Sulcrate
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Sulcrate - Scientific Information

Manufacture: Actavis
Country: Canada
Condition: Duodenal Ulcer Prophylaxis, Duodenal Ulcer, GERD, Hyperphosphatemia of Renal Failure, Stress Ulcer Prophylaxis, Stomatitis, Stomach Ulcer (Gastric Ulcer)
Class: Miscellaneous GI agents
Form: Tablets, Syrup
Ingredients: sucralfate, hydrogenated vegetable oil, calcium carboxy-methylcellulose, magnesium stearate, microcrystalline cellulose, glycerine, sodium methylparaben, sodium propylparaben, sodium phosphate monobasic, xanthan gum, caramel artificial flavour

Pharmaceutical information

Drug Substance

Proper name: sucralfate
Chemical name: C12H14035S8 8[Al2(OH)x]
Structural formula:



Physical Characteristics: Sucralfate occurs as a white to slightly yellowish white, amorphous powder.

Chemistry

Sucralfate is an aluminum salt of a sulfated disaccharide. Chemically it is 3,4,5,6-Tetra-(polyhydroxyaluminum)-alpha-D-glucopyranosylsulfate-2,3,4,5,-tetra-(polyhydroxyaluminum)-beta-D-fructofuranoside sulfate (C12H14035S8 8[A12(OH)x]).

It is soluble in dilute hydrochloric acid and sodium hydroxide but practically insoluble in water, boiling water, ethanol or chloroform.

Composition

Each SULCRATE tablet contains 1 g of sucralfate. Each tablet also contains as nonmedicinal ingredients: hydrogenated vegetable oil, calcium carboxy-methylcellulose, magnesium stearate and microcrystalline cellulose.

Each 5 mL of suspension contains 1 g of sucralfate. The suspension also contains as non-medicinal ingredients: glycerine, sodium methylparaben, sodium propylparaben, sodium phosphate monobasic, xanthan gum, caramel artificial flavour.

Stability and Storage Recommendations

SULCRATE SUSPENSION PLUS should be stored at room temperature between 15 and 30°C. Avoid freezing.

Availability of Dosage Forms

  1. Tablets

    Each white, capsule-shaped, biconvex tablet, embossed with "SULCRATE" on one side and debossed with "HMR" on the other side, contains 1 g of sucralfate.

    To be kept and dispensed in a well-closed container. Bottles of 100 tablets.

  2. Suspension

    SULCRATE SUSPENSION PLUS

    Each 5 mL of off-white, creamy, suspension with a caramel odour contains 1 g of sucralfate. Supplied in bottles of 500 mL. Shake well before using.

Pharmacology

Sulfated polysaccharide has been known for a long time to possess an inhibitory action on proteolytic activity of pepsin and a preventive action on experimental peptic ulcerations.

Sucralfate, a disaccharide sulfate, has been shown to have a strong antipepsin and antiulcer action.

Contrary to the more polymerized saccharides, sucralfate is devoid of any anti-coagulant activity.

Moreover, it has been found that enhanced antiulcerogenic activity was more pronounced with the aluminum salt of the disaccharide sucralfate.

In vitro and clinical studies have shown that sucralfate is not an antacid. Sucralfate has no effect on the cardiovascular system or central nervous system and on the hematopoietic system including blood coagulation factors.

Antiulcerogenic Activity

Studies in rats involving the action of sucralfate against ulcers induced by pyloric ligation revealed that the drug reduces the incidence and size of the lesions 80-90% at single doses of 30 to 50 mg/rat. Other studies using rat restraint and stress models showed a similar level of protection with single doses of 50 to 400 mg/rat. In addition, the drug was effective in reducing the number of hemorrhagic areas.

Thermocautery-induced ulcers in the rat were used to demonstrate the promotion of mucosal regenerating activity of 200 mg of sucralfate. In addition, a quantity of 5 mg sucralfate was found to hinder the digestion on the gastric mucosa by gastric juice in vitro.

The rat clamping/cortisone ulcer model was used to examine healing, mucosal regeneration and collagen fiber growth. Investigators showed that, compared to controls, the administration of sucralfate was associated with an increase of 161% in healing index as measured by the degree of contraction of the ulcer, a 132% increase in mucosal regeneration index and a 100% greater growth of collagen fibers.

Another series of experiments was conducted involving rat models where ulcers were induced by acetic acid, pylorus ligation, prednisolone, reserpine and restraint. In the acetic acid model, the presence of sucralfate at a dose of 500 mg/kg/day significantly reduced the ulcer index approximately 44% based on surface area measurement of the ulcer. Similar results were obtained in the restraint test, 100 and 200 mg reduced the ulcer index as measured by the number of rats with ulcers, the total number of ulcers and ulcer severity in the prednisolone and reserpine models at least 53% and 84%, respectively. At 50 and 100 mg ulcer index was decreased 80% and 100%, respectively, in the pyloric ligation model.

When histamine injection was used to elicit ulcers in guinea pigs, administration of 200 and 400 mg sucralfate reduced the incidence of gastric ulcers by approximately 90% as compared to the untreated controls. Parallel responses were seen in terms of the duodenal lesions.

Mechanism of Action

Sucralfate produces distinct morphologic and functional changes in the normal gastric mucosa: mucus release, changes in ion transport and increased release of luminal prostaglandins. Several studies have shown that it can increase the synthesis and release of prostaglandin E2 from the mucosa. This mechanism may in part explain its effective cytoprotective properties.

Results of in vivo and in vitro studies show that sucralfate produced an adherent and cytoprotective barrier at the ulcer site which resisted degradation by acid and pepsin.

Laboratory and clinical studies indicate that sucralfate promotes the healing of gastric and duodenal ulcers by a three-way action:

  1. Formation of a chemical complex that binds to the ulcer site to establish a protective barrier.
  2. Direct inhibition of the action of pepsin and bile.
  3. Blockage of the back diffusion of gastric acid across the barrier.

The binding of sucralfate was demonstrated in rats with experimentally-induced ulcers. After a single dose of sucralfate, the ulcerated organs were excised and washed with a fluorescent compound that was taken up by sucralfate. Under ultraviolet light, the sucralfate showed affinity for the areas of ulceration, substantiating the binding action.

The affinity of sucralfate for the ulcer site was further substantiated in a study where patients were scheduled for gastric resection. Each patient received the same daily dose of sucralfate, with the interval from the last dose to operation time varying from 2 to 16 hours. At all of these intervals, the concentrations of sucralfate in ulcer craters were 4 to 30 times higher than the concentrations in tissue specimens from the normal mucosa in the same patients.

The antipepsin activity of sucralfate has been demonstrated in several in vivo and in vitro studies.

In in vitro studies and on pylorus ligated rat models, the presence of sucralfate inhibits pepsin activity of the gastric juice, reduces the total acidity and is associated with an elevation of gastric fluid pH.

In a clinical study, sucralfate was administered to ulcer patients and the effects on pepsin activity was monitored for 30 minutes after ingestion of the drug. Sucralfate doses of 1, 1.5, 2, 2.5 and 3 g reduced pepsin activity by 32%, 34%, 44% and 55% respectively.

Sucralfate was shown to reduce bile salt concentration in vitro by adsorbing the bile salts onto sucralfate in suspension. Glycocholic acid in a buffered solution was used in the test. The maximum amount adsorbed was approximately 112 mg per gram of sucralfate.

Sucralfate's capacity to block the diffusion of acid was demonstrated in an in vitro diffusion cell experiment. Sucralfate was bonded to an albumin film and placed between two solutions of equal acidity. When the acidity on the sucralfate side of the film was increased, a lowering of pH on the other side was delayed. Sucralfate delayed the change more than twice as long as albumin alone and nearly twice as long as albumin plus an antacid.

The capacity of sucralfate to block acid diffusion was further substantiated in a clinical study. Gastric transmural potential difference was measured in normal volunteers after the administration of either glycocholic acid or sucralfate followed with glycocholic acid. The drop in potential difference produced by the administration of glycocholic acid was reduced when sucralfate was administered before glycocholic acid, indicating a reduction in the back diffusion of acid.

During therapy, the physiological functions of the digestive system remain virtually unchanged.

Clinical Experience

Duodenal Ulcer

The safety and efficacy of SULCRATE (sucralfate) in duodenal ulcer has been demonstrated in a number of controlled as well as non-controlled studies involving more than 1000 patients. The drug was compared under double-blind conditions to a placebo or cimetidine.

Diagnosis and clinical findings were controlled with endoscopic examinations. The average daily dosage utilized was 3 to 4 g a day and the duration of treatment varied between 4 to 12 weeks.

Complete healing of duodenal ulcers was observed in 83.9% of patients treated with SULCRATE tablets compared to 57.2% of patients treated with a placebo.

When SULCRATE suspension was compared to placebo the healing rate observed after 8 weeks treatment was 76% of patients treated with SULCRATE suspension and 53% of patients given placebo. In another study the healing rates of SULCRATE suspension and SULCRATE® tablets administered as 1 g qid for 8 weeks, were similar: 84% vs 85% respectively.

In an eight week double-blind study of SULCRATE SUSPENSION PLUS administered as 2 g BID versus placebo suspension and involving 184 patients, the healing rate after 8 weeks of treatment for patients treated with SULCRATE SUSPENSION PLUS was 74% versus 55% for placebo.

In two comparative studies of SULCRATE tablets and cimetidine, there was no statistical difference in healing rates between the two drugs.

Duodenal Ulcer Recurrence

Over 300 patients have participated in controlled clinical trials evaluating the efficacy of SULCRATE tablets in preventing duodenal ulcer recurrence. A multicenter, double-blind, placebo-controlled study conducted in the US resulted in a significantly lower incidence of duodenal ulcer recurrence in patients treated with SULCRATE tablets for up to one year. Endoscopic evaluations at 6 and 12 months showed the following incidences of recurrence: at 6 months, 20% of SULCRATE treated patients had recurred, compared to 74% of patients treated with a placebo. At 12 months, the recurrence rate for patients receiving SULCRATE tablets was 27%, compared to 80% in patients receiving a placebo. In the course of the trial, some investigators have noted symptoms that could be suggestive of duodenal ulcer in some patients receiving prophylaxis with SULCRATE tablets. However, these symptoms did not result in duodenal ulcer disease.

Gastric Ulcer

The effect of SULCRATE tablets in gastric ulcer was evaluated under doubleblind conditions in approximately 450 patients. The healing rate for patients receiving SULCRATE tablets was 74.1% as compared to 53.1% in patients receiving a placebo.

In a comparative study of SULCRATE and cimetidine in 41 patients, the healing rate was comparable in both groups of patients.

Toxicology

Acute Toxicity

LD50 acute toxicity studies were completed in various rodent species and LD50 could not be determined. Doses utilized in these studies were as high as 12 g/kg of body weight orally in the rat and 8 g/kg of body weight administered intraperitoneally in the mouse. Dogs received sucralfate at doses up to 5 g/kg. No drug-related toxicity or deaths were observed.

Subacute Toxicity

Two subacute toxicity studies were conducted in the rabbit and guinea pig to determine the effect of sucralfate on the cecum and large bowel. Doses up to 1000 mg/kg/day for 30 days were used and detailed gross and histopathological examinations of the entire digestive tract were accomplished at the termination of the study. The results indicated that the administration of sucralfate under the conditions of these studies did not have any adverse effect on any area of the digestive tract or in any other organ system.

In addition, no effect was seen in terms of the hematological or blood chemical parameters examined in the guinea pig study. In this study, blood was also analyzed for aluminum content and no increases in blood aluminum levels were seen when test groups were compared with controls.

In a 30-day subacute study, sucralfate was given to groups of rats at doses of 2, 4 and 8 g/kg/day. No toxicity was evidenced in terms of general condition, behavior, hematology, blood chemistry or organ weights. The high dose rats did exhibit some weight gain depression. Histological examination of tissues revealed some neutrophil infiltration in the submucosa and the tunica propria mucosae of the stomach in 6 of 20 animals of the 8 g/kg/day group. A similar finding was seen in 3 rats receiving 4 g/kg/day but it was lesser in degree. No other findings were noted. The no-effect level was 2 g/kg/day.

Chronic Toxicity - Carcinogenicity

The effect of prolonged administration of sucralfate was examined in mice, rats and dogs. Sucralfate was given to mice at doses of 1 and 5% of the diet in both a one-year chronic toxicity study and a two-year carcinogenicity study. No untoward deleterious effects were reported in either study and no evidence of carcinogenic potential was manifested. A second 109 week carcinogenic study was conducted in mice using doses up to 1000 mg/kg/day. This study confirmed those findings reported in the two earlier studies.

In a six month rat chronic study, sucralfate was given at doses of 0.5, 1, 2, and 4 g/kg/day by oral gavage. No evidence of toxicity was noted in appearance, hematology, blood chemistry or organ weights.

The stomachs of animals in the 2 and 4 g/kg/day groups that were sacrificed after 90 days exhibited some neutrophilic infiltration of the submucosa and the tunica propria with concurrent hydropic degeneration or slight thickening of the mucosal epithelium. These responses were more advanced after six months. Degenerative changes were also seen in the epithelial cells of the renal tubules at 4 g/kg/day and to a lesser extent at 2 g/kg/day. The no-effect levels were in between 1 and 2 g/kg/day. These doses are in excess of 15 times that recommended for humans.

A twenty-four month chronic toxicity/carcinogenicity study was also conducted in rats. Eosinophilic cytoplasmic droplets were seen in renal tubule epithelial cells in rats of the 1000 and 250 mg/kg/day groups. Untreated control animals and those receiving 50 mg/kg/day did not have this renal finding. Behavioral observations, blood chemistry assays and urinalysis tests were comparable among all groups indicating normal kidney function. Therefore, the renal findings were not considered clinically meaningful. In addition, the findings of the microscopic examination of all other tissues were similar among the groups. Finally, no carcinogenic potential was apparent.

Dogs received sucralfate at doses up to 2 g/kg/day for six months. No untoward drug-related effects were reported. Similar results were obtained in a one-year dog study where the dogs received 50, 250 and 500 mg/kg/day sucralfate. However, microscopic examination together with subsequent electron microscopic analysis disclosed a vacuolation of some of the epithelial cells in the proximal convoluted tubules in some of the 250 and 500 mg/kg/day animals. No morphological alterations were seen with other compounds such as mannitol, dextran, sucrose or polyvinylpyrrolidone.

The changes were non-progressive since they may be seen after 4 weeks and they are reversible. In addition, none of the blood chemistry or kidney function tests conducted indicated renal damage nor was the normal function of the kidneys hindered.

It is noted that no drug-associated cellular changes in renal tissues were cited in the 28-day guinea pig, 30-day rabbit or 109-week mouse studies discussed previously.

Reproduction and Teratology

Reproduction and teratological studies with sucralfate doses up to 4 g/kg/day body weight in mice and rats and up to 1000 mg/kg of body weight in rabbits did not demonstrate any teratogenic or other associated abnormalities. No deleterious drug-associated effects were seen in terms of general reproductive performance, fertility or perinatal/post-natal responses. The drug levels employed represented doses ranging from 15 to 45 times those recommended in humans.