Oral platform for site-specific release to the colon

Abstract

The present invention relates to an oral drug delivery system capable of releasing the active ingredient it carries in a highly targeted, specific and complete mode to the colon.

Description

[0001] “ORAL PLATFORM FOR SITE-SPECIFIC RELEASE TO THE COLON”

[0002] Summary of the Invention

[0003] The present invention relates to an oral drug delivery platform (drug delivery system) capable of releasing, in a highly targeted, specific and complete mode, the active ingredient carried therein to the colon.

[0004] Technical Background

[0005] In the field of modified release, the development of oral delivery platforms that target as the release site the colonic environment has been extensively investigated due to the various advantages said platforms can offer. Firstly, targeted release to the colon enables more effective local treatment of intestinal disorders, which may be of various types, such as bacterial, viral, or parasitic infections, or inflammatory diseases (IBD, Inflammatory Bowel Disease), or irritable bowel syndrome (IBS), also including colorectal adenoma. In addition, colon-targeted delivery systems can be employed to effectively restore the microbiota.

[0006] Moreover, the distal part of the intestine, namely the colon, has been identified as an attractive site for the oral administration of biotechnological drugs, particularly peptides, proteins, oligonucleotides and nucleic acids. These types of compounds, when administered orally, typically undergo degradation due to the action of digestive enzymes and the physiological role of the gastrointestinal tract, which is inherently designed to break down peptides and proteins to allow subsequent absorption of amino acids. The administration of this category of compounds within a delivery platform that enables their selective release exclusively at the colonic level allows for their release in an environment, such as the distal intestine, which presents less harsh conditions compared to the stomach and the small intestine, due to the lower concentrations of digestive enzymes, thereby preserving their integrity.

[0007] Over the years, various technologies have been proposed to allow an active ingredient incorporated within a delivery system to reach the colon. For example, systems have been developed that exploit specific physiological conditions in the distal tract of the intestine, which differ from those characterizing the upper segments, such as, for example, a different pH value and / or the presence of microorganisms capable of carrying out specific enzymatic reactions. Another proposed approach leverages the relative reproducibility of the transit time within the small intestine and is therefore based on technologies that allow the release of the active ingredient to be deferred for a period of time (lag phase) at least corresponding to or longer than the time required for the system to reach the colon after intake.

[0008] In recent years, these different approaches have also been combined, leading to the development of delivery platforms that simultaneously rely on multiple mechanisms.

[0009] It should be emphasized that research in this field, which is continuously evolving, is driven by the need to have systems capable of releasing, in a timely manner, the entire amount of active ingredient contained therein into the colonic region. The need for precise release of the active ingredient only once the system has reached the colonic environment is fundamental to avoid therapeutic failures: in the event that the active ingredient is released too early, and therefore within a proximal region of the gastrointestinal tract, it could be absorbed into the systemic circulation, potentially leading to the appearance of systemic side effects, and / or undergo degradation, thereby resulting in a lower concentration than that required at the site of action.

[0010] On the other hand, the occurrence of an untimely or excessively slow release once the system has reached the colon also constitutes a potential failure of the delivery platform, as it would result in incomplete release of the active ingredient, which would remain “trapped” within the delivery system leading to a lack of or only partial achievement of the desired therapeutic effect.

[0011] US9023368 describes a modified-release system in which the central core containing the active ingredient is enclosed within a coating composed of a polysaccharide polymer, preferably starch, in combination with a second polymer component that is soluble at pH values above 5. This system allows site-specific release to the colon to be pursued, reducing the risks of failed or incomplete release at the target site due to the fermentation of the polysaccharide component by the intestinal microbiota. However, it is unable to prevent premature release, which could occur due to the dissolution of the pH-dependent soluble polymer coating already in the small intestine, where pH values higher than the claimed dissolution threshold of the polymer are physiologically exceeded. Given the presence of the hydrophilic polymer in the coating, the risk of premature release becomes an even more concrete possibility.

[0012] 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 active ingredient, onto which a double coating is applied: the first inner layer is composed of a swellable hydrophilic cellulose derivative that is not susceptible to degradation by the colonic microbiota; the second outer layer is instead based on a polymer that is soluble at pH > 7 in combination with a natural polysaccharide that is degradable by the colonic microbiota. This system, due to the presence of a double coating layer, is capable of preventing premature release of the active ingredient, which is hindered by the outermost coating layer. However, it still fails to achieve prompt release once the colonic region is reached, as the inner swellable hydrophilic coating takes time to hydrate and dissolve to such an extent as to allow for the release of the active ingredient contained in the core.

[0013] In another recent study, Moutaharrik S. et al. (Pharmaceutics, 2024, 16, 508) presented a different system with two coatings layered one upon the other around the central core containing the active ingredient, consisting of a swellable polysaccharide of natural origin susceptible to degradation by the colonic microbiota as for the inner coating, and a gastro- resistant polymer soluble at pH > 5.5 as for the outer coating. After dissolution of the gastro-resistant outer coating in the intestinal fluid, the inner coating is intended to defer the release of the active ingredient in the small intestine through progressive hydration, dissolution and erosion upon contact with the aqueous medium. In the colon, microbial degradation of any residues of the inner coating would allow for a more rapid onset of release at the target site. However, in order to provide a lag phase of sufficient duration to enable the system to reach the colonic region, the polysaccharide coating has to be relatively thick, which rules out its application in dosage forms that are either inherently large in size — such as those containing high-dose active ingredients — or in multiple-unit dosage forms, as the diameter of the individual subunits has to remain limited. Furthermore, obtaining a polysaccharide coating of adequate thickness requires relatively long processing times and consequently high manufacturing costs.

[0014] Despite the various attempts described in the prior art, there remains a need for an oral sitespecific colon delivery system that allows, with greater precision and accuracy than those currently known, a rapid and complete release of the active ingredient it carries once the target site is reached. Such a system should be capable of delivering any type of compound, including those of biotechnological origin, across a wide range of therapeutic doses for the treatment and / or prevention of local and / or systemic diseases.

[0015] Furthermore, such a system should be able to overcome the two main drawbacks of the previously proposed systems, by overcoming the possibility of premature opening, which would result in the release of the active ingredient to a region other than the targeted one — without, however, increasing the likelihood of failed or incomplete release, which would result in no or only partial exposure of the disease-affected region to the active compound conveyed. Finally, it should be possible to obtain such a system through scalable and efficient manufacturing processes.

[0016] Objectives of the Invention

[0017] An objective of the present invention is to provide an oral delivery platform for the sitespecific release of active ingredients at the colonic level.

[0018] Another objective of the present invention is to provide a process for the production of said oral platform for the site-specific release of active ingredients at the colonic level.

[0019] A further objective of the present invention is the use of said platform for the site-specific release of active ingredients at the colonic level to administer drugs for the treatment and / or prevention of local and / or systemic diseases.

[0020] These and other objectives are achieved by the subject matter of the present invention, which relates to an oral platform for the site-specific release of active ingredients at the colonic level.

[0021] Description of the Figures

[0022] Figure 1: Schematic representation of an embodiment of the delivery platform according to the present invention, highlighting (1) the core containing at least one active ingredient, (2) the first coating layer, and (3) the second coating layer.

[0023] Figure 2: Release profiles of systems coated with high-methoxyl pectin (•) or low- viscosity HPMC (□) up to a 50% weight gain - dissolution medium: phosphate buffer pH 6.5.

[0024] Figure 3: Release profiles of systems coated with high-methoxyl pectin (•) or low- viscosity HPMC (□) up to a 50% weight gain - dissolution medium: phosphate buffer pH 6.5 supplemented with pectinolytic enzymes (Pectinex Ultra SP-L).

[0025] Figure 4: Release profiles of systems coated with high-methoxyl pectin (first coating (2)) and Eudragit® S / high-methoxyl pectin-chitosan (second coating (3)) - dissolution medium: 0.1N HC1 for the first 2 hours, subsequently replaced with phosphate buffer pH 7.4.

[0026] Figure 5: Release profiles of systems coated with high-methoxyl pectin (first coating (2)) and Eudragit® S / high-methoxyl pectin-chitosan (second coating (3)) - dissolution medium: phosphate buffer pH 6.5 with (A) or without (□) pectinolytic enzymes (Pectinex Ultra SP-L).

[0027] Description of the Invention

[0028] The subject matter of the present invention is an oral delivery platform for the site-specific release of active ingredients at the colonic level, characterized by the presence of a core (1) containing at least one active ingredient, covered by two successive and distinct coating layers of different nature (2) and (3), as schematically shown in Figure 1.

[0029] More specifically, the present invention relates to an oral delivery platform for the sitespecific release of active ingredients to the colon comprising: a core (1) containing at least one active ingredient; a first coating (2) comprising at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota; and a second coating (3) comprising at least one polymer soluble at pH > 6.8 in combination with at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota.

[0030] In the present invention, the terms “delivery platform,” “delivery system,” and “drug delivery system” are used interchangeably and refer to advanced oral systems designed to control, through their characteristics, the release of the at least one active ingredient contained therein.

[0031] The at least one active ingredient may be of any nature; for example, it may be a low molecular weight active ingredient used in the treatment or prevention of IBD, IBS, dysentery, diverticulitis, or it may be a biological / biotechnological active such as a microorganism, an oligonucleotide, a peptide or a protein. In particular, the core of the delivery platform of the present invention can convey all active ingredients, drugs and / or health-promoting compounds that provide a therapeutic advantage if released only upon reaching the colonic region. For example, but not limited to, anti-inflammatory agents such as 5-aminosalicylic acid (5-ASA) or mesalazine, sulfasalazine, olsalazine, balsalazide, budesonide, prednisolone, methylprednisolone, prednisone, dexamethasone; antibiotics such as azithromycin, ciprofloxacin, doxycycline, vancomycin, fidaxomicin, metronidazole, tinidazole, nitazoxanide, paromomycin; immunomodulators such as azathioprine, cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil, infliximab, adalimumab, certolizumab, golimumab.

[0032] A preferred active ingredient is 5-aminosalicylic acid (5-ASA), also known as mesalazine. The term “coating layer” refers to a continuous layer, having a thickness on the order of tens or hundreds of microns, which continuously covers / coats the surface of the core to which it is applied.

[0033] According to a preferred embodiment of the present invention, the core containing at least one active ingredient on which the coating layers are sequentially applied may be in the form of tablets, capsules, mini-tablets (i.e., tablets with a diameter of less than 3 mm) and / or pellets. The first coating layer (2) of the present invention is the innermost layer that directly covers the core containing the at least one active ingredient. This first coating layer (2) comprises at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota, preferably selected from: pectins; guar gum; gum arabic; tragacanth gum; alginates; inulins; chitosan; starches and mixtures thereof. More preferably, said polymer is selected from: high-methoxyl pectin (HM pectin); medium -viscosity guar gum, or more preferably high-viscosity guar gum, for example with a viscosity of at least 2,000 cP; a mixture of HM pectin and chitosan; high-viscosity sodium alginate, for example sodium alginate with a viscosity of at least 450 cP; and high-amylose com starch.

[0034] The second coating layer (3) of the present invention is the outermost layer, deposited in contact with the first coating layer, which covers the system constituted by the core containing the at least one active pharmaceutical ingredient (1) coated with the first coating layer (2). This second coating layer (3) comprises at least one polymer soluble at pH > 6.8 in combination with at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota. Preferably, said at least one polymer soluble at pH > 6.8 and said at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota are mixed in a weight ratio ranging from 1 : 1 to 8:2 relative to the total weight of the two polymers, preferably in a 7:3 ratio.

[0035] The at least one polymer soluble at pH > 6.8 belongs to the class of polymethacrylates or cellulose esters, preferably selected from methacrylic acid derivatives and H-type hypromellose acetate succinate. More preferably, said polymer is a methacrylic addin ethyl methacrylate copolymer (1 :2) (currently marketed under the name Eudragit® S). The at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota contained within the second coating layer (3) may be the same as or different from that contained in the first coating layer (2). In particular, the at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota contained within the second coating layer (3) is preferably selected from: pectins; guar gum; gum arabic; tragacanth gum; alginates; inulins; chitosan; starches and mixtures thereof. More preferably, said polymer is selected from: high-methoxyl pectin (HM pectin); mediumviscosity guar gum, or more preferably high-viscosity guar gum, for example with a viscosity of at least 2,000 cP; a mixture of HM pectin and chitosan; high-viscosity sodium alginate, for example sodium alginate having a viscosity of at least 450 cP; and high- amylose com starch. According to a preferred embodiment, the oral delivery platform of the present invention is characterized in that it comprises a core (1) containing at least one active ingredient, and in that said at least one polysaccharide s of natural origin susceptible to degradation by colonic microbiota of the first coating layer (2) is high-methoxyl pectin (HM pectin), that said at least one polymer soluble at pH > 6.8 of the second coating layer (3) is a methacrylic acid-methyl methacrylate copolymer (1 :2), and that said polysaccharide of natural origin susceptible to degradation by colonic microbiota of the second coating layer (3) is selected from high-viscosity guar gum, for example with a viscosity of at least 2,000 cP, HM pectin, chitosan, and mixtures thereof.

[0036] According to another preferred embodiment, the oral delivery platform of the present invention is characterized in that it comprises a core (1) containing at least one active ingredient, and in that said at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota of the first coating layer (2) is HM pectin, that said at least one polymer soluble at pH > 6.8 of the second coating layer (3) is a methacrylic acid- methyl methacrylate copolymer (1 :2), and that said polysaccharide of natural origin susceptible to degradation by colonic microbiota of the second coating layer (3) is high- viscosity guar gum, for example with a viscosity higher than 2,000 cP.

[0037] According to a further preferred embodiment of the invention, the oral delivery platform is characterized in that it comprises a core (1) containing at least one active ingredient, and in that said at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota of the first coating layer (2) is HM pectin, that said at least one polymer soluble at pH > 6.8 of the second coating layer (3) is a methacrylic acid-methyl methacrylate copolymer (1 :2), and that said polysaccharide of natural origin susceptible to degradation by colonic microbiota of the second coating layer (3) is a mixture of HM pectin and chitosan.

[0038] According to a preferred aspect of the present invention, both coating layers according to the invention can be applied using any technique known to the person skilled in the art.

[0039] Preferably, the coating layers are applied by a process of spraying a film-forming solution / suspension (coating) and / or by a powder layering process, using appropriate equipment known to the person skilled in the art, for example in a fluidized bed or in a perforated or non-perforated pan coater.

[0040] If desired or necessary, and in order to obtain an effective coating with the required technical characteristics, other technological / functional excipients may be added to said at least one polymer during the coating / film-forming process, such as, but not limited to, solvents, plasticizers, colorants, binders, opacifiers, anti-adherents, surfactants, flavoring agents, antioxidants, etc.

[0041] The process for the production of the oral delivery platform according to the present invention is also an object of the present invention.

[0042] According to a preferred embodiment of the present invention, said production process comprises 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) by a film-coating process, by spraying a solution or suspension onto the cores under appropriate motion, for example using a fluidized bed apparatus; iii) application of the second coating (3) layer by a film-coating process, by spraying a solution or suspension onto the coated cores obtained in step (ii) under appropriate motion, for example using a fluidized bed apparatus, preferably the same apparatus used in step (ii).

[0043] According to a preferred embodiment of the invention, when the coating processes of steps (ii) and (iii) are carried out in a fluidized bed, said coating processes are characterized by the following operating conditions: inlet air temperature of 40-60 °C, product temperature of 28-45 °C, outlet air temperature of 30-45 °C, air atomization pressure of 1-2 bar, nozzle diameter of 0.5-0.8 mm, inlet air volume of 40-60 m3 / h, spray rate of 35-45 g / min / kg.

[0044] According to a particularly preferred embodiment of the invention, said first coating layer (2) has a thickness of 100 pm to 1000 pm, preferably from 150 pm to 350 pm or from 550 pm to 750 pm.

[0045] According to a particularly preferred embodiment of the invention, said second coating layer (3) has a thickness of 25 pm to 500 pm, preferably from 70 pm to 90 pm or from 150 pm to 300 pm.

[0046] The use of the oral delivery platform according to the present invention for the colonic release of active ingredients for the treatment and / or prevention of local and / or systemic diseases is a further object of the invention.

[0047] The delivery platform according to the present invention offers numerous advantages over the prior art. Firstly, and as will be extensively demonstrated in the experimental section that follows, it is capable of providing prompt release of the active ingredient at the colonic level after the delivery platform passes through the ileocecal valve and enters the colon. The presence of a double coating, in particular the two coating layers comprising the polymers as previously described, allows the system to avoid the two main causes of failure of the performance of colon-targeted delivery systems currently used in the prior art, namely premature release of the active ingredient or failed or incomplete release even after reaching the target site.

[0048] Furthermore, thanks to the carefully designed and calibrated polymeric composition, the delivery platform of the present invention exhibits behavior that is independent of the physiological or pathological conditions of the subject taking it, making the platform robust in performance and versatile with respect to the type of disease / symptom to be treated or prevented.

[0049] The delivery platform of the present invention is also independent, for its operation, from the physicochemical properties of the active ingredient carried therein and can, therefore, be used to administer a wide range of compounds / molecules, including known compounds, improving their therapeutic profile through site-specific release, which can, for example, increase their concentration at the site of action and / or their systemic bioavailability.

[0050] Moreover, as previously described, a further advantage of the delivery platform according to the present invention is that it can be implemented on cores containing at least one active ingredient of different sizes and shapes, such as tablets, capsules, mini-tablets and / or pellets.

[0051] Regarding the production process, it is important to emphasize that it is easily scalable and can be carried out by means of equipment in common use within pharmaceutical manufacturing facilities. Moreover, the materials that may constitute the two coating layers are commonly used in the food and / or pharmaceutical fields and are recognized as safe for human use as well as being easily available.

[0052] The specific features and advantages of the present invention will now be further illustrated, by way of example and without limitation, in the experimental section that follows.

[0053] Experimental Section

[0054] Example 1

[0055] 1.1 Preparation of the Core (1)

[0056] Immediate-release tablets were prepared as the core, containing an analytical tracer (directly compressible paracetamol, 80%), microcrystalline cellulose (Avicel® PH-101, 12.5%), sodium starch glycolate (Explotab® CLV, 4.5%), vinylpyrrolidone-vinyl acetate copolymer (Kollidon® VA 64, 2%), colloidal silica (Aerosil® 200, 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 rotary tablet press (AM-8S, Officine Ronchi, IT) equipped with concave punches (4 mm diameter, 4 mm curvature radius) to produce 40 mg tablets.

[0057] 1.2 Preparation and Application of the First Coating Laver (2)

[0058] A solution of high-methoxyl pectin (commercial name Aglupectin® HS-RP, 1.74% w / w) was prepared by dispersing the powder in deionized water and heating to 60°C.

[0059] Separately, glycerol monostearate (GMS; 10% by weight relative to the dry polymer weight, i.e., HM pectin) was dispersed in water with polysorbate 80 (Tween® 80) (40% by weight relative to the dry weight of GMS), heating at 75°C for 15 min. After adding glycerol (20% by weight relative to the dry polymer weight, i.e., HM pectin) dropwise to this second dispersion, the dispersion was added dropwise to the previously prepared HM pectin solution to obtain the coating formulation.

[0060] This coating formulation was applied to the tablets using a bottom-spray fluidized bed coating process (GPCG 1.1, Glatt, DE), and the resulting systems were subjected to heat treatment at 50°C for 4 h (Table I).

[0061] Alternatively, for comparative purposes, the first coating layer (2) was also prepared using low-viscosity hydroxypropyl methylcellulose (HPMC) (commercial name Methocel™ E50, with a viscosity of 50 cP) 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 relative to the dry polymer weight, i.e., HPMC) was then added to the dispersion as a plasticizer to obtain the coating formulation.

[0062] This coating formulation was applied to the tablets using a tangential-spray fluidized bed coating process (GPCG 1.1, Glatt, DE) (Table I).

[0063] 1.3 Preparation and Application of the Second Coating Laver (3)

[0064] The systems coated with HM pectin or low-viscosity HPMC, obtained as described in Section 1.2 above, were further coated with a dispersion of methacrylic acid-methyl methacrylate copolymer (1 :2) (commercial name Eudragit® S), HM pectin and chitosan (degree of deacetylation 90%). A weight ratio of 7:3 was maintained between Eudragit® S and the mixture of the two polysaccharides. Triethyl citrate (TEC) and glycerol monostearate (GMS) were added as plasticizer and anti-adherent, respectively.

[0065] The Eudragit® S dispersion was prepared in distilled water at 21.4% w / w, with the addition of IN ammonia solution to achieve a theoretical neutralization of 15%. After one hour, TEC (70% by weight relative to the dry weight of Eudragit® S) and a fine dispersion of GMS (10% by weight relative to the dry weight of Eudragit® S) were added, stirring for another hour. The GMS dispersion (5% w / w) was prepared as previously described by adding GMS to an aqueous solution of Tween® 80 (40% by weight relative to the dry weight of GMS), stirring vigorously and heating at 75°C for 15 min.

[0066] HM pectin was dissolved at 2% w / w in 0.1N HC1, and the resulting solution was then slowly added to a 2% w / w chitosan solution in 0.1N HC1, maintaining an HM pectin: chitosan ratio of 5 : 1. The pH was finally adjusted to 6 using IN NaOH.

[0067] The aqueous suspension of Eudragit® S, TEC and GMS previously prepared was then added dropwise to the pectin and chitosan dispersion to obtain the coating formulation.

[0068] This coating formulation was applied to the tablets previously coated with HM pectin (Section 1.2) using a bottom-spray fluidized bed coating process (Mini -Glatt, Glatt, DE) (Table I). The coated systems were finally subjected to heat treatment in an oven at 40°C for 48 hours.

[0069] Table I: Coating process conditions with HM pectin or low-viscosity HPMC (first coating layer (2)) and Eudragit® S / HM pectin-chitosan (second coating layer (3) applied onto the HM pectin-coated cores)

[0070] 1.4 Characterization of the systems obtained according to the coating processes described in Sections 1.2 and 1.3

[0071] The resulting systems were characterized in terms of percentage weight gain (n = 100%) and the amount of material applied per unit surface area (mg / cm2) (Table II). The coating layer thickness was measured using a digital micrometer (Absolute, Mitutoyo Mexicana, MX; n = 20).

[0072] Table II: Physico-technological characterization of the systems coated with HM pectin or low-viscosity HPMC (first coating layer (2)) and Eudragit® S / HM pectin-chitosan (second coating layer (3) applied onto the HM pectin-coated cores)

[0073] The release of the analytical tracer (paracetamol) from the systems coated solely with the first coating layer (2) consisting of HM pectin or low-viscosity HPMC as controls was evaluated using a USP paddle dissolution apparatus 43 (Dissolution System 2100B, Distek Strumenti & Misure, IT; n = 3, 37 ± 0.5 °C, 50 rpm) in 500 mL of phosphate buffer pH 6.5. Fluid samples were automatically withdrawn at predetermined time intervals and analyzed using a spectrophotometer (Lambda 35, PerkinElmer® Italia, IT; 248 nm) to determine the amount of tracer released. The lag time (tl0%) was calculated as the time required for the release of 10% of the tracer.

[0074] Additionally, these systems, placed in sinkers to prevent adhesion to the vessel walls after hydration, were further tested in phosphate buffer pH 6.5 supplemented with 5 mL of a commercial liquid preparation of pectinolytic enzymes (Pectinex Ultra SP-L, Novozymes, DK) using the same dissolution apparatus and measuring the amount of tracer released as previously described.

[0075] The double-coated systems were initially tested using 0.1N HC1 as the dissolution medium for 2 h followed by phosphate buffer pH 7.4 in the same dissolution apparatus under the previously described conditions. To assess the effect of colonic enzymes on the release performance, these systems were also tested in 500 mL of phosphate buffer pH 6.5 with or without the addition of pectinolytic enzymes (5 mL of Pectinex Ultra SP-L, Novozymes, DK).

[0076] In Figure 2, the release profiles of systems coated (paragraph 1.2) up to approximately 50% weight gain with either high methoxyl pectin (HM) or, for comparison, low-viscosity HPMC are shown, tested in phosphate buffer pH 6.5. It can be noted that coatings prepared with both hydrophilic / swelling polymers are capable of deferring the onset of release over time, release occurring promptly and quantitatively after relatively reproducible lag phases. In Figure 3, the release profiles of systems coated (paragraph 1.2) with HM pectin or HPMC up to approximately 50% weight gain are reported, tested in phosphate buffer pH 6.5 supplemented with pectinolytic enzymes (Pectinex Ultra SP-L). These profiles show that in the presence of pectinase, the lag phase imparted by the HM pectin-based coating is reduced in duration, supporting the use of this hydrophilic swelling polymer to defer the onset of release to avoid premature release in the small intestine. Indeed, the same polymer, when exposed to the colonic microbiota, would allow for more rapid exposure of the core to the aqueous medium, thus enabling a prompter onset of release at the target site. In Figure 4, the release profiles of systems coated with HM pectin (first coating layer (2)) and Eudragit® S / HM pectin-chitosan (second coating layer (3)) are shown, tested first in 0.1N HC1 for 2 h, followed by phosphate buffer pH 7.4. It is evident that, as intended, the second coating is capable of protecting the system in a fluid simulating gastric pH (with no release of the active ingredient observed during the first 120 min), while the first coating imparts a lag phase preceding release in simulated intestinal pH fluid, above the dissolution threshold of the polymer having pH-dependent solubility used in the second coating.

[0077] In Figure 5, the release profiles of systems coated with HM pectin (first coating layer (2)) and Eudragit® S / HM pectin-chitosan (second coating layer (3)) are shown, tested in phosphate buffer pH 6.5, simulating pH values typical of the proximal colon, with or without pectinolytic enzymes. The obtained profiles first show that although the pH of the medium does not reach the dissolution threshold of the polymer having pH-dependent solubility (> pH 7, as indicated by the manufacturer), release can still occur due to the enzymatic degradation of the polysaccharide component of the second coating. Additionally, the data demonstrate that in the presence of pectinase, the lag phase imparted by the first coating is reduced in duration, owing to more rapid exposure of the core to the aqueous medium owing to degradation of the hydrated polymeric layer.

[0078] Experimental Section

[0079] Example 2

[0080] 2.1 Core Preparation

[0081] Immediate-release tablets were prepared as cores, containing granulated mesalazine (also referred to as 5-aminosalicylic acid (5-ASA)), (micronized mesalazine powder, 87.0%; povidone, Vivapharm® PVP K30, 2.6%), microcrystalline cellulose (Avicel® PH-302, 8.0%), sodium starch glycolate (Explotab® CLV, 2.0%) and magnesium stearate (0.5%). The components were mixed (Turbula mixer, 10 + 2 min, 200 rpm), and the mixture was then fed into a rotary tablet press (AM-8S, Officine Ronchi, IT) equipped with oblong punches (22x10 mm diameter) to produce tablets of 1380 mg with a drug mesalazine dose of 1200 mg.

[0082] 2.2 Preparation and Application of the First Coating Layer (2)

[0083] A solution of high-methoxyl pectin (HM; commercial name Aglupectin® USP) (4% w / w) was prepared by dispersing the powder in deionized water and heating to 60°C. After complete dissolution of the polymer and cooling to room temperature, a suitable plasticizer (e.g., low-molecular weight propylene glycol, PEG 400) was added at an appropriate concentration (e.g., 30% by weight relative to the dry polymer weight, i.e., HM pectin). This coating formulation was applied onto the tablets by a pan (GS Coating, Morandi, IT) coating process under the following conditions: inlet air temperature 60-70°C, core temperature 25-35°C, spray rate 1-2 g / min.

[0084] 2.3 Preparation and Application of the Second Coating Layer (3)

[0085] The systems coated with HM pectin, prepared as described in previous Section 2.2, were further coated with a dispersion of methacrylic acid-methyl methacrylate copolymer (1 :2) (commercial name Eudragit® S), HM pectin (Aglupectin® USP) and chitosan (degree of deacetylation 90%). A 7:3 weight ratio was maintained between Eudragit® S and the mixture of the two polysaccharides. Triethyl citrate (TEC) and glyceryl monostearate (GMS) were added as plasticizer and anti-adherent, respectively. The Eudragit® S / HM pectin+chitosan dispersion was prepared as described in Example 1.3. This coating formulation was then applied onto the tablets previously coated with HM pectin (Section 2.2) by pan (GS Coating, Morandi, IT) coating under the following conditions: inlet temperature 40-50°C, core temperature 20-30°C, spray rate 1-2 g / min. The coated systems were finally subjected to thermal treatment in an oven at 40°C for 48 h.

[0086] 2,4 Characterization of the Systems Obtained according to the Coating Processes of Sections 2,2 and 2,3

[0087] The resulting systems were characterized in terms of percentage weight gain (n = 20) and amount of material applied per unit surface area (mg / cm2) (Table III). The coating thickness was measured using a digital micrometer (Absolute, Mitutoyo Mexicana, MX; n = 10). Table III: Physico-technological characterization of systems coated with HM pectin (first coating (2)) and Eudragit® S / HM pectin-chitosan (second coating (3) applied onto HM pectin-coated cores)

Claims

CLAIMS1. An oral delivery platform for site-specific release of active ingredients to the colon, 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 colonic microbiota; and a second coating (3) comprising at least one polymer soluble at pH > 6.8 in admixture with at least one polysaccharide of natural origin susceptible to degradation by colonic microbiota.

2. The delivery platform according to claim 1, characterized 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; tragacanth gum; alginates; inulins; chitosan; starches and mixtures thereof.

3. The delivery platform according to claim 1 or 2 characterized in that said at least one polymer soluble at pH > 6.8 of the second coating (3) is preferably selected from polymethacrylates and H-grade hypromellose acetate succinate.

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

5. The delivery platform according to any one of the preceding claims characterized 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 in admixture with each other in a ratio ranging from 1 : 1 to 8:2 by weight relative to the total weight of the sum of the two polymers, preferably in a ratio of 7:3.

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

7. The delivery platform according to any one of the preceding claims characterized 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, in 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 in that said polysaccharide of natural origin susceptible to degradation by the colonic microbiota of the second coating (3) is selected from guar gum having a viscosity of at least 2,000 cP, HM pectin, chitosan and mixtures thereof.

8. The delivery platform according to any one of the preceding claims characterized in that said first coating layer (2) has a thickness from 100 pm to 1000 pm.

9. The delivery platform according to any one of the preceding claims characterized in that said second coating layer (3) has a thickness from 25 pm to 500 pm.

10. A production process of the oral delivery platform according to claim 1, comprising the following steps: i) preparing cores containing the active ingredient (1), in the form of tablets, capsules, mini-tablets and / or pellets; ii) applying the first coating layer (2) by a film-coating process, spraying a solution or suspension onto the cores under appropriate motion, preferably using a fluidized bed apparatus; iii) applying the second coating layer (3) by a film-coating process, spraying a solution or suspension onto the coated cores obtained in step (ii) under appropriate motion, preferably by using a fluidized bed apparatus.

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