Delivery Considerations of Highly Viscous Polymeric Fluids Mimicking Concentrated Biopharmaceuticals: Assessment of Injectability via Measurement of Total Work Done "WT".

An account is given of the recent development of the highly viscous complex biopharmaceuticals in relation to syringeability and injectability. The specific objective of this study is to establish a convenient method to examine problem of the injectability for the needle-syringe-formulation system when complex formulations with diverse viscosities are used. This work presents the inter-relationship between needle size, syringe volume, viscosity, and injectability of polymeric solutions having typical viscosities encountered in concentrated biologics, by applying a constant probe crosshead speed on the plunger-syringe needle assembly and continuously recording the force-distance profiles. A computerized texture analyzer was used to accurately capture, display, and store force, displacement, and time data. The force-distance curve and area under the curve are determined, and total work done for complete extrusion of the syringe content was calculated automatically by applying an established Matlab program. Various concentrations (i.e., 0.5-4% w/v of polymeric fluids/dispersions) of polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) with viscosity ranges of 5-100 cP mimicking concentrated monoclonal antibody solutions and complex biopharmaceutical formulations are investigated. Results indicate that calculated values of total work done to completely extrude the syringe content are the most appropriate parameter that describes viscosity-injection force of dispersed formulations. Additionally, the rheological properties of HPMC and PEO fluids in the context of syringeability and injectability are discussed.

MR enterography with oral contrast agent composed of methylcellulose, low-dose barium sulfate, sorbitol, and lactulose: assessment of diagnostic performance, reliability, image quality, and patient tolerance.

OBJECTIVE: The objective was to show efficiency of magnetic resonance enterography (MRE) with our previously assessed new oral contrast agent. MATERIALS AND METHODS: Each bowel segments was evaluated for luminal distension, wall conspicuity, wall thickening, and hyperintensity on fat-saturated (FS) T2-weighted and contrast enhancement on postcontrast FS T1-weighted images. Also, consensus scoring results of MRE exams were compared with the gold standard tests in terms of active inflammatory bowel disease detection. RESULTS: Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of MRE for active inflammatory bowel disease detection were 62%, 98%, 80%, 96%, and 71.4%, respectively. CONCLUSION: MRE obtained with the new mixture has a high reliability and shows good correlation with endoscopic examination±biopsy.

Efficacy of ophthalmic viscosurgical devices in maintaining corneal epithelial hydration and clarity: in vitro assessment.

PURPOSE: To determine the efficacy of hydroxypropyl methylcellulose (HPMC) and hyaluronic acid (HA) in maintaining corneal hydration and optical clarity. SETTING: Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. DESIGN: Experimental study. METHODS: In porcine autopsy eyes, the effect of 13 ophthalmic viscosurgical devices (OVDs) (5 formulations of HPMC; 8 formulations of HA) in maintaining corneal hydration and optical clarity was tested. The main outcome variables were the time to reach optical clarity of the cornea during dissipation of the OVD and duration of corneal hydration. These variables were assessed after the first application of the OVD, after balanced salt solution application to rehydrate the gel matrix, and after the second application of OVD on top of the first layer. RESULTS: The study used 57 porcine eyes. High-molecular-weight HA 1.5% (zero shear viscosity [ZSV] 55,122 millipascal seconds [mPa.s]) took a significantly shorter time to reach optical clarity than HA 1.4% (ZSV 36,882 mPa.s) (P=.04). Hyaluronic acid 1.4% and HA 1.5% maintained corneal hydration significantly longer than HPMC 2.0% (P<.001). CONCLUSIONS: For corneal hydration during short-lasting surgical procedures such as cataract surgery, the results suggest using HPMC because it distributes quickly and provides an adequate duration of sufficient corneal hydration. For corneal hydration during prolonged surgical procedures, such as vitreoretinal surgery, results suggest using HA 1.5% in the formulation because it provides long-lasting corneal hydration. FINANCIAL DISCLOSURE: Dr. Prinz has a proprietary interest in Croma Pharma GmbH, Leobendorf, Austria. Dr. Findl is a scientific advisor to Croma Pharma GmbH. No other author has a financial or proprietary interest in any material or method mentioned.

An integrated system for dissolution studies and magnetic resonance imaging of controlled release, polymer-based dosage forms-a tool for quantitative assessment of hydrogel formation processes.

Controlled release (CR) dosage forms are often based on polymeric matrices, e.g., sustained-release tablets and capsules. It is crucial to visualise and quantify processes of the hydrogel formation during the standard dissolution study. A method for imaging of CR, polymer-based dosage forms during dissolution study in vitro is presented. Imaging was performed in a non-invasive way by means of the magnetic resonance imaging (MRI). This study was designed to simulate in vivo conditions regarding temperature, volume, state and composition of dissolution media. Two formulations of hydrodynamically balanced systems (HBS) were chosen as model CR dosage forms. HBS release active substance in stomach while floating on the surface of the gastric content. Time evolutions of the diffusion region, hydrogel formation region and "dry core" region were obtained during a dissolution study of L-dopa as a model drug in two simulated gastric fluids (i.e. in fed and fasted state). This method seems to be a very promising tool for examining properties of new formulations of CR, polymer-based dosage forms or for comparison of generic and originator dosage forms before carrying out bioequivalence studies.

Assessment of small bowel Crohn disease: noninvasive peroral CT enterography compared with other imaging methods and endoscopy--feasibility study.

A feasibility study was conducted to evaluate two biphasic computed tomographic (CT) enterography protocols, a noninvasive CT technique with water administered perorally and CT enteroclysis with methylcellulose administered through a nasojejunal tube, in 23 patients known or suspected to have Crohn disease. Results were compared with the results of fluoroscopic small bowel examination and terminal ileoscopy for the detection of active Crohn disease in the terminal ileum. Luminal distention did not differ significantly between the two CT protocols. Arterial phase imaging was noncontributory in 22 of 23 cases. The noninvasive peroral water CT enterography protocol had similar accuracy (12 of 15 cases, 80%) for enabling the detection of active Crohn disease in comparison with CT enteroclysis with nasojejunal tube (seven of eight, 88%) and fluoroscopic small bowel examination (17 of 23, 74%). No fistulas were missed with use of either CT technique. The authors conclude that noninvasive peroral portal venous phase CT enterography with use of water is an accurate and feasible technique for detecting active small bowel inflammation in patients with Crohn disease.

Cost-effectiveness of magnetic resonance imaging and enteroclysis in the diagnostic imaging of Crohn's disease.

OBJECTIVES: To compare the cost-effectiveness of magnetic resonance imaging (MRI) and enteroclysis in patients with Crohn's disease (CD). METHODS: A decision analytic model was performed considering the correct diagnoses of CD and complications such as fistulas and abscesses as effects. Costs were estimated in Euro([symbol: see text]) using German fee schedules. RESULTS: MRI was more effective and more costly compared with enteroclysis. Incremental cost-effectiveness of MRI versus enteroclysis was [symbol: see text]1,595 per additional correctly diagnosed patient. CONCLUSIONS: The use of MRI in the work-up of patients with CD cannot be generally recommended from an economical perspective, but results of sensitivity analysis suggest that in patients with high prevalence of complications, MRI becomes as cost-effective as enteroclysis, which is accepted standard diagnostic imaging.

[Radiological assessment of small bowel obstructions: Value of conventional enteroclysis and dynamic MR-enteroclysis]. / Radiologische Diagnostik obstruktiver Dünndarmläsionen: Wertigkeit von konventionellem Enteroklysma und dynamischem MR-Enteroklysma.

PURPOSE: To compare small bowel lesions, especially stenoses, with conventional enteroclysis, static MRI and dynamic MR-enteroclysis. MATERIALS AND METHODS: Forty-two patients with Crohn's disease or other suspected small bowel lesions were examined. MRI was performed in a static and a dynamic way either within one hour after conventional enteroclysis (n = 30) or a few days afterwards (n = 12). In order to monitor bowel filling and to characterize stenoses in a dynamic fashion, 4 series of coronal T2w HASTE breath hold sequences were used, first without additional bowel opacification and then during administration of 1,5 l methyl cellulose via a naso-intestinal tube in the MR unit. Intravenously applied Buscopan was used to reduce bowel movement. RESULTS: In 4 out of 42 Patients, application of methylcellulose was limited to 1000 ml because of gastrointestinal complaints or visible gastral reflux. All patients could be evaluated. Static MRI performed within one hour after conventional enteroclysis and no additional bowel opacification showed insufficient bowel distension. Distension was still better than in MRI without prior application of contrast medium. On the contrary, dynamic MR - enteroclysis lead to controlled and complete bowel distension which allowed for significantly better evaluation of normal bowel anatomy and pathological alterations of the gut. Because of a better bowel distension and dynamic evaluation, MR-enteroclysis revealed significantly more stenoses (n = 42) than MRI obtained with less distension (n = 27, p < 0.001), and characterization of lesions was comparable to conventional enteroclysis (p < 0.001). Fixed and non-fixed stenoses could be differentiated by dynamic MR-enteroclysis. Furthermore, extraluminal complication of Crohn's disease such as abscesses and fistulae or large bowel manifestation of disease were shown in 13 patients. CONCLUSIONS: Dynamic MR-enteroclysis is feasible in routine diagnostic work-up of the small bowel. It is superior in depicting intra- and extraluminal manifestation of small bowel lesions and enables characterization of stenoses comparable to conventional enteroclysis.

Assessment of the precorneal residence of an ophthalmic ointment in healthy subjects.

1. The precorneal residence of an ophthalmic ointment radiolabelled by inclusion of technetium-99m tin colloid was assessed in seven volunteer subjects using the technique of gamma scintigraphy and compared with a solution of 0.3% w/v hydroxypropylmethylcellulose, (HPMC) radiolabelled by inclusion of technetium-99m diethylenetriaminepentaacetic acid in the same subjects. 2. The mean half-times (+/- s.d.) of corneal residence were 6490 +/- 5404 s (108 min) for the ointment and 13 +/- 24 s for the 0.3% w/v HPMC solution (P < 0.01). 3. The area-under-curve value (AUC(0,540 s)), which reflects the total residence time of the preparation on the ocular surface, was calculated for each vehicle in each subject. The mean (+/- s.d.) AUC(0,540 s) value for the ointment was 42170 (+/- 5032)% s and for the 0.3% w/v HPMC solution it was 8394 (+/- 4641)% s (P < 0.01).