EP1381386A2 - Gemische von enzymen aus pilzen und deren verwendung zur behandlung der maldigestion - Google Patents

Gemische von enzymen aus pilzen und deren verwendung zur behandlung der maldigestion

Info

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Withdrawn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)
French (fr)
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/de
Withdrawn legal-status Critical Current

Links

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

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (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)
EP02716661A 2001-01-19 2002-01-16 Gemische von enzymen aus pilzen und deren verwendung zur behandlung der maldigestion Withdrawn EP1381386A2 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10102495 2001-01-19
DE10102495 2001-01-19
DE10144711 2001-09-11
DE10144711A DE10144711A1 (de) 2001-01-19 2001-09-11 Neue Gemische mikrobieller Enzyme
PCT/EP2002/000374 WO2002060474A2 (de) 2001-01-19 2002-01-16 Gemische von enzymen aus pilzen und deren verwendung zur behandlung der maldigestion

Publications (1)

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

Family

ID=26008287

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02716661A Withdrawn EP1381386A2 (de) 2001-01-19 2002-01-16 Gemische von enzymen aus pilzen und deren verwendung zur behandlung der maldigestion

Country Status (17)

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

Families Citing this family (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6632429B1 (en) * 1999-12-17 2003-10-14 Joan M. Fallon Methods for treating pervasive development disorders
US20010046493A1 (en) * 2000-02-24 2001-11-29 Alex Margolin Lipase-containing composition and methods of use thereof
US20070053895A1 (en) * 2000-08-14 2007-03-08 Fallon Joan M Method of treating and diagnosing parkinsons disease and related dysautonomic disorders
IT1319655B1 (it) 2000-11-15 2003-10-23 Eurand Int Microsfere di enzimi pancreatici con elevata stabilita' e relativometodo di preparazione.
US8030002B2 (en) 2000-11-16 2011-10-04 Curemark Llc Methods for diagnosing pervasive development disorders, dysautonomia and other neurological conditions
US8100844B2 (en) * 2002-04-25 2012-01-24 Ultraflex Systems, Inc. Ambulating ankle and knee joints with bidirectional dampening and assistance using elastomeric restraint
KR20060127857A (ko) * 2003-10-29 2006-12-13 알투스 파마슈티컬스 인코포레이티드 혈장 콜레시스토키닌(ｃｃｋ) 농도 조절 및 통증 치료를위한 비-췌장 프로테아제
AU2005227090B2 (en) 2004-03-22 2010-12-09 Abbott Laboratories Gmbh Oral pharmaceutical compositions of lipase-containing products, in particular of pancreatin, containing surfactants
RU2389504C2 (ru) * 2004-05-24 2010-05-20 Новозимс А/С Ферменты для фармацевтического применения
US20060198838A1 (en) * 2004-09-28 2006-09-07 Fallon Joan M Combination enzyme for cystic fibrosis
UA91521C2 (ru) * 2004-10-14 2010-08-10 Элтус Фармасьютикалз Инк. Композиции, содержащие липазу, протеазу и амилазу, предназначенные для лечения недостаточности поджелудочной железы
BRPI0611932A2 (pt) * 2005-06-24 2011-01-04 Novozymes As amilase, uso da mesma, composição farmacêutica, e, método para o tratamento de uma doença
BRPI0611936A2 (pt) * 2005-06-24 2011-02-22 Solvay Pharm Gmbh protease, uso de uma protease, composição farmacêutica, e, método para o tratamento de doença
CN101208429A (zh) * 2005-06-24 2008-06-25 诺维信公司 用于药物用途的脂肪酶
US20070148151A1 (en) 2005-07-29 2007-06-28 Martin Frink Processes for the manufacture and use of pancreatin
US11266607B2 (en) 2005-08-15 2022-03-08 AbbVie Pharmaceuticals GmbH Process for the manufacture and use of pancreatin micropellet cores
US9198871B2 (en) 2005-08-15 2015-12-01 Abbott Products Gmbh Delayed release pancreatin compositions
EP1931317B1 (en) * 2005-08-15 2008-12-24 Solvay Pharmaceuticals GmbH Pancreatin micropellets suitable for enteric coating
US20080058282A1 (en) 2005-08-30 2008-03-06 Fallon Joan M Use of lactulose in the treatment of autism
US20070116695A1 (en) * 2005-09-21 2007-05-24 Fallon Joan M Pharmaceutical preparations for attention deficit disorder, attention deficit hyperactivity disorder and other associated disorders
US20100196344A1 (en) * 2005-10-14 2010-08-05 Cystic Fibrosis Foundation Therapeutics, Inc. Compositions and methods for treating pancreatic insufficiency
US8071089B2 (en) * 2005-11-01 2011-12-06 Bio-Cat, Inc. Composition with a fungal (yeast) lipase and method for treating lipid malabsorption in cystic fibrosis as well as people suffering from pancreatic lipase insufficiency
US10072256B2 (en) 2006-05-22 2018-09-11 Abbott Products Gmbh Process for separating and determining the viral load in a pancreatin sample
US20080081035A1 (en) * 2006-10-03 2008-04-03 National Enzyme Company Therapeutic protease compositions
JP2010510310A (ja) 2006-11-22 2010-04-02 スタンダード バイオロジックス インコーポレイテッド コウジカビプロテアーゼを使用する処置の方法
US8273348B2 (en) 2006-12-21 2012-09-25 Novozymes A/S Lipase variants for pharmaceutical use
US20080199448A1 (en) * 2007-02-16 2008-08-21 Ross Mairi R Enzyme composition for improving food digestion
ES2674681T3 (es) 2007-02-20 2018-07-03 Allergan Pharmaceuticals International Limited Composiciones estables de enzimas digestivas
US20090068174A1 (en) * 2007-09-12 2009-03-12 Kansas University Medical Center Research Institute, Inc. Therapeutic alkaline protease compositions and use in facilitating the transport of agents across the gastrointestinal mucosal lining
US20090130063A1 (en) * 2007-11-15 2009-05-21 Solvay Pharmaceuticals Gmbh Process for separating and determining the viral load in a pancreatin sample
AU2008333313A1 (en) 2007-12-04 2009-06-11 Novozymes A/S Protease variants for pharmaceutical use
US20110008423A1 (en) * 2008-01-03 2011-01-13 Abbott Products Gmbh Pharmaceutical compositions comprising granules of purified microbial lipase and methods for preventing or treating digestive disorders
US10087493B2 (en) 2008-03-07 2018-10-02 Aptalis Pharma Canada Ulc Method for detecting infectious parvovirus in pharmaceutical preparations
US8658163B2 (en) 2008-03-13 2014-02-25 Curemark Llc Compositions and use thereof for treating symptoms of preeclampsia
US8084025B2 (en) 2008-04-18 2011-12-27 Curemark Llc Method for the treatment of the symptoms of drug and alcohol addiction
US9320780B2 (en) 2008-06-26 2016-04-26 Curemark Llc Methods and compositions for the treatment of symptoms of Williams Syndrome
US20090324730A1 (en) * 2008-06-26 2009-12-31 Fallon Joan M Methods and compositions for the treatment of symptoms of complex regional pain syndrome
WO2010002972A1 (en) * 2008-07-01 2010-01-07 Curemark, Llc Methods and compositions for the treatment of symptoms of neurological and mental health disorders
US10776453B2 (en) * 2008-08-04 2020-09-15 Galenagen, Llc Systems and methods employing remote data gathering and monitoring for diagnosing, staging, and treatment of Parkinsons disease, movement and neurological disorders, and chronic pain
WO2010037695A1 (en) * 2008-09-30 2010-04-08 Dsm Ip Assets B.V. Enzyme composition and application thereof in the treatment of pancreatic insufficiency
US20100092447A1 (en) 2008-10-03 2010-04-15 Fallon Joan M Methods and compositions for the treatment of symptoms of prion diseases
AU2015252099B2 (en) * 2009-01-06 2017-08-10 Galenagen, Llc Compositions and methods for the treatment or prevention of staphylococcus aureus infections and for the eradication or reduction of staphylococcus aureus on surfaces
NZ593831A (en) 2009-01-06 2013-09-27 Curelon Llc Compositions and methods for the treatment or prevention of staphylococcus aureus infections and for the eradication or reduction of staphylococcus aureus on surfaces
ES2727746T3 (es) 2009-01-06 2019-10-18 Galenagen Llc Composiciones orales para el tratamiento o la prevención de infecciones por E. Coli
US9056050B2 (en) * 2009-04-13 2015-06-16 Curemark Llc Enzyme delivery systems and methods of preparation and use
WO2011050135A1 (en) 2009-10-21 2011-04-28 Curemark Llc Methods and compositions for the prevention and treatment of influenza
MX2012010755A (es) * 2010-03-19 2013-03-08 Aptalis Pharma Canada Inc Composiciones farmaceuticas de enzimas gastro-resistentes.
RS53587B1 (en) 2010-10-01 2015-02-27 Aptalis Pharma Limited ENTERICALLY LOWER PANCRELIPASE FORMULATIONS
CA2822637C (en) 2010-12-22 2020-06-30 Novozymes North America, Inc. Processes for producing fermentation products
WO2012145651A2 (en) 2011-04-21 2012-10-26 Curemark, Llc Compounds for the treatment of neuropsychiatric disorders
ES2734221T3 (es) 2011-08-08 2019-12-04 Allergan Pharmaceuticals Int Ltd Método para la prueba de disolución de composiciones sólidas que contienen enzimas digestivas
US20140315243A1 (en) * 2011-12-02 2014-10-23 Novozymes A/S Processes for producing fermentation products
US10350278B2 (en) 2012-05-30 2019-07-16 Curemark, Llc Methods of treating Celiac disease
ES2681343T3 (es) 2012-09-19 2018-09-12 Grespo Ab Composiciones para la mejora de la función cerebral
CN105209062A (zh) 2013-03-15 2015-12-30 阿普塔利斯制药有限公司 适于经肠施用的包含消化酶和营养物的组合物
US11939552B2 (en) 2013-06-24 2024-03-26 Novozymes A/S Process of recovering oil
WO2014209789A1 (en) 2013-06-24 2014-12-31 Novozymes A/S Process of extracting oil from thin stillage
AU2014304176A1 (en) * 2013-07-22 2016-02-11 Aptalis Pharma Ltd. High potency pancreatin pharmaceutical compositions
WO2015020943A2 (en) 2013-08-09 2015-02-12 Aptalis Pharma Ltd. Digestive enzyme composition suitable for enteral administration
MX2016000480A (es) 2013-11-05 2016-10-21 Allergan Pharmaceuticals Int Ltd Composiciones farmaceuticas de pancreatina de alta potencia.
JP2017519490A (ja) 2014-06-19 2017-07-20 アプタリス ファルマ リミテッド 膵臓抽出物からのウイルス汚染の除去方法
GB201501081D0 (en) 2015-01-22 2015-03-11 Cilian Ag Use of enzymes with a wide pH activity range as medicaments for promoting digestion
WO2016126970A1 (en) 2015-02-04 2016-08-11 Abbvie Inc. Pharmaceutical compositions and methods of use thereof to treat pancreatic enzyme insufficiency
US20200291375A1 (en) * 2017-09-24 2020-09-17 Bio-Cat, Inc. Fungal protease mixtures and uses thereof
FR3079146B1 (fr) 2018-03-23 2020-04-17 Karim Ioualalen Formulation gastroprotectrice de complexes d’enzymes permettant de restaurer la fonction digestive.
FR3111559A1 (fr) * 2020-06-18 2021-12-24 Azurrx Biopharma, Inc. Formulations non porcines et leurs procédés
US11541009B2 (en) 2020-09-10 2023-01-03 Curemark, Llc Methods of prophylaxis of coronavirus infection and treatment of coronaviruses

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1084431A (en) * 1964-05-06 1967-09-20 Analyses Et De Rech S Biolog M Improvements in and relating to lipases
DE2638088C3 (de) * 1976-08-24 1979-06-21 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler, 6000 Frankfurt Verwendung von SuBmolkenpulver
JP3152958B2 (ja) * 1991-06-14 2001-04-03 天野エンザイム株式会社 微生物起源リパーゼの安定化組成物及び安定化法
DE4332985A1 (de) * 1993-09-28 1995-03-30 Konrad Peter Maria Dr Sommer Arzneimittel zur Behandlung der Dysfunktion des exokrinen Pankreas
US5750104A (en) * 1996-05-29 1998-05-12 Digestive Care Inc. High buffer-containing enteric coating digestive enzyme bile acid compositions and method of treating digestive disorders therewith
US6013680A (en) * 1997-10-21 2000-01-11 Amano Pharmaceutical Co., Ltd. Digestive enzyme-containing medicament

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02060474A2 *

Also Published As

Publication number Publication date
RU2003124078A (ru) 2005-01-27
CN1236817C (zh) 2006-01-18
HUP0500560A3 (en) 2006-06-28
WO2002060474A2 (de) 2002-08-08
CN1487837A (zh) 2004-04-07
JP2004524838A (ja) 2004-08-19
NZ527148A (en) 2005-01-28
SK9292003A3 (en) 2003-12-02
MXPA03005960A (es) 2003-09-05
NO20033261L (no) 2003-07-18
BR0206521A (pt) 2004-02-17
HUP0500560A2 (hu) 2005-09-28
US20040057944A1 (en) 2004-03-25
WO2002060474A3 (de) 2003-10-30
PL362646A1 (en) 2004-11-02
AR032392A1 (es) 2003-11-05
NO20033261D0 (no) 2003-07-18
IL157004A0 (en) 2004-02-08
CZ20031900A3 (cs) 2003-10-15
CA2434808A1 (en) 2002-08-08

Similar Documents

Publication Publication Date Title
EP1381386A2 (de) Gemische von enzymen aus pilzen und deren verwendung zur behandlung der maldigestion
DE69634248T2 (de) Zusammensetzungen zur verbesserung der verdaulichkeit und ausnutzung von nähestoffen
DE2626109C2 (cs)
DE502007010071C5 (de) Verwendung einer zusammensetzung aus mineralstoffen und gegebenenfalls acetogenen und/oder butyrogenen bakterien zur vermeidung oder reduzierung von gasbildung im dickdarm eines säugetiers und dadurch bedingter abdominaler beschwerden
EP2391382B1 (de) Pharmazeutisches präparat enthaltend lipase bakteriellen ursprungs
EP2445510B1 (de) Zusammensetzung zur behandlung von degenerativen gelenkerkrankungen
DE60004879T2 (de) Tierfuttermittelzusatz
DE202006021153U1 (de) Stabile, haltbare Granulate mit aktiven Mitteln
WO2000054799A2 (de) Arzneimittel zur behandlung von diabetes
DD300405A5 (de) Pharmazeutische rezepturen
EP1858536A2 (de) Arzneimittel aus pflanzenextrakten als lipaseinhibitor
WO2003051345A2 (de) Verwendung von verdauungsenzymgemischen zur behandlung pathologischer bakterieller überwucherung des dünndarms von säugetieren und menschen
DE60304723T2 (de) VERZWEIGTE ALPHA-GLUCANE FüR DAS GEWICHTSMANAGEMENT
EP1330262A1 (de) Verwendung von aus ciliaten gewonnenen enzymen als verdauungsfördernde arzneimittel
EP3525769B1 (de) Schmelztablette enthaltend burlulipase und daraus hergestellte pharmazeutische zusammensetzung
DE2935546C2 (de) Diätetische Lebensmittel mit Monoglyceriden von Fettsäuren
DE60037197T2 (de) Verwendung funktioneller oraler präparate
EP1687014B1 (de) Verwendung einer zusätzlich fermentierten getreideschlempe zur vorbeugung und/oder behandlung erhähter blutzucker-werte
DE10144711A1 (de) Neue Gemische mikrobieller Enzyme
DE2006514C3 (de) Ein Verfahren zur Herstellung von proteolytischen enzymatischen Produkten, die in vivo dem Schleim des Darmkanals, dem Bronchialschleim und dem Zervixschleim die optimale Viskosität verleihen und deren Verwendung als Zusatz in Nahrungs- und Futtermitteln
DE102017104482A1 (de) Pharmazeutische Zusammensetzung umfassend Pankreatin und einen lipasehaltigen Überzug
DE4236064C2 (de) Selektiv-toxisches Mittel und seine Verwendung
EP0341527A2 (de) Mittel zur Wachstumssteigerung bei Tieren
EP1902723A1 (de) Arzneimittel aus Extrakten von Capsicum, Knoblauch und/oder Sabal als Lipaseinhibator
DE2315006A1 (de) Pankreasenzympraeparat

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17P Request for examination filed

Effective date: 20040503

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060201