EP1381386A2 - Nouveaux melanges d'enzymes microbiens - Google Patents

Nouveaux melanges d'enzymes microbiens

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Publication number
EP1381386A2
EP1381386A2 EP02716661A EP02716661A EP1381386A2 EP 1381386 A2 EP1381386 A2 EP 1381386A2 EP 02716661 A EP02716661 A EP 02716661A EP 02716661 A EP02716661 A EP 02716661A EP 1381386 A2 EP1381386 A2 EP 1381386A2
Authority
EP
European Patent Office
Prior art keywords
fip
lipase
amylase
protease
enzymes
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Withdrawn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
EP02716661A
Other languages
German (de)
English (en)
Inventor
Manfred Galle
Peter-Colin Gregory
Andreas Potthoff
Friederike Henniges
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.)
Abbott Products GmbH
Original Assignee
Solvay Pharmaceuticals GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE10144711A external-priority patent/DE10144711A1/de
Application filed by Solvay Pharmaceuticals GmbH filed Critical Solvay Pharmaceuticals GmbH
Publication of EP1381386A2 publication Critical patent/EP1381386A2/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Withdrawn legal-status Critical Current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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes

Definitions

  • the present invention relates to new enzyme mixtures which contain a certain combination of microbial lipase, protease and amylase. Furthermore, the invention relates to pharmaceutical preparations containing these mixtures of microbial enzymes. These new pharmaceutical preparations are particularly well suited for the treatment and / or prophylaxis of maldigestion in mammals and humans, in particular for the treatment and / or prophylaxis of maldigestion based on chronic exocrine pancreatic insufficiency.
  • pancreatic insufficiency the organ that produces the most important endogenous digestive enzymes. If there is pathological pancreatic insufficiency, this can be congenital or acquired. Acquired chronic pancreatic insufficiency can be due to alcoholism, for example. Congenital pancreatic insufficiency can, for example, be due to the congenital disease of cystic fibrosis.
  • the consequences of the lack of digestive enzymes can be severe symptoms of malnutrition and malnutrition, which can be associated with an increased susceptibility to secondary diseases.
  • pancreatin preparations intended for oral administration should be coated with gastro-resistant protective layers to protect against acid-induced denaturation in the stomach.
  • gastro-resistant protective layers protect the acid-sensitive pancreatin components from irreversible destruction and only release their contents after passage through the stomach in the upper part of the small intestine, where usually higher, harmless pH values - for example between pH 5.5 and pH 8 - prevail.
  • the upper part of the small intestine for example the duodenum, is the place where the majority of the enzymatically split food components are usually absorbed by the body.
  • pancreatin Since pancreatin is a natural product, it requires a considerable amount of technical effort to provide it in a uniform, high-quality form. In addition, the supply of raw materials suitable for processing into pancreatin can fluctuate.
  • substitution enzymes In order to be suitable for the substitution of digestive enzymes in humans, all substitution enzymes must be one Fulfill a number of requirements (see, for example, BG Peschke, "Active Components and Galenic Aspects of Enzyme Preparations" in: Pancreatic Enzymes in Health and Disease, publisher: PG Lankisch, Springer Verlag Berlin, Heidelberg 1991, pages 55 to 64; hereinafter cited as “Peschke”).
  • these substitution enzymes should be stable to pepsin and other endogenous proteases such as pancreatic proteases. Substitution enzymes should remain active even in the presence of the body's bile salts.
  • the various substitution enzymes contained in the pharmaceutical preparation are able to develop their activities in sufficient amounts at the intended site of action (which is usually the upper part of the small intestine). Since under physiological conditions during or shortly after the food intake in the human stomach there is usually a higher pH value, for example pH 4-5, than in the empty stomach (approx.
  • the object of the present invention was therefore to provide improved mixtures of digestive enzymes and pharmaceutical compositions containing such mixtures for the treatment and / or prophylaxis of maldigestion in mammals and humans which can substitute the body's own lipolytic, proteolytic and amylolytic enzyme activities and which can be more specific Activity of the substitution enzymes contained therein allow relatively small dosage amounts.
  • the substitution enzymes contained in the digestive enzyme mixtures lipase, protease, amylase), both individually and in a mixture with one another, should meet as well as possible all the requirements which are placed on digestive enzymes intended for therapy in humans.
  • the substitution enzymes should have good pH stability and good pH activity in the pH range usually prevailing at the respective physiological site of action.
  • substitution enzymes should be well tolerated with endogenous active substances such as bile salts or endogenous proteases, for example pepsin or pancreatic proteases. Another object was to select, for the purpose according to the invention, those substitution enzymes which can be obtained in manufacturing quality which can always be standardized in terms of process sequence and product quantity and which can always be of constant quality and in any quantity.
  • the task is solved by providing a new mixture of microbial enzymes, which
  • a) a concentrated lipase from Rhizopus delemar, b) a neutral protease from Aspergillus melleus and c) an amylase from Aspergillus oryzae contains.
  • Mixtures of microbial enzymes according to the invention can be contained in conventional pharmaceutical preparations together with customary auxiliaries and / or carriers. These pharmaceutical preparations contain only mixtures according to the invention of microbial enzymes of certain molds as active substances and are suitable for the total substitution of the body's own digestive enzymes from mammals and humans.
  • the individual enzymes (lipase, protease, amylase) contained in the mixture of microbial enzymes according to the invention have in common that they are in the physiological to pathophysiological pH range of the digestive tract (approximately pH 4 to 8) and in particular below those at or shortly after eating prevailing conditions have good pH stability and good pH activity.
  • the pharmaceutical preparations are also characterized by good effectiveness and good tolerability.
  • the Rhizopus delemar strain is considered a subspecies of the Rhizopus oryzae strain. Lipases from molds of the Rhizopus delemar strain are known per se and can be used e.g. B. can be obtained by per se known methods from culture broths of the corresponding mushroom. Processes for the fermentation of molds and for the isolation of the enzyme products formed by these molds are known to the person skilled in the art, for example from relevant textbooks in biotechnology (cf., for example, H. Diekmann, H.
  • the isolated lipases z. B. freed from accompanying substances in a manner known per se and enriched or concentrated to the specific activity desired according to the invention.
  • the lipase (EC No. 3.1.1.3) "Lipase D Amano 2000 ® “(also referred to as” Lipase D2 ® ) from Rhizopus delemar from Amano Pharmaceuticals, Japan.
  • This lipase like the natural pancreatic lipase, has a 1,3-position specificity compared to fatty acid glycerides specific activity, depending on the batch, is between approximately 1,800,000 FIP-E / g and approximately 2,250,000 FIP-E / g.
  • "Lipase D Amano 2000 ®” is characterized by a high stability towards pancreatic protease from pancreatin the lipolytic activity of "Lipase D Amano 2000 ® " in a laboratory test after two hours of exposure to pancreatic protease from pancreatin in a pH range from pH 6 to 8 still at 55% of the initial activity.
  • the pH stability of the "Lipase D Amano 2000 ® " was in a laboratory test in a pH range from pH 4 to 8 at 37 ° C over a period of 120 min with at least 70% of the initial activity.
  • a concentrated lipase from Rhizopus delemar for example, its pH profile is suitable.
  • the pH profile of the "Lipase D Amano 2000®” was therefore determined as a specific activity as a function of the pH.
  • the specific activities at the individual pH values were measured after a modification of the FIP methods for determining the activity of microbial lipases.
  • the pH profiles were also determined in the presence of variable concentrations of bile salts.
  • Samples of 19 ml each at 37 ° C. are thermostatted from the above-mentioned substrate emulsions, in which certain bile salt concentrations are present.
  • pH values of 3, 4, 5, 6, 7 and 8 are then set by adding 0.1 M NaOH or 1 M HCl.
  • 1 ml of the above-mentioned enzyme solution is then added to the samples of substrate emulsions prepared in this way (note: in order to determine the optimal titration rate, the suitable amount of ideally contained lipase in the enzyme solution can in principle be determined in a manner known per se by means of a series of dilutions ).
  • An end point titration to pH 9 is then carried out within 30 seconds in order to completely dissociate the released fatty acids.
  • the total consumption of 0.1 M NaOH required is in lipase activity units E converted: a lipase activity unit E corresponds to a consumption of 1 ⁇ mol per minute.
  • the lipase activity units determined can be converted into units of E / mg by referring to the amount of dry enzymes used in g. To create the pH profile, the units of E / mg for each pH value and each bile salt concentration examined are tabulated in Table 1 and the tabulated values are graphically plotted in FIG. 1.
  • the pH optimum for "Lipase D Amano 2000 ®” as the maximum value of lipase activity at the FIP standard bile salt concentration of 0.5 mmol / l can be determined from the pH profile given above to be about pH 7.
  • the neutral protease from Aspergillus melleus has a specific activity of at least 7,500 FIP-E / g. Their pH optimum is between pH 6 and pH 8.
  • Neutral proteases of molds from the Aspergillus melleus strain are known per se and can be used e.g. B. can be obtained by per se known methods from culture broths of the corresponding mushroom. Processes for the fermentation of molds and for the isolation of the enzyme products formed by these molds are known to the person skilled in the art, for example from relevant textbooks in biotechnology (cf., for example, H. Diekmann, H. Metz, "Fundamentals and Practice of Biotechnology", Gustav Fischer Verlag Stuttgart, New York 1991) or from relevant scientific publications. If desired, the isolated proteases can then be freed of accompanying substances in a manner known per se and enriched or concentrated to the specific activity desired according to the invention.
  • the neutral protease "Prozyme 6 ®” (sometimes also referred to as "alkaline proteinase", EC No. 3.4.21.63) from Aspergillus melleus from Amano Pharmaceuticals, Japan, can be used.
  • This microbial Protease hydrolyzes 1,4- ⁇ -D-glucosidic bonds of polysaccharides which contain at least three 1,4-D-glucose units and has a specific activity of approximately 7,800 FIP-E / g.
  • the pH stability of the protease "Process e 6 ® " in a pH range from pH 5 to 8 at 37 ° C was over a period of 120 min. in a laboratory test with at least 60% of the initial activity.
  • a suitable parameter for determining a neutral protease from Aspergillus melleus is, for example, its pH profile.
  • the pH profile of the protease "Prozyme 6 ®” was therefore determined as a specific activity as a function of the pH.
  • various substrate solutions are produced in accordance with the regulations of the FIP method for determining the activity of pancreatic proteases.
  • a 4% hemoglobin solution is used instead of casein as the substrate solution.
  • different pH values of 2, 3, 4, 5, 6, 7 and 8 are set in various substrate solutions by adding appropriate amounts of IM NaOH or IM HCl. Samples of "Prozyme 6 ® " are added to the substrate solutions.
  • protease activities of the "Prozyme 6 ® " samples are then determined in the substrate solutions of different pH values in accordance with the FIP regulations mentioned above.
  • the measured values for the pH profile found for "Prozyme 6 ® " are tabulated in Table 2 and plotted in Fig. 2.
  • "Prozyme 6 ® " is therefore optimally effective in the physiological pH range. From the pH profile given above, the pH optimum for "Prozyme 6 ® " as the maximum value of the protease activity can be determined to be approximately pH 8.
  • Aspergillus oryzae amylase (EC No. 3.21.1.1) used according to the invention is an ⁇ -amylase and has a specific activity of at least 40,000 FIP-E / g (measured at pH 5.8).
  • the pH optimum is in the pH range from pH 4 to 6.5.
  • Amylases from molds of the Aspergillus oryzae strain are known per se and can, for. B. can be obtained by per se known methods from culture broths of the corresponding mushroom. Processes for the fermentation of molds and for the isolation of the enzyme products formed by these molds are known to the person skilled in the art, for example from relevant textbooks in biotechnology (cf., for example, H. Diekmann, H.
  • amylase AI ® from Aspergillus melleus from Amano Pharmaceuticals, Japan and "Amylase EC ®” from Aspergillus melleus from E Gra-Chemie, Germany can preferably be used. "Amylase AI ® " is preferred.
  • the microbial amylase "Amylase Al ®” has a specific activity of about 52,000 FIP-E / g (measured at pH 5.8).
  • the pH stability of the "Amylase AI ® " in a pH range from pH 5 to 8 at 37 ° C was over a period of 120 min. in a laboratory test with at least 85% of the initial activity. In further laboratory tests, good stabilities of the "Amylase AI ® " against pancreatic protease from pancreatin (measured in the pH range pH 6 to 8), against “Prozyme 6 ® " (measured in the pH range pH 4 to 8) and against pepsin were found.
  • a suitable parameter for determining an amylase from Aspergillus oryzae is, for example, its pH profile. The pH profile of the "Amylase AI ® " was therefore determined as a specific activity as a function of the pH.
  • Various substrate solutions are produced in accordance with the FIP method for determining the activity of microbial amylases.
  • various pH values of 3.25 each are obtained in various substrate solutions by adding appropriate amounts of 5 M NaOH or 5 M HCl to the acetate buffer used according to the FIP method; 4; 5; 6; 6.8 and 7.4 set.
  • Samples of "Amylase AI ®" are added to the substrate solutions.
  • amylase activities of the “Amylase Al® ” samples are then determined in substrate solutions of different pH values in accordance with the FIP regulations mentioned above.
  • the measured values for the pH profile found for "Amylase AI ®" are tabulated in Table 3 and plotted in Fig. 3.
  • the optimum pH for "Amylase AI ®” can be determined as the maximum value of the amylase activity at about pH 5.
  • the microbial amylase "Amylase EC ®” has a specific activity of about 42,500 FIP-E / g (measured at pH 5.8). In addition, small amounts of ß-amylase are still detectable.
  • the pH optimum (measured according to the method given above for Amylase AI ® ") is approximately pH 5.
  • solid orally administrable dosage forms can preferably be selected, for example powders, pellets or microspheres, which, if desired, can be filled into capsules or sachets or pressed into tablets.
  • Liquid pharmaceutical preparations such as suspensions or solutions may also be considered.
  • the individual enzymes lipase, protease and amylase can be present together or spatially separated from one another. If the individual enzymes are not spatially separated from one another, dry processing and / or storage is preferred.
  • the pharmaceutical preparations can furthermore contain customary auxiliaries and / or carriers.
  • auxiliaries and / or carriers are, for example, microcrystalline celluloses, polyethylene glycols, for example PEG 4000, or else lower alcohols, in particular straight-chain or branched C 1 -C 4 alcohols such as 2-propanol, and water.
  • the microbial substitution enzymes used according to the invention are notable for good stability over wide pH ranges and can therefore be used directly for the manufacture of pharmaceutical preparations to be administered orally without further treatment (such as filming).
  • the individual substitution enzymes lipase, protease and amylase
  • the individual substitution enzymes can be pelleted together or separately from one another.
  • the individual substitution enzymes can be filmed with a suitable, known gastric juice-resistant layer. Unless all substitution enzymes are to be film-coated in gastric juice-resistant form, it is advisable to pellet the individual types of substitution enzymes separately and to film the pellets of an enzyme type separately. men.
  • the protease and / or the lipase individually and to film them in an enteric coating.
  • all three enzymes present in the enzyme mixture can also be film-coated together with gastric juice-resistant or two enzymes can be film-coated with gastric juice-resistant while one enzyme is not being filmed.
  • the pharmaceutical preparation can be in the form of an orally administrable capsule of size 0. Even in such a dosage form there can be approximately 10,000-50,000 FIP-E lipase, 8,000 FIP-E amylase and 200 FIP-E protease.
  • the substitution enzymes lipase, amylase and protease are expediently present in a ratio of approximately 50-500 FIP-E: 40-120 FIP-E: 1 FIP-E.
  • the homogenate obtained was made up to a volume of 450 ml with ultrapure water.
  • bile dispersion (FIP standard; lipase activation ixture) was dissolved in 50 ml of ultrapure water.
  • the prepared measuring solution was heated to 37 ° C. and adjusted to pH 7 by end-point titration with 1 M NaOH. Immediately after adding the three enzyme solutions, a pH stat titration was carried out for 20 min. started and the consumption of 1 M NaOH was registered every 10 sec. During the titration, 1 ml of a 4 M calcium chloride solution was added manually in steps of 50 ⁇ l in such a way that a maximum reaction rate was achieved. F) Result
  • the good fat digestion performance of a digestive enzyme mixture containing the enzymes which can be used according to the invention can also be demonstrated in vitro on an olive oil test food.
  • Chymus samples were taken from the diversion cannula over 12 hours each on the 20th to 22nd day of the examination period and these were examined for their content of crude fat, crude protein and starch.
  • the feeding experiments and their evaluation were carried out in a manner known per se (cf. PC Gregory, R. Tabeling, J. Kamphues, "Biology of the Pancreas in Growing Animals”; Developments in Animal and Veterinary Sciences 28 (1999) 381-394, Elsevier, Amsterdam; Ed .: SG Pierzynowski and R. Zabielski).
  • precaecal digestibility The apparent precaecal digestibility of crude fat, crude protein and starch in the test animals determined in the aforementioned in vivo test is given in Table A below in percentages, based on the originally fed absolute amount of fat, protein and starch.
  • the values given as “precaecal digestibility” correspond to the "apparent precaecal digestibility", which differ from the actual precaecal digestibility in that they can also contain small amounts of endogenous fractions of the investigated substances, for example endogenous proteins.
  • the precaecal digestibility was determined using the following formula from the chyme of the test animals using the marker method:
  • SV (%) 100 - (% indicator in the F utter% Mahrstoff in chyme 100)% indicator in chyme% nutrient in the diet

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Nutrition Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne de nouveaux mélanges d'enzymes microbiens contenant une lipase concentrée de Rhizopus delemar et en plus une protéase d'Aspergillus melleus ainsi qu'une amylase d'Aspergillus oryzae. L'invention concerne également des préparations pharmaceutiques contenant ces mélanges d'enzymes microbiens. Ces nouvelles préparations pharmaceutiques sont notamment particulièrement adaptées au traitement et/ou à la prévention de troubles digestifs, notamment de troubles digestifs dus à une insuffisance pancréatique, chez les animaux mammifères et chez l'homme.
EP02716661A 2001-01-19 2002-01-16 Nouveaux melanges d'enzymes microbiens Withdrawn EP1381386A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10102495 2001-01-19
DE10102495 2001-01-19
DE10144711A DE10144711A1 (de) 2001-01-19 2001-09-11 Neue Gemische mikrobieller Enzyme
DE10144711 2001-09-11
PCT/EP2002/000374 WO2002060474A2 (fr) 2001-01-19 2002-01-16 Nouveaux melanges d'enzymes microbiens

Publications (1)

Publication Number Publication Date
EP1381386A2 true EP1381386A2 (fr) 2004-01-21

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EP02716661A Withdrawn EP1381386A2 (fr) 2001-01-19 2002-01-16 Nouveaux melanges d'enzymes microbiens

Country Status (17)

Country Link
US (1) US20040057944A1 (fr)
EP (1) EP1381386A2 (fr)
JP (1) JP2004524838A (fr)
CN (1) CN1236817C (fr)
AR (1) AR032392A1 (fr)
BR (1) BR0206521A (fr)
CA (1) CA2434808A1 (fr)
CZ (1) CZ20031900A3 (fr)
HU (1) HUP0500560A3 (fr)
IL (1) IL157004A0 (fr)
MX (1) MXPA03005960A (fr)
NO (1) NO20033261D0 (fr)
NZ (1) NZ527148A (fr)
PL (1) PL362646A1 (fr)
RU (1) RU2003124078A (fr)
SK (1) SK9292003A3 (fr)
WO (1) WO2002060474A2 (fr)

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CA2434808A1 (fr) 2002-08-08
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RU2003124078A (ru) 2005-01-27
CN1487837A (zh) 2004-04-07
HUP0500560A3 (en) 2006-06-28
BR0206521A (pt) 2004-02-17
PL362646A1 (en) 2004-11-02
HUP0500560A2 (hu) 2005-09-28
MXPA03005960A (es) 2003-09-05
IL157004A0 (en) 2004-02-08
NO20033261D0 (no) 2003-07-18
CZ20031900A3 (cs) 2003-10-15
WO2002060474A2 (fr) 2002-08-08
US20040057944A1 (en) 2004-03-25
JP2004524838A (ja) 2004-08-19
AR032392A1 (es) 2003-11-05
SK9292003A3 (en) 2003-12-02
CN1236817C (zh) 2006-01-18

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