COMPOSITION COMPRISING AT LEAST ONE PROTOBERBERINE ALKALOID AND METHOD FOR MANUFACTURING SAME

Abstract

A composition in the form of a thermoformed extrudate includes at least one protoberberine alkaloid and at least one polymer of natural and/or synthetic origin chosen from the group consisting of proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, and derivatives and mixtures thereof.

Claims

1. A composition in the form of a thermoformed extrudate comprising at least one protoberberine alkaloid and at least one polymer of natural and/or synthetic origin selected from the group consisting of proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, derivatives thereof and mixtures thereof.

2. The composition according to claim 1, wherein said thermoformed extrudate comprises a thermoformed mixture of at least one protoberberine alkaloid and at least one polymer of natural and/or synthetic origin selected from the group consisting of proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, derivatives thereof and mixtures thereof.

3. The composition according to claim 1, wherein said at least one protoberberine alkaloid comprises predominantly at least a first amorphous phase.

4. The composition according to claim 3, wherein said at least one protoberberine alkaloid comprises 51 to 100% by mass of an amorphous phase and 0 to 49% of a crystalline phase.

5. The composition according to claim 1, wherein said at least one protoberberine alkaloid is selected from the group consisting of alborine, anibacanine, anisocycline, artavenustine, berberastine, berberine, berberubine, berlambine, canadine, capaurimine, capaurine, caseadine, caseamine, cavidine, cerasodine, cerasonine, cheilanthifoline, clarkeanidine, columbamine, constrictosine, coptisine, coreximine, corybulbine, corycavamine, corycavine, corydalidzine, corydalmine, corymotine, corynoxidine, corypalmine, corysamine, corytenchine, coulteropine, cryptopine, cyclanoline, dauricoside, discretamine, fississaine, govanine, groenlancidine, gusanlung-A, gusanlung-B, gusanlung-D, hunnemanine, jatrorrhizine, lambertine, lienkonine, malacitanine, manibacanine, mecambridine, muramine, orientalidine, pallimamine, palmatine, pessoine, phellodendrine, prechilenine, protopine, schefferine, scoulerine, sinactine, spiduxine, spinosine, stephabinamine, stephabine, stepharanine, stepholidine, stylopine, tetrahydropalmatine, thaicanine, thaipetaline, thalictricavine, thalidastine, thalifendine, xilopinine, yuanamide, dihydroberberine, dehydrocorydalmine, palmatrubine, dehydrodiscretamine, dehydrocheilanthifoline, demethylenberberine, epiberberine, pseudocoptisine, pseudopalmatine, pseudojatrorrhizine, pseudoepiberberine, pseudocolumbamine, dehydrodiscretine, dehydrocoreximine, thalifaurine, corysamine, dehydrothalictrifoline, dehydrothalictricavine, dehydrocorydaline, dehydroapocavidine, lincagenine, dehydrocapaurimine, 13-methyl-pseudoepiberberine, mequinine, derivatives thereof, salts thereof and mixtures thereof.

6. The composition according to claim 1, wherein said proteins of natural and/or synthetic origin are selected from the group consisting: of glycoproteins, collagens, non-gelling collagen hydrolysates, non-gelling collagen peptides, non-gelling collagen polypeptides, vegetable proteins, animal proteins, derivatives thereof and mixtures thereof.

7. The composition according to claim 6, wherein said collagens and/or said non-gelling collagen hydrolysates and/or said non-gelling collagen peptides and/or said non-gelling collagen polypeptides have a molecular weight of between 50 and 300,000 Da.

8. The composition according to claim 1, further comprising at least one plasticizer.

9. The composition according to claim 8, wherein said at least one plasticizer is selected from the group consisting of polyols, lipids, lecithins, sucrose esters, water, triethyl citrate, polyethylene glycol, glycerol, dibutyl sebate, butyl stearate, glycerol monostearate, diethyl phthalate, derivatives thereof and mixtures thereof.

10. The composition according to claim 1, further comprising at least one additive selected from the group consisting: of lubricating agents, surfactants, antioxidants, chelating agents, derivatives thereof and mixtures thereof.

11. The composition according to claim 1, further comprising at least one polyphenolic first additional compound selected from the group consisting of phenolic acids, stilbenes, phenolic alcohols, lignans, flavonoids, derivatives thereof and mixtures thereof.

12. The composition according to claim 1, which is packaged in the form of pellets, flakes, granules, powders, effervescent or non-effervescent tablets, injectable or non-injectable solutions, suspensions, gels, ointments or in a suitable form approved for administration to an animal or to a human being.

13. A method for manufacturing a composition in the form of a thermoformed extrudate according to claim 1, comprising the following steps: a) providing, in a simultaneous or delayed manner, at least one protoberberine alkaloid and at least one polymer of natural and/or synthetic origin selected from the group consisting of: proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, derivatives thereof and mixtures thereof, for feeding an apparatus, b) mixing, in said apparatus, said at least one protoberberine alkaloid and said at least one polymer of natural and/or synthetic origin selected from the group consisting of proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, derivatives thereof and mixtures thereof, to form a mixture, and c) thermoforming of said mixture obtained in step b) in said apparatus, to obtain a thermoformed extrudate.

14. The method according to claim 13, comprising a prior step of pre-mixing said at least one protoberberine alkaloid and said at least one polymer of natural and/or synthetic origin selected from the group consisting of: proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, derivatives thereof and of mixtures thereof so as to form a pre-mixture to be fed into said apparatus.

15. The method according to claim 13, wherein said thermoforming is carried out at an extrusion temperature of between 20 and 180° C.

16. The method according to claim 13, wherein said thermoforming is carried out at a rotation speed of an extrusion screw of between 20 and 900 rpm.

17. The method according to claim 13, comprising an additional cooling step at the outlet of the apparatus.

18. The method according to claim 13, comprising an additional step of processing the thermoformed extrudate at the outlet of the apparatus.

19. The composition in the form of a thermoformed extrudate according to claim 1 for preventive and/or curative treatment, in humans and/or in animals, of pathologies related to the cardiovascular system (hypotension, vasoconstriction, ventricular hypertrophy, arrhythmia, . . . ), pathologies related to blood system (cholesterolemia, platelet aggregation, . . . ), pathologies related to the gastrointestinal system (diarrhoea, digestive inflammation, modulation of the intestinal microbiota, dyspepsia, gastroesophageal reflux, . . . ), pathologies related to the premature aging of cells, pathologies related to the endocrine system (hyperglycaemia, . . . ), 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-tumoral, . . . ), in the preventive and/or curative treatment of diabetes, diseases related to premature aging of cells, obesity, hypercholesterolemia, metabolic syndrome and irritable bowel syndrome (IBS), non-alcoholic hepatic steatosis (NAFLD+NASH or fatty liver disease).

20. The composition in the form of a thermoformed extrudate obtained according to the method of claim 13, said composition comprising at least one protoberberine alkaloid as active ingredient and at least one polymer of natural and/or synthetic origin selected from the group consisting of proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, derivatives thereof and mixtures thereof.

Description

EXAMPLES

Example 1: Thermoforming Manufacturing Method of Compositions According to the Invention in the Form of a Thermoformed Extrudate

[0139] Thermoformed compositions according to the invention comprising at least one protoberberine alkaloid, such as those of the Example 2 below, were obtained according to the following method further representing the object of the present invention:

[0140] a) a step of pre-mixing at least one protoberberine alkaloid in the crystalline state in powder form and at least one polymer selected from the group consisting of proteins of natural and/or synthetic origin, amino acids, peptides and polypeptides of natural and/or synthetic origin, lipids of natural and/or synthetic origin, dextrins of natural and/or synthetic origin, alginates of natural and/or synthetic origin, oligosaccharides of natural and/or synthetic origin, cyclodextrins of natural and/or synthetic origin, hyaluronates of natural and/or synthetic origin, carrageenans of natural and/or synthetic origin, derivatives thereof and mixtures thereof;

[0141] b) a step of providing said pre-mixture formed in step a) to feed an extruder of the Process 11 Hygienic type from Thermo Fisher Scientific®;

[0142] c) a step of mixing, in said extruder, said pre-mixture to obtain a mixture;

[0143] d) a step of thermoforming, by hot extrusion, said mixture obtained in step c) in said extruder to obtain a thermoformed extrudate, the hot extrusion step being carried out at a rotation speed of an extrusion screw of 100 rpm and at a temperature of between 20 and 80° C.;

[0144] e) a step of cooling, at the outlet of the extruder, said thermoformed extrudate obtained in step d); and

[0145] f) a step of cutting/grinding, using a grinder, the cooled thermoformed extrudate obtained in step e) so as to obtain a homogeneous powder.

[0146] The thermoforming 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 polymer and/or plasticizer used, which the skilled person is able to determine. Furthermore, a skilled person, in particular according to the type of extruder used and in accordance with the general principle of hot extrusion (HME), is able to define possible temperature steps in different areas along the extrusion screw(s) such that there is a gradual increase in temperature within the material transported by the extrusion screw(s), this in a feed direction of the material within the extruder. Typically, between areas defined along the extrusion screw(s), temperature differences of about 0 to 40° C. are observed. For example, in the context of the present invention, the compositions tested below were obtained in a Process 11 Hygienic type extruder from Thermo Fisher Scientific® having 8 temperature areas which are as follows in a feed direction of the material moving at a speed of 100 rpm: 20° C.-20° C.-20° C.-60° C.-80° C.-80° C.-80° C. and 80° C.

Example 2: Solubility Tests of Thermoformed Compositions According to the Invention

[0147] Thermoformed compositions, obtained according to the manufacturing method described in example 1, were tested in terms of solubility of berberine. This solubility was measured over time from the thermoformed extrudates obtained according to the invention. As indicated above, the thermoformed extrudates are in the form of a homogeneous powder (ground material) in which berberine (a protoberberine alkaloid) preferentially comprises at least one amorphous phase.

[0148] The solubility tests were carried out with a paddle dissolution apparatus from about 1.5 g of each of the thermoformed extrudates, at a temperature of 37° C., with stirring at 50 rpm in 900 ml of a dissolution medium HCl 0.1 N. These solubility tests were carried out according to the recommendations of the pharmacopoeia Ph. Eur. 9.0 (Recommendations on Dissolution Testing). At determined times (after 15 min, after 30 min, after 1 h and after 2 h), a sample of 1 ml of mixture was taken to carry out a solubility test.

[0149] In order to carry out the solubility tests, each of the tested samples was filtered through a filter (PET, pore size: 0.45 Macherey Nagel) then diluted in the HPLC mobile phase before HPLC analysis (column: Nucleodur 100-5 EC C18 125/4 (Macherey-Nagel); mobile phase: 70%-A (Water-TFA 0.1%) and 30% B (ACN-TFA 0.1%); flow rate: 0.8 ml/min; loop: 20 μl, t°=40° C.).

[0150] The thermoformed compositions according to the invention (Compo 1 and Compo 3) given in Table 1 were formulated according to the method of the invention and tested in terms of solubility over time according to the principle indicated above. Berberine in native crystalline form and in powder form (native BBR) was used as control. A composition not representing the object of the invention (Compo 2) was tested for comparison with starch as polymer. The amounts mentioned in Table 1 are weight percentages of the compounds used (subjected to the method according to the invention) relative to the total weight of the composition.

TABLE-US-00002 TABLE 1 Berberine Protein Starch Dextrin Glycerol (1) (2) (4) (5) (3) Compo 1 40 50 0 0 10 Compo 2 40 0 50 0 10 Compo 3 40 0 0 50 10 (1) Berberine HCl (Shanghai Freemen) (2) Non-gelling collagen peptides Peptan ® B 5000 HD (with a molecular weight of 5,000 Da) (Ingrizo) (3) Glycerol (Brenntag) (4) Modified starch: Cleargum ® CB 90 (Roquette) (5) Pea dextrin: Tackidex ® C760 (Roquette)

[0151] The results obtained are shown in FIG. 1. The results obtained are shown in FIG. 1. As can be seen, the solubilities measured for berberine from compositions in the form of thermoformed extrudates according to the invention (Compo 1—non-gelling collagen peptides as polymer; Compo 3—dextrin as polymer) are higher compared to the control (native BBR) and are also higher compared to a composition not representing the object of the present invention and comprising starch as polymer (Compo 2).

[0152] The present invention has been described in relation to specific embodiments, which are purely illustrative and should not be construed as limiting. In general, it is obvious to a skilled person that the present invention is not limited to the examples illustrated and/or described above.

[0153] The use of the verbs “to comprise”, “to include”, “to contain”, or any other variant, as well as their conjugations, cannot in any way exclude the presence of elements other than those mentioned.

[0154] The use of the indefinite article “a”, “an”, or the definite article “the”, to introduce an element does not exclude the presence of a plurality of these elements.