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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↗

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↗

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↗

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↗

Gel matrix vehicles for growth factor application in nerve gap injuries repaired with tubes: a comparison of biomatrix, collagen, and methylcellulose.

The repair of nerve gap injuries with tubular nerve guides has been used extensively as an in vivo test model in identifying substances which may enhance nerve regeneration. The model has also been used clinical nerve repair. The objective of this study was to compare three different gel matrix-forming materials as potential vehicles for growth factors in this system. The vehicles included a laminin containing extracellular matrix preparation (Biomatrix), collagen, and a 2% methylcellulose gel. The growth factor test substance consisted of a combination of platelet-derived growth factor BB (PDGF-BB) and insulin-like growth factor I (IGF-I). An 8-mm gap in rat sciatic nerve was repaired with a silicone tube containing each of the vehicles alone or with a combination of each vehicle plus PDGF-BB and IGF-I. At 4 weeks after injury, the application of the growth factor combination significantly stimulated axonal regeneration when applied in methylcellulose or collagen, but not in Biomatrix. A similar trend was present between the vehicle control groups. By 8 weeks after injury, nerves repaired with methylcellulose as a vehicle had significantly greater conduction velocity than either collagen or Biomatrix. It was concluded that a 2% methylcellulose gel was the best of the three matrices tested, both in its effects on nerve regeneration and flexibility of formulation.

Animals↗

Clinical evaluation of methylcellulose as a bulk laxative.

We studied a bulk laxative containing methylcellulose in a group of normal subjects as well as in a group of chronically constipated individuals. The initial study in normal subjects was performed to show that the compound could increase fecal weight without significant side effects. Fifty healthy subjects were studied. Methylcellulose in daily doses of 4 g demonstrated a statistically significant increase in fecal frequency, fecal water, and fecal solids. In the second phase, we studied a group of 59 chronically constipated individuals treated with daily doses of the laxative containing either 1, 2, or 4 g of methylcellulose or 3.4 g psyllium. All of these doses resulted in statistically significant increases in stool frequency, water content, and fecal solids. There was no increase in individual stool weight from any of the laxative doses. Methylcellulose, in a daily dose as low as 1 g, is an effective laxative.

Adolescent↗

Methylcellulose during cryopreservation of ventral mesencephalic tissue fragments fails to improve survival and function of cell suspension grafts.

Cryopreservation may allow long-term storage of fetal ventral mesencephalon (VM) for transplantation in patients suffering from Parkinson's disease (PD). We investigated whether the polymer methylcellulose protects fetal rat VM during cryopreservation in liquid nitrogen and improves survival and function of this tissue as intrastriatal suspension grafts in the 6-hydroxydopamine (6-OHDA) rat model. VM tissue fragments (E14-E15) were either immediately dissociated and grafted as a cell suspension (FRESH) or cryopreserved under controlled conditions for 7 days in a conventional cryoprotective medium (CRYO) or a medium containing 0.1% methylcellulose (mCRYO) and then dissociated and grafted. Rats from the cryo-groups showed only limited behavioral compensation in contrast to complete compensation observed in rats from the FRESH group. Cryopreservation of fetal rat VM decreased the viability of cell suspensions in vitro to about 70%, survival of grafted tyrosine hydroxylase-immunoreactive (TH-IR) neurons to 11% and 20%, and transplant volume to 8% and 17% (mCRYO and CRYO, respectively, compared to FRESH). The addition of 0.1% methylcellulose to tissue fragments during freezing did neither improve in vitro viability nor survival of TH-IR neurons nor behavioral compensation when compared to the control CRYO group. These results suggest that methylcellulose failed to improve survival of cryopreserved dopaminergic ventral mesencephalic neurons.

Analysis of Variance↗

Effects of methylcellulose on hepatic glutathione levels and plasma ALAT following single oral administration to male Bom:NMRI mice.

1. A single p.o. dose of 1% w/v methylcellulose 0.013 ml/kg was given to male Bom:NMRI mice using untreated animals as controls. 2. A circadian fluctuation was seen in the hepatic glutathione levels (GSH) of both the methylcellulose and untreated animal group. 3. The methylcellulose administration did not affect the hepatic GSH or plasma ALAT level compared to untreated animals. 4. Histological examination did not reveal any abnormalities of the stomach wall, liver or kidney during the 12 hr trial period. 5. Male Bom:NMRI mice treated with 1% w/v methylcellulose can be considered representative of untreated controls in short-term experiments studying liver GSH and plasma ALAT levels.

Alanine Transaminase↗

The effects of sodium hyaluronate, chondroitin sulfate, and methylcellulose on the corneal endothelium and intraocular pressure.

Sodium hyaluronate (Healon), chondroitin sulfate, and methylcellulose have been used to protect the corneal endothelium from intraocular lens trauma. A study of the efficacy and toxicity of these compounds showed that 1% sodium hyaluronate, 0.4% methylcellulose, and 20% chondroitin sulfate were nontoxic to the corneal endothelium, but that 20% chondroitin sulfate caused a marked decrease in corneal thickness because of its hypertonicity. Anterior chamber injection of these viscous substances resulted in an increase in intraocular pressure. Within one to four hours the maximum intraocular pressure with 1% sodium hyaluronate was 67 +/- 4.1 mm Hg and that with 20% chondroitin sulfate was 55 +/- 3.5 mm Hg. The intraocular pressure did not increase to these high levels with 10% chondroitin sulfate or 0.4% methylcellulose or when the test substances were washed out of the anterior chamber. The corneal endothelium was protected from injury with 1% sodium hyaluronate and 20% chondroitin sulfate, but 10% chondroitin sulfate and 0.4% methylcellulose provided only minimal protection.

Animals↗

Comparison of the protective effects of methylcellulose and sodium hyaluronate on corneal swelling following phacoemulsification of senile cataracts.

The protective effects of two viscoelastic substances (hydroxypropyl methylcellulose and sodium hyaluronate) on the cornea during phacoemulsification of senile cataracts were investigated in a prospective, randomized, clinical study. The viscoelastic substances were placed in the anterior chamber before and during phacoemulsification. The mean increase in central corneal thickness (measured by ultrasonic pachymetry) on the first postoperative day was statistically significantly higher (P less than .05) in the methylcellulose group (35 eyes) than in the sodium hyaluronate group (35 eyes). Five weeks postoperatively the difference in mean central corneal thickness between the two groups was not statistically significant. However, one eye in the methylcellulose group developed bullous keratopathy. The present study indicates that methylcellulose does not protect the corneal endothelium as effectively as sodium hyaluronate during phacoemulsification procedures.

Aged↗

Prevention of fungal colonization and digestion of cellulose by the addition of methylcellulose.

When the attachment of cellulolytic rumen fungi to cellulose is blocked by the addition of methylcellulose, cellulose digestion is entirely inhibited. Even after these fungi have colonized and penetrated the cellulosic fibers of filter paper, the addition of methylcellulose effectively halts cellulose digestion. This effect of methylcellulose is accompanied by the complete inhibition of fungal attachment to cellulose fibers; the addition of methylcellulose does not affect the growth of these organisms on soluble substrates. We conclude that fungal cellulose digestion, like bacterial cellulose digestion, requires the spatial juxtaposition of the cellulolytic organism and its insoluble substrate. The simultaneous inhibition of both attachment and digestion by the same inhibitor suggests that these two processes are functionally linked in the fungi.

Animals↗