WO2023280908A1 - Galenic form based on baobab pulp, processes for preparing same, and uses thereof - Google Patents
Galenic form based on baobab pulp, processes for preparing same, and uses thereof Download PDFInfo
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- WO2023280908A1 WO2023280908A1 PCT/EP2022/068715 EP2022068715W WO2023280908A1 WO 2023280908 A1 WO2023280908 A1 WO 2023280908A1 EP 2022068715 W EP2022068715 W EP 2022068715W WO 2023280908 A1 WO2023280908 A1 WO 2023280908A1
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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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Abstract
The present invention relates to a galenic form for oral controlled release of a substance of interest, said galenic form comprising a combination of biodegradable and biocompatible polymer excipients, said combination of polymer excipients comprising at least one denatured or non-denatured protein, at least one polysaccharide and baobab fruit pulp. It also relates to a controlled-release pharmaceutical or food composition based on such a galenic form, and also to a process for preparing such a composition.
Description
FORME GALENIQUE A BASE DE PULPE DE BAOBAB, PROCEDES DE PREPARATION ET UTILISATIONS GALENIC FORM BASED ON BAOBAB PULP, PREPARATION PROCESSES AND USES
Domaine technique La présente invention se rapporte au domaine de la formulation de compositions pharmaceutiques et/ou alimentaires destinées à être ingérées. Technical field The present invention relates to the field of the formulation of pharmaceutical and/or food compositions intended to be ingested.
Plus précisément, la présente invention concerne une forme galénique pour la libération contrôlée d'une substance d'intérêt par voie orale, notamment pour une libération prolongée et/ou ciblée, ladite forme galénique comprenant une association de polymères à titre d'excipients. Elle concerne en outre une composition pharmaceutique ou alimentaire à libération contrôlée à base d'une telle forme galénique, ainsi qu'un procédé de préparation d'une telle composition. Etat de la technique More specifically, 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. State of the art
Il existe ainsi de nombreuses voies d'administration de principes actifs : locale (transmucosale), entérale (orale, rectale, sublinguale) et parentérale (injectable). There are thus many routes of administration of active principles: local (transmucosal), enteral (oral, rectal, sublingual) and parenteral (injectable).
Grâce à sa simplicité et à son confort d'utilisation, la voie orale est une voie d'administration très largement utilisée. Elle présente des avantages tels que la facilité d'emploi, l'absence de douleur à l'administration et surtout la réduction du risque infectieux. Elle est par ailleurs la voie privilégiée pour la délivrance d'agents actifs absorbables par la paroi intestinale. Elle présente néanmoins des inconvénients. En effet, pour que le principe actif puisse avoir un effet thérapeutique par voie orale, il faut que celui-ci soit absorbé au bon endroit à travers la barrière intestinale pour être présent en quantité suffisante dans la circulation sanguine. Thanks to its simplicity and ease of use, 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.
La forme galénique (du nom de Galien, médecin grec du Ile siècle), ou forme médicamenteuse, ou forme pharmaceutique, est la forme sous laquelle sont mis les principes actifs et les excipients (matières inactives) pour constituer un médicament. La forme galénique correspond à l'aspect physique final du médicament tel qu'il sera utilisé chez un patient : comprimés, gélules, sachets, solutions buvables, suspensions injectables, etc. Ces formes galéniques doivent être adaptée à la voie d'administration
choisie ainsi qu'à la nature même des principes actifs que l'on souhaite administrer. 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.
Ainsi, pour améliorer l'efficacité des principes actifs administrés par voie orale et leur biodisponibilité au niveau de la barrière intestinale, des systèmes d'administration permettant une libération contrôlée dudit principe actif sont fréquemment employés. Ces systèmes permettent par exemple de moduler la solubilité des principes actifs, de restreindre leur libération à un site spécifique ou encore de réduire ou éviter leur dégradation indésirable dans l'estomac. Les formes galéniques à libération contrôlée (ou modifiée) d'un principe actif ou d'un agent bioactif peuvent être classées en plusieurs catégories :Thus, to improve the effectiveness of active principles administered orally and their bioavailability at the level of the intestinal barrier, administration systems allowing controlled release of said active principle are frequently employed. These systems make it possible, for example, to modulate the solubility of the active principles, to restrict their release to a specific site or even to reduce or avoid their undesirable degradation in the stomach. Galenic forms with controlled (or modified) release of an active principle or a bioactive agent can be classified into several categories:
- les formes à libération retardée (par exemple, en utilisant un enrobage entérique); - delayed-release forms (eg, using enteric coating);
- les formes à libération ciblée ou « site spécifique » ou libération dans le temps (par exemple, pour une libération colique); - forms with targeted release or "specific site" or release over time (for example, for colonic release);
- les formes à libération prolongée (par exemple, d'ordre zéro, de premier ordre, biphasique, etc.); et - sustained-release forms (eg, zero-order, first-order, biphasic, etc.); and
- les formes à libération programmée (par exemple, pulsatile, retardée, etc.). Dans le cas des formes à libération prolongée, la libération est prolongée en retenant le principe actif ou l'agent bioactif au sein d'un système contrôlant sa vitesse de libération. Le principe actif ou l'agent bioactif peut être inclus dans un excipient insoluble dans les liquides de l'organisme qui forme ainsi une matrice à partir de laquelle le principe actif ou l'agent bioactif sera libéré lentement. Les formes à libération prolongées procurent un certain nombre d'avantages parmi lesquels on peut notamment mentionner la réduction des prises journalières, l'accroissement du confort du malade, l'amélioration de l'observance du traitement et la diminution des effets secondaires indésirables par suppression des pics plasmatiques. La libération ciblée, telle que par exemple la libération colique, est une libération retardée jusqu'à un site spécifique du tractus gastro-intestinal. La libération colique est obtenue par une formulation galénique qui s'oppose à la libération du principe actif ou de l'agent bioactif durant la phase de transit dans le haut tractus gastro-intestinal (HTGI) (estomac et intestin grêle) et
qui est ensuite dégradée au niveau du côlon. De nombreuses stratégies existent pour que les formes galéniques atteignent le côlon intactes, utilisant les paramètres physico-chimiques spécifiques des différents compartiments du tractus gastrointestinal (pH, temps de transit, densité bactérienne). Cependant, les enrobages sensibles aux enzymes bactériennes de la microflore colique semblent être les plus spécifiques.- the forms with programmed release (for example, pulsatile, delayed, etc.). In the case of 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. Many strategies exist for the dosage forms to reach the colon intact, using the specific physicochemical parameters of the different compartments of the gastrointestinal tract (pH, transit time, bacterial density). However, coatings sensitive to bacterial enzymes of the colonic microflora seem to be the most specific.
Les systèmes à libération colique ont été reconnus comme présentant d'importants avantages thérapeutiques et la recherche dans ce domaine s'intensifie. Ils améliorent considérablement le traitement de nombreuses pathologies à atteintes coliques telles que les maladies inflammatoires chroniques de l'intestin (MICI), le cancer du côlon, le syndrome du côlon irritable et la constipation. Par ailleurs, l'absorption des principes actifs de nature protéique ou peptidique est meilleure au niveau colique. Ce phénomène est dû notamment, à une activité protéolytique nettement plus faible au niveau du côlon qu'au niveau de l'intestin grêle et à l'absence d'une activité peptidasique associée à la membrane des cellules épithéliales coliques. Il y a donc un intérêt pour l'utilisation du côlon comme site d'absorption de ces principes actifs de nature peptidique comme exemple les analgésiques, les contraceptifs, les vaccins ou l'insuline dont l'administration se fait jusqu'à maintenant, essentiellement par voie parentérale, douloureuse et à l'origine d'une mauvaise acceptabilité. 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. There is therefore an interest in using the colon as a site for the absorption of these active ingredients of a peptide nature, such as analgesics, contraceptives, vaccines or insulin, the administration of which has been done until now, essentially by parenteral route, painful and at the origin of a bad acceptability.
Les formes galéniques à libération contrôlée, notamment à libération prolongée et/ou ciblée, peuvent être classées en deux catégories majeures : les formes dites "réservoir" dans lesquelles le principe actif est maintenu à l'intérieur d'un compartiment délimité par une membrane ralentissant sa diffusion, et les formes dites "matricielles" (également dénommé système matriciel) dans lesquelles le principe actif est mélangé de manière homogène au sein d'une matrice polymère ralentissant sa diffusion. 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.
De nombreux polymères sont utilisés de manière intensive comme composants principaux des systèmes de libération contrôlée de principes actifs. Ces systèmes sont conçus pour permettre la libération de la substance d'intérêt (principe actif ou agent bioactif) à un moment contrôlé, après un temps contrôlé, et à un site ciblé particulier tel que par exemple au niveau du colon.
Les systèmes matriciels à base de polymères présentent certains avantages par rapport aux autres types de systèmes d'administration de médicaments et d'agents bioactifs à libération contrôlée, par exemple la facilité de fabrication. En général, les dispositifs matriciels peuvent être préparés en mélangeant le médicament sous forme de poudre avec le ou les excipient(s) polymère(s) également sous forme de poudre. Ce mélange est ensuite placé dans un moule approprié (matrice) d'un dispositif de compression et les comprimés résultants sont prêts à être utilisés. Many polymers are used extensively as main components of controlled release systems of active ingredients. These systems are designed to allow the release of the substance of interest (active principle or bioactive agent) at a controlled moment, after a controlled time, and at a particular targeted site such as for example at the level of the colon. Polymer-based matrix systems have certain advantages over other types of controlled-release drug and bioactive agent delivery systems, such as ease of manufacture. In general, 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.
La demande internationale WO 2002/094224 décrit une composition de support pour des agents bioactifs comprenant des polymères glucidiques tels que des polysaccharides modifiés par un groupement hydrophobe, associés à des protéines de lait (par exemple le caséinate de calcium et/ou des protéines de lactosérum). Les formulations peuvent être utilisées dans divers systèmes de délivrance comprenant des billes, des comprimés, des agents de microencapsulation et des revêtements pour des formes posologiques orales, des implants pour des dispositifs sous-cutanés et des films. Ces formulations présentent une résistance chimique améliorée et exercent leur activité pendant une durée prolongée dans le tractus gastro intestinal (GIT) et la circulation sanguine. Il est indiqué que l'association de chitosan modifié ou d'alginate modifié et de protéines de lait aboutit à une structure stabilisée capable de contrôler la libération de médicaments, bactéries, bactériocines, enzymes, nutraceutiques, etc. par voie entérique, thématique ou systémique. Cependant, cette composition de support ne donne pas entièrement satisfaction dans la mesure où elle ne permet pas une administration optimale des molécules chargées comme les protéines et les peptides thérapeutiques qui peuvent déstabiliser le réseau (interaction ionique) ou des molécules de bas poids moléculaires qui peuvent diffuser à travers les pores trop larges du réseau polymère. En particulier, les polymères présents dans une telle composition ne présentent pas un taux d'encapsulation et de rétention satisfaisant pour les molécules de bas poids moléculaires chargées ce qui diminue notamment la biodisponibilité des substances d'intérêt véhiculées au niveau de la barrière intestinale.
Par ailleurs, le baobab, ou Adansonia digitata L, est un arbre fruitier indigène important dans les terres arides d'Afrique, de Malaisie, de Chine, de Jamaïque et d'Australie. Les fruits du baobab, les akoussas, calebasses ou bien encore pains de singe, ont des usages alimentaires ou cosmétiques variés. Le baobab est également utilisé en médecine populaire comme antipyrétique ou fébrifuge pour venir à bout des fièvres, ou bien encore pour ses propriétés anti-inflammatoires (C. M. K. Humar et al., J. Intercuit. Ethnopharmacol., 2016, vol. 5, no. 1, pp. 79-85 ; E. S. A. Ramadan et al., 1994, "Anti-inflammatory, analgésie 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 Lettre 7(5): 341-347). International application 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. However, 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. In particular, 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. On the other hand, the baobab, or Adansonia digitata L, is an important indigenous fruit tree in the drylands of Africa, Malaysia, China, Jamaica and Australia. The fruits of the baobab, the akoussas, calabashes or even monkey breads, have various food or cosmetic uses. 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).
Le fruit du baobab est composé d'une coque extérieure (épicarpe) renfermant de nombreuses graines entourées d'une pulpe sèche, acidulée et farineuse, et riche en mucilage, pectine, tartrate et acides tartriques libres. La pulpe du fruit contient une grande quantité d'hydrates de carbone, de pectine, peu de protéines et extrêmement peu de graisses. 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.
Dans certaines études, la poudre de fruit de pulpe de baobab a de bonnes caractéristiques lubrifiantes, liantes et diluantes. Elle a été utilisée comme excipient hydrophile pour la préparation de comprimés de paracétamol et de théophylline avec un effet durable (Arama E. et al., Famarco Ed. Pr., 1988, 43, p. 303-304 ; Arama E. et al., Pharm. Acta Helv., 1989, 64, p. 116-120). In some studies, 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).
Cependant, la potentialité de la pulpe de fruit comme excipient mucoadhésif n'a jamais été étudiée jusqu'à présent. However, the potentiality of fruit pulp as a mucoadhesive excipient has never been studied so far.
Les Inventeurs se sont donc fixés pour but de pourvoir à une forme galénique pour la libération contrôlée d'une substance d'intérêt par voie orale ne présentant pas les inconvénients de l'art antérieur et/ou ayant des propriétés améliorées par rapport aux compositions de l'art antérieur. Ce but est atteint par les objets de l'invention décrits ci-après. 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.
Objets de l'invention Objects of the invention
La présente invention a pour premier objet une forme galénique pour la libération contrôlée d'une substance d'intérêt par voie orale, ladite forme galénique comprenant au moins une association de polymères
biodégradables et biocompatibles à titre d'excipients, ladite forme galénique étant caractérisée en ce que : 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:
- ladite association de polymères comprend de 20 à 90 % en masse d'au moins une protéine, de 2,5 à 20 % en masse d'au moins un polysaccharide et de 8 à 75 % en masse de pulpe de fruits de baobab, lesdits pourcentages étant exprimés en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab) ; - 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);
- le rapport massique protéine(s)/pulpe de fruits de baobab, exprimé en masse de matières sèches, est compris entre 0,5 et 5 bornes incluses ; et - le rapport massique polysaccharide(s)/pulpe de baobab, exprimé en masse de matières sèches, est compris entre 0,05 et 1, bornes incluses.- 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.
Un deuxième objet de l'invention est une composition à libération contrôlée pour l'administration par voie orale d'au moins une substance d'intérêt, ladite composition étant caractérisée en ce qu'elle comprend une forme galénique selon le premier objet de l'invention et au moins une substance d'intérêt. 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.
Enfin, l'invention a pour troisième objet un procédé de préparation d'une composition telle que définie selon le deuxième objet de l'invention, ledit procédé étant caractérisé en ce qu'il comprend au moins une étape d'incorporation d'au moins une substance d'intérêt dans une forme galénique telle que définie selon le premier objet de l'invention et au moins une étape de mise en forme finale de ladite composition. Finally, 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.
Avantages de l'invention Advantages of the invention
La forme galénique conforme à l'invention permet d'accéder à des compositions pharmaceutiques ou alimentaires à libération contrôlée, notamment à libération ciblée et prolongée dans le temps, en particulier sur une période pouvant aller de 4 à 24 heures. De telles compositions sont utilisables pour l'administration par voie orale de substances d'intérêt telles que des principes actifs, en particulier de nature protéique ou peptidique, et de probiotiques dans le cadre d'un traitement, notamment chronique. Ainsi, la forme galénique conforme à l'invention, utilisant des excipients ayant de bonne propriétés de mucoadhésivité intestinale, assure la libération ciblée et prolongée de substances d'intérêt, ce qui permet d'accéder à des compositions pharmaceutiques ou alimentaires autorisant
la réduction des prises répétées de médicament, d'améliorer la biodisponibilité ou bioaccessibilité de ladite substance d'intérêt, de favoriser la compliance du patient et de réduire les effets secondaires potentiels. L'association de polymères présente dans la forme galénique conforme à l'invention permet en outre d'accroître les propriétés intrinsèques de chacun d'eux et de conduire à des compositions pharmaceutiques dont les propriétés biopharmaceutiques sont optimisées. Enfin, la présence de pulpe de fruits baobab dans l'association de polymères utilisée à titre d'excipient dans la forme galénique conforme à l'invention, permet de réduire les doses de substances actives anti-inflammatoires et/ou analgésiques administrées lorsque la forme galénique est utilisée pour formuler une composition pharmaceutique destinée à des patients atteints de maladies inflammatoires chroniques de l'intestin (MICI), compte tenu des propriétés anti inflammatoires et analgésiques intrinsèques de la pulpe de fruits de baobab. Définitions 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. Thus, 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. Finally, 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. Definitions
Dans la présente invention, l'expression « polymère biodégradable » signifie un polymère qui peut être dégradé ou digéré par des réactions d'hydrolyse, c'est-à-dire des coupures de liaisons covalentes par réaction avec un milieu aqueux (conformément à la norme NF EN 13 432). Dans la présente invention, l'expression « polymère biocompatible » signifie un polymère ayant la capacité à ne pas interférer et à ne pas dégrader le milieu biologique dans lequel il est utilisé. En particulier, ils ne doivent pas provoquer de réaction inflammatoire forte (e.g. allergies) et/ou ne doivent pas être toxiques pour l'être humain. Au sens de la présente invention, on entend par substance d'intérêt, l'ensemble formé par les principes actifs et les probiotiques. In the present invention, the expression “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). In the present invention, the expression “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. Within the meaning of the present invention, the term “substance of interest” means the assembly formed by the active principles and the probiotics.
Un principe actif est une substance chimique ayant un effet thérapeutique. Selon la définition donnée par en 2001 par l'Organisation mondiale de la Santé (OMS) et l'Organisation des Nations unies pour l'alimentation et l'agriculture (FAO) les probiotiques sont des micro-organismes vivants qui, lorsqu'ils sont ingérés en quantité suffisante, exercent des effets positifs sur la santé, au-delà des effets nutritionnels traditionnels. An active principle is a chemical substance having a therapeutic effect. According to the definition given in 2001 by the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO), probiotics are living micro-organisms which, when ingested in sufficient quantity, exert positive effects on health, beyond the traditional nutritional effects.
La dénaturation d'une protéine correspond à la désorganisation de la structure spatiale sans rupture des liaisons covalentes et en particulier des
liaisons peptidiques, car seules les liaisons secondaires sont concernées. La chaîne polypeptidique est alors partiellement ou totalement dépliée. Ainsi, selon l'invention, une protéine dénaturée est une protéine ayant perdu sa configuration tridimensionnelle et dans laquelle la chaîne polypeptidique est partiellement ou totalement dépliée. The denaturation of a protein corresponds to the disorganization of the spatial structure without breaking the covalent bonds and in particular the peptide bonds, because only the secondary bonds are concerned. The polypeptide chain is then partially or totally unfolded. Thus, according to the invention, a denatured protein is a protein having lost its three-dimensional configuration and in which the polypeptide chain is partially or totally unfolded.
Description détaillée detailed description
Le premier objet de l'invention est une forme galénique pour la libération contrôlée d'une substance d'intérêt par voie orale, ladite forme galénique comprenant au moins une association de polymères biodégradables et biocompatibles à titre d'excipients, ladite forme galénique étant caractérisée en ce que : 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 :
- ladite association de polymères comprend de 20 à 90 % en masse d'au moins une protéine, de 2,5 à 20 % en masse d'au moins un polysaccharide et de 8 à 75 % en masse de pulpe de fruits de baobab, lesdits pourcentages étant exprimés en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab) ; - 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);
- le rapport massique protéine(s)/pulpe de fruits de baobab, exprimé en masse de matières sèches, est compris entre 0,5 et 5 bornes incluses ; et- the protein(s)/baobab fruit pulp mass ratio, expressed as mass of dry matter, is between 0.5 and 5 limits inclusive; and
- le rapport massique polysaccharide(s)/pulpe de baobab, exprimé en masse de matières sèches, est compris entre 0,05 et 1, bornes incluses.- the polysaccharide(s)/baobab pulp mass ratio, expressed as mass of dry matter, is between 0.05 and 1, limits included.
La ou les protéines présentes dans l'association de polymères de la forme galénique conforme à l'invention peuvent être d'origine végétale ou animale. Elles constituent un ingrédient à part entière de la forme galénique conforme à l'invention. Elles sont en particulier distinctes des protéines qui peuvent être naturellement contenues dans la pulpe de fruit de baobab. La ou les protéines sont utilisées sous forme non dénaturée ou sous forme dénaturée. La dénaturation des protéines peut par exemple être réalisée par traitement thermique de la protéine en solution aqueuse à pH neutre, par exemple à une température d'environ 70 à 80°C pendant 30 à 60 minutes. La solution de protéines dénaturées est ensuite séchée selon les techniques classiques telles que l'atomisation ou la lyophilisation. 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.
Parmi les protéines d'origine végétale, on peut en particulier mentionner les protéines de pois ; les protéines de grains de maïs telles que la zéine ; les protéines de céréales telles que les protéines de blé (par exemple les
prolamines comme la gliadine et les gluténines), d'orge, de riz, d'épeautre, d'avoine, etc... ; les protéines de soja ; les protéines de graines de courges, etc... Among the 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.
Parmi les protéines d'origine animale, on peut en particulier mentionner les protéines de lait telles que les protéines de lactosérum (ou protéines du petit lait) et les caséinates ainsi que les gélatines telles que par exemple les gélatines de poissons. Among the proteins of animal origin, mention may in particular be made of milk proteins such as whey proteins (or whey proteins) and caseinates as well as gelatins such as for example fish gelatins.
Selon une forme de réalisation préférée de l'invention, la ou les protéines sont des protéines de lait et encore plus préférentiellement des protéines de lactosérum. A titre d'exemple, on peut notamment mentionner l'isolat de protéines de lactosérum vendu sous la dénomination commerciale Alacen® 845 par la société NZMP (Wellington, Nouvelle Zélande). According to a preferred embodiment of the invention, the protein or proteins are milk proteins and even more preferentially whey proteins. By way of example, mention may in particular be made of the whey protein isolate sold under the trade name Alacen® 845 by the company NZMP (Wellington, New Zealand).
Selon une forme de réalisation préférée de l'invention, la forme galénique comprend de 55 à 80 % environ en masse de protéines, ledit pourcentage étant exprimé en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab). According to a preferred embodiment of the invention, 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).
Le ou les polysaccharides présents dans l'association de polymères de la forme galénique conforme à l'invention constituent un ingrédient à part entière de la forme galénique conforme à l'invention. Ils sont en particulier distincts des polysaccharides qui peuvent être naturellement contenus dans la pulpe de fruit de baobab. Le ou les polysaccharides sont de préférence choisis parmi les polysaccharides anioniques ayant une masse moléculaire moyenne supérieure ou égale à 75 000 Daltons environ, et encore plus préférentiellement de 75 000 à 250 000 Daltons environ. Selon une forme de réalisation préférée de l'invention, le ou les polysaccharides anioniques sont choisis parmi les alginates, les pectines, les dérivés cellulosiques, les gommes polysaccharidiques telles que l'agar-agar, la gomme de xanthane et la gomme gellane, les carraghénanes, les dextranes et dextranes modifiés, l'acide poly(lactique-co-glycolique) (PLGA) et l'acide hyaluronique. 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. According to a preferred embodiment of the invention, 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.
Selon une forme de réalisation particulièrement préférée de l'invention, le polysaccharide est un polysaccharide anionique choisi parmi les alginates, encore plus préférentiellement les alginates de sodium.
Les alginates sont des hydrocolloïdes naturels extraits d'algues récoltées de manière durable. Chimiquement, les alginates sont formés à partir de polysaccharides avec des éléments constitutifs (blocs) constitués de sels d'acide mannuronique et guluronique. La proportion, la distribution et la longueur de ces blocs déterminent les propriétés chimiques et physiques des molécules d'alginate. According to a particularly preferred embodiment of the invention, 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.
Parmi les alginates, on préfère tout particulièrement les alginates dans lesquels le rapport molaire unités acide guluronique (G) / unités acide mannuronique (M) (G/M) varie de 0,5 à 2,5. Selon une forme de réalisation préférée de l'invention, les alginates sont choisis parmi ceux dans lesquels la proportion d'unités acide guluronique varie de 50 à 70 % en moles environ. En effet, selon l'invention, le choix de l'alginate de sodium utilisé est important dans la mesure où les alginates de sodium ayant un taux en acide guluronique trop élevé (supérieur à 70 % en moles) conduisent à des gels trop fermes et cassants avec synérèse, tandis que les alginates de sodium ayant un taux en acide guluronique inférieur à 50 % en moles, c'est-à-dire dans lesquels la proportion en unités acide mannuronique est supérieure à 50 % en moles, conduisent à des gels ayant une structure trop molle ce qui les rend difficiles à travailler et à manipuler. Parmi de tels alginates, on peut notamment mentionner les alginates de sodium dans lesquels le rapport molaire G/M est supérieur à 1, 5/1,0 tels que les produits vendus sous les dénominations commerciales Manugel® DMB et Manugel® LBA par la société FMC BioPolymer, les alginates de sodium dans lesquels le rapport molaire G/M est inférieur à 1, 0/1,0 tels que les produits vendus sous les dénominations commerciales Manucol® DH et Manucol® LKX par la société ISP (Wayne, New Jersey, USA), ainsi que sous les dénominations commerciales Keltone® HVCR et Keltone® LVCR par la société FMC BioPolymer ; les alginates de basse viscosité tels que le produit vendu sous la dénomination commerciale Protanan® CR 8133 et les alginates de haute viscosité tels que le produit vendu sous la dénomination Protanal® CR 8233. Among the alginates, 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. According to a preferred embodiment of the invention, the alginates are chosen from those in which the proportion of guluronic acid units varies from 50 to 70% by moles approximately. Indeed, according to the invention, 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. Among such alginates, mention may in particular be made of sodium 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.
Le ou les polysaccharides présents dans l'association de polymères de la forme galénique conforme à l'invention peuvent également être choisis parmi les polysaccharides cationiques ayant une masse moléculaire
moyenne supérieure ou égale à 100 000 Daltons environ, et encore plus préférentiellement de 150 000 à 600 000 Daltons environ. The 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.
Parmi de tels polysaccharides cationiques, on peut en particulier mentionner le chitosan, l'acide hyaluronique et le dextrane. Selon une forme de réalisation préférée de l'invention, la forme galénique comprend de 4 à 15 % environ en masse de polysaccharide(s), ledit pourcentage étant exprimé en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab). La pulpe de fruits de baobab présente dans l'association de polymères de la forme galénique conforme à l'invention se présente généralement sous la forme d'une poudre. Elle est obtenue à partir de la pulpe des fruits de baobab après séchage. A titre d'exemple, on peut notamment mentionner la poudre de pulpe de fruits de baobab vendue sous la dénomination commerciale PBA-BIO BAOMIX par la société Agoji (Sète, France). Among such cationic polysaccharides, mention may in particular be made of chitosan, hyaluronic acid and dextran. According to a preferred embodiment of the invention, 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. By way of example, mention may in particular be made of the baobab fruit pulp powder sold under the trade name PBA-BIO BAOMIX by the company Agoji (Sète, France).
Selon une forme de réalisation préférée de l'invention, la forme galénique comprend de 17 à 72 % environ en masse de pulpe de fruits de baobab, ledit pourcentage étant exprimé en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab). According to a preferred embodiment of the invention, 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).
Selon une première forme de réalisation, la forme galénique conforme à la présente invention se présente sous la forme solide, par exemple sous la forme de poudre, de granulés (granulation sèche ou humide de la poudre), sous la forme de comprimés résultant de la compression directe des différents polymères utilisés sous forme de poudre ou des granulés ou bien encore sous forme de gélules contenant la poudre ou les granulés. According to a first embodiment, 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.
Selon cette première forme de réalisation, le rapport massique protéine(s)/pulpe de fruits de baobab, exprimé en masse de matières sèches, est de préférence compris entre 0,7 et 2 bornes incluses. Egalement selon cette première forme de réalisation, le rapport massique polysaccharide(s)/pulpe de baobab, exprimé en masse de matières sèches, est de préférence compris entre 0,05 et 0,5 bornes incluses. According to this first embodiment, the protein(s)/baobab fruit pulp mass ratio, expressed as mass of dry matter, is preferably between 0.7 and 2 limits inclusive. Also according to this first embodiment, the polysaccharide(s)/baobab pulp mass ratio, expressed as mass of dry matter, is preferably between 0.05 and 0.5 limits inclusive.
Selon une deuxième forme de réalisation de l'invention, la forme galénique se présente sous la forme de suspensions gélifiées ou de microparticules
gélifiées (hydrogel) et sont obtenues par mélange (sans agent gélifiant) ou par gélification (agent gélifiant), notamment par gélification ionotropique, des différents polymères en solution en présence d'un agent provoquant la gélification de la solution de polymères, la ou les protéines étant alors utilisées sous forme dénaturée. Les microparticules peuvent être produites manuellement à l'aide d'une seringue et d'une aiguille (23G selon la taille de microparticules voulue) ou avec un encapsulateur. According to a second embodiment of the invention, 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.
Selon cette deuxième forme de réalisation, la taille des microparticules varie généralement de 500 μm à 3 mm environ, et encore plus préférentiellement de 1,5 à 3,0 mm environ. According to this second embodiment, the size of the microparticles generally varies from 500 μm to 3 mm approximately, and even more preferably from 1.5 to 3.0 mm approximately.
Selon cette deuxième forme de réalisation, le rapport massique protéine(s) dénaturée(s)/pulpe de fruits de baobab, exprimé en masse de matières sèches, est de préférence compris entre 2,2 et 4,5 bornes incluses. Egalement selon cette deuxième forme de réalisation, le rapport massique polysaccharide(s)/pulpe de baobab, exprimé en masse de matières sèches, est de préférence compris entre 0,1 et 0,4 bornes incluses. According to this second embodiment, 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. Also according to this second embodiment, the polysaccharide(s)/baobab pulp mass ratio, expressed as mass of dry matter, is preferably between 0.1 and 0.4 limits inclusive.
La forme galénique telle que définie selon le premier objet de l'invention peut avantageusement être utilisée pour la préparation d'une composition pharmaceutique ou d'une composition alimentaire à libération contrôlée pour l'administration par voie orale d'au moins une substance d'intérêt.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.
L'invention a donc pour deuxième objet une composition à libération contrôlée pour l'administration par voie orale d'au moins une substance d'intérêt, ladite composition étant caractérisée en ce qu'elle comprend une forme galénique selon le premier objet de l'invention et au moins une substance d'intérêt. 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.
Ladite composition peut en particulier se présenter sous la forme d'une composition pharmaceutique et la substance d'intérêt est choisie parmi les principes actifs, les probiotiques, et leurs mélanges. 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.
Bien que la nature des substances d'intérêt pouvant être présentes dans la composition pharmaceutique conforme à l'invention ne soit pas critique, ladite composition est cependant particulièrement adaptée à la formulation de principes actifs et/ou de probiotiques nécessitant une libération contrôlée, en particulier une libération prolongée et ciblée au niveau de la muqueuse intestinale.
Parmi de tels principes actifs, on peut en particulier mentionner les principes actifs appartenant aux classes 2 et 4 du système de classification biopharmaceutique (BCS en anglais) des substances médicamenteuses, dont les protéines et les peptides thérapeutiques. Ce système permet de classer les principes actifs en fonction de leur solubilité et de leur perméabilité intestinale (Mehul Mehta, Biopharmaceutics Classification System (BCS) : Development, Implémentation, and Growth, Wiley, 2016, 456 p. (ISBN 978-1-118-47661-1)). Selon cette classification, les principes actifs de la classe 2 ont une haute perméabilité intestinale et une faible solubilité, alors que les principes actifs de la classe 4 ont une faible perméabilité intestinale et une faible solubilité. Although the nature of the substances of interest which may be present in the pharmaceutical composition in accordance with the invention is 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. Among such active principles, mention may in particular be made of active principles belonging to classes 2 and 4 of the biopharmaceutical classification system (BCS) for medicinal substances, including therapeutic proteins and peptides. 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)). According to this classification, class 2 active ingredients have high intestinal permeability and low solubility, while class 4 active ingredients have low intestinal permeability and low solubility.
Selon une forme de réalisation préférée de l'invention, le principe actif est choisi parmi les protéines thérapeutiques et les peptides thérapeutiques. Parmi les protéines et peptides thérapeutiques, et à titre d'exemples non limitatifs, on peut tout particulièrement mentionner l'insuline, la calcitonine, les facteurs de coagulation, les hormones de croissance telles que par exemple l'érythropoïétine (EPO), la triptoréline, l'orgulatran (anti-GnRH), les anticorps monoclonaux (IgG, Inflimixab), les cytokines (IL-10, IFN, G- CSF), l'urokinase (embolie pulmonaire), les antigènes vaccinaux, les antithrombotiques tels que l'hirudine et ses analogues, les antiagrégants plaquettaires tels que l'intégrine, et les peptides vecteurs permettant le transport d'ARN tels que le Transportan. According to a preferred embodiment of the invention, the active principle is chosen from therapeutic proteins and therapeutic peptides. Among the 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.
Parmi les probiotiques utilisables à titre de substance d'intérêt dans les compositions conformes à l'invention, et à titre d'exemples non limitatifs, on peut mentionner les bactéries, et en particulier les bactéries lactiques telles que les lactobacilles (bactéries du genre Lactobacillus), les bifidobactéries (bactéries du genre Bifidobacterium) et certains streptocoques (bactéries du genre Streptococcus) ; les levures, et en particulier les levures du genre Saccharomyces telles que Saccharomyces cerevisiae (ou levure de bière) et Saccharomyces boulardii. Among the 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.
Selon que la forme galénique telle que définie selon le premier objet de l'invention se présente sous forme solide ou sous forme de microparticules, la composition la comprenant peut également prendre des formes différentes.
Selon une première variante de l'invention, la composition est préparée à partir d'une forme galénique sous forme solide. Dans ce cas, la composition conforme à l'invention se présente également sous forme solide, par exemple sous la forme de poudre ou sous la forme de comprimés résultant de la compression des différents polymères de la forme galénique utilisés sous forme de poudre en mélange avec au moins une substance d'intérêt ou bien encore sous forme de gélules après éventuellement une granulation humide des différents polymères de la forme galénique initialement sous forme de poudre en mélange avec au moins une substance d'intérêt. Dans ce cas, c'est-à-dire, lorsque la composition comprend la forme galénique sous forme solide et qu'elle se présente également sous forme solide, alors ladite forme galénique représente de préférence de 20 à 50 % en masse, et encore plus préférentiellement de 25 à 35 % en masse, par rapport à la masse totale de ladite composition. Le reste à 100 % est par ailleurs constitué de la ou des substances d'intérêt et du ou des excipients additionnels éventuellement présents au sein de ladite composition. Toujours selon cette forme de réalisation, la quantité de pulpe de fruits de baobab représente de préférence de 8 à 35 % en masse, et encore plus préférentiellement de 18 à 25 % en masse, par rapport à la masse totale de ladite composition. Depending on whether the pharmaceutical form as defined according to the first object of the invention is in solid form or in the form of microparticles, the composition comprising it can also take different forms. According to a first variant of the invention, the composition is prepared from a pharmaceutical form in solid form. In this case, 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. In this case, that is to say, when the composition comprises the galenic form in solid form and it is also in solid form, then 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. Still according to this embodiment, 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.
En effet, lorsque la quantité de pulpe de fruits baobab est inférieure à 8 % en masse par rapport à la masse totale de ladite composition, alors la libération prolongée est moins efficace, et lorsque la quantité de pulpe de fruits de baobab est supérieure à 35 % en masse par rapport à la masse totale de ladite composition, alors la production de la composition, notamment des comprimés, est complexe et moins reproductible (en termes d'écoulement, de remplissage de la matrice et de compression). Lorsque la composition se présente sous la forme d'un comprimé, celui-ci peut être nu, pelliculé ou enrobé. Lorsque la composition se présente sous la forme d'une poudre, ladite poudre peut être conditionnée par exemple dans une capsule. Indeed, when the amount of baobab fruit pulp is less than 8% by mass relative to the total mass of said composition, then the sustained release is less effective, and when the amount of baobab fruit pulp is greater than 35 % by mass relative to the total mass of said composition, then the production of the composition, in particular tablets, is complex and less reproducible (in terms of flow, filling of the matrix and compression). When the composition is in the form of a tablet, the latter may be plain, film-coated or coated. When the composition is in the form of a powder, said powder can be packaged, for example, in a capsule.
Selon une deuxième variante de l'invention, la composition est préparée à partir d'une forme galénique sous forme de microparticules gélifiées. Dans ce cas, la composition conforme à l'invention peut se présenter sous forme
d'une suspension desdites microparticules gélifiées dans un excipient liquide, ou semi-solide (gel), ou bien se présenter sous forme solide après séchage desdites microparticules gélifiées qui sont ensuite formulées sous forme de gélules ou de comprimés. Dans ce cas, c'est-à-dire lorsque la composition est préparée à partir de la forme galénique sous forme de microparticules gélifiées, ladite forme galénique représente de préférence de 11 à 14 % et encore plus préférentiellement de 11 à 12 % en masse, par rapport à la masse totale de ladite composition. Le reste à 100 % est par ailleurs constitué de la ou des substances d'intérêt, du ou des excipients additionnels éventuellement présents au sein de ladite composition, et du ou des solvants utilisés pour dissoudre les polymères, en particulier de l'eau. Toujours selon cette forme de réalisation, la quantité de pulpe de fruits de baobab représente de préférence de 1 à 4 % en masse, par rapport à la masse totale de ladite composition. According to a second variant of the invention, the composition is prepared from a pharmaceutical form in the form of gelled microparticles. In this case, 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. In this case, that is to say when the composition is prepared from the galenic form in the form of gelled microparticles, 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. Still according to this embodiment, the quantity of baobab fruit pulp preferably represents from 1 to 4% by mass, relative to the total mass of said composition.
En effet, lorsque la quantité de pulpe de fruits baobab est inférieure à 1 % en masse par rapport à la masse totale de ladite composition, alors les interactions entre les polymères sont plus limitées, et lorsque la quantité de pulpe de fruits de baobab est supérieure à 4 % en masse par rapport à la masse totale de ladite composition, alors la réalisation de la formulation n'est pas entièrement satisfaisante et peut aboutir à des microparticules non sphériques. Indeed, when the amount of baobab fruit pulp is less than 1% by mass relative to the total mass of said composition, then the interactions between the polymers are more limited, and when the amount of baobab fruit pulp is greater at 4% by mass relative to the total mass of said composition, then the production of the formulation is not entirely satisfactory and may lead to non-spherical microparticles.
Ainsi que cela est bien connu du galéniste, la composition conforme à l'invention peut en outre renfermer un ou plusieurs excipients additionnels habituellement utilisés pour la formulation de compositions pharmaceutiques destinées à une administration par voie orale ou pour la formulation de compositions alimentaires. Parmi de tels excipients, on peut notamment mentionner les excipients généralement incorporés dans les compositions se présentant sous forme solide tels que les agents d'écoulements, les lubrifiants, les colorants, les agents de masquage du goût, etc..., ainsi que les excipients incorporés dans les compositions se présentant sous forme liquide ou gélifiée tels que les agents émulsionnants, les agents tensioactifs, les agents densifiants, etc. ...
A cette occasion, l'homme du métier veillera à ce que l'ajout de ce ou ces excipients n'altère pas de manière rédhibitoire les propriétés intrinsèques de la composition conforme à l'invention. As is well known to the galenist, 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. Among such 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. ... On this occasion, 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.
Enfin, l'invention a pour troisième objet un procédé de préparation d'une composition telle que définie selon le deuxième objet de l'invention, ledit procédé étant caractérisé en ce qu'il comprend au moins une étape d'incorporation d'au moins une substance d'intérêt dans une forme galénique telle que définie selon le premier objet de l'invention et au moins une étape de mise en forme finale de ladite composition. Finally, 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.
Selon une première forme de réalisation particulière de ce procédé, la composition est solide et se présente sous la forme d'un comprimé. Dans ce cas, un tel comprimé peut être obtenu à partir des ingrédients en poudre (polymères de la forme galénique, substance(s) d'intérêt et excipients additionnels éventuels) soit par compression directe, soit par granulation humide puis compression ; ces techniques étant couramment employées par l'homme du métier. According to a first particular embodiment of this method, the composition is solid and is in the form of a tablet. In this case, such 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.
Selon une deuxième forme de réalisation particulière de ce procédé, la composition se présente sous la forme de microparticules gélifiées. Dans ce cas, lesdites microparticules peuvent être obtenues par gélification ionotropique des polymères de la forme galénique en solution ou en suspension dans un solvant renfermant au moins une substance d'intérêt en présence d'un agent de réticulation. According to a second particular embodiment of this method, the composition is in the form of gelled microparticles. In this case, 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.
Dans ce cas, le procédé de préparation de la composition est un procédé de préparation de microparticules gélifiées et il comprend les étapes suivantes : i) la préparation d'une solution de protéines dénaturées, ii) la préparation d'une solution de pulpe de fruits de baobab et d'au moins un polysaccharide, iii) le mélange des solutions préparées ci-dessus aux étapes i) et ii), iv) l'ajout à la solution résultante d'au moins une substance d'intérêt, v) l'extrusion de la solution obtenue ci-dessus à l'étape iv) dans une solution contenant un agent de réticulation de façon à provoquer la gélification de ladite solution et l'obtention desdites microparticules gélifiées.
L'extrusion de l'étape v) peut notamment être réalisée à l'aide d'une aiguille sous l'effet d'une pression ou à l'aide d'un encapsulateur industriel, par exemple de type Buchi B390. In this case, 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.
Selon une forme de réalisation particulièrement préférée de ce procédé, le polysaccharide est un alginate de sodium et l'agent de réticulation est choisi parmi les cations divalents tels que le chlorure de calcium. According to a particularly preferred embodiment of this process, the polysaccharide is a sodium alginate and the crosslinking agent is chosen from divalent cations such as calcium chloride.
Brève description des dessins Brief description of the drawings
D'autres particularités et avantages de l'invention ressortiront de la description détaillée des exemples qui suivent, ainsi que dans les figures annexées. Other features and advantages of the invention will become apparent from the detailed description of the examples which follow, as well as from the appended figures.
[Fig 1] est un graphe représentant la force d'interaction entre les polymères PL/BB, ALG/BB, PL/ALG et PL/(ALG/BB) calculée en mesurant la viscosité (G") de solutions préparées avec le rapport massique 80/20 (en Pa) en fonction de la fréquence (en rad/s). [Fig 2] est un graphe représentant l'interaction G" d'échantillons individuels de polymères et de solutions comprenant des mélanges de polymère en présence de mucine (en Pa), en fonction de la fréquence (en rad/sec).[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] est un graphe représentant la capacité mucoadhésive de différentes solutions de polymères seuls ou en association. [Fig 4] est un graphe représentant la cinétique de libération du bleu dextran (BD) à partir de microparticules préparées à partir de différentes solutions de polymère (% de libération du BD en fonction du temps en minutes), à pH 1,2. [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.
[Fig 5] est un graphe représentant la cinétique de libération du BD à partir de microparticules préparées à partir de différentes solutions de polymère (% de libération du BD en fonction du temps en minutes), à pH 6,8. [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] est une photographie de microscopie électronique à balayage au grossissement xlOOO de microparticules préparées à partir de différentes solutions de polymères comparatives PL, ALG, BB, PL/BB, ALG/BB, PL/ALG comparativement à des particules gélifiées conformes à l'invention préparées à partir d'une solution de polymères PL/ (ALG/BB). [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] est un graphe comparant le gonflement de microparticules gélifiées obtenues à partir d'une solution comprenant l'association de polymères PL/ALG non conforme à l'invention à celui de microparticules gélifiées
conformes à l'invention obtenues à partir d'une solution comprenant l'association de polymères PL/(ALG/BB). La figure 7a donne la variation de diamètre (en %) en fonction du temps (en minutes). [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] est un graphe comparant le gonflement de microparticules gélifiées obtenues à partir d'une solution comprenant l'association de polymères PL/ALG non conforme à l'invention à celui de microparticules gélifiées conformes à l'invention obtenues à partir d'une solution comprenant l'association de polymères PL/(ALG/BB). La figure 7b donne la variation de la quantité d'eau absorbée (en %) en fonction du temps (en minutes). [Fig 8a] est un graphe représentant la cinétique de libération de la théophylline à partir de comprimés préparés avec différents mélanges de polymères à base de protéines de lait (en %) en fonction du temps (en minutes) à pH 1,2. [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] est un graphe représentant la cinétique de libération de la théophylline à partir de comprimés préparés avec différents mélanges de polymères à base de protéines de lait (en %) en fonction du temps (en minutes) à pH 6,8. [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] est un graphe représentant la cinétique de libération de la théophylline à partir de comprimés préparés avec différents mélanges de polymères à base de protéines de lait ou de protéines de pois (en %) en fonction du temps (en minutes) à pH 1,2. [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] est un graphe représentant la cinétique de libération de la théophylline à partir de comprimés préparés avec différents mélanges de polymères à base de protéines de lait ou de protéines de pois (en %) en fonction du temps (en minutes) à pH 6,8 (figure 9b). [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] est un graphe représentant la capacité de cicatrisation de différentes solutions de polymères, exprimée en pourcentage de cicatrisation. [Fig 10] is a graph representing the healing capacity of different polymer solutions, expressed as a percentage of healing.
[Fig 11] rapporte les résultats d'un test in vitro de croissance de cellules HT-29 MTX (en %) en présence de différentes solutions de polymères.[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] rapporte les résultats d'un test d'évaluation des propriétés anti inflammatoires de différentes solutions de polymères effectué sur une lignée de macrophages murins. Sur la figure 12, le taux de Tnf-alpha (en pg/mL) est donné pour chacune des solutions de polymères testées.
[Fig 13] rapporte les quantités de FITC dosée dans le sérum des souris après inflammation au DSS (DSS 0,5 %) ou témoin (Eau) pendant 12 jours avec pré-traitement et traitement avec de l'eau (témoin négatif Eau + Eau ou DSS 0,5 % + Eau), du BB (DSS 0,5 % + BB à 5 % m/m), un mélange PL/ALG (DSS 0,5 % + PL/ A LG à 5 % m/m) ou un mélange de PP/(ALG/BB) (DSS 0,5 % + P P/ (A LG/ B B) à 5 %) pendant 21 jours. [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. In FIG. 12, 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] rapporte l'effet dose-réponse de l'administration orale de polymères sur la sensibilité viscérale (aires sous la courbe AUC 60-80 mmHg). Le seuil de douleur en réponse à la distension colorectale a été testé à 12 jours de DSS (0,5 %) pour : Eau + Eau (témoin négatif), DSS à 0,5 % + Eau (témoin inflammation), DSS à 0,5 % + BB à 5 % (m/m), DSS à 0,5 % + PP/ALG à 5 % (m/m) et DSS à 0,5 % + PP/(ALG/BB) à 5 % (m/m). [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).
EXEMPLES Matières premières : Les matières premières utilisées dans les exemples sont les suivantes :EXAMPLES Raw materials: The raw materials used in the examples are as follows:
- Isolat de protéines de lactosérum Alacen® 845, société NZMP (Wellington, Nouvelle Zélande), ayant un taux de protéines à 93 % (matières sèches) déterminé par la méthode de Kjeldahl ; - Alacen® 845 whey protein isolate, from NZMP (Wellington, New Zealand), having a protein content of 93% (dry matter) determined by the Kjeldahl method;
- Alginate de sodium Manucol® DH pur à plus de 99 % (matières sèches), société ISP (Wayne, New Jersey, USA) ; - Manucol® DH sodium alginate more than 99% pure (dry matter), ISP company (Wayne, New Jersey, USA);
- Pulpe native de fruits de baobab (Adansonia digitata L.) PBA-BIO BAOMIX, société Agoji, (Sète, France) ; - Native baobab fruit pulp (Adansonia digitata L.) PBA-BIO BAOMIX, Agoji company, (Sète, France);
- Acétonitrile, méthanol, chlorure de calcium dihydrate (CaCI2), hydroxyde de sodium (NaOH), acide chlorhydrique (HCl), mucine, sulfate de sodium anhydre (Na2S04), acide phosphorique extra pure (H3P04) : société Fisher Scientific (Illkirch Graffenstaden, France) ; - Acetonitrile, methanol, calcium chloride dihydrate (CaCl2), sodium hydroxide (NaOH), hydrochloric acid (HCl), mucin, anhydrous sodium sulfate (Na2S04), extra pure phosphoric acid (H3P04): Fisher Scientific (Illkirch Graffenstaden) , France) ;
- Blue Dextran, Sigma-Aldrich (Saint Quentin Fallavier, France), - Blue Dextran, Sigma-Aldrich (Saint Quentin Fallavier, France),
- Lactose monohydraté tamisé (Capsulac ® 60), Cooper (Melun, France),- Screened lactose monohydrate (Capsulac ® 60), Cooper (Melun, France),
- Poudre de silice pyrogénée hydrophile vendue sous la dénomination commerciale Aérosil® 200, société Degussa AG (Frankfort, Allemagne),- Hydrophilic fumed silica powder sold under the trade name Aérosil® 200, company Degussa AG (Frankfort, Germany),
- Stéarate de magnésium vendu sous la référence 209-150-3 par la société Cooper (Melun, France),
Les matières premières utilisées dans les exemples qui suivent étaient de grade laboratoire et ont été mises en œuvre sans purification supplémentaire. - Magnesium stearate sold under the reference 209-150-3 by the company Cooper (Melun, France), The raw materials used in the examples which follow were of laboratory grade and were implemented without additional purification.
EXEMPLE 1 : Préparation d'une composition solide conforme à l'invention sous forme de comprimé par compression directe de poudres EXAMPLE 1 Preparation of a solid composition in accordance with the invention in the form of a tablet by direct compression of powders
Dans cet exemple, on a préparé une composition solide conforme au deuxième objet de l'invention se présentant sous la forme d'un comprimé ayant la composition indiquée dans le Tableau 1 ci-après : [TABLEAU 1]
In this example, a solid composition in accordance with the second object of the invention was prepared, in the form of a tablet having the composition indicated in Table 1 below: [TABLE 1]
Les ingrédients listés dans le Tableau 1 ci-dessous, sous forme de poudre, ont été mélangés puis le mélange de poudre a été compressé pour former un comprimé. EXEMPLE 2 : Préparation de formes galéniques solides conformes à l'invention par atomisation The ingredients listed in Table 1 below, in powder form, were mixed and then the powder mixture was compressed to form a tablet. EXAMPLE 2: Preparation of solid dosage forms in accordance with the invention by atomization
Dans cet exemple on a préparé des comprimés conformes à l'invention à partir de solutions ou de suspensions des différents polymères, à des pourcentages définis qui ont été séchés par atomisation à l'aide d'un atomiseur Buchi B290. Les poudres résultantes peuvent être utilisées pour formuler des gélules ou des comprimés après mélange avec au moins une substance d'intérêt. In this example, 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.
La composition des comprimés est donnée dans le Tableau 2 ci-après :
[TABLEAU 2]
The composition of the tablets is given in Table 2 below: [TABLE 2]
EXEMPLE 3 : Préparation de formes galéniques conformes à l'invention sous forme de microparticules gélifiées Dans cet exemple, on a préparé plusieurs formes galéniques conformes à l'invention sous la forme de microparticules gélifiées, par gélification ionotropique en présence de chlorure de calcium à titre d'agent de réticulation. EXAMPLE 3 Preparation of galenic forms in accordance with the invention in the form of gelled microparticles In this example, 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.
La composition des microparticules est donnée dans le Tableau 3 ci-après : [TABLEAU 3]
The composition of the microparticles is given in Table 3 below: [TABLE 3]
EXEMPLE 4 : Préparation de microparticules gélifiées conformes à l'invention et préparation de microparticules comparatives ne faisant pas partie de l'invention Dans cet exemple, on a préparé des microparticules gélifiées conformes à l'invention, c'est-à-dire à base de protéines de lait ou de protéines de pois, ainsi que d'alginate et de pulpe de fruit de baobab. On a également préparé
des microparticules comparatives ne faisant pas partie de l'invention, c'est- à-dire ne contenant qu'un seul ou que deux des polymères ci-dessus. EXAMPLE 4: Preparation of gelled microparticles in accordance with the invention and preparation of comparative microparticles not forming part of the invention In this example, 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. We also prepared comparative microparticles not forming part of the invention, that is to say containing only one or only two of the above polymers.
4.1 Réalisation des solutions de polymères : 4.1 Production of polymer solutions:
Solutions de protéines de lait (PL) (11 % m/m) : 4,73 g de poudre de PL ont été pesés dans un flacon de 50 mL (SHOTTMilk protein (PL) solutions (11% m/m): 4.73 g of PL powder was weighed into a 50 mL vial (SHOTT
Duran) et on a complété avec de l'eau désionisée qsp 40 g. Le flacon a été placé sous-agitation durant 5 min à 500 rotations par minutes (rpm) pour dissoudre la poudre de PL, puis à 200 rpm pendant 1 h afin de réhydrater les protéines. Le pH a été ajusté à 7 à l'aide d'une solution de NaOH IM. Le mélange a ensuite été agité pendant 5 min puis les protéines de lait ont été dénaturées sous-agitation (300 rpm) dans un bain marie pendant 40 min à 80°C. La solution de PL dénaturées a ensuite été laissée au repos pendant une nuit à température ambiante. Des solutions diluées de PL ont été réalisées à partir de la solution PL à 11 % m/m (PL 4,4 % m/m, PL 5,5 % m/m et PL 8,8 % m/m). Duran) and supplemented with deionized water qs 40 g. The flask was stirred for 5 min at 500 rotations per minute (rpm) to dissolve the PL powder, then at 200 rpm for 1 h in order to rehydrate the proteins. The pH was adjusted to 7 using 1M NaOH solution. The mixture was then stirred for 5 min then the milk proteins were denatured with stirring (300 rpm) in a water bath for 40 min at 80°C. The denatured PL solution was then allowed to stand overnight at room temperature. Diluted solutions of PL were made from the PL solution at 11% m/m (PL 4.4% m/m, PL 5.5% m/m and PL 8.8% m/m).
- Solution de protéines de pois (PP) (11 % m/m) : - Pea protein solution (PP) (11% m/m):
4,73 g de poudre de PP (Nutralys F85F Roquette) ont été pesés dans un flacon de 50 mL (SHOTT Duran) et on a complété avec de l'eau désionisée qsp 40 g. Le flacon a été placé sous-agitation durant 5 min à 500 pour dissoudre la poudre de PP puis à 200 rpm pendant 1 h afin de réhydrater les PP. Le pH a été ajusté à 7 à l'aide d'une solution de NaOH IM. Le mélange a ensuite été agité pendant 5 min puis les protéines de pois ont été dénaturées sous-agitation (300 rpm) dans un bain marie pendant 40 min à 80°C. La solution de PP dénaturées a ensuite été laissée au reposer pendant une nuit à température ambiante. Des solutions diluées de PP ont été réalisées à partir de la solution de PP à 11 % (m/m) (PP 4,4 % m/m, PP 5,5 % m/m et PP 8,8 % m/m). 4.73 g of 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 ).
- Solution aqueuse d'alginate ALG (3 % m/m) : - Aqueous solution of alginate ALG (3% m/m):
3 g de poudre d'ALG ont été pesés dans une coupelle et 97 g d'eau désionisée ont été pesés dans un bêcher de 250 mL. Le bêcher a été placé sous agitation (700 rpm), et la poudre d'ALG a été saupoudrée dans l'eau contenue dans le bêcher. Afin d'obtenir une homogénéisation plus rapide de la solution l'agitation a été maintenue pendant 1 h. Des solutions diluées
d'ALG ont été réalisées à partir de la solution d'ALG à 3 % m/m (ALG 0,3 % m/m, ALG 0,6 % m/m et ALG 1,5 % m/m). 3 g of ALG powder 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).
- Solution mixte d'alginate ALG (3% m/m) et de pulpe de fruit de baobab BB (10 %) : 10 g de BB de poudre de pulpe de fruit de baobab ont été pesés dans un bêcher de 100 mL puis on a complété à 100 g avec de l'eau désionisée. Le mélange a été placé sous-agitation (700 rpm) pendant 1 h, puis le pH a été ajusté à 7 à l'aide d'une solution de NaOH IM. 3 g de poudre d'ALG ont été pesés dans une coupelle et introduits dans la solution de BB (10 % m/m). Le bêcher a ensuite été placé sous agitation (700 rpm) pendant 1 h. - Mixed solution of ALG alginate (3% m/m) and BB baobab fruit pulp (10%): 10 g of BB baobab fruit pulp powder were weighed in a 100 mL beaker and then made up to 100 g with deionized water. The mixture was stirred (700 rpm) for 1 hour, then the pH was adjusted to 7 using 1M NaOH solution. 3 g of ALG powder were weighed into a dish and introduced into the BB solution (10% m/m). The beaker was then placed under agitation (700 rpm) for 1 h.
- Solution de pulpe de fruit de baobab BB (10 % m/m) : - Baobab fruit pulp solution BB (10% m/m):
5 g de poudre de fruit de baobab ont été pesés dans un bêcher de 50 mL puis on a complété à 50 g qsp avec de l'eau désionisée. Le mélange a été placé sous-agitation (700 rpm) pendant 1 h, puis le pH a été ajusté à 7 à l'aide d'une solution de NaOH IM. Des solutions diluées de BB ont été réalisées à partir de la solution BB à 10% m/m (BB 0,1 % m/m, BB 0,5 % m/m, BB 1,0 % m/m, BB 1,5 % m/m, BB 2,0 % m/m et BB 6,0 %m/m).5 g of baobab fruit powder were weighed into a 50 mL beaker and then made up to 50 g qsp with deionized water. The mixture was stirred (700 rpm) for 1 hour, then the pH was adjusted to 7 using 1M NaOH solution. Diluted solutions of BB were made from the 10% m/m BB solution (BB 0.1% m/m, BB 0.5% m/m, BB 1.0% m/m, BB 1 .5% m/m, BB 2.0% m/m and BB 6.0%m/m).
- Solutions composites de polymères : - Polymer composite solutions:
Des solutions composites de polymères PL / [ALG / BB] ont été obtenues en modifiant le rapport massique des polymères dans la solution finale, conformément aux détails donnés dans le Tableau 4 ci-après. Des mélanges de PL 11 % et d'ALG 3 % réalisés directement dans la solution de pulpe de fruit de baobab BB (10 %) ont été réalisés en modifiant le rapport PL / [ALG / BB] pour obtenir les solutions composites PL / [ALG / BB] 90/10 ; 80/20 ; 70/30, 40/60 et 10/90. 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.
(*) solution non conforme à l'invention (*) solution not in accordance with the invention
Des microparticules gélifiées ont été fabriquées à partir des solutions détaillées dans le Tableau 4 ci-dessus ayant différents ratios de PL/(ALG/BB). Chaque solution composite a été prélevée avec une seringue
de 5 mL, puis extrudée à travers une aiguille (23G Neolus, Terumo®, Somerset, USA) dans un bêcher de 250 mL, placé sous-agitation (300 rpm) et contenant 100 mL de solution de CaCI2 (Peser 14,7 g de CaCI2 dans une fiole jaugée de 1 L. Ajuster jusqu'au trait de jauge avec de l'eau désionisée. Placer sous-agitation (700 rpm) pendant 30 min). Les microparticules ont été maintenues sous-agitation pendant 5 min, puis ont été filtrées à l'aide d'un tamis. Avec les ratios de PL/(ALG/BB) de 90/10 et 80/20 (m/m), des microparticules sphériques ont été obtenues (symétrie de la particule). Avec le ratio de PL/(ALG/BB) 10/90 (m/m), aucune microparticule n'a été obtenue, la gélification n'étant pas optimale pour permettre une formation instantanée des microparticules. Les microparticules peuvent avoir une grande diversité de formes non sphériques (ovales, étalées, asymétriques...). Avec le ratio PL/(ALG/BB) de 70/30, des microparticules non symétriques ont été obtenues. - Solutions polymériques chargées en bleu dextran BD : 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. With the PL/(ALG/BB) ratios of 90/10 and 80/20 (m/m), spherical microparticles were obtained (symmetry of the particle). With the PL/(ALG/BB) ratio of 10/90 (m/m), no microparticles were obtained, the gelation not being optimal to allow instantaneous formation of the microparticles. The microparticles can have a wide variety of non-spherical shapes (oval, spread, asymmetrical...). With the PL/(ALG/BB) ratio of 70/30, non-symmetrical microparticles were obtained. - Polymeric solutions loaded with BD blue dextran:
Le BD a été additionné à 0,83 % (m/m) dans la solution finale de polymères. 4.2 Rhéologie des solutions gélifiées : BD was added at 0.83% (m/m) to the final polymer solution. 4.2 Rheology of gelled solutions:
La rhéologie des solutions a été mesurée à température ambiante avec un rhéomètre rotatif (Ares 509954812), à contrainte croissante ou imposée, équipé d'une géométrie cône-plan (Angle du cône 0,1 radians, gap 0,048 mm, fréquence 1,0 rad/s). Après avoir défini au préalable le domaine linéaire et donc la fréquence comme paramètre, on a mesuré la viscosité (G") de chacune des solutions de polymères préparées selon les proportions données dans le Tableau 4 ci-dessus. Le développement de G" a été suivi par un balayage dans le temps généralement pendant 20 min à une fréquence constante. 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.
Les paramètres de synergie rhéologique, qui sont les différences entre les valeurs viscoélastiques réelles du mélange d'essai polymère A / polymère B et les valeurs théoriques définies comme la somme des composants viscoélastiques du polymère A et du polymère B, ont été calculés comme suit : 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" mélange = G" polymère A + G" polymère B + G" interaction où : G" mixture = G" polymer A + G" polymer B + G" interaction where:
- G" mélange est le coefficient de viscosité du mélange,
- G" polymère A et G" polymère B sont les coefficients de viscosité individuels du polymère A et du polymère B respectivement, et - 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, and
- l'interaction G" est la composante de l'interaction qui peut être obtenue en réorganisant l'équation : Interaction G" = mélange G" - polymère G" A - polymère G" B. - the interaction G" is the component of the interaction which can be obtained by rearranging the equation: Interaction G" = mixture G" - polymer G" A - polymer G" B.
Les forces d'interaction entre les polymères PL/BB, ALG/BB, PL/ALG et PL/(ALG/BB) ont été calculées en mesurant la viscosité (G") de solutions préparées avec le rapport massique 80/20 et ayant la composition donnée dans le Tableau 5 ci-après. [TABLEAU 5]
The interaction forces between the polymers PL/BB, ALG/BB, PL/ALG and PL/(ALG/BB) were calculated by measuring the viscosity (G") of solutions prepared with the mass ratio 80/20 and having the composition given in Table 5 below [TABLE 5]
Les résultats obtenus sont présentés sur la figure 1 annexée sur laquelle la force d'interaction mesurée G" (en Pa) est fonction de la Fréquence (en rad/s). Sur cette figure, la courbe avec les ronds vide correspond à la solution comparative PL/BB, la courbe avec les ronds pleins correspond à la solution comparative ALG/BB, la courbe avec les losanges pleins correspond à la solution comparative PL/ALG et la courbe avec les carrés pleins correspond à la solution PL/(ALG/BB) conforme à l'invention. 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). In this figure, 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 and the curve with the solid squares corresponds to the solution PL/(ALG/ BB) in accordance with the invention.
Les résultats présentés sur cette figure montrent : - PL/BB : Le mélange de polymères présente une augmentation de G" en fonction de la fréquence (G" PL/BB > G" PL+BB). Il existe donc une interaction entre les deux polymères.
- ALG/BB : Il n'existe pas d'interaction entre les deux polymères (G" ALG/BB < G" ALG+BB). The results presented in this figure show: - PL/BB: The mixture of polymers shows an increase in G" as a function of frequency (G" PL/BB >G" PL+BB). There is therefore an interaction between the two polymers. - ALG/BB: There is no interaction between the two polymers (G" ALG/BB <G" ALG+BB).
- PL/ALG : Le mélange de polymères présente une forte augmentation de G" en fonction de la fréquence (G" Pb/ALG > G" PL+ALG). Il existe donc une forte interaction entre les deux polymères. - PL/ALG: The mixture of polymers shows a strong increase in G" as a function of frequency (G" Pb/ALG > G" PL+ALG). There is therefore a strong interaction between the two polymers.
- PL/(ALG/BB) : Le mélange de polymères présente une très forte augmentation de G" en fonction de la fréquence (G" Pb/(ALG/BB) > G" PL+ALG+BB). Il existe donc une interaction forte entre les trois polymères. 4.3. Mucoadhésion des solutions gélifiées : - PL/(ALG/BB): The mixture of polymers shows a very strong increase in G" as a function of frequency (G" Pb/(ALG/BB) > G" PL+ALG+BB). There is therefore a strong interaction between the three polymers 4.3 Mucoadhesion of gelled solutions:
- Rhéologie des solutions avec mucine : - Rheology of solutions with mucin:
Une étude de mucoadhésion de solutions de polymères a été réalisée à l'aide d'un rhéomètre rotatif (Ares 509954812-TA Instruments). La rhéologie des solutions a été mesurée à température ambiante, avec des contraintes croissantes ou imposées, équipées d'une géométrie cône-plan (angle du cône 0,1 radians, écart 0,048 mm, fréquence 1,0 rad/s) comme décrit dans la section 4.2. A study of the mucoadhesion of polymer solutions was carried out using a rotational rheometer (Ares 509954812-TA Instruments). The rheology of the solutions was measured at room temperature, with increasing or imposed stresses, equipped with a cone-plane geometry (cone angle 0.1 radians, deviation 0.048 mm, frequency 1.0 rad/s) as described in Section 4.2.
- Rhéologie des solutions gélifiées - Rheology of gelled solutions
Les concentrations de mucine ont été sélectionnées dans la plage physiologique (5 % m/m). Des échantillons de mucus homogénéisé (10 % de mucine porcine m/m) ou d'eau (témoin) ont été mélangés avec une quantité égale de la solution de polymère d'essai et le pH a été ajusté à 7,0 en utilisant une solution de NaOH 0,1 M ou de l 'HCI 0,1 M à température ambiante pendant lh avant l'examen rhéologique. 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.
L'interaction G" de ces échantillons individuels ainsi que des mélanges de solutions de polymères avec des solutions de mucine (1:1 m/m, sur la base de la quantité de solution) a été mesurée. The G" interaction of these individual samples as well as mixtures of polymer solutions with mucin solutions (1:1 m/m, based on the amount of solution) was measured.
Les résultats sont reportés sur la figure 2 annexée sur laquelle l'interaction G" (en Pa) est exprimée en fonction de la fréquence (en rad/sec). Sur cette figure, la courbe en trait discontinu et avec les ronds pleins correspond à la solution Pb/Mucine, la courbe en trait continu et avec les carrés pleins correspond à la solution ALG/Mucine, la courbe en pointillés et avec les triangles pleins correspond à la solution BB/Mucine, la courbe en trait plein avec les losanges pleins correspond à la solution Pb/BB/Mucine, la courbe en trait discontinu et avec les carrés pleins correspond à la solution
PL/(ALG/BB)/Mucine conforme à l'invention, la courbe en trait pointillé avec les croix correspond à la solution de Mucine seule, la courbe avec les traits discontinus et les ronds vides correspond à la somme de la viscosité de la solution PL seule et de la viscosité de la solution de Mucine seule, la courbe avec le trait continu et le carré vide correspond à la somme de la viscosité mesurée avec la solution ALG seule et de la viscosité mesurée avec la solution de Mucine seule, la courbe avec le trait en pointillés et les triangles vide correspond à la somme des viscosités mesurées avec la solution de BB seule et la solution de Mucine seule, la courbe en trait plein avec les losanges vides correspond à la somme des viscosités mesurées avec la solution de PL seule, la solution de BB seule et la solution de mucine, la courbe en trait plein et avec les ronds vides correspond à la somme des viscosités mesurées avec la solution ALG seule, la solution de BB seule et la solution de Mucine seule, la courbe avec le trait plein et les triangles vides correspond à la somme des viscosités mesurées avec la solution de PL seule, la solution de ALG seule et la solution de Mucine seule, et la courbe en trait discontinu et avec les carrés vides correspond à la somme des viscosités mesurées avec la solution de PL seule, la solution de ALG seule, la solution de BB seule et la solution de Mucine seule. Ce travail induit des changements de viscosité et contribue ainsi à une composante de bioadhésion conduisant à l'équation empirique suivante : n mélange = η mucine + η polymère + η bioadhésion où : The results are shown in the appended figure 2 in which the interaction G" (in Pa) is expressed as a function of the frequency (in rad/sec). In this figure, the curve in broken line and with the solid circles corresponds to the Pb/Mucin solution, the curve in solid line and with solid squares corresponds to the ALG/Mucin solution, the dotted curve and with solid triangles corresponds to the BB/Mucin solution, the curve in solid line with solid diamonds corresponds to the Pb/BB/Mucin solution, the curve in broken line and with the filled squares corresponds to the solution PL/(ALG/BB)/Mucin in accordance with the invention, the curve in dotted line with the crosses corresponds to the solution of Mucin alone, the curve with the broken lines and the empty circles corresponds to the sum of the viscosity of the PL solution alone and the viscosity of the Mucin solution alone, the curve with the solid line and the empty square corresponds to the sum of the viscosity measured with the ALG solution alone and the viscosity measured with the Mucin solution alone, the curve with the dotted line and the empty triangles corresponds to the sum of the viscosities measured with the BB solution alone and the Mucin solution alone, the curve with the solid line with the empty diamonds corresponds to the sum of the viscosities measured with the solution of PL alone, the BB solution alone and the mucin solution, the curve in solid line and with the empty circles corresponds to the sum of the viscosities measured with the ALG solution alone, the BB solution alone and the Mucin solution alone e, the curve with the solid line and the empty triangles corresponds to the sum of the viscosities measured with the PL solution alone, the ALG solution alone and the Mucin solution alone, and the curve with the broken line and with the empty squares corresponds to the sum of the viscosities measured with the PL solution alone, the ALG solution alone, the BB solution alone and the Mucin solution alone. This work induces viscosity changes and thus contributes to a bioadhesion component leading to the following empirical equation: n mixture = η mucin + η polymer + η bioadhesion where:
- η mélange est le coefficient de viscosité du mélange, - η mixture is the viscosity coefficient of the mixture,
- η mucine et η polymère sont les coefficients de viscosité individuels de la mucine et du polymère testé respectivement et - η mucin and η polymer are the individual viscosity coefficients of the mucin and the polymer tested respectively and
- η bioadhésion est la composante de la bloadhésion qui peut être obtenue en réorganisant l'équation : η bioadhésion = η mélange - η mucine - η polymère - η bioadhesion is the component of bloadhesion which can be obtained by rearranging the equation: η bioadhesion = η mixture - η mucin - η polymer
Les résultats présentés sur la figure 2 annexée montrent que pour tous les polymères (seuls ou en association), la somme des G" des solutions polymériques avec la mucine donne une valeur de viscosité plus faible que la mesure de viscosité de l'association de ces polymères avec la mucine. Il existe donc une interaction entre les polymères et la mucine. L'interaction
est plus forte pour l'association des 3 polymères conforme à la présente invention. The results presented in the appended FIG. 2 show that for all the polymers (alone or in combination), the sum of the G" of the polymeric solutions with the mucin gives a lower viscosity value than the viscosity measurement of the combination of these polymers with mucin, so there is an interaction between polymers and mucin. is stronger for the combination of the 3 polymers in accordance with the present invention.
4.4 Mucoadhésion ex vivo des solutions : 4.4 Ex vivo mucoadhesion of the solutions:
La mucoadhésion des solutions de polymères a également été testée ex- vivo sur des rats WISTAR de laboratoire acheté chez Janvier Labs. The mucoadhesion of the polymer solutions was also tested ex-vivo on WISTAR laboratory rats purchased from Janvier Labs.
Après l'anesthésie des rats, des tissus intestinaux (10 cm de long) ont été prélevés, rincés avec du sérum physiologique (0,9 % NaCI) pour enlever le mucus libre et ouverts longitudinalement. L'intestin a été monté sur un appareil et le plan a été incliné à 45° (Riley et al., Int. J. Pharm., 217 (2001) 87-100). Les polymères contenants de la mélatonine à titre de marqueurAfter the rats were anesthetized, intestinal tissues (10 cm long) were removed, rinsed with saline (0.9% NaCl) to remove free mucus and opened longitudinally. The intestine was mounted on a device and the plane was tilted at 45° (Riley et al., Int. J. Pharm., 217 (2001) 87-100). Polymers containing melatonin as a marker
(substance active dosée par chromatographie en phase liquide (CLHP)) ont été étalés sur le dessus du côté muqueux et conservés 5 min pour permettre les interactions mucus/polymères. Du tampon phosphate salin (PBS) à 37°C, mimant le fluide biologique, a été utilisé pour rincer la muqueuse en continu (débit 24 mL/min). Après 5, 10 ou 30 minutes de lavage, la quantité de substance active a été dosée afin de déterminer la quantité de polymères encore présente sur l'intestin. (active substance assayed by liquid phase chromatography (HPLC)) were spread on top of the mucosal side and kept for 5 min to allow mucus/polymer interactions. Phosphate buffered saline (PBS) at 37°C, mimicking the biological fluid, was used to rinse the mucosa continuously (flow rate 24 mL/min). After 5, 10 or 30 minutes of washing, the quantity of active substance was measured in order to determine the quantity of polymers still present on the intestine.
La capacité mucoadhésive a été calculée en pourcentage de substance active retenue par le tissu muqueux à la fin du processus. L'expérience a été réalisée en triplicata. 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.
Les résultats obtenus sont donnés à la figure 3 annexée sur laquelle la mucoadhésion est donnée pour chacune des solutions testées (solution témoin de milieu de culture DMEM ; BB 2 %, PL/ALG avec PL 8,8 et ALG 0,6 % final, et PL/(ALG/BB) avec PL 8,8 %, ALG 0,6 % et BB 2 % final) au bout de 5 minutes (barres noires), 10 minutes (barres grises) et 30 minutes (barres blanches). The results obtained are given in appended FIG. 3 in which the mucoadhesion is given for each of the solutions tested (control solution of DMEM culture medium; BB 2%, PL/ALG with PL 8.8 and ALG 0.6% final, and PL/(ALG/BB) with PL 8.8%, ALG 0.6% and BB 2% final) at 5 minutes (black bars), 10 minutes (grey bars) and 30 minutes (white bars).
Ces résultats montrent que la solution BB de pulpe de fruit de baobab à 2 % ne présente pas de mucoadhésion sur l'intestin de rat car sa viscosité est trop faible à 2 %. La solution comprenant l'association PL/ALG permet une rétention de la substance active modèle significative par rapport au témoin (DMEM), avec 45 % de rétention au bout de 30 min. L'association des 3 polymères est largement améliorée avec plus de 80 % de rétention à 30 min (> à la somme BB+PL/ALG =64 %). Il existe donc une interaction entre
la solution de polymères et le mucus intestinal plus forte quand les 3 polymères sont associés conformément à la présente invention. These results show that the 2% baobab fruit pulp BB solution does not exhibit mucoadhesion on the rat intestine because its viscosity is too low at 2%. The solution comprising the PL/ALG combination allows significant retention of the model active substance compared to the control (DMEM), with 45% retention after 30 min. The combination of the 3 polymers is greatly improved with more than 80% retention at 30 min (> the sum of BB+PL/ALG =64%). So there is an interaction between the solution of polymers and the intestinal mucus stronger when the 3 polymers are combined in accordance with the present invention.
4.5 Réalisation des microparticules : 4.5 Production of the microparticles:
Des microparticules ont été préparées à partir des solutions composites. Pour ce faire, la solution composite a été prélevée avec une seringue de 5 ml_, puis extrudée à travers une aiguille (23G Neolus, Terumo®, Somerset, USA) dans un bêcher de 250 ml_, placé sous-agitation (300 rpm) et contenant 100 ml_ de solution de CaCI2 préalablement préparée en mélangeant 14,7 g de CaCI2 dans une fiole jaugée de 1 L, puis en ajustant jusqu'au trait de jauge avec de l'eau désionisée puis agitation (700 rpm) pendant 30 min. Les microparticules formées dans la solution de CaCI2 ont été laissées sous agitation pendant 5 min, puis ont été filtrées à l'aide d'un tamis. 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.
4.6. Cinétique de libération du BD : Des microparticules ont été préparées à partir des solutions de polymères chargées en BD (0,83 % (m/m) comme décrit ci-dessus au point 4.1. Une cinétique de libération du BD a été effectuée en triplicat dans un appareil à palettes tournantes (USP2, AT7, Sotax, Suisse). Dix grammes de microparticules ont été introduits par réacteur (37°C+/- 0,5°C) contenant 500 mL de tampon pharmacopée pH 1,2 ou 6,8 pour représenter le milieu gastrique et intestinal. La vitesse de rotation des palettes a été fixée à 50 rpm. Des prélèvements ont été réalisés durant 24 h à des intervalles prédéterminés (15, 30, 45, 60, 90, 120, 180, 240, 300, 360 et 1440 minutes) puis dosés via un spectrophotomètre 7315 Visible-UV à 618 nm (Jenway, Etat-Unis). 4.6. 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).
Les résultats obtenus sont donnés aux figures 4 et 5 annexée. La figure 4 correspond à l'expérience réalisée à pH 1,2 et la figure 5 correspond à l'expérience réalisée à pH 6,8. Sur ces figures, la libération du BD (en %) est fonction du temps (en minutes). Les courbes en train plein et avec les carrés pleins correspond aux microparticules obtenues avec une solution de PL à 11 % m/m, la courbe en trait plein et avec les ronds vides correspond aux microparticules obtenues avec la solution comprenant l'association PL/BB avec PL 11 % m/m et BB 3 % m/m dans un rapport massique PL/BB de 80/20, la courbe en trait plein et avec les triangles pleins correspond aux
microparticules obtenues avec la solution d'alginate seul à 3 % m/m, la courbe en trait plein et avec les ronds pleins correspond aux microparticules obtenues avec la solution comprenant l'association ALG/BB avec ALG 3 % m/m et BB 10 % m/m dans un rapport massique ALG/BB de 80/20, la courbe avec le trait en continu et les losanges pleins correspond aux microparticules obtenues avec la solution comprenant l'association PL/ALG avec PL 11 % m/m et ALG 3 % m/m dans un rapport massique PL/ALG de 80/20 et la courbe en trait discontinu et avec les carrés pleins correspond aux microparticules obtenues avec la solution comprenant l'association PL/ (ALG/BB) avec PL 11 % m/m, ALG 3 % m/m et BB 10 % m/m dans un rapport massique PL/(ALG/BB) de 80/20. Selon cet essai, seules les microparticules obtenues avec la solution comprenant l'association PL/(ALG/BB) sont conformes à la présente invention, les particules obtenues avec les autres solutions étant comparatives et non conformes à la présente invention. Sur les figures 4 et 5, les valeurs représentent les moyennes ± l'erreur standard de mesure (esm) (n=3). The results obtained are given in Figures 4 and 5 appended. Figure 4 corresponds to the experiment carried out at pH 1.2 and Figure 5 corresponds to the experiment carried out at pH 6.8. In these figures, the release of BD (in %) is a function of time (in minutes). 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/ALG of 80/20 and the curve in broken line and with the solid squares corresponds to the microparticles obtained with the solution comprising the combination PL/ (ALG/BB) with PL 11% m /m, ALG 3% m/m and BB 10% m/m in a mass ratio PL/(ALG/BB) of 80/20. According to this test, only the microparticles obtained with the solution comprising the PL/(ALG/BB) combination are in accordance with the present invention, the particles obtained with the other solutions being comparative and not in accordance with the present invention. In FIGS. 4 and 5, the values represent the means ± the standard error of measurement (sem) (n=3).
Les résultats présentés sur les figures 4 et 5 montrent que la libération du BD des microparticules à pH 1,2 est inférieure à 10 % en 24 h quelle que soit la formulation testée. Les microparticules sont donc gastrorésistantes. A pH 6,8, la libération est fonction de la formulation testée. Les microparticules préparées à partir de la solution comprenant de l'alginate (ALG 3 % m/m) avec ou sans pulpe de fruit de baobab sont les formulations qui libèrent le plus rapidement le BD (>50 % en 3 h) pour atteindre 80% en 6 h. Les microparticules obtenues à partie de la solution contenant de la protéine de lait (PL 11 % m/m) avec ou sans pulpe de fruit de baobab libèrent moins rapidement le BD avec moins de 25 % en 3 h et moins de 40 % en 6 h. Les microparticules obtenues avec la solution comprenant de la protéine de lait et contenant ou non de la pulpe de fruit de baobab libèrent le plus lentement le BD avec moins de 25 % en 6 h. L'ajout de pulpe de fruit de baobab dans la solution comprenant l'association PL/ALG ralentit la libération de la substance active à pH 6,8 et améliore l'effet prolongé de la substance active. 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. The 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.
La microporosité de ces différentes microparticules a été observée en microscopie électronique à balayage. La figure 6 annexée est une
photographie de microscopie électronique à balayage au grossissement xlOOO des microparticules PL, ALG, BB, PL/BB, ALGBB, PL/ALG comparativement aux particules PL/(ALG/BB) conformes à l'invention.The microporosity of these different microparticles was observed by scanning electron microscopy. 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.
Le gonflement (significatif de la prise d'eau) des microparticules PL/ALG comparativement aux particules PL/(ALG/BB) conformes à l'invention a également été évalué par mesure de leur diamètre et les résultats sont reportés sur la figure 7a et la figure 7b annexées. Les résultats concernant le changement de diamètre correspondent à la figure 7a sur laquelle la variation de diamètre (en %) est fonction du temps (en minutes). Les barres noires correspondent aux microparticules PL/ALG comparatives alors que les barres grises correspondent aux microparticules PL/(ALG/BB) conformes à la présente invention. Les résultats concernant la prise en eau correspondent à la figure 7b sur laquelle la variation de la quantité d'eau (en %) est fonction du temps (en minutes). Sur ces figures 7a et 7b, les barres noires correspondent aux microparticules PL/ALG comparatives alors que les barres grises correspondent aux microparticules PL/(ALG/BB) conformes à la présente 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). In these FIGS. 7a and 7b, 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.
Ces résultats montrent que les microparticules obtenues avec la solution conforme à la présente invention, c'est-à-dire comprenant de la pulpe de fruit de baobab associée au mélange de protéines de lait et d'alginate de sodium se présentent sous la forme d'un gel polymère plus dense avec une diminution de la taille du réseau poreux des polymères [Fig.6] et ainsi l'entrée d'eau dans les microparticules est freinée (moins de diffusion de substance active) (figures 7a et 7b). EXEMPLE 5 : Préparation de comprimés conformes à l'invention et préparation de comprimés comparatifs ne faisant pas partie de l'invention - Etude de leurs propriétés These results show that the microparticles obtained with the solution in accordance with the present invention, that is to say comprising baobab fruit pulp associated with the mixture of milk proteins and sodium alginate, are in the form of a denser polymer gel with a reduction in the size of the porous network of the polymers [Fig.6] and thus the entry of water into the microparticles is slowed down (less diffusion of active substance) (figures 7a and 7b). EXAMPLE 5: Preparation of tablets in accordance with the invention and preparation of comparative tablets not forming part of the invention - Study of their properties
5.1 Réalisation des comprimés : 5.1 Making the tablets:
Pour obtenir des poudres de protéines de lait, la solution de PL 11 % m/m telle que préparées ci-dessus à l'exemple 4, section 4.1, a été atomisée à 160°C en utilisant un mini-séchoir à pulvérisation BÜCHI Mini Spray Dryer B-290 (Suisse). Les paramètres du procédé de séchage par pulvérisation ont été définis comme suit : 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:
- taille de la buse = 1,5 mm,
- température d'entrée = 160°C, - nozzle size = 1.5 mm, - inlet temperature = 160°C,
- débit de solution = 20 %, - solution flow = 20%,
- pression = 50 bar avec un nettoyage de buse de l'ordre de 5 pulsations/sec. L'humidité résiduelle des poudres de PL a été déterminée par une méthode thermogravimétrique. L'essai a été réalisé sur une masse de 2 g de poudre avec une balance à infrarouge (Melter Toledo LJ 16 moisture analyser, Viroflay Switzerland). L'humidité résiduelle a été fixée comme devant être inférieure à 5 %. Quatorze formulations ont été réalisées avec un mélange composé de 36,5 % (m/m) de poudre des trois polymères naturels et d'un excipient de charge, à savoir du lactose monohydraté tamisé vendu sous la dénomination commerciale Capsulac ® 60 par la société Cooper (Melun, France) (qsp 36,5 %). A ces 36,5 % ont été ajoutés d'autres excipients indispensables pour la production des comprimés : Stéarate de Magnésium ref 209-150-3, (Cooper) à titre de lubrifiant :1,0 % (m/m) et de la silice colloïdale vendue sous la dénomination commerciale Aérosil (Degussa Ag), à titre d'agent d'écoulement : 0,5 % (m/m). La substance active modèle choisie est la théophylline monohydratée TPH (23722, Pierre Fabre) et représente 62 % (m/m) de la masse totale du comprimé. - pressure = 50 bar with nozzle cleaning of the order of 5 pulses/sec. 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%). To this 36.5% were added other essential excipients for the production of the tablets: Magnesium Stearate ref 209-150-3, (Cooper) as a lubricant: 1.0% (m/m) and colloidal silica sold under the trade name Aerosil (Degussa Ag), as flow agent: 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.
Le détail des différentes formulations F0 à F13 réalisées est donné dans le Tableau 6 ci-après :
The details of the various formulations F0 to F13 produced are given in Table 6 below:
(*) : Formulations comparatives, non conformes à la présente invention (**) la quantité d'agent de charge ajoutée est choisie pour que la masse totale du ou des polymères et de l'agent d'écoulement représente 36 ,5 % en masse par rapport à la masse totale des comprimés. (*): Comparative formulations, not in accordance with the present invention (**) the quantity of bulking agent added is chosen so that the total mass of the polymer(s) and the flow agent represents 36.5% by mass relative to the total mass of the tablets.
Les comprimés ont été préparés par compression directe des formulations FO à F13, à l'aide d'une machine à comprimé alternative. The tablets were prepared by direct compression of the FO to F13 formulations, using a reciprocating tablet machine.
Des analyses classiques des poudres décrites dans la Pharmacopée Européenne (lOème édition) (test d'écoulement) et des comprimés (tests de friabilité, de prise d'eau à pH 6,8 et de gonflement ; mesure la libération de la substance active et Erosion (E)/Diffusions (D)) ont été réalisées afin de valider les formulations. Les résultats sont présentés dans le Tableau 7 ci-après :
[TABLEAU 7]
Conventional analyzes of the powders described in the European Pharmacopoeia (10th edition) (flow test) and tablets (friability tests, water uptake at pH 6.8 and swelling; measures the release of the active substance and Erosion (E)/Diffusions (D)) were carried out in order to validate the formulations. The results are presented in Table 7 below: [TABLE 7]
(*) Formulations comparatives, non conformes à l'invention Concernant les mesures d'écoulement, la signification des abréviations E, B, EM, C, NC, et ND est la suivante : - E : Excellent (*) Comparative formulations, not in accordance with the invention Concerning the flow measurements, the meaning of the abbreviations E, B, EM, C, NC, and ND is as follows: - E: Excellent
- B : Bonne - B: Good
- EM : extrêmement médiocre - EM: extremely mediocre
- C : Conforme - C: Compliant
- NC : Non conforme - ND : Non déterminé. - NC: Non-compliant - ND: Not determined.
Le remplissage de la chambre de compression par écoulement des poudres et la compression des poudres sont les deux paramètres clefs pour fabriquer les comprimés. En effet, un mauvais écoulement des poudres peut entraîner une non-conformité des masses de comprimés obtenus et empêche
l'homogénéité au sein du comprimé. La coulabilité de la poudre peut s'améliorer par granulation ou par mélange avec d'autres excipients. 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.
Les résultats présentés dans le tableau 7 ci-dessus montrent que l'aptitude à l'écoulement des poudres est extrêmement médiocre pour la formulation F13 non conforme à l'invention et composée majoritairement de PL mais qu'elle est bonne ou excellente pour toutes les autres formulations testées. Sur les 13 formulations, seules 4 ont une friabilité supérieure à 1 %, donc non conforme. Ces 4 formulations correspondent à des formulations contenant beaucoup de PL (18 %) ou uniquement de l'ALG (35 %). Pour confirmer le rôle matriciel des polymères, une étude du gonflement a été effectuée pendant laquelle le changement d'épaisseur des comprimés a été déterminé après 2 h de dissolution à pH 6,8. En effet, les comprimés produits dans cet exemple sont des systèmes à libération contrôlée par le gonflement puisqu'ils contiennent des polymères hydrophiles. Pour un polymère hydrophile, l'absorption de solvant est une des façons d'atteindre cet état d'équilibre. Il absorbe spontanément une quantité suffisante de solvant. Ce processus finit par former une solution vraie ou un gel gonflé. Le solvant se distribue au sein du comprimé avec une augmentation de l'entropie et du volume de système. Les chaînes de polymère entre les jonctions du réseau sont soumises à une extension. The results presented in Table 7 above show that the flowability of the powders is extremely mediocre for the F13 formulation not in accordance with the invention and composed mainly of PL but that it is good or excellent for all the other formulations tested. Of the 13 formulations, only 4 have a friability greater than 1%, therefore non-compliant. These 4 formulations correspond to formulations containing a lot of PL (18%) or only ALG (35%). To confirm the matrix role of the polymers, a swelling study was carried out during which the change in thickness of the tablets was determined after 2 h of dissolution at pH 6.8. Indeed, the tablets produced in this example are swelling controlled release systems since they contain hydrophilic polymers. For a hydrophilic polymer, solvent absorption is one of the ways to reach this state of equilibrium. It spontaneously absorbs a sufficient quantity of solvent. This process eventually forms a true solution or a swollen gel. The solvent distributes within the tablet with an increase in entropy and system volume. The polymer chains between network junctions are subject to extension.
Un gonflement important correspondant à une prise d'eau des comprimés est observé pour toutes les formulations. Ainsi, la prise d'eau importante des comprimés prouve la capacité d'hydratation des PL > ALG > BB qui peut être due à une formation de ponts hydrogène entre les chaînes de polymère et les molécules d'eau (formation d'une couche gélifiée autour du comprimé). Significant swelling corresponding to water uptake of the tablets is observed for all the formulations. Thus, the high water uptake of the tablets proves the hydration capacity of PL > ALG > BB which may be due to the formation of hydrogen bridges between the polymer chains and the water molecules (formation of a gelled layer around the tablet).
Ces résultats montrent également que plus on augmente le pourcentage de BB dans la formulation et moins le comprimé a tendance à gonfler. Le BB peut donc jouer un rôle dans la diffusion de la substance active en la limitant à pH 6,8. D'après ces résultats, on peut déduire que la diffusion et l'érosion semblent être le mécanisme de libération de la substance active à partir des comprimés (modèle de Korsmeyer-Peppas, Weibull, Higuchi et Harland ; Dmitry Yu. Murzin & Teemu Heikkilà (2014) MODELING OF DRUG DISSOLUTION KINETICS WITH SIGMOIDAL BEHAVIOR FROM ORDERED
MESOPOROUS SILICA, Chemical Engineering Communications, 201:5, 579- 592, DOI: 10.1080/00986445.2013.782290). These results also show that the more the percentage of BB in the formulation is increased, the less the tablet tends to swell. BB can therefore play a role in the diffusion of the active substance by limiting it to pH 6.8. From these results, it can be deduced that diffusion and erosion seem to be the release mechanism of the active substance from the tablets (model of Korsmeyer-Peppas, Weibull, Higuchi and Harland; Dmitry Yu. Murzin & Teemu Heikkilà (2014) MODELING OF DRUG DISSOLUTION KINETICS WITH SIGMOIDAL BEHAVIOR FROM ORDERED MESOPOROUS SILICA, Chemical Engineering Communications, 201:5, 579-592, DOI: 10.1080/00986445.2013.782290).
Une cinétique de libération de la théophylline a été effectuée en triplicat dans un appareil à palettes tournantes (USP2, AT7, Sotax, Suisse) pour chaque formulation. Un comprimé est introduit par réacteur (37°C+/- 0,5°C) contenant 1000 ml_ de tampon pharmacopée pH 1,2 ou 6,8 pour représenter le milieu gastrique et intestinal. La vitesse de rotation des palettes est de 50 rpm. Des prélèvements ont été réalisés à des intervalles prédéterminés (15, 30, 45, 60, 90, 120, 180, 240, 300 et 360 minutes). Les échantillons ont ensuite été centrifugés à 1000 g pendant 10 min avant dosage par chromatographie en phase liquide (CHLP) avec détecteur UV sans four. Une gamme d'étalonnage d'étalonnage a été réalisée à partir d'une solution mère (SM) de théophylline monohydratée dans une solution tampon de pH 6,8 et dans une solution tampon de pH 1,2 de concentration connue : 0,66 mg/mL. L'analyse CHLP de la théophylline a été réalisée avec un système Elite LaChrom® (Hitachi, Tokyo) et les données ont été traitées avec le Logiciel EZ Chrom Lite®. La colonne utilisée était une colonne Interchim® C18 de dimension 250 mm x 46 mm, particule 5 pm. La phase mobile était un mélange d'acétate d'ammonium/eau 90 % (v/v), acétonitrile 5 % (v/v) et méthanol 5 % (v/v). Le débit a été réglé à 1 mb/min, la détection a été faite à l'aide d'un détecteur UV/Visible à 272 nm et la durée d'analyse d'un échantillon a été réglée à 16 min. 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. 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 μm. 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.
Les résultats obtenus sont donnés à la figure 8a et la figure 8b annexées. La figure 8a correspond à la cinétique de libération de la théophylline mesurée à pH 1,2 et la figure 8b correspond à la cinétique de libération de la théophylline mesurée à pH 6,8. The results obtained are given in appended FIG. 8a and FIG. 8b. Figure 8a corresponds to the theophylline release kinetics measured at pH 1.2 and Figure 8b corresponds to the theophylline release kinetics measured at pH 6.8.
Les résultats présentés sur les figures 8a et 8b annexée montrent qu'à pH 1,2 (Fig. 8a), la libération de la théophylline à partir des comprimés sans polymère (F0) est rapide et totale (80 % en 90 min). L'ajout de polymères (PL, ALG ou BB) diminue la libération de théophylline des comprimés. Quelle que soit la formulation on observe un pourcentage dissous de théophylline inférieur à 50 % au bout de 3 h. L'ajout de ces polymères a donc un impact important sur la cinétique de libération de la théophylline à pH 1,2 et modifie le comportement de la formulation pour obtenir une libération contrôlée et
prolongée. A pH 6,8 (Fig. 8b), comme précédemment observé à pH 1,2, l'ajout de polymères dans les comprimés modifie la vitesse de libération de la théophylline. Les résultats montrent que pour les formulations Fl, F3, F5 et F7, une libération de 100 % de la théophylline est obtenue en 3 h alors que les formulations F2, F4, F6, et F8 n'atteindront les 100 % qu'à partir de 6 h. Afin de déterminer s'il existe des interactions entre les polymères qui influencent la libération de la théophylline, nous pouvons utiliser les profils de libération obtenus à 180 min (T50 %) comme point de comparaison. Pour analyser nos résultats, nous avons effectué une analyse de la variance à trois composantes (en anglais « analysis of variance » ou « ANOVA ») et une analyse par la méthode des probits à T180 min pour les formules Fl à F8. Les résultats obtenus sont reportés dans le Tableau 8 ci-dessous. The results presented in the appended 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 (PL, ALG or BB) decreases theophylline release from the tablets. Whatever the formulation, 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. At pH 6.8 (Fig. 8b), as previously observed at pH 1.2, the addition of polymers in the tablets modifies the release rate of theophylline. The results show that for the formulations Fl, F3, F5 and F7, a release of 100% of theophylline is obtained in 3 h while the formulations F2, F4, F6, and F8 will only reach 100% from from 6 a.m. In order to determine if there are interactions between the polymers that influence the theophylline release, we can use the release profiles obtained at 180 min (T50%) as a point of comparison. To analyze our results, we carried out a three-component analysis of variance (“analysis of variance” or “ANOVA”) and an analysis by the probit method at T180 min for formulas F1 to F8. The results obtained are reported in Table 8 below.
[TABLEAU 8]
Ces résultats montrent qu'au bout de 180 min, la quantité de PL présente dans les comprimés influence significativement le pourcentage de théophylline dissous (p < 0,0001) ainsi que l'interaction entre les PL et l'ALG (p = 0,01). En effet, l'analyse montre que l'ajout d'ALG permet d'améliorer l'effet libération prolongée des PL dans les comprimés. Ces résultats montrent également que le BB (p = 0,5140) et l'ALG (p = 0,2762) utilisés seuls n'ont aucune influence individuellement sur la libération de la théophylline. Le tableau 8 montre également qu'en présence d'une quantité minimale de PL (Fl - PL = 10 %), une libération plus rapide est observée comparativement à la formule F2 qui comprend une quantité de PL de 18
% en masse (85 % vs 50,7 %). Ainsi, l'augmentation de la quantité de PL permet d'augmenter la capacité à créer une matrice et ralentir la libération de la théophylline dans le milieu. Les PL permettent une libération prolongée de la théophylline à un pourcentage de 18 % à pH intestinal. Il est donc possible de conclure que la quantité de PL dans les comprimés a un impact significatif sur la vitesse de libération des substances actives. [TABLE 8] These results show that after 180 min, the amount of PL present in the tablets significantly influences the percentage of dissolved theophylline (p < 0.0001) as well as the interaction between PL and ALG (p = 0, 01). Indeed, the analysis shows that the addition of ALG makes it possible to improve the prolonged release effect of the PL in the tablets. These results also show that BB (p=0.5140) and ALG (p=0.2762) used alone have no influence individually on the release of theophylline. Table 8 also shows that in the presence of a minimum amount of PL (Fl - PL = 10%), a faster release is observed compared to formula F2 which includes an amount of PL of 18 % by mass (85% vs. 50.7%). Thus, 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.
Pour la formulation F9 contenant un pourcentage de BB supérieur au PL (18% BB pour la formule F9 vs 8 % BB pour la formule Fl), on observe que le profil de libération est ralenti avec un pourcentage plus élevé de BB (56 % de libération pour F9 vs 85 % pour Fia u bout de 180 minutes à pH 6,8,For the F9 formulation containing a percentage of BB higher than the PL (18% BB for the F9 formula vs 8% BB for the Fl formula), it is observed that the release profile is slowed down with a higher percentage of BB (56% release for F9 vs 85% for Fia after 180 minutes at pH 6.8,
Fig. 8b). Concernant les formulations avec 35 % de polymère seul (formulations comparatives ne faisant pas partie de l'invention), la formulation Fil (ALG seul) libère très rapidement la théophylline avec un pourcentage dissous de 100 % au bout de 240 min à pH 6,8 (Fig 8b), les formulations F12 (BB seule) et F13 (PL seules) atteignent seulement 35-40 % de libération au bout de 240 min à pH 6,8 puis 50 % au bout de 360 min (Fig. 8b). Les formulations contenant un fort pourcentage d'ALG ont donc tendance à libérer plus facilement la théophylline, le polymère ne possédant pas d'effet libération prolongée quand il n'est pas associé aux autres polymères. En effet, dans le cas de microparticules contenant de l'ALG, il a été montré à l'exemple 4 ci-dessus un gonflement plus important indiquant que le flux d'eau qui entre dans les microparticules était dû à la sensibilité de ces polymères au pH intestinal. L'association des PL et du BB aurait donc tendance à limiter le gonflement de l'ALG afin de retarder la libération de la substance d'intérêt. Les résultats de l'étude statistique sont présentés dans le Tableau 9 ci-après :
[Tableau 9]
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. Indeed, in the case of microparticles containing ALG, it was shown in example 4 above a greater swelling indicating that the flow of water which enters the microparticles was due to the sensitivity of these polymers to intestinal pH. The combination of PL and BB would therefore tend to limit the swelling of ALG in order to delay the release of the substance of interest. The results of the statistical study are presented in Table 9 below: [Table 9]
Dans ce tableau « DDL « correspond au degré de liberté, Type III SS correspond à la somme des carrés (SS) de type III. Le tableau 9 présente les résultats statistiques obtenus sur les 13 formulations Fl à F13 et met en évidence l'impact des polymères seuls ou en association sur la libération de la substance active (SA) modèle au cours
du temps. Après 15 min en pH 6,8, les polymères impliqués dans la libération de la SA sont principalement les PL et le BB ainsi que la combinaison PL/BB. A partir de 180 min, il existe une interaction entre ALG et PL qui entre aussi en jeu dans la libération de la SA. Enfin à partir de 360 min, tous les polymères seuls ont un impact ainsi que l'association ALG/BB et PL/BB sur la libération. Les polymères seuls et les interactions polymériques ont un impact sur la libération de la SA à pH intestinal, en modulant les propriétés d'érosion et de diffusion en fonction du temps. Ainsi, l'étude statistique de la variance à 3 composantes sur l'ensemble des formulations (Fl à F13) permet de voir les influences des pourcentages de polymères sur la libération de la théophylline des comprimés. Les résultats étaient significativement différents à partir de 45 min (p <0,0001) quelle que soit la formulation. L'influence des PL est donc significative à partir de 45 min (p <0,0001). Au temps 180 min, on observe également une influence significative du BB avec un fort pourcentage (p = 0,0002) ainsi que l'influence de l'interaction entre les PL et l'ALG comme vu précédemment. Pour finir, à 240 min, il existe des interactions entre BB, ALG (p = 0,0577) et PL (p = 0,0571) qui rentrent en compte dans la libération de la théophylline. Le BB à un pourcentage plus élevé ( >25 %) possède donc des propriétés de libération prolongée, augmentées par des interactions avec l'ALG et les PL. L'ensemble de ces résultats démontre que l'association des polymères conforme à la présente invention est un bon candidat comme excipient matriciel. In this table “DDL” corresponds to the degree of freedom, 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. After 15 min at pH 6.8, the polymers involved in the release of SA are mainly PL and BB as well as the PL/BB combination. From 180 min, there is an interaction between ALG and PL which also comes into play in the release of SA. Finally, from 360 min, 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. Thus, the statistical study of the 3-component variance on all of the formulations (F1 to F13) makes it possible to see the influences of the percentages of polymers on the release of theophylline from the tablets. The results were significantly different from 45 min (p <0.0001) whatever the formulation. The influence of PL is therefore significant from 45 min (p <0.0001). At time 180 min, a significant influence of BB is also observed with a high percentage (p=0.0002) as well as the influence of the interaction between PL and ALG as seen previously. Finally, at 240 min, there are interactions between BB, ALG (p = 0.0577) and PL (p = 0.0571) which are taken into account in the release of theophylline. BB at a higher percentage (>25%) therefore has sustained release properties, increased by interactions with ALG and PL. All of these results demonstrate that the combination of polymers in accordance with the present invention is a good candidate as a matrix excipient.
Afin de supprimer l'utilisation des protéines animales dans la formulation PL/(ALG/BB), les protéines de lait peuvent être remplacées par des protéines végétales comme les protéines de pois PP/(ALG/BB). In order to eliminate the use of animal proteins in the PL/(ALG/BB) formulation, milk proteins can be replaced by vegetable proteins such as PP/(ALG/BB) pea proteins.
Deux formulations F'2 et F'10 ont été réalisées avec un mélange composé de 36,5 % (m/m) de poudre des trois polymères naturels (PP, ALG et BB) et d'un excipient de charge (qsp 36,5 %). Dans les formulations F'2 et F'10, les quantités de polymères (PP, ALG et BB) utilisées sont respectivement les mêmes que celles indiquées précédemment pour les formules F2 et F10 dans le Tableau 6 ci-dessus, soit 8 % m/m de BB, 18 % m/m de PP et 2 % m/m d'ALG pour la formule F'2 et 25 % m/m de BB, 8 % m/m de PP et 2 % d'ALG pour la formule F'10. Comme pour les formules F2 et F10, la
quantité d'agent de charge utilisée a été choisie de telle sorte que la masse totale du ou des polymères plus celle de l'agent de charge représente 36,5 % en masse par rapport à la masse totale de la formulation, soit 8,5 % m/m pour la formule F'2 et 1,5 % m/m pour la formule F'10. A ces 36,5 % en masse, d'autres excipients indispensables pour la production des comprimés ont été ajoutés : stéarate de magnésium : 1,0 % (m/m) et silice colloïdale : 0,5 % (m/m). La substance active modèle choisie est la théophylline monohydratée TPH (23722, Pierre Fabre) et représente 62 % (m/m) de la masse totale du comprimé. La cinétique de libération de la théophylline à partir des comprimés préparés avec les formules F'2 et F'10 a été étudiée à pH 1,2 et à pH 6,8 selon le même protocole que pour les formules F0 à F13 ci-dessus, et ceci comparativement à la cinétique de libération de la théophylline à partir des comprimés préparés à partir des formules F2 et F10 à base de PL. Les résultats obtenus sont donnés aux figures 9a et 9b annexées, à pH 1,2 (Fig. 9a) et à pH 6,8 (Fig 9b). Sur ces figures, la libération de la théophylline (en %) est fonction du temps (en min). Les courbes avec les losanges pleins correspondent à la formulation F2, les courbes avec les triangles pleins correspondent à la formulation F10, les courbes avec les losanges vides correspondent à la formulation F'2 et les courbes avec les triangles vides correspondent à la formulation F'10. 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%). In formulations F'2 and F'10, 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. As for formulas F2 and F10, 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. To this 36.5% by mass, other essential excipients for the production of the tablets have been added: magnesium stearate: 1.0% (m/m) and 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). In these figures, 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 and the curves with open triangles correspond to formulation F' 10.
Les résultats présentés sur la figure 9a et la figure 9b montrent que le remplacement des protéines animales par des protéines végétales ne modifie pas les interactions entre les polymères ni le profil de libération de la substance active du comprimé. The results presented in 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.
EXEMPLE 6 : Mise en évidence des propriétés cicatrisantes des solutions gélifiées : EXAMPLE 6 Demonstration of the healing properties of gelled solutions:
6.1 Test de cicatrisation : 6.1 Healing test:
Le principe du test de cicatrisation est la formation d'une zone sans cellule à la suite d'une lésion volontaire d'une monocouche de cellules confluentes, permettant ainsi de visualiser la guérison in vitro. En effet, dans ce contexte, les cellules vont tenter de revenir à une confluence totale, dans un temps plus ou moins long en fonction du traitement évalué.
Des cellules épithéliales de colon humain (HT29-MTX vendues par la société American Type Culture Collection - ATCC) ont été mise en cultures en plaque 6 puits dans un milieu de culture DMEM à 37°C pendant 72h, c'est-à-dire jusqu'à obtention d'une monocouche cellulaire confluente. Une blessure a été formée à l'aide d'une pointe de cône permettant ainsi de gratter la monocouche cellulaire confluente de cellules HT29-MTX. Un rinçage au PBS a été effectué afin d'éliminer les débris cellulaires formés. Des solutions de polymères (même concentration de tous les polymères en mélange) réalisées dans du DMEM, sont déposées dans chaque puit (3 mL/puit) : BB (mélange final 0,05 % m/m), PL/ALG (50/50 m/m avec un mélange final de 0,05 % de polymères), PP/ALG (50/50 m/m avec un mélange final de 0,05 % de polymères), PL/(ALG/BB) (33/33/33 m/m avec un mélange final 0,05 % de polymères), et PP/(ALG/BB) (33/33/33 m/m avec un mélange final 0,05 % de polymères). Après des temps déterminés (0, 4, 8, 12, 24, 48 et 72h), des photos sont prises au microscope optique (grossissement 4x) afin d'observer la migration des cellules et la fermeture de la zone lésée. Entre chaque temps, le milieu de culture est renouvelé et un rinçage au PBS est effectué afin de garantir un environnement favorable à la croissance cellulaire. Le pourcentage de fermeture de la cicatrice est ensuite quantifié à l'aide du logiciel d'analyse d'images ImageJ ®. Les résultats obtenus sont reportés sur la figure 10 annexée sur laquelle le pourcentage de cicatrisation est donné pour chacune des solutions testées. 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). After determined times (0, 4, 8, 12, 24, 48 and 72h), photos are taken under an optical microscope (4x magnification) in order to observe the migration of the cells and the closure of the injured area. Between each time, the culture medium is renewed and rinsing with PBS is carried out in order to guarantee an environment favorable to cell growth. The percentage of scar closure is then quantified using ImageJ ® image analysis software. The results obtained are given in the appended FIG. 10 in which the percentage of healing is given for each of the solutions tested.
Les résultats présentés sur la figure 10 montrent que la solution à base de pulpe de fruit de baobab (BB) permet une cicatrisation des cellules plus rapide que le milieu de culture DMEM seul (80 % vs 42 %). Le BB associé aux autres polymères conserve des propriétés cicatrisantes, avec les protéines de lait ou les protéines de pois. Les associations PL/ALG et PP/ALG n'ont par ailleurs pas de propriétés cicatrisantes supérieures à celle du milieu de culture. 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. Moreover, the PL/ALG and PP/ALG combinations do not have healing properties superior to those of the culture medium.
6.2 Test de croissance cellulaire : 6.2 Cell Growth Test:
Des plaques de 6 puits ont été ensemencées à hauteur de 3,4.105 cellules HT-29 MTX par puit (1 mb/puit). Des solutions de polymères à 0,05 % en masse, préparées dans du DMEM, ont été déposées dans chaque puit (1
mL/puit) en même temps que les cellules. Le milieu de culture cellulaire a été renouvellé tous les jours. Après 72h de croissance à 37°C, les cellules ont été récupérées et comptées à l'aide d'une lame de comtage de cellules Kova® au microscope optique (grossissement 40x). Les résultats obtenus sont reportés sur la figure 11 annexée sur laquelle la croissance cellulaire (en %) est donnée pour chacune des solutions testées : DMEM (témoin), BB (mélange final 0,05 % m/m), PL/ALG (50/50 m/m avec un mélange final de 0,05 % de polymères) et PL/(ALG/BB) (33/33/33 m/m avec un mélange final 0,05 % de polymères). Le DMEM représente 100 % de la croissance cellulaire. Par rapport à ce témoin, les résultats présentés sur la figure 11 montrent que le BB stimule la croissance cellulaire à plus de 185 %, alors que les PL associé aux ALG n'ont pas d'impact sur la croissance des cellules. L'association des 3 polymères conforme à l'invention permet une augmentation de 166 %. La cicatrisation cellulaire est donc liée à une augmentation de la croissance cellulaire avec les polymères contenant le BB. 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). The results obtained are shown in the appended figure 11 in which the cell growth (in %) is given for each of the solutions tested: DMEM (control), BB (final mixture 0.05% m/m), PL/ALG (50 /50 m/m with a final blend of 0.05% polymers) and PL/(ALG/BB) (33/33/33 m/m with a final blend of 0.05% polymers). DMEM represents 100% of cell growth. Compared to this control, the results presented in 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.
EXEMPLE 7 : Mise en évidence des Propriétés anti-inflammatoires des solutions gélifiées : EXAMPLE 7: Demonstration of the anti-inflammatory properties of gelled solutions:
7.1 Expérimentation in vitro : Une lignée de macrophages murins (RAW 264.7) a été cultivée jusqu'à confluence (plaque 12 puits, 1 mL de milieu de culture DMEM avec sérum de veau fœtal (20-25 %) et acide aminé (5 %), température 37°C). Les cellules ont ensuite été inflammées pendant 12h ainsi que pendant l'expérimentation avec une solution de lipopolysaccharide (LPS vendu sous la référence L4391 par la société Sigma Aldrich) à 10 pg/mL. Après 12h, des solutions de polymères (même concentration de tous les polymères en mélange) réalisées dans du DMEM, sont déposées dans chaque puit (3 mb/puit) : BB (mélange final 0,5 % m/m), PL/ALG (50/50 m/m avec un mélange final de 0,5 % de polymères), PP/ALG (50/50 m/m avec un mélange final de 0,5 % de polymères), PL/(ALG/BB) (33/33/33 m/m avec un mélange final 0,5 % de polymères), et PP/(ALG/BB) (33/33/33 m/m avec un mélange final 0,5 % de polymères). 7.1 In vitro experimentation: 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. After 12 h, 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).
Après 6h de traitement, le surnageant a été récupéré et le TNF-alpha, un marqueur de l'inflammation a été dosé par ELISA (Bio-Techne, R&D
Systems, Angleterre). Les résultats obtenus sont reportés sur la figure 12 annexée sur laquelle le taux de Tnf-alpha (en pg/mL) est donné pour chacune des solutions testées : DMEM (témoin négatif), DMEM + LPS (témoin positif), LPS + BB à 0,5 % en masse, PLS + Pb/ALG à 0,5 % en masse, LPS + PL/(ALG/BB) à 0,5 % en masse, LPS + PP/ALG à 0,5 % en masse et LPS + PP/(ALG/BB) à 0,5 % en masse. After 6 hours of treatment, the supernatant was recovered and TNF-alpha, an inflammation marker, was assayed by 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.
Les résultats reportés sur la figure 12 montrent que les cellules traitées au LPS + DMEM (témoin positif) en l'absence de polymère présentent une forte inflammation par rapport aux cellules n'ayant pas été traitées avec le LPS (DMEM - témoin négatif). Ces résultats montrent également que chacune des solutions de polymères ralentit de façon significative la survenue de l'inflammation des cellules. Ces propriétés anti-inflammatoires sont justifiées par la composition de la pulpe de baobab (polyphénols, flavonoïdes, vitamine C...) qui réduit l'activation au niveau de la voie NF-kB. Concernant les PL, elles sont capables de réduire les effets des radicaux oxygène et de la peroxydation lipidique en augmentant l'activité du glutathion antioxydant, stimulant ainsi l'épithélisation et la prolifération des fibroblastes ainsi qu'en augmentant la sécrétion de cytokines pro- et post inflammatoires (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)). The results reported in FIG. 12 show that the cells treated with LPS+DMEM (positive control) in the absence of polymer exhibit strong inflammation compared to the cells which have not been treated with LPS (DMEM-negative control). These results also show that each of the polymer solutions significantly slows down the occurrence of cell inflammation. These anti-inflammatory properties are justified by the composition of the baobab pulp (polyphenols, flavonoids, vitamin C...) which reduces activation at the level of the NF-kB pathway. Regarding PL, 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)).
EXEMPLE 8 : Mise en évidence des propriétés analgésiques des solutions gélifiées : EXAMPLE 8 Demonstration of the analgesic properties of gelled solutions:
Il existe une corrélation entre la perméabilité intestinale et l'intensité des douleurs abdominales chez les patients souffrant du syndrome de l'intestin irritable (SU). Dans cet exemple on a utilisé le modèle animal d'inflammation au Destran Sodium Sulfate (DSS) (Dextran sodium sulfate colitis murine model: An indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis, Derrick D Eichele, Kusum K Kharbanda, World J Gastroenterol. 2017 Sep 7; 23(33): 6016-6029). Des souris C57BL/6J ont reçu un pré-traitement avec une solution de BB à 5 % (250 pb/gavage/souris) 7 jours avant et pendant le traitement au DSS (responsable du déclenchement inflammation, DSS 0,5 % dans l'eau de boisson).
Le pourcentage de perte de poids ainsi que les marqueurs inflammatoires classiques (Lipocaline-2, MPO, MIP-2) ont été mesurés selon la méthode décrite dans l'article de B. Chassaing et al., Affiliations expand 2012, DOI: 10.137 l/journal pone.0044328). Les dommages coliques ont été déterminés quotidiennement par l'indice d'activité de la maladie, le DAI (acronyme de l'expression anglophone « Disease Activity Index ») tel que défini dans la publication de Carvalho et al. (Inflamm. Bowel Dis., Volume 14, Numéro 8, Août 2008). Le saignement rectal a été évalué par le test Hemoccult II (SKD SARL). Les scores vont de 0 (sain) à 12 (plus grande activité de la colite). Le score DAI a été calculé comme la somme du score de perte de poids, du score diarrhéique et du score d'hématochézie. There is a correlation between intestinal permeability and the intensity of abdominal pain in patients with irritable bowel syndrome (SU). In this example we used the Destran Sodium Sulfate (DSS) animal model of inflammation (Dextran sodium sulfate colitis murine model: An indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis, Derrick D Eichele, Kusum K Kharbanda, World J Gastroenterol.2017 Sep 7;23(33):6016-6029). C57BL/6J mice were pre-treated with 5% BB solution (250 bp/gavage/mouse) 7 days before and during DSS treatment (responsible for initiating inflammation, 0.5% DSS in the drinking water). The percentage of weight loss as well as the classic inflammatory markers (Lipocalin-2, MPO, MIP-2) 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.
La perméabilité intestinale totale a été déterminée en mesurant l'intensité de fluorescence dans le plasma 3 heures après gavage par la fluorescéine (400 Da). The total intestinal permeability was determined by measuring the fluorescence intensity in the plasma 3 hours after gavage with fluorescein (400 Da).
Les résultats obtenus sont reportés sur la figure 13 annexée sur laquelle l'intensité de la fluorescence à J12 (quantité d'isothiocyanate de fluorescéine (ou FITC) en unités arbitraires) est donnée pour chacune des solutions testées : Eau + Eau (témoin négatif), DSS à 0,5 % + Eau (témoin inflammation), DSS à 0,5 % + BB à 5 % (m/m), DSS à 0,5 % + PP/ALG à 5 % (m/m) et DSS à 0,5 % + PP/(ALG/BB) à 5 % (m/m). The results obtained are shown in the appended figure 13 on which the intensity of the fluorescence at D12 (quantity of fluorescein isothiocyanate (or FITC) in arbitrary units) is given for each of the solutions tested: Water + Water (negative control) , 0.5% DSS + Water (inflammation control), 0.5% DSS + 5% BB (m/m), 0.5% DSS + 5% PP/ALG (m/m) and DSS at 0.5% + PP/(ALG/BB) at 5% (m/m).
Les résultats présentés sur la figure 13 montrent que la diffusion du FITC- dextran à travers l'épithélium après le traitement DSS était significativement augmentée dans les intestins des souris au jour 12. Avec un traitement au BB, la diffusion du FITC-dextran était plus faible et non significative par rapport au témoin Eau sans DSS mais également non significative par rapport au témoin Eau avec DSS. Avec un traitement PL/ALG, la diffusion du FITC-dextran n'est pas significativement différente du témoin Eau avec DSS. Par contre, l'association PL/(ALG/BB) est significativement différente du témoin Eau avec DSS et permet de restaurer la fonction de barrière intestinale. Il y a donc une synergie d'action avec l'association des polymères conformes à la présente invention. The results presented in Figure 13 show that the diffusion of FITC-dextran through the epithelium after DSS treatment was significantly increased in the intestines of mice on day 12. With BB treatment, the diffusion of FITC-dextran was more weak and not significant compared to the Water control without DSS but also not significant compared to the Water control with DSS. With a PL/ALG treatment, the diffusion of FITC-dextran is not significantly different from the Water control with DSS. On the other hand, the PL/(ALG/BB) association is significantly different from the Water control with DSS and makes it possible to restore the intestinal barrier function. There is therefore a synergy of action with the combination of the polymers in accordance with the present invention.
La sensibilité colique de l'animal est évaluée par distensions colorectales, cette méthode est proche de celle utilisée chez l'Homme (Ritchie, J. 1973.
'Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome', Gut, 14: 125-32.) et consiste en l'inflation d'un ballonnet dans le côlon distal des souris. 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.
Les animaux ont été placés en habituation dans le système de contention durant l'heure précédant le test de distensions colorectales. Le ballonnet associé au capteur de pression est placé dans le colorectum à 1 cm de la marge anale. Le ballonnet est alors fixé à la queue de l'animal grâce à du ruban adhésif. Le protocole de distension consiste en un ensemble de distensions de pression croissante (20, 40, 60 et 80 mmHg), répétées deux fois pour chacune des pressions, pendant 20 secondes avec un intervalle inter-stimulus de 4 minutes. L'analyse des tracés est effectuée à l'aide du logiciel LabChart (AD Intruments). Le signal brut (pression intracolique) est lissé sur une période de 2 secondes puis positivé. La réponse des animaux est calculée pour chaque pression de distension en soustrayant l'intégrale du signal traité correspondant aux 20 secondes précédant la stimulation à l'intégrale du signal traité pendant les 20 secondes de stimulation. 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.
Les résultats obtenus sont reportés sur la figure 14 annexée sur laquelle les aires sous la courbe AUC 60-80 mmHg sont données pour chacune des solutions testées : Eau + Eau (témoin négatif), DSS à 0,5 % + Eau (témoin inflammation), DSS à 0,5 % + BB à 5 % (m/m), DSS à 0,5 % + PP/ALG à 5 % (m/m) et DSS à 0,5 % + PP/(ALG/BB) à 5 % (m/m). The results obtained are shown in the appended figure 14 in which the areas under the AUC 60-80 mmHg curve are given for each of the solutions tested: Water + Water (negative control), 0.5% DSS + Water (inflammation control) , 0.5% DSS + 5% BB (m/m), 0.5% DSS + 5% PP/ALG (m/m) and 0.5% DSS + PP/(ALG/BB ) at 5% (m/m).
A une concentration de 0,5 % et sur une période d'administration de 12 jours, DSS + Eau induit une inflammation à bas bruit significativement différente du témoin Eau + Eau, mesurée par une augmentation de la lipocaline-2 fécale (Lcn2). Le traitement avec BB, PP/ALG et PP/(ALG/BB) diminue significativement cette inflammation à bas bruit. Aucune inflammation locale (mesurée par dosage de MPO et d'IL-6 colique) sèvere n'est cependant retrouvée chez ces souris. At a concentration of 0.5% and over an administration period of 12 days, 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). Treatment with BB, PP/ALG and PP/(ALG/BB) significantly decreases this low noise inflammation. No severe local inflammation (measured by assay of MPO and colonic IL-6) is however found in these mice.
L'application d'un stimulus nociceptif par gonflement d'un ballonnet au niveau du rectum est ressentie de façon plus intense chez les souris traitées au DSS (DSS + Eau) et au PL/ALG (DSS + PL/ALG) comparativement aux souris contrôles (Eau + Eau). Comparé à la mesure basale, le BB (DSS + BB) et plus particulièrement l'association des 3 polymères (DSS + PL/(ALG/BB)) diminuent la sensibilité colique des souris traitées au DSS.
Bien sûr, l'invention n'est pas limitée aux exemples qui viennent d'être décrits et de nombreux aménagements peuvent être apportés à ces exemples sans sortir du cadre de l'invention.
The application of a nociceptive stimulus by inflating a balloon at the level of the rectum is felt more intensely in mice treated with DSS (DSS + Water) and PL/ALG (DSS + PL/ALG) compared to mice controls (Water + Water). Compared to the basal measurement, the BB (DSS+BB) and more particularly the combination of the 3 polymers (DSS+PL/(ALG/BB)) decrease the colonic sensitivity of the mice treated with DSS. Of course, the invention is not limited to the examples which have just been described and many adjustments can be made to these examples without departing from the scope of the invention.
Claims
1. Forme galénique pour la libération contrôlée d'une substance d'intérêt par voie orale, ladite forme galénique comprenant au moins une association de polymères biodégradables et biocompatibles à titre d'excipients, ladite forme galénique étant caractérisée en ce que : 1. Galenic form for the controlled release of a substance of interest orally, said galenic form comprising at least one combination of biodegradable and biocompatible polymers as excipients, said galenic form being characterized in that:
- ladite association de polymères comprend de 20 à 90 % en masse d'au moins une protéine, de 2,5 à 20 % en masse d'au moins un polysaccharide et de 8 à 75 % en masse de pulpe de fruits de baobab, lesdits pourcentages étant exprimés en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab) ;- 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);
- le rapport massique protéine(s)/pulpe de fruits de baobab, exprimé en masse de matières sèches, est compris entre 0,5 et 5, bornes incluses ; et- the protein(s)/baobab fruit pulp mass ratio, expressed as mass of dry matter, is between 0.5 and 5, limits included; and
- le rapport massique polysaccharide(s)/pulpe de baobab, exprimé en masse de matières sèches, est compris entre 0,05 et 1, bornes incluses. - the polysaccharide(s)/baobab pulp mass ratio, expressed as mass of dry matter, is between 0.05 and 1, limits included.
2. Forme galénique selon la revendication 1, caractérisée en ce que ladite au moins une protéine est utilisée sous forme dénaturée ou non dénaturée et est une protéine végétale choisie parmi les protéines de pois ; les protéines de grains de maïs ; les protéines de céréales ; les protéines de soja et les protéines de graines de courges. 2. Galenic form according to claim 1, characterized in that said at least one protein is used in denatured or undenatured form and is a vegetable protein chosen from pea proteins; corn kernel protein; cereal proteins; soy protein and pumpkin seed protein.
3. Forme galénique selon la revendication 1, caractérisée en ce que ladite au moins une protéine est utilisée sous forme dénaturée ou non dénaturée et est une protéine animale choisie parmi les protéines de lait et les gélatines. 3. Galenic form according to claim 1, characterized in that said at least one protein is used in denatured or undenatured form and is an animal protein chosen from milk proteins and gelatins.
4. Forme galénique selon la revendication 1 ou 3, caractérisée en ce que ladite au moins une protéine est une protéine de lactosérum. 4. Galenic form according to claim 1 or 3, characterized in that said at least one protein is a whey protein.
5. Forme galénique selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle comprend de 55 à 80 % en masse de protéines, ledit pourcentage étant exprimé en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab). 5. Galenic form according to any one of the preceding claims, characterized in that it comprises from 55 to 80% by mass of protein, said percentage being expressed by mass of dry matter and relative to the total mass (protein(s) ) + polysaccharide(s) + baobab fruit pulp).
6. Forme galénique selon l'une quelconque des revendications précédentes, caractérisée en ce ledit au moins un polysaccharide est un polymère anionique choisi parmi les alginates, les pectines, les dérivés cellulosiques, les gommes polysaccharidiques, les carraghénanes, les
dextranes et dextranes modifiés, l'acide poly(lactique-co-glycolique) et l'acide hyaluronique. 6. Galenic form according to any one of the preceding claims, characterized in that said at least one polysaccharide is an anionic polymer chosen from alginates, pectins, cellulose derivatives, polysaccharide gums, carrageenans, dextrans and modified dextrans, poly(lactic-co-glycolic) acid and hyaluronic acid.
7. Forme galénique selon l'une quelconque des revendications précédentes, caractérisée en ce que ledit au moins un polysaccharide est un polysaccharide anionique choisi parmi les alginates. 7. Galenic form according to any one of the preceding claims, characterized in that said at least one polysaccharide is an anionic polysaccharide chosen from alginates.
8. Forme galénique selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle comprend de 4 à 15 % en masse de polysaccharide(s), ledit pourcentage étant exprimé en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab). 8. Galenic form according to any one of the preceding claims, characterized in that it comprises from 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).
9. Forme galénique selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle comprend de 17 à 72 % en masse de pulpe de fruits de baobab, ledit pourcentage étant exprimé en masse de matières sèches et par rapport à la masse totale (protéine(s) + polysaccharide(s) + pulpe de fruits de baobab). 9. Galenic form according to any one of the preceding claims, characterized in that it comprises from 17 to 72% 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).
10. Forme galénique selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle se présente sous forme solide et que le ratio massique protéine(s)/pulpe de fruits de baobab, exprimé en masse de matières sèches, est compris entre 0,7 et 2 bornes incluses. 10. Galenic form according to any one of the preceding claims, characterized in that it is in solid form and that the protein(s)/baobab fruit pulp mass ratio, expressed as mass of dry matter, is between 0.7 and 2 terminals included.
11. Forme galénique selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle se présente sous forme solide et que le ratio massique polysaccharide(s)/pulpe de baobab, exprimé en masse de matières sèches, est compris entre 0,05 et 0,5 bornes incluses. 11. Galenic form according to any one of the preceding claims, characterized in that it is in solid form and that the polysaccharide(s)/baobab pulp mass ratio, expressed as mass of dry matter, is between 0, 05 and 0.5 terminals included.
12. Forme galénique selon l'une quelconque des revendications 1 à 9, caractérisée en ce qu'elle se présente sous forme de suspensions gélifiées ou de microparticules gélifiées. 12. Pharmaceutical form according to any one of claims 1 to 9, characterized in that it is in the form of gelled suspensions or gelled microparticles.
13. Forme galénique selon la revendication 12, caractérisée en ce que le rapport massique protéine(s) dénaturée(s) ou non dénaturées/pulpe de fruits de baobab, exprimé en masse de matières sèches, est compris entre 2,2 et 4,5 bornes incluses. 13. Galenic form according to claim 12, characterized in that the mass ratio of denatured or undenatured protein(s)/baobab fruit pulp, expressed as mass of dry matter, is between 2.2 and 4, 5 terminals included.
14. Forme galénique selon la revendication 12 ou 13, caractérisée en ce le ratio massique polysaccharide(s)/pulpe de baobab, exprimé en masse de matières sèches, est compris entre 0,1 et 0,4 bornes incluses.
14. Galenic form according to claim 12 or 13, characterized in that the mass ratio of polysaccharide(s)/baobab pulp, expressed as mass of dry matter, is between 0.1 and 0.4 limits inclusive.
15. Composition à libération contrôlée pour l'administration par voie orale d'au moins une substance d'intérêt, ladite composition étant caractérisée en ce qu'elle comprend une forme galénique telle que définie à l'une quelconque des revendications précédentes et au moins une substance d'intérêt. 15. 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 as defined in any one of the preceding claims and at least a substance of interest.
16. Composition selon la revendication 15, caractérisée en ce que ladite composition est une composition pharmaceutique est en ce que la substance d'intérêt est choisie parmi les principes actifs, les probiotiques et leurs mélanges. 16. Composition according to claim 15, characterized in that said composition is a pharmaceutical composition and in that the substance of interest is chosen from active principles, probiotics and mixtures thereof.
17. Composition selon la revendication 15, caractérisée en ce que le principe actif est choisi parmi les protéines thérapeutiques et les peptides thérapeutiques. 17. Composition according to claim 15, characterized in that the active principle is chosen from therapeutic proteins and therapeutic peptides.
18. Composition selon l'une quelconque des revendications 15 à 17, caractérisée en ce qu'elle comprend ladite forme galénique sous forme solide, qu'elle se présente également sous forme solide et en ce que ladite forme galénique représente de 20 à 50 % en masse, par rapport à la masse totale de ladite composition. 18. Composition according to any one of claims 15 to 17, characterized in that it comprises said galenic form in solid form, that it is also in solid form and in that said galenic form represents from 20 to 50% by mass, relative to the total mass of said composition.
19. Composition selon l'une quelconque des revendication 15 à 18, caractérisée en ce que la pulpe de fruits de baobab représente de 8 à 35 % en masse par rapport à la masse totale de ladite composition. 19. Composition according to any one of claims 15 to 18, characterized in that the baobab fruit pulp represents from 8 to 35% by mass relative to the total mass of said composition.
20. Procédé de préparation d'une composition telle que définie à l'une quelconque des revendications 15 à 19, ledit procédé étant caractérisé en ce qu'il comprend au moins une étape d'incorporation d'au moins une substance d'intérêt dans une forme galénique telle que définie à l'une quelconque des revendications 1 à 14 et au moins une étape de mise en forme finale de ladite composition.
20. Process for preparing a composition as defined in any one of claims 15 to 19, said process being characterized in that it comprises at least one step of incorporating at least one substance of interest into a pharmaceutical form as defined in any one of claims 1 to 14 and at least one step of final shaping of said composition.
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