International Journal of Pharmaceutics (v.223, #1-2)

The sorption–desorption moisture transfer (SDMT) model was used to predict the effect of desiccant quantity, tablet quantity and tablet initial moisture content on the relative humidity inside high density polyethylene (HDPE) bottles containing a moisture sensitive drug product, roxifiban tablets. The effect of these variables on the stability of roxifiban tablets in the HDPE bottles was also evaluated. There was a good correlation between the calculated relative humidity values inside the package and stability results. Tablet degradant concentration increased with the increase in the relative humidity calculated by the SDMT model. Desiccant quantity was the most important factor in controlling degradation rate, which decreased as the quantity of desiccant in the bottle was increased. For a given desiccant quantity, degradation rate increased with an increase in the weight of tablets in the bottle. The inclusion of a desiccant in the package significantly reduced the effect of initial tablet moisture content on stability. Nevertheless, the effect of initial moisture content was still discernible. This study demonstrated the practical utility of the SDMT model in understanding the correlation between packaging variables and the stability of a moisture sensitive product.
Keywords: Sorption; Desorption; Moisture; Packaging; Stability; Humidity;

The purpose of the experiment was to formulate and characterize the dry powder inhalation (DPI) formulation of liposomally entrapped anti-asthmatic drug, Ketotifen fumarate (KF). Liposomes composed of saturated egg phosphatidyl choline (EPC) and cholesterol (CHOL) were prepared by lipid film hydration and sonicated to have the desired size (<5 μm). Process variable such as vacuum, presonication hydration, postsonication hydration, purification and lamellae composition, were optimized for encapsulation efficiency of KF. Liposomal dispersion was blended with cryoprotectant (sugar) in varying bulk and mass ratios and assessed for its influence on retention of encapsulated drug on lyophilization. Characterization of liposomal dispersion was done for size, lamellarity, entrapped volume and oxidation index. DPI formulation was characterized for angle of repose, compressibility index, dispersibility and respirable fraction (British Pharmacopoeia, apparatus A). Process optimization revealed that a vacuum, 20 in.; presonication hydration, 60 min; postsonication hydration, 2 h and purification by dialysis gave maximum encapsulation efficiency. Sucrose was found to be the most suitable cryoprotectant at bulk strength of 500 mM and mass ratio of lipid/sugar, 1/12. Blending of sorbolac before lyophilization showed better retention of encapsulated KF (97.92±0.54%). In the preparation of sonicated MLVs, the presence of nitrogen atmosphere, α-tocopherol and EDTA could not totally eliminate EPC oxidation, expressed as the change in oxidation index from 0.427±0.01 to 1.510±0.01. The respirable fraction of the developed formulation (21.59±1.53%) is comparable with the control (26.49±1.52%). From studies, it may be concluded that an optimal bulk and mass ratio of sucrose, relative to the size of liposomes is necessary for effective cryoprotection. In this investigation, DPI of liposomal KF was successfully prepared and delivered to the required site in the lungs.
Keywords: Lyophilization; Ketotifen fumarate; Liposomes; Pulmonary; Dry powder inhalation;

Cross-linking chitosan-Fe(III), an oral phosphate binder: studies in vitro and in vivo by Cristiani Bürger; Daniela Valcarenghi; Silvana Sandri; Clóvis A Rodrigues (29-33).
The objective was to evaluate the in vitro and in vivo phosphate binding properties of cross-linked chitosan iron (III) (CH-Fe(III)-CL), a potential oral phosphate binder for treating hyperphosphatemia. At equilibrium, the in vitro phosphate binding of CH-Fe(III)-CL was 23.6 mg g−1 for simulated gastrointestinal conditions. In hyperphosphatemic rats, CH-Fe(III)-CL was similar to iron sulfate in reducing serum phosphate by about 35%.
Keywords: Cross-linked chitosan iron (III); Hyperphosphatemia; Phosphate;

The purpose of this study was to investigate the use of 6-carboxycellulose (OC), a biocompatible and bioresorbable polymer, as a prodrug carrier for amine drugs. Phenylpropanolamine hydrochloride (PPA . HCl) was used as a model drug. OC and PPA were reacted in dimethylformamide (DMF) in the presence of 1,3-dicyclohexylcarbodiimide (DCC) for 2.5 days at room temperature. Filtration, followed by washing with methanol, and subsequent drying under vacuum, produced the conjugate in 65–78% yield. The amount of PPA in the product, determined from the difference in the carboxylic content before and after the reaction, was 24.2% (w/w), corresponding to a degree of substitution (DS) value of 0.7. The Fourier transform-infra red (FT-IR) spectrum of the conjugate, compared with that of OC and PPA . HCl, showed a new band at about 1533 cm−1 attributable to a CO (amide II) stretching and NH (amide I and amide II) bending vibrations, a decrease in intensity of the characteristic free carboxylic acid carbonyl stretching band at about 1748 cm−1, and a strong band at 1663 cm−1 due to CO (amide I) stretching vibration, suggesting that the OC is linked to PPA via an amide bond. The solid-state carbon-13 cross polarization/magic angle spinning nuclear magnetic resonance (13CCP/MAS NMR) spectrum of the conjugate was also consistent with this structure. The release studies performed in pH 4.5, 5.5, and 7.4 buffer solutions and in rat liver homogenate (pH 7.4), showed the conjugate to be more susceptible to hydrolysis at a lower pH and in the presence of rat liver homogenate. In conclusion, the results presented show that OC can be covalently linked to amine drugs via an amide bond in DMF using DCC as a coupling agent, and provide a macromolecular prodrug delivery system.
Keywords: Oxidized cellulose; 6-Carboxycellulose; Oxidized cellulose conjugate; Macromolecular prodrug; Polymer conjugate; Phenylpropanolamine; Carbodiimide;

Stability indicating HPLC method for the estimation of oxycodone and lidocaine in rectal gel by Markus G Gebauer; Anna F McClure; Thean L Vlahakis (49-54).
An HPLC method for the quantification of oxycodone and lidocaine in a gel matrix is described. The mobile phase consisted of methanol–water–acetic acid (35:15:1 v/v/v) and was delivered at 1.5 ml/min through a 4.6×250 mm Zorbax® SB-C8 column. Oxycodone was detected at 285 nm and lidocaine at 264 nm. Linear calibration curves were obtained for oxycodone in the range of 0.05–1.5% (w/w) and for lidocaine in the range of 0.1–5.0% (w/w). Oxycodone and lidocaine were treated with hydrogen peroxide and the oxidation products were readily separated on the column. The method was applied to assess the stability of a gel containing oxycodone hydrochloride (0.3% w/w) and lidocaine (1.5% w/w). The gel was stored under refrigeration in ready-to-use syringes and under these conditions oxycodone and lidocaine were stable for at least 1 year. The gel is useful in the management of tenesmus in rectal cancer.
Keywords: Oxycodone; Lidocaine; HPLC; Rectal gel;

Liposomes were prepared by stepwise extrusion through 5, 1, 0.4, 0.2, 0.1 and 0.05 μm pore sizes using two different filter-extruders, the continuous high pressure device Dispex Maximator® (CE) or alternatively the discontinuous Avestin LiposoFast™ (DE). The liposome dispersions obtained were compared in terms of particle size, lamellarity and encapsulation efficiency of calcein. The liposomes were smaller with CE than DE at all stages due to higher flow rates and pressure drops, except for final filter pore size (0.05 μm) where both preparations had similar sizes. The particle size analysis technique itself had a strong influence on the liposome sizes measured. For bigger liposomes (extruded through 0.4 μm filters) the Nicomp 370 revealed bigger volume-based mean particle sizes along with more stringent differences between volume-based and number-based diameters than the Malvern Zetasizer. In contrast, for small liposomes extruded through 0.05 μm filters, similar liposome sizes were found no matter which of the two PCS techniques or cryo-transmission electron microscopy was used. In congruence to the liposome sizes measured, encapsulation efficiencies were smaller for CE than DE at all filter stages except the final (0.05 μm). No lipid loss occurred and lyso-phosphatidylcholine formation was negligible irrespective of which extrusion technique was used.
Keywords: Liposome; Vesicle; Particle size; Filter; Extrusion; Phosphatidylcholine;

A new recombinant human bone morphogenetic protein-2 carrier for bone regeneration by S. Yokota; S. Sonohara; M. Yoshida; M. Murai; S. Shimokawa; R. Fujimoto; S. Fukushima; S. Kokubo; K. Nozaki; K. Takahashi; T. Uchida; S. Yokohama; T. Sonobe (69-79).
A gelatin sponge was formed by foaming and heat treating a gelatin solution, followed by coating the solid with poly(d,l-lactic-co-glycolic acid) to reinforce the gelatin framework. This sponge was tested for its suitability as a biodegradable porous, recombinant human bone morphogenetic protein (rhBMP)-2 carrier. Incorporation of rhBMP-2 into the sponge was closely related to its bulk density of gelatin sponge. The calcium content in the sponges, as assessed by an ectopic bone formation assay in rats, increased with the increasing sponge bulk density. Histologic and peripheral quantitative computed tomography analysis of implants in this ectopic assay system revealed cell growth throughout the carrier in 4 weeks after implantation regardless gelatin bulk density. The carrier containing rhBMP-2 maintained its three-dimensional structure after implantation; the carrier resisted collapse caused by soft tissue pressure during rapid bone formation as assessed by soft X-ray photographs. These results indicate that this newly developed sponge has excellent carrier characteristics to introduce rhBMP-2 into areas needed for bone regeneration.
Keywords: Gelatin; Bone morphogenetic protein; Porous structure; Biodegradable polymer;

The effect of salt form on the stability of an ester prodrug of a IIb/IIIa receptor antagonist was investigated. The pH of maximum stability for the ester prodrug is approximately 4. The mesylate salt is thought to provide lower microenvironment pH, closer to the pH of maximum stability, than the acetate salt. Stability of drug product manufactured using the mesylate salt (DMP 755) was studied and compared with that for the acetate salt (DMP 754). Formulations contained disodium citrate as a pH modifier to control formulation pH, since solid state stability for this compound is dependent on the microenvironment pH. The pH modifier was not able to achieve adequate microenvironment pH control for the DMP 754 drug product when added using a dry manufacturing process. While DMP 754 required the use of a pH modifier added in solution during wet granulation in order to improve drug product stability, DMP 755 was able to achieve similar results using the dry granulation process. Stability of DMP 755 drug product was independent of effectiveness of the pH modifier. This study showed that the choice of the salt form may provide an alternative for maximizing drug product stability.
Keywords: Salt form; DMP 754; Microenvironment PH; Stability;

The use of shellac for coating purposes in pharmacy, food and nutriceutical industry generally involves the use of organic solvents. An aqueous shellac dispersion has been developed by applying high pressure homogenisation. Shellac was dissolved in alkaline solution, precipitated by HCl addition and the obtained suspension homogenised at 1500 bar applying 20 cycles. The volume diameter 50% was 2 μm, a distinct fraction of particles was in the nanometer range. This surfactant-free shellac dispersion with 20% solid content proved to be physically stable and showed good film forming properties.
Keywords: Shellac; Zeta potential; High pressure homogenisation; Surfactant-free;

Notice board (95-98).