WO2023211276A1 - Système de dosage oral et procédés d'administration d'un ou de plusieurs agents thérapeutiques sensibles à l'oxygène au tractus gastro-intestinal inférieur - Google Patents

Système de dosage oral et procédés d'administration d'un ou de plusieurs agents thérapeutiques sensibles à l'oxygène au tractus gastro-intestinal inférieur Download PDF

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WO2023211276A1
WO2023211276A1 PCT/NL2023/050227 NL2023050227W WO2023211276A1 WO 2023211276 A1 WO2023211276 A1 WO 2023211276A1 NL 2023050227 W NL2023050227 W NL 2023050227W WO 2023211276 A1 WO2023211276 A1 WO 2023211276A1
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dosage form
coating
form according
active ingredient
liquid core
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PCT/NL2023/050227
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English (en)
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Henderik Willem Frijlink
Annemarie BROESDER
Anko Cornelus EISSENS
Wouter Leonardus Joseph Hinrichs
Charlotte HENSTRA
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Rijksuniversiteit Te Groningen
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Publication of WO2023211276A1 publication Critical patent/WO2023211276A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars

Definitions

  • the invention relates to pharmacology and delivery systems. More specifically, it relates to means and methods for the site-specific delivery in the gut of an aqueous composition of oxygen sensitive active ingredients, e.g. living anaerobic bacteria, using an oral dosage system.
  • oxygen sensitive active ingredients e.g. living anaerobic bacteria
  • the human gut has a complex intestinal flora and many studies have emphasized the critical importance of the gut microbiota on maintaining human health and wellbeing (Baumler et al. Nature, 535 (7610) (2016), p. 85). In particular, the number, type, and interactions of the different microbial species present within the human colon have been related to a variety of chronic and acute diseases. Increasing evidence indicated that intestinal flora disorders are associated with the occurrence of many diseases, such as autoimmune and allergic diseases, obesity, inflammatory bowel disease, and diabetes (Clemente et al. Cell, 1486 (6) (2012)).
  • FMT Fecal Microbiota Transplantation
  • GDI clostridium difficile infection
  • IBD inflammatory bowel disease
  • FMT is not a convenient method for general use and researchers are examining alternative approaches of manipulating the gut microbiota including oral delivery of prebiotics, probiotics, symbiotics, and postbiotics.
  • Microencapsulation has been proposed as an effective means of protecting probiotics from degradation.
  • An effective microencapsulation system should maintain the stability of the probiotics during storage, protect them from the harsh conditions in the upper GIT, release them in the colon, and then promote their ability to colonize the mucosal surfaces.
  • a number of recent reviews have focused on the various kinds of oral delivery systems that have been developed to encapsulate probiotics. See for example Rodrigues et al. (Food Res. Int. Volume 137, 2020, 109682) and references cited therein discussing the main techniques for encapsulation of probiotic cells, as well as the advantages and possibilities of incorporating produced particles into food matrices.
  • the human gastrointestinal tract is colonised by trillions of commensal bacteria, most of which are obligate anaerobes residing in the large intestine.
  • anaerobic gut inhabitants such as Akkermansia, Bacteroides, or Faecalibacterium may have a huge therapeutic potential in many diseases, the production, storage and delivery of this class of bacteria faces additional challenges. See Andrade et al. (Front. Bioeng. Biotechnol. 2020 Jun 5;8:550).
  • the present inventors aimed at developing a novel type of oral delivery system that allows for the site-specific release, more in particular lower ileum/colon- selective release, of one or more oxygen sensitive therapeutic ingredient(s), such as oxygen sensitive drugs, such as, but not limited to: adrenalin, noradrenalin, levodopa, morphine or cholecalciferol, and/or anaerobic bacteria.
  • oxygen sensitive drugs such as, but not limited to: adrenalin, noradrenalin, levodopa, morphine or cholecalciferol, and/or anaerobic bacteria.
  • the dosage form e.g. capsule
  • the dosage form passes through the upper part of the GI tract, without release of the bacterial content, whereas the anaerobic bacteria are released in the terminal ileum and the colon.
  • They also sought to provide a dosage form having a composition and structure that allows the anaerobic bacteria to survive (i.e. be protected from oxygen) during a reasonable shelf life.
  • An aqueous core comprising an oxygen sensitive agent e.g. drug and/or viable bacteria that are of therapeutic relevance
  • aqueous core being surrounded with an inner lipid/fat-based protective coating, which preserves the structure and thus the functionality of the product during storage;
  • the lipid/fat-coated core being surrounded with an exterior coating allowing for colon-specific delivery.
  • This outer coating can suitably be applied directly onto the lipid/fat-coated core.
  • the invention relates to an oral dosage form for site-specific delivery of an aqueous composition of an active ingredient to the lower gastro-intestinal tract, wherein said oral dosage form comprises the following elements:
  • a liquid core bead comprising an aqueous composition of at least one active ingredient
  • the fat-coated core bead being surrounded with an exterior coating allowing for site-specific delivery to the lower gastro-intestinal tract.
  • liquid core bead herein also referred to as ‘’water sphere” or ‘’liquid- core gel sphere”, is meant to refer to a liquid-core-shell structure wherein a liquid core is surrounded by a thin, but very strong membrane that allows for the application of a coating, or wherein the liquid core consists of an aqueous composition that is immobilized by polymers in the desired shape (e.g. spherical or oblong).
  • the liquid core of the water spheres typically comprises (oxygen free) water or an aqueous composition suitable for e.g. maintaining cultures of anaerobic bacteria alive.
  • liquid core beads are suitably produced with the help of hydrogel forming polymers such as alginate or agar- agar or similar polysaccharides. They may contain a culture of anaerobic bacteria in oxygen-free water or culture medium. To protect the core component(s) (including the anaerobic bacteria) from oxygen, the water spheres are coated by at least two coating layers to achieve the desired site specific release performance of the enclosed agent(s).
  • Ouyang et al. J Pharm Pharmaceut Sci 7(3):315-324, 2004 developed multilayer alginate/poly-l-lysine/pectin/poly-l-lysine/alginate (APPPA) microcapsules that were characterized in-vitro for bacterial cell oral delivery using Lactobacillus reuteri cells as a model. Compared to alginate/poly-l-lysine/alginate (APA) microcapsules, they displayed a superior stability in simulated GI conditions. In a subsequent study (Afkhami et al.
  • WO2019/157066 relates to modified-release multiparticulates (in bead or granule from) comprising a core including pharmaceutical agent and/or probiotic, optionally with additional excipients or binders to aid in creation of the core, one or more functional coatings disposed on the core and configured to provide a modified-release profile of the pharmaceutical agent when given orally.
  • a coating of hypromellose acetate succinate (HPMCAS) is disposed on the one or more functional coatings and configured to impart multiparticulate stability in aqueous acidic media. It also discloses the optional presence of a ‘’modified release layer” including a substance that gives the resulting multiparticulate a modified-release profile.
  • This functional coating may include enteric polymer (e.g., methacrylic acid copolymer, cellulose acetate phthalate), an enteric resin (e.g., shellac), an insoluble cellulose-based polymer (e.g., ethylcellulose), a combination insoluble cellulose-based polymer system with a water- soluble pore former (e.g., ethylcellulose in conjunction with a water soluble ingredient), a protein-based coating, a lipid coating, or wax coatings, such as hydrogenated cottonseed oil and beeswax.
  • enteric polymer e.g., methacrylic acid copolymer, cellulose acetate phthalate
  • an enteric resin e.g., shellac
  • an insoluble cellulose-based polymer e.g., ethylcellulose
  • a combination insoluble cellulose-based polymer system with a water- soluble pore former e.g., ethylcellulose in conjunction
  • EP3205216 relates to a microcapsule comprising: (i) a core comprising at least one probiotic, prebiotic or a mixture thereof embedded in a polymer selected from alginate and pectin, (ii) an inner layer surrounding the core comprising at least one probiotic, prebiotic or a mixture thereof embedded in alginate or pectin, and (iii) an outer layer surrounding the inner layer comprising hydrophobic material having a melting point comprised from 35 to 90 °C (e.g. bees wax).
  • the core of EP3205216 is dried to a water activity value lower than 0.4 before application of the hydrophobic outer layer.
  • EP3205216 fails to teach or suggest dosage forms comprising a fat-coated liquid core.
  • the hydrophobic outer layer does not allow for site-specific delivery.
  • US2013/0202667 Al relates to hydrogel particles coated with lipid, which are made from dispersing hydrogel particles in an organic solvent in which lipids are dissolved, and to a method for manufacturing same.
  • the lipid may be one or more selected from a group consisting of soybean lecithin, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, phosphatidylglycol and hydrogenated phosphatidylcholine.
  • the hydrogen particles particularly find their use in cosmetic compositions.
  • US2013/0202667 is silent about oral dosage forms wherein a lipid-coated core bead is surrounded with an exterior coating for site- specific delivery to the lower Gl-tract.
  • the present invention provides a dosage form wherein the liquid core bead comprises a matrix comprising a hydrogel-forming polymer, and contained in the matrix an aqueous composition of the at least one active ingredient.
  • the matrix comprises a hydrogel-forming polymer selected from alginate, gelatin, agar, agarose, and carrageenan, or a combination thereof.
  • alginate is used.
  • Alginates are large water-soluble molecules mainly derived from brown seaweed (Phaeophyceae). They are non-toxic, biodegradable and naturally occurring, which makes them an appealing component for gelation. Alginates are linear unbranched polymers consisting of B-(1 ⁇ 4) -linked D-mannuronic acid residues (M-blocks) and ct-(1 ⁇ 4) -linked L-guluronic acid residues (G-blocks) (2,3). The M- and G-blocks are sequentially assembled in either alternating blocks (MG) or repeating blocks (MM or GG) thereby forming different alginate molecules. It is known that the ratio of M- and G-blocks is of importance in gel formation.
  • a low M/G ratio causes gels to be dense but fragile, while a high M/G ratio causes gels to be more elastic.
  • Gel membranes made of alginate are formed by ionotropic gelation, where the negatively charged G-block of alginate and a positively charged divalent cation, in this case calcium, form physical cross-links (4).
  • Physical gels are defined by the fact that they do not contain covalent interactions, but keep the polymers together by ionic interactions, hydrogens bonds and/or Van der Waals forces (5).
  • Calcium is not the only divalent cation that shows affinity for alginates. Magnesium, strontium and barium also show affinity for alginates, in the order Mg 2+ Ca 2+ ⁇ Sr 2+ ⁇ Ba 2+ (2,3).
  • the protective fat/lipid-based coating serves to minimize or prevent exposure of the aqueous composition to the environment, in particular to an oxygen atmosphere, during manufacture, storage and delivery of the oral dosage form.
  • this inner coating layer (fat layer) is very important since it a) protects the aqueous solution from oxygen, b) allows for the coating of the water spheres with enteric (e.g. ColoPulse) coating and c) allows for the major advantage of having an aqueous solution in the core, whereas the system will still dissolve in the aqueous fluids of the GI tract.
  • a lipid-based coating comprising or consisting of a fat that melts at body temperature of a mammal, preferably a human.
  • the lipid-based coating comprises a hard fat having a melting point in the range of about 27-37 °C, such as a fat that melts at a temperature of 33-35°C as base material for the protective coating. This ensures that the fat is solid/hard at processing and storage temperatures e.g. up to room temperature or even up to 30°C.
  • the hard fat protects against oxygen entering the aqueous solution, and also allows for the coating with a second layer (e.g.
  • the fat/lipid-based coating serves to protect the environment, in particular the outer coating, from the effects of the liquid in the core, during storage.
  • the fat- based protective layer forms a unique shielding wall between, on the one hand, the aqueous liquid core and the oxygen-containing environment, and, on the other hand, the enteric coating and the aqueous core. Still further, at body temperature the fat will melt and the release of core content (e.g. bacteria, drug) is possible.
  • Preferred hard fats for use in a protective coating are those with hydroxyl values between 20—50.
  • the fat comprises a mixture of 65—80% of triglycerides, 10—35% of diglycerides and 1—5 % of monoglycerides.
  • Adeps solidus can be suitably used.
  • Adeps solidus is the collective name of semi-synthetic hard fats consisting of mono-, di- or triglycerides of C10- C18 fatty acids that are widely used in suppository bases. They have a melting range of 33-36°C, which makes them useful for suppository bases because they will melt when they are administered into the body.
  • Witepsol® W25 is a preferred adeps solidus since it does not contain any hygroscopic compounds which is very beneficial for coating the water spheres.
  • An oral dosage form as herein disclosed is further characterized by having an exterior coating that allows for site-specific delivery of the active ingredient(s) in the lower GI tract.
  • the exterior coating is readily applied directly onto the fat-coated liquid core bead.
  • the exterior coating allows for site-specific delivery in the terminal ileum and/or colon.
  • Time-response delivery systems are characterized by the fact that the drug is released after a certain period following the moment at which the system has got in contact with water (swallowing of the system).
  • the reliability of these systems is rather limited by the significant variations that occur in the orocaecal transit time (OCTT).
  • OCTT orocaecal transit time
  • the drug may be released at the wrong site or outside the absorption window of the drug.
  • a second strategy exploits the differences that occur in environmental conditions at different sites in the GI- tract, thereby circumventing problems that may arise from variations in the OCTT.
  • systems can be designed such that they respond to bacterial enzymes may be used to target the colon, or systems that respond to pH variations may be used to target different sites in the GI tract.
  • the bacterial-enzyme dependent systems suffer from two major limitations in their performance.
  • the bacterial flora may vary from individual to individual, if the required bacteria are not present in a patient the drug may not be released at all.
  • the release from these systems is in general very slow and pulsatile release is difficult to obtain.
  • a pH-controlled drug delivery system has the advantage that it is site- specific. It is largely independent of the OCTT, which may vary between individuals. Furthermore, it is independent of the presence of bacteria.
  • pH-sensitive polymers that allow for a site-specific release are readily commercially available.
  • Enteric coating materials exhibit resistance to acidic gastric fluids yet are readily soluble or permeable in intestinal fluid.
  • Enteric polymeric materials are primarily weak acids containing acidic functional groups, which are capable of ionization at elevated pH. In the low pH of the stomach, the enteric polymers are protonized, and therefore, insoluble. As the pH increases in the intestinal tract, these functional groups ionize, and the polymer becomes soluble in the intestinal fluids.
  • an enteric polymeric film coating allows the coated core to pass intact through the stomach to the small intestine, where the drug is then released in a pH-controlled fashion. The drug can become available for absorption to in the systemic circulation or locally in the Gl-tract (intracellular) where it can exert its pharmacologic effects.
  • Enteric polymers typically used to coat oral pharmaceutical dosage forms include cellulose, vinyl, and acrylic derivatives.
  • the most common enteric coatings are methacrylic acid copolymers (e.g. Eudragit®), cellulose acetate phthalate, cellulose acetate succinate, and styrol maleic acid co-polymers (Ritschel, W.A., Angewante Biopharmazie, Stuttgart (1973), pp. 396-402; Agyilirah, G.A., et al., "Polymers for Enteric Coating Applications” in Polymers for Controlled Drug Delivery, Tarcha, P.J. ed., CRC Press, (1991) Boca Raton, pp. 39-66).
  • methacrylic acid copolymers e.g. Eudragit®
  • cellulose acetate phthalate cellulose acetate succinate
  • styrol maleic acid co-polymers Rostyrol maleic acid co-polymers
  • enteric coating material refers to a pH-sensitive gastroresistant, coating material or mixtures thereof.
  • suitable coating materials include cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate and the Eudragit® acrylic polymers. The latter include anionic, cationic, and neutral copolymers based on copolymers derived from esters of acrylic and methacrylic acid.
  • Eudragit® S 100 is used for delivery to the lower ileum and ascending part of the colon (pH 6.0 to 7.5). Site specific drug delivery can also be achieved by combining Eudragit® S 100 with Eudragit® L types.
  • enteric coatings a possible limitation of enteric coatings is the fact that the dissolution of the pH sensitive coating materials at pH values that are only slightly above their setpoint pH is rather slow. Since intestinal pH variations may lead to a situation in which the that the environmental pH is hardly above the setpoint pH at the target site, the dissolution/disintegration of the coating is often slow. Therefore, it is preferred that swellable particles are embedded in a continuous matrix of the pH-sensitive polymer. An initial pH-dependent erosion of the composite coating layer due to dissolution of the pH-sensitive polymer, allows for the absorption of aqueous fluid by particles of swellable agent just beneath the surface of the coating layer.
  • the outer shelf of the coating layer will be disrupted by the swelling of the swellable agent and the fluid can reach the underlying particles of swellable agent, as well as the still unwetted coating polymer.
  • the coating layer will thus be progressively and irreversibly disrupted, resulting in complete and fast disintegration of the coating once the pH threshold has been reached.
  • the structure of the coating is such that the swellable agent is embedded in a non-percolating fashion, i.e. in a continuous matrix of the pH sensitive coating polymer in a concentration below the percolation threshold.
  • This technology also referred to in the art as ColoPulse (W02007/013794), has successfully been used on solid capsules and tablets for release in the ileocolonic region.
  • the exterior coating comprises a pH- sensitive enteric polymer wherein a super- disintegrant (swellable agent) is incorporated, preferably in a non-percolating manner, to achieve a reproducible delivery of the content of the liquid core beads (e.g. anaerobic bacteria) in the colon.
  • a super- disintegrant swellable agent
  • the super- disintegrant is capable of taking up at least 1.1 times, preferably at least 5 times, more preferably at least 10 times its weight in water.
  • Suitable swelling agents for use in the present invention include sodium starch glycolate (PrimojelTM, ExplotabTM) or cross-linked carboxymethyl cellulose (Ac-Di- SolTM).
  • Na starch glycolate PrimojelTM, ExplotabTM
  • Ac-Di- SolTM cross-linked carboxymethyl cellulose
  • swellable compounds whether known or yet to be discovered, are also encompassed.
  • a combination of two or more swellable agents may be used.
  • the exterior coating layer comprises the combination of Eudragit® S 100 and a swellable agent allows pulsatile drug release into the lower ileum and ascending part of the colon (pH 6.0 to 7.5).
  • the exterior coating may also comprise one or more additives, for example a plasticizer which enhances film formation of the polymer and allows for the formation of a continuous, well cured and flexible exterior coating layer.
  • Suitable coating additives include polyethylene glycol (PEG), triethyl citrate (TEC), and dibutyl sebacate (DBS), tributyl citrate, diethyl phthalate, and acetyl tributyl citrate.
  • the invention also provides a method for the manufacture of an oral dosage form as herein disclosed.
  • the method comprises comprising the steps of preparing an aqueous composition of an active ingredient, formulating the aqueous composition into a liquid core bead, providing the liquid core bead with a protective lipid-based coating; and surrounding the lipid-coated core bead with an exterior coating allowing for site- specific delivery to the lower gastro-intestinal tract.
  • Formulating the aqueous composition into a liquid core bead i.e. encapsulation of an aqueous bacterial suspension, optionally comprising a cryoprotectant such as glycerol, in liquid core beads, can be achieved using technology known per se in the art, for instance by spherification.
  • Spherification is a production process of making spherical beads by means of gelation.
  • Spheres consisting of a gel membrane surrounding a liquid (aqueous) core can be made by physical cross- linking of a suitable polymer, e.g. alginate, using calcium ions.
  • Spherification can be performed via direct spherification or via reverse spherification. Both spherification processes can be performed using the extrusion dripping method, where liquid droplets are extruded into a solution (7). The difference between the two spherification processes lies in the solutions that are used in the gelation bath and in the liquid core of the water spheres.
  • the liquid core solution either contains alginate or calcium ions and the gelation bath contains the other compound.
  • direct spherification the gelation bath is filled with calcium ions, wherein the liquid core solution with sodium alginate and the drug of interest is dripped to form water spheres.
  • the gelation occurs from the outside in, because the calcium ions from the gelation bath will migrate into the liquid core solution and start the gelation process.
  • the gelation bath is filled with sodium alginate and the liquid core solution is mixed with calcium and the drug of interest.
  • the calcium in the liquid core solution will form the gel membrane with alginate from the inside out when dripped into the gelation bath.
  • direct spherification the formed spheres are gelled in its entirety while in reverse spherification a gel membrane around a liquid core is developed.
  • a secondary gelation step can be added to the spherification process.
  • the formed water spheres are taken out of the first gelation bath, rinsed with demineralized water and added to a secondary gelation bath filled with calcium ions.
  • the calcium ions will diffuse into the weak gel membrane and enhance its properties by strengthening the membrane (8,14).
  • the calcium source for the spherification in this figure is calcium chloride.
  • the method comprises formulating an aqueous bacterial suspension into alginate water spheres using the reverse spherification under fully anaerobic conditions. For example, 1.5% w/v of calcium chloride and 1.5% w/v of CMC is added to the bacterial suspension.
  • the liquid core beads e.g. water spheres that are formed by reverse spherification, cannot target the colon on their own. They must be coated with a special coating to protect them from the environment of the upper gastrointestinal tract and prevent release before reaching the colon. To that end, at least two distinct coating layers are applied.
  • the first coating step comprises providing the liquid core bead with a protective lipid-based coating.
  • a protective lipid-based coating For example, Witepsol® W25 or similar a hard fat having a melting point in the range of about 27-37 °C, preferably about 33-36°C, is applied as the inner, protective coating by spray coating of the molten fat (e.g.
  • the lipid coating can be applied as a single application or in a multi-step process involving the application of several (e.g. 2-4) layers of the hard fat.
  • the coating layer can be applied using methods known in the art such as panning or spray coating with molten fat(s).
  • the liquid core beads are covered with a thin layer of talc and/or or magnesium stearate particles prior to applying the lipid coating with the lipid layer, in order to prevent sticking of the beads to each other during coating, and/or to improve the adhesion of the lipid layer to the core beads.
  • the lipid-coated core bead is provided with an exterior coating allowing for site- specific delivery to the lower gastro-intestinal tract.
  • This coating preferably has a delayed and pulsatile release profile to obtain the best colonic delivery. This can be achieved by taking advantage of the pH gradient in the gastro-intestinal tract.
  • the method comprises providing fat coated spheres, e.g. liquid core beads containing the bacteria, with an ColoPulse enteric coating using spray coating (about 10 mg/cm 2 ) as described herein above. These processes are carried out under anaerobic conditions.
  • the ColoPulse coating is suitable for colon targeting and is invented by Schellekens et al. (1, 9; W02007/013794).
  • the super disintegrant Ac-Di-Sol® croscarmellose sodium
  • the pH sensitive Eudragit S polymer a poly-acrylate
  • the ColoPulse coating has successfully been used on capsules and tablets for release in the ileocolonic region.
  • the coating has shown to withstand pH-values below 7 but the Eudragit S will dissolve at a pH of 7 and above, which is reached in the ileocolonic region.
  • Eudragit S in the ColoPulse coating is slowly dissolving at a pH-value of 7 or above, the coating will disintegrate due to liquid penetrating into the coating.
  • This liquid dissolves the Eudragit S and can then reach the disintegrant particles in the coating, which will swell and break the coating causing the deeper placed disintegrant particles to be wettened and swollen as well. Consequently, the coating will disintegrate and the surface underneath will be exposed to the environment.
  • an oral dosage form according to the invention is advantageously used to deliver any type of active ingredient(s), in particular oxygen sensitive and/or living microbial agents.
  • oxygen sensitive drugs include catecholamines (e.g. adrenalin, noradrenalin), levodopa, morphine and cholecalciferol, and salts thereof.
  • an oral dosage form of the invention comprises natural or engineered live microbial cells, preferably bacterial cells.
  • the liquid core may comprises an aqueous microbial cell culture. Combinations of two or more distinct micro-organisms are also envisaged.
  • the oral dosage form comprises anaerobic micro-organisms, more preferably a therapeutically effective or health promoting anaerobic bacterium such as bacterial strains known in the art as human commensal obligate anaerobic bacteria or "next-generation probiotics” (NGPs).
  • NGPs have been shown therapeutic promise in intra- and extra-intestinal, chronic inflammation- related diseases such as colitis, obesity/metabolic syndromes, diabetes mellitus, liver diseases, cardiovascular diseases, and also cancer and neurodegenerative diseases. They may function through enhancing the integrity of the intestinal epithelial layer, increasing in optimal IgA production, modulation of homeostatic bile acids production and secretion, and increasing in the production of antimicrobial peptides.
  • the bacterium produces short chain fatty acids (SCFAs), for example butyrate.
  • SCFAs short chain fatty acids
  • Butyrate is one of the most important metabolites of the gut microbiota for host health, as it provides the preferential energy source of intestinal epithelium, stimulates the production of regulatory T cells, inhibits inflammation and regulates gene expression as histone deacetylase inhibitor. All the butyrate we need is produced by Butyrate-producing bacteria (BPB) living in the gut, and BPB are generally considered to be beneficial members of the gut microbiota. Depletion of BPB has been associated with inflammatory bowel diseases (IBDs), irritable bowel syndrome (IBS), type 2 diabetes, colorectal cancer, and Parkinson’s disease.
  • IBDs inflammatory bowel diseases
  • IBS irritable bowel syndrome
  • type 2 diabetes colorectal cancer
  • Parkinson’s disease inflammatory bowel diseases
  • the oral dosage form comprises one or more butyrate-producing bacteria (BPB), such as butyrogenic anaerobic bacteria.
  • BPB butyrate-producing bacteria
  • Particularly interesting bacteria include Akkermansia muciniphila (phylum Verrucomicrobia ⁇ ), Faecalibacterium prausnitzii, Eubacterium hallii, Prevotella copri, Bacteroides spp., Chirstensenella minuta, Butyricicoccus pullicaecorum, Parabacteroides goldsteinii, and any combination thereof.
  • an oral dosage of the invention comprises Bacteroides fragilis, preferably strain BF839 collected in the China general microbiological culture Collection center (preservation number CGMCCNO.0157; see CN113908177A).
  • the invention provides an oral dosage form for the delivery of Bacteroides thetaiotaomicron to the lower gastro-intestinal tract.
  • the at least one active ingredient is a drug compound.
  • the liquid core comprises an oxygen-free aqueous composition.
  • it comprises an anaerobic aqueous culture of anaerobic microbial cells, preferably one or more strains of probiotic anaerobic bacteria.
  • a further aspect of the invention relates to a method for administering an active ingredient to the lower gastro-intestinal tract, preferably to the terminal ileum and/or colon, comprising the oral administration of a dosage form as herein disclosed to a subject in need thereof.
  • a dosage form as herein disclosed to a subject in need thereof.
  • Any type of active ingredient(s) is/are envisaged.
  • the method is particularly suitable for administering at least one therapeutically effective or prophylactically acting living (anaerobic) bacterium.
  • the unique double layer dosage form provides excellent protection of the anaerobic bacteria during processing and shelf life/storage and during passage through stomach and small intestine. Furthermore, the novel system ensures site-specific delivery in the colon.
  • a water-containing core that can also be oxygen free is suitable for anaerobic bacteria, whereas it in spite of the presence of an aqueous solution in the core, it will dissolve in the aqueous fluids of the gastro-intestinal tract.
  • the core preferably comprises spheres of (oxygen free) water or aqueous composition e.g. culture medium suitable for maintaining and supporting live cultures of anaerobic bacteria.
  • water spheres are suitably produced with the help of hydrogel forming polymers such as alginate, agar-agar or similar polysaccharides.
  • the water spheres are coated by two coating layers.
  • probiotics should preferably reach the ileo- colonic environment at a so-called “minimal therapeutic” level, which is generally considered in a range of about 10 6 -10 10 CFU, for instance 10 7 -10 9 CFU per product dose.
  • the method comprises the treatment or prevention of a disease that benefits from delivery of probiotics in the lower Gl-tract.
  • a method to change the microbial content of the colon of a host comprising administering an active ingredient to the lower gastro-intestinal tract by the administration of anaerobic bacteria by means of an oral dosage form of the present invention.
  • Changing the so-called microbiome can be of therapeutic benefit in the treatment of a wide variety of diseases.
  • the invention provides a method of treatment or prevention of a disease selected from the group of inflammatory bowel diseases, irritable bowel syndrome, colon cancer, diabetes, metabolic syndrome, coeliac disease, Alzheimer’s disease, Parkinson’s disease, rheumatic diseases, allergies (e.g. of the skin), or to ameliorate side effects of other therapies, like cytostatic therapy or radiotherapy in cancer treatment.
  • Figure 2 Set up for applying the protective/lipid-based coating: The coating pan in the pan holder/stirrer is wrapped in ice.
  • Figure 3 Set up for applying the exterior/enteric coating.
  • FIG. 1 Water spheres containing diluted methylene blue.
  • the size bar indicates a diameter of about 7 mm.
  • FIG. Scanning electron microscopy (SEM) images of the surface (Panel A) and cross-section (Panel B) of a representative double coated water sphere. In the cross-section image the exterior enteric coating is indicated by the orange arrow and the lipid-based protective coating by the blue arrow.
  • Figure 7. (A) Microscopic image of viable Bacteroides thetaiotaomicron released from the double coated water spheres in phase III and phase IV. (B) Microscopic image of viable Bacteroides thetaiotaomicron released from the double coated water spheres, followed by 6 days storage under aerobic conditions. Bacteria were cultured in YCFAG medium. See Example 2 for details.
  • EXAMPLE 1 Design and evaluation of novel multi-layer oral dosage form.
  • PEG 6000 was obtained from BUFA Spruyt Hillen (IJsselstein, The Netherlands). Eudragit® S100 was provided by Evonik Industries (Essen, Germany). Croscarmellose sodium Ac-Di-Sol® was obtained from FMC BioPolymer (Brussels, Belgium). Demineralized water was used in all cases.
  • the liquid core solution for reverse spherification was made by dissolving 1.5% w/v of calcium chloride and 1.5% w/v of CMC in water.
  • the CMC in the LCR solution is a viscosity enhancer to increase the density of the solution.
  • the first gelation bath for reverse spherification (GBR1) consisted of 0.5% w/v of sodium alginate in water.
  • the second gelation bath for reverse spherification (GBR2) contained 1.0% w/v calcium chloride in water. These concentrations were based on previous optimization, but other concentrations can also be used.
  • the prepared solutions were stirred overnight at a low speed to obtain a complete dissolution without entrapped air.
  • the ColoPulse coating suspension was prepared as described by Schellekens et al. (9).
  • the ratio of PEG 6000:Eudragit®S100:Ac-Di-Sol®:talc was 1:7:3:2 (w/w/w/w) and this mixture was dissolved in ethanol:water with a ratio of 145.5:4.5 (v/v).
  • Table 1 the exact quantities of the substances for the ColoPulse coating are given.
  • the Gastro-Intestinal Simulation System was used.
  • the GISS is a system that simulates the pH profile of the human gastrointestinal tract by use of dissolution vessels filled with GISS solutions to create the environments of the stomach, jejunum, terminal ileum and colon.
  • the GISS solutions were made according Schellekens et al. (13) and the compositions of the solutions are given in tables 2. Where necessary, pH adjustment of the solutions was performed with solutions of 2.0 M NaOH or 3.0 HCI. Table 2. Solutions of the Gastro-Intestinal Simulation System: phase 1 to 4 composed of switch A, B and C. Methods
  • the water spheres (liquid core beads) were formed by means of the extrusion dripping method.
  • the method of producing water spheres is described below, however other methods can be used as well. https://www.degruyter.com/document/doi/10.1515/polyeng-2014-0174/html
  • the LCR was extruded from a tube with an inner diameter of 6 mm with a syringe pump, set on 3 mL/min, (NE-300, ProSense B.V. Oosterhout, The Netherlands) into 225 mL of GBR1 which was stirred on a multiple stirring plate (MIX 8 XL, 2mag AG Munchen, Germany) with a magnetic stirrer bar (25 x 6 mm) at a speed of 400 rpm.
  • the GBR 1 solution had a liquid height of approximately 5 cm in a 400 mL beaker glass (SCHOTT DURAN® Mainz, Germany) and the dripping height, distance between the liquid surface and the dripping tip, was set at approximately 9 cm.
  • the spheres were removed and rinsed under continues stirring at 400 rpm in 500 mL of demi water in a 800 mL beaker glass (SIMAX Kavalierglass Praha, Czech Republic) for at least 10 minutes.
  • the spheres were then transferred to 225 mL of GBR2 in a 400 mL beaker glass (SCHOTT DURAN® Mainz, Germany) for the second gelation step, in which the spheres were stirred at 400 rpm for 30 minutes.
  • the spheres were rinsed again in 500 mL demi water for at least 10 minutes.
  • the uncoated water spheres were stored in their LCR at 4-8°C. When the water spheres were stored in their own LCR, the liquid core contents was preserved because no diffusion/evaporation occurred.
  • Water spheres were pre-coated with a protective coating of Witepsol® W25.
  • the Witepsol® was applied onto the water spheres with panning.
  • the water spheres were added to a 250 mL glass coating pan (in house made) clamped in a pan holder/stirrer driven by a motor (type RW 18 from IKA-Werke Staufen im Breisgau, Germany).
  • the coating pan rotated with a constant speed of 27 rpm while a molten amount of Witepsol® was added.
  • This Witepsol® was melted on a stirring/heating plate (type MR 3001 K from Heidolph Instruments GmbH & CO Schwabach, Germany) at different temperatures above the melting range, between 33.5 and 35.5 °C.
  • the angle that the pan makes relative to the horizon is of importance. Just like the site of introduction of the Witepsol® into the pan, where the 2 /3- 2 /3 rule was used (14).
  • Witepsol® W25 was also applied by spray coating.
  • Spray coating has a similar set up as panning. The difference is that the coating is not added to the coating pan manually, but with a spray nozzle with the aid of atomizing air.
  • the following utensils were used: a 250 mL glass coating pan, a pan holder/stirrer driven by a motor (Heidolph Instruments GmbH & CO Schwabach, Germany), two heat guns, ice packs, an air atomizing nozzle (Mod.
  • the coating pan wrapped in ice packs was rotating at 32 rpm while the nozzle sprayed the coating onto the water spheres.
  • the two heat guns were pointed at the tube/nozzle and at the tube/peristaltic pump to ensure that the Witepsol® W25 did not solidify. A visualisation of this set up can be seen in figure 2.
  • the fat-coated water spheres were coated with the ColoPulse suspension using essentially the same set up as used in the spray coating process with Witepsol® W25.
  • the same utensils as with the previous spray coating process were used, excluding one heat gun and the ice packs.
  • the ColoPulse suspension was kept stirring in a beaker glass on a stirring plate, while a peristaltic pump and 2.54 mm tube (Watson- Marlow Limited, marprene manifold tube purple/orange, Falmouth, Cornwall, UK) transported the suspension with a speed of approximately 4.00 to the nozzle.
  • the coating pan was rotating at 32 rpm while the nozzle sprayed the suspension onto the water spheres inside the pan.
  • a heat gun was pointed at the coating pan. This set up can be seen in figure 3.
  • the settings of this spray coating process were varied during this research to optimize the spray coating with the enteric coating suspension.
  • the water spheres were weighed before and after coating. The mass difference divided by the surface of the sphere determines the amount of coating per cm 2 :
  • a dissolution test was performed with the GISS to simulate the release of drug in the gastro-intestinal tract.
  • the protocol by Schellekens et al. was followed (13).
  • a paddle apparatus SOTAX AT 7 Sotax, Allschwil, Switzerland
  • WinSotax software was installed to an in-line UV-VIS spectrophotometer (EvolutionTM 300, Thermo Fisher Scientific, Madison, USA).
  • the release of drug from the water spheres was measured under sink conditions at a temperature of 37°C with a paddle speed of 50 rpm.
  • the absorbance was measured every three minutes at 664 nm in a cuvette with a pathlength of 1 cm.
  • the water spheres were also visually analysed with a light microscope (Olympus SZX16 Stereo Microscope, Tokio, Japan) to look at the diameter and sphericity of the spheres.
  • a light microscope Olympus SZX16 Stereo Microscope, Tokio, Japan
  • OLYMPUS cellSens Standard 2.2 A 0.7x lens was used and the light source was adjusted until the water spheres were in focus.
  • the diameter of the water spheres can be used to determine whether the water spheres are spherical or not.
  • the sphericity factor (SF) derived from B. Lee et al. (7) and F. Tsai et al. (4) can be calculated, which reads as follows: where d m ax and d m in are the biggest and smallest diameters measured, respectively. These two values are perpendicular to each other.
  • SF 0
  • a perfect sphere has been formed and a line is indicated by a SF of 1.
  • Figure 4 shows a representative image of uncoated water spheres, containing a diluted methylene blue solution.
  • the gelation bath solutions were used up to three times before they were renewed with fresh solutions.
  • the dye methylene blue was chosen as a marker to be encapsulated in the water spheres.
  • Methylene blue has a high water solubility and a high molar extinction coefficient, making it a suitable marker.
  • the panning method was used.
  • the ColoPulse suspension was applied directly onto the Witepsol® coating by means of spray coating.
  • the Witepsol® coating was as smooth as possible so the ColoPulse coating could be applied equally over the surface of this coating, resulting in an even thickness of the coating.
  • the coating speed and the temperature of the coating pan were varied to determine the optimal settings. It became clear that it was of importance to keep the distance between the nozzle and the water spheres in the pan coater and the angle of the nozzle the same in every coating session.
  • the GISS was used to determine the amount of marker that is released from the water spheres in the ileum and the colon.
  • the release of the marker should start after 240 minutes (phase III), when the simulated “stomach” and “jejunum” phase have passed and the “terminal ileum” phase has been reached.
  • phase III the simulated “stomach” and “jejunum” phase have passed and the “terminal ileum” phase has been reached.
  • the marker methylene blue was used because of its high water solubility and high molar extinction coefficient.
  • Figure 5 shows that the three water spheres coated with the lipid pre-coating and ColoPulse coating (9.86 mg/cm 2 ) started to show release at 252 minutes, during phase III. These spheres released approximately 100% methylene blue in 8 hours. GISS phase III simulates the terminal ileum of the gastro intestinal tract, indicating that the coated water spheres are able to target the ileo-colonic region.
  • FIG. 6 shows a SEM picture of (panel A) the surface and (panel B) a cross section of the two coating layers of a representative double coated water sphere.
  • EXAMPLE 2 Production and testing of oral dosage forms comprising anaerobic bacteria.
  • This example describes the production and evaluation of an oral dosage form for the delivery of living anaerobic bacteria to the lower gastro-intestinal tract.
  • Dulbecco's Phosphate Buffered Saline (DPBS) was obtained from ThermoFisher (Waltham, Massachusetts).
  • Yeast Casitone Fatty Acid Glucose (YCFAG) medium was prepared according to the composition and procedure described by Lopez- Siles et al. (Applied and Environmental Microbiology, 2012; 78(2): 420—428).
  • a culture of anaerobic Bacteroides thetaiotaomicron isolated from a healthy individual, was obtained through the Department of Medical Microbiology, UMCG, Groningen, Netherlands. MilliQ water was used in all cases.
  • the liquid core solution for reverse spherification was made by dissolving 1.35% w/v of calcium chloride and 1.5% w/v of CMC in water.
  • the CMC in the LCR solution is a viscosity enhancer to increase the density of the solution.
  • the gelation bath for reverse spherification consisted of 1 % w/v of sodium alginate in water.
  • the prepared solutions were stirred overnight at a low speed to obtain a complete dissolution without entrapped air.
  • the solutions were autoclaved at 121°C for 15 minutes and subsequently placed in a chamber which was flushed with dry N 2 gas.
  • the coating suspension was prepared as described in Example 1, with the difference that acetone was used instead of ethanol. In table 3 the exact quantities of the substances for the coating are given. Table 3. Enteric coating suspension and its substances.
  • mGISS Gastro-Intestinal Simulation System
  • the mGISS is a dissolution system that simulates the pH profile of the human gastrointestinal tract by use of vials filled with buffer solutions that simulate the pH of the content of the stomach, jejunum, terminal ileum and colon, respectively.
  • the vials containing 20 ml dissolution medium and the test formulation are kept in a shaking water bath at 37°C.
  • the mGISS I and II solutions were made according to Schellekens et al. [3](table 3).
  • phase HI DPBS was used with a pH which was set at 7.5 and for phase IV the YCFAG medium (pH 6.8) was used.
  • the pH of the dissolution media I and II was adjusted to the desired values with solutions of 2.0 M NaOH or 3.0 M HC1.
  • the water spheres (liquid core beads) were formed by means of the extrusion dripping method in a chamber flushed with dry N 2 gas.
  • the method of producing water spheres is described by Lee et al.
  • Bacteroides thetaiotaomicron cells were cultured in YCFAG medium under fully anaerobic conditions (90% N 2 , 5% CO2, 5% H2).
  • the resulting aqueous bacterial suspension was subsequently formulated into alginate water spheres using the reverse spherification under fully anaerobic conditions (100% N 2 ).
  • the aqueous bacterial suspension was mixed with the LCR in a volume ratio of 1:2 and added to a 50 mL syringe.
  • the bacterial suspension was subsequently extruded from the syringe using a tube with an inner diameter of 6 mm with a syringe pump, set on 3 mL/min, (NE- 300, ProSense B.V. Oosterhout, The Netherlands) into 225 mL of GBR which was stirred on a multiple stirring plate (MIX 8 XL, 2mag AG Mimchen, Germany) with a magnetic stirrer bar (25 x 6 mm) at a speed of 400 rpm.
  • MIX 8 XL 2mag AG Mimchen, Germany
  • the GBR 1 solution had a liquid height of approximately 5 cm in a 400 mL beaker glass (SCHOTT DURAN® Mainz, Germany) and the dripping height, distance between the liquid surface and the dripping tip, was set at approximately 9 cm. After 5 minutes of gelation, the spheres were removed and rinsed with 0.9% NaCl in water. Secondary gelation was not necessary since the spheres were sufficiently strong to allow for coating.
  • Bacteria-containing water spheres were coated manually with a protective coating of Witepsol® W25 in a chamber flushed with dry N 2 gas.
  • the Witepsol® was heated to a temperature above the melting range (between 33.5 and 35.5 °C) in a tray above hot water.
  • the spheres were covered with magnesium stearate powder and subsequently coated with the molten Witepsol®. This step was repeated two more times, to obtain a coherent coating layer with the Witepsol®.
  • the mGISS dissolution test of the double coated water spheres was performed with GISS phase I and II buffers [3], DPBS pH 7.5 as phase III and YCFAG medium as phase IV to simulate the release of drug in the gastro-intestinal tract.
  • a shaking water bath was used to maintain the temperature of the solutions at 37°C.
  • the bacteria-containing oral dosage form was incubated in 20 mL GISS phase I for 2 hours under aerobic conditions. Subsequently, GISS phase I medium was removed and 20 mL GISS phase II medium was added, in which the spheres were incubated under aerobic conditions. After 2 hours, the tubes were transferred to an anaerobic chamber which was flushed with dry N 2 gas. GISS phase II medium was removed and 20 mL oxygen free DPBS at pH 7.5 was added in which the spheres were incubated for 30 minutes.
  • the medium with the residue of the water spheres was filtered over an 0.2 pm membrane filter (Supor® 200 47 mm 0.2 pm sterile, PALL Corporation).
  • the filter with its contents was transferred to a tube with YCFAG medium and incubated at 37°C under anaerobic conditions for 72 hours.
  • the cultured bacteria were then stained using Gram staining and analysed with light microscopy.
  • the bacteria were subjected to MALDLTOF MS (Matrix-Assisted Laser Desorption lonization-Time-of- Flight Mass Spectrometry) analysis for identification.
  • MALDLTOF MS Matrix-Assisted Laser Desorption lonization-Time-of- Flight Mass Spectrometry
  • the mGISS was used. In order to reach the simulated lower intestinal tract (terminal ileum and colon), the release of the bacteria should start after 240 minutes (phase III; DPBS pH 7.5), when the simulated “stomach” and “jejunum” phase have passed and the “terminal ileum” phase has been reached. In the first two phases of the mGISS no release from the water spheres was observed. The Gram staining and MALDI-TOF analysis of the YCFAG medium (of phase III and phase IV) confirmed the presence of viable Bacteroides thetaiotaomicron released from the double coated water spheres in the medium.
  • Figure 7 A show a microscopic image of the bacteria found in the YCFAG medium.
  • the image shows Gram negative rod shaped bacteria which indicate that the Bacteroides thetaiotaomicron was present. It was confirmed by MALDI- TOF MS that the bacteria in phase III and IV of the mGISS were indeed the Bacteroides thetaiotaomicron.
  • Figure 7B show a microscopic image of the bacteria found in the YCFAG medium which was inoculated with the content of the water sphere.
  • the image shows Gram negative rod shaped bacteria which indicate that the Bacteroides thetaiotaomicron was present. It was confirmed by MALDI-TOF MS that the bacteria in the water spheres were indeed the Bacteroides thetaiotaomicron.
  • Beckett ST Fowler MS, Ziegler GR. Beckett’s industrial chocolate manufacture and use / edited by Stephen T Beckett, Mark Fowler, Prof Gregory Ziegler. 5th ed. Chichester, West Wales, UK; 2017. 760 p.

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Abstract

L'invention concerne des systèmes de pharmacologie et d'administration, plus spécifiquement des moyens et des procédés pour l'administration spécifique à un site dans l'intestin d'une composition aqueuse d'ingrédients actifs, par exemple des bactéries anaérobies vivantes. L'invention concerne une forme posologique orale pour l'administration spécifique à un site d'une composition aqueuse d'un principe actif, de préférence un principe actif sensible à l'oxygène, au tractus gastro-intestinal inférieur, ladite forme posologique orale comprenant les éléments suivants : (i) une bille de noyau liquide comprenant une composition aqueuse d'au moins un ingrédient actif ; (ii) la bille de noyau liquide étant entourée d'un revêtement à base de lipide protecteur ; (iii) la bille de noyau revêtue de lipide étant entourée d'un revêtement extérieur permettant une administration spécifique à un site au tractus gastro-intestinal inférieur.
PCT/NL2023/050227 2022-04-29 2023-04-28 Système de dosage oral et procédés d'administration d'un ou de plusieurs agents thérapeutiques sensibles à l'oxygène au tractus gastro-intestinal inférieur WO2023211276A1 (fr)

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Publication number Priority date Publication date Assignee Title
GB2388581A (en) * 2003-08-22 2003-11-19 Danisco Coated aqueous beads
WO2007013794A1 (fr) 2005-07-29 2007-02-01 Stichting Groningen Centre For Drug Research Système de distribution pulsatile commandé par le ph, procédés de préparation et utilisation
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GB2388581A (en) * 2003-08-22 2003-11-19 Danisco Coated aqueous beads
WO2007013794A1 (fr) 2005-07-29 2007-02-01 Stichting Groningen Centre For Drug Research Système de distribution pulsatile commandé par le ph, procédés de préparation et utilisation
US20130202667A1 (en) 2010-10-14 2013-08-08 Amorepacific Corporation Hydrogel particle coated with lipid and method for manufacturing same
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WO2019157066A1 (fr) 2018-02-06 2019-08-15 Robert Niichel Produit multiparticulaire comprenant des substances actives pharmaceutiques ou probiotiques
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