WO2007060532A2 - Novel therapeutic compositions and method for producing active principles - Google Patents

Abstract

The invention concerns the field of necessities and more precisely the field of phytotherapy. More specifically, it concerns pharmaceutical or parapharmaceutical compositions containing as active principle a powder or a plant extract of the genus Hypericum in an inert and non-toxic carrier or a vehicle. The inventive compositions may also contain one or such minerals derived from magnesium at a concentration ranging between 10 mg and the maximum of the daily supplement intake. The inventive compositions may further contain a polyunsaturated fatty acid of series n-3. The invention is useful as tranquilizer and anti-stress medicine.

Description

New therapeutic compositions and the method of producing the active ingredients

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 principles from plants rich in flavonoids and diacylphloroglucinols, the oxidability of which has a major drawback for their storage and storage 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 properties "tranquillizers and anti-stress" are better and better known because of many recent scientific works, including publications 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 attributed with certainty to one or more specific components, but it is clear that among these, the hyperforins provide a contribution preponderant to the establishment of this efficiency (see EP-A-0599 307) undoubtedly superior to that of hypericins of formula (I):

These are highly oxidizable and easily labile molecules.

The raw medicinal drug is formed from the aerial parts of Hypericum perforatum which contain, inter alia, hypericin-like compounds and hyperforin-like compounds (see J. Hertz et al Pharmazeutische Zeitung 139 (46) 3959-3977 (1994)). A St. John's Wort extract preparation having a higher hypericin content is described in 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. Berghöfer and J.Hôlzl in Deutsche Apotheker Zeitung 126 (47) (1987) 2569-2573 who found that hyperforin in the extracts of St. John's wort, 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 efficacy 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 with addition of antioxidants (octyldodecanol, BHT, BHA) to improve the stability of the extracts. Extractions of St. John's Wort by conventional solvents such as water and / or alcohol already lead to pharmaceutical compositions which contain less than 1% of hyperforin. During storage, this value obviously decreases and can even be zero depending on the storage conditions, as a result of oxidation phenomena which lead to the decomposition of hyperforin.

According to US Pat. No. 6,280,736, this problem could be solved by adding St. John's wort extracts, antioxidant agents and / or stabilizing agents which bind oxygen, or else reducing agents. The applicant of said US patent also recommends carrying out the extraction under an inert atmosphere and / or away from light or by extracting with a solvent having a reduced oxygen content.

Another method of preserving Tryperforin has been 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 the storage at 30 ^° C. under a normal atmosphere and at -

20 ^° C, 4 ° C and 20 ° C under nitrogen or in the nitrogen at -196 ° C did not give different results with regard to the stability of hyperforin and that the method of conservation -70 ⁰ C under nitrogen provided the best 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 stability of hyperforins has also been envisaged by synthesizing artificial hyperforins such as those described in US Patent 6,656,510 (Indena). These are hyperforins corresponding to formula (II),

in which R 1 is an acyl radical or hydrogen, for which, for hyperforin: R = CH 3, the adhyperforin: R = CH ₂ -CH ₃

These are described as being more stable and more active in the anti-depressive action tests. This method of synthesis 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. Moreover, extraction with supercritical fluid is a delicate operation requiring equipment resistant to very high pressures and high temperatures.

Stabilized alkaloids have also been described as hydrogenation products of the allyl chain of hyperforins. The resulting hexahydro- and octahydrogen ketone compounds, become enolated to give metal enolates or enol esters

(see PCT Patent No. 03/091191 and No. 99/64388).

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 active ingredients and the resulting loss of progressive activity. In the earlier French application whose priority is claimed, 05/12908, filed on December 19, 2005 the Applicant Company has described and claimed a new process for extracting the active ingredients of plants from previously minced raw materials. These active principles such as naphthodianthrones, flavonoids, and acylphloroglucinols may be supplemented with other active ingredients such as magnesium salts and / or drugs from the gastrointestinal or central nervous system. In this respect, mention may be made of polyunsaturated fatty acids of the omega-3 type or of products which act on intestinal motility of the antispasmodic type.

The present patent application is more particularly intended to provide additional details on the addition of such active ingredients and in particular on the addition of magnesium salts.

The process according to the invention aims to improve the processes already described making it possible to obtain 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 derivatives of oligomeric.

The subject of the invention is a process for extracting plants, especially those containing iridoids, quinole derivatives and particularly acylphloroglucinols, flavonoids and naphthodianthrones, such as in Hypericum perforatum, which makes it possible to obtain stable extracts and pharmaceutically acceptable, enriched in hyperforin and depleted if possible in hypericin derivatives.

The extraction process according to the invention is characterized mainly by a search for the pH of the extraction media where the active ingredients are the most stable and which makes it possible to obtain, after drying by dehydration under vacuum, at low temperature, on zeolites, a process which also called zeodration, extracts in the form of a crystalline powder. This process makes it possible to increase the levels of hyperforin in the plant extracts and to maintain or even reduce the levels of pseudohypericin and ditypericin. These extracts are preserved either in the form of crystalline powders when the hyperforine is in 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 citric acid, is still attached to inert materials such as sugars such as maltodextrin or a similar carrier, to have a pharmacotechnically manipulable powder.

The choice of the extraction method is carried out among those already described, according to the desired and required levels of hyperforin and hypericin and as a function of the quantities required for the manufacture of pharmaceutical formulations.

The invention also relates to pharmaceutical or para-pharmaceutical preparations containing these different extracts obtained by the methods of the invention for use in health.

For some products, the extraction pH may be between 1 and 2 / or 6.4 and 12 as for St. John's wort depending on the quantities of asset to be extracted (between 3 and 5 for the most unfavorable cases). For other products containing iridoids (Globular, etc.), the pH should be between 6.5 and 8.

In all cases, this type of extract is sensitive to temperature rises, oxidation or light, so it will be dehydrated and dried by vacuum dehydration at low temperature on zeolites, also called zeodration process.

It is known that the wet plant, according to its origin, contains according to different authors, from 2 to 4% of hyperforin. This rate continues to decrease as the various manipulations such as the maceration time before extraction, the concentration of the extracts, the storage time of the extracts, etc. It can become very low.

In the arsenal of the various means known and used against these instability problems, classical methods are used, such as: • the nature of extraction solvents that can be used in pharmacies

"the use of anti-oxidants 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 the various manipulations

"the use of low temperatures during the various manipulations.

Because of the chemical structure of the phloroglucinic derivatives and more particularly because of the presence of hyper-allyl and ketonic groups of hyperforforin, it is logical to think of blocking them to bring a better stability to the entire molecule.

This has been very well described by Chatterjee et al in the patent

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 the corresponding hydroxides.

The object of the invention is to use one or more methods which improve the stability of the phloroglucinic derivatives during the extraction process without altering the other constituents of the extract and to obtain a pharmaceutically acceptable final product, enriched in hyperforins, that is to say containing from 1 to at least 10%, and containing the other constituents such as flavonoids, naphthodianthrones, at the usual levels as for hypericine (from 0.1 to 0.7%).

Various alkalizing or acidifying agents can be used to form a salt (sodium hydroxide, metal hydroxide such as magnesium hydroxide and other alkaline agents, organic bases such as primary or secondary amines, basic amino acids, for example arginine or citrulline bu other organic cyclic bases such as piperidine or morpholine, 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 plants to evaluate the influence of different extraction media such as a basic medium (sodium hydroxide) or an acidic medium (phosphoric acids and / or citric acid). The procedures are identical in all cases and gave the following results.

Table I

HpF = Hyperforine PseudoHp = PseudoHypericin HpR = Hypericin

It can be seen 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 quantities extracted by this same solvent in a neutral medium but, on the other hand, 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, the extractions of which tend to acidify: initial pH 7.74 pH of the extracts 4.83 pH of the solvent + H ₃ PO4 3, PH of the extracts 3.33 pH solv + Ac. Citric 2.66 pH of the extracts 4.46 For extractions in an alkaline medium, the amounts of extracts are enriched in hyperforin as a function of the amount of alkaline agent used while at the same time the amounts of pseudo-hypericin and hypericin decrease. This enrichment in hyperforin can reach double whereas the amounts of hypericin derivatives can decrease by half.

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 extracts obtained.

The procedure described above gave the following results:

TO: 1) two different extractions are carried out on 23 g of moist 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.

At T1: 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).

A total of 4 extractions to TO

4 extractions at T 1 month

The following operating diagram I summarizes the various operations [Figure 9). This approach has made it possible to evaluate and choose a process that may be the alkaline medium when it is desired to increase the rate of hyperfine in the extracts and improve the stability, 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.

The impact of pH of the extraction medium and especially its effect on the stability of certain extract components as well as the transformation of other compounds, made it possible to study more deeply the extraction possibilities as a function of pH, way to realize industrial processes.

Description of the processes:

A first extraction study was carried out in the laboratory from the same batch of plants to compare the influence of alkalinization on the extraction medium compared to conventional extractions performed with hydro-alcoholic solvents.

Brief description of the process:

The process consists in suspending at room temperature a portion of the dried plant in 10 volumes of a 60% aqueous alcoholic solution of 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 yields in these conditions are close to 20 to 25

%.

The dry extracts obtained are in the form of a fine and 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 the following results in HPLC at the following wavelengths (300 and 590 nm) as shown in FIG. 1 and in Tables II, III and IV:

1) acylphloroglucinols

Table II

The results collected from these two extracts show that the extracts obtained by the alkaline route are twice as concentrated in hyperforin than those made in an acid medium.

In contrast, the derivatives of lypericin are present in comparable amounts. The pseudo-hypericin found in the CI 1 extract at neutral pH was transformed into hypericin under the effect of alkalinity.

The study of the naphthodianthrone profiles is carried out from these two extracts using the analytical method of acid extraction in liiexane. This allows to characterize these derivatives. Flavonoids can also be characterized and identified for a deeper approach to the chromatographic profile of the extracts. 2) naphthodianthrones HPLC determination

Table III

3) flavonoids

as shown in the chromatograms according to FIG.

The characterization of a salified form of hyperforin in the presence of other constituents of the extract was carried out by a return in acidic medium of the extraction to recover the lipophilic form of the molecule with its low solubilities in an aqueous medium. Table IV shows the influence of the medium on the stability of hyperforin (salification) as well as its lack of effect on naphthodianthrone derivatives such as trypericin and its derivatives.

Ces résultats sont également figurés à la figure M Exemple de dégradation de l'huperforine non salifiée.

These results are also shown in Figure M Example of degradation of unsalted huperforin.

10 mg / l solution in an apolar solvent for 3 days.

The degradation of hyperfine in three days is evident, giving rise to a multiplicity of by-products.

All these results show that in alkaline medium, powdered extracts containing a higher percentage of hyperforin are much more stable, soluble and salified.

These results are obtained in contrast to the processes described in US Pat. No. 6,444,662, which use chromatographic methods to enrich the hyperforin extracts, and adhyperforine, and then salify them by different chemical methods in order to obtain stabilized but practically free products. other components (flavonoids, naphthodianthrones, etc.) of the plant. The process according to the invention is based on a more pharmaceutical approach since it makes it possible, from dried plants, to obtain stable extracts, the main parameters of which in content of flavonoids, naphthodianthrones and acylphloroglucinols (ie 1 to 10%) are respected. and correspond classically to those defined by the recognized pharmacopoeial methods and adapted here to the case of PHypericum perforatum. Main steps of the process according to the invention (according to FIG. 10)

The process according to the invention is characterized mainly by:

The use of a hydro-alcoholic extraction solvent of known proportions, or an entirely aqueous solvent.

2- the practice of an extraction medium to alkalize or acidify sufficiently, so that the pH is always outside the neutral.

3- the use of a solid / liquid separation method carried out in the absence of light and oxygen from the air (eg under nitrogen, argon or inert gas of the same type).

4- Evaporation of the extraction solvent during the concentration of the extract to dryness, under very high vacuum and under inert gas at low temperatures.

The use of a method 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, a crystallized powder very little hygroscopic and easily used in pharmacotechnics.

7- Finally, by obtaining an extract with well-defined chromatographic characteristics which is represented by the chromatogram of 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 of excipients not exceeding 1 to 8% and which are pharmaceutically acceptable. For obtaining 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 such as maltodextrin to promote the production of a more easily manipulated form during ratomization .

The extract thus obtained is dried as in step 5 and kept in sealed bags or drums protected from moisture, heat and light.

Different extracts of St. John's wort were obtained from hydroalcoholic solvents with varying proportions of alcohol and neutralized with different bases, mineral or organic, such as mainly sodium hydroxide, calcium or magnesium, triethanolamine, triethylamine, lithium or by acidification as, mainly, with mineral 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 acylphloroglucinols hyperforine type.

The subject of the invention is also plant extracts and in particular extracts of hypericum perforatum obtained by the process of the invention, added for the therapeutic use of one or more magnesium salts at a concentration which may be as high as maximum nutritional intake of daily magnesium supplement. Such intake can go according to pharmaceutical standards up to 420 mg / day in men and up to 360 mg / day in women. For the elderly, the maximum recommended amount is 400 mg / day of magnesium element.

Magnesium will be present as magnesium oxide or hydroxide or salt form such as magnesium chloride, magnesium sulfate, magnesium phosphate, magnesium acetate or magnesium pyrrolidone carboxylate, magnesium salts are poorly resorbed digestive but to avoid digestive disorders related to saline overload, the safety limit was set at 840 mg magnesium element per day.

The compositions according to the invention thus contain from 100 to 500 mg of a St. John's wort extract of 1 to 10% of hyperforforins and from 10 to 400 mg of magnesium element in the form of magnesium or magnesium salt. A preferred formulation is for example that which is in the form of tablets or powder sachets containing 0.200 g of St. John's wort extract and 0g250 to 0g400 of magnesium oxide. Magnesium oxide has the advantage that its low solubility in water has a low flavor and thus the acceptability of such preparations is significantly improved. In the absence of magnesium oxide, it is possible to use magnesium phosphate, which is also sparingly soluble in water or any other low water-solubility magnesium salt, such as magnesium carbonate or magnesium thiosulfate.

The magnesium salts used are preferably selected from the group consisting of acetate, lactate, propionate, benzoate, ascorbate, pidolate, citrate, glucose-phosphate or any other therapeutically magnesium salt. compatible.

Magnesium salts provide greater stability to hyperforin at high concentrations and further enhance the activity of the active ingredients on the central nervous system. They are used at a dose up to the maximum recommended dose for daily needs, such as for example 10 to 260 mg of magnesium element, and preferably at a dose of 20 to 180 mg per day in magnesium salt and preferably at a dose of 1 to 12 mg of magnesium element per milligram of hyperforins.

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 hydroalcoholic solution containing 60% of alcohol are introduced therein. 003339

17

Moderate stirring is carried out for 5 to 10 minutes at room temperature in order to have good wettability of the plant.

It is alkalinized with a 50% sodium hydroxide solution (# 100 .mu.m).

Still at ambient temperature, the mixture is left stirring for 24 hours and then the extraction solution is separated from the insoluble material 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 in order not to alter the extract.

Between 2 and 2.5 kg of dry extract are obtained, the acylphloroglucinols contained therein being in the form of sodium salts.

This extract is put into stability study under ICH conditions. He gave the following results in Table V and Figure 6.

Table V

EXAMPLE 2 1 kg of 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, and this by successive dilutions. 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 and in particular tablets.

HPLC chromatographic profile of an extract-based tablet of Example 2, shown in Figure 7. Example 3

10 kg of finely chopped plant (Hypéricum 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 hydroalcoholic solution containing 60% of alcohol 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 made alkaline with a 50% sodium hydroxide solution (# 100 .mu.m).

Always at room temperature, stirring is allowed for 24 hours.

The solution is neutralized with hydrochloric acid to a pH of less than 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

About 2 kg of dry extract are obtained, the acylphloroglucinols being in the base form.

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 formulation for therapeutic use with the extract of Hypericum p. obtained as in example 2 Extract of Hypericum perforatum 31, i 63 kg

Croscarmellose sodium 5,200 kg

Microcrystalline cellulose 14.753 kg

Glycerol dibehenate 0.676 kg

Colloidal silica 0,208 kg

Ascorbic acid 1,111 kg

Citric acid 0.52 kg

The powders are blended and 520 mg tablets are prepared which contain 300 mg of extract plus 11.11 mg of ascorbic acid and 0.52 mg of citric acid.

These tablets can then be dandruffed with agents to protect them from light and moisture such as stearic acid in the presence of HPMC.

Results of pilots in stability. The results obtained are shown in Table VI below:

Example 5

Preparation of a formulation for therapeutic use with the extract of Hypericum perforatum obtained as in Example 2 and a magnesium salt:

Extract of Hypericum perforatum 31, 163 kg at 2% of hyperforin

Magnesium citrate 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 100,000 640 mg tablets are made which each contain 300 mg of extract plus 11.11 mg of ascorbic acid, 0.52 mg of citric acid and 120 mg of magnesium citrate. These tablets can then be dandruffed with agents to protect them from light and moisture such as stearic acid in the presence of HPMC.

Magnesium citrate can be replaced by the equivalent amount of magnesium of another magnesium salt such as magnesium biphosphate or magnesium pidolate.

Example 6

Preparation of a formulation for therapeutic use with Hypericum perforatum extract containing 4% of hyperforforin

Hypericum perforatum extract 30,000 kg

Magnesium citrate 12.00 kg

Croscarmellose sodium 5,200 kg

Microcrystalline cellulose 14.905 kg

Glycerol dibehenate 0.676 kg

Colloidal silica 0.219 kg

Ascorbic acid 1, 111 kg

Citric acid 0.052 kg

The powders are mixed and 640 mg tablets are prepared which contain 300 mg of extract plus 11.11 mg of ascorbic acid, 0.52 mg of citric acid and 120 mg of magnesium citrate.

These tablets are oblong with a bar of breakability, which allows to have adjustable tablets in dosage, ranging from 6 mg tryperforine for a half-tablet to 12 mg of hyperforforine for a whole tablet.

These tablets can then be dandruffed with agents to protect them from light and moisture such as stearic acid in the presence of HPMC. Example 7

Preparation of a Therapeutic Use Formula with Hypericum Perforatum Extract Containing 4% Hyperforin

Hypericum perforatum extract 30,000 Kg at 4% of hyperforin

Magnesium carbonate 17,70 Kg

Croscarmellose sodium 6.10 Kg

Microcrystalline Cellulose 5,197 Kg

Glycerol dibehenate 0.80 Kg

Colloidal silica 0.24 Kg

Ascorbic acid 1,111 Kg

Citric acid 0.052 Kg per 100,000 tablets

The powders are mixed and 612 mg tablets are prepared which each contain 300 mg of extract plus 11.11 mg of ascorbic acid and 0.52 mg of citric acid and 177 mg of magnesium carbonate. These tablets can then be dandruffed with agents to protect them from light and moisture such as stearic acid in the presence of HPMC.

Example 8 Preparation of a Therapeutic Use Formulation with Hypericum Perforatum Extract Containing 4% Hyperforforin

Hypericum perforatum extract 30,000 kg

Magnesium citrate 20.69 kg Croscarmellose sodium 7.15 kg

Microcrystalline cellulose 4.944 kg

Glycerol dibehenate 0.845 kg

Colloidal silica 0.26 kg

Ascorbic acid 1,111 kg

The powders are mixed and 100,000 650 mg tablets are made which each contain 300 mg of extract plus 11.11 mg of ascorbic acid and 206.9 mg of magnesium citrate. These tablets can then be dandruffed with agents to protect them from light and moisture such as stearic acid in the presence of HPMC.

Example 9

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 form.

Hypericum perforatum extract 30,000 Kg

Croscarmellose sodium 5,200 Kg

Microcrystalline cellulose 14,905 Kg

Glycerol dibehenate 0.676 Kg

Colloidal silica 0.219 Kg

The nuclei are dandruffed by a first layer of Sepilim LP with a deposit of about 25 mg per nucleus and then a layer of a suspension prepared in advance of daring 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.

Example 10

Gastro-resistant tablets>

Preparation obtained with the extract obtained according to Example 1 containing 4% of hyperforin, per 100,000 nuclei of 510 mg per unit form

Hypericum perforatum extract 30,000 Kg

Croscarmellose sodium 5,200 Kg

Microcrystalline Cellulose 14,905 Kg Glycerol Dibehenate 0.676 Kg

Colloidal silica 0.219 Kg per 100,000 gastro-resistant tablets

The nuclei are dandruffed by a first layer of Sepilim LP with a deposit of about 25 mg per core and then a layer of a suspension prepared in advance of Eudragit L30 D 55, talc and triethyl citrate for a deposit from about 40 to 45 mg. This gives a finished tablet with an average weight after coating close to 580 mg. These tablets contain 12 mg of hyperforforine.

Example 11

Orodispersible Tablets Preparation of a formula for therapeutic use with the extract obtained according to Example 1, containing 4% of hyperforin, per 100,000 orodispersible tablets of 4 g per unit form.

Hypericum perforatum extract 40,000 kg (at 4% hyperforforin)

Sodium bicarbonate 174,000 kg

Citric acid 100,000 kg

Tartaric acid 50,00 kg

Glycine 10,000 kg Povidone 1,000 kg

Wheat starch 25,000 kg

Colloidal silica 0.219 kg per 100,000 tablets

The amount of citric acid and tartaric acid on the one hand and bicarbonate on the other hand, makes it possible to have an effervescent mixture whose pH must be close to 5 rather than 7 or close to 8 to 8.5. This makes it possible to have orodispersible tablets allowing a dosage of 16 mg of hyperforforin per tablet.

Example 12

Orodispersible tablets

Preparation of a formula for therapeutic use with the extract obtained according to Example 1, but containing 2% of hyperforin, per 100,000 tablets of 3,652 g per unit form

Hypericum perforatum extract 30,000 kg (2% hyperforforine) Sodium bicarbonate 174,000 kg

Citric acid 100,000 kg

Tartaric acid 50,00 kg

Glycine 10,000 kg Povidone 1,000 kg

Colloidal silica 0.219 kg per 100,000 tablets

The amount of citric acid and tartaric acid makes it possible to have an effervescent mixture whose pH should be close to 5 rather than 7, when there is only citric acid or tartaric acid or close from 8 to 8.5 when sodium bicarbonate is present.

This makes it possible to have orodispersible tablets providing a dosage of 6 mg of hyperforforine per tablet.

Example 13

Breakable tablet without magnesium

Preparation obtained with the extract obtained according to Example 1 but containing 4% of hyperforin per 100,000 nuclei of 510 mg per unit form

Hypericum perforatum extract 30 ^ 000 Kg

Croscarmellose Sodium 5 ^ 200 Kg Microcrystalline Cellulose ^ f 14,905 Kg

Glycerol dibehenate 0.676 Kg

Colloidal silica 0.219 Kg

These tablets are oblong with a score bar, which allows to have flexible tablets in dosage ranging from 6 mg diiyperforine for a half-tablet to 12 mg of hypertrophin for one tablet.

The nuclei are dandruffed with a layer of Seppilm LP with a deposit of approximately 30 mg per tablet. There are thus obtained 100,000 finished tablets of average weight after coating, close to 540 mg.

Example 14

Soft capsules

Extract of Hypericum perforatum 250 mg

Polyethylene glycol 600 35 mg

Borage oil with 30% unsaturated fatty acids 100 mg

Colloidal silica 45 mg Cremophor EL 7 mg

Lipid emulsion of the Intralipid type

QS for a soft capsule of 650 mg

The plant extracts according to the invention may be further added to other active ingredients and in particular active principles exhibiting antispasmodic properties on the gastrointestinal sphere or tranquillizing on the central nervous system. In this respect, mention may be made of polyunsaturated fatty acids of the Omega-3 type which act on anxiety such as α-linolenic acid concentrates; These additional active ingredients can be contained at doses ranging from 5 to 100 mg per unit dose.

The St. John's wort extracts thus obtained are used at doses of 100 to 500 mg per unit dose.

The polyunsaturated fatty acids are introduced in the form of an oil or an oil concentrate containing such polyunsaturated fatty acids, such as evening primrose oil, borage oil, camelina oil, linseed oil, lemon oil, blackcurrant seed oil or kiwi seed oil. Their presence expressed in milligrams per unit dose ranges from 10 to 100 mg according to daily nutritional needs.

Claims

1. 1 -Pharmaceutical or parapharmaceutical compounds containing as an active ingredient a powder or plant extract of the genus Hypericum containing 1 to 10% of hyperforins in a physiologically acceptable excipient or inert vehicle, which is non-toxic. 5. Pharmaceutical or parapharmaceutical compositions according to claim 1, containing, as active ingredient, the solids content of Hypericum perforatum (St. John's Wort) containing from 1 to 10% of hyperfine. 3 -Pharmaceutical or parapharmaceutical compositions according to claim 1 or claim 2, containing from 100 to 500 mg of dry extract of Hypericum perforatum. 10. 4-Pharmaceutical or parapharmaceutical compositions according to one of claims 1 to 3, wherein the extract or the powder of Hypericum is supplemented with one or more therapeutically active mineral salts. Pharmaceutical or parapharmaceutical compositions according to one of the preceding claims, in which the mineral salts are a magnesium derivative chosen from among the oxide, the hydroxide, the magnesium mineral salts, the organic magnesium salts and the complexes. magnesium. Pharmaceutical or parapharmaceutical compositions according to one of the preceding claims, in which the extracts of Hypericum perforatum are supplemented with one or more magnesium salts at a concentration ranging from 10 mg up to the maximum of the supplement intake. daily. 7-Pharmaceutical or parapharmaceutical compositions according to one of the preceding claims wherein the magnesium is present in the form of 25. oxide, magnesium hydroxide or in the form of salts selected from chloride, citrate, lactate, carbonate glycerophosphate, propionate, benzoate, sulfate, phosphate, acetate, pyrolidonecarboxylate (or pidolate), glucose-1 phosphate, methanesulfonate and magnesium thiosulfate. 8-Pharmaceutical or parapharmaceutical compositions according to any one of the preceding claims which contains from 100 to 500 mg of St. John's wort extract containing from 2 to 4% of hyperphorins, and from 10 to 60 mg of magnesium element in the form of salt magnesium. 9- Pharmaceutical or parapharmaceutical compositions containing, in addition to St. John's wort extract, a polyunsaturated fatty acid of the omega 3 type. 35. 10-Process for obtaining a dry extract of a plant of the Hypericum genus stabilized and concentrated in active principles of the acylphloroglucinol type, characterized in that the plants are extracted by means of a hydro-alcoholic solvent in a zone of PH between 1 and 2 or between 6.4 and 12, then evaporates the alcohol by azeotropy and dries the residue under a very high vacuum and under inert gas at low temperature 40. up to negative values and obtains a dry extract whose active principles of the acylphloroglucinol type are in the form of metal salts, stable, well crystallized, little hygroscopic, having a hyperforine content of between 1 and 10% and a hypericin content of between 0.1 and 0.7%. 11- Process for obtaining the dry extract of a plant of the genus Hypericum according to claim 45, characterized in that a plant of the genus Hypericum is subjected to a hydroalcoholic extraction, the PH is adjusted in an alkaline zone by adding On an inorganic or organic base, the alcohol is separated by azeotropic distillation, the residue is dried by zeodration to obtain a dry extract of a plant of the genus Hypercum in which the active principles of the acylphloroglucinol type are in the form of salts. 12-Process according to claims 10 and 11 wherein the treated plant is St. John's Wort (Hypericum perforatum).