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New chitosan formulations for the prevention and treatment of diseases and dysfunctions of the digestive tract (Hypercholesterolemia, overweight, ulcerative colitis and celiac disease (CHITOSANPEROS)

Final Report Summary - CHITOSANPEROS (New Chitosan Formulations for the Prevention and Treatment of diseases and dysfunctions of the digestive tract ...)

At present, chitosan tablets are commercially available as over-the-counter dietary supplements for hypercholesterolemia and overweight. Nevertheless, their formulation is primitive because the chitosan used is not in the most suitable physical and biochemical form. Thus the consumers are forced to take large daily doses, and face exceedingly high costs and poor results. Moreover for celiac disease, no dietary food incorporating chitosan exists. These kinds of patients have to use expensive gluten-free dietary foods instead of bread and pasta, with economical, nutritional and psychological distress: all these inconveniences could be removed by a proper incorporation of chitosan. Finally it is likely (but not yet investigated) that colitis patients might have benefits from chitosan intake, chitosan being a carrier for colitis-specific drugs.

This project developed new chitosan physical forms and formulations useful for the prevention and treatment of said widely occurring diseases and dysfunctions of the digestive system, that eventually develop into serious chronic diseases (heart diseases, obesity, diabetes, malabsorption, Crohn disease) that constitute heavy social burdens. The rationale is that chitosan has to be put into a special form, increasing its surface area, porosity, solubility and compressibility: in this way tableting becomes feasible without the use of binders and higher efficiency is obtained. This has been achieved by spray-drying, freeze-drying and other techniques available in the food industry. As for celiac disease, the rationale resides in the capacity of chitosan to sequester the toxic gliadin fraction responsible for intolerance. Pasta and bakery products containing minor quantities of chitosan were produced and tested with the aim of making these common foods accessible to celiac patients.

The general aim of the project was to improve the quality of life in the European society. Hypercholesterolemia, overweight, ulcerative colitis and celiac disease are currently increasing. They lead to chronic diseases such as diabetes, heart diseases, malabsorption and Crohn disease, i.e. to very high social costs. Development of new products for the treatment and prevention of these modern diseases will be surely of high impact in the dietary supplements market. SMEs from different countries involved in a collaborative work aimed at this result can surely gain advantage in the European market.

At the present time, various producers offer chitosan tablets as over-the-counter dietary supplements for hypercholesterolemia and overweight control. Some other producers market glucosamine tablets (glucosamine coming from chitosan by depolymerisation) intended for osteoarthrosis prevention and for promoting healthy joint function. The size of the market at the European level can be appreciated based on this example: the production in Italy amounts to at least 24 tons / year of chitosan, corresponding 30 million tablets containing 0.8 g each. The retail price of this production at an average EUR 0.5 per tablet is EUR 15 million / year for the Italian production alone (conservative estimate). Producers are also based in other countries (Spain, Portugal, England, Norway and more) but chitosan tablets are also sold over the internet web by US companies.

The pivotal point of this project was the consideration that the present production of chitosan tablets for hypercholesterolemia and overweight control makes use of semi-crystalline chitosan, i.e. the powder already available for other applications, which is not the best chitosan for the purpose of collecting lipids and cholesterol in vivo. Requirements are in fact that chitosan dissolves immediately in the stomach or reaches the stomach as a solution, to promptly react with bile acids and form insoluble chitosan bile acid salts. The latter prevent the assimilation of lipids by hydrophobic interactions as detailed in the project. In order to satisfy these requirements, novel amorphous, porous and instant soluble chitosans have to be developed with the aid of innovative technologies described in this project. On the other hand, the current market does not offer any chitosan-based product for the prevention of the celiac disease and joint regeneration, nor for the treatment of colitis.

Nevertheless, in the case of celiachia, the scientific literature indicates that chitosan sequesters the toxic fraction of the gliadin responsible for the intolerance to gluten in those patients, and therefore perspectives exist for the preparation of dietary foods that can alleviate the deprivations faced by the patients. For joint regeneration, a large body of scientific literature supports the view that, instead of depolymerising chitosan to glucosamine with great expenses, it might be convenient to put chitosan in a suitable physical form for easy depolymerisation in vivo. In the case of ulcerative colitis, a number of scientific articles propose chitosan as a drug carrier for specific drugs such as aminoacetyl salicylic acid.

A method to produce microspheres of chitosan by spray dryer has been developed: this method was appropriated to be used in the tablet manufacturing. The inclusion of flavours in the microspheres doesn't modify the chitosan characteristics to be used in the production of tablets. Instant soluble powders with chitosan microspheres and lemon flavour have been obtained. Chitosan tablets having weight of 350 mg have been obtained. Gelatine capsules containing chitosan and chitosan oligosaccharides microspheres have been manufactured. Other products as Chitocol Sponge with Chitosan 0.5 % and Bovine Collagen MG 0.5 % has been elaborated. Additionally, it was demonstrated that micronized chitosan, with the application of spray drying technology, not only possesses very good properties to be used in tablets production, but also improves rolls quality when used to enrich wheat flour. It was demonstrated by viscosity measurements that there are no essential changes in molecular weight of chitosan during heat treatment at 100 degrees Celsius (no significant changes in integrity of chitosan). Furthermore a valid method for obtaining quaternary chitosan was developed, thus allowing its comparison against the different chitosans previously prepared. The degree of quaternisation could be easily modified by varying the reaction time or temperature, since all the difficulties were found at the purification process. A valid synthesis method for this kind of chitosan has been established.

Wheat flour enriched with chitosan was produced and used in the fabrication of experimental batches of noodles, rolls and bread containing chitosan and chitosan oligosaccharides. In such a way feasibility for chitosan-bearing breads and related bakery items was demonstrated. Estimation of the organoleptic properties of the products shows that concentration of chitosan in rolls and bread must not exceed one percent. Such concentration is consistent with recommended doses of chitosan oligosaccharide succinate for antidiabetic action and hypercholesteremia treatment - 700 mg / d. Moreover by DSC and mechanical tests the effect of chitosan and chitosan oligosaccharides on the moisture migration from crumb to crust and between starch and gluten during bread staling was investigated. Finally scanning electron microscopy data gave information on structural changes in bread crumb and crust. It was also demonstrated that oligosaccharides have good prospects for the use in bakery in the future for dietary foods as well as for functional foods. Beneficial properties of chitosan and chitosan oligosaccharides in treatment of diseases of the digestive tract, hypercholesterolemia and atherosclerosis have been demonstrated. In particular the effect of celiac diet with chitosan was more significant. Chitosan application caused an increase of stool pH and at the beginning an increased short chain fatty acids production. At the end of chitosan application, the level of short chain fatty acids decreased. The decrease was fully compensated by omitting chitosan from the diet as was seen on short chain fatty acids production and pH values. During the chitosan application increased counts of chitinolytic bacteria in faeces were observed.

Volunteers obtaining chitosan were losing their body weight and confirmed earlier observations. Chitosan caused deeper changes in fecal microflora. Regarding the effect of chitosan on intestinal microflora no influence could be detected on body weight and blood pressure and plasma levels of calcium did not change. Moreover significant increase of levels of plasma magnesium and phosphorus and significant decrease of plasma bilirubin were observed. In addition no-significant increase of erythrocyte and leukocyte was observed. Furthemore the chitosan preparations showed different antibacterial properties and the commensal bacteria were sensitive to the chitosan treatment. Additionally, beyond the initial task, antidiabetic action of chitosan oligosaccharide succinate was demonstrated. Furthermore chitosan oligosaccharide succinate demonstrated its effectiveness with hypercholesteremia. It is advisable to prescribe them as a main cholesterol-lowering drug for patients with moderate hypercholesteremia and as an adjunct for patients with higher levels of cholesterol - more than 8 mmol/l. Recommended doses of chitosan oligosaccharide succinate for hypercholesteremia correction are 700 mg/d. The minimal course duration is 21 days. Furthermore it was demonstrated that the chitosan glycocholate and taurocholate insoluble salts subtract bile salts from the circulation thus forcing the organism to replete the bile pool at the expenses of cholesterol and that the activity of lipases is depressed as a consequence of the poor emulsification of lipids due to the lowered availability of taurocholate. When the bile salts become scarce, their capacity as emulsifiers leads to inadequate emulsions and then to limited hydrolysis of triglycerides.