US3876766A - Glycoside-hydrolase enzyme inhibitors - Google Patents

Glycoside-hydrolase enzyme inhibitors Download PDF

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US3876766A
US3876766A US213066A US21306671A US3876766A US 3876766 A US3876766 A US 3876766A US 213066 A US213066 A US 213066A US 21306671 A US21306671 A US 21306671A US 3876766 A US3876766 A US 3876766A
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good
brown
glycoside
agar
spg
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Werner Frommer
Walter Puls
Dietmar Schafer
Delf Schmidt
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Bayer AG
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Bayer AG
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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • C12P1/04—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using bacteria
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P1/00—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes
    • C12P1/06—Preparation of compounds or compositions, not provided for in groups C12P3/00 - C12P39/00, by using microorganisms or enzymes by using actinomycetales
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/886—Streptomyces
    • Y10S435/896—Streptomyces fradiae
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/907—Streptosporangium

Definitions

  • the invention also contemplates the provision of methods of inhibiting the reaction of carbohydrates and glycosidehydrolase enzymes and particularly carbohydratesplitting glycoside-hydrolase enzymes of the digestive tract by means of conducting said reaction of said carbohydrates and glycoside-hydrolase enzymes in the presence of a glycoside-hydrolase enzyme inhibitor for said glycoside-hydrolase enzyme derived from a strain of microorganism of the order Actinomycetales.
  • the invention further contemplates the provision of methods for the treatment of indications of the group consisting of obesity. hyperlipidemia (atheriosclerosis). diabetes. pre-diabetes. gastritis, gastric ulcer. duodenal ulcer. and caries induced by the action of glycoside-hydrolase enzymes and carbohydrates. the improvement which comprises employing an enzyme inhibitor for glycoside-hydrolase enzymes produced by a strain of microorganism of the order Actinomycetales.
  • starch begins in the mouth.
  • Saliva contains an enzyme. amylase. which attacks starch and similar polysaccharides. reducing the size of the molecule.
  • Starch is made up of chains of glucose molecules linked in a particular way. and amylase attacks the links between the glucose units. The enzyme acts at many points in the chain. and the smallest units it produces are molecules of the sugar maltose. Maltose is made up of two glucose units; this sugar is thus a disaccharide.
  • tase also splits each molecule of maltose produced from starch into two molecules of glucose. which are then absorbed and metabolized by the body.
  • Some of the sugars of food are disaccharides; common sugar (sucrose) is made up of a molecule of glucose joined to a molecule of fructose. and lactose (the sugar of milk) is also a disaccharide. These sugars are split into their component monosaccharides by specific enzymes in the intestine.
  • a-amylases can be inhibited by the use of various low molecular substances.
  • various low molecular substances such as. for example. salicylic acid and abiscisin IT. Hemberg. J. Larsson. Physiol. Plant. 14. 86l
  • Point of action of amylase l l l Starch also contains branched chains of glucose units.
  • amylase If the branched-chain structure of starch is thought of as resembling a bush. the enzyme can prune the outer branches until it reaches a fork and then its action stops. Thus. as well as molecules of maltose. amylase produces from starch fragments of the original molecule which are like hard-pruned bushes and which are called limit dextrins. Glycogen. the carbohydrate storage material of animal tissues. is also made up of much-branched chains of glucose units.
  • the dextrins resulting from the pruning by amylase are attacked by an enzyme in the small intestine which can break the inter-chain links.
  • a specific enzyme malthe activity of certain amylases non-specifically by physical adsorption (T. Chrzaszcz J. Janicki. Bioch. Z. 260. 354 ([933) and Bioch. J. 28. 296 (l934)] or by denaturation and precipitation of the enzyme [8. S. Miller. E. Kneen. Arch. Bioch. Biophys. 15. 251 ([947). D. H. Struhmeyer. M. H. Malin. Biochem. Biophys. Acta I84. 643 (l969)].
  • the present invention now relates to inhibitors for glycoside-hydrolases from ucrinomyceles. and in particular to inhibitors for glycoside-hydrolases of preferably carbohydrate-splitting enzymes of the digestive tract from ar'linamyceres.
  • These inhibitors are formed by microorganisms of the order Actinomycerales. especially by those of the family of Srreprmnycemceae. Thernmucrr'nomyceraceae. Micromonosporaceae. Nocardiaceae and above all those of the family Aclinuplanaceae. They are also formed to a particularly high degree of strains of the genera Acrinoplunes, Ampullariella. Srrepruspurangium. Strepromyces. Chainia. Pilimel'iu. Plummmlmsporn. and Aclinobrfida.
  • this invention provides. as a new product, a glycoside-hydrolase inhibitor of microbial origin.
  • This invention further provides a method for the production of a glycoside-hydrolase inhibitor comprising culturing a microbe of the order Aclinomycemles and extracting the inhibitor from the resultant culture.
  • the preferred microorganisms are preferably of the family Slrepmmyceraceae or Acrinuplunuceue.
  • a wide variety of microorganism of the order Acrinumycemles have been found to make glycosidehydrolase enzyme inhibitors and the methods described below can be used to test the microorganisms to determine whether or not the desired glycoside-hydrolase enzyme inhibitor activity is present and the approximate relative value of this activity.
  • Strains of the order Acrinomycelales. especially those of the families Srreprrmryceraceae and Aclinoplanaceae. are isolated in a known manner from samples of soil or strains of these order bought from culture collections. Culture flasks containing nutrient solutions which permit the growth of these strains are inoculated with inoculum of these strains.
  • the glycerineglycine nutrient solution according to von Plotho of compositions 2% glycerine, 0.25% glycine, 0.1% NaCl. 0.1% K HPO4, 0.01% FeSO 7 H O, 0.01% MgSo. 7 H and 0.1% QaCo can be used.
  • a nutrient solution complex sources of carbon, such as, for example, corn-steep liquor or soya flour or yeast extract or protein hydrolysates. for example NZ-amines, or mixtures of these substances.
  • sources of carbon such as, for example, corn-steep liquor or soya flour or yeast extract or protein hydrolysates. for example NZ-amines, or mixtures of these substances.
  • the pH value of the solution must be adjusted.
  • An initial pH of the nutrient solution of between 6.0 and 80. especially between 6.5 and 7.5. is preferred.
  • the glycerine of the nutrient solution can also be replaced by other sources of carbon. such as. for example. glucose or sucrose or starch or mixtures of these substances.
  • sources of carbon such as. for example. glucose or sucrose or starch or mixtures of these substances.
  • sources of nitrogen such as. for example. yeast extract. soya flour. NZ-amines. pharmamedia and others.
  • concentrations of the sources of carbon and nitrogen. and also the concentrations of the salts. can vary within wide limits.
  • FeSO.. CaCQ, and MgSO can also be entirely absent. l00200 ml. for example of the nutrient solution are introduced into 1 liter Erlenmeyer flasks. sterilized in a known manner and inoculated with the strain to be investigated.
  • the flask in incubation on shaking machines at ]560C.. preferably at 24-50C. If the culture shows growth. which generally takes place after 1-10 days. and in most cases after 3-5 days. a sample of. for example 5 ml is taken and the mycelium in this sample is separated off by filtration of centrifugation. l-l00 p l of the culture broths are employed in the tests described below. and the inhibiting capacity per ml is calculated.
  • the mycelia are extracted twice with 5 volumes (relative to the volume of mycelium) of acetone at a time, and subsequently l X 5 volumes of diethyl ether.
  • the extracted mycelium residue is dried in vacuo at 20 and the resulting dry mycelium powder is extracted with 4-8 parts by weight of dimethyl sulphoxide (DMSO).
  • DMSO dimethyl sulphoxide
  • the two acetone extracts and the ether extract are combined and concentrated almost to dryness in vacuo.
  • the residue from these extracts is taken up with the dimethyl sulphoxide (DMSO) extract from the dry powder and 0-100 pl thereof are employed in the tests described below.
  • DMSO dimethyl sulphoxide
  • Amylase Test One amylase inhibitor unit l AIU is defined as the amount of inhibitor which inhibits two amylase units to the extent of 50%.
  • One amylase unit (AU) is the amount of enzyme which in 1 minute. under the test conditions indicated below. splits l u equivalent of glu' coside bonds in starch. The ,uVal of split bonds are determined colorimetrically as uVal of reduced sugar formed. by means of dinitrosalicylic acid. and are specified as p.Val of maltose equivalents by means ofa maltose calibration curve.
  • 0.l ml of amylase solution (20-22 AU/ml) are treated with l-400 pg of inhibitor or 1-100 pl of the culture solution or mycelium extracts to be tested.
  • amylase activity which is still active after addition of the inhibitor is read off from a previously recorded amylase calibration curve. and the percentage inhibition of the amylase employed is calculated therefrom. The percentage inhibition is plotted as a function of the quotient:
  • STU Saccharase inhibitor unit
  • SU One saccharase unit
  • saccharase solution comprising a solubilized saccharase from intestinal mucous membrane of pigs. [according to B. Borgstrom. A. Dahlquist. Acta Chem. Scand. 12. (I958) page 1977] in the amount of 0.3-0.4 SU/ml are mixed with -400 pg of inhibitor or 0-50 t] of the culture solution of the mycelium extract which is to be investigated. in 0.l ml of a 0.l M Na maleate buffer of pH 6.0. and the mixture is equilibrated for about 10-20 minutes in a waterbath at 35C. It is then incubated for 60 minutes at 35C.
  • the saccharase units which are still active after addition of inhibitor are determined from Dahlquist. Acta Chem. Scand. 12. (1958). page I997], or maltase in the form of human pancreatic juice lyophilizatc. (0.09-0.12 MU/ml) are equilibrated with 0-400 p.g of inhibitor or 0-20 p.l of the culture solution to be investigated or of the mycelium extract in 0.05 ml of 0.1 M sodium maleate buffer at pH 6.0 for about 10-20 minutes in a waterbath at 35C. The mixture is then incubated for minutes at C.
  • the maltase units still active after addition of inhibitor are calculated on the basis of a molar extinction coefficient of E 13.2 X [0 for the pnitrophenolate anion at pH 7.6. and from the maltase units still active the percentage inhibition of the maltase employed is calculated. The percentage inhibition is plotted as a function of the quotient:
  • the glucose produced during the ac L1 tron of maltase on maltose 15 measured enzymatically by means of colorimetry. using glucose oxidase. peroxil+ lati 0 lids. S n nn it d miX Of the dase and dianisidine. All the maltase inhibitors desame series). and the 50% inhibition point is read off ib d h e also inhibit in this test.
  • maltase solution pullariella and Streptosporangium.
  • those listed below proved particularly active in cous membrane of pigs [according to B. Borgstrom. A. one or more of the tests indicated.
  • Shape of Sporangia bottle shaped. cylindrical. money pouch-shaped" I spherical with wrinkled surface. in pan irregular Size of Sporangia 3 l0 x 5 16 p. 3.5 12 p. Shape of Spores small rods spherical Size of Sores 0.5 0.7 x approx.
  • Actinopltmes Actinoplanes Aclinnplam'i' Acrinuplaues sgec. s ec. Spec. 5 18 S 27 S 50 Date of isolation December 4. 1966 December 8. 1966 March 3. [967 December 22. 1969 Method pollen pollen pollen pollen Origin Hattenheim. Kuhkopf. Nature Neuhot'. Fulda Kenya. near Ruiru Rheingau. potato Reserve. Altrhein. district. turf coffee plantation. field in the riverside wood. soil. ed e of pH 6.2 "Sandaue". pH 8.0 under willows. path. p
  • Flagellation Arrangement of bundles of flagellae coiled chains mobile spores slightly coiled.
  • Shape of sporangia very narrow and relatively long. distally and in part also laterally irregular.
  • G very good G. good Milk agar SM. orange brown SM. colorless (C a) SP. agar gold-brown LM. Spg. SP.
  • Tyrosine G moderate agar SM. black (Ty) SP. black tryosine crystals dissolved p Yeast-glucosc- G. ood G. good soil extract SM. rown SM. colorless a an SP. gold-brown LM. white GS) Spg. SP.
  • Manure extract G moderate a at SM. pale brown :1) LM. white Spg.
  • Tables 2 and 3 list some characteristics of the strains described.
  • the strains listed above are cultured in the nutrient solutions described above. In doing so it should be noted that for optimum production practically every strain requires a different nutrient solution of different qualitative and quantitative composition.
  • the mycelium is separated from the culture solution and. depending on the occurrence of the inhibitorsthe active principle is concentrated using the culture solution and/or the mycelium.
  • the inhibitors are obtained from the culture broths by lyophilization or precipitation with salts or watersoluble organic solvents (such as. for example. lower alcohols and ketones) or by adsorption of the active substances on ion exchangers.
  • the inhibitors are obtained from the mycelia by extraction with organic solvents.
  • organic solvents such as. for example. alcohols. ketones. ethers. esters and sulphoxides.
  • the fermentation batch is centrifuged at 3.000-20.000 revolutions per minute. preferably 6.000-l0,000 revolutions per minute. for -60 minutes. preferably 30 minutes, or is filtered, preferably under pressure and with the help of filter aids, such as. for example. Claricel. and is thus separated into cul' ture broth and mycelium residue.
  • the inhibitor can be isolated from the particular culture broth in various ways:
  • Precipitation of the inhibitors from the culture broth [or from the culture broths concentrated according to (all by adding water-soluble organic solvents. such as, for example, alcohols or ketones. preferably methanol, ethanol. or acetone. up to a content of 60-90%. Since inactive concomitant substances are precipitated at low concentration of solvents. this pre cipitation process is particularly suitable for fractional precipitation to remove undesired concomitant substances.
  • undesired concomitant substances are frequently present in the culture broths.
  • These concomitant substances can be separated off in various ways. for example. by denaturing the concomitant substances by means of heat in the case of inhibitors which are heat-stable. or by dialysis through appropriate membranes in the case of low molecular inhibitors. in which case the undesired concomitant sub stances are retained by the membrane. or by fractional precipitation [compare (b)] by adsorption of the concomitant substances on ion exchangers.
  • the inhibitors are obtained from the mycelia by repeated extraction of the mycelium with organic solvents, preferably two extractions of 10-20 minutes with 3-5 volumes of acetone (relative to the moist mycelium volume) and subsequent single extraction of 5-l0 min utes with ether.
  • the mycelium extracted in this way is dried in vacuo and subsequently extracted for 2-8 hours with 3-l0 parts by weight of dimethyl sulphoxide. while stirring. and thereafter centrifuged at 10.000 to 20.000 revolutions per minute.
  • the acetone extracts and ether extracts are concentrated by dryness in vacuo and taken up with the dimethyl sulfoxide (DMSO) extract.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • the new substances dissolve well in water.
  • One group of the inhibitors is heat-stable at neutral pH values. stable to acid (pH 2 stable to alkali (pH l2). and slowly dialyzable. These inhibitors are not inactivated by trypsin and pepsin and. in turn. do not inhibit the enzymes mentioned. They cannot be dyed with the typical protein dyes and do not show a characteristic absorption in the UV up to 250 nm. The inhibitors cannot be inactivated with urea and B-mercaptoethanol. According to estimates from gel filtration. the molecular weight of these inhibitors is above 500 but below 6.000. On hydrolytic splitting. monosaccharides. for example. glucose. are obtained. According to these findings. these inhibitors are oliogosaccharides or polysaccharides or their derivatives.
  • inhibitors Another group of inhibitors is heat-labile and not dialyzable. or hardly dialyzable. These inhibitors are inactivated more or less rapidly by trypsin. Urea and a-mer captoethanol also inactivate most of these inhibitors. These inhibitors are probably substances of peptide character.
  • amylase maltasc starch maltose glucose or or glycogen saccharase sucrose glucose fructose These hypcrglycaemias are of particularly strong and lasting character in the case of diabetics. in adipose cases. alimentary hyperglycemia frequently causes a particularly strong secretion of insulin. which. in turn. leads to increased synthesis of fat and reduced degradation of fat. In connection with such hyperglycemias. a hypoglycemia frequently occurs in metabolically healthy and adipose persons as a result of the insulin secretion. it is known that not only hypoglycemias but also chyne remaining in the stomach stimulate the production of gastric juice. which for its part participates or encourages the formation of a gastritis. or a gastric or duodenal ulcer.
  • inhibitors of glycosidehydrolases obtained and isolated in accordance with the above methods. considerably reduce alimentary hyperglycemia. hyperinsulinemia and hypoglycemia after dosing rats and/or man with wheat starch or sucrose or maltose. and speed up the passage of these carbohydrates through the stomach.
  • Inhibitors of glycoside-hydrolases are. therefore. suitable for use as therapeutic agents for the following indications; obesity. adiposit. hyperlippidemia (atheriosclerosis] diabetes. pre-diabetes. gastritis. gastric ulcer. duodenal ulcer. and caries.
  • the present invention therefore. provides a pharmaceutical composition containing as active ingredient an inhibitor of the invention in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 (preferably less than 350) except in the pres ence of a surface active agent.
  • the invention further provides a pharmaceutical composition containing as active ingredient an inhibitor of the invention in the form of a sterile or isotonic aqueous solution.
  • the invention also provides a medicament in dosage unit form comprising an inhibitor of the invention either alone or in a admixture with a diluent.
  • the invention also provides a medicament in the form of tablets. (including lozenges and granules). Dragees. capsules. pills. ampoules and suppositories comprising an inhibitor of the invention either alone or in admixture with a diluent.
  • “Medicament” as used in this specification means physically discrete coherent portions suitable for medical administration.
  • Medicament in dosage unit form as used in this specification. means physically discrete coherent portions suitable for medical administration each containing a unit dose or a multiple (up to four times) or submultiple [down to a fortieth] of a unit dose of the inhibitor of the invention.
  • Whether the medicament contains a unit dose or. for example. a half. a third. or a quarter of a unit dose will depend on whether the medicament is to be administered once. for example. twice. three times or four times a day. respectively.
  • a unit dose is the amount of inhibitor to be taken on one occasion.
  • the pharmaceutical composition according to the invention may. for example. take the form of gels. pastes (e.g.. toothpastes). creams. chewing-gums. suspensions. solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents. syrups. gran ules or powders.
  • pastes e.g.. toothpastes
  • the diluents to be used in pharmaceutical composition adapted to be formed into tablets. dragees. capsules and pills include the following: (a) fillers and extenders. e.g.. starch. sugars. mannitol. and silicic acid; (b) binding agents. e.g.. carboxymethyl cellulose and other cellulose derivatives. alginates. gelatine. and polyvinyl pyrrolidone; (c) moisturizing agents. e.g.. glycerol; (d) disintegrating agents. e.g.. agar'agar. calcium carbonate. and sodium bicarbonate. (e) agents for retarding dissolution. e.g...
  • paraffin paraffin
  • resorption accelerators e.g.. quaternary ammonium compounds
  • surface active agents e.g.. cetyl alcohol, glycerol monostearate
  • adsorptive carriers e.g., kaolin and bentonite
  • lubricants e.g., talc, calcium and magnesium stearate, and solid polyethylene glycols
  • elastomeric binders such as chicle.
  • the tablets, dragees, capsules and pills formed from the pharmaceutical compositions of the invention can have the customary coatings, envelopes and protective matrices, which may contain opacifiers. They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.
  • the coatings. envelopes and protective matrices may be made. for example. of polymeric substances or waxes.
  • the ingredient can also be made up in microencapsulated form together with one or several of the abovementioned diluents.
  • the diluents to be used in pharmaceutical composi tions adapted to be formed into suppositories can. for example. be the usual water-soluble or water-insoluble diluents, such as polyethylene glycols and fats [e.g., cocoa oil and, high esters (e.g., -alcohol and C fatty acid)] or mixtures of these diluents.
  • water-soluble or water-insoluble diluents such as polyethylene glycols and fats [e.g., cocoa oil and, high esters (e.g., -alcohol and C fatty acid)] or mixtures of these diluents.
  • compositions which are pastes, creams, and gels can, for example, contain the usual diluents, e.g., animal and vegetable fats, waxes, paraffins, starch. tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
  • diluents e.g., animal and vegetable fats, waxes, paraffins, starch. tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
  • compositions which are powders can, for example, contain the usual diluents, e.g., lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide power or mixtures of these substances.
  • diluents e.g., lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide power or mixtures of these substances.
  • compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the above-mentioned exclusion of solvents having a molecular weight below 20 except in the presence of a surfaceactive agent).
  • solvents such as solvents, dissolving agents and emulsifiers
  • diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1.3- butylene glycol, dimethylformamide, oils (for example, ground nut oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
  • oils for example, ground nut oil
  • glycerol glycerol
  • tetrahydrofurfuryl alcohol polyethylene glycols and fatty acid esters of sorbitol or mixtures thereof.
  • solutions and emulsions should be sterile, and, if appropriate, bloodisotonic.
  • compositions which are suspensions can contain the usual diluents, such as liquid diluents, e.g., water, ethyl alcohol, propylene glycol, surface-active agents (e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters).
  • liquid diluents e.g., water, ethyl alcohol, propylene glycol
  • surface-active agents e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbite and sorbitane esters.
  • microcrystalline cellulose aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures thereof.
  • compositions according to the invention can also contain coloring agents and preservatives as well as perfumes and flavoring additions (e.g., peppermint oil and eucalyptus oil) and sweetening agents (e.g., saccharin).
  • perfumes and flavoring additions e.g., peppermint oil and eucalyptus oil
  • sweetening agents e.g., saccharin
  • chewing gums and toothpastes will contain flavoring agents.
  • compositions according to the invention preferably contain about 0.1 to 99.5, more preferably from about 0.5 to 95% of the inhibitor by weight of the total composition.
  • the pharmaceutical compositions according to the invention can also contain other pharmaceutically active compounds. They may also contain a plurality of different inhibitors of the invention. Particular examples of such other pharmaceutically active compounds are oral antidiabetic agents such as B-cytotropic sulphonyl-urea derivatives and biguanides which influence the blood sugar level.
  • the diluent in the medicament of the present inven tion may be any of these mentioned above in relation to the pharmaceutical compositions of the present invention.
  • Such medicament may include solvents of molecular weight less than 200 as sole diluent.
  • the discrete coherent portions constituting the medicament according to the invention may be. for example, any of the following: tablets (including lozenges and granules), pills, dragees, capsules, suppositories, and ampoules. Some of these forms may be made up from delayed release of the inhibitor. Some, such as capsules. include a protective envelope which renders the portions of the medicament physically discrete and coherent.
  • the preferred unit dose for the medicaments of the invention is 5,0005,000,000 AlU, 2.5250 MlU, or l-l0,000 SlU of inhibitor.
  • a unit dose will be taken orally once or several times daily, usually immediately before, during, or after a meal.
  • Preferred medicaments are, therefore, those adapted for peroral administration, such as tablets, dragees, and portions of chewing gum.
  • mice and rats tolerated l0 AlU/kg.
  • Example 1 Three l-liter Erlenmeyer flasks, containg ml of a nutrient solution of composition: 2% starch, l7c glucose, 0.5% NZ-amines, l.07c yeast extract and 0.4% CaCO (sterilization: minutes, 121C; pH adjusted to 7.2 before sterilization) are each inoculated with 1 ml of a primary cultrue (obtained in the same nutrient solution, inoculated from sloping test-tube cultures with oatmeal agar) of the strain SB 2, and the flasks are incubated at 28C. on a rotary shaking machine. After a period of culture of 5.5 days, the contents of the three flasks are combined and the mycelium is separated off by centrifuging. 425 ml of supernatant liquor, containing 100 AlU/ml, are obtained.
  • the centrifuged supernatant liquor is concentrated to ml on a rotary evaporator at 15-20 mm Hg and approximately 37C. waterbath temperature.
  • the viscous solution is stirred into 8 volumes 480 ml of ehtanol, while stirring.
  • the precipitate formed is collected by centrifuging, again dissovled in 60 ml of water, and dialyzed for 6 hours against distilled water. The dialyzate in lyophilized. Yield: 1.6 g containing 19 X It) AlU/g.
  • Example 2 Using a batch according to Example 1,440 ml of centrifuged supernatant liquor containing [00 AlU/ml are obtained.
  • Example 3 Using a batch according to Example 1. 500 ml of a centrifuged supernatant liquor containing 120 AlU/ml are obtained after 5 days culture. These 500 ml are lyophilized directly. Yield: 7.l g containing 8.3 X "Al- U/g.
  • Example 4 Three l-liter Erlenmeyer flasks containing 200 ml of a nutrient solution of composition: 3% glycerine. 3% soya flour. and 0.2% CaCO (sterilization: 30 minutes. 121C; pH after sterilization 7.2) are each inoculated with one ml ofa primary culture (obtained in the same nutrient solution. inoculated from sloping test-tube cultures containing Czapek-peptone-casein agar) of the strain SB l2. and the flasks are incubated for 3 days at 28C. on a rotary shaking machine. After the incubation. the contents of the flasks are combined and the mycelium is separated off by centrifuging. 500 ml of supernatant liquor containing 450 AlU/ml are obtained.
  • a primary culture obtained in the same nutrient solution. inoculated from sloping test-tube cultures containing Czapek-peptone-casein
  • the supernatant liquor is treated with 250 g of ammonium sulphate added in portions while stirring and the mixture is subsequently centrifuged for 10 minutes at 12.000 revolutions per minute.
  • the liquid is decanted off and the precipitate is washed twice with acetone and once with ether and dried in vacuo. Yield: 13.4 g containing 10 X l0 AlU/g.
  • Example 5 A precipitate obtained according to Example 4 after precipitation with ammonium sulphate is dissolved in l00 ml of water and dialyzed for 6 hours against distilled water. A dialyzate is obtained. which is frozen and lyophilized. Yield: 1.5 g containing 80 AlU/mg.
  • Example 6 If a 1 liter Erlenmeyer flask is inoculated with 120 ml of a nutrient solution according to Example 1. from a sloping test-tube culture of the strain St. 19. a culture solution containing AlU/ml is obtained after 3 days culture at 28C. on a rotary shaking machine.
  • Example 7 If a mix according to Example 4 is incubated for 3 days at 32C.. a culture filtrate containing 350 AlU/ml is obtained after filtering off the mycelium.
  • Example 8 lfa nutrient solution according to Example I is inoculated in accordance with Example 4. culture filtrates containing 270 AlU/ml are obtained after 3 days incubation at 28C.
  • Example 9 Six l'liter Erlenmeyer flasks. each containing 100 ml ofa nutrient solution consisting of 3% glucose. 3% soya flour. and 0.2% CaCO (sterilization: minutes. [2 lC.'. pH after sterilization 7.2) are each inoculated with 1 ml of primary culture (obtained as in Example I l of the strain SB 5. and are incubated for four days at 28C. on rotary shaking machines. The contents of the flasks are combined and the mycelium is separated off by centrifuging. The resulting 500 ml of supernatant liquor containing 150 AlU/ml are frozen and lyophilized. Yield: 6.) g containing ll X 10 AlU/g.
  • Example 10 If 24 flasks of a mix according to Example 4. each containing I20 ml. are inoculated with a primary culture of the strain SB 1] (obtained according to Example 4] and incubated for 5 days at 28C.. 2.0 liters of a supernatant liquor containing l.l MlU/ml are obtained after centrifuging. These 2 liters are concentrated to 200 ml on a rotary evaporator. The 200 ml of concentrate are dialyzed for 24 hours in a Visking dialysis tube (type 27/100 FT. Union Carbide Corporation) against 2 liters of distilled water. at room temperature. The outer medium.
  • a Visking dialysis tube type 27/100 FT. Union Carbide Corporation
  • 1 ml of this concentrate contains MlU/ml.
  • this solution is passed over an anion exchage column (Amberlite IRA 410. acetate form. in 0.05 M NH -acetate. pH 7, 2.5 X 20 cm col umn) and the active fractions are combined and gelfiltered on Sephadex G in H O. The active fractions from the gel filtration are concentrated to 12 ml. 1 ml of this solution contains 150 MlU/ml.
  • anion exchage column Amberlite IRA 410. acetate form. in 0.05 M NH -acetate. pH 7, 2.5 X 20 cm col umn
  • the mycelium (-500 ml) was twice extracted with l liter of acetone and once with 1 liter of ether and the extracts were combined and evaporated to dryness on a rotary evaporator in vacuo.
  • the mycelium residue was dried in vacuo at 20C. and the resulting dry mycelium powder (-51 g) was subsequently extracted for 2 hours at room temperature with l50 ml of dimethyl sulfoxide (DMSO). After centrifuging (30 minutes. [5.000 r.p.m.) the acetone/ether extract which has been concentrated to dryness is taken up with the dimethyl sulfoxide (DMSO) supernatant liquor from the dry mycelium powder. Yield: [20 ml containing 3 MI- U/ml.
  • Example ii If a 1 liter Erlenmeyer flask containing [20 ml of a nutrient solution according to Example l is inoculated according to Example 9 and incubated for 6 days at 28C. on a rotary shaking machine. a culture filtrate containing 0.9 MlU/ml is obtained.
  • Example l2 If five l-liter Erlenmeyer flasks. each containing ml of a nutrient solution of composition: 2.5% starch, 0.5% glucose. 0.5% NZ-amines. 1.0% yeast extract and 0.4% CaCO (sterilization: 30 minutes. l2 lC.; pH adjusted to 7.2 before sterilization) are each inoculated with 2 ml ofa primary culture (obtained according to Example 1) of the strain SB 27 and these flasks are incubated for 4 days at 28C. on a rotary shaking machine. 500 ml of supernatant liquor containing 70 Al' U/ml are obtained after combining the flasks and centrifuging off the mycelium. The centrifuged superna tant liquor is frozen and lyophilized. Yield: 7.7 g con raining 3.5 X it) AlU/g.
  • Example 13 if a mix according to Example I is inoculated with 2 ml of a primary culture of the strain SB 18 (obtained according to Example 1) and incubated for 3 days at 28C.. a culture broth containing 1100 AlU/ml. 0.]7 MIU/ml and [.0 SlU/ml is obtained.
  • the black smeary precipitate which forms is collected by centrifuging at 6000 rpm. for 30 minutes; the precipitate is dissolved in 2.5 liters of water and the black-colored solution is stirred for 60 minutes with 500 g of moist Amberlite ⁇ 1RA 410 (acetate form. pH 7)].
  • the mixture is separated into supernatant liquor and Amberlite sediment by centrifuging for 10 minutes at 6000 rpm. 1n the same way. the supernatant liquor is further stirred three times. in each case with 500 g of Amberlite for 60 minutes. and subsequently with a further 500 g of Amberlite overnight (-1S hours). After this treatment. the supernatant liquor shows a light yellow coloration.
  • Example 1 in a nutrient solution according to Example I.
  • the glucose is replaced by other sugars or sugar alcohols and shaking flasks each containing 120 ml of culture solution are each inoculated with 1 ml of a primary culture of the strain SB 18 (manufactured according to Example 1 culture solutions containing the following amylase inhibitor concentrations are obtained after 3 or 4 days culture at 28C. on rotary shaking machines:
  • lfa nutrient solution consisting of 371 soya flour. 27: starch. 1% glucose. and 0.271 CaCO is inoculated and incubated in accordance with Example 15. a culture broth containing 5.600 AlU/ml is obtained after four days fermentation.
  • Example 17 If a mix according to Example 13 is inoculated and incubated with a morphological variant of SB 18. the strain SB 18/5. a culture broth containing 27.400 Al- U/ml is obtained after 4 days fermentation.
  • strain SB 18/5 was deposited at the Centraal- Bureau voor Schimmelcultures in Baarn. Holland. under CBS No. 613.71.
  • Example 18 If a mix according to Example 13 in inoculated and incubated with a morphological variant of SB 18. the strain SB 18/4. a culture broth containing 13.900 Al U/ml is obtained after 4 days fermentation.
  • strain SB 18/4 was deposited at the Centraal Bureau voor Schimmelcultures in Baarn. Holland. under CBS no. 612.71.
  • Example 19 If a nutrient solution of composition: 2% starch. 1'72 glucose. 0.371 glycine. 0.25% corn-steep liquor. 0.471 soya flour. 0.171 NaCl. 0.1% K- .HPO,. 0.01% FeSO and 0.017: CaCO is inoculated and incubated in accordance with Example 12. a culture broth containing 2.900 AlU/ml is obtained after 3 days incubation.
  • Example 20 If 2 flasks ofa mix according to Example 1 are inoculated with 1 ml of a primary culture of the strain SB 46 and incubated for 4 days at 28C. on a rotary shaking machine. 250 ml of supernatant liquor containing 250 AlU/ml are obtained after centrifuging.
  • Example 21 1f a 1 liter Erlenmeyer flask containing 120 m1 of a nutrient solution according to Example 1 is inoculated with 2 ml of a primary culture of the strain SE 5 (produced according to Example 4) and incubated for 7 days on a rotary shaking machine at 28C.. a culture broth containing 0.09 MlU/ml is obtained.
  • the mycelium is treated with 50 ml of acetone. homegenized for 1 minute on an Ultraturrax homogenizer (Messrs. Janke and Kunkel. Staugen. Breisgau) and the mixture is subsequently centrifuged for 10 minutes at 3.000 rpm. The residue is again extracted. in the same way. with 50 ml of acetone and subsequently extracted once with 50 ml of ether. and the three extracts are combined and concentrated almost to dryness in a rotary evaporator at approximately 10-20 mm Hg and a waterbath temperature of 37C. The mycelium residue is dried in vacuo and subsequently treated with 15 ml of dimethyl sulphoxide (DMSO).
  • DMSO dimethyl sulphoxide

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4010258A (en) * 1974-03-15 1977-03-01 Ajinomoto Co., Inc. Microbial amylase inhibitor and preparation thereof with the use of streptomyces diasticus var. amylostaticus
US4062950A (en) * 1973-09-22 1977-12-13 Bayer Aktiengesellschaft Amino sugar derivatives
US4065557A (en) * 1974-03-21 1977-12-27 Bayer Aktiengesellschaft Amino sugars and their use in improving the meat:fat ratio in animals
US4174439A (en) * 1977-05-04 1979-11-13 Bayer Aktiengesellschaft Process for isolating glucopyranose compound from culture broths
US4226764A (en) * 1977-01-19 1980-10-07 Hoechst Aktiengesellschaft α-Amylase inhibitor from a streptomycete and process for its preparation
US4271067A (en) * 1976-01-22 1981-06-02 Rhone-Poulenc Industries Glycopeptide
USRE30886E (en) * 1975-12-29 1982-03-23 Nippon Shinyaku Company Ltd. Method and composition for reducing blood glucose levels
US4990500A (en) * 1986-08-13 1991-02-05 Hoechst Aktiengesellschaft Oxirane pseudooligosaccharides, a process for their preparation, their use and pharmaceutical preparations
US5464828A (en) * 1988-03-02 1995-11-07 Chugai Pharmaceutical Co., Ltd. Aqueous suspension of sucralfate
US5753501A (en) * 1995-03-02 1998-05-19 Bayer Aktiengesellschaft Acarbose biosynthesis genes from actinoplanes sp., process for the isolation thereof and the use thereof
US6649755B1 (en) 1999-10-28 2003-11-18 Chong Kun Dang Pharmaceutical Corp. Process for preparing acarbose with high purity
US6734300B2 (en) 2001-10-26 2004-05-11 Va, Farmaceutska Industrija, Dd Acarbose purification process
KR100463738B1 (ko) * 1996-09-13 2005-05-03 바이엘 헬스케어 아게 아카르보스제조를위한삼투조절된발효방법
WO2013083566A1 (en) 2011-12-08 2013-06-13 Bayer Intellectual Property Gmbh New actinomycete integrative and conjugative element from actinoplanes sp. se50/110 as plasmid for genetic transformation of related actinobacteria
US8889633B2 (en) 2013-03-15 2014-11-18 Mead Johnson Nutrition Company Nutritional compositions containing a peptide component with anti-inflammatory properties and uses thereof
US9138455B2 (en) 2013-03-15 2015-09-22 Mead Johnson Nutrition Company Activating adiponectin by casein hydrolysate
US9289461B2 (en) 2013-03-15 2016-03-22 Mead Johnson Nutrition Company Reducing the risk of autoimmune disease
US9345727B2 (en) 2013-03-15 2016-05-24 Mead Johnson Nutrition Company Nutritional compositions containing a peptide component and uses thereof
US9345741B2 (en) 2013-03-15 2016-05-24 Mead Johnson Nutrition Company Nutritional composition containing a peptide component with adiponectin simulating properties and uses thereof
US9352020B2 (en) 2013-03-15 2016-05-31 Mead Johnson Nutrition Company Reducing proinflammatory response
US11802838B2 (en) 2020-03-23 2023-10-31 Bay State Milling Company Rapid high amylose wheat seed purity test

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2209834C3 (de) * 1972-03-01 1978-04-20 Bayer Ag, 5090 Leverkusen Herstellung von Saccharase-Inhibitoren
DE2209833C3 (de) * 1972-03-01 1978-06-01 Bayer Ag, 5090 Leverkusen Herstellung eines Amylaseinhibitors
DE2209832C3 (de) * 1972-03-01 1979-03-29 Bayer Ag, 5090 Leverkusen Herstellung von Saccharaseinhibitoren
DE2658563A1 (de) * 1976-12-23 1978-06-29 Bayer Ag Inhibitoren fuer glykosid-hydrolasen aus bacillen
GB2016497A (en) * 1978-02-10 1979-09-26 Taisho Pharmaceutical Co Ltd Microbiological production of amylase inhibitor
CA1121290A (en) * 1978-02-14 1982-04-06 Yasuji Suhara Amino sugar derivatives
JPS62160696A (ja) * 1986-01-07 1987-07-16 シャープ株式会社 電子式自動点滅器
EP0796915A3 (de) * 1996-03-22 1999-04-14 Bayer Ag Verfahren zur Herstellung sowie zur Verwendung von Acarviosyl-Transferase bei der Umwandlung von Acarbose-Homologen in Acarbose, zur Herstellung von Acarbose-Homologen
KR20220081991A (ko) 2019-10-16 2022-06-16 바이엘 악티엔게젤샤프트 아카르보스의 개선된 형성을 위한 방법

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US3127315A (en) * 1964-03-31 Hypocholesterolemic agent m-

Patent Citations (1)

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US3127315A (en) * 1964-03-31 Hypocholesterolemic agent m-

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4062950A (en) * 1973-09-22 1977-12-13 Bayer Aktiengesellschaft Amino sugar derivatives
US4010258A (en) * 1974-03-15 1977-03-01 Ajinomoto Co., Inc. Microbial amylase inhibitor and preparation thereof with the use of streptomyces diasticus var. amylostaticus
US4065557A (en) * 1974-03-21 1977-12-27 Bayer Aktiengesellschaft Amino sugars and their use in improving the meat:fat ratio in animals
USRE30886E (en) * 1975-12-29 1982-03-23 Nippon Shinyaku Company Ltd. Method and composition for reducing blood glucose levels
US4271067A (en) * 1976-01-22 1981-06-02 Rhone-Poulenc Industries Glycopeptide
US4226764A (en) * 1977-01-19 1980-10-07 Hoechst Aktiengesellschaft α-Amylase inhibitor from a streptomycete and process for its preparation
US4174439A (en) * 1977-05-04 1979-11-13 Bayer Aktiengesellschaft Process for isolating glucopyranose compound from culture broths
US4990500A (en) * 1986-08-13 1991-02-05 Hoechst Aktiengesellschaft Oxirane pseudooligosaccharides, a process for their preparation, their use and pharmaceutical preparations
US5464828A (en) * 1988-03-02 1995-11-07 Chugai Pharmaceutical Co., Ltd. Aqueous suspension of sucralfate
US5753501A (en) * 1995-03-02 1998-05-19 Bayer Aktiengesellschaft Acarbose biosynthesis genes from actinoplanes sp., process for the isolation thereof and the use thereof
KR100463738B1 (ko) * 1996-09-13 2005-05-03 바이엘 헬스케어 아게 아카르보스제조를위한삼투조절된발효방법
US6649755B1 (en) 1999-10-28 2003-11-18 Chong Kun Dang Pharmaceutical Corp. Process for preparing acarbose with high purity
US6734300B2 (en) 2001-10-26 2004-05-11 Va, Farmaceutska Industrija, Dd Acarbose purification process
WO2013083566A1 (en) 2011-12-08 2013-06-13 Bayer Intellectual Property Gmbh New actinomycete integrative and conjugative element from actinoplanes sp. se50/110 as plasmid for genetic transformation of related actinobacteria
US9217154B2 (en) 2011-12-08 2015-12-22 Bayer Intellectual Property Gmbh Actinomycete integrative and conjugative element from Actinoplanes sp. SE50/110 as plasmid for genetic transformation of related Actinobacteria
US9562249B2 (en) 2011-12-08 2017-02-07 Bayer Intellectual Property Gmbh Actinomycete integrative and conjugative element from Actinoplanes sp. SE50/110 as plasmid for genetic transformation of related actinobacteria
US8889633B2 (en) 2013-03-15 2014-11-18 Mead Johnson Nutrition Company Nutritional compositions containing a peptide component with anti-inflammatory properties and uses thereof
US9138455B2 (en) 2013-03-15 2015-09-22 Mead Johnson Nutrition Company Activating adiponectin by casein hydrolysate
US9289461B2 (en) 2013-03-15 2016-03-22 Mead Johnson Nutrition Company Reducing the risk of autoimmune disease
US9345727B2 (en) 2013-03-15 2016-05-24 Mead Johnson Nutrition Company Nutritional compositions containing a peptide component and uses thereof
US9345741B2 (en) 2013-03-15 2016-05-24 Mead Johnson Nutrition Company Nutritional composition containing a peptide component with adiponectin simulating properties and uses thereof
US9352020B2 (en) 2013-03-15 2016-05-31 Mead Johnson Nutrition Company Reducing proinflammatory response
US11802838B2 (en) 2020-03-23 2023-10-31 Bay State Milling Company Rapid high amylose wheat seed purity test

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