Method for producing a multilayer continuous cylindrical sheath of a polyanionic compound

Abstract

The invention relates to a multilayer continuous cylindrical sheath of a polyanionic compound comprising at least two co-axial layers, each being based on a polyanionic compound chelated by an at least divalent cation, each layer being able to slide freely relative to the adjacent layer, the continuous central space of the sheath extending around the axis being free of polyanionic compound, and to a method for manufacturing such a sheath.

Description

[0001] I

[0002] METHOD FOR PRODUCING A CONTINUOUS MULTILAYER CYLINDRICAL SHEET OF A POLYANIONIC COMPOUND

[0003] Technical field of the invention

[0004] The present invention relates to the field of polymers based on polyanionic compounds and processes for manufacturing such polymers.

[0005] Previous art

[0006] Alginate-based containers, whether these containers are spherical or cylindrical in shape, for example, have been known for a long time and used in particular for the gradual diffusion of compounds encapsulated within these containers.

[0007] Numerous methods have been described in the literature. US patent 4,614,794 describes the preparation of a collagen / alginate solution that is precipitated in a solution containing a calcium ion, or in a collagen solution containing calcium to which alginate is added. The resulting alginate compound is obtained in the form of spherical beads, or possibly as short, dispersed fibers.

[0008] Document WO 94 / 00164 describes the preparation of a solution comprising an alginate and the active ingredient, this solution being extruded into a calcium chloride bath to obtain a fiber consisting of alginate and the active ingredient. The alginate and the active ingredient are intimately mixed.

[0009] US document 2006 / 0093652 describes a process for forming an alginate-sheathed collagen fiber in which a collagen solution comprising a salt of an alkaline earth metal is injected into an alginate bath so as to form a fiber having a collagen core / alginate sheath structure.

[0010] The alginate sheaths formed may prove to be fragile or have defects that simply increasing the sheath thickness, for example by varying the residence time in the bath, does not resolve.

[0011] Continuing her research, the applicant discovered a process for producing a continuous cylindrical sheath of a multilayer polyanionic compound. Detailed description of the invention

[0012] The invention relates to a continuous multilayer cylindrical sheath of a polyanionic compound comprising at least two coaxial layers, each based on a polyanionic compound chelated by at least one divalent cation, each layer being able to slide freely relative to the adjacent layer, the continuous central space of the sheath extending around the axis being free of polyanionic compound.

[0013] The invention also relates to a cylindrical sheath in which the polyanionic compound is chosen from poly(acrylic acid) and polysaccharides, preferably is chosen from polysaccharides, preferably is chosen from pectins and alginates, and most preferably is an alginate.

[0014] The invention also relates to a cylindrical sheath in which the polyanionic compound at the base of each layer has a number molar mass of at least 100,000 g / mol and a weight molar mass of at least 300,000 g / mol, the molar masses being determined by size exclusion chromatography in the manner described in the Measurement Methods section of the description.

[0015] The invention also relates to a cylindrical sheath in which the at least divalent cation is chosen from the cations of calcium, copper, magnesium, iron, zinc, lead, cobalt, nickel, barium, strontium, aluminum and manganese, preferably chosen from the cations of calcium, copper, magnesium, iron, zinc, and aluminum, preferably chosen from the cations of calcium, copper and aluminum and most preferably is a calcium cation.

[0016] The invention also relates to a cylindrical sheath in which the continuous central space of the multilayer sheath also comprises a compound selected from a dye, a biologically active compound such as a drug or any biologically active compound whose controlled diffusion is desired, a polymer, a biopolymer, proteins or nutrients.

[0017] The invention also relates to a cylindrical sheath in which at least one layer of the multilayer sheath also comprises a compound selected from a dye, a biologically active compound such as a drug or any biologically active compound whose controlled diffusion is desired, a polymer, a biopolymer, proteins or nutrients.

[0018] The invention also relates to a method for manufacturing a continuous multilayer cylindrical sheath in which: a. A matrix is ​​continuously injected, by means of a die, into a chelation bath comprising a polyanionic compound in solution, the matrix comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound, so as to form a wire element; b. The following sequence of steps is carried out at least once: i. The wire element is passed through a bath comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound; ii. The wire element from step i) is passed through a chelation bath comprising a polyanionic compound in solution, identical or different from the polyanionic compound of the chelation bath of step a), so as to form an additional layer around the wire element; c.At the end of step b) we recover the continuous multilayer cylindrical sheath.

[0019] The invention also relates to a process in which the matrix comprises a solution including a biocompatible solvent, preferably chosen from water, ethanol, isopropanol, dimethyl sulfoxide and mixtures thereof.

[0020] The invention also relates to a method in which the matrix also comprises a compound selected from a dye, a biologically active compound, a polymer, a biopolymer, proteins or nutrients.

[0021] The invention also relates to a process in which the matrix is ​​a solution consisting of a biocompatible solvent, preferably chosen from water, ethanol, isopropanol, dimethyl sulfoxide and mixtures thereof, and a salt of at least one divalent cation.

[0022] The invention also relates to a process in which the mass content of salt of at least one divalent cation in the matrix ranges from 2% to 80% relative to the mass of the matrix, preferably from 5% to 40%, and preferably from 5% to 30%.

[0023] The invention also relates to a process in which the salt of at least one divalent cation is selected from salts of calcium, copper, magnesium, iron, zinc, lead, cobalt, nickel, barium, strontium, aluminum, manganese, preferably selected from salts of calcium, copper, magnesium, iron, zinc, and aluminum, most preferably selected from salts of calcium, copper, and aluminum, and most preferably is a calcium salt.

[0024] The invention also relates to a process in which the die comprises one or more injection devices, the injection device or each injection device being a co-injection device allowing simultaneous injection at the periphery of the matrix and at the center of a fluid, said fluid being free of salt of at least one divalent cation.

[0025] The invention also relates to a process in which the polyanionic compound is chosen from poly(acrylic acid) and polysaccharides, preferably is chosen from polysaccharides, preferably is chosen from pectins and alginates, and most preferably is an alginate.

[0026] The invention also relates to a method in which the chelation bath of step a) also comprises a compound selected from a dye, a biologically active compound, a polymer, a biopolymer, proteins or nutrients.

[0027] The invention also relates to a method in which the, or at least one chelation bath of step ii) also comprises a compound selected from a dye, a biologically active compound, a polymer, a biopolymer, proteins or nutrients.

[0028] The invention also relates to a process in which the mass content of polyanionic compound in the chelation bath ranges from 0.5% to 8% relative to the mass of the chelation bath, preferably from 1% to 6% by weight and preferably from 1.1% to 3% by weight.

[0029] The invention also relates to a process in which the mass content of salt of at least one divalent cation in the bath of the at least one step i) goes from 2% to 80% relative to the mass of the bath, preferably goes from 5% to 40%, and preferably goes from 5% to 30% and the mass content of polyanionic compound in the chelation bath of the at least one step ii) goes from 0.5 to 8% relative to the mass of the chelation bath, preferably from 1% to 6% by weight and preferably from 1.1% to 3% by weight.

[0030] The invention also relates to a process in which, at the end of step c), a stabilization step is carried out by passing the continuous multilayer cylindrical sheath through a stabilization bath comprising an aqueous solution of a salt of at least one divalent cation, the mass content of which is at least one divalent cation, from 2% to 80% relative to the mass of aqueous solution, preferably from 5% to 40%, and preferably from 5% to 30%.

[0031] The invention also relates to a method in which the continuous multilayer cylindrical sheath undergoes a heat treatment step. The invention further relates to a method in which each chelation bath is, independently of the others, at a temperature ranging from 10°C to 40°C, preferably ranging from 15°C to 30°C.

[0032] The invention also relates to a process in which each bath of at least one step i) is at a temperature ranging from 10°C to 40°C, preferably ranging from 15°C to 30°C.

[0033] The invention also relates to a continuous single-layer cylindrical sheath based on a polyanionic compound chelated by at least one divalent cation, obtained by a process comprising at least the following steps: ■ a. A matrix is ​​continuously injected, by means of a die, into a chelation bath comprising a polyanionic compound in solution, the matrix comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound, so as to form a wire element. b. The following sequence of steps is carried out at least once: ■ i. The wire element is passed through a bath comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound. ii.The wire element from step i) is passed through a chelation bath comprising a polyanionic compound in solution, identical or different from the polyanionic compound of the chelation bath of step a), so as to form an additional layer around the wire element c. A continuous multilayer cylindrical sheath d is recovered at the end of step b). All the radially innermost layers of the multilayer cylindrical sheath are removed to retain only the radially outermost layer.

[0034] Definitions

[0035] By continuous cylindrical sheath, we mean a wire element of overall cylindrical shape, extending along a main direction coinciding with the axis of the cylinder, whose central space is free, that is to say, able to contain a material different from the material of the sheath such as a gas or a liquid.

[0036] Multilayer is defined as a sheath according to the invention consisting of at least two superimposed coaxial layers, each made of the same or a different material as the adjacent layer and independent of the adjacent layer, i.e., not bonded to the adjacent layer. The adjacent layers of the sheath according to the invention can therefore slide freely relative to one another. Each layer is cylindrical and extends along the principal direction of the sheath, the continuous central space of said layer being free so as to accommodate either an adjacent inner layer or the continuous central space of the multilayer cylindrical sheath.

[0037] The continuous multilayer cylindrical sheath according to the invention is continuous, that is to say, it extends along its main dimension as much as desired, until an external intervention interrupts it, for example by cutting.

[0038] Layers of the sheath according to the invention

[0039] The continuous multilayer cylindrical sheath according to the invention comprises at least two coaxial layers, each based on a polyanionic compound chelated by at least one divalent cation, each layer being able to slide freely relative to the adjacent layer.

[0040] The term "polyanionic compound-based layer" refers to a layer containing the polyanionic compound and / or the product of the reaction between the polyanionic compound and at least one divalent cation via ionotropic gelation. Thus, the basic constituents are the reactants intended to react together during the formation of the layer by gelation.

[0041] The polyanionic compound at the base of each layer of the continuous multilayer cylindrical sheath according to the invention is capable of forming a chelate with at least one divalent cation by ionotropic gelation. Ionotropic gelation is a phenomenon well known to those skilled in the art. This polyanionic compound is an anionic polymer, that is, a polyelectrolyte bearing negative charges. The polyanionic compound is selected from poly(acrylic acid) and polysaccharides, preferably from polysaccharides, preferably from pectins and alginates, and most preferably from alginate. Preferably, the polyanionic compound at the base of each layer has a number molar mass of at least 100,000 g / mol and a weight molar mass of at least 300,000 g / mol. Such compounds exhibit very good chelation kinetics and allow for the production of layers with good mechanical properties.

[0042] The at least divalent cation enabling ionotropic gelation of the polyanionic compound is chosen from the cations of calcium, copper, magnesium, iron, zinc, lead, cobalt, nickel, barium, strontium, aluminum, and manganese, preferably chosen from the cations of calcium, copper, magnesium, iron, zinc, and aluminum, most preferably chosen from the cations of calcium, copper, and aluminum, and most preferably is a calcium cation.

[0043] Each layer can be based on a polyanionic compound chelated by at least one divalent cation, either identical or different from those of the adjacent layer. By choosing the polyanionic compound and / or the cation, it is thus possible to adjust the properties of the continuous multilayer cylindrical sheath according to the invention, such as its degradation rate, permeability, or rigidity.

[0044] Each layer may also include, independently of each layer, a compound selected from among a dye, a biologically active compound such as a drug or any biologically active compound whose controlled release is desired, a polymer such as polyethylene glycol, poly(glycerol sebacate), cyclodextrin, a biopolymer such as lignin, collagen, a polysaccharide such as cellulose or starch, proteins, or nutrients. Thus, in a preferred arrangement, at least one layer of the continuous cylindrical sheath comprises such a compound.

[0045] Each layer of the continuous multilayer cylindrical duct can slide freely relative to the adjacent layer. A defect in an inner layer, such as a hole, therefore does not affect the next layer, which can thus ensure the overall sealing of the duct when its central space is filled with a product, while still allowing the product to permeate through the duct if such a phenomenon is desired.

[0046] Since each layer can slide freely relative to the adjacent layer, the interlayer area can be filled with a solution containing an active ingredient intended to diffuse through the outermost layer(s) or to be released once the outermost layer(s) have been degraded. This allows for the implementation of several active ingredients within a single sheath, each with different diffusion kinetics controlled by their position within the sheath—central or between two layers—and by the nature of the polyanionic compound and / or the cation at the base of each layer.

[0047] Continuous central space of the multilayer sheath

[0048] The continuous central space of the multilayer cylindrical sheath is free of polyanionic compounds. The sheath according to the invention thus has a continuous central space, extending along the main direction of the sheath, and of an overall cylindrical shape.

[0049] This continuous central space offers the advantage of not having "pockets", i.e. closed spaces, which could be generated by the presence of polyanionic compound in this space, this or these compounds being able to chelate and form a wall with the innermost sheath of the multilayer sheath.

[0050] The continuous central space of the multilayer sheath according to the invention can therefore be filled either during the manufacture of the sheath by acting on the composition of the matrix injected into the chelation bath, or subsequently, by any product sufficiently fluid to flow into the central space, for example by a gas or a liquid, possibly including an active ingredient such as a drug, a dye, or any other product for which controlled diffusion is desired.

[0051] The continuous central space of the multilayer sheath can therefore also include a compound chosen from a dye, a biologically active compound such as a drug or any biologically active compound whose controlled diffusion is desired, a polymer such as polyethylene glycol, poly(glycerol sebacate), cyclodextrin, a biopolymer such as lignin, collagen, a polysaccharide such as cellulose or starch, proteins or nutrients.

[0052] The continuous cylindrical sheath according to the invention can be cut leaving the central space accessible, for example by means of a blade, or can be cut by sealing the cut end, for example by pinching the sheath, the central space closing at the pinched part by self-sealing via the ionotropic gelation of the polyanionic compounds.

[0053] Manufacturing process

[0054] The invention also relates to a method for manufacturing a continuous multilayer cylindrical sheath as described above, wherein: a. A matrix is ​​continuously injected, by means of a die, into a chelation bath comprising a polyanionic compound in solution, the matrix comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound, so as to form a wire element; b. The following sequence of steps is carried out at least once: i. The wire element is passed through a bath comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound; ii. The wire element from step i) is passed through a chelation bath comprising a polyanionic compound in solution, identical or different from the polyanionic compound of the chelation bath of step a), so as to form an additional layer around the wire element; c.At the end of step b) the continuous multilayer cylindrical sheath is recovered. Step a) of injection.

[0055] The process according to the invention includes a step a) in which a matrix is ​​continuously injected, by means of a die, into a chelation bath comprising a polyanionic compound in solution, the matrix comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound, so as to form a wire element.

[0056] Matrix

[0057] The matrix injected into a chelation bath is a fluid medium whose characteristics, in particular the viscosity and the size of the particles possibly present in said matrix, allow its injection into the bath by means of a die.

[0058] The matrix comprises a solution of a salt containing at least one divalent cation and is free of polyanionic compounds. The absence of polyanionic compounds within the matrix ensures that no ionotropic gelation occurs prior to the matrix being injected into the chelation bath.

[0059] The salt of at least one divalent cation is preferentially chosen from the salts of calcium, copper, magnesium, iron, zinc, lead, cobalt, nickel, barium, strontium, aluminum, manganese, preferably chosen from the salts of calcium, copper, magnesium, iron, zinc, and aluminum, preferably chosen from the salts of calcium, copper and aluminum, and most preferably is a calcium salt.

[0060] The salt of at least one divalent cation will be selected according to the intended application, with regard in particular to its bio-activity or its impact on the properties of the sheath formed by chelation.

[0061] The mass content of at least one divalent cation in the matrix is ​​preferably from 2% to 80% relative to the mass of the matrix, preferably from 5% to 40%, and preferably from 5% to 30%. These contents, and in particular when the preferred contents are used, allow for the rapid formation of a homogeneous sheath within the chelation bath at the point of matrix injection and around the matrix when it is injected into the chelation bath.

[0062] The salt of at least one divalent cation is in solution in a solvent, preferably biocompatible, and preferably chosen from water, ethanol, isopropanol, dimethyl sulfoxide, and mixtures thereof. JO

[0063] In a preferred arrangement, the matrix is ​​a solution consisting of a solvent, preferably biocompatible, and preferably chosen from water, ethanol, isopropanol, dimethyl sulfoxide, and mixtures thereof, and a salt of at least one divalent cation.

[0064] In another preferred arrangement, the matrix also includes a compound other than a solution of a salt of at least one divalent cation. This compound can be any compound that can pass through the die without clogging it and allows diffusion of the at least divalent cation sufficiently rapid for the chelation reaction to occur. Preferably, this compound is selected from a dye, a biologically active compound such as a drug or any biologically active compound for which controlled diffusion is desired, a polymer such as polyethylene glycol, poly(glycerol sebacate), cyclodextrin, a biopolymer such as lignin, collagen, a polysaccharide such as cellulose or starch, proteins, or nutrients.

[0065] The die may include one or more injection devices, the individual diameter of which determines the internal diameter of the resulting sheath. Preferably, the diameter of the injection device ranges from 50 µm to 5000 µm, and more preferably from 100 µm to 1100 µm.

[0066] The injection device can be any device known to a person skilled in the art used for wet spinning, for example a hole or a needle.

[0067] The matrix is ​​injected into a chelation bath. "Into the bath" means that the injection point is completely immersed in the chelation bath, at a distance from any free surface greater than the thickness of the formed sheath. This injection point position allows for the formation of a uniform sheath with a circular cross-section.

[0068] In a preferred arrangement, the injection device, or each injection device, is a co-injection device allowing the simultaneous injection of a salt-free fluid of at least one divalent cation at the periphery of the matrix and at its center. Such a co-injection device is known to those skilled in the art and can, for example, be a coaxial needle. Under the conditions of the process according to the invention, the sheath forms very rapidly around the matrix, and the matrix and the co-injected fluid do not mix. Thus, the continuous central space of the wire element formed by the co-injected fluid is completely free of salt of at least one divalent cation. This arrangement therefore minimizes the amount of salt of at least one divalent cation used and accelerates the chelation process with increased availability of at least divalent cations.

[0069] Chelation bath

[0070] The chelating bath comprises a polyanionic compound in solution. The polyanionic compound is capable of forming a chelate with at least one divalent cation by ionotropic gelation. This polyanionic compound is an anionic polymer, that is, a polyelectrolyte bearing negative charges. The polyanionic compound is selected from poly(acrylic acid) and polysaccharides, preferably from polysaccharides, preferably from pectins and alginates, and most preferably from alginates.

[0071] Preferably, the mass concentration of the polyanionic compound in the chelating bath ranges from 0.5% to 8% by mass of the chelating bath, preferably from 1% to 6% by weight, and preferably from 1.1% to 3% by weight. The higher the concentration of the polyanionic compound, the greater the viscosity of the bath. When the viscosity becomes too high, defects can appear in the forming layer. Therefore, the viscosity of the chelating bath is preferably limited to a maximum of 1500 cP, and preferably to a maximum of 600 cP. Thus, the higher the molar mass of the polyanionic compound, the lower its concentration in the chelating bath can be.Mass contents of polyanionic compound ranging from 0.5% to 8% relative to the mass of chelation bath, preferably from 1% to 6% by weight and preferably from 1.1% to 3% by weight, allow the formation of a uniform layer and limit the risk of formation of defects as well as at least partial rupture of the wire element being formed.

[0072] The polyanionic compound is, in the chelation bath of step a), in solution in a solvent preferably chosen from water, ethanol, isopropanol, dimethyl sulfoxide and their mixture.

[0073] In another preferred arrangement, the chelating bath in step a) also includes a compound selected from a dye, a biologically active compound such as a drug or any biologically active compound for which controlled diffusion is desired, a polymer such as polyethylene glycol, poly(glycerol sebacate), cyclodextrin, a biopolymer such as lignin, collagen, a polysaccharide such as cellulose or starch, proteins, or nutrients.

[0074] In a preferred arrangement, the chelation bath in step a) is a solution consisting of a solvent selected from water, ethanol, isopropanol, dimethyl sulfoxide, and mixtures thereof, and a polyanionic compound. A filament element is continuously formed at the injection point, said filament element consisting of a central space comprising the matrix and a skin comprising the polyanionic compound chelated by the at least divalent cation. This filament element passes through the chelation bath and then feeds into step b) of the process according to the invention. The residence time of the filament element in the chelation bath is adjusted according to the chelation kinetics. It typically ranges from a few seconds to a few minutes, for example, from 10 s to 2 min. Preferably, the filament element is passed through the chelation bath without tension, for example, by means of pulleys.By "no tension," we mean that the wire element does not undergo any stretching, or undergoes as little stretching as possible. This ensures that the integrity of the formed sheath is maintained.

[0075] Step b) of layer formation

[0076] The process according to the invention includes a step b) of layer formation in which the following succession of steps is carried out at least once: i. The wire element is passed through a bath comprising a solution of a salt of at least one divalent cation and being free of polyanionic compound; ii. The wire element from step i) is passed through a chelation bath comprising a polyanionic compound in solution, identical or different from the polyanionic compound of the chelation bath of step a), so as to form an additional layer around the wire element.

[0077] Each repetition of steps i) and ii) creates an additional layer on the wire element. Therefore, step b), which consists of repeating steps i) and ii), is executed as many times as the number of layers required for the multilayer sheath.

[0078] Step i)

[0079] In step i), the wire element obtained either at the end of step a), or obtained at the end of a previous succession of steps i) and ii), is passed through a bath comprising a solution of a salt of at least one divalent cation and being free of polyanionic compound.

[0080] By "free of polyanionic compounds," we mean that the bath used in step i) does not contain any polyanionic compounds when it is prepared. During its use, it may contain traces of polyanionic compounds that may have been introduced by the filament (so-called "contamination" polyanionic compounds). J 3

[0081] The absence of polyanionic compounds in the bath prevents the sheath of the filament element from continuing to grow, while still exposing its external surface to a fluid medium rich in at least a divalent cation. "Free of polyanionic compounds" means that no polyanionic compounds are introduced into the bath during its preparation. Polyanionic compounds may be present in the bath, introduced by the filament element as it passes through it. However, this contamination remains sufficiently low to prevent the formation of priming agents that would prevent adjacent sheaths from sliding freely against each other.

[0082] The salt of at least one divalent cation is preferentially chosen from the salts of calcium, copper, magnesium, iron, zinc, lead, cobalt, nickel, barium, strontium, aluminum, manganese, preferably chosen from the salts of calcium, copper, magnesium, iron, zinc, and aluminum, preferably chosen from the salts of calcium, copper and aluminum, and most preferably is a calcium salt.

[0083] The salt of at least one divalent cation used in the bath of step i) may be the same as or different from the salt of at least one divalent cation used in step a), and may be the same as or different from the salt of at least one divalent cation used in the bath of a previously carried out step i) if several successions of steps i) and ii) are carried out.

[0084] The salt of at least one divalent cation is, in the bath, in solution in a solvent, preferably a biocompatible solvent, and preferably chosen from water, ethanol, isopropanol, dimethyl sulfoxide and mixtures thereof.

[0085] In a preferred arrangement, the bath is a solution consisting of a solvent chosen from water, ethanol, isopropanol, dimethyl sulfoxide and mixtures thereof and a salt of at least one divalent cation.

[0086] In another preferred arrangement, the bath also includes a compound chosen from among a dye, a biologically active compound such as a drug or any biologically active compound whose controlled release is desired, a polymer such as polyethylene glycol, poly(glycerol sebacate), cyclodextrin, a biopolymer such as lignin, collagen, a polysaccharide such as cellulose or starch, proteins, or nutrients. The presence of such a compound allows for the encapsulation of an active compound between two layers of the multilayer sheath, ensuring controlled release. Thus, by layering several coats and placing different compounds between these coats, controlled and delayed release of multiple compounds can be achieved.This compound may be identical or different from the compound potentially used in step a), and may be identical or different from the compound potentially used in the bath of a previously performed step i) if several sequences of steps i) and ii) are implemented. It is thus possible to introduce compounds of different natures, or of the same nature but with different characteristics (e.g., molar mass, functionalization), between the layers of the multilayer cladding. This allows, particularly when the multilayer cladding is used to implement controlled diffusion of active compounds, for fine-tuning of the release rates of the compounds and / or their release sequence.

[0087] Step ii)

[0088] In step ii), the wire element obtained at the end of step i) is passed through a chelation bath comprising a polyanionic compound in solution, identical or different from the polyanionic compound of the chelation bath of step a), so as to form an additional layer around the wire element.

[0089] Upon contact with the cations deposited on the external surface of the wire element during step i), the polyanionic compound will gel and form a new layer. Surprisingly, this newly formed layer in the process according to the invention can slide freely relative to the adjacent pre-existing layer.

[0090] The chelation bath of step ii) comprises a polyanionic compound in solution. The polyanionic compound is capable of forming a chelate with at least one divalent cation by ionotropic gelation. Said polyanionic compound is an anionic polymer, that is, a polyelectrolyte bearing negative charges. The polyanionic compound is selected from poly(acrylic acid) and polysaccharides, preferably from polysaccharides, preferably from pectins and alginates, and most preferably from alginates.

[0091] The polyanionic compound used in the bath of step ii) may be the same as or different from the polyanionic compound used in step a), and may be the same as or different from the polyanionic compound used in the bath of a previously carried out step ii) if several successions of steps i) and ii) are carried out.

[0092] The polyanionic compound is, in the bath of step ii), in solution in a solvent preferably chosen from water, ethanol, isopropanol, dimethyl sulfoxide and mixtures thereof. In another preferred arrangement, the bath of step ii) also includes a compound chosen from a dye, a biologically active compound such as a drug or any biologically active compound whose controlled release is desired, a polymer such as polyethylene glycol, poly(glycerol sebacate), cyclodextrin, a biopolymer such as lignin, collagen, a polysaccharide such as cellulose or starch, proteins, or nutrients.

[0093] In a preferred arrangement, the bath in step ii) is a solution consisting of a solvent selected from water, ethanol, isopropanol, dimethyl sulfoxide and mixtures thereof and a polyanionic compound.

[0094] Preferably, the mass content of salt of at least one divalent cation in the bath of at least one step i) is preferably from 2% to 80% relative to the mass of bath, preferably from 5% to 40%, and preferably from 5% to 30% and the mass content of polyanionic compound in the chelation bath of at least one step ii) is from 0.5% to 8% relative to the mass of chelation bath, preferably from 1% to 6% by weight and preferably from 1.1% to 3% by weight.

[0095] Preferably, the wire element is subjected to at least one succession of steps i) and ii) without tension, for example by means of pulleys. By "without tension" is meant that the wire element is not stretched, or is stretched as little as possible.

[0096] If steps i) and ii) are repeated multiple times, each step i) and ii) can be carried out in a separate bath. In other words, as many successive baths are used as there are steps i) and ii) performed successively.

[0097] In the case where steps i) and ii) are repeated multiple times, each step i) and ii) can be performed in the same bath. In other words, one bath is used for all steps i), and another bath for all steps ii). In this embodiment, the wire element is guided, at the end of step ii) and as long as steps i) and ii) remain to be performed, through the baths of previously performed steps i) and ii) again.

[0098] The bath in step ii) can also be the same bath as that used for step a). Step c) of collecting the continuous multilayer cylindrical sheath

[0099] At the end of the last step ii) of at least one succession of steps i) and ii), the continuous multilayer cylindrical sheath is recovered. This sheath can then be stored, for example by winding onto a reel or by coiling. When the sheath is stored, it is preferably stored in a humid atmosphere to prevent it from drying out and to maintain its flexibility.

[0100] Preferably, at the end of step c) a stabilization step is carried out by passing the continuous multilayer cylindrical sheath through a stabilization bath comprising an aqueous solution of a salt of at least one divalent cation, the mass content of which is at least one divalent cation, from 2% to 80% relative to the mass of aqueous solution, preferably from 5% to 40%, and preferably from 5% to 30%.

[0101] This finishing process chelates the polyanionic compounds present on the outer surface of the multilayer sheath that had not yet reacted. This reduces the sheath's stickiness while simultaneously strengthening it.

[0102] Preferably, after the stabilization step, a washing step is carried out by passing the continuous multilayer cylindrical sheath through a washing bath containing water in order to clean the salt of at least one divalent cation possibly present on the surface of the multilayer cylindrical sheath.

[0103] Preferably, each chelation bath is, independently of each other, at a temperature ranging from 10°C to 40°C, preferably ranging from 15°C to 30°C.

[0104] Preferably, each bath in at least one step i) is at a temperature ranging from 10°C to 40°C, preferably ranging from 15°C to 30°C.

[0105] The expression "at least one step i)" means "step i)" when the sequence of steps i) and ii) is carried out only once, or "each step i)" when the sequence of steps i) and ii) is carried out several times. The expression "at least one step ii)" is understood in a similar way.

[0106] Preferably, all baths are operated at room temperature, thus allowing for great simplicity in the operation of the process.

[0107] Large inner diameter sheath

[0108] The continuous, multilayer cylindrical sheath obtained by the process according to the invention comprises at least two layers, each layer being able to slide freely relative to the adjacent layer. It is therefore possible to remove the innermost radially positioned layers to obtain a sheath consisting of a single layer and having a larger internal diameter than the sheaths described so far in the prior art. Indeed, the formation of the inner layers creates a skeleton around which the outermost layer forms. By adjusting the number of inner layers, the internal diameter of the outer layer can thus be freely adjusted to a value far greater than that which would be possible by injecting a matrix into a chelating bath alone.

[0109] Thus, the invention also relates to a continuous single-layer cylindrical sheath based on a polyanionic compound chelated by at least one divalent cation, obtained by a process comprising at least the following steps: ■ a. A matrix is ​​continuously injected, by means of a die, into a chelation bath comprising a polyanionic compound in solution, the matrix comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound, so as to form a wire element. b. The following sequence of steps is carried out at least once: ■ i. The wire element is passed through a bath comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound. ii.The wire element from step i) is passed through a chelation bath comprising a polyanionic compound in solution, identical or different from the polyanionic compound of the chelation bath of step a), so as to form an additional layer around the wire element c. A continuous multilayer cylindrical sheath d is recovered at the end of step b). All the radially innermost layers of the multilayer cylindrical sheath are removed to retain only the radially outermost layer.

[0110] Steps a), b) and c) correspond to the steps described previously.

[0111] Description of the figures

[0112] [Fig 1] Figure 1 illustrates schematically an arrangement of the process according to the invention. A matrix is ​​continuously injected from a reservoir (1) via a die (2) into a chelation bath (A) so as to form a wire element (3). The wire element is conveyed from one bath to the other by means of pulleys (4). i8

[0113] The wire element then passes through a bath containing a solution of a salt with at least one divalent cation and free of polyanionic compounds (B), the free surface of which is located at a height lower than that of the chelation bath (A), and then through a chelation bath containing a polyanionic compound in solution (C) so as to form an additional layer around the wire element. A continuous, multilayer cylindrical sheath (5) is obtained at the outlet of this bath.

[0114] The continuous multilayer cylindrical sheath (4) is recovered from the outlet of this bath.

[0115] [Fig. 2] Figure 2 schematically illustrates a cross-section of the multilayer continuous cylindrical sheath when this sheath consists of two layers. A central space (10) is surrounded by a first continuous cylindrical layer (11) and a second continuous cylindrical layer (13), the layers (11) and (13) being coaxial and free to slide relative to each other. The interlayer space (12), the central space (10), and the layers (11) and (13) may optionally, independently of each other, contain a compound selected from among a dye, a biologically active compound such as a drug or any biologically active compound whose controlled release is desired, a polymer such as polyethylene glycol, poly(glycerol sebacate), cyclodextrin, a biopolymer such as lignin, collagen, a polysaccharide such as cellulose or starch, proteins, or nutrients.

[0116] The interlayer space (12) may possibly not exist, that is to say that the two coaxial layers (11) and (13) are in contact with each other, while being free to slide relative to each other.

[0117] Measurement methods

[0118] Analysis of the macrostructure of alginates ■ SEC RI / MA S

[0119] The SEC (Size Exclusion Chromatography) technique separates macromolecules in solution according to their size using columns filled with a porous gel. Macromolecules are separated according to their hydrodynamic volume, with the largest being eluted first.

[0120] While not an absolute method, dual-detector SEC allows for the determination of the molar mass distribution of a polymer. Starting with a chosen model product, the various number-average (Mn) and weight-average (Mw) molar masses can be determined, and the polydispersity index (Ip = Mw / Mn), also called "dispersity," can be calculated. Size-exclusion chromatography analyses of alginates can be performed with two detectors: a refractometer ("Optilab rEX") and a multi-angle light scatterer ("Dawn Heleos") equipped with three PL aquagebOH Mixed M columns, and two detectors: a refractometer ("Optilab rEX") and a multi-angle light scatterer ("Dawn Heleos"). To perform these analyses, 1 mL of a 1 mg / mL sample solution is used. 1The solution in ultrapure water supplemented with Ig / L NaCl is filtered through a 0.45 µm PTFE membrane. 100 pL of this solution is eluted in ultrapure water supplemented with Ig / L NaCl using a flow rate of 1 mL / min 1 at a temperature of 40 °C. The Astra software can be used for data acquisition and analysis. Number molar masses (Mn) are calculated using a dn / dC determined by the 100% recovered method on a Vivapure brand sodium alginate sample, grade FD155.

[0121] The samples are dissolved at a concentration of approximately Ig / L in ultrapure water with added NaCl at a concentration of 1 g / L, then stirred for two hours before being injected.

[0122] The following analytical conditions can be used :

[0123] The light diffusion model used is that of Zimm.

[0124] Examples

[0125] Example 1

[0126] In this example, a continuous multilayer cylindrical sheath is manufactured consisting of a double hollow alginate sheath containing an active ingredient in its center in an aqueous medium.

[0127] A matrix consisting, by weight, of 89% water, 1% amoxicillin, and 10% CaCl2 is injected into a first bath, called the chelation bath, consisting of an aqueous alginate solution with an alginate concentration of 12 g / L, the bath being at a temperature of 24°C. The injection is performed continuously using a drip line consisting of a needle with an internal diameter of 1.1 mm, at a flow rate of 0.6 ml / min, and is carried out below the surface of the chelation bath.

[0128] The formed filament element passes through the chelation bath. The filament element remains in this bath for approximately ten seconds. It is transported by pulleys, minimizing tension on the element. The filament element exits the chelation bath as close as possible to its free surface and then passes through a second bath containing a saturated aqueous solution of CaCl₂, the free surface of which is located at a lower height than the free surface of the chelation bath.

[0129] The formed filament element passes through the chelation bath again. Its residence time in this bath is approximately 5 seconds. The filament element is then transported using pulleys, minimizing tension on the element. At the end of this step, a continuous cylindrical sheath consisting of two layers is obtained.

[0130] The continuous cylindrical sheath made up of two layers then passes through a stabilization bath, the free surface of which is located at a height lower than the free surface of the chelation bath, which consists of an aqueous solution saturated with CaC12.

[0131] The continuous cylindrical sheath made of two layers is wound around a reel and stored in humid conditions (90% humidity) to prevent it from drying out completely.

[0132] This example results in a continuous cylindrical sheath of uniform appearance consisting of two layers of alginate sliding freely relative to each other, the central space of which is filled with an aqueous solution of amoxicillin.

[0133] Example 2

[0134] In this example, a continuous multilayer cylindrical sheath is manufactured consisting of a double hollow alginate sheath containing poly(ethylene glycol) denoted PEG in its center.

[0135] A matrix consisting, by weight, of 4% PEG with a molar mass Mw = 600,000 g / mol, 81% water, and 15% CaCl₂ is injected into a chelation bath containing an aqueous alginate solution with an alginate concentration of 12 g / L, the bath being at a temperature of 24°C. The injection is performed continuously using a die consisting of a needle with an internal diameter of 1.1 mm, at a flow rate of 0.6 mL / min, and is carried out below the surface of the chelation bath.

[0136] The formed filament element passes through the chelation bath. The filament element remains in this bath for approximately ten seconds. It is transported by pulleys, minimizing tension on the element. The filament element exits the chelation bath as close as possible to its free surface and then passes through a second bath containing a saturated aqueous solution of CaCl₂, the free surface of which is located at a lower height than the free surface of the chelation bath.

[0137] The formed filament element passes through the chelation bath again. Its residence time in this bath is approximately 5 seconds. The filament element is then transported using pulleys, minimizing tension on the element. At the end of this step, a continuous cylindrical sheath consisting of two layers is obtained.

[0138] The continuous cylindrical sheath made up of two layers then passes through a stabilization bath, the free surface of which is located at a height lower than the free surface of the chelation bath, which consists of an aqueous solution saturated with CaC12.

[0139] The continuous cylindrical sheath made of two layers is wound around a reel and stored in humid conditions (90% humidity) to prevent it from drying out completely.

[0140] This example results in a continuous cylindrical sheath of uniform appearance consisting of two layers of alginate sliding freely relative to each other, the central space of which is filled with an aqueous solution of poly(ethylene glycol).

[0141] Example 3

[0142] In this example, a continuous multilayer cylindrical sheath is manufactured consisting of a double hollow alginate sheath containing poly(ethylene glycol) denoted PEG in its center.

[0143] A matrix consisting, by weight, of 52% PEG with a molar mass Mw = 35,000 g / mol, 41% water, and 7% CaCl₂ is injected into a chelation bath containing an aqueous alginate solution with an alginate concentration of 12 g / L, the bath being at a temperature of 24°C. The injection is performed continuously using a die consisting of a needle with an internal diameter of 1.1 mm, at a flow rate of 1.4 mL / min, and is carried out below the surface of the chelation bath.

[0144] The formed filament element passes through the chelation bath. The filament element remains in this bath for approximately ten seconds. It is transported by pulleys, minimizing tension on the element. The filament element exits the chelation bath as close as possible to its free surface and then passes through a second bath containing a saturated aqueous solution of CaCl₂, the free surface of which is located at a lower height than the free surface of the chelation bath.

[0145] The formed filament element passes through the chelation bath again. Its residence time in this bath is approximately 5 seconds. The filament element is then transported using pulleys, minimizing tension on the element. At the end of this step, a continuous cylindrical sheath consisting of two layers is obtained.

[0146] The continuous cylindrical sheath made up of two layers then passes through a stabilization bath, the free surface of which is located at a height lower than the free surface of the chelation bath, which consists of an aqueous solution saturated with CaC12.

[0147] The continuous cylindrical sheath made of two layers is wound around a reel and then undergoes a drying step at 24°C for 48 hours.

[0148] This example results in a continuous cylindrical sheath of uniform appearance consisting of two layers of dried alginate, the central space of which is filled with dry poly(ethylene glycol).

[0149] Example 4

[0150] In this example, a continuous multilayer cylindrical sheath is manufactured consisting of a double hollow alginate sheath containing poly(ethylene glycol) denoted PEG in its center, one of the sheaths containing an active ingredient.

[0151] A matrix consisting, by weight, of 4% PEG with a molar mass Mw = 600,000 g / mol, 81% water, and 15% CaCl₂ is injected into a first chelation bath containing an aqueous alginate solution with an alginate concentration of 12 g / L, the bath being at a temperature of 24°C. The injection is carried out continuously using a die consisting of a needle with an internal diameter of 1.1 mm, at a flow rate of 0.6 mL / min, and is performed below the surface of the first chelation bath.

[0152] The formed filament element passes through the first chelation bath. The filament element remains in this bath for approximately ten seconds. It is transported using pulleys, minimizing tension on the element. The filament exits the first chelation bath as close as possible to its free surface and then passes through a second bath containing a saturated aqueous solution of CaCl₂, the free surface of which is located at a lower height than the free surface of the chelation bath.

[0153] The formed filament passes through a second chelation bath consisting of an aqueous alginate solution loaded with amoxicillin. The alginate concentration is 12 g / L and the amoxicillin concentration is 0.5 g / L. The residence time in this bath is approximately 5 seconds.

[0154] The wire element is transported using pulleys, allowing its movement while minimizing tension on the element. At the end of this step, a continuous cylindrical sheath consisting of two layers is obtained.

[0155] The continuous cylindrical sheath made of two layers is wound around a reel and then undergoes a drying step at 50°C for 24 hours.

[0156] This example results in a continuous cylindrical sheath of uniform appearance consisting of two layers of dried alginate, the central space of which is filled with dry poly(ethylene glycol), the outer sheath containing amoxicillin.

[0157] Example 5

[0158] In this example, a continuous multilayer cylindrical sheath is manufactured consisting of a double hollow alginate sheath containing water in its center, and between the two sheaths a layer of PEG.

[0159] A matrix consisting, by weight, of 90% water and 10% CaCla is injected into a first chelation bath consisting of an aqueous alginate solution with an alginate concentration of 12 g / l, the bath being at a temperature of 24°C.

[0160] The injection is performed continuously using a dynamometer consisting of a needle with an internal diameter of 1.1 mm, at a flow rate of 2.0 ml / min, and is carried out below the surface of the first chelation bath.

[0161] The formed filament element passes through the first chelation bath. The filament element remains in this bath for approximately ten seconds. It is transported using pulleys, minimizing tension on the element. The filament element exits the first chelation bath as close as possible to its free surface and then passes through a second bath consisting, by weight, of a solution of 4% PEG (with a molar mass Mw = 600,000 g / mol), 81% water, and 15% CaCh, the free surface of which is located at a lower height than the free surface of the chelation bath.

[0162] The formed filament element passes through a second chelation bath containing an aqueous alginate solution. The alginate concentration is 12 g / L. The residence time in this bath is approximately 5 seconds. The filament element is then transported using pulleys, minimizing tension on the element. At the end of this step, a continuous cylindrical sheath consisting of two layers is obtained.

[0163] The continuous cylindrical sheath made up of two layers then passes through a stabilization bath, the free surface of which is located at a height lower than the free surface of the chelation bath, which consists of an aqueous solution saturated with CaC12.

[0164] The continuous cylindrical sheath made of two layers is wound around a reel and stored in humid conditions (90% humidity) to prevent it from drying out completely.

[0165] This example results in a continuous cylindrical sheath of uniform appearance consisting of two layers of alginate, the central space of which is filled with water, comprising between the two sheaths a thin layer of PEG.

[0166] Example 6

[0167] In this example, a continuous multilayer cylindrical sheath is manufactured consisting of a double alginate sheath containing in its center a PGS core covered with PEG using a die made of two coaxial needles.

[0168] The matrix consists, by weight, of 40% PEG with a molar mass Mw = 35,000 g / mol, 40% water, and 20% CaCh. A fluid consisting of 100% PGS with a molar mass Mw = 260,000 g / mol is also used. The matrix and the fluid are injected simultaneously into a first chelation bath containing an aqueous alginate solution with an alginate concentration of 12 g / L, the bath being at a temperature of 24°C. The matrix and the fluid are then heated to 60°C. 2.5

[0169] The injection is performed continuously using a coaxial dynamometer consisting of two needles: an inner needle and an outer needle, the inner and outer needles being coaxial. The inner needle has an internal diameter of 600 µm. The outer needle has an internal diameter of 1.1 mm. The matrix passes through the outer needle, while the PGS fluid passes through the inner needle. Injections are performed at a flow rate of 0.5 ml / min through the inner needle and 0.1 ml / min through the outer needle, and are carried out below the surface of the first chelation bath.

[0170] The formed filament element passes through the first chelation bath. The filament element remains in this bath for approximately ten seconds. It is transported using pulleys, minimizing tension on the element. The filament element exits the first chelation bath as close as possible to its free surface and then passes through a second bath containing a saturated aqueous solution of CaCl₂, the free surface of which is located at a lower height than the free surface of the chelation bath.

[0171] The formed filament passes through a second chelation bath consisting of an aqueous alginate solution. The alginate concentration is 12 g / L. The residence time in this bath is approximately 5 seconds. The filament is transported using pulleys, minimizing tension on the filament. The filament then passes through a stabilization bath, the free surface of which is lower than the free surface of the chelation bath, containing a saturated aqueous solution of CaCl₂.

[0172] The continuous cylindrical sheath consisting of two layers of alginate, one layer of PEG and a core of PGS is wound around a reel and stored in humid conditions (90% humidity) to prevent it from drying out completely.

[0173] This example results in a continuous cylindrical sheath of uniform appearance consisting of two layers of alginate, the central space of which is filled with a PGS core covered with a layer of PEG.

[0174] Example 7

[0175] Document CN107320780 teaches the molding of a thermosensitive gel object containing a divalent cation. This gel is repeatedly immersed in an alginate solution to form multiple layers of alginate around the thermosensitive gel object. Once the layer has formed, the gel object is immobile in the alginate solution. This document also teaches that between immersions, the object coated with the most recently formed alginate layer may be subjected to one or more of the following treatments. :

[0176] 1. To be placed in the air;

[0177] 2. To be immersed in water;

[0178] 3. To be immersed in an aqueous solution of a salt of a soluble divalent cation.

[0179] We have reproduced the example from this document in the following way ■

[0180] (1) Preparation of the gel nucleus

[0181] We prepared a 15 cm long "thread" with a diameter of 3 mm of 0.05g / ml gelatin containing 0.02g / ml calcium chloride at 4°C.

[0182] (2) Preparation of the first alginate layer

[0183] We immersed the wire in a sodium alginate bath at a concentration of 0.02g / ml at 4°C for 30 seconds, then immersed the wire in deionized water at 4°C for 10 seconds.

[0184] (3) Preparation of the second alginate layer

[0185] We immersed the wire in a sodium alginate bath at a concentration of 0.03g / ml at 4°C for 30 seconds, then immersed the wire in deionized water at 4°C for 10 seconds.

[0186] (4) Preparation of the third to fifth layer

[0187] We proceed in the same way as in step (3) but with an alginate solution concentration of 0.02g / ml, 0.03g / ml then 0.02g / ml in sequence, for 30 seconds, with cleaning with water between each immersion in the alginate bath.

[0188] Once these steps are completed, the gelled core is dissolved by heating the entire assembly to 37°C. The multilayer sheath is cut at its ends with a razor blade to allow the dissolved gelled core to be removed.

[0189] It is impossible to separate the different layers, which are bonded together. Therefore, the illustrated process does not allow for the creation of a multilayer sheath in which the layers slide freely against each other.

Claims

DEMANDS

1. Continuous multilayer cylindrical sheath of a polyanionic compound comprising at least two coaxial layers, each based on a polyanionic compound chelated by at least one divalent cation, each layer able to slide freely relative to the adjacent layer, the continuous central space of the sheath extending around the axis being free of polyanionic compound.

2. Cylindrical sheath according to the preceding claim in which the polyanionic compound is selected from poly(acrylic acid) and polysaccharides, preferably is selected from polysaccharides, preferably is selected from pectins and alginates, and most preferably is an alginate.

3. Cylindrical sheath according to any one of the preceding claims wherein the continuous central space of the multilayer sheath also comprises a compound selected from a dye, a biologically active compound such as a drug or any biologically active compound whose controlled diffusion is desired, a polymer, a biopolymer, proteins or nutrients.

4. Cylindrical sheath according to any one of the preceding claims wherein at least one layer of the multilayer sheath also comprises a compound selected from a dye, a biologically active compound such as a drug or any biologically active compound whose controlled release is desired, a polymer, a biopolymer, proteins or nutrients.

5. A method for manufacturing a continuous multilayer cylindrical sheath in which ■ a. A matrix is ​​continuously injected, by means of a die, into a chelation bath comprising a polyanionic compound in solution, the matrix comprising a solution of a salt of at least one divalent cation and being free of the polyanionic compound, so as to form a filament element b. The following sequence of steps is carried out at least once ■ i. The wire element is passed through a bath comprising a solution of a salt of at least one divalent cation and being free of polyanionic compound. ii. The wire element from step i) is passed through a chelation bath comprising a polyanionic compound in solution, identical or different from the polyanionic compound of the chelation bath of step a), so as to form an additional layer around the wire element. c. The continuous multilayer cylindrical sheath is recovered at the end of step b).

6. A method according to the preceding claim wherein the matrix also comprises a compound selected from a dye, a biologically active compound, a polymer, a biopolymer, proteins or nutrients.

7. A method according to any one of claims 5 to 6 wherein the matrix is ​​a solution consisting of a biocompatible solvent, preferably selected from water, ethanol, isopropanol, dimethyl sulfoxide and mixtures thereof, and a salt of at least one divalent cation.

8. A method according to any one of claims 5 to 7 wherein the salt of at least a divalent cation is selected from the salts of calcium, copper, magnesium, iron, zinc, lead, cobalt, nickel, barium, strontium, aluminum, manganese, preferably selected from the salts of calcium, copper, magnesium, iron, zinc, and aluminum, most preferably selected from the salts of calcium, copper and aluminum and most preferably is a calcium salt.

9. A method according to any one of claims 5 to 8 in which the die comprises one or more injection devices, the injection device or each injection device being a co-injection device allowing simultaneous injection at the periphery of the matrix and at the center of a fluid, said fluid being free of salt of at least one divalent cation.

10. A method according to any one of claims 5 to 9, wherein the polyanionic compound is selected from poly(acrylic acid) and polysaccharides, preferably from polysaccharides, The preferred method is chosen from among pectins and alginates, and the very preferred method is an alginate.

11. A method according to any one of claims 5 to 10 wherein the mass content of polyanionic compound in the chelation bath is from 0.5% to 8% relative to the mass of the chelation bath, preferably from 1% to 6% by weight and preferably from 1.1% to 3% by weight.

12. A method according to any one of claims 5 to 11 wherein the mass content of salt of at least one divalent cation in the bath of the at least one step i) is from 2% to 80% relative to the mass of the bath, preferably from 5% to 40%, and preferably from 5% to 30% and the mass content of polyanionic compound in the chelation bath of the at least one step ii) is from 0.5% to 8% relative to the mass of the chelation bath, preferably from 1% to 6% by weight and preferably from 1.1% to 3% by weight.

13. A method according to any one of claims 5 to 12 wherein, at the end of step c), a stabilization step is carried out by passing the continuous multilayer cylindrical sheath through a stabilization bath comprising an aqueous solution of a salt of at least one divalent cation, the mass content of which is at least divalent and ranges from 2% to 80% relative to the mass of aqueous solution, preferably from 5% to 40%, and preferably from 5% to 30%.

14. A method according to any one of claims 5 to 13 wherein the continuous multilayer cylindrical sheath undergoes a heat treatment step.

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