Medication for treatment of viral disease based on active agents of plant hypericum (St. John's Wort) and method of production of the medication

A medication for treatment of disease caused by virus, and particularly retrovirus, and a method of production of the medication are based on use of the active agents, polycyclic diones (hypericin, pseudohypericin and/or salts thereof), of the plant Hypericum (St. John's Wort) with other components occurring in the plant wherein the concentration of polycyclic diones is between 0.05% and 50% whereby a therapeutic antiretroviral effect is attained while undesirable side effects are largely avoided.

The invention relates to a medication for treatment of a disease caused by
 a virus, particularly a retrovirus, based on the active agents of the
 plant Hypericum (St. John's Wort) and to a method of production of the
 medication.
 BACKGROUND OF THE INVENTION
 The plant St. John's Wort as well as its applicability as a pharmaceutical
 were already known to people of antiquity. Most of the approximately 370
 species of this plant worldwide comprise the red pigment hypericin, a
 naphthodianthrone derivative having a molecular weight of 504.43 and the
 empirical formula C.sub.30 H.sub.16 O.sub.8. In addition to hypericin, a
 number of structural analogs was identified which have been described in
 the literature as pseudohypericin, protohypericin, protopseudohypericin,
 cyclopseudohypericin, isohypericin, Kielcortin etc., so-called polycyclic
 diones. Other components of the plant are, for example, the flavonoid
 quertecine as well as other bioflavonoids and flavonoid glycosides,
 vegetable acids such as chlorogenic and coffeic acid, hyperforin--a
 phloroglucine derivative--tanning agents, flower pigments as well as
 cyanidin chloride and xantophyll, anthraquinone, xanthone derivatives,
 distilled oils such as terpineol, resin-like substances, fats and waxes.
 It has recently been found that polycyclic diones (hypericin,
 pseudohypericin and/or salts thereof) in highly pure form have antiviral
 efficacy. In particular, an inhibiting effect on retrovirus can be
 observed in vitro (cf. EP 0 332 697 B1); this applies also with respect to
 the human immunodeficiency virus (HIV) which in humans causes the acquired
 immune deficiency syndrome (AIDS). Hypericin or pseudohypericin were
 herein used in highly pure form. In order to obtain this form, the extract
 from the plant Hypericum was treated until nearly pure
 hypericin/pseudohypericin was obtained. Alternatively, highly pure
 hypericin was produced synthetically. The medications suggested in this
 connection comprised nearly pure hypericin/pseudohypericin (or
 pharmaceutically efficacious salts thereof) as the sole active agent, and,
 in addition, pharmacologically known solvents and carrier substances
 suitable in known manner for various forms of administration and dosages.
 It has also been suggested to combine for the treatment of diseases caused
 by retrovirus the administration of hypericin/pseudohypericin with the
 administration of nucleoside analogs WO 89/09056. However, herein also
 nearly pure hypericin/pseudohypericin was used.
 However, animal experiments have shown that when using highly pure
 hypericin/pseudohypericin, strong side effects in the form of
 hyperphotosensitization can occur. Due to this effect, the therapeutic
 application of preparations with highly pure hypericin/pseudohypericin
 must be ruled out. Therefore, this approach has not been pursued further
 and no Hypericum preparations for antiviral application have been
 introduced on the market.
 In addition, in the field of medicine, Hypericum preparations have long
 been used based on extracts of the plant for various indications in the
 psychogenic area such as depressions in the absence of endogenous forms,
 sleep disorders and psychogenically caused other disorders such as bed
 wetting. An oily preparation from the plant (oleum hypericin) for external
 application in the treatment of wounds and pain is additionally known. The
 internal application of oleum hypericin has been recommended in the case
 of dyspeptic complaints.
 The currently valid monograph by the Kommission E of the Bundesamt fur
 Arzneimittel und Medizinprodukte (Federal Board for Pharmaceutical Drugs
 and Medical Products) lists as fields of application psychovegetative
 disorders, depressive states, anxiety and/or nervous agitation. All
 currently known Hypericum-containing pharmaceutical drugs concern this
 range of indications of psychogenic disorders and sleep disorders.
 The known Hypericum-containing pharmaceutical drugs are based on the
 extract from the plant with a content of polycyclic diones (hypericin,
 pseudohypericin and/or salts thereof) of less than 1%. The listed active
 agents are thus not present in a pure state. The use of such preparations
 for the indications in viral illnesses is not known.
 This range of indications had previously only been suggested for highly
 pure hypericin/pseudohypericin preparations but which, due to the above
 cited side effects, cannot be used therapeutically.
 SUMMARY OF THE INVENTION
 It is therefore the task of the invention to make therapeutically usable
 the antiviral, in particular antiretroviral, effect of polycyclic diones
 (hypericin, pseudohypericin and/or salts thereof) while largely avoiding
 the described side effects.
 The invention rests on the surprising finding that the inhibition of
 retrovirus known for highly pure hypericin/pseudohypericin can also be
 attained with hypericin/pseudohypericin in lower concentrations provided
 sufficient dosages of hypericin/pseudohypericin are being administered.
 For this purpose, the active agents (hypericin, pseudohypericin and/or
 salts thereof) are mixed with other substances known to be components of
 the plant Hypericum or extracts are used which comprise the active agent
 (hypericin, pseudohypericin and/or salts thereof) in similarly low or
 slightly more concentrated form than in the preparations known for the
 treatment of psychogenic disorders and sleep disorders, thus in
 concentrations from between 0.05% and 50% of polycyclic diones, however
 these extracts do not {comprise the active agent} in highly pure form.
 Surprisingly, herein the side effects known in connection with highly pure
 hypericin/pseudohypericin do not occur and specifically also in dosages
 which exceed by a multiple the dosages which had previously been used for
 Hypericum extract preparations for other indications (psychogenic
 disorders, sleep disorders). The extract obtained from the plant, with
 concentrations of polycyclic diones between 0.05% and 50% while retaining
 other substances comprised in the plant in concentration between 50% and
 99.95% can consequently be used therapeutically for the treatment of viral
 diseases.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT
 In a preferred embodiment the production of the dry extracts from the plant
 Hypericum perforatum Linne takes place according to the rules or the
 Deutsche Arzneibuch (German Pharmacopeia) (DAB) using ethanol 60% V/V. The
 dried and cut pharmaceutical is mixed with ethanol at a ratio of 1:4
 (pharmaceutical to extraction agent) and allowed to stand for at least 14
 days while stirring or shaking the mixture occasionally. Subsequently the
 supernatant is decanted and the residue pressed off.
 Concentration of the polycyclic diones (hypericin and related substances)
 is achieved through the separation of high-molecular extract components by
 means of preparative gel chromatography (molecular sieves). Used are gels
 of the type Sephadex.RTM. G200.
 From the liquid extract obtained according to the above process ethanol,
 water and volatile components are carefully removed in vacuo and
 specifically until a viscous brownish liquid forms. This is placed onto a
 preparative chromatography column and, in the course of the chromatography
 process, is separated into fractions of increasing molecular weight. The
 substances with the highest molecular weight appear last at the end of the
 column and are discarded.
 By optimizing the elution conditions at the column in connection with
 continuous determination of the content, through the above described
 fractionation--by suitably selecting the desired fractions and discarding
 undesirable fractions--the content of the subsequent extracts of
 hypericin/pseudohypericin is determined with high accuracy to 1% g/g.
 The desired fractions are collected and carefully dried in vacuo. The
 brownish powder obtained in the process with a content of
 hypericin/pseudohypericin of 1% g/g is used directly for the production of
 solid oral preparations.
 A pharmaceutically acceptable carrier or a pharmaceutically acceptable
 dilution agent can be combined with the medication for facilitating its
 administration. The medication can be administered parenterally, in a
 solid form which can be administered rectally, in particular as a
 suppository, or in a solid form which can be administered orally, in
 particular a tablet, a coated tablet or a capsule, with or without a
 coating resistant to gastric juices.
 In a further preferred embodiment, the solid form for oral administration
 is provided with a coating resistant to gastric juices. The resorption
 occurring thereby in the duodenum permits reducing the dose.
 The medication can have a content of polycyclic diones (in particular
 hypericin) with a range of from 1 mg to 20 mg per parenteral dose, tablet,
 coated tablet, capsule or suppository, respectively.
 Oral preparations such as for example capsules or tablets with dosages of
 the above described extract correspond to a quantity of 2 mg per dose,
 administered in daily doses of 6 mg and more over a relatively long period
 of time (at least 6 months) have the capability of bringing retrovirus in
 the serum below the minimum level of detection.
 Consequently, the outbreak of diseases caused by retrovirus, such as for
 example AIDS, can be prevented.