FR2908996A1 - NOVEL METHOD OF EXTRACTING ACTIVE INGREDIENTS AND THERAPEUTIC USE THEREOF - Google Patents

Abstract

The invention relates to the field of chemistry and more particularly to the field of pharmacotechnics.It more particularly relates to a new process for extracting active ingredients from plants rich in flavonoids, naphthodianthrones and diacylphloroglucinols likely to undergo a degradation due to their sensitivity to oxidation during storage, hindering their pharmaceutical use.This process is particularly suitable for extracting and concentrating the active ingredients of one or more active principles of St. John's Wort for incorporation into pharmaceutical formulations.

Description

New process of extraction of active ingredients and the use of

  The invention relates to the field of chemistry and more particularly to the field of pharmacotechnics. It relates more particularly to a novel process for extracting active ingredients from plants rich in flavonoids and diacylphloroglucinols, the oxidability of which presents a major drawback for their storage storage and for their pharmaceutical use. The invention relates more specifically to a process for extracting and concentrating active principles in a stable form and enriched with one or more active ingredients, starting from flower heads of St. John's wort (Hypericum perforatum). St. John's wort is indeed a medicinal plant whose tranquillizing and anti-stress properties are becoming better known because of numerous recent scientific works, especially publications made in various European countries, as is common in herbal medicine. According to the literature (see in particular USP 6,280,736), the general anti-depressive effect of St. John's wort can not be reliably attributed to one or more specific components, but it is clear that among these, hyperforins provide a considerable contribution to the establishment of this efficiency (see EP-A-0599 307) probably greater than that of hypericins of formula (I): ## STR1 ## These are highly oxidizable molecules and easily labile. The crude medicinal drug is formed from the aerial parts of Hypericum perforatum which contain, inter alia, hypericin-like compounds and hyperforin-like compounds (see J. H5lzl et al Pharmajentische Zeitung 139 (46) 3959-3977 (1994)). . A St. John's wort extract preparation having a higher hypericin content is described in German Patent DE-1569849 as well as in S. Niesel and H. Schilcher Arch. Pharm. 323 (1990) 755. However, the problem of the conservation of these active principles was posed by R. Berghâfer and J.Hôlzl in Deutsche Apotheker Zeitung 126 (47) (1987) 2569-2573 who found that hyperforin in St John's wort extracts, was completely degraded after a week, although it should be more stable in extracts obtained from fresh plants. These authors hypothesize that fresh plants contain a stabilizing agent for hyperforin but whose effectiveness would be short-lived. This is why the authors conclude that both in the drug and in the conventional extracts of St. John's wort, the Hyperforin content decreases dramatically until the disappearance of this substance within a few months when conventional storage (Marsenbacher P. Ph.D. Thesis (1991), Tubingen). These authors advocated the storage of the plant under argon by addition of antioxidants (octyldodecanol, BHT, BHA) to improve the stability of the extracts. (I) 2908996 Already extractions of St. John's wort by conventional solvents such as water and alcohol, lead to pharmaceutical compositions that contain less than 1% hyperforin. During storage, this value obviously decreases and can even return to zero depending on the storage conditions due to oxidation phenomena that break down the hyperforin. According to US Pat. No. 6,280,736, this problem could be solved by adding St. John's wort extracts, antioxidants and / or stabilizing agents which bind oxygen or reducing agents. The applicant of this patent also recommends extraction under an inert atmosphere and / or protected from light or by extracting with a solvent having a reduced oxygen content. Another method of preserving hyperforin is that described by Orth HC, Rentel C and Schmidt PC in J. Pharm. Pharmacol (1999) 51 193-200 which recommend the removal of peroxides at each stage of the extraction. These authors conclude by stating that storage at 30 ° C under normal atmosphere and at -20 ° C, 4 ° C and 20 ° C under nitrogen and again in nitrogen at -19 ° C did not give different results with respect to the stability of hyperforin and that the -70 C nitrogen storage process provided better results for long-term storage. The same problem arises for topical preparations of St. John's wort extract, especially in the form of gels as a cicatrizing or anti-viral agent (see US publication 2004/0137 088). The problem of the stability of hyperforins has also been envisaged by producing synthetic hyperforins described in US Patent (Indena) 6,656,510. The hyperforins correspond to the formula (II), hyperforin: R = CH3 5 adhyperforin: R = CH2-CH3 and wherein R4 is an acyl radical or hydrogen. They are described as being more stable and more active in the antidepressant action tests. This method of hemisynthesis requires the extraction of hyperforin from St. John's wort by a supercritical gas to obtain an oil rich in hyperforin. However, the esterification yields are particularly low. On the other hand, supercritical fluid extraction is a delicate operation requiring equipment resistant to very high pressures and high temperatures. Hydrogenation products of the allyl chain of hyperforins have also been described. The resulting hexahydro and octahydrogen ketone compounds are etched to give metal enolates or enol esters (see PCT Patent Nos. 03/091191 and 99/64388). Therefore, despite an ever increasing therapeutic interest, St. John's wort extracts have not been used to date to a corresponding extent due to the easy decomposition of the active ingredients and the resulting loss of progressive activity. The process according to the invention aims to improve the processes already described and to lead to more stable and therefore more active St John's Wort extracts. The process according to the invention also aims at obtaining extracts which are richer in hyperforins and depleted of hypericin derivatives. More generally, the invention relates to novel methods of extracting plants, especially those containing iridoids, quinoline derivatives and particularly acylphloroglucinols, flavonoids and naphthodianthrones, as in Hypericum perforatum. which make it possible to obtain stable and pharmaceutically acceptable extracts enriched in hyperforin and, if possible, reduced to hypericin derivatives. These extraction processes are characterized mainly by a pH search of the extraction media where the active ingredients are the most stable and make it possible to obtain, after drying by vacuum dehydration at low temperature on zeolites, a process also known as zeodration. in the form of a crystalline powder. These methods make it possible to increase the levels of hyperforin in the plant extracts obtained and to maintain or even reduce the levels of pseudohypericin and hypericin. These extracts are preserved either in the form of crystalline powders when the hyperforin is in its salified form with a metal salt, or in amorphous form when it is in base form in the presence or absence of an organic acid such as, for example, citric acid, are still attached to sugars such as maltodextrin or a similar carrier to have a pharmacotechnically manipulable powder. The choice of the new extraction methods is chosen from those described according to the desired and necessary levels of hyperforin and hypericin as well as their quantities necessary for the manufacture of the pharmaceutical formulations.

  The invention also relates to pharmaceutical or para-pharmaceutical preparations containing these different extracts obtained by the methods of the invention. For some products, the pH may be between 1 and 2 or 6.4 and 12, as for St. John's Wort, depending on the quantities of active ingredient to be extracted (between 3 and 5 for the most unfavorable). For others containing iridoids (globular, etc.), the pH should be between 6.5 and 8.

In all cases, these types of extracts being sensitive to temperature rise, oxidation or light, will be dehydrated and dried by vacuum dehydration at low temperature on zeolites, also known as zeodration. It is known that the plant in the wet state and according to its origin contains according to various authors 2 to 4% of hyperforin. This rate continues to decrease as and when different manipulations such as the maceration time before extraction, the concentration of extracts, the storage time of extracts, etc ... In the arsenal, different means known and used before These problems of instability are resorted to by conventional methods such as: the nature of the extraction solvents which can be used in pharmacy, the use of antioxidants in acid form, salts or esters protected from light the use of reducing agents; the use of chelating agents; the use of inert gas during various manipulations; the use of low temperatures during the various manipulations. Due to the chemical structure of the phlooglucinic derivatives and more particularly the hydroxyallyl and ketonic functions of hyperforin, it is normal to think of blocking them to bring about a better stability of the entire molecule.

This is very well described by Chatterjee et al in US Pat. No. 6,444,662 of September 3, 2002, which describes three methods of preparing salts in suitable solvents according to the metallation types used on the adhyforine and hyperforin mixture, by alcoholates in an anhydrous medium or in the presence of corresponding hydroxides. The object of the invention is to provide processes which implement the stability of the phloroglucinic derivatives during the extraction process without altering the other constituents of the extract and to obtain a pharmaceutically acceptable end product enriched in hyperforin containing 2 to at least 5% and containing other constituents such as flavonoids, naphthodianthrones at usual levels such as 1 o for hypericin (less than 0.5%). Various alkalizing or acidifying agents can be used (sodium hydroxide, magnesium hydroxide and other alkaline agents, etc.) and acids (any mineral or organic acid) in the process according to the invention. A qualitative study was carried out from the same batch of plant to evaluate the influence of the various extraction media such as a basic medium (sodium hydroxide) or an acidic medium (phosphoric and / or citric acids). . The procedures are identical in all cases and gave the following results. Table I pH of EtOH Water NaOH Q: HpF PseudoHpR HpR pH of solvent in extract 7.74 60 40 0 550 290 250 4.83 12.21 60 40 1 600 280 196 6.04 12.48 60 40 2 750 240 256 6.80 12.55 60 40 3 850 210 320 7.53 12.67 60 40 4 1000 20 200 8.81 12.71 60 40 5 1050 0 160 8.95 pH of EtOH Water H3PO4 Q: HpF PseudoHpR HpR pH of solvent extract 3.11 60 40 0.1% 500 175 80 3.33 pH of EtOH Water Ac. Q: HpF PseudoHpR HpR Citriq solvent pH. the extract 2.66 60 40 4% 550 200 130 4.46 2908996 8 HpF = Hyperforine PseudoHp = PseudoHypericine HpR = Hyperinol It is found that for the same solvent Ethanol / Water 60/40, the extractions differ according to the pH used.

At acidic pH, the amounts of hyperforin extracted are similar to the amounts extracted by this same solvent in a neutral medium, but pseudo-hypericin and hypericin have greatly decreased. The pH of the extracts is slightly more acidic at the end of the extraction compared to the pH of the neutral extraction whose extractions tend to acidify: initial pH 7.74 pH of the extracts 4.83 pH of the solvent H3PO4 3.11 pH extracts 3.33 pH Ac sol. Citric 2.66 pH of the extracts 4.46 For extractions in an alkaline medium, the amounts of extracts are enriched in hyperforine as a function of the amount of alkaline agent used while at the same time the amounts of hypericin and hypericin decrease. This hyperforin enrichment can reach double, while the amounts of hypericin derivatives can be halved. In order to better evaluate the procedures, the alkaline extractions were compared in the presence of an extraction control without alkaline action and its influence on the wet and / or dried plant was compared as well as the stability of the obtained extracts. The procedure described gave the following results: AT: 1) two extractions were carried out on 23 g of wet plant (alkaline extraction and neutral extraction). 2) 150 g of wet plant are dried and then 2 extractions are carried out on the dried product corresponding to 23 g of wet plant. 3) 60 g wet plant are placed in controlled humid atmosphere.

To Ti: 1) 2 extractions were carried out on 23 g of preserved wet plant (alkaline and neutral). 2) 2 extractions are carried out on 23 g of dry plant preserved (alkaline and neutral). In total, 4 extractions at TO 10 4 extractions at T 1 month The following operating scheme summarizes the different operations (Table II).

This approach has made it possible to evaluate and choose a process which may be the alkaline medium when it is desired to increase the level of hyperforin in the extracts and stable, or the acidic medium when it is desired to obtain a standard extract. and stabilized by decreasing the levels of hypericin derivatives. It is known that in acidic and hydro-alcoholic medium, these derivatives precipitate because of their low solubility at these pH and because of the transformation of pseudo-hypericin to isopseudo hypericin at this pH. The impact of the pH of the extraction medium and especially its effect on the stability of certain extract compounds as well as the transformation of other compounds made it possible to study these extraction possibilities more thoroughly in order to carry out industrial processes. . Description of the methods: A first extraction study is carried out in the laboratory from the same batch of plant in order to compare the influence of the alkalization on the extraction medium compared to the conventional extractions carried out with hydro solvents. -alcooliques.

Process Diagram: (Table II) 1 Dried Plant Part 5 H 2 O / EtOH PH = 6.5 24 H at T amb Filter 1 Concentrate under vacuum T <at 35 ° C, Dry extract C 11 Physical form and Weight Amorphous gum 0.2 to 0.25 part Aqueous solubility 0.02 ref. Dry extract C 1110 vol H2O / EtOH + NaOH (100mmol) pH> 9.0- 24H at T amb Filter Vacuum concentrate T <35 C sl, Dry extract C 10 Physical form and Weight Crystalline powder 0.2 to 0 Part Aqueous Solubility 2.0% Cat. Dry extract CIO Brief description of the process: The process consists in suspending at room temperature a part of the dried plant in 10 volumes of a 60% aqueous alcoholic solution in ethyl alcohol for 24 hours. After filtration, the solutions are treated and concentrated in vacuo protected from oxygen from the air as well as light.

The weight efficiencies under these conditions are close to 20 to 25%. The dry extracts obtained are in the form of a fine, crystalline powder in the case of extraction in an alkaline medium and of a very hygroscopic gum in the case of extraction in a neutral medium. Comparative analyzes of these two extracts gave in HPLC at the following wavelengths (300 and 590 nm) as shown in FIG. 1: - 1) acylphloroglucinols TABLE III CIO RT 2. (nm) compound area 9.77 300 458908 Hyperforin I 10.35 300 2964122 Hyperforin II 11.46 300 140894 Hypericin 13.14 300 174313 XXX 11.46 590 290398 Hypericin C 11 RT 2. (nm) Compound 9.64 300 272559 Hyperforin I 10.23 300 1923289 Hyperforin II 11.32 300 83330 Hypericin 13.00 300 411835 XXX 10.16 590 149666 Pseudohypericin 11.32 590 173782 Hypericin The results gathered from these two extracts show that the extracts obtained by the alkaline route are twice as concentrated in hyperforin as those obtained in an acidic medium. By contrast, the derivatives of hypericin are present in comparable amounts. . The pseudo-hypericin found in the neutral pH Cl 1 extract was converted to hypericin by the action of alkalinity. The study of the naphthodianthrone profiles is carried out from these two extracts using the analytical method of acid extraction in hexane. This allows to characterize these derivatives.

The flavonoids can also be characterized and identified for a more in-depth approach to the chromatographic profile of the extracts. 2) naphthodianthrones HPLC determination C10 C11 RT RT compound 8.65 isopseudophypericin 8.70 9.25 flavonoid 9.32 9.86 protopseudohypericin 9.92 10.20 pseudohypericin 10.23 10.82 protohypericin 10.84 11.33 hypericin 11.37 3) flavonoids 10 as shown in the chromatograms according to Figure 3. Characterization of a salified form of hyperforin in the presence of other constituents of the extract was carried out by returning to the acid medium to recover the lipophilic form of the molecule with its low solubilities in an aqueous medium. Table V shows the influence of the alkaline medium on the stability of hyperforin (salification) as well as its inaction on naphthodianthrone derivatives such as hypericin and its derivatives. Table V hyperforin hypericin pH TR Area TR Area 7.5 9.79 1 812 363 10.9 134 583 6.5 10 1 433 748 11.4 134 503 5.5 10.2 1 371 590 11.5 132 061 4.5 10.5 1 212 085 11.7 136 884 3.5 11.2 1 040 653 11.8 135 194 2.5 13.2 273 355 11. 7 137 030 7.5 10 1 089 463 11.3 138 359 These results are also shown in the figure. Example of degradation of unsalified hyperforin.

Solution 10 mg / l in an apolar solvent for 3 days. Solution of hyperforin in hexane 10 mg / 1 Analysis at t = 0.1 day and 3 days day Hyperforin area 0 2331 792 1 3 020 151 3 55218 10 The degradation of hyperforin in three days is manifest, giving birth to a multiplicity of by-products. All of these results show that in alkaline soluble and salified powder medium, the extracts containing a higher percentage of hyperforin are much more stable. In contrast to the processes described in US Pat. No. 6,444,662, which use chromatographic methods to enrich the hyperforin and adhyperforin extracts and then salify them with different chemical methods in order to obtain stabilized products but practically free from the other components (flavonoids, naphthodianthrones, etc ...) of the plant, the present process is based on a more pharmaceutical approach since it allows from 25 dried plants to obtain stable extracts whose main criteria in content flavonoids, naphthodianthrones and acylglucinols ( or 1 to 8%) are respected and correspond classically to those defined by the recognized methods of pharmacopoeia and adapted here to Hypericum perforatum.

Main steps of the process according to the invention (Scheme 1) The process according to the invention is characterized mainly by: the use of a hydro-alcoholic extraction solvent of known proportions, or wholly aqueous. 2- the practice of an extraction medium to alkalize or acidify sufficiently such that the pH is always outside the neutral. 3-the use of a solid / liquid separation carried out in the absence of light and of the oxygen of the air (ex under nitrogen, argon or gas of the same type) 4- the evaporation of the solvent of extraction during concentration of the dry extract under very high vacuum and under inert gas at low temperatures. The use of drying the extract by zeodration which consists of drying the extract in an extreme vacuum drying chamber connected to an adsorption group containing zeolites as drying agent. This technique makes it possible to practice drying at negative temperatures if necessary. 6- By obtaining during the production of metal salts of a crystalline powder very little hygroscopic and easily used in pharmacotechnics. Finally, obtaining such an extract with well-defined chromatographic characteristics is represented by the following chromatogram. (Figure V).

By an extract which is stored as such or in admixture with formulation excipients such as citric acid or ascorbic acid remains stable using percentages not exceeding 1 to 8% and is therefore pharmaceutically acceptable.

In order to obtain non-salified forms from step 4, the solvent is acidified with the corresponding acid, for example citric acid, and the solution is evaporated in the presence or absence of a sugar as a maltodextrin to promote a more manageable form during atomization. The extract thus obtained is dried as in step 5 and kept in sealed sachet or drums protected from moisture, heat and light. EXAMPLES Various St. John's wort extracts were obtained from alcoholic solvents of varying proportions of alcohol and neutralized with different inorganic or organic bases, such as mainly sodium, calcium or magnesium hydroxide, triethanolamine etc. (Ca. (OH) 2, TEA) or by acidification as, primarily, with inorganic or organic acids such as hydrochloric acid; sulfuric acid; phosphoric acids, citric acid, ascorbic acid, etc ... Here are described some tests that have allowed to obtain stable extracts of acylglucinols hyperforine type.

Example 1 10 kg of finely chopped plant (Hypericum perforatum) are introduced into a 300 liter Colette or Olsa stainless steel reactor under a nitrogen atmosphere and protected from light. 100 liters of a 60% alcoholic alcoholic alcohol solution are introduced into it. Moderate stirring is carried out for 5 to 10 minutes at room temperature in order to have good wettability of the plant. It is basified with 50% sodium hydroxide solution (# 100 mol).

Still at room temperature, stirring is continued for 24 hours and then the extraction solution is separated from the insoluble by filtration.

The solution thus filtered is concentrated under vacuum at low temperature to remove the alcohol by azeotropy and the residue is dried by zeodration so as not to alter the extract. Thus, between 2 and 2.5 kg of dry extract are obtained. the acylphloroglucinols contained therein are in the form of sodium salts. This extract is put into stability study under ICH conditions. It gave the following results in Table V and in Figure 6. Table V Tests to T3mojs at 4 C T3 Months at 18 C Hypericines 0.25% 0.23% 0.23% Hyperforine 1.90% 1.81% 1.84 Example 2 1 kg of The extract obtained according to the process described in Example 1 is placed in a 10 liter cubic mixer containing 1.73 grams of citric acid and 36.6 grams of ascorbic acid, in successive elutions. Once the extract is introduced, it is stirred under an inert gas in the absence of light until homogeneity of the mixture, ie about 2 hours. This extract, thus modified, is ready for use in pharmacotechnics for the production of pharmaceutical formulations. EXAMPLE 25 (ex cps and chromatographic profile) HPLC chromatographic profile of an extract-based tablet of Example 2 shown in Figure 7.

Example 3 10 kg of finely chopped plant (Hypericum perforatum) are introduced into a 300 liter Colette or Olsa stainless steel reactor under a nitrogen atmosphere and protected from light. 290 liters of a 60% alcoholic alcoholic solution are introduced into the reactor. Moderate stirring is carried out for 5 to 10 minutes at room temperature in order to have good wettability of the plant.

It is basified with 50% sodium hydroxide solution (# 100 mol). Always at room temperature, stirring is allowed for 24 hours. The solution is neutralized with hydrochloric acid to pH <6. The extraction solution is separated from the insoluble by filtration. The solution thus filtered is concentrated under vacuum at low temperature to remove the alcohol by azeotropy and the residue is dried by zeodration so as not to alter the extract. Thus, about 2 kg of dry extract are obtained, the acylphloroglucinols being in the form of basic. This extract is put into a stability study under ICH conditions and gave the results highlighted in FIG. 8 (FIGS. 8a and 8b). This extract can be used as is or in the presence of acids as described in Example 2. EXAMPLE 4 Preparation of a Therapeutic Use Formulation with Hypericum Extract p. obtained as in Example 2 Hypericum perforatum extract 31.152 kg Croscarmellose sodium 5.200 kg Microcrystalline cellulose 14.953 kg Glycerol dibehenate 0.676 kg Colloidal silica 0.208 kg The powders are mixed and 520 mg tablets containing 300 mg of extract are prepared crude plus 11.11 mg of ascorbic acid and 0.52 mg of citric acid.

These tablets can then be film coated with agents which will protect them from light and moisture such as stearic acid in the presence of HPMC.

5 Results of pilots in stability. The results obtained are shown in Table VI below: Dosages To T: 3 months T: 3 months T: 3 months 25 C / 60% 30 C / 65% 40 C / 70% HR HR HR Hypericine and 0.71 0.67 0 64 0.41 pseudohypericin Hyperforine 5.9 5.8 5.7 5.8 Ascorbic acid 9.7 9. 7 9.4 4.5 1 o Example 5 Preparation of a formulation for therapeutic use with the extract of Hypericum perforatum obtained as in example 2 Hypericum extract. perforatum. 30,000 kg Citrate magnesium 12.00 kg Croscarmellose sodium 5.200 kg Microcrystalline cellulose 14.905 kg Glycerol dibehenate 0.676 kg Colloidal silica 0.219 kg The powders are blended and 640 mg tablets containing 300 mg of crude extract plus 11.11 mg of ascorbic acid and 0.52 mg of citric acid.

These tablets can then be film coated with agents which will protect them from light and moisture such as stearic acid in the presence of HPMC.

EXAMPLE 6 Gastro-resistant Tablets Preparation of a Formula for Therapeutic Use with the Extract Obtained According to Example 1 Per 100,000 Nuclei of 510 mg Per Unit Shape Hypericum Extract perforatum. 30,000 kg Croscarmellose Sodium 5,200 Kg Microcrystalline Cellulose 14,905Kg Glycerol Dibehenate 0.676Kg Colloidal Silica 0.219Kg The cores are film coated with a first layer of Sepilim LP with a deposit of about 25mg per core and then a layer of a suspension prepared Eudragit L30 D 55, talc and triethyl citrate for a deposit of about 40 to 45 mg. This gives a finished tablet with an average weight after coating close to 580 mg. The plant extracts according to the invention can be further added to other active ingredients and in particular active ingredients exhibiting properties on the gastrointestinal sphere. Polyunsaturated fatty acids of the omega-3 type or mucilages such as factin or polymethacrylic acid, laxatives such as senea, may be mentioned for this purpose. or psyllium tegument powder, intestinal motility products such as Trimebutine antispasmodic products such as Tiemonium methylsulfate or anti-diarrheal products such as formulated casein. These additional active ingredients can be contained at doses ranging from 5 to 100 mg per unit dose. 19 10 35 15

Claims (9)

  1 - A novel process for extracting active ingredients from plants which makes it possible to increase the level of acylphloroglucinols in these extracts and to ensure their stabilization in which the plant extracts are subjected to an appropriate pH zone and then to a drying by vacuum dehydration at low temperature on zeolites. 2 - Process according to claim 1 which makes it possible to increase the level of acylphloroglucinols and to ensure their stabilization in which the plant extract is an extract of Hypericum perforatum. 3 - Process according to claims 1 and 2, the extracts obtained have a concentration of hyperforine which is between 2 and 8%. 4 - Process according to claims 1 to 3 wherein the extracts obtained containing on average 3 to 5% of hyperforin. 5 - Process according to claims 1 to 3 wherein the stabilization of acylphloroglucinols is obtained by salifying acylphloroglucinols with metal hydroxides at the beginning of extraction. 6. A process according to claims 1 to 3 and 8 wherein the salification can be effected by organic bases such as primary or secondary amines, amino acids such as arginine or other bases. 7 -Procédé according to claims 1 to 3 and 8 and 9 wherein the salt extract 30 is converted into base by controlled acidification extraction solutions before isolation. 8 - Process according to claims 1 to 3 wherein the salified form extract is isolated and then supplemented with citric and / or ascorbic acid or other antioxidants, to improve its physical state. 9 - Process according to the preceding claims wherein is added to facilitate the pharmaceutical shaping, dilution additives such as 2908996 21 maltodextrins, lubricants such as metal stearates, slip agents such as citric acid or an acid silicic. 10 - Extract obtained according to the process of claims 1 to 3 containing on average 2 to 8% of hyperforin in combination with a mineral salt 11 - extract obtained according to the method of claims 1 to 3 containing more particularly from 3 to 5% d Hyperforin in combination with a magnesium salt in an amount corresponding to 5 to 100 mg of magnesium element. 12 - Extract obtained according to the method of claims 1 to 3 containing from 3 to 5% and more particularly 4% of hyperforine 13 - Compositions based extracts obtained according to claims 1 to 3 used for therapeutic use and or para-pharmaceutical. 14 - Compositions based on extracts obtained according to claims 1 to 3 used for therapeutic and / or para-pharmaceutical purposes containing more particularly 300 mg of extract with approximately 2% of hyperforin and in addition 10 mg of magnesium element brought in the form of different magnesium salts. 15 - Compositions based extracts extracted according to the method of claims 1 to 3 wherein the magnesium element is in the form of a salt selected from citrate, lactate, pidolate, ascorbate, phosphate and the magnesium carbonate. 16 - Compositions based on plant extracts obtained according to the method of claims 1 to 3 wherein is further incorporated one or more active ingredients acting in the gastrointestinal sphere. 17 - Compositions based on plant extracts obtained according to the process of claims 1 to 3, in which a polyunsaturated fatty acid of the Omega-3.15 series of acids is added