WO1998003188A1 - Medicaments containing plant extracts - Google Patents

Abstract

The invention concerns solid active substance preparations containing as active substances plant extracts, with the exception of extracts of Gingko biloba, Glycyrrhiza glabra and Eucalyptus globulus. The preparations are obtained by extruding a mixture of at least one plant extract and at least one meltable polymer and subsequent shaping.

Description

 Pharmaceutical forms containing plant extract

description

The present invention relates to solid active substance preparations comprising, as active substances, plant extracts, with the exception of extracts of gingko biloba, Glycyrrhiza glabra and Eucalyptus globulus, which can be obtained by extrusion of a mixture of at least one plant extract and at least one meltable polymer and subsequent shaping. The invention further relates to a method for producing such dosage forms. It is known to produce pharmaceutical forms by extrusion of polymer melts containing active ingredients and subsequent shaping.

For example, DE-A 12 29 248 describes the extrusion of polymer melts containing active ingredients, followed by shaping by injection molding.

EP-A 240 904 describes the extrusion of active substance-containing melts of homopolymers or copolymers of N-vinylpyrrolidone.

EP-A 240 906 discloses the continuous production of solid dosage forms by extrusion of polymer melts containing active ingredients, followed by shaping the still thermoplastic strand by calendering.

However, the known methods relate exclusively to the processing of chemically clearly defined monosubstances, but not to the processing of plant extracts.

Plant extracts in the sense of this invention are understood to mean the solvent-containing or dry extracts obtained by means of recognized pharmaceutical methods with the aid of water, organic solvents and supercritical gases.

Extracts in the sense of this invention are also understood to mean shredded plant material which has not been treated further. Plant extracts differ from defined chemical active substances in that the total extract of a plant is a multi-substance system that is predetermined by nature and consists of active substances, secondary substances, ballast substances and builders. Often _s i the therapeutic effect another, possibly a more favorable if not only an isolated drug acts on the organism, but the main and secondary materials a t Plant extracts act together. (Voigt, Textbook of Pharm. Technology, 440, (1987)).

From DE-C 44 34 170 orally applicable St. John's wort extracts are known, the extracts being bound to polyvinylpyrrolidone.

Plant extracts also often contain enzymes, which affects the storage stability of the medicinal products. This applies in particular to those enzymes which lead to the partial or total inactivation of pharmacologically active compounds. In contrast to conventional methods, melt extrusion as a thermal process with a possible water removal (evacuation) should also have a stabilizing effect on such formulations, since enzymes as mostly high molecular weight proteins can often be irreversibly damaged by temperatures above 60 ° C (Voigt, textbook of pharm Technologie, 442f (1987)), can also be inactivated by dehydration (vacuum mode on the extruder).

It was an object of the present invention to find plant extract-containing preparations which have good storage stability, allow targeted release of active substances and can be prepared in a simple manner.

Accordingly, the preparations defined at the outset and a process for their preparation have been found.

According to the invention, both bitter-containing drugs, flavonoid drugs, coumarin drugs, tannin drugs, carbohydrate drugs, lipid-containing drugs, cardiac glycoside drugs, saponin drugs, anthrone and anthraquinone drugs, alkaloid drugs, arbutin drugs, essential oil Drugs and numerous other unclassifiable drugs are used. Flavonoid drugs, coumarin drugs, tannin drugs, carbohydrate drugs, lipid-containing drugs, cardiac glycoside drugs, saponin drugs, anthrone and anthraquinone drugs, alkaloid drugs, arbutin drugs are preferred. However, cardiac glycoside drugs, anthrone and anthraquinone drugs, alkaloid drugs and arbutin drugs can be used with particular preference.

The method according to the invention is suitable, for example, for processing extracts from the following plants, extracts from Gingko biloba, Glycyrrhiza glabra, and Eucalyptus globulus being excluded: Extracts from plants containing ethereal oils, such as: Mentha piperita, Melissa officinalis, Orthosiphon aristatus, Salvia officinalis, Lavandula angustifolia, Elettaria cardamomum, Thyus vulgaris, Rosmarinus officinalis, Citrus aurantium, i Juniperus communis, Matricaria recutita, Achilleaaumumumiumin, Achilleaaumumumumin , Cinna omu verum, Coriandrum sativum, Carum carvi, Pimpinella anisum, Foeniculum vulgäre, Petroselini crispum, Apiu graveolens, Valeriana officinalis.

Extracts from plants containing sharp substances such as:

Zingiber officinale, Curcuma xanthorrhiza, Curcuma longa, Acorus cal us, Capsicum annuum, Piper nigrum, Brassica nigra, Allium sativum, Allium cepa.

Extracts from plants containing bitter substances such as: Gentiana lutea, Artemisia absinthium, Cnicus benedictus, Centaurium erythraea, Marsdenia condurango, Humulus lupulus.

Extracts from plants containing cardiac glycosides such as:

Digitalis lanata, Digitalis purpurea, Strophantus gratus, Strophantus kobe, Convallaria ajalis, Adonis vernalis, Nerium Oleander, Urginea maritima, Helleborus niger, Xysmalobium undulatum.

Extracts from saponin-containing plants such as:

Primula veris, Saponaria officinalis, Aesculus hippocastanum, Panax ginseng, Hedera helix, Eleutherococcus senticosus, Herniaria glabra.

Extracts from alkaloid-containing plants such as: Papaver somniferum, Chelidoniu majus, Fumaria officinalis, Hydrastis canadensis, Berberis vulgaris, Atropa belladonna, Hyoscyamus niger, Datura stramonium, Mandragora officinarum, Nicotiana tabacum, Claviceaelis cephalecis aconacis, cephalic acacenus, cephalic acacenus, cephalic acacenus, cephalic acupuncture, cephalic acupuncture, cephalic acupuncture, cephalic acupuncture acupuncture acupuncture acupuncture acupuncture acupuncture acupuncture acupuncture acupuncture, Rauwolfia serpentina, Pausinystalia yohimbe, Vinca minor, Catharanthus roseus, Strychnos toxifera, Chondodendron tomentosum, Coffea arabica, Camellia sinensis, Theobroma cacao, Cola nitida, Hex paraguariensis, Paullinia cupana, Symphytedra distinya, Ephytum officinachya

Catha edulis, Areca catechu, Physostigma venenosum, Pilocarpus jaborandi, Lobelia inflata, Sarothamnus scoparius, Peumus boldus, Colchicum autumnale, Aconitum napellus, Myristica fragrans, Piper methysticum. Extracts from plants containing anhraquinone such as:

Rheu palmatum, Rhamnus frangula, Rhamnus purshianus, Rhamnus catharticus, Aloe ferox, Aloe barbadensis, Cassia angustifolia.

Extracts from arbutin-containing plants such as: Arctostaphylos uva-ursi.

Extracts from flavonoid-containing plants such as: Crataegus onogyna, Arnica ontana, Tilia cordata, Sambucus nigra, Silybum marianum, Verbascum phlomoides, Viola tricolor, Ononis spinosa, Equisetum arvense, Betula pendula, Fagopyrum esculentis, Filendendula ulia, Filendula officia

Extracts from plants containing coumarin such as: Ammi visnaga, Angelica archangelica, Levisticu officinale, Melilotus officinale, Herniara glabra.

Extracts from plants containing tannins such as:

Juglans regia, Solidago virgaurea, Prunus spinosa, Ammi visnaga, Hamamelis virginiana, Quercus robur, Krameria triandra, Potentilla erecta, Vaccinium myrtillus.

Extracts from plants containing carbohydrates such as: Cetraria islandica, Althaea officinalis, Plantago lanceolata, plantago psyllium, Malva sylvestris, Tussilago farfara, Linum usitatissimum, Trigonella foenum-graecum.

Extracts of other commercial herbal drugs such as: Avena sativa, Barosma betulina, Ci icifuga racemosa, Cynara scolymus, Drosera ramentacea, Euphrasia officinalis, Fucus vesiculosus, Gelsemiu se pervirens, Hibiscus sabdariffa, Hypericums perforatlora, P ^ , Rubia tinctörum, Sabal serrulata, Taraxacu officinale, ürtica dioica, iscum album, Vitex agnus castus, Echinacea angustifolia, Echinacea purpurea, Thuja occidentalis.

The amount of extract per dose unit and the concentration can vary within wide limits depending on the effectiveness and the rate of release. The extract content can be in the range from 0.1 to 95, preferably from 20 to 90, in particular 30 to 70% by weight. The combination of different extracts can also be used.

To carry out the method according to the invention, at least one plant extract with a meltable, physiologically compatible binder and, if appropriate, further customary galenical auxiliaries is used at a temperature in the range from 50 to 180 ° C, preferably 60 to 160 ° C, processed. The mixing of the active ingredient or the active ingredients with the polymeric binders and optionally galenical additives can be carried out before or after the melting of the polymeric binder by the methods customary in the art. Mixing is preferably carried out in the extruder, preferably a twin-screw extruder or a single-screw extruder with a mixing compartment.

When using solid plant extracts, the processing is carried out without solvents. When using moist plant materials or extract solutions, the solvents can be removed during the extrusion process with the help of a vacuum.

The glass transition temperature of the mixture should be below 180, preferably below 130 ° C. If necessary, it is replaced by customary pharmacologically acceptable plasticizing auxiliaries, such as long-chain alcohols, ethylene glycol, propylene glycol, trimethylol propane, triethylene glycol, butanediols, pentanols, hexanols, polyethylene glycols, silicones, aromatic carboxylic acid esters (eg dialkyl phthalates, trimellitic acid esters or benzoate thalate acid esters, benzoates) Dicarboxylic acid esters (eg dialkyl adipates, sebacic acid esters, azelaic acid esters, citric and tartaric acid esters) or fatty acid esters are reduced.

Extrudable mixtures are especially pharmaceutical

Mixtures with plant extracts which contain physiologically acceptable thermoplastic polymers (the glass transition temperature of the mixture being below the decomposition temperature of all mixture components), for example polyvinylpyrrolidone (PVP), or preferably copolymers of N-vinylpyrrolidone (NVP) and vinyl acetate. The K values (according to Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 and 74) of such polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, for PVP preferably 12 to 35, in particular 12 to 17, are furthermore copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate, polyvinyl alcohol, ethylene / vinyl acetate copolymers, polyhydroxyethyl methacrylate, cellulose esters such as cellulose acetate, cellulose acetate propionate, cellulose acetate phthalate ethyl acetate, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose acetate cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose ethyl cellulose, cellulose acetate cellulose, cellulose ethyl cellulose, cellulose or hydroxypropyl methyl cellulose acetate succinate, cellulose ethers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ethyl cellulose or sodium carboxymethyl cellulose, polyethylene glycol, polyethylene. The amounts of meltable polymers can range from 1 to 99.9% by weight, preferably 5 to 90% by weight, in particular 20 to 80% by weight.

Common pharmaceutical auxiliaries that can be used in the usual amounts are e.g. Extenders such as silicates or silica, stearic acid or their salts with e.g. Magnesium or calcium, methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, sugar alcohols, e.g. Maltitol, mannitol, sorbitol, xylitol, isomalt, polyvinyl alcohol, also wetting agents, preservatives, disintegrants, adsorbents, colorants, flavorings (see e.g. H. Sucker et al., Pharmaceutical Technology, Thieme Verlag, Stuttgart 1978).

The solid active ingredient-containing molds following extrusion can be produced, for example, by injection molding or by shaping the still thermoplastic strand in accordance with the process described in EP-A 240 906, by passing the strand between two counter-rotating rollers with opposing depressions in the roller jacket, the design of which determines the tablet shape.

Furthermore, pellets or granules can also be produced from the extrudate.

If desired, the preparations produced according to the invention can also be provided with a customary coating to improve the appearance and / or taste (dragee) or for the purpose of additionally delaying the release of active ingredient. The term solid form in the sense of the invention is not tied to a specific form or to oral use. Rather, it also includes suppositories ⁽ not melting at body temperature) for rectal use.

The preparations according to the invention are suitable for use in human medicine or veterinary medicine. They can also be used for other purposes that allow the use of herbal ingredients.

With the aid of the method according to the invention, solid active ingredient forms with good stability can be produced in a simple manner. Above all, the good meterability of the plant-based active substances is advantageous, particularly with regard to the incorporation of comminuted plant material which has not been treated further. In particular, according to the invention, so-called "solid solutions" of plant extracres can also be produced in a polymer. The presence of solid solutions can be determined by DSC measurement solutions. Such "solid solutions" have advantages in terms of bioavailability and stability.

It was not to be expected that plant extracts should be extruded as natural multi-substance systems to the same extent as defined active substances.

It is to be seen as particularly advantageous here that, surprisingly, relatively high amounts of extract can also be incorporated into solid pharmaceutical forms and therefore the sometimes very high therapeutically necessary extract amounts can be applied in relatively small pharmaceutical solid forms. This increases compliance for the patient (lower intake frequency, easier intake).

Examples

The mixtures mentioned in the examples below were processed in a twin-screw extruder ZSK30 from Werner & Pfleiderer at a throughput of 2 kg / hour. The still plastic extrudate was shaped as described in EP-A 240 906.

A powder extract of Hyperici herba with the following composition was used as the plant extract:

75% native extract from Herba Hyperici perforati DAC 86 3. Erg. 91 (ratio of drug to drug preparation = 4-8: 1), 25% inert components (5% silicon dioxide DAB 10, 20% glucose syrup), content: 0.23% dianthrone calculated as Hyperici (manufacturer: Finzelberg) .

example 1

A mixture of 90% by weight of a copolymer with a K value of 30 and 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate (Kollidon VA 64) and 10% by weight of Hyperici herba extract was mixed in a twin-screw extruder mixed and extruded and then calendered. Shot temperature: 40, 80, 125, 125, 130, 120 ° C. Nozzle: 122 ° C.

Example 2

A mixture of 60 wt -.% Of a copolymer having a K value 30 of 60 wt -.% N-vinylpyrrolidone and 40 wt -.% Vinyl acetate (Kollidon VA 64), 10 wt -.% Klucel ^® EF, from Hercules. (Hydroxy propyl cellulose) and 30% by weight extract from Hyperici herba were mixed and extruded in a twin-screw extruder and then calendered.

Shot temperature: 40, 80, 120, 122, 124, 120 ° C. Nozzle: 124 ° C.

Example 3

A mixture of 5 wt -.% Of an N-vinylpyrrolidone homopolymer (PVP, Kollidon ^® K30), 33 wt .-% Isomalt F (Palatinit ^®, Fa Südzucker.), 2 wt -.% Explotab ^® (disintegrant -Natriumstärkeglycolat, Mendell) and 60% by weight extract from Hyperici herba were mixed and extruded in a twin-screw extruder and then calendered into oblong tablets. Shot temperature: 48, 82, 88, 86, 86, 81 ° C. Nozzle: 81 ° C.

Claims

claims 1. Solid active substance preparations containing active substances as plant extracts, with the exception of extracts of gingko biloba, Glycyrrhiza glabra and Eucalyptus globulus, obtainable by extrusion of a mixture of at least one plant extract and at least one meltable polymer and subsequent shaping. 2. Preparations according to claim 1, containing as meltable polymers, copolymers of N-vinylpyrrolidone. 3. Preparations according to claim 2, containing, as meltable polymers, a copolymer of 60% by weight of N-vinylpyrrolidone and 40% by weight of vinyl acetate. Preparations according to Claim 1, containing, as meltable polymers, hydroxypropyl celluloses. Preparations according to claim 1 or 2, containing an extract of Hyperici herba as plant material. 6. Process for the preparation of solid active substance preparations according to one of claims 1 to 4, characterized in that a mixture of at least one plant extract and at least one meltable polymer is extruded and the extrudate is shaped into customary dosage forms.