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    • 专利摘要:
    The present invention relates to a composition in the form of an extrudate comprising at least one protoberberine alkaloid as active ingredient and at least one polymer, said protoberberine alkaloid comprising at least a first amorphous phase and optionally a second crystalline phase. The present invention also relates to the method of manufacturing such a composition and its use.
    公开号:BE1025649B1
    申请号:E2018/5586
    申请日:2018-08-24
    公开日:2019-05-20
    发明作者:Pastoriza Cristina Loira；Véronique Préat；Fabian Priem；Yvan Larondelle
    申请人:Eleonor Sprl；
    IPC主号:
    专利说明:

    Composition comprising at least one protoberberine alkaloid and its manufacturing process
    The present invention relates to a composition comprising at least one protoberberine alkaloid, to its manufacturing process and to its use.
    Within the meaning of the present invention, the term “protoberberine alkaloid” designates both the protobbererine alkaloids of natural and / or vegetable origin as well as the synthetic protobbererine alkaloids but also all the derivatives of protoberberine alkaloids such as, for example, the salts protobberine alkaloids. By way of example, the term "berberine" which designates a protobbererine alkaloid includes berberine derivatives such as berberine salts, for example berberine hydrochloride or berberine sulfate.
    Protoberberine alkaloids are basic nitrogenous heterocyclic organic substances of essentially vegetable origin, with well-known and widely used therapeutic properties.
    Protoberberin alkaloids are part of the isoquinoline family. According to the publication by Da-Cunha et al. (The Alkaloids: Chemistry and Biology. Protoberberine Alkaloids. Elsevier, 2005, vol. 62, pages 1 to 75), the protoberberine alkaloids can be divided into ten types corresponding to the chemical structures as shown in Table 1 below.
    Among the type III protobberine alkaloids is berberine which responds to the chemical structure below and which is of particular interest.
    BE2018 / 5586
    Table 1: the different types of protobberine alkaloids
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    Hierarchically, berberine or 2,3-methylenedioxy9,10-dimethoxy-protoberberine can therefore be classified as follows: alkaloids> isoquinolines> protobbererine alkaloids> berberine. It is a protobberine alkaloid with multiple therapeutic powers which therefore belongs to the group of isoquinolines, which are natural compounds present in the form of salts in certain plant species.
    The vast majority of protoberberine alkaloids, including berberine, are heat-sensitive molecules, both lipophobic and hydrophobic, this being reflected by their low solubility / miscibility in water but also in lipids and lipid derivatives.
    Note that scientific studies report that berberine has a very low bioavailability of less than 5%, which is even only about 0.68% in laboratory rats subjected to experiments. In addition, efflux pumps, such as the glycoprotein-P (P-gp) of the intestine and the liver, have been shown to decrease the bioavailability of this alkaloid. P-gp is a membrane transporter responsible for the outflow of molecules absorbed by cells to the intestinal lumen. In the case of berberine, the majority of the absorbed molecule is rapidly expelled to the intestinal lumen by this glycoprotein.
    However, despite its low bioavailability (that is to say despite the small fraction of the administered dose which effectively reaches the blood circulation in unchanged form) but also despite its low solubility in particular in the intestinal environment, the positive effects of berberine on many pathologies make it a molecule of interest. This is why, numerous methodologies and numerous processes have been developed in order to formulate berberine for administration to humans and / or for veterinary use. Lipid formulations have mainly been considered but, because of the low
    BE2018 / 5586 solubility / miscibility of berberine in lipids and lipid derivatives, its rate of incorporation in such lipid phases remains very low compared to the dose which should be administered. In addition, the rate of release of berberine from these lipid formulations is very low, which gives rise to a low bioavailability of this molecule.
    Document WO2015 / 097642 describes another process for the preparation of a formulation comprising berberine which is based on a step of mixing a predetermined quantity of berberine with a predetermined quantity of polyethylene glycol in a water-ethanol solution in order to obtain a precipitate viscous, which is recovered before being sieved and dried to finally obtain granules which will be placed in capsules. If the incorporation of berberine into the formulation obtained seems to be improved compared to lipid formulations, the fact remains that this process according to document WO2015 / 097642 is somewhat restrictive and difficult to implement. Indeed, several successive stages must be respected and a passage through a sieve of a viscous substance can give rise to clogging problems which slow down the production of the formulations.
    Other processes are used in order to obtain formulations in the form of spherical particles, pellets or even granules. In particular, for powder shaping, extrusion techniques can be used such as for example the extrusion-spheronization technique, the granulation technique by extrusion (TSG or Tween Screw Granulation) or the extrusion technique using hot (HME or Hot Melt Extrusion).
    The extrusion-spheronization technique makes it possible to produce round particles of homogeneous size from a wet mass (containing an active substance and at least one excipient) which is passed through a grid having a predetermined mesh before drying of the particles thus obtained. More particularly, this method of placing
    BE2018 / 5586 in powder form is based on the following stages: mixing of an active substance and at least one excipient, wet granulation (compaction) of the previously obtained mixture, extrusion of the compacted mixture to obtain an extrudate, spheronization of the extrudate to form spherical particles / granules and drying of the spherical particles / granules obtained.
    The extrusion granulation technique makes it possible to obtain intermediate products for the preparation of tablets and capsules. This technique is based on a granulation (compaction) of substances in the form of powders in an extruder to give rise to the formation of granules at the outlet of the latter.
    The hot extrusion technique makes it possible to carry out the molecular dispersion of an active ingredient (active substance) within a polymer matrix to form solid dispersions. This solid dispersion is possible thanks to a contribution of heat and thanks to the stress applied by the movement of the screws on the material in an extruder. Finally, the hot extrusion gives rise, at the outlet, to the formation of an extrudate in the form of a rod which can then in particular be pelletized or ground.
    If the extrusion-spheronization technique and the extrusion granulation technique are carried out without heat input (heating) and they typically require a liquid phase (generally water) to obtain spherical particles and / or granules , the hot extrusion technique can be carried out without the addition of this liquid phase but is based on an input of heat (heating).
    Furthermore, if the extrusion-spheronization technique and the extrusion granulation technique consist of an agglomeration of granules of powders while trying as much as possible to preserve the initial properties of the constituents of these powders, the hot extrusion technique gives instead a glassy structure under the action of heat (heating), the particles
    BE2018 / 5586 constituting the powders no longer being all present in their initial (native) crystalline form at the end of the hot extrusion process.
    Document CN104997735 describes the preparation of micropills based on berberine hydrochloride and an adjuvant (MCC, starch, sucrose or dextrin) by an extrusion granulation process. Document JPH0959159 also describes the preparation of compositions (in the form of tablets or granules) comprising quinine or berberine, a polymer and lactose by an extrusion granulation process. In all cases, the active substance (berberine hydrochloride or quinine or berberine) and certain adjuvants are mixed and compacted (granulation) to obtain granules at the outlet of an extruder, this avoiding any modification of the properties of the initial particles (native ) crystalline of the active substance and adjuvants. However, it turns out, for each of the compositions according to documents CN104997735 and JPH0959159, that only very small amounts of berberine are released from the micropills, granules and tablets as soon as the berberine being present there is very slightly soluble .
    Unfortunately, it therefore appears, on the one hand, that the current formulations comprising a protoberberine alkaloid, in particular berberine, are unsuitable because of the too low solubility of the protoberberine alkaloid but also because of the low release of this alkaloid at the start of these formulations, which ultimately results in a low bioavailability of this alkaloid (molecule) of interest. On the other hand, it appears that the current methods of manufacturing these formulations are restrictive and difficult to implement.
    The invention aims to overcome the drawbacks of the state of the art by providing (1) a composition comprising a protoberberine alkaloid, such as for example berberine, the solubility of which is increased so that the bioavailability of protobberine alkaloid is significantly increased and (2) a method of
    BE2018 / 5586 manufacture of such a composition which is easy to implement, which is flexible, which is economically profitable and which ensures that the protoberberine alkaloid is present and homogeneously distributed in the final composition obtained. Furthermore, the invention intends to provide a composition which is stable over time, that is to say which retains its properties in terms of the solubility of the protoberberine alkaloid and in terms of the rate of release of this alkaloid at over time.
    To at least partially solve these problems, there is provided according to the invention, a composition in the form of an extrudate comprising at least one protoberberine alkaloid as active ingredient and at least one polymer, said protoberberine alkaloid comprising at least a first phase amorphous and possibly a second crystalline phase.
    By the terms “comprising at least a first amorphous phase and optionally a second crystalline phase”, it is understood, within the meaning of the present invention, that said protoberberine alkaloid can either comprise 100% by mass of an amorphous phase, or that 'It can simultaneously comprise a first amorphous phase and a second crystalline phase, the sum of the percentages by mass of the first and second phases being in this case equal to 100. In other words, the composition according to the invention can comprise said at minus one protoberberine alkaloid (1) totally in its amorphous form or (2) partially in its amorphous form (phase) and partially in its crystalline form (phase).
    Note that a phase is said to be amorphous when the atoms constituting it do not follow any order at medium and long distance, which distinguishes it from a so-called crystalline phase.
    By the term "extrudate" is meant, within the meaning of the present invention, a material which leaves a extruder, in particular from the die of an extruder.
    BE2018 / 5586
    The composition according to the invention is therefore in the form of an extrudate in which the protoberberine alkaloid (active principle) comprises at least a first amorphous phase and optionally a second crystalline phase, which phase or phases is / are dispersed in at least one polymer.
    Unexpectedly, it has been determined, in the context of the present invention, that such a composition in the form of an extrudate comprising at least one protoberberine alkaloid as active ingredient and at least one polymer and in which said protoberberine alkaloid comprises at least a first amorphous phase and optionally a second crystalline phase exhibits a markedly higher solubility of the alkaloid of protoberberine (in particular in the intestinal medium). Furthermore, it has been shown that such a composition according to the invention has a significantly increased bioavailability of the alkaloid of protoberbine compared to the bioavailability observed for the current compositions.
    Surprisingly, it has also been shown, in the context of the present invention, that even if the protoberberine alkaloid is sensitive to heat, it is not degraded even during a manufacturing process by hot extrusion of the composition which however involves the submission of the protobberine alkaloid to high temperatures as will be explained below. In a composition according to the invention, the active principle, that is to say the protoberberine alkaloid comprising at least a first amorphous phase and optionally a second crystalline phase, is dispersed within the polymer, the active principle and the polymer being melted during the manufacturing process used according to the invention and described below.
    In addition, a composition according to the invention can be stored for several months without its properties being altered. In particular, it has been demonstrated that a composition according to the invention retains its properties in terms of the solubility of the alkaloid.
    BE2018 / 5586 protoberbérine and in terms of rate of release of this alkaloid over time.
    Advantageously, according to the invention, said protoberberine alkaloid mainly comprises at least one first amorphous phase. By the terms “predominantly at least a first amorphous phase”, it is understood, within the meaning of the present invention, that said protoberberine alkaloid comprises between 50 and 100% by mass of an amorphous phase and between 0 and 50% of a crystalline phase, more particularly that said protoberberine alkaloid comprises between 51 and 100% by mass of an amorphous phase and between 0 and 49% of a crystalline phase
    Preferably, according to the invention, said protoberberine alkaloid is chosen from the group consisting of alborine, anibacanine, anisocycline, artavenustine, berbérastine, berbérine, berbérubine, berlambine, canadine, la capaurimine, capaurine, caseadine, caseamine, cavidine, cerasodine, cerasonine, cheilanthifoline, clarkeanidine, columbamine, constrictosine, coptisine, coreximine, corybulbine, corycavamine, corycavin, corydine corydalmine, corymotine, corynoxidine, corypalmine, corysamine, corytenchine, coulteropine, cryptopine, cyclanoline, dauricoside, discramine, fississaine, govanine, groenlancidine, gusanlung-A, gusan B, gusanlung-D, hunnemanine, jatrorrhizine, lambertine, lienkonine, malacitanine, manibacanine, mecambridine, muramine, orientamine, pallimamine, palmatine, pés soine, phellodendrine, prechilenin, protopin, schefferin, scoulerin, sinactin, spiduxin, spinosin, stéphabinamine, stéphabine, stépharanine, stépholidine, stylopine, tetrahydropalmatine, thaaline, thaicanine thalictricavin, thalidastine, thalifendine, xilopinine, yuanamide, dihydroberberine, dehydrocorydalmine, palmatrubine, dehydrodiscretamine, dehydrocheilanthifoline, demethylenberberine, epiberberine, la
    BE2018 / 5586 pseudocoptisin, pseudopalmatine, pseudojatrorrhizine, pseudoepiberbérine, pseudocolumbamine, dehydrodiscretine, dehydrocoreximine, thalifaurine, corysamine, dehydrothalictrifoline lahydrocharine dehydrocrocine laurocine dehydrocrocine methyl-pseudoepiberberine, mequinine, their derivatives, their salts and their mixtures.
    Preferably, according to the invention, said polymer of a composition according to the invention is chosen from the group consisting of copolymers of ammonium methacrylates, hydroxypropylcellulose (HPC), polyvinyl acetate, ethylcellulose, hydroxypropyl methylcellulose phthalate, polyvinylpyrrolidone (PVP), hydroxypropymethylcellulose (HPMC), hydroxypropymethylcellulose acetosuccinate, cellulose acetobutyrate, cellulose acetophthalate, polyvinylpyrrolidone acetate co-vinyl, polyethylene acetate-co-vinyl, polyvinyl acetate-co-methacrylic acid, polyethylene oxide, polylactide-co-glycolide, polyvinyl alcohol, pectin, polycarbophile, polycaprolactone, carnauba wax, ethylene-vinyl copolymer acetate, lecithin, castor oil and hydrogenated soybeans, waxes (microcrystalline wax, .. .), natural or synthetic starch (corn starch, pregelatinized starch, potato starch, ...), maltodextrin, isomalt, chitosan, gums (xanthan gum,. ..), agar, lactose, natural or synthetic soluble or insoluble fibers such as inulin, ß-glucan and Konjac fibers, their derivatives and mixtures.
    Preferably, according to the invention, said protoberberine alkaloid is a protoberberine alkaloid of natural and / or vegetable origin. It is understood that the synthetic protoberberine alkaloids are also envisaged as active principles within the meaning of the present invention. Likewise, all the derivatives of protobberine alkaloids and their salts are envisaged as active principles within the meaning of the present invention.
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    Advantageously, the composition according to the invention also comprises at least one plasticizing agent. The addition of a plasticizing agent in a composition according to the invention is advantageous and makes it possible to further increase the solubility and the bioavailability of the alkaloid (active principle). Furthermore, the presence of a plasticizing agent makes it possible to obtain a composition according to the invention through a manufacturing process where temperatures below the melting points of the protoberberine alkaloid and of the polymer can be used in order to still guarantee a melting of these two compounds and the dispersion of the alkaloid of protoberberine within the polymer. For example, when a composition according to the invention comprises berberine as protoberberine alkaloid, whose melting point is of the order of 142 to 145 ° C., and hydroxypropylcellulose as polymer, whose point of melting is of the order of 130 to 140 ° C., the presence of glycerol as a plasticizing agent makes it possible to ensure a melting of the berberine and of the hydroxypropylcellulose, and thus a dispersion of the alkaloid of protoberberine at within the polymer, already at a temperature of the order of 80 to 90 ° C. This has the effect, by minimizing the temperatures applied, that the alkaloid of protoberberine is not subject to degradation by heat and that it thus preserves all the better its properties. In addition, a reduction in the temperatures used makes it possible to apply a manufacturing process which is more economical and faster.
    Preferably, according to the invention, said plasticizing agent is chosen from the group consisting of polyols, lipids, lecithins, sucrose esters, triethyl citrate, polyethylene glycol, glycerol, dibutyl sebate, stearate butyl, glycerol monostearate, diethyl phthalate and mixtures thereof.
    According to the invention, the preferred plasticizing agents are glycerol, polyethylene glycol and triethyl citrate.
    Preferably, the composition according to the invention also comprises at least one additive chosen from the group consisting of agents
    BE2018 / 5586 lubricants, surfactants, antioxidants, chelating agents and mixtures thereof.
    By way of example, the following compounds may be used, alone or as a mixture, as lubricating agents in a composition according to the invention: glycerol dibehenate, talc, silica, stearic acid, boric acid, starches, waxes, sodium oleate, sodium acetate, magnesium stearate, calcium stearate, sodium stearate, sodium benzoate, sodium lauryl sulfate, glycerol distearate , glycerol palmitostearate, microcrystalline cellulose or even polyoxyl-8-glycerides.
    By way of example, the following compounds can be used, alone or as a mixture, as surfactants in a composition according to the invention: Pluronic®, Span®, Cremophor®, polysorbates (Tween®, ...), vitamin E TPGS and sodium ducosate.
    By way of example, the following compounds can be used, alone or as a mixture, as antioxidant agents and / or chelating agents in a composition according to the invention: butylated hydroxytoluene, butylated hydroxyanisiole, EDTA , citric acid and vitamin E.
    Advantageously, the composition according to the invention also comprises at least one first additional active principle of polyphenol type chosen from the group consisting of phenolic acids, stilbenes, phenolic alcohols, lignans, flavonoids and their mixtures. In particular, the glycosylated and aglycone forms of the polyphenols are envisaged as an additional active principle according to the present invention. More particularly, within the meaning of the present invention, the term “polyphenol” designates both polyphenols of natural origin and synthetic polyphenols, but also all derivatives of polyphenols.
    By way of example, within the meaning of the present invention, derivatives of hydroxybenzoic acid (gallic acid, tannic acid, etc.) and derivatives of hydroxybenzoic acid can be cited as phenolic acids.
    BE2018 / 5586 hydroxycinamic acid (curcumin, coumaric acid, caffeic acid, acidferulic, ...).
    By way of example, within the meaning of the present invention, there may be mentioned as stilbenes, resveratrol, sirtinol, piceatannol or even polydatin.
    By way of example, within the meaning of the present invention, the flavonoids, the flavanoles (quercetin, myricetin, kaempferol, isorhamnetin, morine, rutin, tiliroside, trihydroxyethylrutin, fisetin, etc.) can be cited as flavonoids. apigenin, luteolin, baicalein, chrysin, diosmin, nobiletin, tangeretin, wogonin, aminogenistein, ...), flavanones (bavachine, 8-isopentenylnaringenin, isoxanthohumole, naringenin, eriodictyole, hesperetin, silybin ...) isoflavones (genistein, daidzein, daidzine, formonetin, genistin, neobavoflavone, pueranine, ...), antocianidines (cianidine, pelargonidine, delphinidine, petphinidin, malvidine, ...) and flavanols (cathechins, gallocatechin, epigallocatechin .. .).
    Preferably, the composition according to the invention further comprises at least second additional active principle of triterpene type such as, for example, limonoids.
    According to the invention, said at least one first additional active ingredient of polyphenol type and said at least second additional active ingredient of triterpene type constitute inhibitors / modulators of efflux pumps including P-gp.
    Preferably, the composition according to the invention also comprises at least one inhibitor and / or a modulator of the activity of P-gp. For example, said at least one inhibitor and / or modulator of P-gp activity can be piperine (an alkaloid).
    Preferably, the composition according to the invention is packaged in the form of pellets, granules, powders, effervescent tablets or not, solutions for injection or not, suspensions,
    BE2018 / 5586 gels, ointments or in any other suitable form allowing administration to an animal or a human being.
    Other embodiments of a composition according to the invention are indicated in the appended claims.
    The invention also relates to a process for manufacturing a composition according to the invention, characterized in that it comprises the following steps:
    a) a step of simultaneous or delayed introduction of at least one protoberberine alkaloid and at least one polymer to feed an extruder,
    b) a step of mixing, in said extruder, said at least one protoberberine alkaloid and said at least one polymer to form a mixture, and
    c) a hot extrusion (HME) step of said mixture obtained in step b) in said extruder to obtain an extrudate in which said protoberberine alkaloid comprises at least a first amorphous phase and optionally a second phase crystalline.
    Such a method according to the invention gives rise to a composition in the form of an extrudate in which said at least one protoberberine alkaloid as active ingredient comprises at least a first amorphous phase and optionally a second crystalline phase dispersed within said at least one polymer. This composition according to the invention has a significantly higher solubility of the protoberberine alkaloid (especially in the intestinal environment) and simultaneously a significantly increased bioavailability of the protoberberine alkaloid compared to the solubilities and bioavailability of this alkaloid for the current compositions. . It has been shown that the composition according to the invention is in the form of an extrudate in which said protoberberine alkaloid (active principle) comprising at least a first phase
    BE2018 / 5586 amorphous and optionally a second crystalline phase is dispersed within at least one polymer.
    Unexpectedly, it has also been shown, in the context of the present invention, that even if the protoberberine alkaloid is sensitive to heat, it is not degraded even during the process for manufacturing the composition in the form of 'an extrudate which, however, involves subjecting the alkaloid to high temperatures (HME). Furthermore, unexpectedly, it has also been pointed out that the protobberine alkaloid in a composition in the form of an extrudate according to the invention is distributed (distributed) therein homogeneously.
    More particularly, hot extrusion (Hot Melt Extrusion - HME) carried out according to the process according to the invention gives rise to a melting of the active principle (the protobberine alkaloid) and of the polymer at a temperature greater than or equal to their point. of fusion. However, according to certain embodiments of a composition according to the invention, this melting of the active principle and of the polymer can take place at a temperature below their melting point. This is for example the case if the composition according to the invention comprises a plasticizing agent or if the active principle itself has plasticizing properties. Such a melting of the active principle and of the polymer gives rise to a solid dispersion in which the active principle (the protobberine alkaloid) comprising at least a first amorphous phase and optionally a second crystalline phase is dispersed within at least one polymer. .
    Advantageously, the method according to the invention comprises a preliminary step of premixing said at least one protoberberine alkaloid and said at least one polymer so as to form a premix intended to supply the extruder.
    Preferably, according to the method according to the invention, said hot extrusion step is carried out at an extrusion temperature between 20 and 180 ° C, preferably at a temperature between 40 and 115 ° C, preferably at a temperature between 80 and
    BE2018 / 5586
    90 ° C, preferably at a temperature of 110 ° C, more preferably at a temperature of 100 ° C.
    Advantageously, according to the method according to the invention, said hot extrusion step is carried out at a speed of rotation of an extrusion screw of between 20 and 300 rpm, preferably between 100 and 250 rpm , preferably equal to 200 revolutions / min.
    Preferably, the method according to the invention comprises an additional step of cooling at the outlet of the extruder.
    Advantageously, the method according to the invention comprises an additional step of processing the extrudate at the outlet of the extruder, for example cutting at a pelletizer and / or grinding said extrudate.
    Other embodiments of the process according to the invention are indicated in the appended claims.
    The present invention also relates to a use of a composition according to the invention as a food supplement and / or as a cosmetic product and / or as a medicament for human or veterinary use.
    In particular, the present invention relates to a composition for use in the preventive and / or curative treatment, in humans and / or in animals, of pathologies related to the cardiovascular system (hypotension, vasoconstriction, ventricular hypertrophy, arrhythmia ...), pathologies linked to the blood system (cholesterolemia, platelet aggregation, ...), pathologies linked to the gastrointestinal system (diarrhea, digestive inflammation, modulation of the intestinal microbiont, ...) , pathologies related to the endocrine system (hyperglycemia, ...), pathologies related to the immune system, pathologies related to the central nervous system, skin diseases, diseases due to the presence of microorganisms and cancers (anti-tumor, ...) and in the preventive and / or curative treatment of diabetes.
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    More particularly, the present invention relates to a composition for use in the preventive and / or curative treatment, in humans and / or in animals, of obesity, diabetes, high cholesterol, metabolic syndrome and irritable colon (IBS).
    Other forms of use of a composition according to the invention are indicated in the appended claims.
    Other characteristics, details and advantages of the invention will emerge from the examples given below, without implied limitation and with reference to the appended figures.
    FIG. 1 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of berberine (BBR solubilized (%)) over time for two compositions according to the invention comprising berberine (BBR), a polymer (PVP) and a plasticizer (PEG or glycerol).
    FIG. 2 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of berberine (BBR solubilized (%)) over time for two compositions according to the invention comprising berberine (BBR), a polymer (HPC or PVP) and a plasticizer (glycerol).
    FIG. 3 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of berberine (BBR dissolved (%)) over time for three compositions according to the invention comprising berberine (BBR), a polymer (HPC) and a plasticizing agent in variable proportions (glycerol 0%, glycerol 5% or glycerol 10%).
    FIG. 4 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of berberine (BBR solubilized (%)) over time for two compositions according to the invention comprising berberine (BBR) in variable proportions (BBR 40% or BBR 50%), a polymer (HPC) and a plasticizing agent (glycerol).
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    FIG. 5 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of berberine (BBR dissolved (%)) over time for two compositions according to the invention comprising berberine, a polymer (HPC) and a plasticizing agent (glycerol), the "ages" of these two compositions being 0 days or 3 months.
    FIG. 6 is a graph illustrating the content of a protoberberine alkaloid, in this case the berberine content, in a composition according to the invention according to whether the latter is freshly obtained (T0), is 3 months old (T3M) , is 5 months old (T5M) or is 8 months old (T8M).
    FIG. 7 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of berberine, in a composition according to the invention according to whether the latter is freshly obtained (T0), is aged 3 months (T3M), is 5 months old (T5M) or is 8 months old (T8M).
    FIG. 8 is a thermogram obtained by DSC analysis of compositions according to the invention comprising berberine as protoberberine alkaloid and by analysis of crystalline berberine in powder form.
    FIG. 9 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of tetrahydropalmatine (THP dissolved (%)) over time for two compositions according to the invention comprising tetrahydropalmatine (THP).
    FIG. 10 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of tetrahydropalmatine (solubilized THP (%)) over time for compositions according to the invention comprising tetrahydropalmatine (THP), hydroxypropylcellulose as a polymer (HPC) and various types of plasticizers.
    BE2018 / 5586
    FIG. 11 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of tetrahydropalmatine (THP solubilized (%)) over time for compositions according to the invention comprising tetrahydropalmatine (THP), polyvinylpyrrolidone (PVP) as a polymer (HPC) and various types of plasticizers.
    FIG. 12 is a graph illustrating the rate of solubilization of a protoberberine alkaloid, in this case the rate of solubilization of tetrahydropalmatine (solubilized THP (%)) over time for two compositions according to the invention comprising tetrahydropalmatine (THP), a polymer and a plasticizer.
    Examples
    Example 1: process for manufacturing a composition according to the invention in the form of an extrudate comprising berberine as a protoberberine alkaloid
    Compositions according to the invention with berberine as protoberberine alkaloid (active principle), such as those which are the subject of example 2 below, were obtained according to the following process which is also the subject of the present invention:
    a) a step of premixing berberine in the crystalline state in the form of powder and at least one polymer;
    b) a step of supplying said premix formed in step a) to feed a Pharma 11 type extruder from Thermo-Fischer®;
    c) a step of mixing, in said extruder, said premix to obtain a mixture;
    d) a hot extrusion step of said mixture obtained in step c) in said extruder to obtain an extrudate, the hot extrusion step
    BE2018 / 5586 being produced at a speed of rotation of an extrusion screw of 200 rpm and at a temperature between 40 ° C and 110 ° C; and
    e) a step of cutting, at a pelletizer, the extrudate obtained in step d) so as to obtain pellets whose size is of the order of 2 to 3 mm.
    The temperature at which the hot extrusion step is carried out is determined by the type of constituents used, in particular according to the type of alkaloid of protoberberine, of polymer and / or of plasticizing agent used, this that the skilled person is able to determine.
    Example 2: Solubility test of compositions according to the invention comprising berberine as a protoberberine alkaloid
    Different compositions, obtained according to the manufacturing process described in Example 1, were tested in terms of solubility over time of the protobberine alkaloid from the extrudates obtained. Berberine was chosen as the protoberberine alkaloid to perform the solubility tests. As indicated above, the extrudates are in the form of pellets whose size is of the order of 2 to 3 mm.
    The solubility tests were all carried out with a paddle dissolution device at a temperature of 37 ° C. with stirring at 50 revolutions / minute in 900 ml of 0.1 N HCl dissolution medium. These solubility tests were conducted according to the recommendations of pharmacopoeia 07/2010: 51701 (Recommendations on Dissolution Testing).
    BE2018 / 5586
    a) Solubility test 1: influence of the addition of a plasticizing agent in a composition according to the invention comprising berberine, a polymer and a plasticizing agent
    Two different plasticizing agents were tested to formulate the following two compositions to be extruded according to the invention comprising berberine, a polymer and a plasticizing agent:
    Composition 1: 40% by weight of berberine (BBR) in the crystalline state in powder form + 50% by weight of polyvinylpyrrolidone (PVP Kollidon 12 PF, BASF) as a polymer + 10% by weight of glycerol (Roth) as a plasticizer;
    Composition 2: 40% by weight of berberine (BBR) in the crystalline state in powder form + 50% by weight of polyvinylpyrrolidone (PVP Kollidon 12 PF, BASF) as a polymer + 10% by weight of polyethylene glycol (PEG - Kollisolv PEG 400, BASF) as a plasticizing agent.
    These two compositions were compared in terms of solubilization of berberine over time according to the solubility test mentioned above, berberine alone in the crystalline state in powder form being also tested (control).
    The results obtained are presented in FIG. 1. As can be seen, the percentage of berberine solubilized over time is significantly higher for the compositions according to the invention (BBR + PVP + glycerol and BBR + PVP + PEG) in comparison with berberine alone in the crystalline state. The solubility of BBR alone in the crystalline state is around 35% while it is around 40% for composition 2 above (BBR + PVP + PEG) and around 60 at 70% for composition 1 above (BBR + PVP + glycerol).
    This demonstrates the advantage of a composition according to the invention in order to optimize the solubility of berberine and therefore to promote the bioavailability of berberine, the berberine comprising at least one amorphous phase.
    BE2018 / 5586
    b) Solubility test 2: influence of polymers present in a composition according to the invention comprising berberine, a polymer and a plasticizing agent
    Two different polymers were tested to formulate the following two compositions to be extruded according to the invention comprising berberine, a polymer and a plasticizing agent:
    Composition 1: 40% by weight of berberine (BBR) in the crystalline state in powder form + 50% by weight of polyvinylpyrrolidone (PVP Kollidon K30, BASF) as a polymer + 10% by weight of glycerol (Roth) as a plasticizing agent;
    Composition 2: 40% by weight of berberine (BBR) in the crystalline state in powder form + 50% by weight of hydroxypropylcellulose (HPC HPC SSL, Nisso) as a polymer + 10% by weight of glycerol (Roth ) as a plasticizer.
    These two compositions were compared in terms of solubilization of berberine over time according to the solubility test mentioned above, berberine alone in the crystalline state in powder form being also tested (control).
    The results obtained are presented in FIG. 2. As can be seen, the percentage of berberine solubilized over time is very significantly higher for the compositions according to the invention (BBR + PVP + glycerol and BBR + HPC + glycerol) in comparison with berberine alone in the crystalline state.
    This demonstrates that different polymers can be added to a composition according to the invention further comprising a plasticizing agent in order to optimize the solubility of berberine comprising at least one amorphous phase and therefore to promote the bioavailability of berberine. In addition, this also demonstrates the advantage of combining berberine with a polymer and a plasticizing agent since the solubility of berberine can then reach 100%.
    BE2018 / 5586
    c) Solubility test 3: influence of the proportion of the plasticizing agent in a cpmppsitipn according to the invention comprising berberine, a pplymer and a plasticizing agent
    Three proportions of glycerol as a plasticizing agent were tested to formulate the following three compositions to be extruded according to the invention comprising berberine, a polymer and a plasticizing agent:
    Composition 1: 50% by weight of berberine (BBR) in the crystalline state in powder form + 50% by weight of hydroxypropylcellulose (HPC HPC SSL, Nisso) as a polymer + 0% by weight of glycerol (Roth ) as a plasticizer;
    Composition 2: 50% by weight of berberine (BBR) in the crystalline state in the form of powder + 45% by weight of hydroxypropylcellulose (HPC HPC SSL, Nisso) as a polymer + 5% by weight of glycerol (Roth ) as a plasticizer;
    Composition 3: 50% by weight of berberine (BBR) in the crystalline state in powder form + 40% by weight of hydroxypropylcellulose (HPC HPC SSL, Nisso) as a polymer + 10% by weight of glycerol (Roth ) as a plasticizer.
    These three compositions were compared in terms of solubilization of berberine over time according to the solubility test mentioned above, berberine alone in the crystalline state in powder form being also tested (control).
    The results obtained are presented in FIG. 3. As can be seen, the percentage of berberine solubilized over time is significantly higher for the compositions according to the invention (BBR + HPC + 0% glycerol and BBR + HPC + glycerol 5 % and BBR + HPC + glycerol 10%) in comparison with berberine alone in the crystalline state.
    Note that the composition BBR + HPC + 0% glycerol makes it possible to demonstrate that the only addition of a polymer (in this case HPC
    BE2018 / 5586 in the present case) already makes it possible to optimize the solubility of berberine over time, the addition of a plasticizing agent (in this case glycerol in the present case) making it possible to further optimize the solubility of berberine over time since 100% solubility can be achieved.
    A comparison of the glycerol proportions shows that the 10% glycerol ensures faster dissolution of berberine over time during the first 30 minutes compared to the 5% glycerol.
    This demonstrates the advantage of adding a composition according to the invention to a plasticizing agent in order to further optimize the solubility of berberine and therefore to further promote the bioavailability of berberine comprising at least one amorphous phase. This also demonstrates that a higher proportion of plasticizing agent in a composition according to the invention makes it possible to dissolve the berberine more quickly at least at the start, that is to say in the first 30 minutes of the solubility test.
    d) Solubility test 4: influence of the proportion of alkaloid (berberine) in a composition according to the invention comprising berberine, a polymer and a plasticizing agent
    Two different proportions of berberine were tested to formulate the following two compositions to be extruded according to the invention comprising berberine, a polymer and a plasticizing agent:
    Composition 1: 40% by weight of berberine (BBR) in the crystalline state in powder form + 50% by weight of hydroxypropylcellulose (HPC HPC SSL, Nisso) as a polymer + 10% by weight of glycerol (Roth ) as a plasticizer;
    BE2018 / 5586
    Composition 2: 50% by weight of berberine (BBR) in the crystalline state in powder form + 40% by weight of hydroxypropylcellulose (HPC HPC SSL, Nisso) as a polymer + 10% by weight of glycerol (Roth ) as a plasticizer.
    These two compositions were compared in terms of solubilization of berberine over time according to the solubility test mentioned above, berberine alone in the crystalline state in powder form being also tested (control).
    The results obtained are presented in FIG. 4. As can be seen again, the percentage of berberine (comprising at least one amorphous phase) solubilized over time is very significantly higher for the compositions according to the invention (BBR + HPC + glycerol) in comparison with berberine alone in the crystalline state. With regard to the proportions of berberine (40 or 50%), it can be seen that whatever this proportion, the solubilization of the berberine is total (100%).
    e) Solubility test 5: stability over time of compositions according to the invention comprising berberine, a polymer and a plasticizing agent
    Two extrusion compositions comprising berberine, a polymer and a plasticizer of different "ages" (To and T3 months) were tested.
    These compositions comprise 40% by weight of berberine (BBR) in the crystalline state in powder form + 50% by weight of hydroxypropylcellulose (HPC - HPC SSL, Nisso) as a polymer + 10% by weight of glycerol ( Roth) as a plasticizer.
    These two compositions were compared in terms of solubilization of berberine over time according to the solubility test
    BE2018 / 5586 mentioned above, berberine alone in the crystalline state in powder form being also tested (control).
    The results obtained are presented in FIG. 5. As can be seen, the percentage of berberine (comprising at least one amorphous phase) solubilized over time is identical, whether the composition according to the invention is fresh (To) or whether the composition according to the invention is “aged” by 3 months (T3 months).
    Example 3: Homogeneity test - homogeneity of the berberine content within pellets obtained after extrusion
    In order to determine the homogeneity of the actual berberine content present in the extrudates obtained according to the process according to the invention with respect to the amount of berberine used during hot extrusion, pellets of a size of l 'order of 2 mm (n = 3 to 5 per batch tested) of different compositions according to the invention were solubilized before quantifying the berberine actually solubilized.
    To do this, 1 to 3 mg of extrudate were weighed and then dissolved in 1 to 2 ml of DMSO. The solution obtained was then analyzed by HPLC analysis after dilution in the mobile phase (1/20 or 1/50 dilution). More specifically, the assay was carried out using a Shimadzu HPLC apparatus according to the conditions given in Table 2 below to define the experimental berberine content (% by weight) in the pellets analyzed.
    Table 2
    Column Nucleodur EC (100x4.6 mm; 5pm) (C18) MachereyNagel Mobile phase A: Water-TFA 0.1%; B: Acetonitrile-TFA * 0.1% Isocratic: 70:30* TFA: trifluoroacetic acid Debit 0.8 ml / min Injection volume 20 μΙ Wave length 346 nm
    BE2018 / 5586
    The results obtained are presented in Table 3 below.
    Table 3
    Formulation (% by weight) Glycerol content (% by weight) Theoretical BBR content (% by weight) Experimental BBR content (% by weight) 50% HPC + 40% BBR 10 40 35.9 ± 1.8 40% HPC + 50% BBR 10 50 45.8 ± 0.1 45% HPC + 50% BBR 5 50 40.3 ± 1.6 50% HPC + 50% BBR 0 50 50.1 ± 3.6 50% PVP + 40% BBR 10 40 34.6 ± 4.4
    As can be seen, the standard deviations calculated for the experimental contents dosed are low, which indicates that according to the different batches tested for a given composition according to the invention, the distribution of berberine is homogeneous among the different pellets, c that is to say within the extrudate obtained.
    Example 4: Tests of stability over time of a composition according to the invention in terms of content of a protoberberine alkaloid and in terms of solubilization rate of this same protoberberine alkaloid
    A test was carried out in order to determine the stability over time of a composition according to the invention comprising 50% by weight of berberine (BBR), 40% by weight of hydroxypropylcellulose (HPC - HPC SSL, Nisso) in as a polymer and 10% by weight of glycerol (Roth) as a plasticizing agent, the composition being obtained according to the manufacturing process repeated in Example 1. The compositions (samples) were stored at room temperature in bottles closed and protected from light.
    At each analysis time (T0, T + 3 months, T + 5 months and T + 8 months), a study of the release of berberine as well as an analysis of the
    BE2018 / 5586 berberine content were carried out. For each of these analyzes, the procedure was as follows:
    Content: 1 to 3 mg of extrudate was dissolved in 1 ml of DMSO. The solution obtained was analyzed by HPLC after dilution in the mobile phase (1/20 or 1/50 dilution) (see example 3 for the HPLC analysis);
    -Test of solubility (relarqaqe): 500 mg of pellets of a composition according to the invention (500 mg of pellets contain 250 mg of berberine) and 250 mg of crystalline berberine in powder form were used for the study solubility. These tests were carried out with a paddle dissolution apparatus (see example 2) under the conditions mentioned in table 4.
    Table 4
    Mass 500 mg of extrudate or 250 mg of berberine Temperature 37 ° C Speed 50 rpm Dissolution medium 900 ml 0.1 N HCl
    The results are presented in Figures 6 and 7. In Figure 6 which illustrates the berberine content in a composition depending on whether the latter is freshly obtained (T0), is 3 months old (T3M), is 5 months old (T5M) or is 8 months old (T8M), we can see that the berberine content is almost constant over time.
    In FIG. 7 which illustrates the rate of release of berberine from a composition according to whether the latter is freshly obtained (T0), is 3 months old (T3M), is 5 months old (T5M) or is aged 8 months (T8M), it can be seen that the salting out is almost identical for each aging period of the composition.
    Furthermore, advantageously, this figure again illustrates that a composition according to the invention in the form of an extrudate in which the alkaloid (berberine) comprises at least a first amorphous phase
    BE2018 / 5586 is significantly more soluble than crystalline berberine in powder form.
    EXAMPLE 5 Thermal Analysis by Differential Scanning Calorimetry (PSC)
    A differential scanning calorimetry (DSC) analysis which is well known to those skilled in the art makes it possible to measure the difference in heat exchange between a reference and a product studied. This technique makes it possible to determine the melting temperatures, the crystallization temperatures or the phase transition temperatures but also the reaction enthalpies.
    In particular, such an analysis makes it possible to obtain curves where the presence of an endothermic peak (absorption of heat) shows the fusion of the sample analyzed. A melting peak indicates the presence of a crystalline form in the sample. On the contrary, when the melting peak is not present, the material is in the amorphous state.
    Such a thermal analysis was carried out on the following compositions:
    - 10 mg of berberine alone in the crystalline state in powder form;
    - 10 mg of a composition according to the invention comprising 50% by weight of berberine (BBR) and 50% by weight of hydroxypropylcellulose (HPC - HPC SSL, Nisso) as a polymer, the composition being obtained according to the process of manufacture shown in Example 1;
    - 10 mg of a composition according to the invention comprising 50% by weight of berberine (BBR), 40% by weight of hydroxypropylcellulose (HPC - HPC SSL, Nisso) as a polymer and 10% by weight of glycerol ( Roth) as a plasticizing agent, the composition being obtained according to the manufacturing process repeated in Example 1.
    The DSC analysis was performed according to the protocol shown in Table 5 below according to several segments. Several segments were produced in order to evaporate the residual water present in the berberine in the crystalline state in the form of powder or in the compositions according to the invention.
    BE2018 / 5586
    Table 5
    Segment Initial temperature (° C) Final temperature (° C) Heater(° C / min) Heating time (min) 1 30 30 0 1 2 30 90 10 6 3 90 90 0 15 4 90 30 -10 6 5 30 30 0 1 6 30 165 10 13.5 7 165 165 0 1
    The results obtained are presented in FIG. 8 which illustrates segment No. 6 from 30 to 165 ° C with a heating rate of 10 ° C / min. This thermogram shows that the compositions according to the invention comprising a plasticizing agent and a polymer (curve in solid lines) or comprising a polymer but no plasticizing agent (dotted curve) are compositions in which berberine (the alkaloid protobberine) comprises at least a first amorphous phase. In fact, unlike berberine alone in the crystalline state in powder form (curve with wide spaced lines), the curves relating to the compositions according to the invention do not have a peak indicating the passage from a crystalline phase to a amorphous phase.
    BE2018 / 5586
    Example 6: Bioavailability of a composition according to the invention in rats, in particular of a composition according to the invention comprising berberine as protoberberine alkaloid
    An in-vivo study was carried out on rats weighing 250 g (female Sprague Dawley rat). Three groups of 6 rats were formed as follows:
    1. control: hydroxypropylcellulose (n = 6);
    2. berberine alone in the crystalline state in powder form (n = 6);
    3. extruded composition according to the invention: 50% berberine + 40% HPC + 10% glycerol (pellets) (n = 6).
    For groups 2 and 3, berberine was administered orally to rats at a dose of between 50 and 500 mg / kg before blood samples were taken at the rate of 200-300 μΙ_ via the tail vein . For the control group, hydroxypropylcellulose was administered orally at a dose between 60 and 750 mg / kg.
    The blood samples were taken according to the following sampling times: 0, 30, 60 and 90 min, 2, 4, 6, 8, 12 and 24 hours, the collected samples being collected in heparinized tubes. After mixing, the heparinized tubes were centrifuged (3000 xg) for 15 minutes at 4 ° C. Then, the plasma (supernatant) was collected and stored at -80 ° C until analysis -LC-MS
    The HPLC analysis carried out in order to detect the quantity of berberine present in the plasma has made it possible to demonstrate that a significantly higher quantity of berberine and of its metabolites is detected in the blood samples taken in group 3 rats compared to to the quantities of berberine detected in the blood samples taken from the mice of group 2. This indicates that a composition according to the invention, comprising a polymer and in which said protoberberine alkaloid comprises at least a first amorphous phase and possibly a second phase crystalline, is characterized
    BE2018 / 5586 by an increased bioavailability, this in comparison with a prior art composition comprising berberine only in the crystalline state in powder form.
    EXAMPLE 7 Process for the Manufacture of a Composition According to the Invention in the Form of an Extrudate Comprising Tetrahydropalmatine as the Protoberberine Alkaloid
    Compositions according to the invention with tetrahydropalmatine as protoberberine alkaloid (active ingredient), such as those which are the subject of Example 8 below, were obtained according to the following process which is also the subject of the present invention:
    a) a step of premixing tetrahydropalmatine in the crystalline state in the form of powder and at least one polymer;
    b) a step of supplying said premix formed in step a) to feed a Pharma 11 type extruder from Thermo-Fischer®;
    c) a step of mixing, in said extruder, said premix to obtain a mixture;
    d) a step of hot extrusion of said mixture obtained in step c) in said extruder to obtain an extrudate, the step of hot extrusion being carried out at a speed of rotation of an extrusion screw of 200 revolutions / minute and at a temperature between 40 ° C and 110 ° C; and
    e) a step of cutting, at a pelletizer, the extrudate obtained in step d) so as to obtain pellets whose size is of the order of 2 to 3 mm.
    The temperature at which the hot extrusion step is carried out is determined by the type of constituents used, in particular according to the type of alkaloid of protoberberine, of polymer and / or of plasticizing agent used, this that the skilled person is able to determine.
    BE2018 / 5586
    Example 8: Solubility test of tetrahydropalmatine as a protobberine alkaloid from compositions according to the invention
    Different compositions, obtained according to the manufacturing process described in Example 7, were tested in terms of solubility over time of the protobberine alkaloid from the extrudates obtained. Tetrahydropalmatine was chosen as the protobberine alkaloid to perform the solubility tests. As indicated above, the extrudates are in the form of pellets whose size is of the order of 2 to 3 mm.
    The solubility tests were all carried out with a paddle dissolution apparatus at a temperature of 37 ° C. with stirring at 50 revolutions / minute in 900 ml of an H2O dissolution medium. These solubility tests were carried out according to the recommendations of pharmacopoeia 07/2010: 51701 (Recommendations on Dissolution Testing).
    a) Solubility test 1: influence of the presence of a polymer or of the presence of a polymer and of a plasticizing agent on the solubility of tetrahydropalmatine for compositions according to the invention
    Hydroxypropylcellulose was used as a polymer and glycerol was used as a plasticizer to formulate and compare two compositions to be extruded according to the invention. The following two compositions to be extruded were formulated:
    Composition 1: 50% by weight of tetrahydropalmatine (THP) in the crystalline state in powder form + 50% by weight of hydroxypropylcellulose (HPC - HP SSL, Nisso) as a polymer;
    Composition 2: 50% by weight of tetrahydropalmatine (THP) in the crystalline state in the form of powder + 40% by weight of hydroxypropylcellulose
    BE2018 / 5586 (HPC - HPC SSL, Nisso) as a polymer + 10% by weight of glycerol (Roth) as a plasticizing agent.
    After extrusion, these two compositions were compared in terms of solubilization of tetrahydropalmatine over time according to the solubility test mentioned above, tetrahydropalmatine alone in the crystalline state in powder form being also tested (control).
    The results obtained are presented in FIG. 9. As can be seen, the percentage of tetrahydropalmatine solubilized over time is significantly higher for the compositions according to the invention (THP + HPC and THP + HPC + glycerol) in comparison with the tetrahydropalmatine alone in the crystalline state.
    This demonstrates the advantage of a composition according to the invention in order to optimize the solubility of tetrahydropalmatine and therefore to promote the bioavailability of tetrahydropalmatine. Indeed, these results show that:
    a composition according to the invention in the form of an extrudate comprising a polymer and a protoberberine alkaloid having at least a first amorphous phase and optionally a second crystalline phase makes it possible to significantly increase the solubility of tetrahydropalmatine and therefore to promote bioavailability tetrahydropalmatine;
    - an addition of a plasticizing agent (in this case glycerol) makes it possible to further increase the solubility of tetrahydropalmatine and therefore to further promote the bioavailability of tetrahydropalmatine.
    BE2018 / 5586
    b) Solubility test 2: influence of the type of plasticizing agent on the solubility of tetrahydropalmatine for compositions according to the invention comprising tetrahydropalmatine, a polymer and a plasticizing agent
    Different plasticizers have been tested in compositions according to the invention, namely glycerol, polyethylene glycol (PEG) and triethyl citrate (TEC), depending on whether the composition according to the invention comprises hydroxypropylcellulose (HPC). or polyvinylpyrrolidone (PVP) as a polymer.
    The following compositions to be extruded were formulated:
    Composition 1: 50% by weight of tetrahydropalmatine (THP) + 40% by weight of hydroxypropylcellulose (HPC - HPC SSL, Nisso) as a polymer + 10% by weight of glycerol (Roth) as a plasticizing agent;
    Composition 2: 50% by weight of tetrahydropalmatine (THP) + 40% by weight of hydroxypropylcellulose (HPC - HPC SSL, Nisso) as a polymer + 10% by weight of polyethylene glycol (PEG - PEG 6000, VWR) as as a plasticizing agent;
    Composition 3: 50% by weight of tetrahydropalmatine (THP) + 40% by weight of hydroxypropylcellulose (HPC - HPC SSL, Nisso) as polymer + 10% by weight of triethyl citrate (TEC - SIGMA) as plasticizer;
    Composition 4: 50% by weight of tetrahydropalmatine (THP) + 40% by weight of polyvinylpyrrolidone (PVP - Kollidon 30, BASF) as a polymer + 10% by weight of glycerol (Roth) as a plasticizing agent;
    Composition 5: 50% by weight of tetrahydropalmatine (THP) + 40% by weight of polyvinylpyrrolidone (PVP - Kollidon 30, BASF) as a polymer + 10% by weight of polyethylene glycol (PEG - 6000, VWR) as plasticizer;
    BE2018 / 5586
    Composition 6: 50% by weight of tetrahydropalmatine (THP) +
    40% by weight of polyvinylpyrrolidone (PVP - Kollidon 30, BASF) as a polymer + 10% by weight of triethyl citrate (TEC - SIGMA) as a plasticizing agent.
    After extrusion, these compositions were compared in terms of solubilization of tetrahydropalmatine over time according to the solubility test mentioned above, tetrahydropalmatine alone in the crystalline state in the form of powder being also tested (control).
    The results are presented in Figures 10 and 11 depending on whether the polymer used is hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP). As can be seen, whatever the polymer used (HPC or PVP) and whatever the type of plasticizing agent used (glycerol or PEG or TEC), a significantly higher solubility of tetrahydropalmatine for the compositions according to the invention in which tetrahydropalmatine comprises at least one amorphous phase is observed in comparison with tetrahydropalmatine alone in the crystalline state.
    c) Solubility test 3: influence of the type of polymer on the solubility of tetrahydropalmatine for compositions according to the invention comprising tetrahydropalmatine, a polymer and a plasticizing agent
    Two different polymers were tested in compositions according to the invention, namely hydroxypropylcellulose (HPC) and polyvinylpyrrolidone (PVP).
    The following compositions to be extruded were formulated:
    Composition 1: 50% by weight of tetrahydropalmatine (THP) + 40% by weight of hydroxypropylcellulose (HPC - HPC SSL, Nisso) as a polymer + 10% by weight of glycerol (Roth) as a plasticizing agent;
    BE2018 / 5586
    Composition 2: 50% by weight of tetrahydropalmatine (THP) +
    40% by weight of polyvinylpyrrolidone (PVP 30, BASF) as a polymer + 10% by weight of glycerol (Roth) as a plasticizing agent.
    After extrusion, these compositions were compared in terms of solubilization of tetrahydropalmatine over time according to the solubility test mentioned above, tetrahydropalmatine alone in the crystalline state in the form of powder being also tested (control).
    The results are presented in FIG. 12. As can be seen, whatever the polymer used (HPC or PVP), a significantly higher solubility of tetrahydropalmatine for the compositions according to the invention in which the tetrahydropalmatine comprises at least one phase amorphous is observed in comparison with tetrahydropalmatine alone in the crystalline state.
    It is understood that the present invention is in no way limited to the embodiments described above and that many modifications can be made thereto without departing from the scope of the appended claims.
    权利要求:
    Claims (17)
    [1]
    1. Composition in the form of an extrudate comprising at least one protoberberine alkaloid as active ingredient and at least one polymer, said composition being characterized in that said protoberberine alkaloid comprises at least a first amorphous phase and optionally a second crystalline phase.
    [2]
    2. Composition according to claim 1, characterized in that said protoberberine alkaloid is chosen from the group consisting of alborine, anibacanine, anisocycline, artavenustine, berberastine, berberine, berberubine, berlambine , canadine, capaurimine, capaurine, caseadine, caseamine, cavidine, cerasodine, cerasonin, cheilanthifoline, clarkeanidine, columbamine, constrictosine, lacoptisine, lacoreximine, lacorybulbine, lacorycavamine, corycavin, corycavin , corydalmine, corymotine, corynoxidine, corypalmine, corysamine, corytenchine, coulteropine, cryptopine, cyclanoline, ladauricoside, ladiscretamine, fississaine, govanine, groenlancidine, gusanlung-A, gusanlung-A , gusanlung-D, hunnemanine, jatrorrhizine, lambertine, lienkonine, malacitanine, manibacanine, mecambridine, muramine, orientalidine, pallimamine, p almatine, pessoine, phéllodendrine, préchilénine, protopine, schéfférine, scoulérine, sinactine, spiduxine, spinosine, stéphabinamine, stéphabine, stépharanine, stépholidine, stylopine, tetrahydropine thaipetaline, thalictricavin, thalidastine, thalifendine, xilopinine, yuanamide, dihydroberberine, dehydrocorydalmine, palmatrubine, dehydrodiscretamine, dehydrocheilanthifoline, demethylenberberine, epiberberinine pseudorea pseudoepiberberine, pseudocolumbamine, dehydrodiscretin, ldehydrocoreximine, lathalifaurine, corysamine,
    BE2018 / 5586 dehydrothalictrifoline, dehydrothalictricavin, dehydrocorydaline, dehydroapocavidin, lincagenin, dehydrocapaurimine, 13-methylpseudoepiberberine, mequinine, their derivatives, their salts and mixtures.
    [3]
    3. Composition according to claim 1 or 2, characterized in that said polymer is chosen from the group consisting of copolymers of ammonium methacrylates, hydroxypropylcellulose, polyvinyl acetate, ethylcellulose, hydroxypropylmethylcellulose phthalate , polyvinylpyrrolidone, hydroxypropymethylcellulose, hydroxypropymethylcellulose acetosuccinate, cellulose acetobutyrate, cellulose acetophthalate, polyvinylpyrrolidone-covinyl acetate, polyethylene acetate-co- vinyl, polyvinyl acetate-comethacrylic acetate, polyethylene oxide, polylactide-co-glycolide, polyvinyl alcohol, pectin, polycarbophile, polycaprolactone, carnauba wax, ethylene-vinyl copolymer acetate, lecithin, castor oil and hydrogenated soybean, waxes (microcrystalline wax, ...), natural starch or synthesis (corn starch, pregelatinized starch, potato starch, ...), maltodextrin, isomalt, chitosan, gums (xanthan gum, ...), agar, lactose from natural or synthetic soluble or insoluble fibers such as inulin, ßglucane and Konjac fibers, and mixtures thereof.
    [4]
    4. Composition according to any one of the preceding claims, characterized in that it also comprises at least one plasticizing agent.
    [5]
    5. Composition according to claim 4, characterized in that said at least one plasticizing agent is chosen from the group consisting of polyols, lipids, lecithins, sucrose esters, triethyl citrate, polyethylene glycol, glycerol, dibutyl sebate,
    BE2018 / 5586 butyl stearate, glycerol monostearate, diethyl phthalate and mixtures thereof.
    [6]
    6. Composition according to any one of the preceding claims, characterized in that it also comprises at least one additive chosen from the group consisting of lubricants, surfactants, antioxidants, chelating agents and mixtures thereof.
    [7]
    7. Composition according to any one of the preceding claims, characterized in that it also comprises at least one first additional active principle of polyphenol type chosen from the group consisting of phenolic acids, stilbenes, phenolic alcohols, lignans, flavonoids and their mixtures.
    [8]
    8. Composition according to any one of the preceding claims, characterized in that it also comprises at least one second additional active principle of triterpene type such as, for example, limonoids.
    [9]
    9. Composition according to any one of the preceding claims, characterized in that it further comprises at least one inhibitor and / or a modulator of the activity of P-gp.
    [10]
    10. Composition according to any one of the preceding claims, characterized in that it is packaged in the form of pellets, granules, powders, effervescent tablets or not, solutions for injection or not, suspensions, gels, ointments or in any other suitable form allowing administration to an animal or a human being.
    [11]
    11. Method for manufacturing a composition according to any one of claims 1 to 10, characterized in that it comprises the following steps:
    a) a step of simultaneous or delayed introduction of at least one protoberberine alkaloid and at least one polymer to feed an extruder,
    BE2018 / 5586
    b) a step of mixing, in said extruder, said at least one protoberberine alkaloid and said at least one polymer to form a mixture, and
    c) a step of hot extrusion of said mixture obtained in step b) in said extruder to obtain an extrudate in which said protoberberine alkaloid comprises at least a first amorphous phase and optionally a second crystalline phase.
    [12]
    12. Method according to claim 11, characterized in that it comprises a prior step of premixing said at least one alkaloid and said at least one polymer so as to form a premix intended to supply the extruder.
    [13]
    13. Method according to claim 11 or 12, characterized in that said hot extrusion step is carried out at an extrusion temperature between 20 and 180 ° C, preferably at a temperature between 40 and 115 ° C, preferably at a temperature between 80 and 90 ° C, preferably at a temperature of 110 ° C, more preferably at a temperature of 100 ° C.
    [14]
    14. Method according to any one of claims 11 to
    13, characterized in that said hot extrusion step is carried out at a speed of rotation of an extrusion screw of between 20 and 300 rpm, preferably between 100 and 250 rpm, preferably equal to 200 rpm.
    [15]
    15. Method according to any one of claims 11 to
    14, characterized in that it comprises an additional cooling step at the outlet of the extruder.
    [16]
    16. Method according to any one of claims 11 to
    15, characterized in that it comprises an additional step of treatment of the extrudate at the outlet of the extruder, for example a cut at a pelletizer and / or a grinding of said extrudate.
    [17]
    17. Composition according to any one of claims 1 to 10 for use in preventive and / or curative treatment, in humans
    BE2018 / 5586 human and / or in animals, pathologies linked to the cardiovascular system, pathologies linked to the blood system, pathologies linked to the gastrointestinal system, pathologies linked to the endocrine system, pathologies related to the system
    5 immune, pathologies related to the central nervous system, skin diseases, diseases due to the presence of microorganisms and cancers and in the preventive and / or curative treatment of diabetes.
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    同族专利:
    公开号 | 公开日
    BE1025649A1|2019-05-15|
    EP3672575A1|2020-07-01|
    WO2019038430A1|2019-02-28|
    FR3070390A1|2019-03-01|
    引用文献:
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    WO2005079760A1|2004-02-12|2005-09-01|Euro-Celtique S.A.|Particulates|
    WO2007001451A2|2004-11-09|2007-01-04|Board Of Regents, The University Of Texas System|Stabilized hme composition with small drug particles|
    CN104997735A|2006-09-19|2015-10-28|太阳石（唐山）药业有限公司|Berberine hydrochloride taste-masked pellet, and preparation thereof|
    WO2017172406A1|2016-03-31|2017-10-05|Mallinckrodt Llc|Extended release, abuse deterrent dosage forms|
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    WO2015097642A1|2013-12-26|2015-07-02|Rao Raavi Chandra Sekhar|Composition for treating cancer and method of synthesizing the same|BE1027350B1|2019-06-28|2021-06-22|Eleonor|Composition comprising at least one triterpene and / or at least one triterpenoid and / or at least one of their glycosylated forms|
    CN110664809B|2019-10-14|2021-06-29|佳木斯大学|Pharmaceutical composition for preventing and treating cerebral infarction|
    WO2021090214A2|2019-11-04|2021-05-14|Alesco S.R.L.|Sucrosomial® berberine, its compositions and their use|
    CN111803448A|2020-08-19|2020-10-23|河南牧业经济学院|Berberine hydrochloride solid dispersion, preparation process and application|
    法律状态:
    2019-06-13| FG| Patent granted|Effective date: 20190520 |
    优先权:
    申请号 | 申请日 | 专利标题
    BE2017/5588|2017-08-25|
    BE201705588|2017-08-25|
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