions (2–9%) of the in acid insoluble ECA decreased the release rate. In an acid medium, ECA acts as a physical barrier obstructing the diffusion path, dissolving after the pH change to 7.4. Both circumstances flattening the release profile. Apparent zero order release was observed at ECA concentrations of about 10%. The presence of ECA compensates the effect of decreased solubility of 4-AP at pH 7.4. Unexpectedly, higher ECA proportions (10–50%) act increasing the dissolution rate. This is attributed to a void space formation around the insoluble ECA, after HPMC hydration, which percolates after a critical ECA proportion of approximately 10%. Moreover, decreasing release constant values (k) show a logarithmic relationship with increasing values of the exponent (n). This indicates that an apparent zero-order release can be obtained at a given release constant.
Keywords: 4-Aminopyridine; Release mechanism; HPMC; Enteric citric acid; pH effect;

Sucrose cocoate, a component of cosmetic preparations, enhances nasal and ocular peptide absorption by Fakhrul Ahsan; John J Arnold; Elias Meezan; Dennis J Pillion (195-203).
Sucrose cocoate (SL-40), an emulsifier employed in emollient, skin-moisturizing cosmetic formulations, contains a mixture of sucrose esters of coconut fatty acids in aqueous ethanol solution. In order to determine its potential utility in enhancing nasal and ocular drug delivery, absorption studies were performed in anesthetized Sprague-Dawley male rats with calcitonin and insulin, two distinct therapeutic peptides. Administration of a nasal insulin formulation containing 0.5% sucrose cocoate caused a rapid and significant increase in plasma insulin levels, with a concomitant decrease in blood glucose levels. When insulin was administered ocularly in the presence of 0.5% sucrose cocoate, a smaller increase in plasma insulin levels, and a decrease in blood glucose levels, were observed. Administration of a nasal calcitonin formulation containing 0.5% sucrose cocoate caused a rapid increase in plasma calcitonin levels and a concomitant decrease in plasma calcium levels. Mass spectrometric analyses were used to characterize the nature of the sucrose fatty acid esters in the mixture. The most abundant sucrose ester in sucrose cocoate was sucrose monododecanoate, with smaller amounts of sucrose monodecanoate and sucrose monotetradecanoate. In vivo experiments confirmed that this ester was an effective enhancer of nasal peptide drug absorption.
Keywords: Nasal absorption; Sucrose cocoate; Insulin; Calcitonin; Ocular absorption; Sucrose fatty acid esters;

Enhanced stability of rubbery amylose-rich maize starch films plasticized with a combination of sorbitol and glycerol by K Krogars; J Heinämäki; M Karjalainen; A Niskanen; M Leskelä; J Yliruusi (205-208).
Well known aging problems with rubbery starch films are the migration of plasticizer and increased crystallinity leading to embrittlement. The effects of a combination of sorbitol and glycerol used as plasticizers on mechanical, moisture permeability and solid-state properties of rubbery amylose maize starch (Hylon VII) films were studied. The films were prepared by casting and were exposed to conditions of 25 °C/60% relative humidity (RH) and 40 °C/75% RH for 9 months. The starch films plasticized with a combination of sorbitol and glycerol (1:1) at equal amount to the polymer weight, were shown to be the most stable alternative of the studied films during the 9 months storage period. The water vapor transmission (WVTR) of the films did not change during the period of storage and neither did the elongation at break, but the tensile strength increased. X-ray diffraction (XRD) results showed that during storage no crystallization had occurred. The combination of sorbitol and glycerol prevented the migration of the plasticizer molecules out of the film.
Keywords: Plasticizer; Sorbitol; Glycerol; High amylose maize starch; Film properties;

Noticeboard (211-214).