EP4366704A1 - Galenische form auf basis von baobab-pulpe, verfahren zu ihrer herstellung und ihre verwendung - Google Patents
Galenische form auf basis von baobab-pulpe, verfahren zu ihrer herstellung und ihre verwendungInfo
- Publication number
- EP4366704A1 EP4366704A1 EP22746984.8A EP22746984A EP4366704A1 EP 4366704 A1 EP4366704 A1 EP 4366704A1 EP 22746984 A EP22746984 A EP 22746984A EP 4366704 A1 EP4366704 A1 EP 4366704A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mass
- protein
- alg
- polysaccharide
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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Definitions
- the present invention relates to the field of the formulation of pharmaceutical and/or food compositions intended to be ingested.
- the present invention relates to a pharmaceutical form for the controlled release of a substance of interest orally, in particular for prolonged and/or targeted release, said pharmaceutical form comprising a combination of polymers as excipients. It also relates to a controlled-release pharmaceutical or food composition based on such a galenic form, as well as a process for preparing such a composition.
- a pharmaceutical form for the controlled release of a substance of interest orally in particular for prolonged and/or targeted release
- said pharmaceutical form comprising a combination of polymers as excipients.
- a controlled-release pharmaceutical or food composition based on such a galenic form, as well as a process for preparing such a composition.
- the oral route is a very widely used route of administration. It has advantages such as ease of use, the absence of pain during administration and above all the reduction of the risk of infection. It is also the preferred route for the delivery of active agents that can be absorbed by the intestinal wall. However, it has drawbacks. In fact, for the active ingredient to be able to have a therapeutic effect orally, it must be absorbed at the right place through the intestinal barrier in order to be present in sufficient quantity in the bloodstream.
- the galenic form (named after Galen, Greek physician of the 2nd century), or medicinal form, or pharmaceutical form, is the form in which the active principles and excipients (inactive materials) are put to constitute a drug.
- the galenic form corresponds to the final physical appearance of the drug as it will be used in a patient: tablets, capsules, sachets, oral solutions, suspensions for injection, etc. These dosage forms must be adapted to the route of administration chosen as well as to the very nature of the active principles that one wishes to administer.
- Galenic forms with controlled (or modified) release of an active principle or a bioactive agent can be classified into several categories:
- - sustained-release forms eg, zero-order, first-order, biphasic, etc.
- sustained-release forms the release is prolonged by retaining the active principle or the bioactive agent within a system controlling its rate of release.
- the active principle or the bioactive agent can be included in an excipient which is insoluble in body fluids which thus forms a matrix from which the active principle or the bioactive agent will be released slowly.
- the sustained-release forms provide a certain number of advantages, among which mention may be made in particular of the reduction of daily intake, the increase in the patient's comfort, the improvement of treatment compliance and the reduction of undesirable side effects by suppressing plasma peaks.
- Targeted release, such as colonic release is delayed release to a specific site in the gastrointestinal tract.
- Colonic release is obtained by a galenic formulation which opposes the release of the active principle or the bioactive agent during the transit phase in the upper gastrointestinal tract (HTGI) (stomach and small intestine) and which is then broken down in the colon.
- HTGI upper gastrointestinal tract
- pH specific physicochemical parameters of the different compartments of the gastrointestinal tract
- bacterial density physicochemical parameters of the different compartments of the gastrointestinal tract
- coatings sensitive to bacterial enzymes of the colonic microflora seem to be the most specific.
- Colonic delivery systems have been recognized as having significant therapeutic benefits and research in this area is increasing. They considerably improve the treatment of many pathologies with colonic attacks such as inflammatory bowel disease (IBD), colon cancer, irritable bowel syndrome and constipation. Furthermore, the absorption of active ingredients of a protein or peptide nature is better at the colonic level. This phenomenon is due in particular to a markedly lower proteolytic activity in the colon than in the small intestine and to the absence of a peptidasic activity associated with the membrane of the colonic epithelial cells.
- IBD inflammatory bowel disease
- colon cancer colon cancer
- constipation constipation
- the absorption of active ingredients of a protein or peptide nature is better at the colonic level. This phenomenon is due in particular to a markedly lower proteolytic activity in the colon than in the small intestine and to the absence of a peptidasic activity associated with the membrane of the colonic epithelial cells.
- Galenic forms with controlled release in particular with prolonged and/or targeted release, can be classified into two major categories: so-called “reservoir” forms in which the active principle is maintained inside a compartment delimited by a membrane slowing down its diffusion, and the so-called “matrix” forms (also called matrix system) in which the active ingredient is mixed homogeneously within a polymer matrix slowing down its diffusion.
- reservoir forms in which the active principle is maintained inside a compartment delimited by a membrane slowing down its diffusion
- matrix also called matrix system
- matrix devices can be prepared by mixing the drug in powder form with the polymer excipient(s) also in powder form. This mixture is then placed in a suitable mold (die) of a compression device and the resulting tablets are ready for use.
- WO 2002/094224 describes a carrier composition for bioactive agents comprising carbohydrate polymers such as polysaccharides modified by a hydrophobic group, associated with milk proteins (for example calcium caseinate and / or whey proteins ).
- the formulations can be used in various delivery systems including beads, tablets, microencapsulants and coatings for oral dosage forms, implants for subcutaneous devices and films. These formulations exhibit improved chemical resistance and exert their activity for a prolonged duration in the gastrointestinal tract (GIT) and bloodstream. It is stated that the combination of modified chitosan or modified alginate and milk proteins results in a stabilized structure capable of controlling the release of drugs, bacteria, bacteriocins, enzymes, nutraceuticals, etc. by enteric, thematic or systemic route.
- carbohydrate polymers such as polysaccharides modified by a hydrophobic group
- milk proteins for example calcium caseinate and / or whey proteins
- the formulations can be used in various delivery systems including beads, tablets, microencapsulants and coatings
- this support composition is not entirely satisfactory insofar as it does not allow optimal administration of charged molecules such as proteins and therapeutic peptides which can destabilize the network (ionic interaction) or low molecular weight molecules which can diffuse through the overly large pores of the polymer network.
- the polymers present in such a composition do not have a satisfactory rate of encapsulation and retention for charged molecules of low molecular weight, which in particular decreases the bioavailability of the substances of interest conveyed at the level of the intestinal barrier.
- the baobab, or Adansonia digitata L is an important indigenous fruit tree in the drylands of Africa, Malaysia, China, Jamaica and Australia.
- Baobab is also used in popular medicine as an antipyretic or febrifuge to overcome fevers, or even for its anti-inflammatory properties (CMK Humar et al., J. Intercuit. Ethnopharmacol., 2016, vol. 5, no. 1, pp. 79-85; ESA Ramadan et al., 1994, "Anti-inflammatory, analgesia and antipyretic effects of the fruit pulp of Adansonia digitata.” Corpus ID: 88592892; V. Selvarani et al., 2009, J. Med. Plants Res., vol. 3, no. 8, pp. 576-582; S. Fatema et al., 2015, Der Pharmacia Letter 7(5): 341-347).
- the baobab fruit is composed of an outer shell (epicarp) containing many seeds surrounded by a dry, acidulous and floury pulp, and rich in mucilage, pectin, tartrate and free tartaric acids.
- the fruit pulp contains a large amount of carbohydrates, pectin, little protein and extremely little fat.
- baobab pulp fruit powder has good lubricating, binding and thinning characteristics. It has been used as a hydrophilic excipient for the preparation of paracetamol and theophylline tablets with a lasting effect (Arama E. et al., Famarco Ed. Pr., 1988, 43, p. 303-304; Arama E. et al ., Pharm. Acta Helv., 1989, 64, pp. 116-120).
- the inventors have therefore set themselves the goal of providing a galenic form for the controlled release of a substance of interest orally which does not have the drawbacks of the prior art and/or which has improved properties compared to the compositions of prior art. This object is achieved by the objects of the invention described below.
- a first subject of the present invention is a dosage form for the controlled release of a substance of interest orally, said dosage form comprising at least one combination of polymers biodegradable and biocompatible as excipients, said galenic form being characterized in that:
- said combination of polymers comprises from 20 to 90% by mass of at least one protein, from 2.5 to 20% by mass of at least one polysaccharide and from 8 to 75% by mass of baobab fruit pulp, said percentages being expressed by mass of dry matter and relative to the total mass (protein(s)+polysaccharide(s)+baobab fruit pulp);
- the protein(s)/baobab fruit pulp mass ratio, expressed as mass of dry matter, is between 0.5 and 5 limits inclusive; and - the polysaccharide(s)/baobab pulp mass ratio, expressed as mass of dry matter, is between 0.05 and 1, limits included.
- a second object of the invention is a controlled-release composition for the oral administration of at least one substance of interest, said composition being characterized in that it comprises a galenic form according to the first object of the invention and at least one substance of interest.
- the third object of the invention is a method for preparing a composition as defined according to the second object of the invention, said method being characterized in that it comprises at least one step of incorporating at least a substance of interest in a pharmaceutical form as defined according to the first object of the invention and at least one step of final shaping of said composition.
- the pharmaceutical form in accordance with the invention provides access to pharmaceutical or food compositions with controlled release, in particular with targeted and sustained release over time, in particular over a period which can range from 4 to 24 hours.
- Such compositions can be used for the oral administration of substances of interest such as active principles, in particular of protein or peptide nature, and probiotics in the context of a treatment, in particular chronic.
- the galenic form in accordance with the invention using excipients having good properties of intestinal mucoadhesiveness, ensures the targeted and prolonged release of substances of interest, which makes it possible to access pharmaceutical or food compositions authorizing the reduction of repeated doses of medication, to improve the bioavailability or bioaccessibility of said substance of interest, to promote patient compliance and to reduce potential side effects.
- the combination of polymers present in the pharmaceutical form in accordance with the invention also makes it possible to increase the intrinsic properties of each of them and to lead to pharmaceutical compositions whose biopharmaceutical properties are optimized.
- the presence of baobab fruit pulp in the combination of polymers used as an excipient in the galenic form in accordance with the invention makes it possible to reduce the doses of anti-inflammatory and/or analgesic active substances administered when the form formulation is used to formulate a pharmaceutical composition intended for patients suffering from inflammatory bowel diseases (IBD), given the intrinsic anti-inflammatory and analgesic properties of baobab fruit pulp.
- IBD inflammatory bowel diseases
- biodegradable polymer means a polymer which can be degraded or digested by hydrolysis reactions, that is to say covalent bond cleavages by reaction with an aqueous medium (in accordance with the standard NF EN 13 432).
- biocompatible polymer means a polymer having the capacity not to interfere and not to degrade the biological medium in which it is used. In particular, they must not cause a strong inflammatory reaction (e.g. allergies) and/or must not be toxic to humans.
- the term “substance of interest” means the assembly formed by the active principles and the probiotics.
- An active principle is a chemical substance having a therapeutic effect.
- WHO World Health Organization
- FEO Food and Agriculture Organization of the United Nations
- a denatured protein is a protein having lost its three-dimensional configuration and in which the polypeptide chain is partially or totally unfolded.
- the first object of the invention is a dosage form for the controlled release of a substance of interest orally, said dosage form comprising at least one combination of biodegradable and biocompatible polymers as excipients, said dosage form being characterized in that :
- said combination of polymers comprises from 20 to 90% by mass of at least one protein, from 2.5 to 20% by mass of at least one polysaccharide and from 8 to 75% by mass of baobab fruit pulp, said percentages being expressed by mass of dry matter and relative to the total mass (protein(s)+polysaccharide(s)+baobab fruit pulp);
- polysaccharide(s)/baobab pulp mass ratio expressed as mass of dry matter, is between 0.05 and 1, limits included.
- the protein(s) present in the combination of polymers of the galenic form in accordance with the invention may be of plant or animal origin. They constitute an ingredient in its own right of the pharmaceutical form in accordance with the invention. They are in particular distinct from the proteins which may be naturally contained in baobab fruit pulp.
- the protein or proteins are used in undenatured form or in denatured form.
- the denaturation of the proteins can for example be carried out by heat treatment of the protein in aqueous solution at neutral pH, for example at a temperature of approximately 70 to 80° C. for 30 to 60 minutes.
- the solution of denatured proteins is then dried using conventional techniques such as atomization or lyophilization.
- proteins of plant origin mention may in particular be made of pea proteins; corn kernel proteins such as zein; cereal proteins such as wheat proteins (for example prolamins such as gliadin and glutenins), barley, rice, spelled, oats, etc.; soy protein; pumpkin seed proteins, etc.
- milk proteins such as whey proteins (or whey proteins) and caseinates as well as gelatins such as for example fish gelatins.
- the protein or proteins are milk proteins and even more preferentially whey proteins.
- the galenic form comprises approximately 55 to 80% by mass of proteins, said percentage being expressed by mass of dry matter and relative to the total mass (protein(s)+polysaccharide( s) + baobab fruit pulp).
- the polysaccharide(s) present in the combination of polymers of the galenic form in accordance with the invention constitute an ingredient in its own right of the galenic form in accordance with the invention. They are in particular distinct from the polysaccharides which may be naturally contained in baobab fruit pulp.
- the polysaccharide(s) are preferably chosen from anionic polysaccharides having an average molecular mass greater than or equal to approximately 75,000 Daltons, and even more preferably from approximately 75,000 to 250,000 Daltons.
- the anionic polysaccharide(s) are chosen from alginates, pectins, cellulose derivatives, polysaccharide gums such as agar-agar, xanthan gum and gellan gum, carrageenans, dextrans and modified dextrans, poly(lactic-co-glycolic) acid (PLGA) and hyaluronic acid.
- the polysaccharide is an anionic polysaccharide chosen from alginates, even more preferably sodium alginates.
- Alginates are natural hydrocolloids extracted from sustainably harvested seaweed. Chemically, alginates are formed from polysaccharides with building blocks (blocks) consisting of mannuronic and guluronic acid salts. The proportion, distribution and length of these blocks determine the chemical and physical properties of the alginate molecules.
- alginates in which the guluronic acid units (G)/mannuronic acid units (M) (G/M) molar ratio ranges from 0.5 to 2.5 are very particularly preferred.
- the alginates are chosen from those in which the proportion of guluronic acid units varies from 50 to 70% by moles approximately.
- the choice of the sodium alginate used is important insofar as sodium alginates having an excessively high guluronic acid content (greater than 70% by mole) lead to gels that are too firm and brittle with syneresis, while sodium alginates having a guluronic acid content of less than 50% by mole, that is to say in which the proportion of mannuronic acid units is greater than 50% by mole, lead to gels having a too soft structure which makes them difficult to work and handle.
- alginates in which the G/M molar ratio is greater than 1.5/1.0, such as the products sold under the trade names Manugel® DMB and Manugel® LBA by the company FMC BioPolymer, sodium alginates in which the G/M molar ratio is less than 1.0/1.0 such as the products sold under the trade names Manucol® DH and Manucol® LKX by the company ISP (Wayne, New Jersey , USA), as well as under the trade names Keltone® HVCR and Keltone® LVCR by the company FMC BioPolymer; low viscosity alginates such as the product sold under the trade name Protanan® CR 8133 and high viscosity alginates such as the product sold under the name Protanal® CR 8233.
- Manugel® DMB and Manugel® LBA by the company FMC BioPolymer
- sodium alginates in which the G/M molar ratio is less than 1.0/1.0 such as the products sold under the trade names Manucol®
- polysaccharide(s) present in the combination of polymers of the galenic form in accordance with the invention can also be chosen from cationic polysaccharides having a molecular mass average greater than or equal to approximately 100,000 Daltons, and even more preferably from approximately 150,000 to 600,000 Daltons.
- the galenic form comprises approximately 4 to 15% by mass of polysaccharide(s), said percentage being expressed by mass of dry matter and relative to the total mass (protein(s) + polysaccharide(s) + baobab fruit pulp).
- the baobab fruit pulp present in the combination of polymers of the pharmaceutical form in accordance with the invention is generally in the form of a powder. It is obtained from the pulp of baobab fruits after drying.
- the galenic form comprises from 17 to 72% approximately by mass of baobab fruit pulp, said percentage being expressed by mass of dry matter and relative to the total mass (protein(s) ) + polysaccharide(s) + baobab fruit pulp).
- the pharmaceutical form in accordance with the present invention is in solid form, for example in the form of powder, granules (dry or wet granulation of the powder), in the form of tablets resulting from the direct compression of the various polymers used in the form of powder or granules or even in the form of capsules containing the powder or granules.
- the protein(s)/baobab fruit pulp mass ratio expressed as mass of dry matter, is preferably between 0.7 and 2 limits inclusive.
- the polysaccharide(s)/baobab pulp mass ratio, expressed as mass of dry matter is preferably between 0.05 and 0.5 limits inclusive.
- the pharmaceutical form is in the form of gelled suspensions or microparticles gelled (hydrogel) and are obtained by mixing (without gelling agent) or by gelling (gelling agent), in particular by ionotropic gelling, of the various polymers in solution in the presence of an agent causing the gelling of the polymer solution, the proteins are then used in denatured form.
- the microparticles can be produced manually using a syringe and a needle (23G depending on the desired microparticle size) or with an encapsulator.
- the size of the microparticles generally varies from 500 ⁇ m to 3 mm approximately, and even more preferably from 1.5 to 3.0 mm approximately.
- the mass ratio of denatured protein(s)/baobab fruit pulp, expressed as mass of dry matter is preferably between 2.2 and 4.5 limits inclusive.
- the polysaccharide(s)/baobab pulp mass ratio, expressed as mass of dry matter is preferably between 0.1 and 0.4 limits inclusive.
- the galenic form as defined according to the first object of the invention can advantageously be used for the preparation of a pharmaceutical composition or of a food composition with controlled release for the oral administration of at least one substance of interest.
- a second object of the invention is therefore a controlled-release composition for the oral administration of at least one substance of interest, said composition being characterized in that it comprises a galenic form according to the first object of the invention and at least one substance of interest.
- Said composition may in particular be in the form of a pharmaceutical composition and the substance of interest is chosen from active principles, probiotics, and mixtures thereof.
- compositions in accordance with the invention are not critical, said composition is however particularly suitable for the formulation of active principles and/or probiotics requiring controlled release, in particular a prolonged and targeted release at the level of the intestinal mucosa.
- active principles belonging to classes 2 and 4 of the biopharmaceutical classification system (BCS) for medicinal substances, including therapeutic proteins and peptides.
- BCS biopharmaceutical classification system
- This system makes it possible to classify the active ingredients according to their solubility and their intestinal permeability (Mehul Mehta, Biopharmaceutics Classification System (BCS): Development, Implementation, and Growth, Wiley, 2016, 456 p. (ISBN 978-1-118 -47661-1)).
- class 2 active ingredients have high intestinal permeability and low solubility
- class 4 active ingredients have low intestinal permeability and low solubility.
- the active principle is chosen from therapeutic proteins and therapeutic peptides.
- therapeutic proteins and peptides and by way of non-limiting examples, mention may very particularly be made of insulin, calcitonin, coagulation factors, growth hormones such as for example erythropoietin (EPO), triptorelin , orgulatran (anti-GnRH), monoclonal antibodies (IgG, Inflimixab), cytokines (IL-10, IFN, G-CSF), urokinase (pulmonary embolism), vaccine antigens, antithrombotics such as hirudin and its analogues, antiplatelet agents such as integrin, and vector peptides allowing the transport of RNA such as Transportan.
- EPO erythropoietin
- anti-GnRH monoclonal antibodies
- IgG, Inflimixab monoclonal antibodies
- cytokines IL-10, IFN, G-CSF
- probiotics which can be used as a substance of interest in the compositions in accordance with the invention, and by way of non-limiting examples, mention may be made of bacteria, and in particular lactic acid bacteria such as lactobacilli (bacteria of the genus Lactobacillus ), bifidobacteria (bacteria of the genus Bifidobacterium) and certain streptococci (bacteria of the genus Streptococcus); yeasts, and in particular yeasts of the genus Saccharomyces such as Saccharomyces cerevisiae (or brewer's yeast) and Saccharomyces boulardii.
- lactic acid bacteria such as lactobacilli (bacteria of the genus Lactobacillus ), bifidobacteria (bacteria of the genus Bifidobacterium) and certain streptococci (bacteria of the genus Streptococcus)
- yeasts and in
- the composition comprising it can also take different forms.
- the composition is prepared from a pharmaceutical form in solid form.
- the composition in accordance with the invention is also in solid form, for example in the form of powder or in the form of tablets resulting from the compression of the various polymers of the galenic form used in the form of powder mixed with at least one substance of interest or alternatively in the form of gelatin capsules optionally after wet granulation of the various polymers of the galenic form initially in powder form mixed with at least one substance of interest.
- the composition comprises the galenic form in solid form and it is also in solid form
- said galenic form preferably represents from 20 to 50% by mass, and even more preferably from 25 to 35% by weight, relative to the total weight of said composition.
- the remainder at 100% moreover consists of the substance(s) of interest and the additional excipient(s) optionally present within said composition.
- the amount of baobab fruit pulp preferably represents from 8 to 35% by mass, and even more preferably from 18 to 25% by mass, relative to the total mass of said composition.
- the sustained release is less effective
- the amount of baobab fruit pulp is greater than 35 % by mass relative to the total mass of said composition
- the production of the composition, in particular tablets is complex and less reproducible (in terms of flow, filling of the matrix and compression).
- the composition is in the form of a tablet, the latter may be plain, film-coated or coated.
- the composition is in the form of a powder, said powder can be packaged, for example, in a capsule.
- the composition is prepared from a pharmaceutical form in the form of gelled microparticles.
- the composition in accordance with the invention may be in the form of a suspension of said gelled microparticles in a liquid or semi-solid (gel) excipient, or alternatively be in solid form after drying of said gelled microparticles which are then formulated in the form of capsules or tablets.
- said galenic form preferably represents from 11 to 14% and even more preferentially from 11 to 12% by mass , relative to the total mass of said composition.
- the remainder at 100% moreover consists of the substance(s) of interest, the additional excipient(s) optionally present within said composition, and the solvent(s) used to dissolve the polymers, in particular water.
- the quantity of baobab fruit pulp preferably represents from 1 to 4% by mass, relative to the total mass of said composition.
- the composition in accordance with the invention may also contain one or more additional excipients usually used for the formulation of pharmaceutical compositions intended for oral administration or for the formulation of food compositions.
- excipients usually used for the formulation of pharmaceutical compositions intended for oral administration or for the formulation of food compositions.
- excipients mention may in particular be made of the excipients generally incorporated in the compositions which are presented in solid form, such as flow agents, lubricants, dyes, taste masking agents, etc., as well as the excipients incorporated into the compositions in liquid or gelled form, such as emulsifying agents, surfactants, densifying agents, etc. ...
- emulsifying agents such as surfactants, densifying agents, etc.
- those skilled in the art will ensure that the addition of this or these excipients does not adversely affect the intrinsic properties of the composition in accordance with the invention.
- the third object of the invention is a method for preparing a composition as defined according to the second object of the invention, said method being characterized in that it comprises at least one step of incorporating at least a substance of interest in a pharmaceutical form as defined according to the first object of the invention and at least one step of final shaping of said composition.
- the composition is solid and is in the form of a tablet.
- a tablet can be obtained from powdered ingredients (polymers of the galenic form, substance(s) of interest and any additional excipients) either by direct compression, or by wet granulation then compression; these techniques being commonly employed by those skilled in the art.
- the composition is in the form of gelled microparticles.
- said microparticles can be obtained by ionotropic gelation of the polymers of the pharmaceutical form in solution or in suspension in a solvent containing at least one substance of interest in the presence of a crosslinking agent.
- the method for preparing the composition is a method for preparing gelled microparticles and it comprises the following steps: i) the preparation of a solution of denatured proteins, ii) the preparation of a solution of fruit pulp baobab and at least one polysaccharide, iii) mixing the solutions prepared above in steps i) and ii), iv) adding to the resulting solution at least one substance of interest, v) l extrusion of the solution obtained above in step iv) into a solution containing a crosslinking agent so as to cause said solution to gel and to obtain said gelled microparticles.
- the extrusion of step v) can in particular be carried out using a needle under the effect of pressure or using an industrial encapsulator, for example of the Buchi B390 type.
- the polysaccharide is a sodium alginate and the crosslinking agent is chosen from divalent cations such as calcium chloride.
- FIG 1 is a graph representing the interaction force between the polymers PL/BB, ALG/BB, PL/ALG and PL/(ALG/BB) calculated by measuring the viscosity (G") of solutions prepared with the ratio mass 80/20 (in Pa) as a function of frequency (in rad/s)
- FIG 2 is a graph representing the interaction G" of individual samples of polymers and solutions comprising polymer mixtures in the presence of mucin (in Pa), as a function of frequency (in rad/sec).
- FIG 3 is a graph representing the mucoadhesive capacity of different solutions of polymers alone or in combination.
- FIG 4 is a graph representing the release kinetics of blue dextran (BD) from microparticles prepared from different polymer solutions (% release of BD as a function of time in minutes), at pH 1.2.
- BD blue dextran
- FIG 5 is a graph representing the BD release kinetics from microparticles prepared from different polymer solutions (% BD release as a function of time in minutes), at pH 6.8.
- FIG 6 is a scanning electron microscopy photograph at magnification x1000 of microparticles prepared from different solutions of comparative polymers PL, ALG, BB, PL/BB, ALG/BB, PL/ALG compared to gelled particles conforming to the invention prepared from a solution of PL/(ALG/BB) polymers.
- FIG 7a is a graph comparing the swelling of gelled microparticles obtained from a solution comprising the combination of PL/ALG polymers not in accordance with the invention with that of gelled microparticles in accordance with the invention obtained from a solution comprising the combination of PL/(ALG/BB) polymers.
- Figure 7a gives the variation in diameter (in %) as a function of time (in minutes).
- FIG. 7b is a graph comparing the swelling of gelled microparticles obtained from a solution comprising the combination of PL/ALG polymers not in accordance with the invention with that of gelled microparticles in accordance with the invention obtained from a solution comprising the combination of PL/(ALG/BB) polymers.
- FIG. 7b gives the variation in the amount of water absorbed (in %) as a function of time (in minutes).
- FIG. 8a] is a graph representing the release kinetics of theophylline from tablets prepared with different mixtures of polymers based on milk proteins (in %) as a function of time (in minutes) at pH 1.2.
- FIG 8b is a graph representing the release kinetics of theophylline from tablets prepared with different mixtures of polymers based on milk proteins (in %) as a function of time (in minutes) at pH 6.8.
- FIG 9a is a graph representing the release kinetics of theophylline from tablets prepared with different mixtures of polymers based on milk proteins or pea proteins (in %) as a function of time (in minutes) at pH 1.2.
- FIG 9b is a graph representing the release kinetics of theophylline from tablets prepared with different mixtures of polymers based on milk proteins or pea proteins (in %) as a function of time (in minutes) at pH 6.8 (Fig. 9b).
- FIG 10 is a graph representing the healing capacity of different polymer solutions, expressed as a percentage of healing.
- FIG 11 reports the results of an in vitro test of growth of HT-29 MTX cells (in %) in the presence of different polymer solutions.
- FIG. 12 reports the results of a test to evaluate the anti-inflammatory properties of different polymer solutions carried out on a line of murine macrophages.
- the Tnf-alpha level (in pg/mL) is given for each of the polymer solutions tested.
- FIG 13 reports the quantities of FITC assayed in the serum of mice after inflammation with DSS (DSS 0.5%) or control (Water) for 12 days with pre-treatment and treatment with water (negative control Water + Water or DSS 0.5% + Water), BB (DSS 0.5% + BB at 5% m/m), a PL/ALG mixture (DSS 0.5% + PL/ A LG at 5% m/ m) or a mixture of PP/(ALG/BB) (0.5% DSS + 5% PP/(A LG/BB)) for 21 days.
- FIG 14 reports the dose-response effect of oral administration of polymers on visceral sensitivity (areas under the AUC curve 60-80 mmHg).
- the pain threshold in response to colorectal distension was tested at 12 days of DSS (0.5%) for: Water + Water (negative control), DSS at 0.5% + Water (inflammation control), DSS at 0 .5% + BB at 5% (m/m), DSS at 0.5% + PP/ALG at 5% (m/m) and DSS at 0.5% + PP/(ALG/BB) at 5% (m/m).
- tablets in accordance with the invention were prepared from solutions or suspensions of the various polymers, in defined percentages, which were dried by atomization using a Buchi B290 atomizer.
- the resulting powders can be used to formulate capsules or tablets after mixing with at least one substance of interest.
- EXAMPLE 3 Preparation of galenic forms in accordance with the invention in the form of gelled microparticles
- several galenic forms in accordance with the invention were prepared in the form of gelled microparticles, by ionotropic gelling in the presence of calcium chloride as crosslinking agent.
- composition of the microparticles is given in Table 3 below: [TABLE 3]
- EXAMPLE 4 Preparation of gelled microparticles in accordance with the invention and preparation of comparative microparticles not forming part of the invention
- gelled microparticles were prepared in accordance with the invention, that is to say based milk protein or pea protein, as well as alginate and baobab fruit pulp.
- comparative microparticles not forming part of the invention that is to say containing only one or only two of the above polymers.
- PP powder (Nutralys F85F Roquette) were weighed into a 50 mL bottle (SHOTT Duran) and supplemented with deionized water qsp 40 g. The flask was stirred for 5 min at 500 to dissolve the PP powder then at 200 rpm for 1 h in order to rehydrate the PPs. The pH was adjusted to 7 using 1M NaOH solution. The mixture was then stirred for 5 min then the pea proteins were denatured with stirring (300 rpm) in a water bath for 40 min at 80°C. The denatured PP solution was then left to stand overnight at room temperature. Diluted PP solutions were made from the 11% (m/m) PP solution (PP 4.4% m/m, PP 5.5% m/m and PP 8.8% m/m ).
- ALG powder 3 g was weighed into a cup and 97 g of deionized water was weighed into a 250 mL beaker. The beaker was placed under agitation (700 rpm), and the ALG powder was sprinkled into the water contained in the beaker. In order to obtain faster homogenization of the solution, stirring was maintained for 1 hour. Diluted solutions of ALG were produced from the ALG solution at 3% m/m (ALG 0.3% m/m, ALG 0.6% m/m and ALG 1.5% m/m).
- Composite solutions of PL/[ALG/BB] polymers were obtained by modifying the mass ratio of the polymers in the final solution, in accordance with the details given in Table 4 below. Mixtures of PL 11% and ALG 3% made directly in the baobab fruit pulp solution BB (10%) were made by modifying the ratio PL / [ALG / BB] to obtain the composite solutions PL / [ ALG/BB] 90/10; 80/20; 70/30, 40/60 and 10/90.
- Gelled microparticles were made from the solutions detailed in Table 4 above having different ratios of PL/(ALG/BB). Each composite solution was withdrawn with a syringe of 5 mL, then extruded through a needle (23G Neolus, Terumo®, Somerset, USA) into a 250 mL beaker, placed under stirring (300 rpm) and containing 100 mL of CaCl2 solution (Weigh 14.7 g of CaCl2 in a 1 L volumetric flask. Adjust to the mark with deionized water. Place under agitation (700 rpm) for 30 min). The microparticles were kept under agitation for 5 min, then were filtered using a sieve.
- the rheology of the solutions was measured at room temperature with a rotating rheometer (Ares 509954812), with increasing or imposed stress, equipped with a cone-plane geometry (Angle of the cone 0.1 radians, gap 0.048 mm, frequency 1.0 rad/s). After having previously defined the linear range and therefore the frequency as a parameter, the viscosity (G") of each of the polymer solutions prepared according to the proportions given in Table 4 above was measured. The development of G" was followed by a time sweep typically for 20 min at a constant frequency.
- the rheological synergy parameters which are the differences between the actual viscoelastic values of the polymer A / polymer B test mixture and the theoretical values defined as the sum of the viscoelastic components of polymer A and polymer B, were calculated as follows:
- G" mixture G" polymer A + G" polymer B + G" interaction where:
- - G" mixture is the viscosity coefficient of the mixture
- - G"polymer A and G"polymer B are the individual viscosity coefficients of polymer A and polymer B respectively
- the results obtained are presented in the appended figure 1 on which the measured interaction force G" (in Pa) is a function of the Frequency (in rad/s).
- the curve with the empty circles corresponds to the solution comparative PL/BB
- the curve with the solid circles corresponds to the comparative solution ALG/BB
- the curve with the solid diamonds corresponds to the comparative solution PL/ALG
- the curve with the solid squares corresponds to the solution PL/(ALG/ BB) in accordance with the invention.
- Mucin concentrations were selected within the physiological range (5% w/w). Samples of homogenized mucus (10% m/m porcine mucin) or water (control) were mixed with an equal amount of the test polymer solution and the pH was adjusted to 7.0 using a 0.1 M NaOH or 0.1 M HCl solution at room temperature for 1 h before the rheological examination.
- bioadhesion ⁇ mixture - ⁇ mucin - ⁇ polymer
- the mucoadhesion of the polymer solutions was also tested ex-vivo on WISTAR laboratory rats purchased from Janvier Labs.
- the mucoadhesive capacity was calculated as the percentage of active substance retained by the mucosal tissue at the end of the process. The experiment was carried out in triplicate.
- Microparticles were prepared from the composite solutions. To do this, the composite solution was withdrawn with a 5 ml_ syringe, then extruded through a needle (23G Neolus, Terumo®, Somerset, USA) into a 250 ml_ beaker, placed under stirring (300 rpm) and containing 100 ml_ of CaCl2 solution previously prepared by mixing 14.7 g of CaCl2 in a 1 L volumetric flask, then adjusting to the mark with deionized water then stirring (700 rpm) for 30 min. The microparticles formed in the CaCl2 solution were left under stirring for 5 min, then were filtered using a sieve.
- BD release kinetics Microparticles were prepared from polymer solutions loaded with BD (0.83% (m/m) as described above in point 4.1. BD release kinetics were carried out in triplicate in a rotating paddle apparatus (USP2, AT7, Sotax, Switzerland).Ten grams of microparticles were introduced per reactor (37°C +/- 0.5°C) containing 500 mL of Pharmacopoeia buffer pH 1.2 or 6, 8 to represent the gastric and intestinal environment. The rotation speed of the paddles was set at 50 rpm.
- Samples were taken for 24 h at predetermined intervals (15, 30, 45, 60, 90, 120, 180, 240 , 300, 360 and 1440 minutes) then measured using a 7315 Visible-UV spectrophotometer at 618 nm (Jenway, United States).
- the curves in solid line and with the solid squares correspond to the microparticles obtained with a solution of PL at 11% m/m
- the curve in solid line and with the empty circles corresponds to the microparticles obtained with the solution comprising the association PL/BB with PL 11% m/m and BB 3% m/m in a PL/BB mass ratio of 80/20
- the curve in solid line and with the solid triangles corresponds to the microparticles obtained with the alginate solution alone at 3% m/m
- the curve in solid line and with the solid circles corresponds to the microparticles obtained with the solution comprising the combination ALG/BB with ALG 3% m/m and BB 10 % m/m in an ALG/BB mass ratio of 80/20
- the curve with the continuous line and the solid diamonds corresponds to the microparticles obtained with the solution comprising the combination PL/ALG with PL 11% m/m and ALG 3% m/m in a mass ratio PL/
- the results presented in FIGS. 4 and 5 show that the release of BD from the microparticles at pH 1.2 is less than 10% in 24 h regardless of the formulation tested.
- the microparticles are therefore gastroresistant. At pH 6.8, the release depends on the formulation tested.
- the microparticles prepared from the solution comprising alginate (ALG 3% m/m) with or without baobab fruit pulp are the formulations which release BD the fastest (>50% in 3 h) to reach 80 % in 6 hours.
- the microparticles obtained from the solution containing milk protein (PL 11% m/m) with or without baobab fruit pulp release BD less rapidly with less than 25% in 3 h and less than 40% in 6 h.
- microparticles obtained with the solution comprising milk protein and containing or not baobab fruit pulp release the BD the slowest with less than 25% in 6 h.
- the addition of baobab fruit pulp to the solution comprising the PL/ALG association slows down the release of the active substance at pH 6.8 and improves the prolonged effect of the active substance.
- Figure 6 appended is a scanning electron microscopy photograph at x1000 magnification of the PL, ALG, BB, PL/BB, ALGBB, PL/ALG microparticles compared to the PL/(ALG/BB) particles in accordance with the invention.
- the swelling (significant of the water uptake) of the PL/ALG microparticles compared to the PL/(ALG/BB) particles in accordance with the invention was also evaluated by measuring their diameter and the results are reported in FIG. 7a and Figure 7b appended.
- the results concerning the change in diameter correspond to FIG. 7a in which the variation in diameter (in %) is a function of time (in minutes).
- the black bars correspond to the comparative PL/ALG microparticles while the gray bars correspond to the PL/(ALG/BB) microparticles in accordance with the present invention.
- the results concerning the water uptake correspond to FIG. 7b in which the variation in the quantity of water (in %) is a function of time (in minutes).
- the black bars correspond to the comparative PL/ALG microparticles whereas the gray bars correspond to the PL/(ALG/BB) microparticles in accordance with the present invention.
- Example 4 To obtain milk protein powders, the 11% m/m PL solution as prepared above in Example 4, section 4.1, was atomized at 160°C using a BÜCHI Mini spray dryer. Spray Dryer B-290 (Switzerland). The spray drying process parameters were defined as follows:
- the residual humidity of the PL powders was determined by a thermogravimetric method. The test was carried out on a mass of 2 g of powder with an infrared balance (Melter Toledo LJ 16 moisture analyzer, Viroflay Switzerland). Residual moisture was set to be less than 5%. Fourteen formulations were produced with a mixture composed of 36.5% (m/m) of powder of the three natural polymers and a filler excipient, namely sieved lactose monohydrate sold under the trade name Capsulac ® 60 by the company Cooper (Melun, France) (qsp 36.5%).
- Aerosil Degussa Ag
- the model active substance chosen is theophylline monohydrate TPH (23722, Pierre Fabre) and represents 62% (m/m) of the total mass of the tablet.
- the tablets were prepared by direct compression of the FO to F13 formulations, using a reciprocating tablet machine.
- the filling of the compression chamber by the flow of the powders and the compression of the powders are the two key parameters for manufacturing the tablets. Indeed, a poor flow of the powders can lead to non-conformity of the masses of tablets obtained and prevents homogeneity within the tablet.
- the flowability of the powder can be improved by granulation or by mixing with other excipients.
- Theophylline release kinetics were performed in triplicate in a rotating paddle apparatus (USP2, AT7, Sotax, Switzerland) for each formulation.
- a tablet is introduced per reactor (37° C. +/- 0.5° C.) containing 1000 ml of Pharmacopoeia buffer pH 1.2 or 6.8 to represent the gastric and intestinal environment.
- the rotation speed of the vanes is 50 rpm.
- Samples were taken at predetermined intervals (15, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes). The samples were then centrifuged at 1000 g for 10 min before assaying by liquid phase chromatography (CHLP) with UV detector without oven.
- CHLP liquid phase chromatography
- a calibration calibration range was carried out from a stock solution (SM) of theophylline monohydrate in a buffer solution of pH 6.8 and in a buffer solution of pH 1.2 of known concentration: 0.66 mg/mL.
- CHLP analysis of theophylline was performed with an Elite LaChrom® system (Hitachi, Tokyo) and the data was processed with EZ Chrom Lite® Software.
- the column used was an Interchim® C18 column of dimension 250 mm ⁇ 46 mm, particle 5 ⁇ m.
- the mobile phase was a mixture of 90% (v/v) ammonium acetate/water, 5% (v/v) acetonitrile and 5% (v/v) methanol.
- the flow rate was set at 1 mb/min, the detection was made using a UV/Visible detector at 272 nm and the sample analysis time was set at 16 min.
- FIG. 8a corresponds to the theophylline release kinetics measured at pH 1.2
- Figure 8b corresponds to the theophylline release kinetics measured at pH 6.8.
- FIGS. 8a and 8b show that at pH 1.2 (FIG. 8a), the release of theophylline from the polymer-free tablets (F0) is rapid and total (80% in 90 min).
- the addition of polymers decreases theophylline release from the tablets.
- a dissolved percentage of theophylline of less than 50% is observed after 3 h.
- the addition of these polymers therefore has a significant impact on the release kinetics of theophylline at pH 1.2 and modifies the behavior of the formulation to obtain a controlled release and prolonged.
- pH 6.8 Fig. 8b
- the addition of polymers in the tablets modifies the release rate of theophylline.
- the increase in the quantity of PL makes it possible to increase the capacity to create a matrix and to slow down the release of theophylline in the medium.
- PLs allow a prolonged release of theophylline at a percentage of 18% at intestinal pH. It is therefore possible to conclude that the amount of PL in the tablets has a significant impact on the rate of release of the active substances.
- Fig. 8b Concerning the formulations with 35% of polymer alone (comparative formulations not forming part of the invention), the Fil formulation (ALG alone) very quickly releases theophylline with a dissolved percentage of 100% after 240 min at pH 6, 8 (Fig 8b), formulations F12 (BB alone) and F13 (PL alone) reach only 35-40% release after 240 min at pH 6.8 then 50% after 360 min (Fig. 8b) .
- the formulations containing a high percentage of ALG therefore tend to release theophylline more easily, the polymer not having a sustained release effect when it is not combined with the other polymers.
- Type III SS corresponds to the sum of the squares (SS) of type III.
- Table 9 presents the statistical results obtained on the 13 formulations F1 to F13 and highlights the impact of the polymers alone or in combination on the release of the model active substance (AS) during time.
- AS model active substance
- the polymers involved in the release of SA are mainly PL and BB as well as the PL/BB combination.
- all the polymers alone have an impact as well as the association ALG/BB and PL/BB on the release. Polymers alone and polymeric interactions impact SA release at intestinal pH, modulating erosion and diffusion properties over time.
- milk proteins can be replaced by vegetable proteins such as PP/(ALG/BB) pea proteins.
- Two formulations F'2 and F'10 were produced with a mixture composed of 36.5% (m/m) of powder of the three natural polymers (PP, ALG and BB) and a filler excipient (qsp 36, 5%).
- the quantities of polymers (PP, ALG and BB) used are respectively the same as those indicated previously for formulas F2 and F10 in Table 6 above, i.e. 8% m/ m of BB, 18% m/m of PP and 2% m/m of ALG for the F'2 formula and 25% m/m of BB, 8% m/m of PP and 2% of ALG for the formula F'10.
- the amount of bulking agent used was chosen such that the total mass of the polymer(s) plus that of the bulking agent represents 36.5% by mass relative to the total mass of the formulation, i.e. 8.5 % m/m for formula F'2 and 1.5% m/m for formula F'10.
- magnesium stearate 1.0% (m/m)
- colloidal silica 0.5% (m/m).
- the model active substance chosen is theophylline monohydrate TPH (23722, Pierre Fabre) and represents 62% (m/m) of the total mass of the tablet.
- the release kinetics of theophylline from the tablets prepared with the formulas F'2 and F'10 were studied at pH 1.2 and at pH 6.8 according to the same protocol as for the formulas F0 to F13 above. , and this compared to the kinetics of release of theophylline from the tablets prepared from the formulas F2 and F10 based on PL.
- the results obtained are given in the appended Figures 9a and 9b, at pH 1.2 (Fig. 9a) and at pH 6.8 (Fig 9b).
- the release of theophylline (in %) is a function of time (in min).
- the curves with filled diamonds correspond to formulation F2
- the curves with filled triangles correspond to formulation F10
- the curves with open diamonds correspond to formulation F'2
- the curves with open triangles correspond to formulation F' 10.
- FIG. 9a and FIG. 9b show that the replacement of animal proteins by vegetable proteins does not modify the interactions between the polymers nor the release profile of the active substance of the tablet.
- the principle of the healing test is the formation of a cell-free zone following voluntary lesion of a monolayer of confluent cells, thus making it possible to visualize healing in vitro. Indeed, in this context, the cells will attempt to return to total confluence, in a more or less long time depending on the treatment evaluated.
- Human colon epithelial cells (HT29-MTX sold by the company American Type Culture Collection - ATCC) were cultured in a 6-well plate in a DMEM culture medium at 37° C. for 72 h, that is to say until a confluent cell monolayer is obtained. A wound was formed using a cone point thus scraping the confluent cell monolayer of HT29-MTX cells. Rinsing with PBS was carried out in order to eliminate the cellular debris formed.
- Polymer solutions (same concentration of all the polymers in the mixture) produced in DMEM, are deposited in each well (3 mL/well): BB (final mixture 0.05% m/m), PL/ALG (50/ 50 m/m with a final blend of 0.05% polymers), PP/ALG (50/50 m/m with a final blend of 0.05% polymers), PL/(ALG/BB) (33/ 33/33 m/m with a final blend of 0.05% polymers), and PP/(ALG/BB) (33/33/33 m/m with a final blend of 0.05% polymers).
- the results presented in FIG. 10 show that the solution based on baobab fruit pulp (BB) allows cells to heal faster than the DMEM culture medium alone (80% vs. 42%).
- the BB associated with other polymers retains healing properties, with milk proteins or pea proteins.
- the PL/ALG and PP/ALG combinations do not have healing properties superior to those of the culture medium.
- 6-well plates were seeded at 3.4 ⁇ 10 5 HT-29 MTX cells per well (1 mb/well).
- Polymer solutions at 0.05% by weight, prepared in DMEM, were added to each well (1 mL/well) along with the cells.
- the cell culture medium was renewed daily. After 72 h of growth at 37° C., the cells were recovered and counted using a Kova® cell counting slide under an optical microscope (40x magnification).
- DMEM control
- BB final mixture 0.05% m/m
- PL/ALG 50 /50 m/m with a final blend of 0.05% polymers
- PL/(ALG/BB) 33/33/33 m/m with a final blend of 0.05% polymers.
- DMEM represents 100% of cell growth.
- FIG. 11 show that BB stimulates cell growth by more than 185%, whereas the PL associated with ALG have no impact on cell growth.
- the combination of the 3 polymers in accordance with the invention allows an increase of 166%. Cell healing is therefore linked to an increase in cell growth with polymers containing BB.
- a line of murine macrophages (RAW 264.7) was cultured to confluence (12-well plate, 1 mL of DMEM culture medium with fetal calf serum (20-25%) and amino acid (5% ), temperature 37°C). The cells were then inflamed for 12 h as well as during the experiment with a solution of lipopolysaccharide (LPS sold under the reference L4391 by the company Sigma Aldrich) at 10 pg/mL.
- LPS lipopolysaccharide
- polymer solutions (same concentration of all the polymers in the mixture) produced in DMEM, are deposited in each well (3 mb/well): BB (final mixture 0.5% m/m), PL/ALG (50/50 m/m with a final blend of 0.5% polymers), PP/ALG (50/50 m/m with a final blend of 0.5% polymers), PL/(ALG/BB) (33/33/33 m/m with a final blend of 0.5% polymers), and PP/(ALG/BB) (33/33/33 m/m with a final blend of 0.5% polymers).
- TNF-alpha an inflammation marker
- ELISA Bio-Techne, R&D Systems, England.
- the results obtained are shown in the appended figure 12 in which the level of Tnf-alpha (in pg/mL) is given for each of the solutions tested: DMEM (negative control), DMEM + LPS (positive control), LPS + BB at 0.5% by mass, PLS + Pb/ALG at 0.5% by mass, LPS + PL/(ALG/BB) at 0.5% by mass, LPS + PP/ALG at 0.5% by mass and LPS + PP/(ALG/BB) at 0.5% by weight.
- PL lipid peroxidation
- they are able to reduce the effects of oxygen radicals and lipid peroxidation by increasing the activity of the antioxidant glutathione, thus stimulating the epithelization and proliferation of fibroblasts as well as increasing the secretion of pro- and post-inflammatory (Ebaid, H., Salem, A., Sayed, A. et al., Whey protein enhances normal inflammatory responses during cutaneous wound healing in diabetic rats., Lipids Health Dis 10, 235 (2011)).
- DSS Destran Sodium Sulfate
- the percentage of weight loss as well as the classic inflammatory markers were measured according to the method described in the article by B. Chassaing et al., Affiliations expand 2012, DOI: 10.137 l /log pone.0044328).
- Colic damage was determined daily by the disease activity index, the DAI (acronym for the English expression “Disease Activity Index”) as defined in the publication by Carvalho et al. (Inflamm. Bowel Dis., Volume 14, Number 8, August 2008). Rectal bleeding was assessed by the Hemoccult II test (SKD SARL). Scores range from 0 (healthy) to 12 (greatest colitis activity). The DAI score was calculated as the sum of the weight loss score, diarrhea score and hematochezia score.
- the total intestinal permeability was determined by measuring the fluorescence intensity in the plasma 3 hours after gavage with fluorescein (400 Da).
- the animal's colonic sensitivity is assessed by colorectal distension, this method is similar to that used in humans (Ritchie, J. 1973. 'Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome', Gut, 14: 125-32.) and consists of the inflation of a balloon in the distal colon of mice.
- the animals were placed in habituation in the restraint system during the hour preceding the colorectal distension test.
- the balloon associated with the pressure sensor is placed in the colorectum 1 cm from the anal margin.
- the balloon is then attached to the animal's tail with adhesive tape.
- the distension protocol consists of a set of distensions of increasing pressure (20, 40, 60 and 80 mmHg), repeated twice for each pressure, for 20 seconds with an inter-stimulus interval of 4 minutes.
- the analysis of the plots is carried out using the LabChart software (AD Instruments).
- the raw signal (intracolonic pressure) is smoothed over a period of 2 seconds and then positive.
- the response of the animals is calculated for each distension pressure by subtracting the integral of the processed signal corresponding to the 20 seconds preceding the stimulation from the integral of the processed signal during the 20 seconds of stimulation.
- DSS + Water induces a low-noise inflammation that is significantly different from the Water + Water control, measured by an increase in fecal lipocalin-2 (Lcn2).
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FR2107368A FR3124953A1 (fr) | 2021-07-07 | 2021-07-07 | Forme galénique à base de pulpe de baobab, procédés de préparation et utilisations |
PCT/EP2022/068715 WO2023280908A1 (fr) | 2021-07-07 | 2022-07-06 | Forme galenique a base de pulpe de baobab, procedes de preparation et utilisations |
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