Formulations for reducing nutrient absorption and methods of preparation and use thereof

Abstract

A dry composition comprising: high molecular weight (HMW) chitosan; an organic acid; pectin; and alginate; as an active component. Methods of making and using the composition, as well as oral dosage forms based on the composition, are also disclosed.

Description

[0001] TITLE: FORMULATIONS FOR REDUCING NUTRIENT ABSORPTION AND METHODS OF PREPARATION AND USE THEREOF

[0002] Related applications:

[0003] This PCT application claims priority under 35 U.S.C 119(e) of US provisional application 63 / 614,933 filed on December 27, 2023 which has the same title and inventor(s) as the present application and is fully incorporated by reference.

[0004] FIELD OF THE INVENTION

[0005] The invention is in the field of product formulation and production, more specifically formulations intended for weight management.

[0006] BACKGROUND OF THE INVENTION

[0007] Obesity is a major health issue that affects large numbers of people, especially in developed countries. Obesity plays a major role in a long list of health-related issues such as insulin resistance (diabetes), cardiovascular diseases, airway dysfunctions, metabolic syndrome, kidney disease, osteoarthritis, skin diseases, reproductive disorders, retinopathy, nerve damage, heart attack and cancer. These health-related issues create a serious financial burden on the health care system.

[0008] Excess weight has primarily been blamed on high calorie diet in conjunction with a sedentary lifestyle. In addition to the health-related issues there are psychosocial stigmas associated with obesity.

[0009] Research has shown that obesity is the result of multiple causes including an imbalance between energy intake and expenditure, genetic predisposition and obesogens . Obesogens are chemicals that inappropriately alter lipid homeostasis to promote adipogenesis and lipid accumulation. It is believed that obesogens are Endocrine Disrupting Chemicals (EDCs) that resemble natural hormones and disrupt endocrine function by interfering with the body's endogenous hormones.

[0010] While Glucose is an essential energy source, excess consumption of glucose is a key issue in the development of obesity and excess glucose concentration in the blood may cause serious health problems such as diabetes. Prediabetes and diabetes affect hundreds of millions of people throughout the world. The high sucrose) concentration (composed of glucose and fructose) in industrially processed food is believed to be a contributing factor in diabetes.

[0011] Monosodium Glutamate (MSG) is used in many food products as a flavor enhancer. MSG elicits the secretion of glucagon-like peptide, that acts as a hormone controlling appetite and satiety, and / or antagonization of the androgen receptor. MSG's contribution to the early onset of obesity has been found in animal studies.

[0012] Carrageenan is a hydrocolloid substance, commonly present in chocolate milk and ice cream, that impairs glucose tolerance and increases insulin resistance and inhibits insulin signaling. A study on mice showed a significant change in gene expression related to decreased in lipid metabolism. As was noted for MSG, the experimental findings signal a warning and draw attention to the consequences of consuming high concentrations of carrageenan in food products.

[0013] Since obesity is a common health issue as well as an esthetic concern, tremendous efforts have been made to address and solve this problem.

[0014] Minimally invasive procedures to overcome obesity include the intra-gastric balloon (IGB). Limitations of the IGB include rapid inflation and limited adjustability of the device and the necessity for an endoscopic insertion or extraction.

[0015] More drastic measures, such as surgical intervention (e.g., bariatric surgeries) are generally acknowledged as effective but pose the risks common to all surgical interventions. Due to these risks, surgery is typically only considered for individuals with a relatively high BMI.

[0016] SUMMARY OF THE INVENTION

[0017] A broad aspect of some embodiments of the invention relates to a chemical formulation including edible substances which reduces the absorption of known obesity causing substances in the intestine when ingested. This formulation provides simple and effective relief from to a large segment of the population suffering from obesity or at risk for obesity.

[0018] One aspect of some embodiments of the invention relates to a pharmaceutical or nutraceutical composition comprising as active ingredients high molecular weight (HMW) chitosan, pectin and alginate.

[0019] In some exemplary embodiments of the invention, the composition, when ingested, contributes to a reduction of glucose absorption in the intestine (also referred to herein as "glucose uptake "or "glucose uptake restriction." In some embodiments the ingested composition forms a layer that reversibly covers mucosa of the small intestine. In some exemplary embodiments of the invention, this layer serves as a physical barrier that contributes to a reduction of glucose absorption.

[0020] In some exemplary embodiments of the invention, the composition is provided in a dry formulation. Alternatively or additionally, in some embodiments the formulation incudes weight equivalent amounts of an organic acid (e.g. succinic acid and / or ascorbic acid and / or citric acid) and HMW chitosan. According to various exemplary embodiments of the invention the dry formulation is provided as pills, capsules, dragees, or powder. According to various exemplary embodiments of the invention the active components of the dry formulation include at least 25%, at least 27.5%, at least 30%, at least 32.5%, at least 35%, at least 37.5%, at least 40% (w / w) HMW chitosan or intermediate or higher percentages. Alternatively or additionally, according to various exemplary embodiments of the invention the active components of the dry formulation include not more than 40%, not more than 37.5%, not more than 35%, not more than 32.5%, not more than 30%, not more than 27.5%, not more than 25% (w / w) HMW chitosan or intermediate or lower percentages. According to various exemplary embodiments of the invention the active components of the dry formulation include at least 25%, at least 27.5%, at least 30%, at least 32.5%, at least 35%, at least 37%, at least 40% (w / w) organic acid or intermediate or higher percentages. Alternatively or additionally, according to various exemplary embodiments of the invention the active components of the dry formulation include not more than 40%, not more than 37.5%, not more than 35%, not more than 32.5%, not more than 30%, not more than 27.5%, not more than 25% (w / w) organic acid or intermediate or lower percentages. According to various exemplary embodiments of the invention the active components of the dry formulation include at least 15%, at least 17.5%, at least 20%, at least 22.5%, at least 25%, at least 27.5%, at least 30% (w / w) pectin or intermediate or higher percentages. Alternatively or additionally, according to various exemplary embodiments of the invention the active components of the dry formulation include not more than 30%, not more than 27.5%, not more than 25%, not more than 22.5%, not more than 20%, not more than 17.5%, not more than 15% (w / w) pectin or intermediate or lower percentages. According to various exemplary embodiments of the invention the active components of the dry formulation include at least 7.5%, at least 9%, at least 11%, at least 12%, at least 13%, at least 14% , at least 15% (w / w) alginate or intermediate or higher percentages. Alternatively or additionally, according to various exemplary embodiments of the invention the active components of the dry formulation include not more than 15%, not more than 14%, not more than 13%, not more than 12%, not more than 11%, not more than 10%, not more than 9%, not more than 7.5% (w / w) alginate or intermediate or lower percentages.

[0021] In some exemplary embodiments of the invention, the composition is provided as a solution or suspension of the active ingredients in an aqueous solution. In some embodiments the aqueous solution includes weight equivalent amounts of organic acid and HMW chitosan.

[0022] In some exemplary embodiments of the invention, the solution or suspension contains at least 0.25% (w / v), at least 0.35% (w / v), 0.35% (w / v), at least 0.45% (w / v), at least 0.50% (w / v), at least 0.55% (w / v), 0.65% (w / v), at least 0.70% (w / v), or intermediate or greater percentages of a dry composition as described hereinabove.

[0023] In some exemplary embodiments of the invention, the solution or suspension contains not more than 0.7% (w / v), not more than 0.65% (w / v), not more than 0.7% (w / v), not more than 0.65% (w / v), not more than 0.6% (w / v), not more than 0.55% (w / v), not more than 0.5% (w / v), not more than 0.45% (w / v), not more than 0.4% (w / v), not more than 0.35% (w / v), not more than 0.3% (w / v), not more than 0.25% (w / v), or intermediate or lesser percentages of a dry composition as described hereinabove.

[0024] According to various exemplary embodiments of the invention the aqueous solution (or suspension) includes at least 0.7%, at least 1%, at least 1.4%, at least 1.7%, at least 2.0% (w / v) or intermediate or greater amounts of HMW chitosan. Alternatively or additionally, in various exemplary embodiments the aqueous solution includes not more than 2%, not more than 1.7%, not more than 1.4%, not more than 1.0 %, not more than 0.7% (w / v) or intermediate or lesser amounts of HMW chitosan.

[0025] According to various exemplary embodiments of the invention the aqueous solution includes at least 0.7%, at least 1%, at least 1.4%, at least 1.7%, at least 2.0% (w / v) or intermediate or greater amounts of organic acid. Alternatively or additionally, in various exemplary embodiments the aqueous solution includes not more than 2%, not more than 1.7%, not more than 1.4%, not more than 1.0 %, not more than 0.7% (w / v) or intermediate or lesser amounts of organic acid.

[0026] According to various exemplary embodiments of the invention the aqueous solution includes at least 0.5%, at least 0.75%, at least 1.0%, at least 1.25%, at least 1.5%, 1.75%, at least 2.0%, at least 2.25%, at least 2.5%, at least 2.75%, at least 3.0% (w / v) or intermediate or greater amounts of pectin. Alternatively or additionally, in various exemplary embodiments the aqueous solution includes not more than 3.0%, not more than 2.75%, not more than 2.5%, not more than 2.25%, not more than 2.0%, not more than 1.75%, not more than 1.5%, not more than 1.25%, not more than 1.0%, not more than 0.75 %, not more than 0.5% (w / v) or intermediate or lesser amounts of pectin.

[0027] According to various exemplary embodiments of the invention the aqueous solution includes at least 0.5%, at least 0.75%, at least 1.0%, at least 1.25%, at least 1.5%, 1.75%, at least 2.0%, at least 2.25%, at least 2.5%, at least 2.75%, at least 3.0% (w / v) or intermediate or greater amounts of alginate. Alternatively or additionally, in various exemplary embodiments the aqueous solution includes not more than 3.0%, not more than 2.75%, not more than 2.5%, not more than 2.25%, not more than 2.0%, not more than 1.75%, not more than 1.5%, not more than 1.25%, not more than 1.0%, not more than 0.75 %, not more than 0.5% (w / v) or intermediate or lesser amounts of alginate.

[0028] Another aspect of some embodiments of the invention relates to a method including dissolving HMW chitosan in an aqueous solution of organic acid in the amounts set forth hereinabove and also dissolving pectin and alginate in the aqueous solution in the amounts set forth hereinabove in the same solution. In some embodiments the method includes drying the chitosan / pectin / alginate / organic acid solution to produce a dry composition. In some embodiments the drying is by lyophilization and / or by spray drying.

[0029] Another aspect of some embodiments of the invention relates to a method of reducing nutrient absorption in the small intestine comprising orally administering a chitosan / pectin / alginate / organic acid composition as described hereinabove to a subject in a physiologically effective amount. According to various exemplary embodiments of the invention the composition is a dry composition or a solution. In some embodiments, the composition is administered 30 to 90 minutes prior to food consumption. In some exemplary embodiments of the invention, the administered composition forms a mucoadhesive layer. In some embodiments the mucoadhesive layer persists for 2 to 8 hours before being displaced by secretion of mucus by intestinal villi.

[0030] Another aspect of some embodiments of the invention relates to an oral dosage form comprising a chitosan / pectin / alginate / organic acid composition as described hereinabove. According to various exemplary embodiments of the invention the oral dosage form is selected from the group consisting of a pill, a tablet, a sachet of powder, a measured dose of bulk pack powder, a capsule, a dragee, and a container of liquid.

[0031] Another aspect of some embodiments of the invention relates to addition of flavoring agents and / or aromas and / or carbonation to a chitosan / pectin / alginate / organic acid composition as described hereinabove. In some embodiments flavoring agents and / or aromas and / or carbonation contribute to organoleptic properties of the composition. In some embodiments an improvement in organoleptic properties contributes to an improvement in patient compliance.

[0032] It will be appreciated that the various aspects described above relate to solution of technical problems associated with treatment of obesity without requirement for a lifestyle change. In some embodiments the treatment is a prophylactic treatment.

[0033] Alternatively or additionally, it will be appreciated that the various aspects described above relate to solution of technical problems related to reducing absorption of one or more nutrients in the intestine. In some embodiments the one or more nutrients include glucose.

[0034] In some exemplary embodiments of the invention there is provided a dry composition including: high molecular weight (HMW) chitosan; an organic acid; pectin; and alginate; as an active component. In some exemplary embodiments of the invention the organic acid comprises succinic acid and / or ascorbic acid and / or citric acid. Alternatively or additionally, in some embodiments the composition includes at least one member of the group consisting of a flavoring agent, a colorant, a preservative, and a vitamin. Alternatively or additionally, in some embodiments the composition includes at least 25% chitosan on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes not more than 40% chitosan on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes at least 25% organic acid on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes not more than 40% organic acid on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes at least 15% pectin on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes not more than 30% pectin on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes at least 7.5% alginate on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes not more than 15% alginate on a dry matter basis (w / w). In some exemplary embodiments of the invention there is provided at least 0.25% (w / v) of the dry composition as described hereinabove dissolved or suspended in an aqueous medium. In some exemplary embodiments of the invention there is provided not more than 0.7% (w / v) of the dry composition as described hereinabove dissolved or suspended in an aqueous medium. A dry composition as described hereinabove dissolved or suspended in an aqueous medium provided as a carbonated beverage.

[0035] In some exemplary embodiments of the invention, a composition as described hereinabove is used in treatment of obesity or weight management. In some exemplary embodiments of the invention, a composition as described hereinabove is used in treatment of diabetes (e.g. type 2 diabetes).

[0036] In some exemplary embodiments of the invention there is provided a method of manufacture including: (a) dissolving organic acid in water to produce an aqueous solution of organic acid; and (b) dissolving high molecular weight (HMW) chitosan, pectin, and alginate in the aqueous solution to form a mucoadhesive composition. In some embodiments the organic acid comprises succinic acid and / or ascorbic acid and / or citric acid. Alternatively or additionally, in some embodiments the method includes dissolving at least one member of the group consisting of a flavoring agent, a colorant, a preservative, and a vitamin is the aqueous solution or the mucoadhesive composition. Alternatively or additionally, in some embodiments the organic acid is present in the aqueous solution at a concentration of at least 0.7 g per 100 ml. Alternatively or additionally, in some embodiments the organic acid is present in the aqueous solution at a concentration of not more than 2.1 g per 100 ml. Alternatively or additionally, in some embodiments the HMW chitosan is present in the aqueous solution at a concentration of at least 0.7 g per 100 ml. Alternatively or additionally, in some embodiments the HMW chitosan is present in the aqueous solution at a concentration of not more than 2.1 g per 100 ml. Alternatively or additionally, in some embodiments the pectin is present in the aqueous solution at a concentration of at least 0.5 g per 100 ml. Alternatively or additionally, in some embodiments the pectin is present in the aqueous solution at a concentration of not more than 3.0 g per 100 ml. Alternatively or additionally, in some embodiments the alginate is present in the aqueous solution at a concentration of at least 0.5 g per 100 ml. Alternatively or additionally, in some embodiments the alginate is present in the aqueous solution at a concentration of not more than 3.0 g per 100 ml. Alternatively or additionally, in some embodiments the method includes drying the mucoadhesive composition to produce a dried composition. Alternatively or additionally, in some embodiments the drying includes lyophilization. Alternatively or additionally, in some embodiments the drying includes spray drying. Alternatively or additionally, in some embodiments the method includes redissolving the dried composition in an aqueous medium. Alternatively or additionally, in some embodiments the method, includes carbonating the aqueous medium.

[0037] In some exemplary embodiments of the invention there is provided a method of treatment including: administering to a subject with a body mass index (BMI) of at least 30 a physiologically effective amount of a dry composition or a liquid composition as described hereinabove. In some embodiments the subject is a diabetic subject. Alternatively or additionally, in some embodiments d administering occurs 30 to 90 minutes prior to ingestion of food. Alternatively or additionally, in some embodiments the physiologically effective amount of said composition forms a mucoadhesive layer in at least a portion of the intestine which persists for 2 hours to 8 hours.

[0038] In some exemplary embodiments of the invention there is provided an oral dosage form including at least 2 g of a dry composition as described hereinabove. In some embodiments the oral dosage form includes not more than 6 grams of the dry composition as described hereinabove. Alternatively or additionally, in some exemplary embodiments of the invention, the oral dosage form is provided as a powder. Alternatively or additionally, in some exemplary embodiments of the invention, the oral dosage form is provided as a beverage. Alternatively or additionally, in some exemplary embodiments of the invention, the oral dosage form is provided as one or more pills, capsules or tablets.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although suitable methods and materials are described below, methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. In case of conflict, the patent specification, including definitions, will control. All materials, methods, and examples are illustrative only and are not intended to be limiting.

[0040] As used herein, the terms "comprising" and "including" or grammatical variants thereof are to be taken as specifying inclusion of the stated features, integers, actions or components without precluding the addition of one or more additional features, integers, actions, components or groups thereof. This term is broader than, and includes the terms "consisting of" and "consisting essentially of" as defined by the Manual of Patent Examination Procedure of the United States Patent and Trademark Office. Thus, any recitation that an embodiment "includes" or "comprises" a feature is a specific statement that sub embodiments "consist essentially of" and / or "consist of" the recited feature.

[0041] The phrase "consisting essentially of" or grammatical variants thereof when used herein are to be taken as specifying the stated features, integers, steps or components but do not preclude the addition of one or more additional features, integers, steps, components or groups thereof but only if the additional features, integers, steps, components or groups thereof do not materially alter the basic and novel characteristics of the claimed composition, device or method.

[0042] The phrase "adapted to" as used in this specification and the accompanying claims imposes additional structural limitations on a previously recited component.

[0043] The term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of architecture and / or computer science.

[0044] Percentages are (%) w / w (weight per weight) unless otherwise indicated.

[0045] For purposes of this specification and the accompanying claims, the term "w / v" indicates weight per volume. A % weight per volume (%w / v) indicates grams per 100 ml.

[0046] For purposes of this specification and the accompanying claims, the acronym "CS" indicates chitosan.

[0047] For purposes of this specification and the accompanying claims, the acronym "HMW" indicates high molecular weight.

[0048] BRIEF DESCRIPTION OF THE FIGURES

[0049] In order to understand the invention and to see how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying figures. In the figures, identical and similar structures, elements or parts thereof that appear in more than one figure are generally labeled with the same or similar references in the figures in which they appear. Dimensions of components and features shown in the figures are chosen primarily for convenience and clarity of presentation and are not necessarily to scale. The attached figures are: Fig. 1 is a simplified flow diagram of a manufacturing method according to some exemplary embodiments of the invention;

[0050] Fig. 2 is a histogram of %glucose blocked (relative to a mucin control) as a function of time in minutes for a formulation according to exemplary embodiments of the invention (F34 and F34*) and each of the components of F34 in an in vitro glucose diffusion assay;

[0051] Fig. 3 is a histogram of % glucose, mono-sodium glutamate and carrageenan blocked (relative to a mucin control) as a function of time in minutes for the formulation according to an exemplary embodiment of the invention (F34*) in an in vitro glucose diffusion assay;

[0052] Fig. 4 is a histogram of % glucose blocked (relative to a mucin control) as a function of time in minutes for a formulation according to an exemplary embodiment of the invention (F34) and F34 dried and re-dissolved in an in vitro glucose diffusion assay;

[0053] Fig. 5 is a histogram of blood glucose concentration (mg / dL) as a function of time in minutes in Sprague Dawley rats treated with a formulation according to an exemplary embodiment of the invention (F34) and a saline control;

[0054] Fig. 6 is a histogram of blood glucose concentration (mg / dL) as a function of time in minutes in Sprague Dawley rats treated with a formulations F34 and F34* according to exemplary embodiments of the invention and a saline control;

[0055] Fig. 7 is a histogram of blood glucose concentration (mg / dL) as a function of time in minutes in Sprague Dawley rats treated with a formulations F34 and F34 which had been dried and re-dissolved according to exemplary embodiments of the invention and a saline control;

[0056] Fig. 8 is a photograph of the device used in in vitro glucose diffusion assays;

[0057] Fig. 9 is a photograph of strips of porcine intestine tissue coated with formulation F34 according to an exemplary embodiment of the invention; and

[0058] Fig. 10 is a histogram of % glucose blocked as a function of time in minutes for a formulation F34 prepared using 2% citric acid and F34 prepared using 2% succinic acid dried and re-dissolved in an in vitro glucose diffusion assay.

[0059] DETAILED DESCRIPTION OF EMBODIMENTS

[0060] Embodiments of the invention relate to compositions, oral dosage forms, methods of manufacture and methods of treatment.

[0061] Specifically, some embodiments of the invention can be used to reduce uptake of glucose and / or lipids ion the digestive tract. This reduction in nutrient uptake can contribute to weight management or weight reduction and / or can be useful in the context of diabetes or other disorders where weigh gain is a problem (e.g. Prader Willi Syndrome).

[0062] The principles and operation of compositions and methods according to exemplary embodiments of the invention may be better understood with reference to the drawings and accompanying descriptions.

[0063] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and is not limiting.

[0064] Exemplary dry composition

[0065] Some exemplary embodiments of the invention relate to a dry composition including high molecular weight (HMW) chitosan, an organic acid, pectin and alginate as an active component.

[0066] For purposes of this specification and the accompanying claims, the term "high molecular weight" or "HMW" indicates at least 250,000 Daltons. In experimental examples presented hereinbelow a commercially available chitosan with a molecular weight of "'310,000 Daltons was employed.

[0067] According to various exemplary embodiments of the invention the organic acid includes succinic acid and / or ascorbic acid and / or citric acid. Alternatively or additionally, in some embodiments the composition includes at least 25% chitosan on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes not more than 40% chitosan on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes at least 25% organic acid on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes not more than 40% organic acid on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes at least 15% pectin on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes not more than 30% pectin on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes at least 7.5% alginate on a dry matter basis (w / w). Alternatively or additionally, in some embodiments the composition includes not more than 15% alginate on a dry matter basis (w / w). Alternatively or additionally, in some embodiments a dry composition according to an exemplary embodiment of the invention includes at least one member of the group consisting of a flavoring agent, a colorant, a preservative, and a vitamin.

[0068] Exemplary liquid compositions

[0069] Various exemplary embodiments of the invention relate to a composition including at least 0.25% (w / v), at least 0.5% (w / v), at least 1.0% (w / v), at least 1.25% (w / v), at least 1.5% (w / v), at least 1.75% (w / v), at least 2.0% (w / v), at least 2.5% (w / v), or intermediate amounts of a dry composition as described hereinabove dissolved or suspended in an aqueous medium.

[0070] Alternatively or additionally, various exemplary embodiments of the invention relate to a composition including not more than 0.7% (w / v), not more than 1.0% (w / v), not more than 2.0% (w / v), not more than 3.0% (w / v), not more than 4.0% (w / v), not more than 5.0% (w / v), not more than 6.0% (w / v), not more than 7.0% (w / v), not more than 8.0% (w / v), not more than 9.0% (w / v), not more than 10% (w / v), or intermediate or lower percentages of a dry composition as described hereinabove dissolved or suspended in an aqueous medium.

[0071] In some exemplary embodiments of the invention, a liquid composition according to an exemplary embodiment of the invention is provided as a carbonated beverage. Alternatively or additionally, in some embodiments a liquid composition according to an exemplary embodiment of the invention includes at least one member of the group consisting of a flavoring agent, a colorant, a preservative, and a vitamin.

[0072] Exemplary use scenarios

[0073] According to various exemplary embodiments of the invention a dry composition or a liquid composition as described hereinabove is used in treatment of obesity and / or weight management (i.e. prophylactic treatment of obesity, and / or diabetes management (e.g. type 2 diabetes) and / or in a subject with a metabolic disorder that contributes to obesity (e.g. Prader Willi syndrome). As demonstrated in the experimental examples hereinbelow, the composition has a short period of activity in rats. Once human trials begin it will be necessary to calibrate the system in order to determine how far in advance of a meal the composition should be ingested in order to achieve the desired reduction in nutrient uptake.

[0074] In some embodiments formulations according to exemplary embodiments of the invention are advantageously employed in the context of diabetes management either alone, or in conjunction with other therapies. Specifically, formulations according to exemplary embodiments of the invention are useful in the management of type 2 diabetes because they can prevent the level of glucose in the blood from becoming too high. By using the disclosed formulation(s) that reduces the absorption of glucose in the blood it a need to administer insulin can be reduced or eliminated.

[0075] Exemplary Manufacturing method

[0076] Fig. 1 is a simplified flow diagram of a manufacturing method, indicated generally as 100, according to some exemplary embodiments of the invention. Depicted exemplary method 100 includes dissolving organic acid in water to produce an aqueous solution of organic acid 110 and dissolving 120 high molecular weight (HMW) chitosan, pectin, and alginate in the aqueous solution to form a mucoadhesive composition 130.

[0077] In some exemplary embodiments of the invention, method 100 includes dissolving organic acid in water to produce an aqueous solution of organic acid 110 and dissolving in it 120 high molecular weight (HMW) chitosan followed by addition of pectin and alginate previously dissolved in water to the chitosan aqueous solution to form a mucoadhesive composition 130.

[0078] Alternatively, in some embodiments the organic acid is provided as salt crystals (e.g., sodium succinate or sodium ascorbate) and added to water together with high molecular weight (HMW) chitosan, pectin, and alginate so that all the ingredients dissolve concurrently.

[0079] The order of addition events is not critical. For example, in some embodiments high molecular weight (HMW) chitosan, pectin, and alginate are suspended or dissolved in water, which is then acidified with the organic acid or added to an aqueous solution of organic acid.

[0080] Alternatively, in some embodiments the organic acid is provided as salt crystals (e.g. sodium succinate or sodium ascorbate) and added to water together with high molecular weight (HMW) chitosan, pectin, and alginate so that all of the ingredients dissolve concurrently.

[0081] According to various exemplary embodiments of the invention the organic acid includes succinic acid and / or ascorbic acid and / or citric acid.

[0082] Alternatively or additionally, in some embodiments the organic acid is present in the aqueous solution at a concentration of at least 0.7 g per 100 ml.

[0083] Alternatively or additionally, in some embodiments the organic acid is present in the aqueous solution at a concentration of not more than 2.1 g per 100 ml. Alternatively or additionally, in some embodiments the HMW chitosan is present in the aqueous solution at a concentration of at least 0.7 g per 100 ml. Alternatively or additionally, in some embodiments the HMW chitosan is present in the aqueous solution at a concentration of not more than 2.1 g per 100 ml. Alternatively or additionally, in some embodiments the pectin is present in the aqueous solution at a concentration of at least 0.5 g per 100 ml. Alternatively or additionally, in some embodiments the pectin is present in the aqueous solution at a concentration of not more than 3.0 g per 100 ml. Alternatively or additionally, in some embodiments the alginate is present in the aqueous solution at a concentration of at least 0.25 g per 100 ml or at least 0.5 g per 100 ml. Alternatively or additionally, in some embodiments the alginate is present in the aqueous solution at a concentration of not more than 3.0 g per 100 ml.

[0084] Alternatively or additionally, in some embodiments method 100 includes drying 140 the mucoadhesive composition 130 to produce a dried composition. In some exemplary embodiments of the invention, drying 140 includes lyophilization and / or spray drying. Alternatively or additionally, in some embodiments drying 140 includes spray drying. In some exemplary embodiments of the invention, method 100 includes redissolving 150 the dried composition in an aqueous medium. In some exemplary embodiments of the invention, the aqueous medium (whether at 150 or at 110) includes a flavoring agent and / or a colorant and / or a preservative and / or a vitamin.

[0085] In some exemplary embodiments of the invention, method 100 includes carbonating 160 the aqueous medium (at 150 or at 110). In some exemplary embodiments of the invention, the aqueous medium (whether carbonated or not) is paged in in sealed containers so that each container holds a unit dosage form. Exemplary sealed containers include, but are not limited to cans, bottles, polymeric cups with peel off covers (e.g. foil or mylar) and mylar pouches. Exemplary treatment method

[0086] In some exemplary embodiments of the invention there is provided a method of treatment including administering to a subject with a body mass index (BMI) of at least 30 a physiologically effective amount of a dry or liquid composition as described hereinabove. In cases where a dry composition is administered, concurrent administration of water is advised to help the active ingredients disperse in the digestive tract. In some exemplary embodiments of the invention, the subject is a diabetic subject. In some embodiments the subject has type 2 diabetes. A physiologically effective amount of a dry composition as described hereinabove is expected to be at least 1.5 grams, at least 2 grams, at least 2.5 grams or intermediate or greater amounts.

[0087] Exemplary adult oral dosage form In some exemplary embodiments of the invention there is provided an oral dosage form including at least 2 g of a dry composition as described hereinabove. According to various exemplary embodiments of the invention the oral dosage form contains at least 2.2 grams, at least 2.4 grams, at least 2.6 grams, at least 2.8 grams. At least 3.0 grams or intermediate or greater amounts of said dry composition. Alternatively or additionally, according to various exemplary embodiments of the invention the oral dosage form includes not more than 6 grams, not more than 5.5 grams, not more than 5 grams, not more than 4.5 grams, not more than 4 grams, not more than 3.5 grams, not more than 3 grams or intermediate or lesser amounts of said dry composition.

[0088] In some exemplary embodiments of the invention, the oral dosage is provided as a powder. According to various exemplary embodiments of the invention a powdered oral dosage form is provided either in a bulk container with a measuring device and instructions for dilution or is provided in pre-measured packets.

[0089] In some exemplary embodiments of the invention, the oral dosage is provided as a beverage. According to various exemplary embodiments of the invention the beverage is carbonated and / or contains flavoring agents and / or contains aroma agents and / or contains coloring agents.

[0090] In some exemplary embodiments of the invention, the oral dosage is provided as one or more pills, capsules or tablets. In some embodiments the pills, capsules or tablets are provided in a container with instructions to swallow with a prescribed amount of liquid such as 100 ml or 200 ml.

[0091] Exemplary pediatric oral dosage form

[0092] In some embodiments pediatric dosage forms with 25% to 50% of the amount of the dry composition present in an adult dosage form are provided. The nature of the pediatric dosage form, and the amount of dry composition it contains vary in a manner analogous to that described for the adult dosage form hereinabove. Exemplary advantages

[0093] Formulations according to exemplary embodiments of the invention can be advantageously employed in the context of diabetes management either alone, or in conjunction with other therapies. Specifically, it is envisioned that Formulations according to exemplary embodiments of the invention will be useful in the management of type 2 diabetes. Alternatively or additionally, formulations according to exemplary embodiments of the invention can be advantageously employed in the context of weight management either alone, or in conjunction with a moderate adjustment in diet. Specifically, it is envisioned that formulations according to exemplary embodiments of the invention will be useful in preventing absorption of not just glucose (as demonstrated in the examples) but also lipids. This is because the formulations create a physical barrier, which is not specific in its action.

[0094] Alternatively or additionally, formulations according to exemplary embodiments of the invention will be useful in preventing absorption of obesogens (e.g. mono sodium glutamate and / or carrageenan).

[0095] In addition, formulations according to exemplary embodiments of the invention are short acting and reversible. If adverse side effects appear in some subjects, these adverse effects are expected to be transient and self-limiting.

[0096] In addition, formulations according to exemplary embodiments of the invention exhibit no effect on the central nervous system (CNS). The absence of CNS effects means that the potential for abuse and / or addiction is low.

[0097] It is expected that during the life of this patent many formulation technologies will be developed and the scope of the invention is intended to include all such new technologies a priori.

[0098] As used herein the term "about" refers to ± 10 %.

[0099] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0100] Specifically, a variety of numerical indicators have been utilized. It should be understood that these numerical indicators could vary even further based upon a variety of engineering principles, materials, intended use and designs incorporated into the various embodiments of the invention. Additionally, components and / or actions ascribed to exemplary embodiments of the invention and depicted as a single unit may be divided into subunits. Conversely, components and / or actions ascribed to exemplary embodiments of the invention and depicted as sub-units / individual actions may be combined into a single unit / action with the described / depicted function. Alternatively, or additionally, features used to describe a method can be used to characterize an apparatus and features used to describe an apparatus can be used to characterize a method.

[0101] It should be further understood that the individual features described hereinabove can be combined in all possible combinations and sub-combinations to produce additional embodiments of the invention. The examples given above are exemplary in nature and are not intended to limit the scope of the invention which is defined solely by the following claims.

[0102] Each recitation of an embodiment of the invention that includes a specific feature, part, component, module or process is an explicit statement that additional embodiments of the invention not including the recited feature, part, component, module or process exist.

[0103] Alternatively or additionally, various exemplary embodiments of the invention exclude any specific feature, part, component, module, process or element which is not specifically disclosed herein.

[0104] Specifically, the invention has been described in the context of preventing glucose absorption but might also be used to prevent absorption of other nutrients.

[0105] All publications, references, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

[0106] The terms "include", and "have" and their conjugates as used herein mean "including but not necessarily limited to."

[0107] Additional objects, advantages, and novel features of various embodiments of the invention will become apparent to one ordinarily skilled in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below finds experimental support in the following examples. EXAMPLES

[0108] Reference is now made to the following examples, which together with the above descriptions, illustrate the invention in a non-limiting fashion.

[0109] The following materials and methods are used in performance of experiments described in examples hereinbelow:

[0110] HMW chitosan: Sigma (Cat. No. 419419, viscosity 800-2000 CPs) and Chitolytic, Canada (Cat. No. 9012-706-4, MW 250-300 kDa)

[0111] Succinic acid: Sigma Aldrich Cat. No. S7501

[0112] Ascorbic Acid: Sigma Aldrich Cat. No. A92902

[0113] Citric Acid: Sigma Aldrich Cat. No. C1909

[0114] Pectin: Sigma Aldrich Cat. No. 93854

[0115] Alginate: Sigma Aldrich Cat. No. 180947

[0116] Glucose: Sigma Aldrich Cat. No. G8270

[0117] Carrageenan: Sigma Aldrich Cat. No. C1138 mono-sodium glutamate: Sigma Aldrich Cat. No. G1626

[0118] Polymer preparation

[0119] Alginate (sodium): alginate was dissolved at 2.5% w / v in DDW. The solution container was placed on a shaker for 20 minutes at 37°C at 250 RPM.

[0120] Chitosan: Chitosan was dissolved at 1% w / v in double-distilled water (DDW) containing organic acid 2 % v / v. The solution container was placed on a shaker for 10 minutes at 37°C at 250 RPM.

[0121] Pectin: apple Pectin was dissolved at 2.5% w / v in DDW. The solution container was placed on a shaker for 20 minutes at 37°C at 250 RPM.

[0122] Formulation preparation

[0123] Wet formulation preparation (100 g)

[0124] 70 g of a solution of 1 % w / v of Chitosan was prepared as mentioned above and 20 g of 2.5% w / v of Pectin (also prepared as mentioned above) was added and stirred under heating until the entire solution is homogeneous.

[0125] Alginate 2.5 % w / v was prepared as mentioned above and 10 g was added gradually to the vessel containing the Chitosan / Pectin mixture while applying homogenization at 10,000 RPM until a homogenous formulation was obtained. The ratio of ingredients is 50% organic acid, 25% Chitosan, 17% Pectin and 8% Alginate all on dry basis.

[0126] Dry formulation preparation

[0127] For a dried product the formulation is frozen at -20 degrees Celsius overnight and allowed to dry in a lyophilizer for at least 48h until a light powder remains.

[0128] Afterwards, the dry powder is ground and stored in a tightly closed container to avoid moisture uptake.

[0129] For its intended use the dry product is reconstituted with water in the following ratio of 2.85 g dry powder in 100 g water.

[0130] Glucose solution preparation

[0131] Phosphate-buffered saline (PBS) was prepared by dissolving 1.08 g NaH2PO4 and 0.1278 g Na2HPO4 in 1 L of DDW, and 1 g of D-glucose was added. pH of "'6.0 was verified.

[0132] 10% glucose solution in PBS was prepared as described above, followed by the addition of 100 g D-glucose to 1 L solution. pH of "'6.0 was verified.

[0133] Evaluating the glucose blocking efficacy via side-by-side diffusion chamber in vitro

[0134] Mucin- and formulation-coated nitrocellulose membranes were prepared as described hereinbelow(see Example 1) The coated membrane was placed between two diffusion cells of the side-by-side diffusion chamber (as depicted in Fig. 8). PBS containing glucose (10%) was introduced to the donor cell, while PBS (without glucose) was introduced to the acceptor cell. The diffusion chamber was incubated for 360 minutes (= 6 hours) at 37°C and 60 RPM. Samples were collected from the acceptor cell after 0, 30, 60, 120, 240 and 360 minutes. The volume withdrawn from the acceptor cell when sampling was replaced with fresh PBS. The donor cell was also sampled at t=0 and 360 minutes. Glucose levels were analyzed using HPLC and compared to the glucose levels in a control system, i.e., mucin-coated membrane, without formulation-coating.

[0135] Table 1. The scope of the weight percentages of each of the components and their respective concentrations within F34 / F34*.

[0136] Although table 1 indicates ranges of weight percentages, the composition of the formulation actually used in the experimental examples hereinbelow is referred to as "F34 / F34*", is (by weight): 35% organic acid, 35% chitosan, 20% pectin and 10% alginate. When the organic acid is succinic acid the formulation, referred to as F34. When the organic acid is ascorbic acid, the formulation is referred to as F34*.

[0137] In preparing stock solutions succinic / ascorbic acid and chitosan were mixed to an aqueous solution at a ratio of 1:1 and at a concentration of 1% w / v. The pectin and alginate were each added from a stock solution in water having a concentration of 2.5% w / v. The composition of the F34 and F34* aqueous formulations had a gel texture characteristic.

[0138] EXAMPLE 1:

[0139] In vitro glucose diffusion assay

[0140] In order to provide an initial estimation of potential efficacy of the F34 / F34* formulations on blocking glucose absorption in the intestine, in vitro diffusion experiments were conducted.

[0141] F34 and F34* aqueous formulations as defined hereinabove were assayed

[0142] The F34 solution tested comprised: 1% w / v HMW Chitosan in 1% w / v Succinic acid, 2.5% w / v pectin and 2.5% w / v alginate.

[0143] The F34* solution tested comprised: 1% w / v HMW Chitosan in 1% w / v Ascorbic acid, 2.5% w / v pectin and 2.5% w / v alginate.

[0144] F34 / F34* (5 mL) or its components thereof was exposed to simulated gastric fluid solution (SGF, 2 mL) for 30 minutes and then simulated intestine fluid solution (SIF, 2.5 mL) was added for another 30 minutes. SGF and SIF were prepared according to a standard protocol (INFOGEST, static in vitro simulation of gastrointestinal food digestion).

[0145] The composition of the simulated gastric fluid (SGF): 1.45 liters distilled water + 3 g NaCI (Sigma Aldrich Cat. No.: 746398) + 80 pl pepsin (Sigma Aldrich Cat. No.: 77160) from a 36 mg / ml solution. The solution adjusted to pH 1.2 ± 0.1 with HCI.

[0146] The composition of simulated intestine fluid solution (SIF): 1 liter of DW containing 0.8 mM KCI (Sigma Aldrich Cat. No.: P3911), 0.8 mMKH2PO4(Sigma Aldrich Cat. No.: 1048730250), 85 mMNaHC03(Sigma Aldrich Cat. No.: S6014) ,38.4 mM NaCI (Sigma Aldrich Cat. No.: 746398), 0.33 mMMgCk (Sigma Aldrich Cat. No.: M2670). The solution adjusted to pH 7 ± 0.1 with HCI. Mucin from porcine gut (1 mL at 3% w / t, Sigma Aldrich, porcine stomach type III M1778) was spread on a solid support of a cellulose nitrate circle membrane (Whatman, 12 pm, 50 mm Cat. No. CSI 10400014), then coated with F34 / F34* (1 mL) and incubated for 30 minutes. The membrane was washed with distilled water before and after F34 / F34* coating. Holes of 1 cm diameter were made in the membrane using a hole puncher and the membrane was placed between two diffusion chambers, with the barrier agent (mucin or F34 / mucin or F34* / mucin) facing the donor compartment.

[0147] Fig. 8 is a photograph of the device used in the diffusion experiments. The two chambers are connected by a binding-clamp with a semi permeable membrane with the formulation in the middle of the passage between the chambers. The chamber on the right (marked with a green content) is the glucose donor chamber while the chamber on the left is the acceptor chamber with fresh PBS.

[0148] To assess the relative diffusion rates, the coated membrane was exposed to a glucose solution in a diffusion cell: 10 mL of 10% glucose in self-made phosphate bovine solution (PBS) at the donor chamber, and 10 mL fresh PBS in the acceptor, both added simultaneously. The glucose transport was evaluated by quantitative determination of glucose amount that was transported through the F34 / F34* mucin coated membrane and compared to the amount of glucose that was transported in reference systems with a clean membrane or a membrane coated with mucin only under the same conditions. The experiment was performed over 6 hours, at each time point (30, 60, 120, 240, 360 minutes) a sample of 1 mL was taken from the acceptor chamber and replaced with a fresh 1 mL of PBS. All samples were collected, diluted according to their expected glucose concentrations, and quantified using HPLC. The HPLC instrument used: 1260 Infinity of Agilent Technologies with Alltech ELSD 2000ES detector and Hillc-Plus column.

[0149] As shown in Table 2 below, diffusion tests of each component separately have shown the synergistic effect of the ingredients together in a single formulation.

[0150] Table 2. Results obtained in diffusion tests in which each component of the F34 / F34* formulation was tested separately compared to saline after 120 minutes as opposed to F34 / F34* at the same point in time.

[0151] Fig. 2 is a histogram of % glucose blocked diffusion (relative to a mucin control) as a function of time in minutes for a formulation according to an exemplary embodiment of the invention (F34 / F34*) and each of the components of F34 or F34* in an in vitro glucose diffusion experiment. Results summarized graphically in Fig. 2 demonstrate that the F34 and 34* formulations performed significantly better in terms of glucose blockage of diffusion % over time than any of its individual components with 80% glucose blockage of diffusion after lh and a slowly descent to a plateau of 65-70% blockage of diffusion up to 6 hours. Fig. 2 also demonstrates that the changing of succinic acid to ascorbic acid in the formulation of F34 to F34* does not change the effectiveness in the blockage of diffusion.

[0152] These results suggest that both F34 and F34* are good candidates for development as an in-vivo regulator of intestinal glucose absorption.

[0153] EXAMPLE 2:

[0154] In vitro obesogens diffusion experiments

[0155] In order to provide an initial estimation of potential efficacy of the F34* formulation on blocking obesogens absorption in the intestine, in vitro diffusion experiments were conducted. The laboratory equipment used in Example 2 is identical to the equipment used in Example 1. A picture of the diffusion cells used is provided in Fig. 8.

[0156] The F34* solution tested was as in Example 1.

[0157] F34* (5 mL) was exposed to SGF (2 mL) for 30 minutes and then SIF (2.5 mL) was added for another 30 minutes.

[0158] Mucin from porcine gut (1 mL at 3% w / t, Sigma Aldrich) was spread on a solid support of a cellulose nitrate circle membrane (Whatman, 12 pm, 50 mm), then coated with F34* (1 mL) and incubated for 30 minutes. The membrane was washed with distilled water before and after F34* coating. Holes of 1 cm diameter were made in the membrane using a hole puncher and the membrane was placed between two diffusion chambers, with the barrier agent (mucin or F34* / mucin) facing the donor compartment. To assess the relative diffusion rates, the coated membrane was exposed to a mixture of obesogens solution in a diffusion cell: 10 mL of 0.6% Carrageenan with 0.6% Mono Sodium Glutamate (MSG) in self-made phosphate bovine solution (PBS) at the donor chamber, and 10 mL fresh PBS in the acceptor, both added simultaneously. Obesogens transport was evaluated by quantitative determination of carrageenan and MSG amounts that was transported through the F34* mucin coated membrane and compared to their amount that was transported in reference systems with a clean membrane or a membrane coated with mucin only under the same conditions. The experiment was performed over 6 hours, at each time point (30, 60, 120, 240, 360 minutes) a sample of 1 mL was taken from the acceptor chamber and replaced with a fresh 1 mL of PBS. All samples were collected, diluted according to their expected carrageenan or MSG concentrations, and quantified using HPLC. The HPLC instrument used: 1260 Infinity of Agilent Technologies with Alltech ELSD 2000ES detector and Hillc-Plus column.

[0159] Fig. 3 is a histogram of % obesogen blocked diffusion (relative to a mucin control) as a function of time in minutes for a formulation according to an exemplary embodiment of the invention (F34*) in an in vitro obesogen diffusion experiment. Results summarized graphically in Fig. 3 demonstrate that the 34* formulation significantly blocked the carrageenan and MSG diffusion % over time with 100% carrageenan blocked for diffusion for the entire 6h of the experiment and with 55% and 66% MSG diffusion blockage after lh and 6h respectively.

[0160] These results suggest that F34* is a good candidate for development as an in-vivo regulator of intestinal obesogen absorption.

[0161] EXAMPLE 3:

[0162] Comparing the specificity of different organic acids utilized to dissolve chitosan.

[0163] In order to examine the specificity of the organic acid employed to solubilize the HMW chitosan, the in-vitro experiments described in example 1 were performed while replacing the succinic acid in F34 with citric acid, glutaric acid and acetic acid. The results are summarized in Table 3.

[0164] Table 3: Examples of tests performed utilizing different organic acids and their respective glucose blockage of diffusion results.

[0165] The results in Table 3 indicate that using succinic acid or Ascorbic acid to dissolve the HMW chitosan contributes to significantly better blockage of glucose diffusion in comparison to other organic acids.

[0166] EXAMPLE 4:

[0167] Effect of drying and redissolving

[0168] In order to assess the feasibility of storing F34 as a dried product and re-dissolving before use, the F34 formulation was examined for its diffusion performance after drying by lyophilization and being re-dissolved. F34 was able to re-dissolve rapidly in water and its glucose diffusion blocking ability was undiminished after the drying process, maintaining glucose blockage of diffusion levels at 80% after lh and 70% up to 6 hours. The results of diffusion tests, comparing F34 to re-dissolved F34, are summarized graphically in Fig. 4 which is a histogram of % glucose blocked (relative to a mucin control) as a function of time in minutes for a formulation according to an exemplary embodiment of the invention (F34) and F34 dried and redissolved.

[0169] EXAMPLE 5:

[0170] Changing of parameters in the F34 formulations

[0171] To determine the effect of altering concentrations or specific ingredients in the formulation an additional series of experiments was conducted varying pectin amount, replacing alginate with polyvinylpyrrolidone, adding Tween85 as surfactant and using thiolated HMW chitosan. The effect on glucose blockage of diffusion results is summarized in Table 4. Table 4. Results of changing F34 by varying pectin amounts, replacing alginate with polyvinylpyrrolidone, adding Tween85 and using Thiolated HMW chitosan on glucose blockage of diffusion results.

[0172] Results presented in Table 4 indicate that the four tested changes in the F34 formulation resulted in significantly less glucose blocking activity in comparison to the activity of the F34 formulation as seen in Table 3 and Fig. 2.

[0173] EXAMPLE 6:

[0174] Ex vivo experiments.

[0175] In order to determine the ability of F34 to adhere to actual intestinal mucosa, an ex vivo experiment was conducted. The F34 aqueous solution employed was as in previous examples.

[0176] Fresh porcine intestine tissue was procured from a butcher shop and kept on ice all the way to the laboratory. The experiment was performed the same day the tissue was extracted. Fifteen cm segments were cut from the intestine tube and were cut open to expose the inner tissue. The exposed tissue strips were mounted on a solid plastic support platform and the platform was placed at an angle of 45°. Two mL of F34 were dripped at the very top portion of the tissue and allowed to slide downwards, along the tissue. As a control, 2 mL saline were dripped at the very top portion of a tissue strip. The 2 mL of the F34 solution gradually slid downwards. None of the F34 solutions made it all the way to the bottom edge of the tissue demonstrating its intense adhesion. The dripped saline rapidly slid downwards, and the entire volume reached the bottom edge of the tissue. The F34 solution that coated the intestine tissue was visibly observed, as seen in Fig. 9 (white sections seen on the background of the tissue).

[0177] After coating the tissue with the F34 solution an attempt was made to wash off the coating layer by dripping 2 mL of water and 2 mL of simulated intestinal fluid (SIF). Four repetitions of washings with both water and SIF at intervals of 15 minutes did not remove the visibly observed F34 coating layer.

[0178] Fig. 9 shows strips of porcine intestine tissue coated with F34 layers (the white sections seen on the background of the tissue).

[0179] EXAMPLE 7:

[0180] In vivo experiments using a rat model

[0181] In order to confirm the in vitro and ex vivo results presented in Examples 1 through 6 an exemplary formulation (F34 / F34*) was tested in-vivo on rodents.

[0182] Glucose absorption was measured in male Sprague Dawley (SD) rats with and without administration of the tested formulation using gavage followed by oral glucose tolerance test (OGTT).

[0183] Twelve hours prior to the beginning of the experiment, the rodents were fasted. The rodents were weighed to the nearest 0.5g and placed in clean cages with new bedding.

[0184] For the F34 formulation, two sets of experiments were conducted, in each test 24 rodents were used. The rodents in each test were divided into three groups: 8 rats treated with saline, 8 rats treated with a F34 solution (as in previous examples) and 8 rats treated with dried and re-dissolved F34 solution.

[0185] For the F34* (F34 ascorbic acid instead of succinic acid with) a single experiment was conducted using the same experimental protocol as described for F34.

[0186] The tested solutions were warmed to 37°C. Each rodent received 1 mL / 100g of body weight of the warmed solution by gavage according to the protocol for gavage administration.

[0187] One hour later, OGTT gavage was initiated using 3g glucose / Kg body weight provided as a 50% glucose solution. Tail blood was collected at: 0, 15, 30, 45, 60, 120 and 150 min after the OGTT. The rodents were sacrificed at the end of the procedure and their stomach and intestine examined.

[0188] In the first experiments, F34 solution was administered directly (without drying). Results are summarized graphically in Fig. 5 for F34 and for F34* in Fig. 6. The graphs show the significantly (up to ***p. value<0.001) lower blood glucose concentration (mg / dL) in SD rats as a function of time in minutes after F34 and F34* formulations administration compared to the saline control.

[0189] Fig. 7 is a histogram of blood glucose concentration (mg / dL) in SD rats as a function of time in minutes for the F34 formulation that was dried and re-dissolve. The graph shows the significantly (***p. value<0.001) lower blood glucose concentration (mg / dL) in SD rats as a function of time in minutes after dried and re-dissolved formulation administration compared to the saline control.

[0190] In vivo experiments with increased chitosan concentration to 2% w / v in the F34 formulation caused clogging of the stomach of the experimental rats, suggesting that there is an upper limit to the chitosan concentration that can be applied.

[0191] Results presented in Fig. 5, Fig. 6 and Fig. 7 demonstrate a 29-35% reduction in glucose absorption relative to the saline control. In addition to the reduced area under the curve (AUC), the peak blood glucose (30 minutes) was significantly reduced suggesting a beneficial effect on the glycemic index. In addition, the slope during the first 15 minutes of the experiment was significantly reduced, indicating a reduction in the rate of glucose absorption relative to the saline control group.

[0192] Taken together, the results of examples 1, 6 and 7 suggest that the tested exemplary F34 / F34* formulations have the potential to reduce glucose absorption in the short term (1 to 2 hours). While the results of example 2 suggest that the tested formulation F34* (and probably F34 as well) have the potential to reduce other obesogens such as carrageenan and MSG absorption in the short term as well as glucose.

[0193] EXAMPLE:

[0194] Effect ofchanging organic acid on In vitro glucose diffusion assay

[0195] In order to evaluate the effect of using citric acid instead of succinic acid the in vitro glucose diffusion assay of example 1 was repeated using F34 prepared with citric acid. F34 prepared with succinic acid was used as a basis for comparison. Each formulation was dried and resuspended as described in Example 4. SGF indicates simulated gastric fluid.

[0196] Fig. 10 is a histogram of % glucose blocked as a function of time in minutes for a formulation F34 prepared using 2% citric acid and F34 prepared using 2% succinic acid dried and re-dissolved in an in vitro glucose diffusion assay as described hereinabove.

[0197] The results presented in Fig 10 indicate that the use of Citric acid instead of Succinic acid provides the same efficacy results post reconstitution.

Claims

CLAIMS:

1. A dry composition comprising: high molecular weight (HMW) chitosan; an organic acid; pectin; and alginate; as an active component.

2. A composition according to claim 1, wherein said organic acid comprises succinic acid.

3. A composition according to claim 1 or claim 2, wherein said organic acid comprises ascorbic acid.

4. A composition according to any one of claims 1 to 3, wherein said organic acid comprises citric acid.

5. A composition according to any one of claims 1 to 4, wherein, said composition includes at least one member of the group consisting of a flavoring agent, a colorant, a preservative, and a vitamin.

6. A composition according to any one of claims 1 to 5, comprising at least 25% chitosan on a dry matter basis (w / w).

7. A composition according to any one of claims 1 to 6, comprising not more than 40% chitosan on a dry matter basis (w / w).

8. A composition according to any one of claims 1 to 7, comprising at least 25% organic acid on a dry matter basis (w / w).

9. A composition according to any one of claims 1 to 8, comprising not more than 40% organic acid on a dry matter basis (w / w).

10. A composition according to any one of claims 1 to 9 comprising at least 15% pectin on a dry matter basis (w / w).

11. A composition according to any one of claims 1 to 10, comprising not more than 30% pectin on a dry matter basis (w / w).

12. A composition according to any one of claims 1 to 11 comprising at least 7.5% alginate on a dry matter basis (w / w).

13. A composition according to any one of claims 1 to 12, comprising not more than 15% alginate on a dry matter basis (w / w).

14. A composition comprising at least 0.25% (w / v) of the dry composition of any one of claims 1-13 dissolved or suspended in an aqueous medium.

15. A composition comprising not more than 0.7% (w / v) of the dry composition of any one of claims 1-13 dissolved or suspended in an aqueous medium.

16. A composition according to any one of claims 14 to 15, provided as a carbonated beverage.

17. A composition according to any one of claims 1 to 16, for use in treatment of obesity or weight management.

18. A method of manufacture comprising:(a) dissolving organic acid in water to produce an aqueous solution of organic acid; and(b) dissolving high molecular weight (HMW) chitosan, pectin, and alginate in said aqueous solution to form a mucoadhesive composition.

19. A method according to claim 18, wherein said organic acid comprises succinic acid.

20. A method according to claim 18 or claim 19, wherein said organic acid comprises ascorbic acid.

21. A method according to any one of claims 18 to 20, wherein said organic acid comprises citric acid.

22. A method according to any one of claims 18 to 21, comprising dissolving at least one member of the group consisting of a flavoring agent, a colorant, a preservative, and a vitamin is said aqueous solution or said mucoadhesive composition.

23. A method according any one of claims 18 to 22, wherein said organic acid is present in said aqueous solution at a concentration of at least 0.7 g per 100 ml.

24. A method according any one of claims 18to 23, wherein said organic acid is present in said aqueous solution at a concentration of not more than 2.1 g per 100 ml.

25. A method according any one of claims 18 to 23, wherein said HMW chitosan is present in said aqueous solution at a concentration of at least 0.7 g per 100 ml.

26. A method according any one of claims 18 to 25, wherein said HMW chitosan is present in said aqueous solution at a concentration of not more than 2.1 g per 100 ml.

27. A method according any one of claims 18 to 26, wherein said pectin is present in said aqueous solution at a concentration of at least 0.5 g per 100 ml.

28. A method according any one of claims 18 to 27, wherein said pectin is present in said aqueous solution at a concentration of not more than 3.0 g per 100 ml.

29. A method according any one of claims 18 to 28, wherein said alginate is present in said aqueous solution at a concentration of at least 0.5 g per 100 ml.

30. A method according any one of claims 18 to 29, wherein said alginate is present in said aqueous solution at a concentration of not more than 3.0 g per 100 ml.

31. A method according any one of claims 18 to 30, comprising drying said mucoadhesive composition to produce a dried composition.

32. A method according to claim 31, wherein said drying includes lyophilization.

33. A method according to claim 31, wherein said drying includes spray drying.

34. A method according to any one of claim 31 to 33, comprising redissolving said dried composition in an aqueous medium.

35. A method according to any one of claims 18 to 30or claim 34, comprising carbonating said aqueous medium.

36. A method of treatment comprising: administering to a subject with a body mass index (BMI) of at least 30 a physiologically effective amount of a composition according to any one of claims 1 to 17.

37. A method according to claim 36, wherein said subject is a diabetic subject.

37. A method according to claim 36 or 37, wherein said administering occurs 30 to 90 minutes prior to ingestion of food.

39. A method according to any one of claims 36 to 38, wherein said physiologically effective amount of said composition forms a mucoadhesive layer in at least a portion of the intestine which persists for 2 hours to 8 hours.

40. An oral dosage form comprising at least 2 g of a composition according to any one of claims 1 to 17.

41. An oral dosage form according to claim 40, comprising not more than 6 grams of said composition.

42. An oral dosage form according to claim 40 or 41, provided as a powder.

43. An oral dosage form according to claim 40 or 41, provided as a beverage.

44. An oral dosage form according to claim 40 or 41, provided as one or more pills, capsules or tablets.

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