EP2320867A2 - Préparations à base d'artemisia annua, leur conversion en micro- et nanoparticules et leur utilisation - Google Patents

Préparations à base d'artemisia annua, leur conversion en micro- et nanoparticules et leur utilisation

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Publication number
EP2320867A2
EP2320867A2 EP09781132A EP09781132A EP2320867A2 EP 2320867 A2 EP2320867 A2 EP 2320867A2 EP 09781132 A EP09781132 A EP 09781132A EP 09781132 A EP09781132 A EP 09781132A EP 2320867 A2 EP2320867 A2 EP 2320867A2
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EP
European Patent Office
Prior art keywords
nanoparticles
micro
artemisia annua
ganoderma
biomass
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09781132A
Other languages
German (de)
English (en)
Inventor
Wolf-Dieter Juelich
Hans-Peter Welzel
Ulrike Lindequist
Gerold Lukowski
Ottmar Geiger
Sabine Mundt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PATENTHANDEL PORTFOLIOFONDS I GMBH & CO. KG
Universitaet Greifswald
Original Assignee
HC Berlin Pharma Ag
Ernst Moritz Arndt Universitaet Greifswald
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Filing date
Publication date
Application filed by HC Berlin Pharma Ag, Ernst Moritz Arndt Universitaet Greifswald filed Critical HC Berlin Pharma Ag
Publication of EP2320867A2 publication Critical patent/EP2320867A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/074—Ganoderma
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/10—Animal feeding-stuffs obtained by microbiological or biochemical processes
    • A23K10/12—Animal feeding-stuffs obtained by microbiological or biochemical processes by fermentation of natural products, e.g. of vegetable material, animal waste material or biomass
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L31/00—Edible extracts or preparations of fungi; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00—Shaping or working of foodstuffs characterised by the products
    • A23P10/30—Encapsulation of particles, e.g. foodstuff additives
    • A23P10/35—Encapsulation of particles, e.g. foodstuff additives with oils, lipids, monoglycerides or diglycerides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/11—Encapsulated compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9706—Algae
    • A61K8/9722—Chlorophycota or Chlorophyta [green algae], e.g. Chlorella
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9728—Fungi, e.g. yeasts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns

Definitions

  • the subject of the invention are preparations of Artemisia annua and several processes for the production of micro and nanoparticles from the annual mugwort (Artemisia annua).
  • Artemisia annua ultrafine particles with improved properties can be obtained, which can be used as food and feed supplements, for use in cosmetics as well as for medical applications.
  • the annual mugwort (Artemisia annua) has been used for millennia as a medicinal plant.
  • the plant is native to Europe and Asia. It grows 2 to 3 m high and has fresh green, heavily divided leaves and tiny cream-colored flower heads. For medical purposes, the aerial parts of the plant are used.
  • the preparation and use of extracts from Artemisia and their use in the fields of nutrition, cosmetics and medicine is known from the literature (eg Applied Biochemistry and Biotechnology, 1990, VoI 24/25, pp 213-222).
  • the actual active ingredient is artemisinin (artemesin, cotexin), a secondary plant substance (sesquiterpene with peroxide group), which occurs in the leaves and flowers of annual mugwort (Artemisia annua). Like all phytochemicals, these are associated in the biomass with other similar substances, since the biochemical pathways are not single-tracked. Thus, 9 other peroxide-containing substances, which also act against the malaria pathogen, contained in the plants. Over 200 ingredients could be detected in the plant parts in total.
  • artemisinin discussed in the literature is closely related to the chemical structure.
  • the peroxide group contained in the molecule is unstable in the presence of high concentrations of iron ions and forms free radicals. Such high levels are found in red blood cells and also in malaria pathogens that accumulate iron. If artemisinin gets into erythrocytes, free radicals are formed and the parasite may be killed. There is also evidence that artemisinin derivatives inhibit certain enzymes. From the artemisinin or related plant substances, several semi-synthetic derivatives have been prepared, but all must contain the Peroxidgruppierung to the effectiveness.
  • From one hectare of plants can harvest one to two tons of leaves from which about two to three kilograms of artemisinin can be obtained. Extraction from vegetable raw materials is complicated by the fact that the artemisinin content of the plants is very low and has considerable fluctuations. It is usually between 0.1 and 0.4%, based on the dry weight. Ideally, one to two tons of leaves can be harvested from one hectare of plant material, from which approximately 2 to 3 kg of artemisinin can be obtained by extraction with nonpolar solvents such as hexane and subsequent treatment with petroleum ether. The result is an oily-yellow extract of the plant, which is refined to gel and then to white, crystalline powder containing artemisinin as a so-called Blutschizontozid.
  • cyanobacteria have remarkable biosynthetic potencies.
  • Haematococcus pluvialis is a single-celled green alga that can produce up to 5% of its biomass, the astaxanthin keto-carotenoid. Astaxanthin is a valuable cosmetic raw material as a natural antioxidant.
  • cyanobacteria are known to be highly productive producers of secondary metabolites with a variety of biological effects, the eukaryotic microalgae are known in particular as producers of primary substances such as fatty acids, pigments and the like. estimated.
  • the lipid content of fungi can vary from less than 1% up to 15-20% of the dry weight. On average, can be expected with about 2 to 8%.
  • Fungus fat contains all types of lipids such as free fatty acids (predominantly unsaturated fatty acids), mono-, di- and triglycerides, sterols (especially ergosterol), sterol esters and phospholipids (Chang, S. Miles, PG: The nutritional attributes and medicinal value of edible Mushrooms, Edible mushrooms and their cultivation, 27-40, CRC Press, BocaRaton (1989); Garcha, HS, Khanna, PK, Soni, GL: Nutritional importance of mushrooms. Mushroom Biology and Mushroom Products, Ed.
  • KR20030005127 a dietary supplement is described, which in addition to Hoving Dulis Thunb and Alnus rubra Hovenia dulcis contains as main ingredients an addition of 10% Artemisia capillaris.
  • Artemisia capillaris is described in CN1615927 among other things as an anti-hypertensive agent, the prior art is a mixture with various Chinese plants.
  • CN 1969679 describes the combined use of Artemisia capillaris and G. lucidum in the form of a tea.
  • JP2000143437 describes a cosmetic containing at least two of the following plant extracts: Veronica undulata Wall, Ottelia alismoides Pers., Artemisia apiacea Hance, Artemisia annua L., Andrographis paniculata Nees, Dichroa febrifuga Lour., Eclipta prostrata L., Dipsacus asper Wall, Dipsacus japonicus Miq., Boehmeria nivea Gaud., Polygonum aviculare L., Sterculia lychnophera Hance, Carpesium abrotanoides L. and Polyporus mylittae Cook.
  • a combination of sugar alcohols, such as xylitol or erythritol, and plant extracts, which may also contain, among others, Artemisia capillaries, is described in JP2001081008 for external application to the skin.
  • a dietary supplement containing an Artemisia capillaris Thunb. Extract is described in KR20050024920. This nutritional supplement is said to counteract skin aging.
  • Artemisia annua mainly used in combinations.
  • the health-promoting ingredients of the genus Ganoderma are often with extracts of Artemisia spec. combined.
  • the combination described in KR20020078314 contains, inter alia, 3% Artemisia capillaris Thunb. and 2% G. lucidum.
  • JP2006143711 a combination of extracts of plants and fungi is described, including the Artemisia argyi Levl. et Vant and G. lucidum.
  • the food described in KR20040032288 contains Artemisia capillaris Thunb in combination with brewer's yeast and G. lucidum.
  • KR20050001730 describes a dietary supplement with immunoactivating and antitumor activity, which i.a. G. lucidum (FR) Karst and Artemisia Messerschmidtiana Besser contains.
  • CN1351886 describes an agent of 20 components of Chinese medicine which i.a. G. lucidum and Artemisia capillaris and which is to be used in liver diseases. Also, CN 1092295 teaches the use of G. lucidum and Artemisia capillaris in a combination of many herbal extracts to combat various
  • JP2048517 describes a hair care composition, which i.a. Artemisia apiacea Hance and
  • G. lucidum contains.
  • Skin aging is the complex biological process of alteration of the skin associated with aging. While the intrinsic aging, ie the genetically controlled diminished reactivity of skin cells can not be influenced, extrinsic factors (environmental factors such as ultraviolet light, chemical light) can be influenced by extrinsic factors
  • the skin gets deep wrinkles and wrinkles, their dry surface tends to tears and pseudo colors, the epidermis is thinner. It is produced less fat, the skin loses its elasticity and is no longer so regenerative. Because UVA radiation penetrates deep into the skin, it produces singlet oxygen in the dermis. This causes the production of enzymes that damage the collagen fibers and thus reduce the firmness of the skin. At the same time, elastic fibers swell, resulting in loss of elasticity of the skin.
  • UV radiation A major cause of premature skin aging is UV radiation.
  • conventional sunscreens based on titanium dioxide (TiO 2 ) the reflection and adsorption by microfine particles of titanium dioxide or zinc oxide, which reflect the incident UV light, exploited to avoid erythema (sunburn). Act as inorganic UV filters. In modern preparations, the pigment particles are reduced to about 200 nanometers.
  • sunscreen products there are therefore a large number of substances which are intended to neutralize free radicals: vitamin E, vitamin C, glucosylrutin, follicular glucitol, ginkgo extract, thermal water, silymarin, superoxide dismutase, green tea extract, bacterial lysates, organic melanin, ferulic acid or carboxymethyl glucan.
  • vitamin E vitamin E
  • vitamin C glucosylrutin
  • follicular glucitol ginkgo extract
  • thermal water silymarin
  • superoxide dismutase green tea extract
  • bacterial lysates organic melanin
  • ferulic acid or carboxymethyl glucan it is questionable whether they also act as free-radical scavengers when applied topically.
  • a potent scavenger is the flavonoid glucosylrutin, which is applied in combination with vitamin E as a Pre Sun cream for the prevention of polymorphic light dermatosis days before staying in the sun (
  • vitamin E tocopherol
  • Pure vitamin E creams achieve a sun protection factor of about 3.
  • the peroral intake in the epidermis can not achieve sufficiently high tocopherol concentrations.
  • studies have shown that exposure to sunlight can reduce skin vitamin E levels by up to fifty percent (Thiele 1998). Therefore, a local application is required.
  • vitamin E penetrates well into the epidermis, where it is cleaved by esterases into free vitamin E. Due to its structure, it can be stored well in the cell wall and protects it from the attack of radicals. To characterize the quality of a sunscreen protection against sunburn in the future will no longer be in the foreground.
  • the SPF helps to prevent erythema when used properly, it does not provide guidance on how the consumer can avoid immunosuppression or irreparable nuclear damage. This requires new measurement criteria.
  • the photocatalytic reaction produces, inter alia, very reactive free OH radicals which have a strong antimicrobial action (A. Heller: Chemistry and Applications of Photocatalytic Oxidation of Thin Organic Films, Acc. Chem. Res., Vol 12 (1995) 503 / D. Bahnemann: Photocatalytic Detoxification of Polluted Waters.The Handbook of Environmental Chemistry, Springer Verlag 1999, Volume 2, Part L, 285-351. It becomes a very strong reduction under photocatalytic activation by UV light The initial germ content of E. faecium is 0.01%, that of S. aureus is 0.001% and that of E. coli is 0.00002%, and this strong biocidal activity is undesirable in skin applications.
  • Triterpenes isolated from Ganoderma concinna can induce apoptosis in HL-60 cells (Gonzalez AG, Leon F, Rivera A, Padron JI, Gonzalez-Plata J, Zuluaga JC et al., New Lanostanoids from the Fungus Ganoderma concinna J Nat Prod 2002; 65: 417-21).
  • Triterpenes, available from Ganoderma applanatum are effective against murine skin tumors (Chairul, Tokuyama T, Hayashi Y, Nishizawa M, Tokuda H, Chairul SM, Hayashi Y.
  • Applanoxidic acids A, B, C and D biologically active tetracyclic triterpenes from Ganoderma applanatum, Phytochemistry 1991; 30: 4105-9; Chairul, Chairul SM, Hayashi Y. Lanostanoid triterpenes from Ganoderma applanatum, Phytochemistry 1994; 35: 1305-8).
  • a derivative of illudin was effective in clinical studies (Murgo A, Cannon DJ, Blatner G, Cheson BD, Clinical Trials of MGI-114, Oncology 1999, 13: 233-8).
  • lentinan in addition to chemotherapy in patients with gastric cancer, colon cancer and other tumors has proved to be successful (Hazama S, Oka M, Yoshino S, Iizuka N, Wadamori K, Yamamoto et al., Clinical effects and immunological analysis of intraabdominal and intrapleural injection of lentinan for malignant ascites and pleural effusion of gastric carcinoma. Cancer & Chemotherapy 1995; 22: 1595-7).
  • staphylococci are the most common causes of catheter-associated sepsis, of which about 50% are fatal. In an organic film forming on the plastic surface, the staphylococci are partially protected from attack by antibiotics and very often develop multiple resistance.
  • Antiseptic-treated implants may e.g. in the gastrointestinal and genitourinary area (Brauers et al., Biocompatibility, Cell Adhesion and Degradation of Surface Modified Biodegradable Polymers designed for the Upper Unrinary Tract. Tech. Urol. (1998) 4, 214-220, Multanen et al. Bacterial adherence to ofloxacin-hides polyacetone-coated self-reinforced 1-lactide acid polymer uroological stents BJU Intern (2000), 900, 44-56; Schierholz, JM, H.-M. Wenchel, D. König, J. Beuth and G. Pulverer: The Importance of Slow-Release Antimicrobial Systems for the Prevention of Catheter-Associated Infections Hyg. Med. 23 (1998), 548-556.
  • An object to be solved by the invention was to provide from the biomass of Artemisia annua means that can be used after appropriate clinical testing for tumor treatment.
  • An additional object was to provide lipid-containing micro- and nanoparticles for the coating of instruments and / or implants.
  • An urgent object of the present invention was to find new applications for the remaining after separation of Arteminsin from Artemisia annua residues and to provide new formulations for it.
  • micro- and nanoparticles are obtained which can be used for very different tasks.
  • Micro- and nanoparticles characterized in that biomass of the plant Artemisia annua are used for their production, which contain all ingredients including artemisinin (sesquiterpene peroxides), on the one hand provide new means that are used after appropriate clinical examination for tumor treatment On the other hand, agents suitable for coating surfaces and their antimicrobial finish are also obtained.
  • artemisinin sesquiterpene peroxides
  • Artemisia annua contains radical scavenging agents.
  • Micro- and nanoparticles characterized in that biomass of the plant Artemisia annua are used for their production, whose content of artemisinin (sesquiterpene peroxides) has been removed before the conversion into micro- and nanoparticles, use these radical scavenging properties.
  • the microparticles and nanoparticles prepared by separating off the peroxide structures are therefore suitable for anti-aging preparations, skin care products and sun protection products.
  • the conversion into microparticles and nanoparticles required for the solution of the problem can be carried out optionally with the homogenization process, the solvent homogenization process or the solvent emulsion process.
  • the comminuted biomass of Artemisia annua or the residues after separation of the sesquiterpene peroxides are first heated. This fraction is suspended, dispersed or adsorbed in the fatty acids of other lipid-containing fungi or cyanobacteria) or of the entire lipid-containing biomass.
  • a surfactant-water mixture is produced.
  • one or more active ingredients solid or liquid
  • This surfactant-water mixture is heated to a temperature above the Melting temperature of the fatty acids heated.
  • the two phases are combined at the selected temperature.
  • a pre-suspension is produced with the aid of a stirrer (rotor-stator principle) or with the aid of ultrasound.
  • the pre-suspension is then homogenized using a high-pressure homogenizer, the number of homogenization cycles and the working pressure being chosen according to the desired particle size and stability of the preparation. Make sure that the production temperature is set again and again between the individual cycles.
  • the surfactant serves to stabilize the suspension.
  • the method is carried out in the same manner as described above, wherein the active ingredient is adsorbed on the lipid-containing organisms or dispersed with the addition of a small amount of water.
  • crushed biomass of Artemisia Annua or extraction residues after separation of the sesquiterpene peroxides and lipid-containing biomasses of a second species and optionally selected active ingredients preferably vitamin mixtures are suspended in a vaporizable organic solvent. Thereafter, this mixture is predispersed (stator-rotor principle or ultrasound), homogenized
  • This method is based on the preparation of an emulsion of water and a solution of Artemisia annua or the extraction residue of Artemisia annua after separation of the sesquiterpene peroxides in a suitable organic solvent.
  • an emulsifier for dispersing the biomass active ingredient is used. Emulsifier and
  • Biomass are dissolved in a suitable organic solvent.
  • an aqueous phase containing a water-soluble cosurfactant is added and mixed with the lipid-containing biomass of a second type. Thereafter, this mixture is vorisp ergiert (stator-rotor principle or ultrasound).
  • the organic solvent is removed by evaporation, wherein the active substance-containing biomass precipitates in the form of solid particles.
  • the biologically active ingredients from Artemisia annua or from the combination partner can, depending on the charge and size distribution of the ingredients and the production conditions in the solid matrix (nanopellet) and / or in the lipid inconveniencen shell (nanocapsule), enclosed in the shell, and / or distributed in the dissolved or highly dispersed state in the formulation and / or adsorbed or adhered to the edge zones of the nanopellets.
  • ingredients of both components are released in a controlled manner.
  • both artemisin-containing and artemisin-free biomasses with lipid-containing algae can preferably be combined with cyanobacteria having a lipid content of at least 10% and / or with the unicellular green alga Haematococcus pluvialis.
  • artemisin-containing biomasses are combined with microalgae, which additionally have a natural content of carbamidocyclophanes.
  • carbamidocyclophane-containing biomasses of cynanobacteria and the peroxide-containing structures of Artemisia annua exert a strong cytotoxic effect on tumor cells, but have different mechanisms of action, so that there is a synergistic effect.
  • microalgae the Carbamidocyclophane according to the formula image 1, characterized by a symmetrical carbon skeleton with carbamido structures in the side chain and by a different substitution pattern of the Carbamido Modellen opposite side chains, wherein Ri to R 7 is both halogen, hydroxyl, carbonyl - as well as alkyl groups may be included.
  • the carbamidocyclophanes according to formula 1 and preparations prepared therefrom inhibit the growth of various tumor cell lines (MCF-7 cells breast carcinoma, 5637 cells Bladder carcinoma) particularly strong.
  • the proportion of active compounds according to formula 1 or the sesquiterpene peroxides in the inventive preparations can be increased by adding the pure active ingredient.
  • the single-celled green alga Haematococcus pluvialis is used as a combination partner of Artemisia annua.
  • This green alga contains up to 5% of its biomass the astaxanthin ketocarotenoid. Due to the microencapsulation according to the invention, astaxanthin is protected and released in a controlled manner.
  • the radical scavenging properties of the microparticles and nanoparticles according to the invention prevent the premature aging of the skin caused by environmental factors such as UV light, chemical reagents, mechanical stress, stress, heat and cold.
  • both artemisin-containing and artemisin-free biomasses can be combined with lipid-containing fungi in the production of the microparticles and nanoparticles.
  • Particularly preferred are the species Ganoderma lucidum and / or Ganoderma pfeifferi and / or Ganoderma applanatum and / or Ganoderma concinna and / or Ganoderma tsugae and / or Auricularia auricula-judae and / or Grifola frondosa and / or Hericium erinaceus and / or Lentinula edodes and / or Pleurotus ostreatus and / or Pleurotus eryngii.
  • artemisin-containing biomasses or combinations of artemisin-containing biomasses and carbamidocyclophane-containing microalgae are combined with fungi, in particular of the genus Ganoderma, a synergistic effect occurs.
  • the biomass of the genus Ganoderma causes an induction of apoptosis and an immune stimulation in particular by the glucan content of the Ganoderma species.
  • Ingredients of Ganoderma species cause activation of phagocytosis by macrophages.
  • the efficacy may be enhanced when combinations with triterpenes from Ganoderma concinna and / or from Ganoderma applanatum and / or from Ganoderma lucidum, Ganoderma tsugae and / or from Ganoderma pfeifferi are used.
  • triterpenes from these five species of Ganoderma can be combined for this therapeutic use.
  • micro- and nanoparticles according to the invention may contain cytostatic agents, apoptosis-inducing agents and immune immunulants as combinations of two or three.
  • Ganoderma pfeifferi suitable as a combination partner for these applications.
  • FL cells human cells
  • microparticles and nanoparticles prepared from a combination of Artemisia annua and Ganoderma pfeifferi similarly strong stimulating effects on cell metabolism are achieved, even if Ganoderma pfeifferi is greatly reduced in concentration and the Artemisia annua component in the large excess is present.
  • the ingredients of G. pfeifferi reduce oxidative stress and enhance endogenous radical defense.
  • the ingredients ganomycin A and B which are only found in G. pfeifferi, inhibit luminol-induced and spontaneous oxygen radical release at a concentration of 10 ⁇ g / ml.
  • the increased cell permeability under UV influence - measurable by determining the LDH activity in the medium - is reduced.
  • the regeneration capacity of the cells after UV damage is significantly increased.
  • the micro- and nanoparticles also have the advantage of having pronounced radical scavenging properties, which is advantageous for many applications. From the micro- and nanoparticles, the radical-scavenging ingredients are released in a controlled manner by both Artemisia annua and G. pfeifferi.
  • Vitamins can be added both in the homogenization process, in the solvent homogenization process or in the solvent emulsion process during the production of the micro- and nanoparticles, whereby they are integrated into the micro- and nanoparticles.
  • vitamin E is used as the acetate.
  • the vitamins are released from the micro- and nanoparticles in a controlled manner to the skin. As an acetate, vitamin E penetrates well into the epidermis, where it is cleaved by esterases into free vitamin E. Due to its structure, it can be stored well in the cell wall and protects it from the attack of radicals.
  • micro- and nanoparticles for the coating of surfaces, for example of instruments and / or implants, has been achieved by producing micro- and nanoparticles from which the biomass of Artemisia annua is separated without separating the peroxides. This results in micro- and nanoparticles with strong antimicrobial activity. These particles can be used to reduce the adhesion of proteins, cells and germs.
  • PCT / EP2008 / 056730 of 31.05.2008 unpublished at the time of application becomes Process for coating surfaces with micro- and nanoparticles by means of plasma method described, which can be used to prevent adhesion by germs.
  • the micro- and nanoparticles according to the invention can be used for an extension of this method.
  • Example 1 Fatty acid composition of the microalgae suitable for the preparation of micro- and nanoparticles from a combination of Artemisia annua with marine organisms
  • Table 1 shows the fluctuation range of the contents found in this case.
  • the tetradecanoic acid and the tetradecenoic acid are found at a constant high content. Also strikingly high is the content of either n-hexadec-cis-9-enoic acid or 11-hexadecenoic acid. Eight other fatty acids are found, each with a low content, usually ⁇ 1%.
  • n-Hexadecanoic acid was detected at a level between 10 and 14% and n-octadeca-cis-9, cis 12, ice 15-trienoic acid at a level between 20 and 30% in all strains. Also dominant was the octadecadienoic acid, the position of the double bond in the individual strains varied.
  • n-hexadecanoic acid which was detected between 26 and 72%, dominates, while the corresponding undersaturated acid was found only in a small proportion.
  • Combination partners of different orders with sufficiently high lipid content are available.
  • the properties of the micro- and nanoparticles can be varied by selecting the appropriate lipids for each application.
  • FIG. 1 shows the qualitative DPPH test of the Artemsia annua / Ganoderma pfeifferi microparticles (left) in comparison to ascorbic acid (right).
  • Micro- and nanoparticles made from G. pfeifferi, strongly stimulate the metabolism of human cells (FL cells).
  • FL cells human cells
  • a combination of Artemisia annua and Ganoderma pfeifferi, produced according to the invention by conversion into micro- and nanoparticles using the species-specific lipids of G. pfeifferi these effects could be achieved, even if Ganoderma pfeifferi is greatly reduced in its concentration and Artemisia ⁇ nnw ⁇ Component is present in large excess.
  • the cytotoxicity of the carbamidocyclophanes and of the carbamidocyclophan-containing combinations is carried out on in vitro cultured MCF-7 cells, 5637 cells and on Fl cells in 96-well microtiter plates.
  • the MCF-7 cells and the 5637 cells are pre-cultured for 48 h in IMDM (Invitrogen) with 10% fetal bovine serum or the Fl cells in Eagle-MEM + 8% fetal bovine serum (37 ° C, 5% CO2).
  • the inhibition of cell proliferation is calculated from the optical density measured in the batches incubated with the carbamidocyclophanes or the carbamidocyclophan-containing extracts of the aquatic organisms in comparison to the cell control (cells incubated with medium only) and for the isolated carbamidocyclophanes the IC50 values are calculated.
  • the isolated carbamidocyclophanes have IC50 values between 0.7 ⁇ g / mL and 1.7 ⁇ g / mL, for the Fl cells, which are to be regarded as non-transformed cells, IC50 values between 2.5 ⁇ g / mL, 3.1 ⁇ g / mL and 3.5 ⁇ g / mL. With microparticles and nanoparticles containing combinations of sesquiterpene peroxides and carbamidocyclophanes, IC50 values of less than 0.3 ⁇ g / ml are determined.
  • the biomass are combined and heated to a temperature of 80 0 C.
  • an aqueous emulsifier solution is heated to the appropriate temperature (80 0 C).
  • both phases are combined and processed using an Ultra Turrax T25 Fa. Janke and Kunkel GmbH & Co KG (Staufen, Germany) in an emulsification process at 8000 revolutions per minute and a duration of 30 seconds.
  • the suspension is then reacted with a piston-gap high-pressure homogenizer Micron Lab 40 (APV-Gaulin, Lubeck) at a pressure of 500 bar and a temperature of 80 0 C homogenised four times.

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Abstract

L'invention concerne des préparations à base d'Artemisia annua, ainsi que plusieurs procédés servant à préparer des micro- et nanoparticules à partir de l'armoise vulgaire annuelle (Artemisia annua). Ceci permet d'obtenir des particules ultrafines possédant des caractéristiques améliorées et pouvant être utilisées en tant que compléments nutritionnels pour l'homme ou l'animal, en cosmétique ou en médecine.
EP09781132A 2008-07-26 2009-07-27 Préparations à base d'artemisia annua, leur conversion en micro- et nanoparticules et leur utilisation Withdrawn EP2320867A2 (fr)

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DE102008035442A DE102008035442A1 (de) 2008-07-26 2008-07-26 Zubereitungen aus Artemisia Annua, ihre Umwandlung in Mikro- und Nanopartikel und ihre Verwendung
PCT/EP2009/059671 WO2010012687A2 (fr) 2008-07-26 2009-07-27 Préparations à base d'artemisia annua, leur conversion en micro- et nanoparticules et leur utilisation

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EP2320867A2 true EP2320867A2 (fr) 2011-05-18

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