Oral platform for site-specific delivery to the colon

Description

DESCRIPTION of the invention entitled: “Oral platform for site-specific delivery to the colon” on behalf of: University of Milan with headquarters in: Via Festa del Perdono 7, 20100 Milan 5 inventors: Saliha Moutaharrik, Alessandra Maroni, Matteo Cerea, Anastasia A. Foppoli, Luca Palugan, Andrea Gazzaniga *** Summary of the invention The present invention relates to a release platform (drug delivery system) 10 oral capable of releasing the principle in a highly targeted, specific and complete way active in it transported into the colon. Technical context In the field of drug delivery systems, the development of platforms for oral administration that have the colonic environment as the release site is 15 has been widely studied due to the various advantages that these platforms can offer. determine. First of all, in fact, a targeted release at the colon level allows a more effective local treatment of intestinal disorders, which can be of various types nature, for example linked to bacterial, viral or parasitic infections, or of inflammatory bowel disease (IBD), or the syndrome of 20 irritable bowel syndrome (IBS), up to colorectal adenomas. Targeted colonic release systems can also be used to replenish in the microbiota effectively. Furthermore, the distal part of the intestine, consisting of the colon, has been identified as interesting site regarding the possibility of oral administration of biotechnological drugs, in particular peptides, proteins, oligonucleotides and nucleic acids. This type of compounds, in fact, when administered orally, must be normally undergo degradation due to the action of digestive enzymes and 5 nature of the gastrointestinal tract itself, physiologically responsible for the splitting of peptides and proteins to allow the subsequent absorption of amino acids. administration of this class of compounds within a delivery platform which determines its selective release exclusively at the colonic level allows instead their release into an environment, such as that of the distal intestine, which presents 10 conditions less aggressive than the stomach and small intestine, thanks to lower concentrations of digestive enzymes, thus preserving their integrity. Over the years, various techniques have been proposed that allow an active ingredient integrated into a delivery system to reach the colon. For example, they have been placed 15 systems are being developed that exploit the presence of specific physiological conditions within the distal tract of the intestine, different from those that characterize the tracts previous ones, such as, for example, a different pH value and / or the presence of microorganisms capable of carrying out particular enzymatic reactions. Another approach proposed is the one that exploits the relative reproducibility of the transit time inside 20 of the small intestine and which is therefore based on techniques that allow delaying the release of the asset for a period of time (lag phase) at least equivalent to or longer than it takes for the system to reach the colon after ingestion. In recent years, these different approaches have also been integrated with each other giving origin of release platforms that are based, simultaneously, on more than one I wait. It must be emphasized that research in this field, which is ongoing, continuous evolution, both determined by the need to have systems available that 5 are able to release, in a timely manner, all the active ingredient contained in them in the colonic region. The need for precise release of the active ingredient only once inside the colonic environment is essential to avoid failures of the therapy: in case the active ingredient is released too early, and so in a district of the proximal gastrointestinal tract, it could be absorbed 10 in circulation, leading to the possible appearance of systemic side effects, and / or degraded, still resulting in a lower concentration than that necessary at the site of action. On the other hand, even the establishment of a late or too slow release once reaching the colon constitutes a possible failure of the release platform 15 because it would determine an incomplete release of the assets, which would end up become “trapped” inside the release system resulting in failure or only partial achievement of the desired therapeutic effect. US9023368 describes a modified release system in which the central core containing the active ingredient is enclosed within a coating made of a 20 polymer of polysaccharide nature, preferably starch, mixed with a second polymeric component soluble at pH above 5. This system allows for to pursue a site-specific release at the colon level, reducing the risks of a failure or incomplete release to the target site due to fermentation of the polysaccharide component by the intestinal microbiota. However, it is not in able to prevent premature release, which could be caused by the dissolution of the pH-dependent solubility polymer coating already at the of the small intestine where pH values ​​in the range claimed as the threshold for 5 dissolution are physiologically exceeded. Given the presence of the hydrophilic polymer in the coating, the risk of premature release becomes an even greater possibility concrete. Moutaharrik S. et al. (Journal of Drug Delivery Science and Technology, 2021, 66, 102919) instead propose a system consisting of a central core containing the 10 active ingredient, to which a double coating is applied: the first internal layer is consisting of a swelling hydrophilic derivative of cellulose, not susceptible to degradation by the colonic microbiota; the second outermost layer is instead based on a soluble polymer at pH ≥ 7i in a mixture with a polysaccharide of animal origin natural degradable by the colon microbiota. This system, thanks to the presence of 15 a double layer of coating, it can prevent premature release of the active, hindered by the outermost coating, but still unable to determine a prompt release once the colonial district is reached due to the fact that the internal swelling hydrophilic coating takes time to hydrate and dissolve to such an extent as to allow the release of the active substance transported in the nucleus. 20 In another recent study, Moutaharrik S. et al. (Pharmaceutics, 2024, 16, 508) They feature a different system with two coatings, layered one on top of the other around to the central core with the active ingredient, consisting of a swelling polysaccharide of natural origin susceptible to degradation by the colonic microbiota, in the case of the innermost coating, and from a gastro-resistant polymer soluble at pH > 5.5 for the outer coating. After dissolution of the outer gastro-resistant coating in the intestinal fluid, the inner lining has the function of delaying the release of the active in the small intestine through progressive hydration, dissolution and 5 erosion on contact with the aqueous medium. In the colon, microbial degradation of any residues of internal coating would allow a more rapid onset of the release to the site of interest. However, in order for it to impart a lag phase of useful duration to reach the colonic district, the polysaccharide coating must be relatively thick, and its application would thus be precluded in the case 10 of dosage forms of intrinsically large size, containing for example active ingredients at high doses, both in multiple units being the diameter of the single subunits necessarily constituting content. Furthermore, obtaining a polysaccharide coating of adequate thickness involves processing times relatively long and consequently high costs. 15 Despite the various attempts currently available, the need is still felt have a site-specific oral delivery system for the colon that allows, with greater precision and accuracy than those currently known, the rapid and complete release of the principle conveyed in it once it reaches the site target. This system should be able to convey any type of 20 compounds, including those of biotechnological origin, in a wide range of therapeutic doses for the treatment and / or prevention of local and / or systemic diseases. This system must also be able to overcome the two major disadvantages of systems proposed so far are known today, avoiding the possibility of an early opening of the system, with consequent release of the assets in a district other than that desired, without however increasing the probability of a failed or incomplete release, which would determine a null or partial exposure of the district affected by the pathology to the conveyed compound. 5 Finally, this system must be able to be obtained through manufacturing processes scalable and efficient. Purposes of the invention It is an object of the present invention to provide an oral platform for the specific release of active ingredients at colon level. 10 It is another object of the present invention to provide a method for the production of said oral platform for the specific release of active ingredients to colon level. A further aim of the present invention is the use of said platform for the specific release of active ingredients at the colon level for the administration of 15 drugs for the treatment and / or prevention of local and / or systemic diseases. These and other purposes are achieved by the object of the present invention, which concerns an oral platform for site-specific release of active ingredients at the level of the colon. Description of the Figures 20 Figure 1: Schematic of an embodiment of the release platform according to the present invention wherein are highlighted (1) the core containing at least one active ingredient, (2) the first coating layer and (3) the second coating layer coating. Figure 2: Release profiles of systems coated with HM ( ●) or low-temperature HPMC pectin viscosity ( □) up to 50% increase in weight - dissolution medium: buffer phosphate pH 6.5. Figure 3: Release profiles of systems coated with HM ( ●) or low-temperature HPMC pectin 5 viscosity ( □) up to 50% increase in weight - dissolution medium: buffer phosphate pH 6.5 added with pectinolytic enzymes (Pectinex Ultra SP-L). Figure 4: Release profiles of HM pectin coated systems (first coating (2)) and Eudragit® S / pectin HM-chitosan (second coating (3)) - medium dissolution: 0.1N HCl for the first 2 hours, then replaced with buffer 10 phosphate pH 7.4. Figure 5: Release profiles of HM pectin coated systems (first coating ® (2)) and Eudragit S / pectin HM-chitosan (second coating (3)) - medium dissolution phosphate buffer pH 6.5 with ( ∆) or without ( □) pectinolytic enzymes (Pectinex Ultra SP-L). 15 Description of the invention The subject of the present invention is an oral delivery platform for the release site-specific release of active ingredients at the colon level characterized by the presence of a core (1), containing at least one active ingredient, covered by two subsequent and distinct different types of coating layers (2) and (3), as shown in Figure 1. 20 More specifically, the object of this invention is a platform for oral release for site-specific release of active ingredients at the colon level comprising: a core (1) containing at least one active ingredient; a first coating (2) comprising at least one polysaccharide of natural origin susceptible degradation by the colonic microbiota; and a second coating (3) comprising at least one polymer soluble at pH 6,≥8 in mixture with at least one natural polysaccharide susceptible to degradation by the microbiota colonial. 5 In the present invention the terms “release platform” “release system” and “drug delivery system” are used synonymously and refer to oral systems technologically advanced designed to control, thanks to their characteristics, the release of at least one active ingredient contained therein. At least one active ingredient can be of any nature, for example it can 10 be one of the low molecular weight active ingredients used in the treatment or prevention of IBD, IBS, dysentery, diverticulitis or it can be an active ingredient biological / biotechnological origin such as, for example, a microorganism, a oligonucleotide, a peptide, or a protein. In particular, in the core of the platform of release of the present invention, all the active ingredients can be conveyed, 15 drugs and / or compounds with health benefits, which offer a therapeutic advantage if released only once they have reached the colonial district. For example, but not limited to anti-inflammatories such as 5-aminosalicylic acid (5-ASA) or mesalazine, sulfasalazine, olsalazine, balsalazide, budesonide, prednisolone, methylprednisolone, prednisone, dexamethasone, antibiotics such as azithromycin, ciprofloxacin, doxycycline, 20 vancomycin, fidaxomicin, metronidazole, tinidazole, nitazoxanide, paromomycin, immunomodulators such as azathioprine, ciclosporin, tacrolimus, methotrexate, mycophenolate mofetil, infliximab, adalimumab, certalizumab, golimumab. The term “coating layer” refers to a continuous layer of thickness in the order of tens or hundreds of µm, which covers / coats in a I continue the surface of the core on which it is applied. According to a preferred aspect of the present invention, said core containing at least one active ingredient on which the layers of are applied in succession 5 coating can be represented by tablets, capsules, mini-tablets (i.e. tablets with a diameter of less than 3 mm) and / or pellets. The first coating layer (2) according to the present invention is the innermost one, which directly covers the core containing the at least one active ingredient. Said first coating layer (2) comprises at least one polysaccharide of natural origin 10 susceptible to degradation by the colonic microbiota, preferably chosen among: pectins; guar gum; gum arabic; gum tragacanth; alginates; inulins; chitosan; starches and their mixtures. Even more preferably, said polymer is chosen from: highly methoxylated pectin (HM pectin); medium viscosity guar gum; a mixture of HM pectin and chitosan; high viscosity sodium alginate and corn starch 15 high amylose. The second coating layer (3) according to the present invention is the most external, deposited in contact with the first layer of coating, which covers the system consisting of the core containing the at least one active ingredient (1) coated by the first coating layer (2). Said second coating layer (3) comprises at least 20 a soluble polymer at pH ≥ 6.8 in mixture with at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota. Preferably called at least one polymer soluble at pH ≥6.8 and said at least one polysaccharide of origin natural susceptible to degradation by the colonic microbiota are in mixture between them in a ratio of 1:1 to 8:2 by weight compared to the total weight of the sum of the two polymers, preferably in a 7:3 ratio. Said at least one polymer soluble at pH ≥ 6.8 belongs to the class of polymethacrylates or cellulose esters, preferably chosen from methacrylic acid derivatives 5 and hypromellose acetate succinate type H. Even more preferably said polymer is the methacrylic acid-methyl methacrylate copolymer (1:2) (currently marketed ® with the name of Eudragit S). Said at least one polysaccharide of natural origin susceptible to degradation by of the colonic microbiota included within the second lining layer (3) 10 may be the same or different from the one included in the first layer of coating (2). In particular, said at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota within the second layer coating (3) is preferably chosen from: pectins; guar gum; gum arabic; gum tragacanth; alginates; inulins; chitosan; starches and their mixtures. Even more 15 preferably said polymer is chosen from: pectin with a high degree of methoxylation (HM pectin); medium viscosity guar gum; a blend of HM pectin and chitosan; high viscosity sodium alginate and high amylose corn starch. According to a preferred embodiment, the oral delivery platform of the present invention It is characterized by the fact that it comprises a nucleus (1) containing at least one principle 20 active, and from the fact that said at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the first coating (2) is pectin HM, which said at least one polymer soluble at pH ≥ 6.8 of the second coating (3) is a copolymer of methacrylic acid-methyl methacrylate (1:2) and that said polysaccharide of natural origin susceptible to degradation by the colonic microbiota second coating (3) is chosen between high viscosity guar gum, pectin HM, chitosan and their mixtures. According to another preferred aspect, the oral delivery platform of this 5 The invention is characterised by the fact that it comprises a core (1) containing at least an active ingredient, and by the fact that said at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the first lining (2) is pectin HM, which is said to be at least one soluble polymer at pH ≥ 6.8 of the second coating (3) is a copolymer of methacrylic acid-methyl methacrylate (1:2) and that 10 said polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the second lining (3) is high-grade guar gum viscosity. According to a further preferred aspect of the invention, the oral delivery platform It is characterized by the fact that it comprises a nucleus (1) containing at least one principle 15 active, and by the fact that said at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the first coating (2) is pectin HM, which is said to be at least one soluble polymer at pH ≥ 6.8 of the second coating (3) is a copolymer of methacrylic acid-methyl methacrylate (1:2) and that said polysaccharide of natural origin susceptible to degradation by the colonic microbiota 20 second coating (3) is a mixture of HM pectin and chitosan. According to a preferred aspect of the present invention, both layers of coating according to the invention can be applied using all the techniques known to those skilled in the art. Preferably, the coating layers are applied via a process of spraying of a film-forming solution / suspension (filming) and / or through a process of stratification of powders, with suitable equipment known to the expert in the field, to for example in a fluidized bed or in a perforated or non-perforated bottom pan. 5 If desired or necessary, and in order to obtain an effective and well-equipped coating of the required technical characteristics, said at least one polymer can be other excipients added during the coating / filming process technological / functional such as, but not limited to, solvents, plasticizers, colorants, binders, opacifiers, non-stick agents, surfactants, flavorings, antioxidants, 10 etc. The object of this invention is the production process of the platform of oral release according to the present invention. According to a preferred form of the present invention, said manufacturing process includes the following phases: 15 i) preparation of the nuclei containing the active ingredient (1), in the form of tablets, capsules, mini- tablets and / or pellets; ii) application of the first coating layer (2) via filming process, by spraying a solution or suspension, on the appropriately moved nuclei, example using a fluidized bed apparatus; 20 iii) application of the second coating layer via filming process, by spraying a solution or suspension, on the coated cores obtained in step (ii) appropriately moved, for example using a fluidized bed apparatus, preferably the same device used in phase (ii). According to a preferred aspect of the invention, when the filming processes of the phases (ii) and (iii) take place in a fluidized bed, these filming processes are characterized by following operating conditions: inlet air temperature 40-60 °C, temperature of the product 28-45 °C, outlet air temperature 30-45 °C, pressure 5 air atomization 1-2 bar, nozzle diameter 0.5-0.8 mm, air volume in inlet 40-60 m / h, spray rate 35-45 g / min / kg. According to a particularly preferred aspect of the invention, said first layer of coating (2) has a thickness of 100 µm to 1000 µm, preferably 150 µm to 350 µm. 10 According to a particularly preferred aspect of the invention, said second layer of coating (3) has a thickness of 25 µm to 500 µm, preferably 150 µm to 300 µm. The use of the oral delivery platform according to the present invention for the delivery at the colon level of active ingredients for the treatment and / or prevention of pathologies 15 local and / or systemic is a further object of the invention. The release platform according to the present invention has numerous advantages with respect to the prior art. First of all, and as will be amply demonstrated in the experimental section that follows, is able to determine a prompt release of the active at the level of the colon after the release platform passes the ileocecal valve 20 and passes into the colon. The presence of a double lining, and in particular of the two layers coating comprising the polymers as previously described, allows for avoid the two main reasons for performance failure of release systems colonic currently used in the state of the art, namely an early release of the active ingredient or its failure or incomplete release even once it has reached the target site. Furthermore, thanks to the particular polymer composition carefully studied and calibrated, the The release platform of the present invention is found to have a behavior independent of the physio-pathological conditions of the subject by whom it is taken 5 making the platform robust in performance and versatile in relation to the typology of disease / symptom to be treated or prevented. The release platform of the present invention is also independent, for its functioning, from the chemical-physical characteristics of the active ingredient conveyed in it and can, also for this reason, it can be used to administer a wide range of 10 compounds / molecules, also already known, improving their therapeutic profile thanks to the site-specific release which can, for example, increase their concentration at the site of action and / or their systemic bioavailability. Furthermore, as previously described, an additional advantage of the platform is release according to the present invention, is constituted by the fact that it can be 15 implemented on nuclei containing at least one active ingredient of different size and conformation such as, for example, tablets, capsules, mini-tablets and / or pellets. As regards the production process, it is important to underline how it is easily scalable and implementable with commonly available equipment within pharmaceutical manufacturing plants; furthermore, materials that can 20 constitute the two layers of coating are normally used in the food sector and / or pharmaceutical and recognized as safe for human use, as well as easily available. The peculiarities and advantages of the present invention will now be further explained. illustrated, for illustrative and non-limiting purposes, by the experimental section which follows. Experimental section Example 5 1.1 Preparation of the core (1) As a core, ready-to-use tablets containing a ® analytical tracer (paracetamol DC, 80%), microcrystalline cellulose (Avicel PH- ® 101, 12.5%), sodium starch glycolate (Explotab CLV, 4.5%), copolymer ® ® vinylpyrrolidone-vinylacetate (Kollidon VA 64, 2%), colloidal silica (Aerosil 200, 10 0.5%) and magnesium stearate (0.5%). The components were mixed (Turbula mixer, 12 + 3 min, 200 rpm), and the mixture was then fed into a tablet press rotary press (AM-8S, Officine Ronchi, IT) equipped with concave punches (diameter 4 mm, radius of curvature 4 mm) to produce 40 mg tablets. 1.2 Preparation and application of the first coating layer (2) 15 A solution of pectin with a high degree of methoxylation (high methoxyl, HM; name ® commercial Aglupectin HS-RP) (1.74% w / w) was prepared by dispersing the powder in deionized water and heating to 60 °C. Separately, glycerol monostearate (GMS; 10% by weight of the polymer weight ® dry, i.e. HM pectin) was dispersed in water with polysorbate 80 (Tween 20 80) (40% by weight on the dry weight of GMS), heating at 75 °C for 15 min. After having added to this second dispersion glycerol (20% by weight on the weight of the polymer) dry, i.e. HM pectin), this dispersion was added drop by drop to the previously prepared HM pectin solution, to give the coating formulation. This coating formulation was applied to the tablets through a process of film coating in bottom-spray fluidized bed (GPCG 1.1, Glatt, DE), and the obtained systems are were subjected to heat treatment at 50 °C for 4 hours (Table I). Alternatively, for comparison purposes, the first coating (2) was also made 5 with low viscosity hydroxypropyl methylcellulose (HPMC) (trade name TM TM Methocel E50) as follows. A solution of Methocel E50 (8% w / w) was prepared by dispersing the polymer powder in deionized water at 80 °C. Polyethylene glycol (PEG; 10% by weight) was then added to the dispersion. on the weight of the dry polymer, i.e. of the HPMC) with a plasticizer function to give the 10 coating formulation. This coating formulation was applied to the tablets through a process of film coating in tangential-spray fluidized bed (GPCG 1.1, Glatt, DE) (Table I). 1.3 Preparation and application of the second coating layer (3) The systems coated with low viscosity HM or HPMC pectin, obtained as per 15 described in the previous section 1.2, were further coated with a dispersion of methacrylic acid-methyl methacrylate copolymer (1:2) (name ® commercial Eudragit S), pectin HM and chitosan (90% deacetylation degree). Yes ® a 7:3 weight ratio is maintained between Eudragit S and the mixture of the two polysaccharides. Triethyl citrate (TEC) and glycerol monostearate (GMS) have been added 20 respectively as a plasticizer and non-stick agent. ® The Eudragit S dispersion was prepared in distilled water at 21.4% w / w, with addition of 1N ammonia solution to obtain a theoretical neutralization of the ® 15%. After one hour, TEC was added (70% by weight of the dry weight of Eudragit ® S) and a fine dispersion of GMS (10% by weight on the dry weight of Eudragit S), stirring for another hour. The GMS dispersion (5% w / w) was prepared, as ® previously specified, adding GMS to an aqueous solution of Tween 80 (40% by weight on the dry weight of GMS), mixing vigorously and heating to 5 75 °C for 15 min. HM pectin was dissolved, in an amount equal to 2% w / w in 0.1N HCl, and at The resulting solution was then slowly added with a 2% chitosan solution. w / w in 0.1N HCl, maintaining a HM pectin:chitosan ratio of 5:1. The pH was finally adjusted to pH 6 using 1 N NaOH. ® 10 The previously prepared aqueous suspension of Eudragit S, TEC and GMS is was then added drop by drop to the pectin and chitosan dispersion for obtain the coating formulation. This coating formulation was then applied to the tablets. previously coated with HM pectin (section 1.2) in a bottom-spray fluidized bed 15 (Mini-Glatt, Glatt, DE) (Table I). The coated systems were finally subjected to heat treatment in an oven at 40°C for 48 hours. Table I: Process conditions for coating with HM or HPMC pectin at low temperature ® viscosity (first coating (2)) and Eudragit S / Pectin HM-chitosan (second coating (3) applied over the pectin-coated cores (HM) HPMC (2) HM pectin HM pectin (2) - ® Formulation (2) Eudragit S / pectin HM-chitosan (3) GPCG 1.1., GPCG 1.1., Mini-Glatt, bottom- Tangential-bottom-equipment spray spray spray Batch size (g) 1000 200 75 Inlet air temperature (°C) 60 60 40 Outlet air temperature (°C) 53 40-42 - Product temperature (°C) 52 38-42 28-34 Plate rotation speed (rpm) 400 - - Nebulizing air pressure 2 2 1 (bar) Nozzle diameter (mm) 1.2 0.8 0.5 Air volume (m / h) 100 60 40-50 Spray speed (g / min) 3-5 8.5 2.7-3.5 5 1.4 Characterization of the systems obtained according to the filming processes of the paragraphs 1.2 and 1.3 The resulting systems were characterized in terms of percentage weight gain (n = 100%) and amount of material applied per unit area (mg / cm²) (Table II). The thickness of the coatings was measured using a digital micrometer 10 (Absolute, Mitutoyo Mexicana, MX; n = 20). Table II: Physical-technological characterization of systems coated with HM pectin or ® Low viscosity HPMC (first coating (2)) and Eudragit S / pectin HM- chitosan (second coating (3) applied over the HM pectin coated cores) HPMC (2) HM pectin HM pectin (2) - ® Formulation (2) Eudragit S / pectin HM-chitosan (3) Weight increase (%) 48.54 46.95 36.27 Coating quantity 36.86 39.13 34.83 applied (mg / cm ) Amount of polymer applied 33.51 29.22 15.35 (mg / cm ) Thickness of the coating layer 273.24 ± 241.98 ± 303.89 ± 28.74 (µm) 16.66 19.52 5 The release of the analytical tracer (paracetamol) from the systems coated with the first one only coating (2) consisting of low viscosity HM or HPMC pectin as a control, is was evaluated using a USP 43 paddle dissolution apparatus (Dissolution System 2100B, Distek Instruments & Measurements, IT; n = 3, 37 ± 0.5 °C, 50 rpm) in 500 mL of phosphate buffer pH 6.5. Fluid samples were automatically collected at 10 pre-set time intervals and analyzed with a spectrophotometer (Lambda 35, ® PerkinElmer Italia, IT; 248 nm) to determine the amount of tracer released. Lag time (t ) was calculated as the time required for the release of 10% 10% of the tracer. Furthermore, these systems, included in sinker to avoid adhesion to the vessel walls after 15 hydration, were further tested in phosphate buffer pH 6.5 added with 5 mL of a commercial liquid preparation of pectinolytic enzymes (Pectinex Ultra SP-L, Novozymes, DK) using the same dissolving apparatus and measuring the amount of tracer released as previously indicated. Double-coated systems were initially tested using as dissolution medium HCl 0.1 N for 2 hours, then replaced with phosphate buffer pH 7.4 in the same dissolving apparatus and conditions previously described. For 5 to evaluate the effect of colonic enzymes on the release performance, were also tested in 500 mL of phosphate buffer pH 6.5 with or without the addition of enzymes pectinolytics (5 mL of Pectinex Ultra SP-L, Novozymes, DK). In Figure 2, the release profiles of coated systems (paragraph 1.2) up to a weight increase of around 50% with HM pectin or with low viscosity HPMC, 10 as a comparison, tested in phosphate buffer pH 6.5. It is possible to note how the coatings made with both hydrophilic / swelling polymers are able to delay the onset of release, which is prompt and quantitative after phases of relatively reproducible latency. In Figure 3, the release profiles of coated systems (paragraph 1.2) are reported with 15 HM or HPMC pectin up to a weight increase of around 50%, tested in buffer phosphate pH 6.5 added with pectinolytic enzymes (Pectinex Ultra SP-L). These profiles highlight how, in the presence of pectinase, the lag phase imparted by the coating based on HM pectin is reduced in shelf life, supporting the use of this hydrophilic polymer swelling agent as a delaying agent for the onset of release in order to avoid a 20 premature release in the small intestine. The same polymer, in fact, if exposed to the colonic microbiota, would allow a more rapid exposure of the nucleus to the medium aqueous and, therefore, a more timely onset of release at the target site. Figure 4 shows the release profiles of systems coated with HM pectin (first ® coating (2)) and Eudragit S / pectin HM-chitosan (second coating (3)) tested first in 0.1N HCl for 2h and then in phosphate buffer pH 7.4. It is evident that, as desired, the second coating is able to protect the system in a fluid that simulates gastric pH (there is no release of the active ingredient for the first 5 120 minutes) while the first coating imparts a lag phase, preceding the release into a fluid at simulated intestinal pH, above the dissolution threshold of the pH-dependent solubility polymer of the second coating. Finally, the release profiles of HM pectin-coated systems are shown in Figure 5. ® (first coating (2)) and Eudragit S / pectin HM-chitosan (second coating 10 (3)) tested in phosphate buffer pH 6.5, which simulates pH values ​​in the typical range of the proximal colon, with or without pectinolytic enzymes. The profiles obtained show first of all, although the pH of the medium does not reach the dissolution threshold of the pH-dependent solubility polymer (> pH 7, as indicated by the manufacturer), the release can be established thanks to the enzymatic degradation of the component 15 polysaccharide of the second coating. Furthermore, the same data highlight how, in presence of pectinase, the lag phase imparted by the first coating is reduced in duration, thanks to a more rapid exposure of the nucleus to the aqueous medium following the degradation of the hydrated polymer layer.

Claims

1. Oral delivery platform for the site-specific release of active ingredients at the colon level comprising: a core containing at least one active ingredient (1); a first coating (2) comprising at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota; and a second coating (3) comprising at least one polymer soluble at pH > 6.8 in mixture with at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota.

2. The release platform according to claim 1 characterised in that said at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the first coating (2) is preferably selected from pectins; guar gum; gum arabic; gum tragacanth; alginates; inulins; chitosan; starches and mixtures thereof.

3. The release platform according to claim 1 or 2 characterised in that said at least one polymer soluble at pH > 6.8 of the second coating (3) is preferably selected from methacrylic acid derivatives and hypromellose acetate succinate type H.

4. The release platform according to any of the preceding claims characterised in that said at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the second coating (3) is preferably chosen from pectins; guar gum; gum arabic; gum tragacanth; alginates; inulins; chitosan; starches and mixtures thereof.

5. The release platform according to any of the preceding claims characterised in that said at least one polymer soluble at pH > 6.8 and said polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the second coating (3) are mixed with each other in a ratio of 1:1 to 8:2 by weight with respect to the total weight of the sum of the two polymers, preferably in a ratio of 7:

3.

6. The release platform according to any of the preceding claims characterised in that said core containing at least one active ingredient is represented by a tablet, a capsule, a mini-tablet and / or pellets.

7. The delivery platform according to any of the preceding claims characterised in that said at least one polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the first coating (2) is HM pectin, that said at least one polymer soluble at pH > 6.8 of the second coating (3) is a methacrylic acid-methyl methacrylate copolymer (1:2) and that said polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the second coating (3) is selected from high viscosity guar gum, HM pectin, chitosan and mixtures thereof.

8. The release platform according to any of the preceding claims characterised in that said first coating layer (2) has a thickness of 100 µm to 1000 µm.

9. The release platform according to any of the preceding claims characterised in that said second coating layer (3) has a thickness of 25 µm to 500 µm.

10. Production process of the oral release platform according to claim 1 comprising the following steps: i) preparation of the cores containing the active ingredient (1), in the form of tablets, capsules, mini-tablets and / or pellets; ii) application of the first coating layer (2) through a filming process, 5 by spraying a solution or suspension, on the suitably moved cores, preferably using a fluid bed apparatus; iii) application of the second coating layer (3) through a filming process, by spraying a solution or suspension, on the coated cores obtained in step (ii) suitably moved, preferably using a fluid bed apparatus.