European Journal of Pharmaceutics and Biopharmaceutics (v.73, #3)
Oral osmotically driven systems: 30 years of development and clinical use
by Vincent Malaterre; Joerg Ogorka; Nicoletta Loggia; Robert Gurny (pp. 311-323).
The number of marketed oral osmotically driven systems (OODS) has doubled in the last 10years. The main clinical benefits of OODS are their ability to improve treatment tolerability and patient compliance. These advantages are mainly driven by the capacity to deliver drugs in a sustained manner, independent of the drug chemical properties, of the patient’s physiological factors or concomitant food intake. However, access to these technologies has been restricted by the crowded patent landscape and manufacturing challenges. In this review article, we intend to give an overview of the OODS development in the last 30years, detailing the technologies, specific products and their clinical use. General guidance on technology selection is described in light of the recent advances in the field. The clinical performance of these technologies is also discussed, with a focus on food effects and the in vivo–in vitro correlation. Special attention is paid to safety given the controversial case study of Osmosin®. Overall, oral osmotically driven systems appear to be a promising technology for product life-cycle strategies.
Keywords: Abbreviations; ADHD; attention deficit hyperactivity disorder; BCS; biopharmaceutical classification system; CPOP; controlled-porosity osmotic pump; COER; controlled-onset extended-release; DDS; drug delivery system; DOEOP; drug-overcoated elementary osmotic pump; EOP; elementary osmotic pump; GI; gastrointestinal; GITS; gastrointestinal therapeutic system; IP; intellectual property; IVIVC; in vivo–in vitro; correlation; MOTS; muco-adhesive osmotic therapeutic system; OODS; oral osmotically-driven systems; OROS; oral osmotic systems; PPOP; push–pull osmotic pump; PSOP; push-stick osmotic pump; SCOT; single-composition osmotic tablet; SEOP; self-emulsified elementary osmotic pumpOsmotic pumps; Oral osmotic systems; GITS; OROS; Controlled drug delivery; Review; Life-cycle management
Alteration of the glycosylation pattern of monocytic THP-1 cells upon differentiation and its impact on lectin-mediated drug delivery
by V.E. Plattner; G. Ratzinger; E.T. Engleder; S. Gallauner; F. Gabor; M. Wirth (pp. 324-330).
In the present study, human monocytic THP-1 cells were treated with phorbol-12-myristate-13-acetate (PMA) in order to obtain macrophage-like cells. Before and after treatment, plant lectins with distinct sugar specificities were applied in order to elucidate the glycosylation patterns of both monocytic and macrophage-like cell types and to follow changes during differentiation.As a result of flow-cytometric analyses, for untreated as well as for PMA-differentiated cells WGA yielded the highest binding rate without significant changes in the binding capacity. For the other lectins, divergent results were obtained which point to reorganization of sugar residues on the cell surface during differentiation.Additionally, cytoinvasion being beneficial for enhanced drug absorption was studied with WGA which had displayed a high binding capacity together with a high specificity. For both untreated and PMA-differentiated cells decreased fluorescence intensity at 37°C as compared to 4°C was observable pointing to internalization and accumulation within acidic compartments. Moreover, WGA-functionalized PLGA nanoparticles were prepared, and their uptake evaluated. Uptake rates of 55% in case of PMA-differentiated cells suggested that WGA-grafted drug delivery systems might be an interesting approach for treatment of infectious diseases provoked by parasites, facultative intracellular bacteria, or viruses such as HIV.
Keywords: Monocytes/macrophages; Glycosylation pattern; Lectins; Bioadhesion; Drug targeting; Nanoparticles
Sculptured drug-eluting stent for the on-site delivery of tacrolimus
by Paola Minghetti; Francesco Cilurzo; Francesca Selmin; Antonella Casiraghi; Andrea Grignani; Luisa Montanari (pp. 331-336).
This work aimed to evaluate the flexibility of a novel pyrolytic carbon coated drug-eluting stent platform, which presents the peculiarity of deep sculptures realized on the stent’s outer surface (reservoirs). Tacrolimus (TCR) or TCR/excipient mixtures were loaded into the reservoirs, and their permanence into stent’s reservoirs was verified by an in vitro short-time release test in human blood. Moreover, the impact of the excipients on the TCR physical state and surface morphology of the reservoirs and the release kinetics were studied. The reservoirs resulted homogeneously filled. Upon exposure to blood, no loss of materials from reservoirs was observed, and the drug release after 15min was negligible in all cases. The loading procedure caused the drug amorphization and, AFM revealed that the surfaces were smooth and homogeneous with the exception of the TCR/poloxamer 188 mixture where spatial oriented crystals were evident. Poly(N-vinyl pyrrolidone) improved the in vitro TCR release rate constants ( K). Poly(methylmethacrylate) (PMM) significantly reduced the K value both in vitro and in vivo. Indeed, the in vivo drug concentrations in rabbit artery wall significantly decreased, decreasing the TCR/PMM ratio. The characteristics of the stent strut resulted suitable to load material with different physicochemical characteristics.
Keywords: Drug-eluting stent; Janus; Carbo; Stent; Tacrolimus; AFM
Composite microparticles with in vivo reduction of the burst release effect
by A. Sheikh Hassan; A. Sapin; A. Lamprecht; E. Emond; F. El Ghazouani; P. Maincent (pp. 337-344).
The aim of this study was to develop microparticles containing nanoparticles (composite microparticles) for prolonged drug delivery with reduced burst effect in vitro and in vivo. Such composite microparticles were prepared with hydrophobic and biodegradable polymers [poly(ε-caprolactone), poly(lactic-co-glycolic) acid]. Ibuprofen was chosen as the model drug, and microparticles were prepared by the extraction technique with ethyl acetate as the solvent. Nanoparticles and microparticles and an ibuprofen solution (Pedea®) were administered subcutaneously at the dose of 1mg of ibuprofen per kg to overnight-fasted rats (male Wistar). Composite microparticles showed prolonged ibuprofen release and less burst effect when compared to simple microparticles (without nanoparticles inside) or nanoparticles both in vitro (PBS buffer) and in vivo. Moreover, ibuprofen was still detected in the plasma after 96h with composite microparticles. Consequently, it has been demonstrated that composite microparticles were able to reduce burst release and prolong the release of ibuprofen for a long period of time.
Keywords: Composite microparticles; Ibuprofen; Burst effect; In vitro; In vivo; Poly(ε-caprolactone); Poly(lactic-co-glycolic) acid
New amphiphilic and pH-sensitive hydrogel for controlled release of a model poorly water-soluble drug
by I. Colinet; V. Dulong; G. Mocanu; L. Picton; D. Le Cerf (pp. 345-350).
This paper presents the development of new pH-sensitive, amphiphilic and biocompatible hydrogels based on alginate-g-PCL, cross-linked with calcium ions to form beads, prepared for controlled delivery of poorly water-soluble drug. We have focused our study on the effect of the length of PCL chains (530 and 1250gmol−1). Swelling profiles obtained clearly indicated that these hydrogels swell slightly (10–14%) in a simulated gastric fluid (pH 1.2), and strongly (700–1300% before disintegration) in a simulated intestinal fluid (pH 6.8). In both media, rates of swelling were lower for beads based on amphiphilic derivatives than for alginate/Ca2+ ones due to the hydrophobic PCL grafts, and decreased when hydrophobic character increased. A model drug, theophylline, was entrapped into these hydrogels and release studies were carried out. The drug was protected in acidic fluid (only 14–20% of release for alginate-g-PCL hydrogel against 35% of release for alginate hydrogel during 350min). The drug is released completely in neutral fluid due to ion exchanges and disintegration of the hydrogel. PCL leads to decrease in the release kinetics in SIF (2h for alginate-g-PCL/Ca2+ beads against 1h for alginate/Ca2+ beads). It was demonstrated that the establishment of clusters inside beads by intramolecular interactions between PCL grafts of 530gmol−1 in salt media allowed to retain the drug and to slow down its release considerably.
Keywords: Alginate-g-PCL; Hydrogels; Amphiphilic; pH-sensitive; Controlled release
Influence of degree of substitution of HES–HEMA on the release of incorporated drug models from corresponding hydrogels
by Ariane D.A. Schwoerer; Steffen Harling; Kristin Scheibe; Henning Menzel; Rolf Daniels (pp. 351-356).
Hydrogel microparticles were produced by a radical polymerization of hydroxyethyl methacrylate–hydroxyethyl starch (HES–HEMA) in an all aqueous two-phase system (ATPS). The microspheres show a monomodal size distribution and have the ability to entrap high amounts of water. The release of proteins or other testing substances from the HES–HEMA hydrogels can be controlled by the choice of the network density of the hydrogel by varying the degree of substitution (DS), the size of the entrapped substance, and by conditions enhancing the degradation of the hydrogel network.
Keywords: Drug delivery system; Biodegradable hydrogels; Hydroxyethyl starch; Aqueous two-phase separation system; Proteins
Host–guest interactions of 5-fluorouracil in supramolecular organogels
by Hong Wang; Jinye Zhang; Weiping Zhang; Yajiang Yang (pp. 357-360).
Supramolecular organogels were formed by the self-assembly of gelator 1,3:2,4-di-O-benzylidene-d-sorbitol (DBS) in 1,2-propylene glycol. 5-Fluorouracil (5-Fu) was entrapped in the organogels as guest molecules. Field-emission scanning electron microscopic measurements of the organogels indicate that the diameters of the fibrillar aggregates formed by DBS self-assembly were in the range of 20–70nm. The host–guest interactions between 5-Fu and supramolecular gel matrix were investigated by using temperature-dependent differential UV spectroscopy and differential scanning calorimetry. The red shifts of the absorption band of 5-Fu in the organogels are indicative of the interaction between 5-Fu and DBS. The red shifts were enhanced upon decreasing the temperature. Calculation of optimized geometries revealed the formation of hydrogen bonds between 5-Fu and DBS aggregates. The analysis of differential scanning calorimetric data for the organogels with and without 5-Fu further showed that the self-assembly of DBS was interfered by the 5-Fu in the organogels, resulting in a decrease in the dissociating temperature of DBS aggregates.
Keywords: Host–guest interaction; Supramolecular gels; Gelator; 5-Fluorouracil
Preparation of a fast dissolving oral thin film containing dexamethasone: A possible application to antiemesis during cancer chemotherapy
by Hiroyoshi Shimoda; Kazumi Taniguchi; Misao Nishimura; Katsuhiko Matsuura; Tadao Tsukioka; Hirotaka Yamashita; Naoki Inagaki; Kazuyuki Hirano; Mayumi Yamamoto; Yasutomi Kinosada; Yoshinori Itoh (pp. 361-365).
We prepared fast dissolving oral thin film that contains dexamethasone and base materials, including microcrystalline cellulose, polyethylene glycol, hydroxypropylmethyl cellulose, polysorbate 80 and low-substituted hydroxypropyl cellulose. This preparation showed excellent uniformity and stability, when stored at 40°C and 75% in humidity for up to 24weeks. The film was disintegrated within 15s after immersion into distilled water. The dissolution test showed that approximately 90% of dexamethasone was dissolved within 5min. Subsequently, pharmacokinetic properties of dexamethasone were compared in rats with oral administration of 4mg dexamethasone suspension or topical application of the film preparation containing 4mg dexamethasone to the oral cavity. Pharmacokinetic parameters were similar between the two groups in which Cmax (h), Tmax (μg/mL), AUC (μg/mL/h) and half-life (h) were 12.7±6.6 (mean±SD, N=10), 3.4±1.4, 93.6±37.8 and 1.66±0.07, respectively, for oral suspension and 13.3±4.0, 3.2±1.0, 98.0±22.3 and 1.65±0.06, respectively, for film preparation. These findings suggest that the fast dissolving oral thin film containing dexamethasone is likely to become one of choices of dexamethasone preparations for antiemesis during cancer chemotherapy.
Keywords: Fast dissolving oral thin film; Dexamethasone; Antiemesis; Dissolution test; Pharmacokinetic parameters; Rat
Characterisation of quaternary polymethacrylate films containing tartaric acid, metoprolol free base or metoprolol tartrate
by B. Glaessl; F. Siepmann; I. Tucker; J. Siepmann; T. Rades (pp. 366-372).
The aim of this study was to better understand the interactions between metoprolol tartrate and quaternary polymethacrylate (Eudragit RL and Eudragit RS) films. For reasons of comparison, polymeric films containing the free base metoprolol or free tartaric acid were also prepared. Systems containing various amounts of the free base, free acid and the salt were characterised using polarising light microscopy, X-ray powder diffraction, differential scanning calorimetry and mechanical analysis (puncture test). The free base is the most efficient plasticiser of the three species for Eudragit RL and Eudragit RS, but with limited solubility in the polymers. Due to its hydrophobicity, it can interact with the hydrophobic polymer backbones. In contrast, in salt containing films, ionic interactions between the positively charged quaternary ammonium groups and the negatively charged tartrate anions apparently occur, this being suggested by the different effects on Eudragit RL versus RS, which have different contents of quaternary ammonium groups. Importantly, the combination of acid and base as a salt avoids drug precipitation at higher metoprolol contents. The obtained new insight into the occurring drug–polymer interactions can help to facilitate the development/optimisation of this type of dosage forms.
Keywords: Drug–polymer interactions; Polymers; Controlled release; Mechanical properties; Thermal analysis; Glass transition
Effects of liquisolid formulations on dissolution of naproxen
by Ngiik Tiong; Amal A. Elkordy (pp. 373-384).
The aim of this study was to investigate the use of liquisolid technique in improving the dissolution profiles of naproxen in a solid dosage form. This study was designed to evaluate the effects of different formulation variables, i.e. type of non-volatile liquid vehicles and drug concentrations, on drug dissolution rates. The liquisolid tablets were formulated with three different liquid vehicles, namely Cremophor® EL (polyoxyl 35 castor oil), Synperonic® PE/L61 (poloxamer 181, polyoxyethylene–polyoxypropylene copolymer) and poly ethylene glycol 400 (PEG400) at two drug concentrations, 20%w/w and 40%w/w. Avicel® PH102 was used as a carrier material, Cab-o-sil® M-5 as a coating material and maize starch as a disintegrant. The empirical method as introduced by Spireas and Bolton (1999) was applied strictly to calculate the amounts of coating and carrier materials required to prepare naproxen liquisolid tablets. Quality control tests, i.e. uniformity of tablet weight, uniformity of drug content, tablet hardness, friability test, disintegration and dissolution tests were performed to evaluate each batch of prepared tablets. In vitro drug dissolution profiles of the liquisolid formulations were studied and compared with conventional formulation, in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.2) without enzyme. Stability studies were carried out to evaluate the stability of the tablets under humid conditions. Differential scanning calorimetry and Fourier transform infrared were used to investigate physicochemical interaction between naproxen and the excipients. It was found that liquisolid tablets formulated with Cremophor® EL at drug concentration of 20%w/w produced high dissolution profile with acceptable tablet properties. The stability studies showed that the dissolution profiles of liquisolid tablets prepared with Cremophor® EL were not affected by ageing significantly. Furthermore, DSC revealed that drug particles in liquisolid formulations were completely solubilised.
Keywords: Naproxen; Liquisolid tablets; Dissolution; Liquid load factor; Cremophor; ®; EL
Effects of penetration enhancers on Shuangwu traumatic formula: In vitro percutaneous absorption and in vivo pharmacodynamic evaluation of an herb medicine
by Shengying Gu; Jing Gao; Xuemei Hou; Baoyue Ding; Wei Zhang; Shen Gao; Xueying Ding (pp. 385-390).
The purposes of this study were to improve the transdermal permeation of the Shangwu traumatic formula by chemical penetration enhancers and to investigate the pharmacodynamic changes of the formula caused by incorporated enhancers. The effects of different enhancers on the transdermal absorption of piperine, the representative component of formula, were investigated by in vitro permeation studies. The tests showed an increasing enhancement effect in the following order: Azone/N-methylpyrrolidone (NMP)>oleic acid>Azone/peppermint oil>Azone/oleic acid>Azone/propylene glycol>Azone>peppermint oil>NMP>propylene glycol. The ratio and the content of the most effective enhancer Azone/NMP were determined subsequently. The results suggested that the most significant penetration enhancement was achieved by 3% (w/w) Azone/NMP (3:7). Furthermore, the in vivo pharmacodynamic responses of the formula suspension with or without Azone/NMP were compared using hot-plate assay and xylene-induced ears edema test as models. The data indicated that the formula had positive effect on analgesis and anti-inflammatory, which can be enhanced with the addition of enhancers.
Keywords: The Shangwu traumatic formula; Penetration enhancer; Piperine; Hot-plate assay; Xylene-induced ears edema test
Topical delivery of 5-aminolevulinic acid-encapsulated ethosomes in a hyperproliferative skin animal model using the CLSM technique to evaluate the penetration behavior
by Yi-Ping Fang; Yaw-Bin Huang; Pao-Chu Wu; Yi-Hung Tsai (pp. 391-398).
Psoriasis, an inflammatory skin disease, exhibits recurring itching, soreness, and cracked and bleeding skin. Currently, the topical delivery of 5-aminolevulinic acid-photodynamic therapy (ALA–PDT) is an optional treatment for psoriasis which provides long-term therapeutic effects, is non-toxic and enjoys better compliance with patients. However, the precursor of ALA is hydrophilic, and thus its ability to penetrate the skin is limited. Also, little research has provided a platform to investigate the penetration behavior in disordered skin. We employed a highly potent ethosomal carrier (phosphatidylethanolamine; PE) to investigate the penetration behavior of ALA and the recovery of skin in a hyperproliferative murine model. We found that the application of ethosomes produced a significant increase in cumulative amounts of 5–26-fold in normal and hyperproliferative murine skin samples when compared to an ALA aqueous solution; and the ALA aqueous solution appeared less precise in terms of the penetration mode in hyperproliferative murine skin. After the ethosomes had been applied, the protoporphyrin IX (PpIX) intensity increased about 3.64-fold compared with that of the ALA aqueous solution, and the penetration depth reached 30–80μm. The results demonstrated that the ethosomal carrier significantly improved the delivery of ALA and the formation of PpIX in both normal and hyperproliferative murine skin samples, and the expression level of tumor necrosis factor (TNF)-α was reduced after the ALA–ethosomes were applied to treat hyperproliferative murine skin. Furthermore, the results of present study encourage more investigations on the mechanism of the interaction with ethosomes and hyperproliferative murine skin.
Keywords: 5-Aminolevulinic acid; Protoporphyrin IX; Ethosomes; Topical delivery; Penetration behavior; Hyperproliferative skin
A pilot study evaluating the safety of vaginal administration of a multi-particulate pellet formulation
by Guido Lopes dos Santos Santiago; Hans Verstraelen; Nele Poelvoorde; Steven De Corte; Geert Claeys; Marijke Trog; Ellen De Backer; Bart Saerens; Chris Vervaet; Fabienne De Boeck; Lucas Van Bortel; Jean-Paul Remon; Marleen Temmerman; Mario Vaneechoutte; Rita Verhelst (pp. 399-403).
Quantitative evaluation of the effect caused by vaginal administration of gelatin capsules loaded with starch pellets and lyophilized powder, respectively, on vaginal pH and microflora.Administration of gelatin capsules loaded with fast-disintegrating starch pellets (group P) or lyophilized lactose/skimmed milk (group L) was compared to no intervention (group C) in a 3-way randomized, double-blinded, parallel study with 18 volunteers. Follow-up visits were at day 6 (immediately after administration), day 14 (pill stop), day 22 (after withdrawal bleeding) and day 35 (midcycle). Vaginal pH was measured and swabs were taken for Gram staining and culture to assess the presence of hydrogen peroxide-producing lactobacilli. Colposcopy was performed to assess the occurrence of adverse effects on the vaginal and ectocervical mucosa.No severe adverse events occurred. For all women, vaginal pH and Gram stain were normal from screening until pill stop. Although immediately after withdrawal bleeding, 8 out of 18 women had an elevated pH, a disturbed microflora or lacked hydrogen peroxide-producing lactobacilli, all women had hydrogen peroxide-producing lactobacilli and a normal vaginal pH at midcycle, and all but two had a normal Gram stain.No major differences could be observed between the groups, whereby all changes in pH and microflora could be ascribed to withdrawal bleeding, indicating that gelatin capsules, starch pellets and lyophilized powder are acceptable carrier materials for the vaginal delivery of probiotic strains.
Keywords: Probiotics; Starch; Pellet; Vaginal delivery; Bacterial vaginosis
Compatibility studies of acyclovir and lactose in physical mixtures and commercial tablets
by Farnaz Monajjemzadeh; Davoud Hassanzadeh; Hadi Valizadeh; Mohammad R. Siahi-Shadbad; Javid Shahbazi Mojarrad; Thomas A. Robertson; Michael S. Roberts (pp. 404-413).
This study documents drug–excipient incompatibility studies of acyclovir in physical mixtures with lactose and in different tablet brands. Differential scanning calorimetry (DSC) was initially used to assess compatibility of mixtures. The Fourier-transform infrared (FTIR) spectrum was also compared with the spectra of pure drug and excipient. Although DSC results indicated incompatibility with lactose, FTIR spectra were mostly unmodified due to overlapping peaks. Samples of isothermally stressed physical mixture were stored at 95°C for 24h. The residual drug was monitored using a validated high-performance liquid chromatography (HPLC) assay and data fitting to solid-state kinetic models was performed. The drug loss kinetics followed a diffusion model. The aqueous mixture of drug and excipient was heated in order to prepare an adduct mixture. HPLC analysis revealed one extra peak that was fractionated and subsequently injected into the liquid chromatography–mass spectrometry/mass spectrometry (LC–MS/MS) system. The MRM (Multiple Reaction Monitoring) chromatograms characterized the peak with molecular mass corresponding to an acyclovir–lactose Maillard reaction product. The presence of lactose in commercial tablets was checked using a new TLC method. Overall, the incompatibility of acyclovir with lactose was successfully evaluated using a combination of thermal methods and LC–MS/MS.
Keywords: Acyclovir; Solid state; Lactose; Incompatibility; HPLC; FTIR; DSC; LC–MS/MS
The use of the SeDeM Diagram expert system to determine the suitability of diluents–disintegrants for direct compression and their use in formulation of ODT
by Johnny Edward Aguilar-Díaz; Encarnación García-Montoya; Pilar Pérez-Lozano; José María Suñe-Negre; Montserrat Miñarro; José Ramón Ticó (pp. 414-423).
The new SeDeM Diagram expert system was used to analyze the suitability of 43 excipients for direct compression with disintegrant properties from eight chemical families. The SeDeM Diagram expert system is a new method for use in tablet preformulation and formulation studies. It provides the profile of a substance in powder form in terms of its suitability for direct compression.This study, which was based on the current concept of “Quality by Design ICH Q8”, evaluated the pharmacotechnical properties of disintegrants in powder form and selected the candidates that were most suitable for direct compression and their use in formulation of orally disintegrating tablets (ODT). To achieve this, each disintegrant and its chemical families were individually analyzed. It was concluded that nine disintegrants had an SeDeM value with the index of good compression (IGC) over 5. Most of these disintegrants were from the microcellulose family. Other disintegrants had indexes that were close to 5. It is assumed that these excipients can be used in direct compression, when they are added to other excipients.
Keywords: Disintegrant; SeDeM; Diagram expert system; Preformulation; Direct compression (DC); Quality by Design (ICH Q8); Index good compression (IGC); Bucodispersables
Multivariate analysis of relationships between material properties, process parameters and tablet tensile strength for α-lactose monohydrates
by Rahul V. Haware; Ingunn Tho; Annette Bauer-Brandl (pp. 424-431).
The present work describes an approach to quantify relationships between the material properties of various α-lactose monohydrate grades (αLM), process parameters (punch velocity, lubricant fraction) and the tablet tensile strength (TS). Milled, sieved, agglomerated and spray-dried αLMs were studied. Each material was tableted (11mm flat punches, constant true volume of 0.2833cm3) on a compaction simulator at a pressure of 104.4±0.1MPa. The force–displacement data was analyzed by applying a combination of compression descriptors (derived from Kawakita and Heckel equations, work-related parameters). The relationships were evaluated and quantified by principal component analysis (PCA) and partial least square regression (PLS-1). PCA verified fundamental relationships between different powder and compression properties of studied materials. It was found that the compression descriptors Kawakita ‘1/ b’ and WoC were sufficient to distinguish the tested αLM-grades, even in combination with different lubricant fraction or by utilizing different punch velocities; the identified descriptors correlated with TS. These relationships were quantified by PLS-1. Finally, TS were successfully predicted for all αLM with the help of separate optimized PLS-1 models. The present study shows an approach how to extract relevant information about tableting behavior from a limited amount of material.
Keywords: Compression; Heckel equation; Kawakita equation; Multivariate methods; α-Lactose monohydrate; PAT; Prediction
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