KR100285287B1 - Method for preparing stable extract of Hypericum perforatum el - Google Patents

Abstract

Stable extract of Hypericum perforatum el, preparation method thereof and pharmaceutical composition thereof

The present invention provides an improved extract of Hypericum perforatum el (St. John's wort) containing hyperporin, wherein the hyperporin is stable to degradation or degradation by a stabilizer. A stable extract of Hypericum perforatum el.

Description

Method for preparing stable extract of Hypericum perforatum el

Although pharmacological and clinical trials have shown that the extract of St. John Wort can be applied to some degree of severe depression, the overall antidepressant effect with less irritation is one or more. It is clear that this is due to the components: J. H lzl, S. Sattℓer, H.sch tt, Johanniskraut: Eine Alternative zu synthetischen Antidepressiva (St. Johns wort: an alternative to synthetic antidepressants), Phamazeutische Zeitung, No. 46, 139. , Pp. 3959 to 3977. However, there has recently been a strong indication that Hyperforin has a significant effect (EP-A-0 599 307).

Hypericum perforatum el is used as a raw herb with an external part (aerial part, ie, the upper part of the surface), and the representative elements of the hypericum perforumum el Hypophorin; J. H described above see lz1 and so on.

The preparation of hypericum extracts containing high amounts of hyperlipin is described in DE-PS-1 569 849 and in Arch. Pharm., Vol. 323 (1990), 755.

Hyperferin in extracts from stored raw herbs deteriorates completely after a week, but it is believed that hyperferin extracted from fresh plants remains more stable than R. Bergh. fer, J. H Deutsche Apothekerzeitung, Vol. 126, No. 47 (1986), pp. 2569-2573.

J. H 1z1 et al., Planta Med., Vol. There is a report on hypercomic oil on page 601, 55 (1989), presuming that there is a correlation between hyperlipin and peroxide values. Hypercomic oil exhibits a change in peroxide value when exposed to sunlight. However, J. H According to lz1 and so on, there is no relationship between the peroxide value and the concentration of hyperlipin.

P. Maisenbacher, K.-A. Kovar, Planta Med., Vol. 58, (1992), pp. 351 to 354, report on the stability of hyperlipocomb oils, which also contain hyperporin which deteriorates within a few weeks.

EP-A-0 599 307 (corresponding to DE-OS 4 239 959) discloses extracts of the hypericum and their preparation, which extracts contain small amounts of hypericin or similar photosensitive compounds. Nevertheless, it has nevertheless been thought to have been attributed to hyperlipin. This effect can be explained by the presence of hyperporin.

In addition, by extracting the fresh flowers of St. John's wort using a fat oil such as olive oil, soybean oil, malt oil, or sunflower seed oil, crushed (mashed), 11 Hypericum oil (St. John's wort: It is known to make oleum hyperic). Hypercomic oil contains varying amounts of hyperporin and is useful for local treatment of wounds, especially burns and abrasions; P. Maisenbacher, K.-A. Kovar's Planta Med., Vol 58 (1992), pp. 351 to 354, and J. H lzl, L. Denmisch, S. Stock, Planta Med., Vol. 55 (1989) pp. 601-602.

As with the conventional Hypericum extract, the content of hippophorin in these drugs is surprisingly reduced by two conventional storage methods and completely extinguishes within a few months; 1991 123, T bingen, Ph D. Thesis by P. Miasenbacher, and 1987, Mnarburg / L., R. Bergh Ph. D. See paper. Previous experiments with oily Hypericum extracts have demonstrated that compositions containing hyperporin have improved stability when stored in argon; Ph. Maisenbacher, Ph. D. See paper. When antioxidants such as butylhydroxytoluene (BHT) and butylhydroxyanisol (BHA) were used, stabilization of the extracts was not obtained. Moreover, in the case of species of antioxidants such as Oxynex LM and Oxynex 2004, stability cannot be improved. However, in case of hypericum oil, optimum stability is obtained by using octyldodecanol (Eutanol G) as extractant (P. Maisenbacher's Ph. D. ): Ph. Maisenbacher's Ph. D. See papers 151-154.

Hypericin extracts containing hyperporin can be prepared using conventional pharmaceutically inorganic or organic solvents or mixtures thereof (P. List and PC Schmidt, 1984, Stuttgart, Wissensch.Verlagsgesellschaft mbH, Technologie pflanzlicher Arzneizubereitungen).

Conventional aqueous ethanolic hypericcum extracts and final pharmaceutical compositions prepared thereby always contain less than about 1% hyperphorin (based on extract). After storage, the content of the hyperporin decreases visibly and becomes almost zero depending on each storage condition. It is assumed that the degradation of hyperporin in raw herbs and extracts thereof is due to the oxidation process.

The technical task of the present invention is to provide an improved hyperporin-containing stabilized extract of Hypericum perforum el (St. John's wort), in which the hyperporin remains stable for a long time. Yet another technical problem of the present invention is to provide a pharmaceutical composition containing a stable extract in which the required amount of hyperporin remains in a stable state while providing a method for preparing the safe extract.

According to the invention, the above technical problems are solved by extracts according to claims 1 to 8, methods according to claims 9 to 21 and pharmaceutical compositions according to claims 22. Resolved.

The present invention contains certain antioxidants and / or oxygen binding stabilizers or reducing agents capable of degrading oxidants such as groups, peroxides, oxygen in the atmosphere and / or preventing deterioration of hyperporin and containing nitrogen Hypericum extracts obtained by extraction in an inert gas atmosphere such as and / or under the exclusion of light, and / or with a solvent having a significantly reduced oxygen content are more essential than those of untreated hypericum extracts. This is especially based on the unexpected results of maintaining a stable state for longer periods of time. This extract is R. Bergh fer and J. H In contrast to the reports of lzl (above), it can be prepared from dried, stored raw herbs.

Solvents with greatly reduced oxygen content can be prepared by physical treatment such as washing with an inert gas such as nitrogen. When antioxidants are added according to the invention, and preferably preserving or stabilizing the hyperporin extract by excluding light and oxygen from the atmosphere, the hyperporin in the extract remains essentially stable for a long time. In addition, protection from light and oxygen from the atmosphere can be achieved by corresponding pharmaceutical compositions.

In an alternative embodiment of the process of the invention relating to the preparation of a stabilized extract, fresh or preferably dried medicine of St. John's wort is extracted using aqueous methanol or ethanol with a significant decrease in oxygen content by physical treatment. Since the presence of an oxidant is possible in the extract, an antioxidant is added and dissolved as a stabilizer. In another embodiment of the invention, the solvent of the St. John's wort extract is a group consisting of low boiling alkanes having about 5 to 8 carbon atoms, such as pentane, hexane and heptane, especially n-heptane, and liquid and supercritical carbon dioxide It includes the one selected from. Here, “aqueous methanol or ethanol” refers to methanol or ethanol, which preferably has a water content of up to about 40% by volume.

Preferred antioxidant stabilizers or antioxidants include pharmaceutically acceptable substances that can prevent degradation of the hyperporin and / or reduce the oxidizer content in the extract or pharmaceutical composition. For example, organic diol compounds such as cysteine and glutathione, fatty acid esters of ascorbic acid and ascorbic acid (myristate, palmitate, stearate) and And materials selected from the group consisting of ascorbic acid derivatives such as.

This antioxidant stabilizer is added to the extract of the hyperlipom in an amount sufficient to stabilize the hyperporin. In general, it is sufficient to add an antioxidant stabilizer at a concentration of 0.01 to 5% based on the hypericum extract.

According to another embodiment of the invention, the addition of the stabilizer proceeds as described above but after drying of the extract, ie after removing the solvent.

According to another embodiment of the invention, the addition of the antioxidant stabilizer is made in the preparation of the final pharmaceutical product together with other pharmaceutical additives.

All the above embodiments are preferably made under the exclusion of light and oxygen.

The extract obtained by means of a singer can be processed into capsules, tablets and coated tablets together with existing pharmaceutical additives after the stabilizing agent is added to the pharmaceutical composition again as desired.

Pharmaceutical additives here are oils and fats as fillers used in film and coated tablets, binders, disintegrants, lubricants and coatings, and fillers used in soft gelatin capsules.

The invention is now described with reference to the following examples which are not intended to limit the scope of the invention. In the following examples, unless otherwise indicated, percentage means weight percentage. Note that although nitrogen is used as the inert gas (protective gas), other inert gases such as argon or krypton may also be used.

Example 1 a and 1 b (Comparative Example)

a)

One kilogram of St. John's wort was ground well using a grinder and then 7 kg of 70 (v / v)% ethanol was added. A suspension of 1 kg of raw herbs and 7 kg of solvent was then vigorously stirred in an inert gas atmosphere and at a temperature of 55 ° C. for 1 hour. The extract was then separated from the above mixture by centrifugation. The residue of the mixture was extracted secondly using 7 kg of solvent. After mixing the two extracts, the dry residue in the resulting extract was determined by partial sampling. The extract was slowly concentrated under reduced pressure to a dry residue content of about 70%, which was again dried under reduced pressure and at a temperature of 40 ° C. As a result, 0.42 kg of dry extract was obtained. The content of hyperporin in the extract was 2.26%, and the total content of hyperlipin was 0.27%.

b)

The dry extract of Example 1 a) was further treated with polyvinylpyrrolidone (PVP) according to the method of EP-A-0 599 307 to selectively remove hyperlipin. As a result, the hyperporin content was 2.96%.

24 kg of fresh herbs of St. John's wort were ground well using a mill, followed by addition of 156 kg of 80 (v / v) methanol washed with nitrogen. The mixture was then stirred at a temperature of 55 ° C. for 1 hour. Thereafter, the extract was separated by bootie centrifugation into the above mixture. The residue of the mixture was extracted secondary. After the two extracts were mixed, 1.0% by weight of ascorbic acid was added, and the resulting solution was stirred for 15 minutes. Thereafter, the extract was slowly concentrated to a dry residue of about 70%, which was then dried under reduced pressure and at a temperature of 40 ° C. As a result, a stabilized 5.39 kg dry extract with a hyperporin content of 3.2% was obtained. The total hyperlipin content in this extract was 0.48%.

Example 3

8 kg of St. John's wort was ground well using a grinder and 56 kg of 70 (v / v) ethanol was added. Prior to using the solvent, the oxygen content of the solvent was reduced by washing with an inert gas. A suspension of 8 kg of raw herbs and 56 kg of solvent was then vigorously stirred at a temperature of 55 ° C. for 1 hour. Thereafter, the extract was separated from the mixture by centrifugation while washing was performed using nitrogen as an inert gas. The residue of the mixture was extracted secondly in the same manner as above. After the two extracts were mixed, 0.05% by weight of el-cysteine was added and the resulting solution was slowly concentrated to about 70% dry residue, which was again dried under reduced pressure and at a temperature of 40 ° C. As a result, a stabilized 2.524 kg dry extract having a hopper percent content of 3.9% was obtained. The total hyperlipin content in this extract was 0.28%.

Example 4

454 g of finely chopped fresh St. John's wort was compressed in a squeezer, and then dissolved in the resulting juice (160 ml) by adding 1.5 g of ascorbic acid. This juice was added to the squeezed medicine. Thereafter, 1 kg of n-heptane was added to the wet medicine. The resulting mixture was extracted by excitation under light and then continuously stirred for 1 hour at a temperature of 50 ° C. The mixture was then aspirated using a Seitz Supra 1500 filter and secondly the weak residue was extracted in the same manner. After mixing these extracts, the resulting solution was concentrated to a dry residue content of about 70% under the exclusion of light and by rotary evaporator at 35 ° C., which was lyophilized again. As a result, 9.11 g of dry extract having a hyperporin content of 37.2% was obtained.

Example 5

515 g of finely chopped fresh St. John's wort was compressed in a squeezer, and then dissolved in the resulting juice solution (180 ml) by adding 1.7 g of ascorbic acid. This juice was added to the squeezed medicine. The moist drug was then transferred to a high pressure extraction apparatus and extracted using carbon dioxide at a temperature of 40 ° C. and a pressure of 350 bar. 1 kg of carbon dioxide was used per 20 kg of medicine. After extraction, the pressure was reduced to 60 bar to separate the extract. Thereafter, the extract was removed from the high pressure extractor and heated to about 60 ° C. to separate from the jointly extracted water to obtain a dry extract of 12.3 g having 43.1% of hyperporin content.

Example 6

[Hipporin Stability Test]

In the present Example, the extract of the extract according to Example 1 (hyperporin content (measured by HPLC)) of the extract in the state of not making specific precautions and preventive additions to the extracts according to Examples 2 to 5 of the present invention It was compared with the hyperporin content of the extracts prepared according to. The extracts obtained according to the invention were stored in a nitrogen atmosphere and at room temperature in the absence of light. The results are shown in Table 1. According to the results shown, the extracts prepared according to the present invention, the hyperporin content is maintained in a substantially unchanged state after 12 months. For the extracts prepared according to Examples 1 to 3, the total hyperlipin content did not change during this period.

TABLE 1

Example 7

[Soft Gelatin Capsule Containing Hypericum Extract]

- Furtherance

Dry Hypericum Extract 300mg

Ascorbic Acid 0.25mg

Octyldodecanol 200mg

[Produce]

The extracts of Example 3 and Example 4 were used as dry extracts respectively.

The dried extract and ascorbic acid were dispersed together in octyldodecanol and treated with soft gelatin capsules in the presence of oxygen in the atmosphere.

Example 8

[Film Tablets Containing Hypericum Extract]

- Furtherance

Dry Hypericum Extract 300mg

Cellulose 100mg

Denatured Starch 90mg

Na-carboxymethylcellulose 30 mg

Well dispersed silicium dioxide 5.0mg

Ascorbic acid 5.0mg

Magnesium Stearate 5.0mg

Hydroxypropylmethylcellulose-film 20.0 mg

[Produce]

The extract of Example 3 was used as a dry extract.

The components were mixed in a mixer in the dry state and then pressed directly into positive form. The tablets thus obtained were coated with a hydroxypropylmethylcellulose coating.

Example 9

The final pharmaceutical composition of the present invention was compared to a commercial hyperlipcomb pharmaceutical composition (purchased in the German market in September 1995).

In this example, the five hyperlipocomic compositions purchased from the German market in September 1995 were tested according to the present invention based on the extracts contained in the preparation of the hyperporin cavities in accordance with the present invention. Compared with the pharmaceutical composition. The results are shown in Table 2. Referring to Table 2, it can be clearly seen that the pharmaceutical composition prepared according to the present invention is generally high in the hypophorin content and remains stable even after 12 months.

TABLE 2

Claims (21)

In a stable extract of Hypericum perforatum el (St. John's wort) having a hyperporin content, the hyperporin is composed of an organic diol compound, ascorbic acid or ascorbic acid derivative having stability against degradation or degradation. Hypericum perforum el, characterized in that it is stabilized by adding a stabilizer selected from the crowd. According to claim 1, wherein the stabilizer is a stabilizer extract of Hypericum perforum elum, characterized in that to maintain a concentration of 0.01% to 5% based on the extract. According to claim 1 and 3, wherein the stabilizer is a stabilizer extract of Hypericum perforatum El, characterized in that to maintain a state of the concentration of 0.2% to 1% as an optimal state based on the extract. According to claim 1, wherein the stabilizer is a stable extract of Hypericum perforatum El, characterized in that cysteine (cysteine). According to claim 1, wherein the stabilizing agent glutathione (glutathione) characterized in that the stable extract of Hypericum perforum el. According to claim 1, wherein the stabilizer is ascorbic acid (ascorbic acid) characterized in that the stable extract of Hypericum perforum el. The stable extract of Hypericum perforum elum according to claim 1, wherein the stabilizing agent is fatty acid ester of ascorbic acid. In the method for preparing a stable extract containing hyperlipin, the herbal medicine (Hypericum perforatum el) is extracted using a known pharmaceutically organic or inorganic solvent, or a mixture thereof, and organically produced during or after the preparation of the extract. Stable selected from the group consisting of diol compounds (cysteine and glutathione), ascorbic acid and derivatives thereof (fatty acids of ascorbic acid [myristate, palmitate and stearate]) A method for producing a stable extract, characterized in that a topical agent is added in an amount necessary for stabilizing hyperlipin and a dry extract is obtained from the resulting liquid extract. The stable extract according to claim 8, wherein the fresh herbal medicine (Hypercomum perforum el) is extracted. The stable extract according to claim 8, wherein the dried herbal medicine (Hypercomum perforum el) is extracted. The method of claim 8, wherein the stabilizing agent cysteine (cysteine) characterized in that the stable extract of Hypericum perforum el. The method of claim 8, wherein the stabilizer is glutathione (glutathione), characterized in that the stable extract of Hypericum perforum el. The method of claim 8, wherein the stabilizer is ascorbic acid (Ascorbic acid) characterized in that the stable extract of Hypericum perforum el. The method of claim 8, wherein the stabilizing agent is a stable extract of Hypericum perforum el, characterized in that the fatty acid ester of ascorbic acid (fatty acid ester of ascorbic acid). The method of claim 8, wherein the stabilizer is a stabilizer, characterized in that added to the concentration of 0.01% to 5%, preferably 0.2% to 1% based on the extract. 9. The stable extract according to claim 8, wherein the oxygen content of the extraction solvent is low or significantly reduced. The process of claim 8 wherein the extract is aqueous ethanol, aqueous methanol, alkanes having from about 5 to 8 carbon atoms, or aqueous or supercritical carbon dioxide. The method of claim 8, wherein the stabilizer (s) is stabilized extract, characterized in that added after drying the extract. The method of claim 8, wherein the stabilizer is a stabilized hyperporin-containing extract, characterized in that is added in the final pharmaceutical composition with conventional pharmaceutical additives. The method of claim 8, wherein the stable extract, characterized in that light and / or oxygen is excluded in the preparation of the extract. A pharmaceutical composition comprising an extract according to any one of claims 1 to 7 and known pharmaceutical additives for the treatment of depression and mental dystrophy.