Controlled release nutraceutical carrier and its manufacturing

Abstract

A manufacturing process comprising vacuum assisted extraction coupled to ultrasound treatment of food by-products to obtain a controlled release agent comprising polysaccharides and polysaccharide bon

Description

REFERENCE TO RELATED APPLICATIONS Al Apparatus for Instantaneous Expansion with Vacuum and Ultrasound Waves. TECHNICAL FIELD The present invention generally relates to drug or microorganism's protectors and carriers that are able to release drugs or microorganisms at certain rates up to gastrointestinal sites. BACKGROUND OF THE INVENTION Bound polyphenols and bound carotenoids to the polysaccharide matrix are the main dietary fibre (DF) constituents responsible for the antioxidant, functional and biological activity in persimmon (Diospyros kaki Thunb). Persimmon is a remarkable source of bioactive compounds such as carotenoids, polyphenols, and polysaccharides. Persimmon polysaccharides are made up of the monosaccharides rhamnose, fucose, arabinose, mannose, galactose, glucose and uronic acids. This composition provides a matrix with good thermal and chemical stability, high hydrophilicity, and excellent biocompatibility, making it an ideal biomaterial for the study of drug interaction and delivery systems. Persimmon processing also generates a high amount of waste made up from peel and pulp that are often discarded. Phenolic compounds in persimmon have been found bound to the polysaccharide matrix (Salazar-Bermeo et al., 2021). They can provide important health benefits related to their antioxidant and cell regulation activity. Properties such as anti-inflammatory, immunomodulatory activities have been reported in polyphenols, in vitro and in vivo, due to the regulation of cytokines production and gene expression. Also, polyphenols have been reported to interact with other drugs in synergy, such as some anticancer chemotherapeutics. As described in document Al, a drug excipient or carrier is a natural, or synthetic substance formulated for the purpose of bulking up formulations that contain active ingredients or to confer a therapeutic enhancement on the active ingredient in the final dosage form such as facilitating drug absorption. Also, this patent disclosed methods for the preparation of excipients from biomass. However, this method is focused on the separation of lignocellulosic biomass in its components, without taking advantage of biomass bonded molecules such as polyphenols including gallic acid. On another hand, the document discloses methods for obtaining polysaccharides and its use as excipient from sources such as bacterial biomass. Interaction of the polysaccharide uptake with other molecules begins in the oral cavity, where polymeric complexes are formed. The bolus then reaches the stomach where the pH of the medium drops to 1-3. Here, the polysaccharides cause an increase in the viscosity of the medium, inhibit pepsin and an amount of bound phenolic compounds is released, at small rates. After that, in the small intestine, polysaccharides interact with the epithelial cell wall barrier, viscosity continues increasing, enzymes are inhibited, and bioactive compounds bind to other matrices. Hence, bioavailability of compounds is modulated. Finally, in the large intestine, polysaccharides acquire prebiotic functionality, act as probiotic source of energy and after probiotic metabolism, they enhance the production of short fatty acids that stimulate a selective growth of some bacteria. Conventional polysaccharide treatment techniques usually require large amounts of solvents of a high degree of purity in addition to being of low specificity and also may generate a negative impact on the environment. Greener technologies have been developed. Some of these green technologies consist in the application of enzymes, pressurized liquids, microwave, ultrasound, pulsed-electric field, and supercritical fluids. The most applied are ultrasound, enzyme and microwave assisted extraction. These methods have shown an increase and improvement in extraction yields, in addition to considerably reducingthe impact generated by conventional technologies and maintaining the biological potential of the molecules such as the antioxidant capacity and biological activity. Ultrasound-assisted extraction covers a wide range of frequencies (from 20 KHz to 100 MHz), which allows customization of the method depending on the matrix that we need to treat. Ultrasound propagates through any medium by creating cycles of expansions and compressions, which generates a cavitation force that is the main responsible of the bioactive compound's extraction. This technology has been widely accepted in the food industry as it simplifies manipulation and work-up, increases purity of the final product, eliminates posttreatment of wastewater, since the pollution that produces is minimal, and requires much less energy than conventional processes. In addition, it favors the extraction of bioactive compounds avoiding their degradation by high temperatures. The objective of this invention is to apply the combination of novel extraction techniques to generate synergies by increasing the benefits of the processes. Ultrasonic Vacuum Instantaneous Expansion Equipment coupled to ultrasonic waves (USEX) is an example of this synergy. This state-of-the-art technology enhances the effect of ultrasound by subjecting the matrix to a vacuum field. The vacuum field prevents the degradation and oxidation of bioactive compounds and, because of that, it can preserve their functional properties. Moreover, polysaccharides exposed to USEX provide enhanced technological, functional and biological properties. These effects make USEX an appropriate technology for processing persimmon byproducts to obtain polysaccharides for the food, nutraceutical, and pharmaceutical industries. The fact that drugs or nutraceuticals uptake can cause side effects derived from their rapid release, such as gastric mucosal irritation and ulcerogenic effects and that they can also be altered when undergoing gastrointestinal digestion, have brought new drug delivery platforms that have been developed. Processing on polysaccharides from byproducts has a wide application prospect in drug delivery. Hydroxyl (-OH), carboxyl (-COOH), and amino (-NH2) in the polysaccharide molecules are the main active sites used to crosslink polysaccharide-based drug delivery systems. The so obtained polysaccharides may be used as tablet binder, disintegrant, emulsifier, suspending agent, gelling agent, and for controlled release. Under the GRAS category (Generally Recognized As Safe), the food and pharmaceutical applications of persimmon and its byproducts may include its application as an excipient, tablet binder, disintegrant, emulsifier, suspending agent, gelling agent, for colon targeting and for sustained release. Moreover, after appropriate treatment, persimmon polysaccharides show specific properties that can be utilized in formulations for controlled release excipients. This excipient increases bioavailability of the drug and keeps the active principle stable, avoiding its degradation or alteration. The application of treated byproducts for the enhancement of a drug or probiotic efficacy with reduced side effects is a novel aspect to consider. This invention is aimed at improving controlled / sustained drug / probiotic delivery using byproduct-based drug formulations. To achieve this, polymeric materials obtained from byproducts were applied in formulations of a nutraceutical and pharmaceutical composition. These materials are biocompatible, biodegradable, nontoxic, and effective towards the treatment under specific conditions. REFERENCES Al (Nelson et al., 2016). (Andrade de Freitas et al., 2013). SUMMARY OF THE INVENTION The present invention relates to processing a polysaccharide capable of controlling the release rates and release times under gastrointestinal tract allowing the drug / probiotic to be released at specific sites and increase the bioavailability of the drug / probiotic. In some embodiments, during vacuum instantaneous expansion, the antioxidant activity is affected by the pH by hydrolysis of the bound compounds from the polysaccharide matrix to the acidic media and by the increased the release of phenolic compounds that display antioxidant capacity. In some embodiments, vacuum instantaneous expansion causes zeta potential to generate the aggregation of the samples at lower pH, causing weaker repulsions between particles. In some embodiments, the vacuum instantaneous expansion processing step prompted higher antioxidant capacity and led to an aggregation of the fiber particles. The processed polysaccharides act as agglomerative agents in drug interaction. In some embodiments, the more the fiber is exposed to vacuum cycles, the higher the antioxidant capacity. Also, the "vacuum expansion cycles" process is more effective at higher pH ranges. In these embodiments, extraction of polyphenols is higher in phenol content when the extraction is carried out under vacuum pressure than at ambient pressure. In these embodiments, zeta potential values around zero inferred low repulsions between molecules which led to aggregation of fibers. Processed polysaccharides are characterized by weak electrostatic repulsion forces, and in interaction with the drug they may provide agglomerative and protective properties. Application of vacuum drying also led to lower zeta potential values, in comparison to ambient pressure. Three cycles of vacuum expansion treatment gave optimum results. In some embodiments, more vacuum cycles varied from 1 to 3 cycles. In these embodiments the z potential values are very close to zero. In some embodiments, after vacuum assisted extraction, during ultrasound treatment, pH maintains an inversely proportional relationship with the antioxidant capacity, optimum pH range is 1.5-3.5. In these embodiments vacuum assisted extraction altogether with ultrasound treatment enhanced the acid hydrolysis of bounded compounds, leading to an increase of available polyphenols. During the process, time effect is pH dependent. At pH 1.5-3.5, the ultrasound time was the highest variable influencing the antioxidant capacity, bound compounds were released outside the polysaccharide matrix. In some embodiments, after vacuum assisted extraction, ultrasound treatment increases the total phenolic content as a function of processing time, zeta potential behaves accordingly due to an increase in the surface load of the fiber when the ultrasound treatment is applied during the first steps (time and cycle), but a destabilizing effect of the fiber structures takes place when ultrasound is kept for longer periods. Cavitation forces caused the zeta potential of the extracted polysaccharides to decrease. In some embodiments, after the vacuum assisted extraction and the ultrasound treatment, the drying process exerts a significative impact in the polysaccharide behavior. In these embodiments, no antagonistic effect on the antioxidant capacity was found in different treatments at pH 1.5-3.5. At these values, the pH with greater antioxidant capacity was obtained. In some embodiments, the polysaccharide matrix consists of hydroxybenzoic acids covalently linked to the backbone. Approximately 40-60% of the extracted polysaccharides corresponded to the hemicellulose fraction and 10-30% to cellulose, bonded to hydroxybenzoic acids. Cellulose is a long linear polymer made of P(l—4)-linked glucose units, and hemi-cellulose is formed of hexose and pentose sugars with P(l—4) bonds and side chains with galactose, arabinose, and glucuronic acid linked via P(l—2) and P(l—3) bonds. In some embodiments, gallic acid is the main hydroxybenzoic acid found bound to the polymers that are highly branched with strong intramolecular bonds. After vacuum assisted extraction and ultrasound treatment, gallic acid residues are partially released, spatially reordered, and play a significative role during gastric digestion and intestinal absorption. In some embodiments, the optimal conditions varied from 1 to 3 cycles of vacuum instantaneous expansion, and 15-45 minutes of ultrasound assisted extraction time, and a pH value from 1.5-4.5. In these embodiments the experimental values agree with the predicted values. In some embodiments, the obtained polysaccharide is a pharmaceutical excipient, a pharmaceutically anti-adherent, a pharmaceutically binder in a pill, tablet, capsule, powder, absorption enhancer. In other embodiments, the obtained polysaccharide comprises a lubricant glidant, sorbent, preservative, or other component. In a preferred embodiment the obtained polysaccharide may be a source of tannins or gallic acid. In some embodiments, fiber loaded with drug or probiotics provide a higher accumulation of the drug or probiotics when it is integrated into the processed polysaccharide matrix. The effect of polysaccharides on the drug or microorganisms in these cases is to protect them from digestion enzymes and acid pH of digestion fluids. When the polysaccharides come into contact with the acidic medium, it goes through an acid hydrolysis, favoring the release of drug or microorganisms, which, at the same time, do not come into direct contact with the digestive flux. According to this, there is a higher amount of drug or probiotic that is not degraded. In some embodiments, there is also an increase in the antioxidant capacity, a breakdown of hydroxybenzoic terminals and the polysaccharide matrix, after the gastric phase of digestion due to hydrolysis. In some embodiments, the drug release rates when it is administered loaded in the treated polysaccharides follows a kinetic of the Korsmeyer-Peppas type associated with a Super Case-Il diffusion. In these embodiments there is no dependence with the drug concentration, the area of diffusion or the distance. There is a breakdown of the polymeric chain, different diffusion ways are given at the same time: drug release is driven by both diffusion and polysaccharide disaggregation during the intestinal phase. In these embodiments there is an interaction effect between the drug and treated polysaccharides which protected the drug, as a result it accumulates in higher quantity and therefore, permeates (if it is the case) in higher quantity, as it wasn't affected by the digestion. BRIEF DESCRIPTION OF DRAWINGS FIG. 1. Improvement effect of on fiber processing trough instantaneous expansion-ultrasonic treatment (USEX). Effect of the optimization between vacuum expansion cycles and pH in the Antioxidant Capacity. (AC) FIG. 2. Improvement effect of factor interactions on fiber processing. Effect of the interaction between vacuum expansion cycles and Z-potential. FIG. 3. Improvement of the optimization of the interaction between sonication time and pH in the Antioxidant Capacity (AC). FIG. 4. Improvement of the optimization effect of the interaction between vacuum expansion cycles and Z-potential. FIG. 5. Drying effects on the Antioxidant Capacity of the polysaccharides vacuum drying (VD), Tray drying (TD). FIG. 6. Exemplary of drug dosage form the released matrix. The figure shows the drug accumulation during the in vitro digestion process in the gastric phase and in the intestinal phase. Gastric Phase (GP), Intestinal Phase (IP). FIG. 7. Exemplary of drug permeation from the released matrix. The figure shows an ex-vivo duodenal permeation profile percentage of drug crosslinked to polysaccharides after in vitro digestion. FIG. 8 Example of the manufacturing process on the polysaccharide matrix, with the crosslinking effect of the drug with the polysaccharide after treatment and the released polyphenols from 500 to 1500 cm4. FIG's 9 and 10. Examples of the probiotic microorganism after the manufacturing process, FIG. 10 shows the viability of the microorganism after treatment. DETAILED DESCRIPTION OF THE INVENTION The treated food byproducts are derived from persimmon fruits of the Sharon or Triumph variety (non-astringent, seedless, and hard) and are composed of peels and pulp resulting from different stages of industrial processing of persimmon juice. These byproducts had previously been cleaned and washed to obtain free carotenoids and eliminate residual sugars that could interfere with the subsequent processing. Fibers were then milled and sieved (0,5-1.5 mm diameter) before processing to obtain homogenous samples. The optimal parameters to apply in the vacuum instantaneous expansion-ultrasonic treatment (USEX) were assessed. For these processes, zeta-potential and the antioxidant capacity (AC) were measured as response variables derived from each treatment. Samples were diluted with water (1:20) and the pH was adjusted (1.5-4.5). The physical treatment of vacuum expansion was performed where hydrated fibers went through the flash vacuum expansion system at a flow rate of 90-150 ml / min, a vacuum of (-0.6) - (-0.9) atm and a temperature of 25-75 °C. This process was repeated up to three cycles in a row for the same sample. Samples were processed at different periods of time between 15-60 minutes in a 750-Watt ultrasonic processor; the temperature was between 25-75 °C, the amplitude (40-80%) and energy (330 W) of the ultrasound waves were kept constant. Then, the samples were subjected to drying in trays at 40-80 9C or vacuum drying at 40-605C, both methods for 12-24 hours. The measurement of the antioxidant capacity was carried out using a colorimetric method that employs the free radical, 2,2-diphenylpicrylhydrazyl (DPPH). Results were expressed as pmol of Trolox equivalents (TE) per mg of sample. Polysaccharide particles were assessed according to surface charge using a zeta potential analyzer (Brookhaven Instruments Ltd., Brookhaven, USA). Implementation was in accordance to the technical manual and specifications of the equipment manufacturer. The drug or microorganism loading can take place during the manufacturing process before or after vacuum expansion, before or after ultrasonic treatment, before or after the drying processes accordingly to the drug or microorganism loaded into the polysaccharide matrix. The method of the invention was optimized to obtain maximum antioxidant capacity and the lowest zeta potential. The invention provides a polysaccharide that prevents oxidative damage to the drug component or microorganism, does not display strong repulsive forces and avoids rapid dispersion under gastric conditions and promotes absorption during intestinal transit. For drug release studies, an in vitro gastrointestinal digestion of the three treatment samples was simulated following the INFOGEST methodology. Simulated digestion fluids were prepared prior to digestion. Soft gel encapsulated samples of 0.6 g of each extracted fraction (0.3 g of fiber with 0.3 g of loaded drug), a positive control (0.3 g of loaded drug), a negative one (0.3 g of DF) and a blank (water) were put through the three phases: oral, gastric, and intestinal at 37 °C. The pH, time and simulated digestion fluids were adjusted for each phase. After each digestion phase, a 2 ml aliquot was extracted to analyze the percentage of the drug released to the chyme and chyle. The intestinal permeability and absorption dynamics of loaded polysaccharides were analyzed ex vivo. The intraduodenal part of the pig intestine was isolated and taken for the ex vivo permeation studies. Samples were analyzed by UV-VIS spectrophotometry in the UV-1603 UV-Visible Spectrophotometer (Shimadzu, Japan). The absorbance was measured at wavelength of 243.2 nm (Amax). The in vitro permeation data was evaluated kinetically by various mathematical models like zero-order, first-order, Higuchi, and Korsmeyer-Peppas models. The manufacturing invention provides significant differences when increasing the number of cycles. During the first example (FIG. 1), a gradual increase in AC was not observed as the cycles of expansion increased. After the second example, after two cycles, there was an increase of 70% and after three cycles, there was an increase of 90% on the antioxidant capacity of the polysaccharides. For the third example, increases of 61% from cycle 1 to 2, and 112% from cycle 1 to 3 were observed. The invention provides an inverse relationship as pH increases the antioxidant capacity of the polysaccharide decreased (FIG. 1). Increasing the pH from 1.5 to 3, led to a fall of 57% at the first cycle, 60% at the second cycle (p <0.01) and 22% at the third cycle. When the pH increases from 3 to 4.5 the antioxidant capacity decreased 68% at the first cycle, 70% at the second cycle and 65% at the third cycle. When the pH treatment ranges are compared, decreases of 86% for the first cycle, 80% for the second cycle and 72% for the third cycle, are observed. The invention provides the highest antioxidant activity at pH ranges from 1.5-4.5 in all cases, depending on the number of cycles, with values of 0.166, 0.182 and 0.174 pmol of TE per mg of fiber sample. The invention provides a zeta potential for the different treatment combinations between 7.7 and -7.85 mV (FIG. 2). There is a pattern of decrease in repulsion between particles as the number of cycles increases, at pH ranges from 1 to 4.5. As a result, the repulsion between particles is inversely proportional to the number of cycles and for pH 4.5, this relationship is directly proportional. After the 1st cycle the range of zeta potential values is the lower between -6.51 and +3.87 mV, for 2 cycles it stays the between -1.32 and +1.42 mV and for 3 cycles between -2.11 and +2.4 mV. The lowest zeta potential values are recorded after 3 cycles with means of -0.314 mV (o=1.69) and -0.52 mV (o=1.42). The highest ranges of zeta potential are observed at pH 4.5 and 3 cycles. After vacuum assisted extraction, the ultrasonic process step takes place. FIG 3. is an example of the effect of pH and time of ultrasound sonication in the antioxidant activity of treated fibers. Ranges from 15 minutes to 30 minutes increase the antioxidant activity up to 261%; and from 15 to 60 minutes up to 294%. For pH 4.5, the antioxidant activity increased 49% from 30 to 60 minutes (p <0.01), and 99% from 15 to 60 minutes. The invention provides an inversely proportional relationship between pH and antioxidant activity FIG 3. Increasing the pH led to a fall of 78% of the antioxidant activity after 15 minutes of treatment and 14% after 60 minutes of treatment. When the pH was increased, the antioxidant activity decreased 48% after 30 minutes of treatment. When increasing the pH a decrease of 79% of AC was observed at 15 minutes, 52% at 30 minutes and 39% at 60 minutes. The zeta potential for the different treatment combinations varied between -27.72 mV and +5.24 mV FIG 4. The invention provides a pattern of variation of the repulsion forces when varying the time of treatment; there is a maximum range of repulsion forces at ranges between -27.72 mV and 10.27 mV. At different pH's of treatment, the minimum ranges of repulsion forces between particles surface, corresponded to 15 minutes with values of 1.906 mV (o=5.56), 0.152 mV (o=0.43) and -0.279 mV (o=4.26) for pH's 1.5-4.5. The lowest zeta potential values were -0.28 mV (o=4.26). The highest ranges of zeta potential occur after 30 minutes of treatment and pH's of 1.5-3.0, with values of -0.02 to -4.098 mV. Regarding the drying process, the highest antioxidant capacity is observed after vacuum drying (see FIG. 5.) After processing, the neutral detergent polysaccharide fraction is higher than the acid detergent fiber, with values from 40-60% of the extracted polysaccharides corresponded to the hemicellulose fraction and 10-30% to cellulose, bonded hydroxybenzoic acids. To evaluate the potential of DF for drugs or nutraceuticals-controlled delivery, the release and dynamics of drug loaded polysaccharides were studied after in vitro digestion steps FIG. 6. shows the cumulative release during gastric and intestinal digestion. In a certain embodiment, there is a higher increase in the accumulation of the drug as the digestion progresses for the loaded polysaccharide in the intestinal phase. The polysaccharide loaded sample of first releases around 41% of the total loaded drug in the gastric phase, and 63% of the total loaded drug in the intestinal phase. This represented a 54% increase in accumulation in the intestinal phase with respect to the amount accumulated in the gastric phase. In this embodiment, in both phases of digestion, there is a greater accumulation of the drug in the loaded polysaccharide than in the positive control. In the gastric phase, the accumulation of the drug is 70% higher than in the control, and in the intestinal phase it was 54% higher. Ex vivo intraduodenal permeation methodology was used to analyze previously digested products composed of drug loaded polysaccharides (see FIG. 7). Results were compared to corresponding control samples without polysaccharides. Intraduodenal analysis of samples taken measured at multiple time-points revealed that the loaded polysaccharide delivery kinetics varied, as seen in FIG. 7. The drug from loaded polysaccharide permeates at least 29% of total encapsulated drug at the latest time-point checked (4 h) and at least 15% of total drug amount (half of the loaded drug that permeates) permeated at about 130 minutes. In contrast, unloaded drug permeated up to 20% at 4 h, and 10% of total drug content at about 150 min. Polysaccharide particles before and after treatment and drug loading were observed through infrared spectroscopy to identify the effect of the loaded drug on the polysaccharide matrix. FIG. 8 is an example of the crosslinking effect between the extracted polysaccharide and the drug. To assess whether the loaded drug polysaccharides improve upon the highly efficient release rates shown, permeation dynamics were also studied. In this example, the loaded polysaccharides modify the release curves by increasing the amount of drug liberated without altering the general dynamic profile. Exemplary kinetic release models are shown in Table 1. In interaction with polysaccharides, the loaded drug diffuses according to Korsmeyer-Peppas model; moreover, the release exponent (n) or the diffusion exponent was found to be higher than 0.89, which implies that the drug release from the system follows a Super case II transport. These examples imply that the absorption is modified by means of the method of the invention, through the macromolecular relaxation of the polymeric chains. Zero Order First Order Higuchi Korsmeyer-Peppas K0 R2 KI R2 KH R2 K n R2 Control 0,08 0,94 0,00 0,93 0,98 0,67 0,00 3,02 -0,59 Fiber 0,10 0,85 0,01 0,94 1,21 0,92 0,01 1,42 0,97 Table 1. Comparative kinetic values among different release models for the drug and polysaccharide interaction during permeation. Best adjustments are indicated in bold. These embodiments are examples of the use of the manufacturing method Vacuum Flash Expansion Coupled to Ultrasound Assisted Extraction, in the processing of polysaccharides which showed a direct impact in drug interaction. The optimal parameters for both treatments are determined by the consecutive characterization of the biomaterial where the obtained polysaccharide showed increased antioxidant capacity, which, in addition to being beneficial for the patient, kept the drug stable and increased its permeability. These embodiments are examples of processed polysaccharides from byproducts as a suitable invention to obtain material for its application as a functional excipient within the nutraceutical, pharmaceutical, prebiotic areas. The invention is applicable to drugs or active agents that may be acidic, basic or neutral, organic or inorganic, natural or synthetic, at different dose levels and solubility. The active agents are molecules that include analgesics, antihistamines, digestives, antibiotics, anti-inflammatory agents, polyphenolic extracts, cannabinoids, vitamins, probiotics.

Claims

1. A manufacturing process comprising vacuum assisted extraction coupled to ultrasound treatment of food by-products to obtain a controlled released agent comprising polysaccharides and polysaccharide bonded phenols.

2. A manufacturing process for food by-products comprising 3 cycles of vacuum instantaneous expansion, 15 minutes of ultrasound assisted extraction and pH of 1.5 to obtain polysaccharides with an increased range of antioxidant activity and a decreased zeta potential.

3. A manufacturing process according to claim 1 which maintains the probiotic availability or provides a postbiotic mixture.

4. An controlled release medicine comprising the controlled release agent obtained according to the method of any of claims 1 to 3 comprising a therapeutically effective amount of active substance or beneficial microorganism.

5. A controlled release medicine according to claim 4 loaded with active ingredients such as analgesics, antihistamines, digestives, antibiotics, anti-inflammatory agents, polyphenolic extracts, carotenoids, cannabinoids, vitamins.

6. A controlled release medicine according to claim 4 loaded with probiotics such as Lactobacillus acidophilus, Saccharomyces boulardii, Bifidobacterium infantis, Lactobacillus acidophilus, Streptococcus thermophilus, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgarius, Lactobacillus reuteri, Bifidobacterium bifidum. Akkermansia muciniphila.

7. A controlled release medicine according to any of claims 4 to 6 wherein gallic acid or polyphenols are covalently bonded to the polysaccharides.

8. A controlled release medicine according to claim 7 wherein gallic acid or polyphenols amount up to 30% by weight of the composition.

9. A controlled release medicine as claimed in any of claim 4 to 8 comprising a controlled released agent comprising the monosaccharide mannose up to 10%, galacturonic acid up to 10%, rhamnose up to 7%, glucose up to 15%, galactose up to 20%, arabinose up to 30%, and fucose up to 10% in weight.

10. A controlled release medicine according to any of claims 4 to lOcomprising a binder, gel capsule, lubricant, and / or diluent.

11. A controlled release agent manufactured as per any of claims 1 to 3 wherein gallic acid or polyphenols are covalently bonded to the polysaccharides.

12. A controlled release agent according to claim 11 wherein gallic acid or polyphenols amount up to 30% by weight of the composition.

13. A controlled release agent manufactured as per any of claims 1 to 3 comprising the monosaccharide mannose up to 10%, galacturonic acid up to 10%, rhamnose up to 7%, glucose up to 15%, galactose up to 20%, arabinose up to 30%, and fucose up to 10% in weight.

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