Influence of an Acrylic Polymer Blend on the Physical Stability of Film-Coated Theophylline Pellets

The purpose of this study was to investigate the physical stability of a coating system consisting of a blend of two sustained release acrylic polymers and its influence on the drug release rate of theophylline from coated pellets. The properties of both free films and theophylline pellets coated with the polymer blend were investigated, and the miscibility was determined via differential scanning calorimetry. Eudragit^® RS 30 D was plasticized by the addition of Eudragit^® NE 30 D, and the predicted glass transition temperature (T _g) of the blend was similar to the experimental values. Sprayed films composed of a blend of Eudragit^® NE 30 D/Eudragit^® RS 30 D (1:1) showed a water vapor permeability six times greater than films containing only Eudragit^® NE 30 D. The presence of quaternary ammonium functional groups from the RS 30 D polymer increased the swellability of the films. The films prepared from the blend exhibited stable permeability values when stored for 1 month at both 25°C and 40°C, while the films which were composed of only Eudragit^® NE 30 D showed a statistically significant decrease in this parameter when stored under the same conditions. Eudragit^® NE 30 D/Eudragit^® RS 30 D (1:1)-sprayed films decreased in elongation from 180% to 40% after storage at 40°C for 1 month, while those stored at 25°C showed no change in elongation. In coated pellets, the addition of Eudragit^® RS 30 D to the Eudragit^® NE 30 D increased the theophylline release rate, and the pellets were stable when stored at 25°C for a period of up to 3 months due to maintenance of the physico-mechanical properties of the film. Pellets stored at 40°C exhibited a decrease in drug release rate over time as a result of changes in film physico-mechanical properties which were attributed to further coalescence and densification of the polymer. When the storage temperature was above the T _g of the composite, instabilities in both drug release rate and physical properties were evident. Stabilization in drug release rate from coated pellets could be correlated with the physico-mechanical stability of the film formulation when stored at temperatures below the T _g of the polymer.     

Taste Masking of Griseofulvin and Caffeine Anhydrous Using Kleptose Linecaps DE17 by Hot Melt Extrusion

The objective of this project was to investigate the potential of Kleptose Linecaps DE17 (KLD) in masking the unpleasant/bitter taste of therapeutic agents by hot melt extrusion (HME). Griseofulvin (GRI) and caffeine anhydrous (CA) were used as a bitter active pharmaceutical ingredient (API) model drugs. Thermogravimetric studies confirmed the stability of GRI, CA, and KLD at the employed extrusion temperatures. The differential scanning calorimetry (DSC) studies revealed a characteristic melting endotherm of GRI at 218–220°C and CA at 230–232°C in the physical mixtures as well as in all extrudates over the period of study, indicating the crystalline nature of drug. HME of KLD was achieved only in the presence of plasticizer. Among the several plasticizers investigated, xylitol showed improved processability of KLD at 15% w/w concentration. Dissolution studies of HME extrudates using simulated salivary medium exhibited ～threefold less release compared to physical mixture at the end of 5 min (the lesser drug release, better the taste masking efficiency). Furthermore, the results from the sensory evaluation of products in human panel demonstrated strong bitter taste in the case of physical mixture compared to the HME formulation, suggesting the potential of Kleptose Linecaps DE17 as taste masking polymer in melt extruded form.     

Stabilization of hot-melt extrusion formulations containing solid solutions using polymer blends

This study was aimed at enhancing the physical stability of the drug clotrimazole (CT) and the polymer contained within hot-melt extrusion (HME) films using polymer blends of hydroxypropyl cellulose (HPC) and poly(ethylene oxide) (PEO). The HME films were investigated for solid-state characteristics, moisture sorption, bioadhesivity, mechanical properties, glass transition temperature, release characteristics, and physical and chemical stability of the drug and the polymer within the HME films. The solid-state characterization of the drug and the polymer was performed using differential scanning calorimetry, x-ray diffractometry, and dynamic mechanical analysis. A texture analyzer was used to study the bioadhesive and mechanical properties of the HME films. The physical and chemical stability of the films, stored at 25°C/60% relative humidity or in a desiccator, was studied for up to 12 months. CT was found to be in solid solution within all of the formulations extruded. The physical stability of the drug and PEO in the HME films increased with increasing HPC concentration, but the bioadhesivity and flexibility of the PEO films decreased with increasing HPC concentration. Films containing HPC: PEO∶CT in the ratio of 55∶35∶10 demonstrated optimum physical-mechanical, bioadhesive, and release properties. In conclusion, polymer blends of HPC and PEO were used successfully to tailor the drug release, mechanical and bio-adhesive properties, and stability of the HME films. Published: June 29, 2007     

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME

Hypromellose is a hydrophilic polymer widely used in immediate- and modified-release oral pharmaceutical dosage forms. However, currently available grades of hypromellose are difficult, if not impossible, to process by hot melt extrusion (HME) because of their high glass transition temperature, high melt viscosity, and low degradation temperature. To overcome these challenges, a modified grade of hypromellose, AFFINISOL? HPMC HME, was recently introduced. It has a significantly lower glass transition temperature and melt viscosity as compared to other available grades of hypromellose. The objective of this paper is to assess the extrudability and performance of AFFINISOL? HPMC HME (100LV and 4M) as compared to other widely used polymers in HME, including HPMC 2910 100cP (the currently available hypromellose), Soluplus®, Kollidon® VA 64, and EUDRAGIT® E PO. Formulations containing polymer and carbamazepine (CBZ) were extruded on a co-rotating 16-mm twin-screw extruder, and the effect of temperature, screw speed, and feed rate was investigated. The performance of the solid dispersions was evaluated based on Flory–Huggins modeling and characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Raman spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and dissolution. All formulations extruded well except for HPMC 2910 100cP, which resulted in over-torqueing the extruder (machine overloading because the motor cannot provide efficient energy to rotate the shaft). Among the HME extrudates, only the EUDRAGIT® E PO formulation was crystalline as confirmed by DSC, XRD, and Raman, which agreed with predictions from Flory–Huggins modeling. Dissolution testing was conducted under both sink and non-sink conditions. Sink dissolution testing in neutral media revealed that amorphous CBZ in the HME extrudates completely dissolved within 15 min, which was much more rapid than the time for complete dissolution of bulk CBZ (60 min) and EUDRAGIT® E PO solid dispersion (more than 6 h). Non-sink dissolution in acidic media testing revealed that only CBZ contained in the AFFINISOL? HPMC HME, and EUDRAGIT® E PO solid dispersions rapidly supersaturated after 15 min, reaching a twofold drug concentration compared to the CBZ equilibrium solubility. In summary, AFFINISOL? HPMC HME 100LV and AFFINISOL? HPMC HME 4M are useful in the pharmaceutical HME process to increase wetting and dissolution properties of poorly water-soluble drugs like CBZ.     

Hot Melt Extrusion for Sustained Protein Release: Matrix Erosion and <Emphasis Type="Italic">In Vitro</Emphasis> Release of PLGA-Based Implants

The design of biodegradable implants for sustained release of proteins is a complex challenge optimizing protein polymer interaction in combination with a mini-scale process which is predictive for production. The process of hot melt extrusion (HME) was therefore conducted on 5- and 9-mm mini-scale twin screw extruders. Poly(lactic-co-glycolic acid) (PLGA) implants were characterized for their erosion properties and the in vitro release of the embedded protein (bovine serum albumin, BSA). The release of acidic monomers as well as other parameters (pH value, mass loss) during 16 weeks indicated a delayed onset of matrix erosion in week 3. BSA-loaded implants released 17.0% glycolic and 5.9% lactic acid after a 2-week lag time. Following a low burst release (3.7% BSA), sustained protein release started in week 4. Storage under stress conditions (30°C, 75% rH) revealed a shift of erosion onset of 1 week (BSA-loaded implants: 26.9% glycolic and 9.3% lactic acid). Coherent with the changed erosion profiles, an influence on the protein release was observed. Confocal laser scanning and Raman microscopy showed a homogenous protein distribution throughout the matrix after extrusion and during release studies. Raman spectra indicated a conformational change of the protein structure which could be one reason for incomplete protein release. The study underlined the suitability of the HME process to obtain a solid dispersion of protein inside a polymeric matrix providing sustained protein release. However, the incomplete protein release and the impact by storage conditions require thorough characterization and understanding of erosion and release mechanisms.     

Investigations on the Thermal Stability of Fullerene-Based (Ag-C<Subscript>70</Subscript>) Nanocomposite Thin Films

Fullerene-based bi-functional nanocomposite thin film (Ag nanoparticles embedded in fullerene C₇₀ matrix) is synthesized by thermal co-deposition method. Thermal stability of Ag-C₇₀ nanocomposite is investigated by annealing the nanocomposite thin film at different temperatures from 80 to 350 °C for 30 min. Optical and structural properties of nanocomposite thin film with respect to high temperature are studied by UV-visible spectroscopy and x-ray diffraction, respectively. Transmission electron microscopy is performed to observe the temperature-dependent size evolution of Ag nanoparticles in fullerene C₇₀ matrix. A large growth of Ag nanoparticles is observed with temperature especially above 200 °C due to enhanced diffusion of Ag in fullerene C₇₀ at higher temperature and Ostwald ripening. The properties of metal-fullerene nanocomposite is not significantly affected up to a temperature of 150 °C. With a further increase in temperature, a major blue shift of ~?33 nm in SPR wavelength is seen at a temperature of 300 °C due to the thermal induced structural transformation of fullerene C₇₀ matrix into amorphous carbon. A very large-sized Ag nanoparticle with a wide size distribution varying from 27.8 ± 0.6 to 330.0 ± 4.5 nm is seen at 350 °C and due to which, a red shift of ~?16 nm is obtained at this temperature. This study throws light on the thermal stability of the devices based on metal-fullerene bi-functional nanocomposite.     

Development of an Abuse- and Alcohol-Resistant Formulation Based on Hot-Melt Extrusion and Film Coating

This study focused on the development of flexible (i.e., deformable) multiple-unit pellets that feature (i) a prolonged drug release, (ii) drug abuse deterrence, and (iii) a minimal risk of alcohol-induced dose dumping (ADD). Deformable pellets were prepared via an advanced continuous one-step hot-melt extrusion (HME) technique, with the drug (i.e., antipyrine and codeine phosphate) fed as an aqueous solution into the molten matrix material (i.e., cornstarch, gum arabic, and xanthan). Formulations that had suitable mechanical characteristics (i.e., high compression strength) were coated with a flexible Aquacoat^® ARC film to ensure prolonged release and to avoid ADD. The pellets were characterized in terms of their mechanical properties and in vitro drug release behavior in alcoholic media. All formulations were abuse deterrent: they had a high compression strength and grinding the pellets into powder was impossible. Since the pellets comprising gum arabic and xanthan as a matrix did not remain intact during dissolution testing, they had a very fast drug release rate. Cornstarch-based pellets that swelled but remained intact in the dissolution media had a slower drug release. Coated cornstarch-based pellets had a prolonged release over 8 h and resistance to dose dumping in 20 and 40% ethanol. Our results indicate that cornstarch-based pellets manufactured via the advanced HME process followed by coating are a promising formulation that makes tampering difficult due to a high compression strength combined with robustness in alcoholic media.     

The effect of temperature exposure during shipment on a commercially available demineralized bone matrix putty

During August and September of 2013, temperature data loggers were shipped to and from an AATB accredited and FDA registered allograft tissue processing facility in Belgrade, MT (Bacterin International, Inc.) to five warm climate cities (Dallas, TX, El Paso, TX, New Orleans, LA, Phoenix, AZ, and Tampa, FL). Shipping data acquired from 72 independent shipments were analyzed to generate an assessment of temperature exposure, shipment times, and shipping event durations experienced during routine distribution. Overall the packages experienced an average temperature of 26.2 ± 2.3 °C which mirrored the average external ambient temperature of 25.8 ± 3.0 °C. However, temperature spikes above 40 °C were frequently observed. The data from the model shipments were extrapolated to provide a worst-case high temperature spike of 52.9 °C for 12 h and 14 min. Multiple lots of a commercially available demineralized bone matrix (DBM) putty (OsteoSelect^® DBM Putty) were subjected to continuous heating at 50 °C, to multiple worst-case temperature spikes, and to multiple freeze–thaw cycles to assess the effects of these temperature extremes on the handling and osteoinductivity of the allograft tissue. Five weeks of continuous exposure to 50 °C and 12 simulated worst-case one-way shipments did not adversely affect the handling characteristics or the in vivo osteoinductivity of the product.     

Novel Strategy to Fabricate Floating Drug Delivery System Based on Sublimation Technique

The present study aims to develop floating drug delivery system by sublimation of ammonium carbonate (AMC). The core tablets contain a model drug, hydrochlorothiazide, and various levels (i.e., 0–50% w/w) of AMC. The tablets were then coated with different amounts of the polyacrylate polymers (i.e., Eudragit® RL100, Eudragit® RS100, and the mixture of Eudragit® RL100 and Eudragit® RS100 at 1:1 ratio). The coated tablets were kept at ambient temperature (25°C) or cured at 70°C for 12 h before further investigation. The floating and drug release behaviors of the tablets were performed in simulated gastric fluid USP without pepsin at 37°C. The results showed that high amount of AMC induced the floating of the tablets. The coated tablets containing 40 and 50% AMC floated longer than 8 h with a time-to-float of about 3 min. The sublimation of AMC from the core tablets decreased the density of system, causing floating of the tablets. The tablets coated with Eudragit® RL100 floated at a faster rate than those of Eudragit® RS100. Even the coating level of polymer did not influence the time-to-float and floating time of coated tablets containing the same amount of AMC, the drug release from the tablets coated with higher coating level of polymer showed slower drug release. The results suggested that the sublimation technique using AMC is promising for the development of floating drug delivery system.     

Influence of Defined Shear Rates on Structural Changes and Functional Properties of Highly Concentrated Whey Protein Isolate-Citrus Pectin Blends at Elevated Temperatures

The functional properties of whey proteins can be improved by conjugation with citrus pectin. Although protein-polysaccharide conjugates can be performed using extrusion processing, little is known about the influence of the extrusion conditions (e.g., temperature, shear stress, time) on the reactions taking place. As during extrusion processing, thermal and mechanical stresses are coupled to each other, their influence on the reactions taking place cannot be investigated separately. This study aims to get a deeper understanding of the influence of defined shear rates on structural changes and functional properties of highly concentrated whey protein-citrus pectin blends treated at elevated temperatures by using a closed-cavity rheometer (CCR). The CCR provides the opportunity to examine the impact of thermal and mechanical stresses in highly concentrated systems independently. The analyses of structural changes showed that the formation of disulfide bonds was accelerated with increasing shear. Temperature treatments at 120 °C and 140 °C resulted in the formation of non-disulfide covalent cross-links (e.g., Maillard reaction products and isopeptides), while shear inhibited their formation at treatment conditions up to 140 °C and 2 min. The samples treated at 140 °C and 2 min (with and without the application of shear) exhibited improved emulsifying capacities which is attributed to changes in their interfacial properties. This might be due to high concentrations of fluorescent compounds indicating the formation of Maillard reaction products (e.g., conjugates).     

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

Thermal processing technologies continue to gain interest in pharmaceutical manufacturing. However, the types and grades of polymers that can be utilized in common thermal processing technologies, such as hot-melt extrusion (HME), are often limited by thermal or rheological factors. The objectives of the present study were to compare and contrast two thermal processing methods, HME and KinetiSol® Dispersing (KSD), and investigate the influence of polymer type, polymer molecular weight, and drug loading on the ability to produce amorphous solid dispersions (ASDs) containing the model compound griseofulvin (GRIS). Dispersions were analyzed by a variety of imaging, solid-state, thermal, and solution-state techniques. Dispersions were prepared by both HME and KSD using polyvinylpyrrolidone (PVP) K17 or hydroxypropyl methylcellulose (HPMC) E5. Dispersions were only prepared by KSD using higher molecular weight grades of HPMC and PVP, as these could not be extruded under the conditions selected. Powder X-ray diffraction (PXRD) analysis showed that dispersions prepared by HME were amorphous at 10% and 20% drug load; however, it showed significant crystallinity at 40% drug load. PXRD analysis of KSD samples showed all formulations and drug loads to be amorphous with the exception of trace crystallinity seen in PVP K17 and PVP K30 samples at 40% drug load. These results were further supported by other analytical techniques. KSD produced amorphous dispersions at higher drug loads than could be prepared by HME, as well as with higher molecular weight polymers that were not processable by HME, due to its higher rate of shear and torque output.     

Effects of Hasten Drying and Storage Conditions on Properties and Microstructure of Konjac Glucomannan-Whey Protein Isolate Blend Films

Impact of drying process and storage conditions on properties of konjac glucomannan (KGM) and whey protein isolate (WPI) blend films was investigated. Hundred grams of film solution contained 0.4 g KGM, 3.8 g WPI and 1.5 g glycerol. During drying process, air velocity was varied to produce fast drying (3 h) and slow drying (15 h) in tray dryers under 50 °C. The high air velocity resulted in a significant higher drying rate in fast drying than low air velocity in slow drying. Drying curves from both processes were well-fitted with Page model and Henderson and Pabis model (R² ≥ 0.98). Fast drying improved transparency and mechanical properties without impairing color, solubility or water vapor permeability (WVP). Fast-dried film had less surface roughness and contained larger protein clusters. It also had greater melting enthalpy of protein aggregates, implying stronger networks. For stability study, fast-dried film was stored at 4-35 °C for 24 days. Transparency decreased over time. Overall mechanical properties have improved during storage. Color, solubility and WVP did not significantly change over time at all conditions (p?>?0.05). Microstructure of aged films was relatively similar to that of the freshly prepared film. Overall, the fast-dried KGM-WPI film exhibited reasonable storage stability.     

Mechanistic Evaluation of the Effect of Sintering on Compritol® 888 ATO Matrices

The present research studied the effect of sintering technique in the development of a controlled release formulation for ketorolac tromethamine. The method consisted of mixing drug and wax powder (Compritol® 888 ATO) along with lactose as diluent and talc as lubricant followed by direct compression at room temperature. The compressed fluffy matrices were kept at 80°C for 1, 2, and 3 h for sintering. The sintered tablets were characterized by their physical parameters and in vitro dissolution profile. The sintering time markedly affected the drug release properties of Compritol® 888 ATO matrices. It is notable that the release rate of ketorolac tromethamine from matrices was inversely related to the time of sintering. This may be due to the increase in the extent and firmness of sintering which further compacts the mass so that drug release is affected. Contact angle measurement and scanning electron microscopy analysis indicated that heat treatment caused the wax to melt and redistribute. This redistributed wax formed a network-like structure in which the drug along with lactose is entrapped. This particular formed matrix is responsible for retarding the drug release. Fourier transform infrared spectroscopy results did not show any drug–wax interaction due to sintering. Differential scanning calorimetric and powder X-ray diffraction studies ruled out the occurrence of solid solution and polymorphic changes of the drug. Drug release from the wax tablets with or without sintering was best described by the Higuchi equation.     

Effects of different processing methods of flaxseed on ruminal degradability and in vitro post-ruminal nutrient disappearance

The aim of the study was to determine the effects of different heat-processing methods of flaxseed on the in situ effective dry matter degradability (EDMD) and the in situ effective crude protein degradability (ECPD). The treatments included roasting, steep roasting, rolled roasting, rolled steep roasting, microwave irradiation and extrusion. Three rumen-fistulated sheep were used for in situ incubations. Furthermore, the effects of heat-processing methods on post-ruminal in vitro nutrient disappearance and total tract disappearance were measured by a three-step in vitro technique. The seeds were roasted and extruded at 140°C to 145°C. One lot of roasted seeds was gradually cooled for about 1 h (roasting) and another lot was held in temperature isolated barrels for 45 min (steep roasting). Moreover, roasted and steep roasted flaxseed was rolled in a roller mill. The lowest and highest EDMD was observed for unheated and extruded flaxseed, respectively (p < 0.05). The highest ECPD was observed for extruded flaxseed (p < 0.05). Roasting and microwave irradiation reduced ECPD of flaxseed (p < 0.05). In vitro post-ruminal disappearance of crude nutrients including fibre fractions was highest for rolled-roasted and rolled steep-roasted flaxseed (p < 0.05). The lowest and highest total tract disappearance rates of crude nutrients and fibre fractions were estimated for unheated and extruded flaxseed, respectively (p < 0.05). The post-ruminal disappearance of crude nutrients was also increased by roasting, in which rolling enhanced this effect. In conclusion, all investigated heat treatments had significant effects on in situ and in vitro degradability of nutrients. As well, rolling of roasted flaxseed enhanced the respective effects. Therefore, different methods of heat processing can be used to modify the feed value of flaxseed for specific purposes.     

Evaluation of Rosin Gum and Eudragit® RS PO as a Functional Film Coating Material

Polymers are essential tools in the research and development of new therapeutic devices. The diversity and flexibility of these materials have generated high expectations in the composition of new materials with extraordinary abilities, especially in the design of new systems for the modified release of pharmaceutically active ingredients. The natural polymer rosin features moisture protection and pH-dependent behavior (i.e., it is sensitive to pH > 7.0), suggesting its possible use in pharmaceutical systems. The synthetic polymer Eudragit® RS PO is a low-permeability material, the disintegration of which depends on the time of residence in the gastrointestinal tract. The present study developed a polymeric material with desirable physicochemical characteristics and synergistic effects that resulted from the inherent properties of the associated polymers. Isolated films were obtained by solvent evaporation and subjected to a water vapor transmission test, scanning electron microscopy, calorimetry, Fourier transform-infrared (FT-IR) spectroscopy, micro-Raman spectroscopy, and mechanical analysis. The new polymeric material was macroscopically continuous and homogeneous, was appropriately flexible, had low water permeability, was vulnerable in alkaline environments, and was thermally stable, maintaining an unchanged structure up to temperatures of ～400°C. The new material also presented potentially suitable characteristics for application in film coatings for oral solids, suggesting that it is capable of carrying therapeutic substances to distal regions of the gastrointestinal tract. These findings indicate that this new material may be added to the list of functional excipients.     

Melt-Extruded Eudragit® FS-Based Granules for Colonic Drug Delivery

The purpose of this study is to characterize the properties of Eudragit® FS-based granules prepared using melt extrusion process for colonic drug delivery. 5-Aminosalicylic acid (5-ASA), theophylline, and diclofenac sodium were used as the model compounds. Drug and polymer blends were melt-extruded into thin rods using a single screw extruder. Drugs were found to be dispersed as crystalline particles in the granules. A hammer mill was used to reduce the extrudate into 16–40 mesh granules, which were mixed with lactose and filled into hard gelatin capsules. Three-stage dissolution testing performed using USP paddle method was used to simulate drug release in gastrointestinal tract. In this study, melt extrusion has been demonstrated to be a suitable process to prepare granules for colonic delivery of 5-amino salicylic acid. At 30% drug loading, less than 25% 5-ASA was released from melt-extruded granules of 20–30 mesh in the first two stages (0.1 N hydrochloric acid solution and phosphate buffer pH 6.8) of the dissolution testing. All 5-ASA was released within 4 h when dissolution medium was switched to phosphate buffer pH 7.4. Drug loading, granule size, and microenvironment pH induced by the solubilized drug were identified as the key factors controlling drug release. Granules prepared with melt extrusion demonstrated lower porosity, smaller pore size, and higher physical strength than those prepared with conventional compression process. Eudragit® FS was found to be stable even when processed at 200°C.     

A biophysically-defined hyaluronic acid-based compound accelerates migration and stimulates the production of keratinocyte-derived neuromodulators

Hyaluronic acid (HA) preparations are widely used in clinical practice and recent data suggest that commercially available HA-based compounds promote ulcer re-epithelialization and induce pain relief. However, the pathophysiological basis of these effects remains poorly understood. In the present study, we investigated the biophysical, biomolecular and functional properties of a HA preparation combined with a pool of collagen precursor synthetic aminoacids, namely l-proline, l-leucine, l-lysine and glycine (Aminogam®). Hydrodynamic characterization of Aminogam® by size exclusion chromatography-triple detector array (SEC-TDA) revealed an average molecular weight in the range of 700–1700 kDa. Rheological measurements of the 1700kDa M_w lot showed a pseoudoplastic behaviour with a zero-shear viscosity (η₀) equal to 90 ± 9 Pa?s at 25°C and 55 ± 6 Pa?s at 37°C. Automated time-lapse videomicroscopy studies in a fibroblast-free system demonstrated that 1% (v/v) Aminogam® significantly reduced the healing time of wounded keratinocyte monolayers. In AKGOS assays, Aminogam® stimulated cellular locomotion (chemokinesis) and directional migration (chemotaxis) of keratinocytes. Analysis of microarray data suggested that keratinocytes had a functional neuroendocrine machinery, and this was confirmed by testing the secretion of six neuroactive molecules by ELISA, namely α-MSH, β-endorphins, melatonin, substance P, cortisol, and neurotensin. Interestingly, Aminogam® regulated the production of several neuropeptides, including β-endorphins. In conclusion, our data shed light on the epithelial-dependent mechanisms that underlie the efficacy of Aminogam®, particularly in reference to wound healing and nociception.     

Dissolution Enhancement of a Drug Exhibiting Thermal and Acidic Decomposition Characteristics by Fusion Processing: A Comparative Study of Hot Melt Extrusion and KinetiSol® Dispersing

In this study, hot melt extrusion (HME) and KinetiSol® Dispersing (KSD) were utilized to prepare dissolution-enhanced solid dispersions of Roche Research Compound A (ROA), a BCS class II drug. Preformulation characterization studies showed that ROA was chemically unstable at elevated temperatures and acidic pH values. Eudragit® L100-55 and AQOAT® LF (HPMCAS) were evaluated as carrier polymers. Dispersions were characterized for ROA recovery, crystallinity, homogeneity, and non-sink dissolution. Eudragit® L100-55 dispersions prepared by HME required the use of micronized ROA and reduced residence times in order to become substantially amorphous. Compositions containing HPMCAS were also prepared by HME, but an amorphous dispersion could not be obtained. All HME compositions contained ROA-related impurities. KSD was investigated as a method to reduce the decomposition of ROA while rendering compositions amorphous. Substantially amorphous, plasticizer free compositions were processed successfully by KSD with significantly higher ROA recovery values and amorphous character than those achieved by HME. A near-infrared chemical imaging analysis was conducted on the solid dispersions as a measure of homogeneity. A statistical analysis showed similar levels of homogeneity in compositions containing Eudragit® L100-55, while differences were observed in those containing HMPCAS. Non-sink dissolution analysis of all compositions showed rapid supersaturation after pH adjustment to approximately two to three times the equilibrium solubility of ROA, which was maintained for at least 24 h. The results of the study demonstrated that KSD is an effective method of forming dissolution-enhanced amorphous solid solutions in cases where HME is not a feasible technique.     

Effect of antifungal gels incorporated into a tissue conditioning material on the growth of Candida albicans

doi:10.1111/j.1741‐2358.2009.00337.x
Effect of antifungal gels incorporated into a tissue conditioning material on the growth of Candida albicans Objective: The aim of this study was to examine the effectiveness of antifungal gels incorporated into a tissue conditioner which inhibits the growth of Candida albicans in vitro. Background: The release of drugs from relining materials has been demonstrated earlier. However, the incorporation of antifungal agents in gel form has not yet been studied. Materials and methods: Visco‐gel^® tissue conditioner was prepared with chlorhexidine digluconate and miconazole in gel form in a concentration of 5, 10, 15, 20 and 25% by volume. Sample discs were prepared and placed on Sabouraud Dextrose Agar (SDA) plates which had been previously inoculated with C. albicans, and incubated aerobically at 37°C. To investigate antifungal activity over time, Visco‐gel discs containing 20%v/v miconazole were prepared and immersed in water for different time periods before being placed on SDA plates inoculated with C. albicans. Results: Chlorhexidine digluconate gel added to tissue conditioner had no inhibition effect on the growth of C. albicans. Incorporation of miconazole gave a dose‐related inhibitory effect on candidal growth. Immersion of the discs in water showed an inverse relationship between time of immersion and degree of inhibition. Conclusion: Miconazole added in gel form to Visco‐gel^® had an inhibitory effect on the growth of C. albicans in vitro.     

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

The objective of the study was to develop an amorphous solid dispersion (ASD) for an insoluble compound X by hot melt extrusion (HME) process. The focus was to identify material-sparing approaches to develop bioavailable and stable ASD including scale up of HME process using minimal drug. Mixtures of compound X and polymers with and without surfactants or pH modifiers were evaluated by hot stage microscopy (HSM), polarized light microscopy (PLM), and modulated differential scanning calorimetry (mDSC), which enabled systematic selection of ASD components. Formulation blends of compound X with PVP K12 and PVP VA64 polymers were extruded through a 9-mm twin screw mini-extruder. Physical characterization of extrudates by PLM, XRPD, and mDSC indicated formation of single-phase ASD’s. Accelerated stability testing was performed that allowed rapid selection of stable ASD’s and suitable packaging configurations. Dissolution testing by a discriminating two-step non-sink dissolution method showed 70–80% drug release from prototype ASD’s, which was around twofold higher compared to crystalline tablet formulations. The in vivo pharmacokinetic study in dogs showed that bioavailability from ASD of compound X with PVP VA64 was four times higher compared to crystalline tablet formulations. The HME process was scaled up from lab scale to clinical scale using volumetric scale up approach and scale-independent-specific energy parameter. The present study demonstrated systematic development of ASD dosage form and scale up of HME process to clinical scale using minimal drug (～500 g), which allowed successful clinical batch manufacture of enabled formulation within 7 months.