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
  • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
• • 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
  • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to an improved multi-step method for preparing an extract from ginkgo biloba having a reduced content of 4′-O-methyl pyridoxine and/or biflavones, wherein the depletion is effected by filtration over an adsorber resin and/or an ion exchanger and the substances to be removed are retained on the resin.
• the invention further relates to an extract from ginkgo biloba having a reduced content of 4′-O-methyl pyridoxine and/or biflavones which is obtainable by the method according to the present invention, as well as to its use.
• extracts from the leaves of ginkgo biloba are used as a medicament. They are currently used for the treatment of different kinds of dementia and symptoms thereof as well as cerebral and peripheral blood circulation disorders. Ingredients, the efficacy is associated with, are terpene lactones (ginkgolides A, B, C and bilobalide) as well as glycosides of flavones (quercetin, kaempferol and isorhamnetin).
• the leaves of ginkgo biloba also contain components which do not contribute to the desired efficacy, but which may be responsible for risks and side effects.
• unpolar plant ingredients such as ginkgolic acids, those components are 4′-O-methyl pyridoxine and biflavones.
• ginkgo extract which is efficacious and at the same time as safe as possible and as low in side effects as possible, these compounds should thus not be present to the largest possible extent.
• 4′-O-methyl pyridoxine may cause symptoms of poisoning such as convulsive seizures and unconsciousness.
• this compound is also referred to as ginkgo-toxin.
• the biflavones contained in ginkgo exhibit an immunotoxic potential and may elicit contact allergies.
• These biflavones contained in ginkgo are predominantly the compounds amentoflavone, bilobetin, ginkgetin, isoginkgetin and sciadopitysin.
• EP 1 037 646 B1 page 3
• the method of EP 1 037 646 B1 is based on the method originally described in DE 39 40 091 C2.
• step f the depletion of the biflavones and 4′-O-methyl pyridoxine is carried out at a stage of the method (step f)), wherein relatively high contents of lead salts and ammonium salts are present such that an increased amount of ion exchanger has to be employed.
• the flavonoids are determined in the form of quercetin, kaempferol and isorhamnetin after acidic hydrolysis and calculated as flavonoid glycosides.
• This object could be solved by separating the biflavones using adsorber resins and/or separating 4′-O-methyl pyridoxine via acidic ion exchangers.
• the depletion step is carried out at the end of the method.
• a smaller amount of the ion exchanger has to be employed and particularly low contents of 4′-O-methyl pyridoxine and/or biflavones are obtained.
• Preferred adsorber resins in step l) are resins based on optionally substituted styrenes/divinylbenzenes such as Diaion HP-20, HP-21 or Sepabeads SP-207 and SP-850.
• Preferred ion exchangers are strongly acidic ion exchangers such as Merck I or Amberlite IR-120.
• the filtration optionally includes the usual rinsing using further solvent.
• the aqueous alkanol in step k) is aqueous methanol, ethanol, n-propanol or isopropanol having a content of 20-90% by weight, respectively, preferably aqueous ethanol, a concentration of 40 to 60% by weight being particularly preferred.
• a subject of the present invention are extracts, in particular dry extracts, which are obtainable by the method according to the present invention and which exhibit the following contents:
• extracts in particular dry extracts, which are obtainable by the method according to the present invention and which exhibit the following further contents:
• a further subject of the present invention are extracts, in particular dry extracts, which are obtainable by the method according to the present invention and which exhibit the following contents:
• dry extracts generally have a dry residue of at least 95% by weight.
• the extracts according to the present invention can be administered in the form of powders, granules, tablets, dragées (coated tablets) or capsules, preferably orally.
• the extract is mixed with suitable pharmaceutically acceptable adjuvants such as lactose, cellulose, silicon dioxide, croscarmellose and magnesium stearate, and pressed into tablets which are optionally provided with a suitable coating, for example made of hydroxymethylcellulose, polyethyleneglycol, pigments (such as titanium dioxide, iron oxide) and talcum.
• suitable coating for example made of hydroxymethylcellulose, polyethyleneglycol, pigments (such as titanium dioxide, iron oxide) and talcum.
• the extract according to the present invention can also be filled into capsules, optionally under the addition of adjuvants such as stabilizers, fillers and the like.
• the dosage is such that 10 to 2000 mg, preferably 50 to 1000 mg and particularly preferred 100 to 500 mg extract are administered per day.
• a further subject of the present invention are medicaments, food products and other preparations containing these extracts, optionally in combination with other substances such as active ingredients and/or pharmaceutically acceptable adjuvants.
• food product as used herein particularly refers to dietetic food products, dietary supplement products as well as medical food and dietary supplements.
• Dried leaves of ginkgo biloba (drug) were extracted at a temperature of about 50° C. using seven times their weight (w/w) (i.e. drug-solvent ratio is 1:7) made up of acetone/water 60/40 (w/w) (step a)).
• step b) The organic solvent was largely separated from the extract (step b)) and the remaining concentrated aqueous solution was diluted with water to a solids content of about 10% by weight. The solution was cooled to a temperature of about 12° C. under agitation and the resulting precipitate was removed (step c)).
• the extract obtained was largely concentrated and the concentrate thus obtained was diluted with water and ethanol such that a solution containing 50% by weight water and 50% by weight ethanol at a solids content of about 10% by weight was obtained (step e)).
• the solution was filtered and the filtrate was added with an aqueous solution of lead hydroxide acetate (step f)).
• aqueous alcoholic solution was concentrated under reduced pressure to an ethanol content of about 5% and ammonium sulfate was added such that a content of about 20% by weight based on the water content was achieved.
• the solution obtained was extracted using a mixture of methyl ethyl ketone and ethanol in a ratio of 6:4 (step h)).
• step i The resulting organic phase was largely concentrated (solids content of about 55% by weight) (step i)). Then the product was diluted with ethanol and water such that a solution having an ethanol content of about 75% and a solids content of about 15% was obtained (step k)).
• Example 1 Ginkgo Extract Having a Reduced Content of 4′-O-methyl pyridoxine
• Example 2b Ginkgo Extract Having a Reduced Content of 4′-O-methyl pyridoxine and biflavones
• Example 2a 90% of the solution obtained in Example 2a) (2334.1 g) were applied to 25 ml (corresponding to 0.40 ml/g of the dry extract) Amberlite IR-120 (strongly acidic ion exchanger) (column: about 1.5 ⁇ 11 cm; flow: about 10 ml/min) (step l)), followed by rinsing with 100 ml of 40% ethanol (w/w).
• the resulting solution was concentrated on a rotary evaporator and freeze-dried (step m)): 61.67 g.
• Dried leaves of ginkgo biloba were extracted at a temperature of about 50° C. using seven times their weight (w/w) (i.e. drug-solvent ratio is 1:7) made up of acetone/water 60/40 (w/w).
• the organic solvent was largely separated from the extract and the remaining concentrated aqueous solution was diluted with water to a solids content of about 10% by weight, cooled to a temperature of about 12° C. under agitation and the resulting precipitate was removed.
• the extract obtained was largely concentrated and the concentrate thus obtained was diluted with water and ethanol such that a solution containing 50% by weight water and 50% by weight ethanol at a solids content of about 10% by weight was obtained.
• the solution was filtered, the filtrate was added with an aqueous solution of lead hydroxide acetate and filtered again (step f)).
• the combined eluates were extracted by shaking using 3 ⁇ 70 ml n-hexane.
• the ethanol/water phase was concentrated on a rotary evaporator and diluted with water to 100 g.
• the extract solution thus obtained was extracted with 1 ⁇ 40 ml, 2 ⁇ 30 ml and 1 ⁇ 20 ml of a mixture of methyl ethyl ketone:ethanol in a ratio of 3:2, wherein 15 g ammonium sulfate was added to achieve phase separation.
• the organic phase was stirred for 1 h at room temperature after adding 25 g ammonium sulfate.
• the undissolved ammonium sulfate as well as the aqueous phase formed were separated.
• the extract solution was concentrated on a rotary evaporator at 50° C. and dried in vacuum at 60° C.: 14.8 g.

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