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Characterization of impurities formed by interaction of duloxetine HCl with enteric polymers hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate.

Duloxetine hydrochloride ((S)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine hydrochloride) has been found to react with polymer degradation products or residual free acids present in the enteric polymers hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) in dosage formulations to form succinamide and phthalamide impurities, respectively. The rate of formation of the impurities is accelerated by heat and humidity. The structures were deduced using molecular weights obtained from LC-MS experiments and confirmed by comparison of UV spectra, HPLC retention times, and electrospray mass spectra to independently synthesized material. It is proposed that polymer-bound succinic and phthalic substituents can be cleaved from the polymer, resulting in the formation of either the free acids or the anhydrides. It is postulated that the reaction is enabled by migration of either (1) the free acid or anhydride or (2) the parent drug through the formulation. The formation of these impurities was minimized by increasing the thickness of the physical barrier separating the enteric coating from the drug.

Adrenergic Uptake Inhibitors↗

Sodium hyaluronate and methylcellulose in extracapsular cataract extraction. A controlled study of the intraocular inflammation following the peroperative use of sodium hyaluronate and methylcellulose.

In a controlled prospective trial the peroperative use of sodium hyaluronate and methylcellulose (2%) was compared. Two hundred and fifteen patients received sodium hyaluronate and 189 methylcellulose during extracapsular cataract extraction. We found no significant difference in postoperative anterior chamber inflammation, intraocular pressure, frequency of fibrin in the anterior chamber, nor need for additional medication during the first 5 postoperative days.

Aged↗

Methylcellulose, a healing inhibitor factor in an animal model of trabeculectomy.

PURPOSE: To use an experimental animal model to study the effect on intraocular pressure (IOP) of methylcellulose 2% application in trabeculectomy, followed by histologic assessment. METHODS: Trabeculectomy was performed on albino rabbits' eyes. The study comprised two groups, each group consisting of five rabbits. The right eyes were subjected to trabeculectomy, and the left eyes served as the control. In both groups 1 and 2, trabeculectomy was performed in the right eyes, but in group 2, trabeculectomy was followed by injection of methylcellulose 2% into the anterior chamber. The methylcellulose was allowed to pass through the trabeculectomy site into the subconjunctival space, and an extra amount was injected by the same cannula under the conjunctiva in the area of the trabeculectomy from the edge of the periotomy. Measurement of IOP was performed with a Shiotz tonometer once weekly for 4 weeks. Specimens were obtained from the operative site, and semithin sections were prepared, stained with toluidine blue, and examined by light microscopy (LM). RESULTS: A significant difference in the decrease of IOP (P<0.0001) was observed between the two groups after 4 weeks of surgery. During the 4 weeks after trabeculectomy, the mean IOP was 18.2+/-0.45 mm Hg without methylcellulose injection and 18.3+/-0.77 mm Hg in the control eyes, and 9.8+/-0.84 mm Hg with methylcellulose injection, 18.25+/-0.7 mm Hg in the control eyes. The histopathological findings in group 1 (without methylcellulose injection) showed the subscleral spaces to be less fenestrated, with deposition of dense collagen bundles intermingled with the fibrocytes, some of which were active with prominent mitosis. In contrast, in group 2 (injected with methylcellulose), the subscleral space appeared fenestrated with irregularly and widely spaced segmented collagen bundles. CONCLUSIONS: Methylcellulose may have antihealing properties that serve to decrease IOP in trabeculectomy. Although more work is needed in humans, because human tissue may be different in its response to the same procedure, the use of methylcellulose could be very promising.

Animals↗

Synthesis and electrorheological behavior of sterically stabilized polypyrrole-silica-methylcellulose nanocomposite suspension.

Various polypyrrole (PPy)-silica-methylcellulose nanocomposite particles were synthesized by suspension polymerization in the presence of silica nanoparticles controlling the ratio of pyrrole, silica, and methylcellulose during the polymerization. The electrorheological (ER) and dielectric properties of the sterically stabilized PPy-silica-methylcellulose nanocomposite suspensions were investigated. The ER response increases with the increase in the silica/pyrrole ratio. The ER behavior also depends on the methylcellulose amount during the polymerization. The yield stress initially increases with the methylcellulose amount, passes through a maximum, and then decreases with the methylcellulose amount. The dielectric constants and dc conductivities of the PPy-silica-methylcellulose nanocomposite particles and the dielectric properties of their suspensions indicate that the increased ER response arises from the enhanced interfacial and particle polarization which depends on the silica/pyrrole ratio and the methylcellulose amount during the polymerization.

Journal Article↗

Effect of methylcellulose on upper gastrointestinal quality in dogs.

This study was performed to evaluate and optimize a small bowel contrast technique using barium and methylcellulose in dogs. Ten healthy dogs underwent both a conventional upper gastrointestinal study that used only barium and a modified study that used barium and methylcellulose. The control group received 10 mL/kg of 40% barium suspension. Experimental groups were divided into three subgroups given 15 mL/kg of different viscosities (low, moderate, and high viscosity) of 0.5% methylcellulose after 4 mL/kg of 40% barium suspension. Compared with the control group, dogs receiving methylcellulose had higher-quality upper gastrointestinal studies. Moderate viscosity of methylcellulose was superior to the other methylcellulose groups. In conclusion, the use of methylcellulose is a simple and effective method for improving the image quality in an upper GI examination.

Administration, Oral↗

Electron microscopic study of the methylcellulose-mediated detachment of cellulolytic rumen bacteria from cellulose fibers.

The presence of methylcellulose prevents the attachment of cellulolytic rumen bacteria to cellulose fibers. The addition of methylcellulose to pure cultures of these organisms in which the cells are already adherent to cellulose causes their detachment from this insoluble substrate and the inhibition of their growth. Methylcellulose is not used as a carbon source by these organisms and has no effect on their growth when glucose and cellobiose are the carbon sources. Attached cells of Bacteroides succinogenes orient themselves in the plane of the individual cellulose fibers and their methylcellulose-induced detachment, which is complete (almost 100%), leaves grooves where the cellulose has been digested. Attached cells of Ruminococcus albus colonize the cellulose in a looser and less regular pattern and their almost complete methylcellulose-induced detachment leaves less regular pits in the cellulose surface. On the other hand, attached cells of Ruminococcus flavefaciens colonize the cellulose surface in a random orientation by means of a discernible exopolysaccharide network, and their less complete methylcellulose-induced detachment leaves no residual impressions on the cellulose surface. These data support the suggestion that bacterial attachment is necessary for the digestion of highly ordered crystalline cellulose, and that cellulolytic species differ in the nature of their attachment to this insoluble substrate and in the nature of their enzymatic attack. Methylcellulose is an effective agent for detaching major rumen cellulolytic bacteria from their cellulosic substrate.

Animals↗

Bacterial culture preservation in frozen and dry-film methylcellulose.

Forty-seven of 61 bacterial cultures, including strains of Pseudomonas, Xanthomonas, Erwinia, Agrobacterium, Corynebacterium, Serratia, Klebsiella, and Escherichia, remained viable after storage in frozen methylcellulose or in dried methylcellulose for up to 38 months. Pathogenicity remained intact for those strains tested. Bacteria were grown on a solid medium and then removed and placed in 1.0% methylcellulose (cellulose methyl ether) to make a final suspension of 10 colony-forming units (CFU) per ml. For storage in dried form, the bacteria-methylcellulose suspension was placed in a petri dish and dried in a forced-air incubator. After 24 h of storage at 25 degrees C, viable populations of 10 CFU/mg (equivalent to 10 CFU/ml) were recovered. Populations of 10 to 10 CFU/mg were recovered after storage of up to 38 months. Similar results were obtained in frozen methylcellulose. Survival was greatly enhanced when the growth medium for the bacteria was potato dextrose peptone rather than nutrient agar, yeast dextrose calcium carbonate peptone, or King's medium B. Addition of 0.1 M MgSO(4) to the methylcellulose suspension and to the resuspending liquid also increased survival and recovery from storage for some strains. Methylcellulose storage should be a simple, inexpensive, and reliable method of maintaining cultures for short or long periods of time.

Journal Article↗

Safety and efficacy of 2% methylcellulose in cat and monkey cataract-implant surgery.

We evaluated the safety and efficacy of 2% methycellulose as an adjunct for cataract extraction with implantation in cat and monkey models. When used intraoperatively, methylcellulose reduced the iridovitreal bulge during surgery. No significant increase in clinical inflammation occurred nor was there statistically significant intraocular pressure elevation at 24 hours, 7 days, or 90 days. In the cat model, the central corneal thickness increased at day seven in both control and methylcellulose eyes; this thickness persisted to 90 days. The endothelial cell loss decreased significantly at day 90 in methylcellulose eyes. In the monkey model, no statistically significant increase in corneal thickness occurred in control or methylcellulose eyes at day seven. The endothelial cell loss was greater than in the cat model in both control and methylcellulose eyes; there was no statistically significant difference between the two. Two percent methylcellulose was safe in both the cat and monkey models. It facilitated surgery in both models and reduced the endothelial cell loss in the cat eye.

Animals↗

Increased motility of Helicobacter pylori by methylcellulose could upregulate the expression of proinflammatory cytokines in human gastric epithelial cells.

The inflammatory reaction in the human gastric mucosa to Helicobacter pylori could be initially triggered by an array of cytokines expressed in infected gastric epithelial cells. The spiral morphology and flagella of these organisms could increase their velocity in a viscous environment such as methylcellulose solution. The goal of this study was to determine whether modification of H. pylori motility could influence the expression of cytokine genes from gastric epithelial cells infected with H. pylori. Adherent human gastric epithelial cells were cultured and overlaid with methylcellulose solutions of varying viscosity. These epithelial cell layers covered with methylcellulose solution were inoculated with H. pylori. RNAs were then extracted from the gastric epithelial cells. Various cytokine gene expressions were assessed and quantified by reverse transcription-polymerase chain reaction (RT-PCR) and standard synthetic RNA. Cytokine proteins were also measured by enzyme-linked immunosorbent assay (ELISA). Expression of mRNA for interleukin(IL)-8 was upregulated in H. pylori-infected gastric epithelial cells overlaid with methylcellulose of 15 centipoise (cp) viscosity. The expression of mRNA for IL-1 alpha, IL-8, monocyte chemotactic protein (MCP)-1 and granulocyte macrophage colony-stimulating factor (GM-CSF) was also upregulated in H. pylori-infected gastric epithelial cells overlaid with methylcellulose solution of the same viscosity. The number of molecules of the expressed cytokine transcripts also paralleled the amounts of protein secreted from gastric epithelial cells infected with H. pylori. These results suggest that methylcellulose solution (simulating the mucus layer in vivo) could increase contact of H. pylori with gastric epithelial cells by increasing its motility. This could result in the upregulation of mRNA for proinflammatory cytokines in gastric epithelial cells, therefore enhancing inflammatory reaction at H. pylori-infected sites.

Cell Line↗

Polysaccharide-protein interaction: a rheological study of the gel-sol transition of a gelatin-methylcellulose-water system.

Viscoelastic parameters for mixtures of gelatin and methylcellulose were measured as a function of temperature, in order to study the gel-sol transition of the system in which biopolymers forming thermo-setting and thermo-melting gels coexist. At higher temperatures than 45 degrees C, the gel network is mainly formed by methylcellulose while at lower temperatures around 5 degrees C, it is mainly formed by gelatin. At higher temperatures than 45 degrees C, gelatin inhibits the gelation of methylcellulose. A small amount of methylcellulose helps gelatin to form a network at lower temperatures. However, excessive amounts of methylcellulose inhibit the growth of network structure. Therefore, this mixture forms a phase separated gel at higher temperatures while it is not completely phase separated at lower temperatures, probably by some interaction between non-substituted hydroxyl groups in methylcellulose with carboxylic groups in gelatin.

Animals↗

Reduced dialysis of nitrofurantoin and hydrocortisone acetate from methylcellulose solutions.

Factors affecting reduction in the permeation rate of nitrofurantoin and hydrocortisone acetate from methylcellulose solutions through a cellulose membrane were investigated. The factors evaluated were the effect of polymer agglomeration and whether the drugs formed a complex with the polymer. The influence of polymer agglomeration was evaluated by dynamic dialysis studies of nitrofurantoin dissolved in solutions of methylcellulose 400 cps, which agglomerates, and in methylcellulose 50 cps, which does not exhibit this behavior. Dialysis rates of this drug were measured as a function of polymer concentration, ionic strength, heating time prior to measurement, and temperature. The effect of polymer agglomeration on the permeation rates of hydrocortisone acetate was studied by varying the ionic strength of the drug-polymer solution. Complex formation studies were conducted for both drugs by the equilibrium dialysis method. Polymer agglomeration caused a substantial reduction in the dialysis rate of both drugs in methylcellulose 400 cps solutions. There was less reduction in the dialysis rate of nitrofurantoin with increased polymer concentration of methylcellulose 50 cps solutions, which was attributed to the increase in the bulk viscosity of the solution. There was no evidence of complex formation of the drugs with the polymers.

Chemical Phenomena↗

Cloning ovarian carcinoma cells in an agar double layer versus a methylcellulose monolayer system. A comparison of two methods.

Human ovarian cancer cells from ten patients were cultured in the agar double layer assay as described by Hamburger and Salmon and in a methylcellulose monolayer system. The assays were compared under the same experimental conditions. The rate of positives (defined as greater than 30 colonies/dish) was 75% in the methylcellulose assay and 69% in the agar double layer. Plating efficiency ranged in the methylcellulose assay between 0.021% and 0.089% and in the agar double layer from 0.015% to 0.094%. Cytological and cytochemical staining of cells obtained from colonies in both test systems and of the tumour cells prior to plating revealed the same morphology. The methylcellulose monolayer system requires less additives than necessary in the agar double layer system. Furthermore, it is easier to handle with respect to the plating procedure and less time consuming. In addition, the effect of the anti-oestrogen tamoxifen on colony formation was tested. The dose response curves for colony formation with tamoxifen proved to be identical in both systems. At a concentration of 10(-6) M an inhibition of colony formation of more than 70% of controls was observed in the agar and in the methylcellulose system.

Agar↗

Comparison of eye protection with methylcellulose an paraffin ointments during general anaesthesia.

A total of 120 patients who were all anaesthetized for more than 90 minutes were given eye protection with paraffin-based oculentum simplex, Ph. Nord. 63, in one eye, and water-based four per cent methylcellulose in the other. Anaesthesia was conducted with halothane, or thiopentone an meperidine, or by a neurolept technique. Peri-ocular oedema and reaction in the conjunctiva resembling conjunctivitis was less pronounced after methylcellulose. When both paraffin-based ointment and halothane anaesthesia were used, there were signs of drug interaction, as the patients' conjunctivae were now distinctly red. In all three types of anaesthesia, methylcellulose produces a firm gluing of the eyelids with the result that the eye is not dried out and the eye is protected mechanically so that foreign bodies and corneal abrasions are avoided. There were no untoward effects of methylcellulose. It is concluded that methylcellulose four per cent provides better eye protection than paraffin during general anaesthesia.

Adolescent↗

Hydroxypropyl methylcellulose: A better submucosal fluid cushion for endoscopic mucosal resection.

BACKGROUND: Formation of a submucosal fluid cushion has become integral to endoscopic mucosal and polyp resection. Solutions available for injection into the submucosa of the GI tract create short-lasting submucosal fluid cushions or are costly. The feasibility, durability, and histologic response to submucosal fluid cushions created by injection of hydroxypropyl methylcellulose were studied in the esophagus of pigs. METHODS: Thirty-six esophageal submucosal fluid cushions created with hydroxypropyl methylcellulose were studied in 12 animals divided in 2 groups of 6 animals each. In Group I, 18 submucosal fluid cushions were created by submucosal injection of hydroxypropyl methylcellulose followed by tattooing. In Group II, 18 submucosal fluid cushions were created by submucosal injection of hydroxypropyl methylcellulose, with sites marked by an endoscopically placed suture. In all cases, the duration of the submucosal fluid cushion was measured. After 7 days, submucosal fluid cushion sites were assessed by EGD, necropsy, and histologic evaluation. RESULTS: The mean submucosal fluid cushion duration was 36 minutes (3-45 minutes) and 38 minutes (5-45 minutes) for, respectively, Groups I and II. EGD and necropsy after 1 week showed normal-appearing mucosa at the site of all submucosal fluid cushions in both groups. Some Group I animals additionally had nodules at the tattoo sites. Histologic assessment demonstrated minimal alterations in 33 of 36 (92%) submucosal fluid cushion sites and localized mild inflammatory reaction in 3 of 36 (8%). In Group I, 8 of 18 (44%) tattoo sites exhibited a significant inflammatory reaction, including 3 abscesses. CONCLUSIONS: Hydroxypropyl methylcellulose creates a long-lasting submucosal fluid cushion with minimal tissue reaction and should be considered a low-cost option for creating submucosal fluid cushions. The use of tattooing with carbon black should be carefully considered when histologic study is required to assess potential inflammatory tissue responses to an invasive technique or instillation of foreign material in the GI tract.

Animals↗

Preliminary investigations in matrix-based tablet formulations of diltiazem hydrochloride containing succinic acid-treated methylcellulose.

The feasibility of using succinic acid-treated methylcellulose in matrix-based tablets of diltiazem hydrochloride was investigated in this study. A 2(3) factorial design was employed to investigate the effect of ratio of methylcellulose to succinic acid, amount of ethyl alcohol, and drying time on the percentage drug dissolved in 300 min. The tablets were prepared by wet granulation technique. The ratio of methylcellulose to succinic acid was found to significantly influence the swelling and gelling characteristics of the polymer. Carbonyl peak was found in the infrared (IR) spectra of the samples modified using succinic acid, suggesting the presence of an ester group. The results of an ANOVA test revealed that the significance of the ratio of methylcellulose to succinic acid and drying time was greater in magnitude than that of amount of alcohol in controlling the drug release in 300 min. The results of F-test revealed that the zero-order model fits well to the in vitro dissolution data. The characteristics of methylcellulose can be changed by reacting it with succinic acid and the resultant product can be used as a hydrophilic matrixing agent.

Calcium Channel Blockers↗

The effect of methylcellulose on symptoms of constipation.

The efficacy of methylcellulose was evaluated in 538 patients with a history of constipation. The patients were seen both by primary care physicians and by consultants. Patients were selected on the basis of passage of fewer than three stools per week. Frequency, consistency, and ease of passage of the stools were measured before and after one to three tablespoonsful per day of methylcellulose. The frequency of bowel movements as well as the consistency and ease of passage of the stools returned to normal with methylcellulose treatment; 61% of the patients were judged to have less constipation. The response to methylcellulose was not altered by the sex or age of the patients nor by the presence of colonic diverticular disease. This study suggests that methylcellulose is beneficial for the treatment of chronic and acute constipation.

Adolescent↗