Patent Application
20230081517
The present invention relates to an orally administered hydrogel composition, a kit comprising such a composition, and the use of such a composition for treating overweight or obese individuals, or for delivering active pharmaceutical or nutritional ingredients into the stomach of an individual, in a time-delayed manner.
The prevalence of obesity, which is defined as a Body Mass Index (BMI)>30 kg/m2, has doubled in 34 years. The World Health Organization (WHO) estimates that in 2016, 1.9 billion adults (over 18 years old) and 41 million children (over 5 years old) were overweight or obese. These figures have been increasing continuously ever since. It is estimated that by 2030, a record 3.3 billion adults will be overweight or obese. Obesity has a significant societal and economic impact. It is generally associated with serious or even fatal complications. It is estimated that more than 5.3 people die every minute worldwide as a direct result of obesity or being overweight.
Depending on their BMI, patients are offered three types of treatment: drug treatment, surgical treatment and gastric balloon treatment.
Treatment with a gastric balloon is generally intended for patients with moderate to severe obesity with a BMI of more than 30 and less than 40 kg/m2.
Gastric balloons are inflatable medical devices, generally made of silicone, which can be filled either with a gas, a liquid or both. The procedure for inserting a balloon is simple: it is inserted in deflated form by endoscopy into the stomach of a patient. It is then filled by means of a catheter. The insertion and inflation procedure can take up to 20 minutes. After inflation the catheter is then removed. At the end of the treatment period, which lasts 3 to 6 months depending on the balloons, the balloon is removed, again by endoscopy.
However, the treatment of patients with gastric balloons according to the prior art has various disadvantages. In particular, the procedures for inserting and removing gastric balloons by endoscopy are invasive and dangerous. There have been reports of quite serious complications associated with the long-term presence of gastric balloons in the stomach. These include changes to the gastric mucosa with the formation of ulcers and/or the presence of gastric perforations, the crushing of underlying organs which sometimes result in acute pancreatitis, or intestinal obstructions in the case of balloon migration.
In view of the above, one problem that the invention proposes to solve is to provide means for treating overweight or obese individuals which avoid the use of inflatable gastric balloons which require insertion into the stomach or removal by endoscopy.
The solution of the invention to this problem is firstly an orally administered hydrogel composition comprising:
an alginate polymer that forms a gel in aqueous solution in the presence of a cation;
a cation for polymerizing the alginate polymer in aqueous solution;
an aqueous solution, in a sufficient quantity;
a dissolving agent of said alginate polymer in the aqueous solution;
a gelation retarder; and
a floating agent for forming CO2 bubbles in the hydrogel composition;
the hydrogel formed by means of said hydrogel composition being dissolved by means of an orally administered final dissolving agent.
In an advantageous manner:—the composition further includes an agent for strengthening the mechanical structure of the hydrogel;—the composition further includes a radio-opaque agent;—the alginate polymer is a sodium alginate polymer, and the cation is calcium;—the dissolving agent of the alginate polymer in the aqueous solution is sucrose;—the gelation retarding agent is Na2HPO4;—the agent for strengthening the mechanical structure of the hydrogel is selected from sorbitol, spermine, chitosan, agarose, sodium dodecyl sulfate, phosphatidylcholine, microcrystalline cellulose;—the radio-opaque agent is selected from compounds including barium, for example BaSO4 and compounds including iodine;—the final dissolving agent is selected from citrates, calcium chelators, for example sodium citrate, citric acid or EDTA;—the floating agent is CaCO3, glucono-δ-lactone or a microorganism; the composition comprises 0.5 to 5% sodium alginate with a viscosity of between 20-200 mPa·s, 1 to 3% CaSO4, 0.10 to 0.20% Na2HPO4, 8 to 15% sucrose, 2 to 8% CaCO3 or 0.1 to 2% yeast, 0.5% to 8% BaSO4, and 0.5 to 8% chitosan with a viscosity between 10 and 50 mPa·s or 0.5 to 8% cellulose, the percentages being percentages by weight given in g/100 ml.
The second subject-matter of the invention is a use of a composition as defined above, for the treatment of overweight individuals who have a Body Mass Index greater than or equal to 25 kg/m2.
In an advantageous manner: the use is for the treatment of obese individuals who have a Body Mass Index greater than or equal to 30 kg/m2.
The third subject-matter of the invention is a use of a composition as defined above, for delivering active pharmaceutical or nutritional ingredients into the stomach of an individual in a time-delayed manner.
The fourth subject-matter of the invention comprises a composition as defined above and an orally administered dissolving agent.
The invention will be better understood from reading the following non-limiting description which is prepared with reference to the attached drawings in which:
The invention relates to a hydrogel composition. This composition is orally administered to an individual or a human patient, in the form of a drinkable syrup. This individual is an adult for example. However, they can also be adolescents or even children of at least 5 years of age.
The composition according to the invention comprises an alginate polymer. This alginate polymer forms a gel in aqueous solution, in the presence of a cation. Advantageously, the alginate polymer is a sodium alginate polymer, the polymerization of which is initiated by calcium. The source of calcium is provided for example by CaSO4.
The aqueous solution is water for example. It is present in the solution in a sufficient quantity for the hydrogel to form.
The composition according to the invention further includes a dissolving agent of the alginate polymer in the aqueous solution.
The composition according to the invention also includes a gelation retarder. Preferably, the gelation retarder is Na2HPO4.
Lastly, the composition according to the invention includes a floating agent. The floating agent causes the formation of gas bubbles in the hydrogel composition. In an advantageous manner, the floating agent is CaCO3, glucono-δ-lactone or a microorganism. The floating of the hydrogel according to the invention in an acidic solution, simulating in vitro the acidic solution of a human stomach, is illustrated in
The composition according to the invention comprises advantageously a strengthening agent. This strengthening agent is an agent for strengthening the mechanical structure of the hydrogel. The strengthening agent is preferably of the polymeric type, forming macromolecules which are incorporated into the hydrogel to increase its mechanical strength. Preferably, the agent for strengthening the mechanical structure of the hydrogel is selected from sorbitol, spermine, chitosan, agarose, sodium dodecyl sulfate, phosphatidylcholine, microcrystalline cellulose.
The composition according to the invention also comprises, in an advantageous manner, a radio-opaque agent. Preferably, the radio-opaque agent is selected from compounds including barium, and compounds including iodine. More preferably, the radio-opaque agent is BaSO4.
In other words, the composition according to the invention comprises 0.5 to 5% sodium alginate with a viscosity between 20-200 mPa·s and/or 1 to 3% CaSO4 and/or 0.10 to 0.20% Na2HPO4 and/or 8 to 15% sucrose and/or 2 to 8% CaCO3 or 0.1 to 2% yeast and/or 0.5% to 8% BaSO4 and/or 0.5 to 8% chitosan with a viscosity between 10 and 50 mPa·s or 0.5 to 8% cellulose, the percentages being weight percentages given in g/100 ml.
According to the invention, the hydrogel formed by the hydrogel composition is dissolved by means of an orally administered dissolving agent. This dissolving agent is referred to as the final dissolving agent. It is advantageously selected from citrates, calcium chelators, for example phytic acid, oxalic acid, sodium citrate, citric acid or EDTA. The dissolution of hydrogel is advantageously complete and does not produce aggregates, as decomposing products.
For the implementation of the invention, a kit is provided to a patient for example, or to a healthcare worker.
This kit comprises a first container and a second container.
The first container includes the following compounds in powder form: alginate polymer, the compound forming a cation for the polymerization of the alginate polymer, the dissolving agent of the alginate polymer, gelation retarder, floating agent, and advantageously strengthening agent, and radio-opaque agent.
The second container comprises the dissolving agent of the hydrogel, also in powder form.
The contents of the first container are dissolved in the aqueous solution to form the hydrogel composition.
As shown in step A of
The orally administered composition is then delivered to the patient's stomach via the esophagus.
The polymerization retardant has a temporary action. As shown in
The stomach has an acidic pH, which varies over time. This acidity is due to the presence of hydrochloric acid in the stomach. The gelation is accompanied by a reaction of the floating agent. In one example, the floating agent reacts with the hydrochloric acid present in the stomach to form gas bubbles, namely CO2, in the composition which is gelating. The gas bubbles formed are trapped in the forming gel. This gel is therefore an aerogel. It can be described as a hybrid hydrogel/aerogel. In another example, the floating agent is formed by microorganisms contained in the hydrogel composition. The microorganisms are for example yeasts, which are trapped in the gel and produce CO2 bubbles after consuming the sucrose also contained in the gel. They perform the glycolysis of glucose to pyruvate with the release of CO2, or the glycolysis of glucose to ethanol, in the presence of O2. The resulting gel, which is shown in
For digestion, the stomach contracts then relaxes. The strengthening agent strengthens the structure of the gel according to the invention. Its presence makes it possible to extend the time the hydrogel resides inside the stomach. It allows it to mechanically resist the contraction forces exerted by the layers of muscle in the stomach.
Alginate gels are resistant to acidic medium, and are not degraded by human α-amylase, unlike chitosan gels and starch gels. The gel according to the invention, which is established in the stomach, is stable. Its stability is maintained for several weeks or months.
As shown in
To remove the hydrogel, as shown in
This dissolving agent is dissolved for example in an aqueous solution. It is then drunk by the patient. The solution including this agent is then fed into the stomach via the duodenum. Once in contact with the hydrogel of the invention, it dissolves it and the latter is evacuated from the patient's stomach during gastric emptying. This latter step is denoted F in
According to the invention, the hydrogel composition is thus able to be used for the treatment of overweight individuals who have a Body Mass Index which is greater than or equal to 25 kg/m2. In an advantageous manner, it is used for the treatment of obese individuals who have a Body Mass Index greater than or equal to 30 kg/m2.
According to the invention, the hydrogel composition can be used for the delivery of active pharmaceutical or nutritional ingredients into the stomach of an individual, in a time-delayed manner. The active ingredients are advantageously contained in the hydrogel composition, then trapped in therein, and their release into the stomach is delayed.
Ultimately, the invention relates to an innovative class III intragastric device capable of reducing both the safety problems associated with the gastric balloon and also the costs. It has been developed preferably for adults with a BMI between 30 and 40 kg/m2, but may be eventually offered to adolescents or children. The formulation of the gel composition according to the invention is unique, and composed of biocompatible agents. No toxic agents are used. The composition is finally administered orally, in the form of syrup. It forms a spherical or ovoid structure, aerated due to the presence of bubbles, radio-opaque when in the presence of gastric juices in particular at a pH between 2 and 3. This structure is stable for more than 4 months in the simulated intragastric environment. It retains 80% of its weight/volume at the end of the treatment. It can then be completely dissolved without forming aggregates after a few hours via the second solution, similarly aqueous, also administered orally and consisting of a food additive.
The hydrogel composition was prepared according to the following invention, the percentages are given in weight relative to volume w/v:
12%
For the preparation of this hydrogel, all of the ingredients were mixed in the form of powder in a beaker and then water was added to obtain a volume of hydrogel of 250 mL corresponding to a balloon internalized in one intake by a patient.
The hydrogel composition was prepared according to the following invention, wherein the percentages are given in weight relative to volume w/v:
It should be noted that the scientific literature is poor regarding the compressive forces encountered inside the lumen of the human stomach. According to a first document, these forces do not exceed 13 kPa. According to a second document, during digestion, these forces vary between 5 kPa and 67 kPa. According to a third document, they are on average 96±12 Pa for a fed human stomach. The mechanical properties of the hydrogel according to the invention were evaluated by static compression tests by means of a Lloyd™ LRX PLUS material compressive strength measuring machine. Before this, the parameters of this machine were optimized according to the properties of the gels and in particular the dimensions of the gels, the range of forces, the deformation range, the maximum deformation. A preload of 0.5 N and a compression speed of 10 mm/min were selected.
The hydrogel of example 1 has been tested. Before breakage, this gel which does not include strengthening agent, is able to withstand an average stress of 1342±50 Pa corresponding to an average deformation of 26±9% of its length.
The photos in
The strengthening agents contained in the table below were introduced into the gel of example 1 at concentrations ranging from 0.1 to 20% w/v. A summary of the gels produced and their stress/strain data can be found in the table below.
In this example, gelation times were determined for alginate gel compositions comprising a strengthening agent, and which are capable of resisting a maximum stress of at least 4000 Pa. This gelation time should not be less than 5 minutes so that the patient has the time to drink the composition according to the invention and it is administered into the stomach. These compositions are those of example 2, which comprise chitosan HV (0.1 and 1% w/v) and LV (0.1, 1.5 and 10% w/v), agarose (1.5 and 10% w/v), cellulose (10% w/v), barium sulfate (1.5, 10 and 20% w/v), calcium carbonate (20% w/v) and chitosan LV-barium sulfate (both at 5% w/v). First of all, the setting time of these strengthened gels was determined. For this purpose, once mixed, the powders are added to distilled water then the solution is stirred with a spatula for several seconds. The aqueous dispersion is stirred at ambient temperature on a rocker plate set at 10 rpm. Every minute the container is inclined 90° to verify whether the solution is still flowing or not. The measurements were stopped after 25 minutes. This time limit was selected by taking into account that half of the stomach emptying time after water ingestion is 13±1 min.
The results are shown in
Hydrogels according to the invention were placed in a simulated gastric juice for 4 months, oscillating from an extremely acidic pH, pH=2.4 for 3 hours or 16 hours, to a quasi-neutral pH of 6.4 for 3 hours as shown in
In
As can be seen from the curves shown in
The physicochemical stability of hydrogels according to the invention in a simulated gastric liquid (pH 2.5 and 6.4) was evaluated by measuring their weight and their volume each week for a period of six weeks. Four gel compositions were compared in this study: the base composition of example 1, as well as compositions including chitosan LV 10% w/v, agarose 10% w/v, BaSO4 10% (w/v).
As shown in
The hydrogel composition according to Example 2 was tested for stability by means of artificial in vitro digestion tests. An amount of hydrogel corresponding to a volume of 50 mL was placed at 37° C. for 14 consecutive days under agitation in a digestion buffer, at pH=3, with or without food containing high levels of calcium chelators, namely lentils, which contain phytic acid, spinach, which contain oxalic acid, or orange juice, which contains citric acid. As shown in
The foaming and swelling capabilities of the hydrogels according to the invention are related to the content and to the reactivity of the floatation agents. Calcium carbonate was used successfully to produce CO2 and aerogels. By adopting the base composition of example 1, an acidic medium proved to be sufficient to trigger the dissolution of calcium carbonate and the floating of the gels. Alternatively, the calcium carbonate system can be replaced either by a gluconolactone-sodium bicarbonate system or by a yeast-sucrose system. The three systems are shown in
The calcium carbonate system is easy to use. It is safe. It has been studied with hydrogels including chitosan as a strengthening agent. All of the gels tested have been found to be mechanically stable. However, at pH 2.5, after one day, none of them were able to float, although some bubbles could be observed on their surface. On the contrary, just after their incubation in an acidic medium at pH 1.2, all of the samples tested were able to float rapidly. After 7 days, no change was observed.
The gluconolactone-sodium bicarbonate system shown in
The yeast-sucrose system (Saccharomyces Cerevisiae/sucrose) is a system currently used in baking to ensure the expansion of the bread dough prior to its solidification by cooking. In this bio-fermentation process, CO2 is produced by the consumption of sucrose followed by aerobic or anaerobic glycolysis. This system was tested with alginate gels strengthened with chitosan. For all compositions the gels are mechanically stable, probably due to the cross-kinking of the chitosan. From day one, some of the tested compositions, which contain 0.6 and 0.9% (w/v) dry yeast, are able to generate sufficient gas to form an aerogel. After 3 days of incubation, hydrogels containing 0.3% (w/v) dry yeast, were also able to float.
| Number | Date | Country | Kind |
|---|---|---|---|
| FR2003982 | Apr 2020 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/060435 | 4/21/2021 | WO |
