MXPA99009261A - Stable extract of hypericum perforatum l., a method for producing the same, and corresponding pharmaceutical preparations - Google Patents
Stable extract of hypericum perforatum l., a method for producing the same, and corresponding pharmaceutical preparationsInfo
- Publication number
- MXPA99009261A MXPA99009261A MXPA/A/1999/009261A MX9909261A MXPA99009261A MX PA99009261 A MXPA99009261 A MX PA99009261A MX 9909261 A MX9909261 A MX 9909261A MX PA99009261 A MXPA99009261 A MX PA99009261A
- Authority
- MX
- Mexico
- Prior art keywords
- extract
- stabilizer
- process according
- stable
- hyperforin
- Prior art date
Links
- 239000000284 extract Substances 0.000 title claims abstract description 83
- 240000008526 Hypericum perforatum Species 0.000 title claims abstract description 10
- 235000017309 Hypericum perforatum Nutrition 0.000 title claims abstract description 9
- 230000000875 corresponding Effects 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 title 1
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- IWBJJCOKGLUQIZ-HQKKAZOISA-N Hyperforin Chemical compound OC1=C(CC=C(C)C)C(=O)[C@@]2(CC=C(C)C)C[C@H](CC=C(C)C)[C@](CCC=C(C)C)(C)[C@]1(C(=O)C(C)C)C2=O IWBJJCOKGLUQIZ-HQKKAZOISA-N 0.000 claims abstract description 60
- 239000003381 stabilizer Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000321 herbal drug Substances 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 13
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 12
- 239000003963 antioxidant agent Substances 0.000 claims description 12
- 229960005070 ascorbic acid Drugs 0.000 claims description 12
- 235000010323 ascorbic acid Nutrition 0.000 claims description 12
- 239000011668 ascorbic acid Substances 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 235000006708 antioxidants Nutrition 0.000 claims description 11
- 238000000605 extraction Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 230000015556 catabolic process Effects 0.000 claims description 8
- 230000004059 degradation Effects 0.000 claims description 8
- 238000006731 degradation reaction Methods 0.000 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 7
- 230000003078 antioxidant Effects 0.000 claims description 6
- 235000003261 Artemisia vulgaris Nutrition 0.000 claims description 5
- 239000000546 pharmaceutic aid Substances 0.000 claims description 5
- 241000196324 Embryophyta Species 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- -1 thiol organic compounds Chemical class 0.000 claims description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N Glutathione Chemical group OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 3
- 229960003180 Glutathione Drugs 0.000 claims description 3
- 108010024636 Glutathione Proteins 0.000 claims description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 3
- 239000001569 carbon dioxide Substances 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000003638 reducing agent Substances 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims 2
- 239000000194 fatty acid Substances 0.000 claims 2
- 230000004075 alteration Effects 0.000 claims 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims 1
- 238000000354 decomposition reaction Methods 0.000 claims 1
- 150000002894 organic compounds Chemical class 0.000 claims 1
- 239000008063 pharmaceutical solvent Substances 0.000 claims 1
- 150000003573 thiols Chemical class 0.000 claims 1
- 235000002197 St. John’s wort Nutrition 0.000 abstract description 23
- 241000546188 Hypericum Species 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- BTXNYTINYBABQR-UHFFFAOYSA-N Hypericin Chemical compound C12=C(O)C=C(O)C(C(C=3C(O)=CC(C)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 BTXNYTINYBABQR-UHFFFAOYSA-N 0.000 description 10
- 239000011261 inert gas Substances 0.000 description 10
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 230000000111 anti-oxidant Effects 0.000 description 5
- 239000003640 drug residue Substances 0.000 description 5
- 229940005608 hypericin Drugs 0.000 description 5
- 238000007792 addition Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 150000002978 peroxides Chemical class 0.000 description 4
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 3
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 description 3
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000001590 oxidative Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N Butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 235000010678 Paulownia tomentosa Nutrition 0.000 description 2
- 240000002834 Paulownia tomentosa Species 0.000 description 2
- 230000001430 anti-depressive Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229910000833 kovar Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- 229940005513 ANTIDEPRESSANTS Drugs 0.000 description 1
- 240000006891 Artemisia vulgaris Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010049796 Excoriation Diseases 0.000 description 1
- 239000001293 FEMA 3089 Substances 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 229940105132 Myristate Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 230000000593 degrading Effects 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000469 ethanolic extract Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000542 fatty acid esters of ascorbic acid Substances 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 150000002448 hyperforins Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton(0) Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-M myristate Chemical compound CCCCCCCCCCCCCC([O-])=O TUNFSRHWOTWDNC-UHFFFAOYSA-M 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical class CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- 200000000019 wound Diseases 0.000 description 1
Abstract
The invention relates to an improved extract of Hypericum perforatum (St. John's-wort) containing approximately 0.1%to 2%hyperforine. The hyperforine contained in the inventive extract is stable for a longer period of time.
Description
STABLE EXTRACT OF HYPERICUM PERFORATUM L. , PROCESSES FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS
BACKGROUND OF THE INVENTION It has been ascertained from pharmacological and clinical trials that extracts from the St. John (extracts of Hypericum) can be used successfully in cases of mild to moderately severe depression. The total anti-depressant effect can not be assigned exactly to one or more of the components; cf. J. Hólzl, S. Sattler and H. Schütt, Johanniskraut: Eine Alternative zu synthetischen Antidepressiva (St. John Plant: An Alternative to Synthetic Antidepressants), Phar azeu ti sche Zei tung, No. 46, 139. Jahrgang, 17 November 1994, pages 3959-3977 and E. Steinegger and R. Hánsel, Pharmakognosie, 5th edition 1992, pages 672-674, Pringer Verlag. However, recently there are stronger indications that Hiperforin provides a considerable contribution to achieve effectiveness (EP-A-0 599 307). The raw herbal drug consists of the aerial parts of Hypericum perforatum L. The components of Hypericum perforatum L. are among others, Hypericin and -Hyperforin; cf. J. Hólz et al., See above. The preparation of extracts of Hypericum with
P1542 / 99MX an enriched content of Hypericin are described in DE-PS-1 569 849 as well as in S. Niesel and H. Schilcher in Arch. Pharm. , Vol. 323 (1990), page 755. From R. Berghófer and J. Hólzl, Deu tsche
Apo thekerzei tung, Vol. 126, No. 47 (1986) pages 2569-2573, it is known that hyperforin in extracts from herbal drugs stored in crude oil is already completely degraded after one week, whereas it should be more stable in the extract of fresh plants. These authors assume that fresh plants contain a stabilizer for Hyperforin. J. Hólzl et al., Plan ta Med. , Vol. 55 (1989) pages 601-602 reports about Hypericum oil and supposes a correlation between the concentration of Hypericin and the value of the peroxide. Hypericum oil products exposed to sunlight show different peroxide values. But according to J. Hólzl et al, there is no relationship between the value of the peroxide and the concentration of Hypericin. P. Maisenbacher and K. -A. Kovar report in Plan ta Med., Vol. 58, (1992), pages 351 to 354 about the stability of Hypericum oil. This oil also contained hyperforin, which degraded in a few weeks. From EP-A-0 599 307, the
P1542 / 99MX primary extracts of the crude herbal drug from the St. John (see examples 1-3). These primary extracts are obtained simply by the extraction of crude herbal drug with 96% and 60% aqueous ethanol, respectively, without any precautionary measure and without any addition. In Example 1 the Hiperforin content of the primary (fresh) extract is stated to be 6.3%. In the other two examples the content of Hyperforin is not established at all. We have found that Hyperforin extracts are extremely unstable; see description, example 5, Table I. The primary extract obtained according to example 1 (comparison) by means of extracting the drug with 70% aqueous ethanol, after 13 weeks, does not contain any detectable amount of hyperforin. In addition, it is known how to prepare Hypericum oil (St. Johns plant oil, Oleum hyperici) by extracting fresh crushed (crushed) flowers from St. John, with a fatty oil such as olive oil, soy bean oil, wheat germ oil or sunflower seed oil. Hypericum oil contains varying amounts of hyperforin and is useful for the topical treatment of wounds, particularly burns and abrasions; cf. P. Maisenbacher and K.-A. Kovar, Planta Med. , Vol. 58 (1992), pages 351-354 and
P1542 / 99MX J. Hólzl, L. Demisch and S. Strock, Planta Med. , Vol. 55 (1989), pages 601-602. In the drug, as in conventional extracts of Hypericum, the content of Hyperforin decreases dramatically until the disappearance of the substance within a few months in conventional storage; cf. doctoral thesis of P. Maisenbacher, Tübingen 1991 and PhD thesis of R. Berghófer, Marburg / L. 1987. In previous experiments with oily extracts of Hypericum, the stability of the compositions containing Hyperforin could only be improved in a better way, by storage under argon; cf. doctoral thesis of P. Maisenbacher, see above. A stabilization with anti-oxidants such as bu ilhydroxytoluene (BHT) and butylhydroxyanisole
(BHA) was not achieved in these extracts. In addition, conventional anti-oxidants such as Oxynex LM and
Oxynex 2004 does not improve stability either. In the case of Hypericum oil, the best stability is achieved (according to the doctoral thesis of P.
Maisenbacher) by using octyldodecanol
(Eutanol G) as an extraction agent. On pages 154-155, Maisenbacher describes historical preparation methods. The raw herbal drug is extracted with hot vegetable oil, sometimes under the addition of turpentine oil. In this case, Maisenbacher also observed degradation, in
P1542 / 99MX particularly under the influence of water. On pages 158-166, Maisenbacher describes the conditions for an optimal preparation process. The following instructions are particularly revealing: the water must have been removed; Eutanol G should be used as extraction agent; conventional anti-oxidants now provide protection against oxidation. After an induction period of 3 weeks, a uniform degradation of the Hyperforins begins for the olive oil extract; cf. Fig. 7-10. Despite flooding with inert gas, complete degradation occurs after 3 months; cf. page 160. The oil prepared by the use of Eutanol G is stable for half a year at room temperature under argon. At 30 ° C slow degradation occurs; cf. p. 161. Hypericum extracts containing Hyperforin can be prepared with pharmaceutically conventional inorganic or organic solvents or mixtures thereof (P. List and P.C. Schmidt, Technologie pflanzlicher Arzneizubereitungen, issensch.Verlagsgesellschaft mbH, Stuttgart, 1984). The conventional aqueous ethanolic extracts of Hypericum and the finished pharmaceutical compositions prepared therefrom, usually contain less than about 1% of
P1542 / 99MX Hyperforin (on the basis of the extract). After storage the value obviously decreases and moves towards zero depending on the individual storage conditions. One assumes that the oxidation processes are responsible for the degradation of hyperforin in the raw herbal drug and in the extract. The technical problem of the present invention is to provide stabilized extracts of Hypericum perforatum L. (St. John Plant) containing Hiperforin in which Hyperforin remains stable. A further technical problem of the invention is to provide a process for the preparation of these stabilized extracts, as well as to provide the pharmaceutical compositions containing these stabilized extracts in which the content of Hyperforin also remains stable. According to the present invention, these technical problems are solved by extracts according to claims 1 to 8, by the process according to claims 9 to 21 as well as by the pharmaceutical compositions according to claim 22. The present invention is based, among other things, on the unexpected result that a Hypericum extract with certain anti-oxidant and / or oxygen binding stabilizers and agents
P1542 / 99MX í
reducers, which "are capable of degrading oxidants such as radicals, peroxides, atmospheric oxygen, etc. in the extract and / or to inhibit the degradation of Hyperforin and, optionally, carry out the extraction under inert gas such as nitrogen and / or the exclusion of light and / or with a solvent with a highly reduced oxygen content, is essentially stable longer than an extract of untreated Hypericum. This extract may be derived, contrary to the observations made by T. Berghófer and J. Hólzl (see above), from a raw herbal drug, dried and stored. A solvent with a highly reduced oxygen content can be prepared by physical treatment such as flooding with an inert gas such as nitrogen. In case the Hypericum extract is preserved or stabilized according to the present invention, in particular by the addition of an anti-oxidant and preferably by the exclusion of light and atmospheric oxygen, then the hyperforin in this extract remains essentially stable. Protection against light and atmospheric oxygen can also be achieved by a corresponding pharmaceutical formulation. In a preferred embodiment, of the process of the present invention for the preparation of the stabilized extracts, the fresh drug or
P1542 / 99MX preferably dried from-- "the St. John's plant is extracted with aqueous ethanol, and the oxygen content is highly reduced by physical treatment." To the extract solution an anti-oxidant agent is added as a stabilizer and it dissolves therein due to possibly present oxidants Additional examples of preferred solvents for the St John plant extraction comprise aqueous methanol, alkanes with low boiling points having about 5 to 8 carbon atoms such as pentanes, hexanes and heptanes, in particular n-heptane, and liquid or supercritical carbon dioxide The term "methanol or aqueous ethanol" denotes methanol or ethanol having a water content of preferably up to about 40% by volume. Preferred anti-oxidants or anti-oxidants are pharmacologically acceptable substances, capable of inhibiting the degradation of Hyperforin and / or and reduce the oxidants in the extract or the pharmaceutical composition. Particular examples are organic thiol compounds, such as cysteine and glutathione, as well as ascorbic acid and derivatives thereof, such as fatty acid esters of ascorbic acid, such as myristate, palmitate and stearate. Anti-oxidant stabilizers are added
P1542 / 99MX to the preparation of Hypericum extract in an amount sufficient to stabilize Hyperforin. In general, concentrations of 0.01 to 5% anti-oxidant stabilizer based on Hypericum extract are sufficient. In a further embodiment the procedure will be as described above, but the addition of the stabilizer is carried out in the stage after drying the extract solution, ie, after removing the solvent. In a further preferred embodiment of the invention, the anti-oxidant stabilizer is added in the step of the finished pharmaceutical together with other pharmaceutical additives. Preferably, all modalities are carried out under the exclusion of light and oxygen. The obtained extracts can be processed together with conventional pharmaceutical additives, optionally after adding again a stabilizer to the pharmaceutical compositions, such as capsules, tablets and coated tablets. Pharmaceutical additives are fillers, binders, disintegrants, lubricants and coating agents for film tablets and coated tablets, as well as oils and fats as fillers for soft gelatine capsules. The present invention is explained by
P1542 / 99MX of the following examples. Percentages are given as hundreds by weight if not stated otherwise. The nitrogen was used as or an inert gas (protective gas). It should be noted that other inert gases such as argon or krypton can also be used.
EXAMPLE 1 (Comparison Example) 1 kg of crude herbal drug from St. John in a mill and 7 kg of ethanol added to 70 (v / v)%. The suspension of 1 kg of crude herbal drug and 7 kg of solvent was stirred vigorously at 55 ° C for one hour under inert gas. Then, the resulting extract was separated from the crude herbal drug by means of centrifugation. The drug residue was extracted according to the above for a second time with 7 kg of solvent. The two extract solutions were combined and the dry residue in the extract was determined with an aliquot. The extract was concentrated little by little under reduced pressure to a dry residue content of 72% and dried again at 40 ° C under reduced pressure. A dry extract of 0.44 kg was obtained. The content of Hyperforin was 0.37%.
Example 2 Finely crushed in a mill, 8 kg of raw herbal drug from St. John and he
P1542 / 99MX added 56 kg of ethanol to 70 (v / v)%. The oxygen content of the solvent used was reduced earlier by means of rinsing with inert gas. The suspension of 8 kg of crude herbal drug and 56 kg of solvent was stirred vigorously under inert gas at 55 ° C for one hour. So, the extract obtained was separated from the drug by means of centrifugation while rinsing with nitrogen as an inert gas. The drug residue was extracted once again in the same manner. The two extract solutions were combined and 0.1% ascorbic acid was added. The solution was stirred vigorously for 10 minutes under nitrogen as an inert gas and then concentrated little by little under reduced pressure to a dry residue content of 70% and dried again at 40 ° C under reduced pressure. 2.52 kg of stabilized dry extract with a Hyperforin content of 0.9% were obtained.
Example 3 A 40.0 g dry from the St. John, finely ground, was added 3.2 kg of n-heptane. 12 mg of ascorbic acid palmitate was added and the mixture was then extracted for one hour by permanent stirring at 50 ° C under the exclusion of light. Then, the mixture was sucked through a Seitz Supra 1500 filter and the drug residue was extracted a second time from it.
P1542 / 99MX way. The combined extract solutions were concentrated by means of a rotary evaporator at 35 ° C under exclusion of light to a dry residue content of about 70% and then lyophilized. 9.21 g of dry extract with a Hiperforin content of 1.7% were obtained.
Example 4 A 470 dry g of the St. John, finely ground, 15 mg of ascorbic acid palmitate was added and then the mixture was placed in a high pressure extraction unit and extracted under 200 bar at 35 ° C. Approximately 7.5 kg of carbon dioxide was used. After extraction, the pressure was reduced to 60 bar in order to separate the extract. The extract was separated from the unit and mixed with 10 mg of ascorbic acid palmitate. 12.2 g of dry extract with a content of Hiperforina of 1.9% were obtained.
In the mill, 2.4 kg of raw herbal drug from the St. John and 16 kg of methanol were added to 80 (v / v)%, which were rinsed before with nitrogen. This mixture was then stirred for one hour at 55 ° C. The extract solution obtained was separated from the drug residue
P1542 / 99MX by means of centrifugation. The drug residue was extracted according to the above for a second time. The two extract solutions were combined and 1.0 wt.% Ascorbic acid was added. This solution was stirred for 15 minutes. Then, the extract solution was concentrated little by little to a dry residue content of 70% and then dried again at 40 ° C under reduced pressure. 0.5 kg of stabilized dry extract with a Hyperforin content of 0.7% was obtained. The content of total Hypericin in this extract was 0.46%.
Example 6 Verification of the stability of Hyperforin. In this example the content of H-iperforin of an extract according to Example 1, without particular precautionary measures and additions during the preparation, was compared with extracts prepared according to Examples 2 to 5 of this invention. The extracts prepared according to the present invention were stored under nitrogen and the exclusion of light at room temperature. The results are summarized in Table I. The result shows a substantially unchanged Hiperforin content of the extracts prepared according to the present invention after 6 months.
P1542 / 99MX Table I Dry extract Hyperforin Content of Hyperforin%
Example Content After 13 After 6 initial% weeks months
Example 1 0.37 0.0 0.0
Example 2 0.9 0.9 0.88
Example 3 1.7 1.7 1.68
Example 4 1.9 1.9 1.89
Example 5 0.7 0.7 0.63
Example 7 Soft gelatin capsules with an extract of Hypericum. -Composition: 300 mg dry extract Hypericum ascorbic acid 0.25 mg octyldodecanol 200 mg
Preparation; The dry extract and the ascorbic acid were dispersed together in octyldodecanol and processed under the exclusion of atmospheric oxygen for soft gelatin capsules.
Example 8 Tablet with a film with extract of
Hypericum.
P1542 / 99MX -Composition: dry extract of Hypericum 300 mg cellulose 100 mg modified starch 90 mg Na-carboxymethylcellulose 30 mg highly disperse silicon dioxide 5.0 mg ascorbic acid 5.0 mg magnesium stearate 5.0 mg hydroxypropyl methylcellulose coating 20- m-?
Preparation: The components were mixed in dry condition in a mixer and pressed directly into tablets. The obtained tablets were covered with a coating of hydroxypropylmethylcellulose.
TO,
P1542 / 99MX
Claims (22)
- NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. Stable extract of Hypericum perforatum L. (plant of St. John) with a Hyperforin content of about 0.1% to 2%, characterized in that Hyperforin is stabilized against decomposition or degradation by means of a stabilizer selected from the group consisting of anti-oxidant and oxygen binding stabilizers and reducing agents.
- 2. The stable extract according to claim 1, characterized by a content of a stabilizer selected from the group ~ of thiol organic compounds, ascorbic acid and derivatives thereof in an amount sufficient to stabilize Hyperforin.
- 3. The stable extract according to claim 1 or 2, characterized in that the stabilizer is present in a concentration of 0.01% to 5% based on the extract.
- 4. The stable extract according to claim 1 or 2, characterized in that the stabilizer is present in a concentration of 0.2% to 1% based on the extract.
- 5. The stable extract according to any of P1542 / 99MX claims 1 to 4, characterized in that the stabilizer is cysteine.
- 6. The stable extract according to any of claims 1 to 4, characterized in that the stabilizer is glutathione.
- 7. The stable extract according to any of claims 1 to 4, characterized in that the stabilizer is ascorbic acid.
- 8. The stable extract according to any of claims 1 to 4, characterized in that the stabilizer is a fatty acid ester of ascorbic acid.
- 9. The process for the preparation of a stable extract of Hypericum perforatum L. (St. John plant) containing approximately 0.1% to 2% Hiperforin, wherein a crude herbal drug from the St. John is extracted with conventional inorganic or organic pharmaceutical solvents or mixtures thereof, with the proviso that the solvents are not oily extraction agents and where a stabilizer selected from the group of organic compounds is added which consists of: thiol, ascorbic acid and derivatives thereof, optionally during or after the preparation of the extract, in an amount sufficient to stabilize Hyperforin and wherein a dry extract is obtained from the liquid extract as well P1542 / 99MX obtained.
- 10. The process according to claim 9, characterized in that a fresh herbal drug from St. John 11. The process according to claim 9, characterized in that a dried herbal drug from St. John The process according to any of claims 9 to 11, characterized in that the cysteine is used as a stabilizer. 13. The process according to any of claims 9 to 11, characterized in that glutathione is used as a stabilizer. The process according to any of claims 9 to 11, characterized in that the ascorbic acid is used as a stabilizer. 15. The process according to any of claims 9 to 11, characterized in that a fatty acid ester of ascorbic acid is used as a stabilizer. 16. The process according to any of claims 9 to 15, characterized in that the stabilizer is added in a concentration of 0.01% to 5%, preferably 0.2% to 1%, based on the extract. 17. The process according to any of claims 9 to 16, characterized in that the oxygen content of the extraction solvent is P1542 / 99MX low or was considerably reduced. The process according to any of claims 9 to 17, characterized in that a solvent for extraction is used, selected from the group consisting of: ethanol, n-heptane, aqueous methanol and liquid or supercritical carbon dioxide. 19. The process according to any of claims 9 to 18, characterized in that the stabilizer is added after drying the solvent of the extract solution. The process according to any of claims 9 to 19, characterized in that the stabilizer is added in the step of the finished pharmaceutical composition together with conventional pharmaceutical additives. 21. The process according to any of claims 9 to 20, characterized in that the process is carried out under the exclusion of light and / or oxygen. 22. The pharmaceutical composition containing an extract according to any of claims 1 to 8 and conventional pharmaceutical additives for the treatment of depressions and psycho-vegetative alterations. P1542 / 99MX
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19714450.0 | 1997-04-08 |
Publications (1)
Publication Number | Publication Date |
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MXPA99009261A true MXPA99009261A (en) | 2000-07-01 |
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