Insights into the Structure of Sucralfate by Advanced Solid- and Liquid-State NMR.

Sucralfate, which is a sucrose octasulfate aluminum complex, is an active pharmaceutical ingredient (API) falling in the category of cytoprotective agents which are very effective for gastric and duodenal ulcers. On interaction with stomach acid, it ionizes into aluminum and sucrose octasulfate ions to form a protective layer over the ulcerated region inhibiting further attack from acid. The mechanism of action of sucralfate in the context of its structure is not well understood. Considering that at least two forms of this API are available in the market, there are no reports on the various forms of sucralfate and differences in their pharmacological action. We characterized the two forms of sucralfate using multinuclear, multidimensional solid-state NMR, and the results show significant structural differences between them arising from variation in the aluminum environment and the level of hydration. The impact of structural differences on pharmacological action was examined by studying acid-induced Al release by 27Al liquid-state NMR. The sucralfate, European pharmaceutical standard, Form I, undergoes faster disruption in acid compared to Form II. The difference is explained on the basis of structural differences in the two forms which gives significant insights into the action of sucralfate in relation to its structure.

Design Strategy for a Hydroxide-Triggered pH-Responsive Hydrogel as a Mucoadhesive Barrier to Prevent Metabolism Disorders.

Excess nutrient uptake is one of the main factors of complications related to metabolism disorders. Therefore, efforts have emerged to modulate nutrient transport in the intestine. However, current approaches are mainly invasive interventions with various side effects. Here, a pH-responsive hydrogel is formulated by acidifying the hydroxide compounds within sucralfate to allow electrostatic interactions between pectin and aluminum ions. The pH responsiveness relies on the alternation of cations and hydroxide species, providing reversible shifting from a hydrogel to a complex coacervate system. It acts as a transient physical barrier coating to inhibit intestinal absorption and changes the viscosity and barrier function in different parts of the gastrointestinal tract, showing enhanced mucoadhesive properties. The therapeutic hydrogel remarkably lowers the immediate blood glucose response by modulating nutrient contact with bowel mucosa, suggesting potential in treating diabetes. In addition, it significantly reduces weight gain, fat accumulation, and hepatic lipid deposition in rodent models. This study provides a novel strategy for fabricating pH-responsive hydrogels, which may serve as a competent candidate for metabolism disorder management.

Novel self-assembled mesalamine-sucralfate complexes: preparation, characterization, and formulation aspects.

Two well-known active agents, mesalamine (MES) and sucralfate (SUC), were investigated for possible utilization as fixed-dose combination product. The anti-inflammatory action of MES in association with bioadhesiveness and mucosal healing properties of SUC were considered promising for the development of a new compound containing both molecules, aimed as an improved treatment of ulcerative colitis. The present study investigates the capacity of the two active agents to interact and generate a new and stable entity via self-assembling. Spray-drying was used to co-process the two active principles from an aqueous mixture where the ratio MES:SUC was in the range 25:75, 50:50, and 75:25. The structural data (X-Ray, FTIR, SEM, DSC, and (1)H NMR) have shown that MES and SUC are interacting leading to complexes with properties differing from those of each separate active agent and from their physical blends. (1)H NMR results indicated that complexation occurred when the aqueous suspensions of drugs were mixed, prior to spray-drying. Drug-drug self-assembling was the driving mechanism in the formation of the new entity. Based on the structural data, a hypothetical structure of the complex was proposed. Co-processing of MES and SUC represents a simple and useful procedure to prepare new self-assembled compounds by valorizing the ionic interactions between the two entities. Preliminary studies with oral solid dosage forms based on MES-SUC complexes tested in vitro have shown a controlled MES release, opening the perspective of a new colon-targeted delivery system and a novel class of compounds with therapeutic application in inflammatory bowel diseases.

The corneal micropocket assay: a model of angiogenesis in the mouse eye.

The mouse corneal micropocket assay is a robust and quantitative in vivo assay for evaluating angiogenesis. By using standardized slow-release pellets containing specific growth factors that trigger blood vessel growth throughout the naturally avascular cornea, angiogenesis can be measured and quantified. In this assay the angiogenic response is generated over the course of several days, depending on the type and dose of growth factor used. The induction of neovascularization is commonly triggered by either basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF). By combining these growth factors with sucralfate and hydron (poly-HEMA (poly(2-hydroxyethyl methacrylate))) and casting the mixture into pellets, they can be surgically implanted in the mouse eye. These uniform pellets slowly-release the growth factors over five or six days (bFGF or VEGF respectively) enabling sufficient angiogenic response required for vessel area quantification using a slit lamp. This assay can be used for different applications, including the evaluation of angiogenic modulator drugs or treatments as well as comparison between different genetic backgrounds affecting angiogenesis. A skilled investigator after practicing this assay can implant a pellet in less than 5 min per eye.

Interaction study of moxifloxacin and lomefloxacin with co-administered drugs.

Moxifloxacin and lomefloxacin are fluoroquinolone antibiotics used in treating urinary and respiratory tract infections. Fluoroquinolones are known to have interactions with drugs that are active in gastro intestinal tract. Being moxifloxacin and lomefloxacin fluoroquinolones the interaction study of was carried out with sucralfate, gelusil, erythromycin and multi minerals. The interaction was studied at neutral, acidic and basic conditions both at room temperature and 37°C. The effect of dissolution medium simulating various body environments with response to pH has been examined in order to elucidate the interactions. The response of moxifloxacin and lomefloxacin after interaction with co-administered drugs at different conditions and temperature were noted using a Shimadzu HPLC system with PDA detector. It was seen that interaction of these fluoroquinolones was more at 37°C than at room temperature. Moxifloxacin and Lomefloxacin reacts faster with sucralfate and gelusil in acidic media whereas with erythromycin in basic media and multi-minerals in neutral media. The study ensures the interaction of fluoroquinolones with selected class of drugs. In order to achieve the effective therapeutic effect appropriate time intervals between administrations of drugs is essential.

Slow release of tetracycline from a mucoadhesive complex with sucralfate for eradication of Helicobacter pylori.

Treatment composed of a gastric mucoadhesive antibiotic with slow release drug delivery is expected to be effective for the eradication of Helicobacter pylori (H. pylori). In this study, we evaluated the slow release property of the tetracycline-sucralfate acidic complex. Tetracycline was the antibiotic selected because of its complexation capacity with sucralfate. Sustained release was tested using two different dissolution test methods: paddle and flow-through cell. The adhesive paste formed from the acidic complex displayed a longer sustained release profile of tetracycline using flow-through cell method. The milder conditions of the flow-through cell method better mimicked the fasted state of the stomach, suggesting that the oral administration with fasting is appropriate for the acidic complex. Furthermore, the paste formation protected the tetracycline from decomposition under an acidic condition, which apparently contributes to long-term release. Change in the zeta potential of the acidic complex particles was helpful in clarifying the release mechanisms of the tetracycline. The data indicated that the immediate release of tetracycline in the early stage of the test was indispensable to the subsequent paste formation that enables slow release. If administrated orally with fasting, the acidic complex rapidly adheres to the gastric mucosa and sustains long-term release of the tetracycline to the gastric lumen or mucus layer. This antibiotic delivery mechanism, which requires only a minimum dosage, may be effective for efficient eradication of H. pylori.

Floating in situ gelling system for stomach site-specific delivery of clarithromycin to eradicate H. pylori.

Floating in situ gelling system of clarithromycin (FIGC) was prepared using gellan as gelling polymer and calcium carbonate as floating agent for potentially treating gastric ulcers, associated with Helicobacter pylori. Gellan based FIGC was prepared by dissolving varying concentrations of gellan in deionized water to which varying concentrations of drug and sucralfate were dispersed well. The formulation parameters like concentrations of gellan gum and sucralfate influenced the rate and extent of in vitro drug release significantly from FIGC. The addition of sucralfate to the formulation significantly suppressed the degradation of clarithromycin at low pH. The in vivo H. pylori clearance efficacy of prepared FIGC and clarithromycin suspension following oral administration, to H. pylori infected Mongolian gerbils was examined by polymerase chain reaction (PCR) technique and by a microbial culture method. FIGC showed a significant anti-H. pylori effect than that of clarithromycin suspension. The in situ gel formulation with sucralfate cleared H. pylori more effectively than that of formulation without sucralfate. In addition, the required amount of clarithromycin for eradication of H. pylori was found to be less from FIGC than from the corresponding clarithromycin suspension. It was concluded that prolonged gastrointestinal residence time and enhanced clarithromycin stability resulting from the floating in situ gel of clarithromycin might contribute better for complete clearance of H. pylori.

Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2-bias in their offspring.

The treatment of dyspeptic disorders with anti-acids leads to an increased risk of sensitization against food allergens. As these drugs are taken by 30-50% of pregnant women due to reflux and heartburn, we aimed here to investigate the impact of maternal therapy with anti-acids on the immune response in the offspring in a murine model. Codfish extract as model allergen was fed with or without sucralfate, an anti-acid drug, to pregnant BALB/c mice during pregnancy and lactation. These mothers developed a codfish-specific allergic response shown as high IgG1 and IgE antibody levels and positive skin tests. In the next step we analyzed whether this maternal sensitization impacts a subsequent sensitization in the offspring. Indeed, in stimulated splenocytes of these offspring we found a relative Th2-dominance, because the Th1- and T-regulatory cytokines were significantly suppressed. Our data provide evidence that the anti-acid drug sucralfate supports sensitization against food in pregnant mice and favors a Th2-milieu in their offspring. From these results we propose that anti-acid treatment during pregnancy could be responsible for the increasing number of sensitizations against food allergens in young infants.

In vitro investigation of sodium diclofenac adsorption on sucralfate.

Adsorption of sodium diclofenac was investigated in the presence of sucralfate--a cytoprotective agent preventing gastropathy, adverse effect of diclofenac. Evaluation of adsorption was performed by means of a static method in vitro taking into account pH of the environment, temperature, concentration of the investigated agents and the form of sucralfate. Findings obtained prove that sodium diclofenac is adsorbed on sucralfate in all investigated pH ranges and the capability of sucralfate binding depends on its form, temperature and environmental pH. The highest binding was observed at pH 5.0 in the presence of sucralfate, which at this pH has the form of a suspension, while the lowest--at pH 1.5 in the presence of sucralfate in the form of paste. Low values of adsorption temperature of diclofenac as well as the relationship between the level of its adsorption and environmental pH are the dominating factors pointing to the physical and exothermic adsorption.

Effect of residual water content on the physico-chemical properties of sucralfate dried gel obtained by microwave drying.

The purpose of this study was to investigate the physico-chemical characteristics of sucralfate humid gel dried by microwaves, in relation to the residual water content. Differential scanning calorimetry (DSC) allowed for the determination of the water state in sucralfate samples. Fourier-transform infrared (FT-IR) spectroscopy was used to monitor the changes in sucralfate gel structure induced by the microwave drying. A boundary value of total water content for sucralfate gel samples was found at 42% (w/w). Below this value only bound water was present, whereas above this value, the increase in total water was due to free water. In the physical form of gel, the strength of the coordination between sulfate anions and the positively charged aluminum hydroxide was dependent on the residual water content. The study of the sedimentation behavior of water suspensions prepared with dried sucralfate allowed for the evaluation of the retention of gel properties. We found that the microwave drying process affected the sedimentation of sucralfate dried gel suspensions independent of the residual water content: when suspensions were prepared from sucralfate dried gel powders containing more than 42% (w/w) of residual water, the sedimentation ratio was higher than 0.9. The non-gel powder suspension showed a sedimentation ratio of 0.68 +/- 0.02, whereas the sucralfate humid gel suspension did not sediment.

Study on interaction of gastrointestinal agents in the presence of cytoprotective drugs. Part III. In vitro study on the adsorption of selected prokinetic drugs on sucralfate.

Adsorbance of certain prokinetic drugs, regulating the motility of the digestive tract, on a cytoprotective drug--sucralfate was investigated. The evaluation of adsorbance capability was carried out by means of a statistical method in in vitro conditions, taking into account environmental pH, concentration of the investigated drugs as well as the form of sucralfate. Obtained results prove that the analyzed active agents are adsorbed on sucralfate at all the investigated pH ranges and the capability of sucralfate binding depends on its form and environmental pH. The highest binding capability was revealed by samples with pH = 3.6 in the presence of sucralfate in the form of suspension, while the lowest binding capability was observed at pH = 1.5 in the presence of sucralfate in the form of paste. The adsorbance capacity of sucralfate (k) at pH = 3.6 is the highest for cisaprid (k = 8.5) and it is significantly lower for metoclopramide (k = 1.5)

Desmodium gangeticum: a potent anti-ulcer agent.

The present study was designed to investigate anti-ulcerogenic property of ethanolic extract of Desmodium gangeticum (DG) against cold restraint (CRU, 2 hr cold restraint stress), aspirin (ASP, 150 mg/kg orally), alcohol (AL, absolute alcohol 1 ml/200gm) and pyloric ligation (PL, 4 hr pylorus ligation) induced gastric ulcer models in Sprague Dawley rats, and histamine (HST, 0.25 mg/kg) induced duodenal ulcer in guinea pigs. We found that DG at a dose of 200mg/kg, (orally), markedly decreased the incidence of ulcers in all the above models. DG showed significant protection against CRU (68.37%), AL (88.87%), ASP (38.2%), PL (40.63%) and HST (63.15%) induced ulcer models, whereas standard drug omeprazole (OMZ) showed protection index of 83.86, 56.35, 70.31 and 84.21%, respectively in CRU, ASP, PL and HST models. Sucralfate as standard drug showed 92.64% protection in AL model. DG significantly reduced acid secretion 41.61%, whereas OMZ produced 43.13% reduction. Treatment with DG showed increase in mucin secretion by 56.17%, whereas OMZ showed 12.45% increase. Anti-ulcer effect of DG may be due to its cytoprotective effect along with antisecretory activity and could act as a potent therapeutic agent against peptic ulcer disease.

The acidic complexation of tetracycline with sucralfate for its mucoadhesive preparation.

The complex of antibiotics with sucralfate (SF) was prepared with acid. The mechanism of the complexation and some factors concerning the preparation, which influence the mucoadhering property, were studied. The complexation was confirmed by the change in color and instrumental analysis. The acidic complex appeared to be produced by reagglomeration of SF preliminary particles. It was suggested that the amide or amine groups of tetracycline (TC) and aluminum moieties of SF serve as the binding sites. The potential of multiple binding sites and a priority in them were suggested by the Scatchard plot analysis. The additional amounts of acid and the increase in the surface area increased the number of sites. The amount of the additional acid appeared to be the most important factor during the preparation of the acidic complex. The appropriate amount of acid added appeared to produce a complex rich in TC. However, an excess amount might cause the excess dissociation of aluminum moieties, which destroys the mucoadhesive paste-forming property.

[Pharmacobezoar in a patient operated on for pyloric stenosis]. / Farmacobezoar en un paciente intervenido de estenosis pilórica.

Bezoars are concretions made up of a variety of partially digested materials seen in several portions of the gastrointestinal tract; they may result in gastrointestinal obstruction. Bezoar types described in the scientific literature include bezoars resulting from drugs. Their development is usually associated with some predisposing risk factor. The case of a patient is described, who was admitted to the hospitals Emergency Department because of a clinical event suggesting a gastrointestinal bleeding episode. After admission, endoscopy demonstrated the presence of a bezoar whose components included a great number of Adalat Oros tablets. A review of the drugs that induced bezoar formation is made, and associated risk factors, formation mechanisms, bezoar appearance, and treatments used are all described.

Study of interaction of gastrointestinal agents in the presence of cytoprotective drugs. Part II. In vitro study on the adsorption of selected spasmolytic drugs on sucralfate.

The subject of the research was the adsorption of selected musculotropic and cholinolytic spasmolytics on a cytoprotective drug--sucralfate. Adsorption evaluation was made by a static method, in vitro, the environment reaction, the concentrations of the tested drugs and the sucralfate form being taken into account. The obtained results prove that the analysed therapeutic substances are adsorbed on the sucralfate in all pH. The highest bonding capacity was observed in tests at pH=3.6, in the presence of sucralfate, which at this pH occurs in the form of suspension. The lowest capacity was at pH=1.5 in the presence of sucralfate in the paste form. In the group of the tested drugs, scopolamine butylbromide is adsorbed best, drotaverine hydrochloride little less and papaverine hydrochloride least of all.

Study of interaction of gastroenterological agents in the presence of cytoprotective drugs. Part I: Adsorption of the chosen inhibitors of histamine H2 receptors on sucralfat in vitro.

We investigated adsorption of the chosen histamine H2 receptor inhibitors on sucralfat. Evaluation of adsorption was conducted by statistic methods in vitro taking into account environment reaction and sucralfat form. The obtained results prove that the tested therapeutic substances are adsorbed on sucralfat in all used pH ranges and the ability of sucralfat bounding depends on its form and environment reaction. The highest adsorption value was observed in the samples with pH 3.6 in the presence of sucralfat suspension, and the lowest in environment pH 1.5 in the presence of sucralfat paste. From among the tested histamine receptors ranitidine hydrochloride is adsorbed in the best way and cimetidine hydrochloride and famotidine in much worse way.

Effect of drying methods on retention of moist sucralfate gel properties.

The aim of this work was to find a drying procedure for moist sucralfate gel capable of producing dried sucralfate gel that retains the original gel properties of bioadhesion, rheology, and micromeritics. Spray-drying and microwave-drying procedures were employed. Mannitol was used as a gel-protective substance during the drying processes. The spray drying of moist sucralfate gel gave rise to a powder whose water suspensions showed significantly reduced viscosity. The bioadhesion of spray-dried sucralfate gel was strongly reduced by drying. When mannitol was used as a gel protector, the spray-dried sucralfate in part maintained the original bioadhesion of moist sucralfate gel. The preparation of a dried sucralfate gel retaining the bioadhesion characteristics, avoiding the use of mannitol, was made possible using the microwave-drying procedure. The microwave-dried product possesses a granular morphology suitable for direct compression because it is a free flowing and strongly coherent granular powder.

[Bronchial lobar obstruction from a sucralfate tablet: a rare cause of acute respiratory insufficiency]. / Obstruction d'une bronche lobaire par un comprimé de sucralfate: une cause rare d'insuffisance respiratoire aiguë.

We report two cases of patients with chronic respiratory disease who experienced an asphyxia after aspirating a sucralfate tablet that occluded a lobar bronchus. In adults, a foreign body is a rare cause of acute respiratory failure from tracheobronchial occlusion. The sucralfate tablet has the physical property of expanding rapidly when wet (contact with mucosa). After aspiration, the tablet expands to a larger size and can occlude a lobar bronchus, causing acute respiratory failure. In patients at risk of aspiration, we recommend the use of sucralfate in liquid or suspension form.

Effects of sucralfate and its components on acid- and pepsin-induced damage to rat gastric epithelial cells.

We have established models of cell damage induced by acid and pepsin using rat gastric epithelial cells (RGM1). In the present study, the effects of aluminum hydroxide [Al(OH)3] and potassium sucrose octasulfate (KSOS), which are components of sucralfate, and sucralfate on cell damage and peptic activity of pepsin were examined. Pretreatment of cells with sucralfate (0.1-3 mg/ml) or Al(OH)3 (0.1-1 mg/ml) for 2 hr prevented both acid- (pH 4.0) and pepsin- (pH 4.5) induced cell damage. However, KSOS (0.1-1 mg/ml) did not show any effects on two different types of cell damage. The peptic activity of pepsin at pH 4.5 was about 10% of that at pH 2.0. Sucralfate and KSOS slightly inhibited peptic activity at pH 4.5. Al(OH)3 inhibited peptic activity by approximately 50%; however, no concentration-dependent pattern was observed. Pepstatin (0.003-0.1 mg/ml), a specific inhibitor of pepsin, inhibited the peptic activity in a concentration-dependent manner. Here, we confirmed that sucralfate and Al(OH)3 have cytoprotective effects against acid- and pepsin-induced cell damage. The mechanism behind the cytoprotective effects of sucralfate seems to relate to adhesion of the cell surface and neutralization of hydrogen ion by aluminum that prevents the penetration of hydrogen ions into the cells.