WO2000032168A1 - Utilisation of capsules containing one or more antigenic substances for the prevention and/or treatment of autoimmune diseases - Google Patents

Utilisation of capsules containing one or more antigenic substances for the prevention and/or treatment of autoimmune diseases Download PDF

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Publication number
WO2000032168A1
WO2000032168A1 PCT/DE1999/003687 DE9903687W WO0032168A1 WO 2000032168 A1 WO2000032168 A1 WO 2000032168A1 DE 9903687 W DE9903687 W DE 9903687W WO 0032168 A1 WO0032168 A1 WO 0032168A1
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capsules
use according
antigenic substances
neutral
treatment
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PCT/DE1999/003687
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German (de)
French (fr)
Inventor
Hans-Jürgen HAHN
Hans-Werner Heinrich
Udo Meyer
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Bioserv Ag
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Priority to JP2000584864A priority Critical patent/JP2002531391A/en
Priority to EP99962060A priority patent/EP1135107A1/en
Priority to AU18562/00A priority patent/AU1856200A/en
Priority to CA002352487A priority patent/CA2352487A1/en
Publication of WO2000032168A1 publication Critical patent/WO2000032168A1/en

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    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to the use of capsules, in particular microcapsules, in which one or more antigenic substances are included, for maintaining the state of immune tolerance in organisms and for the prevention and / or treatment of autoimmune diseases.
  • IDDM insulin-dependent diabetes
  • rheumatoid arthritis are characterized by the destruction of the body's own parenchymatous cells by the body's own immune cells.
  • a genetic load and triggered by exogenous stimuli environment
  • a disproportionate increase in autoimmune diseases could be observed in the last decade, so that the health-political and health-related importance of these diseases steadily increased.
  • a morbidity of 1.5% was calculated for the IDDM in the industrialized nations.
  • Japan and the EU approximately 11.5 million patients with IDDM can therefore be assumed, which, at an average age of 16, cause enormous costs for life. It is currently assumed that the number of prediabetics, ie subjects with the potential risk of developing IDDM, can be identical.
  • other autoimmune diseases especially rheumatoid arthritis, the incidence of the disease is even higher.
  • the object of the invention was therefore to find substances and to package them by suitable methods so that they are protected against the degrading action of the digestive enzymes. This should make it possible to use these substances, in particular as a food component, for the prevention of autoimmune diseases in small quantities, without genetic engineering and / or their elaborate purification.
  • the invention assumes that the selective decrease in external stimuli is of primary importance for the onset of autoimmune diseases.
  • All mammals including the In their phylogenetic development, humans have developed mechanisms which prevent the ingested food from acting as an antigenic stimulus, so that the food supplied acts as an energy source and not as a potential antigen load. Mammals are immunologically tolerant of the food components that, due to their intermittent intake, maintain this tolerance for life. In the event of long-lasting drastic changes in eating habits, there is a possibility of an inadequate or insufficient antigen supply, so that a partial or total intolerance to the food can develop consecutively.
  • the capsules are preferably mixed as a food additive with the mixed antigen contained therein, the usual foods such as meat, milk, cereals, delicatessen and / or juice products so that the components can be administered in a tasteless and odorless manner.
  • the food produced in this way causes a state of immune tolerance to the administered antigen mixtures through continuous and lifelong intake and thereby helps to prevent the development of an autoimmune disease.
  • the invention furthermore has the advantage that the intermittent but lifelong continuous supply of the enriched antigens means that effectiveness can be expected even without the diagnosis of acute autoimmunity flare-ups.
  • the invention relates to the use of taste-neutral capsules, in which one or more antigenic substances are included, for maintaining the state of an immune tolerance in mammalian organisms, for the prophylaxis and / or treatment of autoimmune diseases, such as e.g. insulin-dependent diabetes (IDDM), multiple sclerosis and / or rheumatoid arthritis, polysaccharides, polyesters and polyamides which are customary per se being used as the shell material of the capsules, alone or in combinations.
  • IDDM insulin-dependent diabetes
  • multiple sclerosis and / or rheumatoid arthritis polysaccharides
  • polyesters and polyamides which are customary per se being used as the shell material of the capsules, alone or in combinations.
  • digestible oligosaccharides and / or polysaccharides e.g. Alginic acid, polymers of alginic acid, alginates, pectins and / or xanthans, optionally together with a physiologically tolerable metal salt, such as e.g. a calcium salt used, which additionally contain digestible constituents in the capsule wall with a ratio of 30% to 80%, preferably mono-, oligo- and / or polysaccharides, (poly) hydroxycarboxylic acids, fatty acids and their salts and derivatives and amino acids , their salts and their derivatives.
  • a physiologically tolerable metal salt such as e.g. a calcium salt used
  • Antigenic substances to be encapsulated are preferably organs, tissues, cells or cell contents of animal or plant organisms in treated or untreated form, the human equivalents of which can be damaged or destroyed by an autoimmune reaction so-called inferior food, such as the brain, pancreas, cartilage and / or offal.
  • encapsulated porcine pancreas or encapsulated porcine pancreatic islets are used for the prophylaxis and / or treatment of insulin-dependent diabetes (IDDM), starch is optionally added to the alginate.
  • IDDM insulin-dependent diabetes
  • the capsules for maintaining the state of immune tolerance are added to any substance, preferably to a food, preferably to meat, milk, cereals, delicatessen and / or juice products, during or after manufacture, without the sensory properties to influence the end product sustainably.
  • the invention also relates to taste-neutral capsules, comprising a casing material which is conventional per se and in which one or more antigenic substances, preferably in the form of mixed proteins, are encapsulated for the prophylaxis and / or treatment of autoimmune diseases, preferably IDDM, multiple sclerosis and / or rheumatoid Arthritis, where the antigenic substances are essential mixed proteins of all naturally occurring antigens or a part thereof, as they occur in so-called inferior food, and the capsules preferably have a size of 0.2 ⁇ m to 500 ⁇ m, for microcapsules preferably 0.5 ⁇ m to 20 ⁇ m.
  • IDDM insulin-dependent diabetes
  • the effectiveness of the "designer food” was demonstrated by tests on BB rats and NOD mice, animals that develop an IDDM.
  • the decisive advantage of the procedure according to the invention lies in the use of all naturally occurring antigens (application as enriched mixed antigens), since on the one hand the detection of autoantibodies (and thus a partial intolerance) against> 15 proteins with IDDM clearly relativized the importance of a single protein, so that the singular protein application clearly limits the preventive efficiency.

Abstract

The invention relates to the utilisation of capsules, especially micro-capsules, comprising one or more antigenic substances for maintaining the state of immune tolerance in organisms and for preventing and/or treating autoimmune diseases.

Description

Verwendung von Kapseln, die eine oder mehrere antigeneUse capsules that contain one or more antigens
Substanzen enthalten, zur Prävention und/oder Behandlung von Autoimmunerkran ungenContain substances for the prevention and / or treatment of autoimmune diseases
Die Erfindung betrifft die Verwendung von Kapseln, insbesondere von Mikrokapseln, in denen eine oder mehrere antigene Substanzen eingeschlossen sind, zum Erhalt des Zustandes der Immuntoleranz in Organismen sowie zur Prävention und/oder Behandlung von Autoimmunerkrankungen.The invention relates to the use of capsules, in particular microcapsules, in which one or more antigenic substances are included, for maintaining the state of immune tolerance in organisms and for the prevention and / or treatment of autoimmune diseases.
Spätestens, nachdem erkannt wurde, daß Vitaminmangel das Entstehen von Krankheiten verursacht, besteht Einigkeit darüber, daß die quantitative und qualitative Zusammensetzung der Nahrung die Gesundheit entscheidend beeinflußt. Neben einem absoluten Mangel durch eine generell verminderte Aufnahme essentieller Nahrungsmittelbestandteile (z.B. Hunger) kann ein ähnlicher Zustand auch bei langfristigen Veränderungen der Ernährungsgewohnheiten (absoluter Mangel essentieller Bestandteile bei kalorisch ausreichender Nahrungsaufnahme) beobachtet werden.At the latest after it has been recognized that vitamin deficiency causes disease to develop, there is agreement that the quantitative and qualitative composition of food has a decisive influence on health. In addition to an absolute deficiency due to a generally reduced intake of essential food components (e.g. hunger), a similar condition can also be observed in the case of long-term changes in eating habits (absolute deficiency of essential components with adequate caloric intake).
Autoimmunerkrankungen, wie der insulinabhängige Diabetes (IDDM), die Multiple Sklerose und Rheumatoide Arthritis, sind durch eine Zerstörung körpereigener parenchymatöser Zellen durch körpereigene Immunzellen charakterisiert. Basierend auf einer genetischen Belastung und ausgelöst durch exogene Reize (Umwelt) konnte in der letzten Dekade eine überproportionale Zunahme von Autoimmunerkrankungen beobachtet werden, so daß die gesundheitspolitische und kassenärztliche Bedeutung dieser Erkrankungen stetig zunahm. So wurde beispielsweise für den IDDM in den Industrienationen eine Morbidität von 1,5 % errechnet. In den USA, Japan und der EU kann daher von ca. 11,5 Mill. Patienten mit IDDM ausgegangen werden, die bei einem durchschnittlichen Manifestationsalter von 16 Jahren lebenslang enorme Kosten verursachen. Gegenwärtig wird angenommen, daß die Zahl der Prädiabetiker, d.h. Probanden mit dem potentiellen Risiko, an IDDM zu erkranken, identisch hoch sein kann. Bei anderen Autoimmunerkrankungen insbesondere der Rheumatoiden Arthritis, ist die Erkrankungsinzidenz noch höher.Autoimmune diseases such as insulin-dependent diabetes (IDDM), multiple sclerosis and rheumatoid arthritis are characterized by the destruction of the body's own parenchymatous cells by the body's own immune cells. Based on a genetic load and triggered by exogenous stimuli (environment), a disproportionate increase in autoimmune diseases could be observed in the last decade, so that the health-political and health-related importance of these diseases steadily increased. For example, a morbidity of 1.5% was calculated for the IDDM in the industrialized nations. In the USA, Japan and the EU, approximately 11.5 million patients with IDDM can therefore be assumed, which, at an average age of 16, cause enormous costs for life. It is currently assumed that the number of prediabetics, ie subjects with the potential risk of developing IDDM, can be identical. In other autoimmune diseases, especially rheumatoid arthritis, the incidence of the disease is even higher.
Durch familien- und populationsgenetische Untersuchungen und durch immunologische Diagnostik ( insbesondere dem Nachweis von Autoantikörpern) werden zur Zeit ca.10 % der Prädiabetiker als Hochrisikoprobanden eingestuft, die therapiert werden müßten. Allerdings sind die bisher vorgeschlagenen Therapiestrategien (intermittierende Insulingabe, temporäre Immunsuppression, NAD- Applikation) nicht geeignet, die Manifestation der Erkrankung zu verhindern, da der phasenhafte Verlauf der Zellzerstörungen nicht eindeutig diagnostizierbar und deshalb auch kaum therapierbar ist.Family and population genetic studies and immunological diagnostics (especially the detection of autoantibodies) currently classify around 10% of prediabetic patients as high-risk subjects who should be treated. However, the previously proposed therapy strategies (intermittent insulin administration, temporary immunosuppression, NAD application) are not suitable for preventing the manifestation of the disease, since the phased course of the cell destruction cannot be clearly diagnosed and can therefore hardly be treated.
Aus tierexperimentellen Untersuchungen ist bekannt, daß durch Langzeitverfütterung einzelner Substanzen, die mit dem IDDM in Beziehung stehen (z.B. Insulin, GAD) , an prädiabetische Versuchstiere die Manifestation des IDDM verhindert werden kann (Nat. Med. (1997) 7:793-796; Diabetologica (1997) 40:902-909). Diese Substanzen müssen hochgereinigt oder als gentechnisch veränderte Organismen (GVO) in einer bestimmten Verarbeitungsstufe aufgenommen werden.It is known from animal experiments that long-term feeding of individual substances related to the IDDM (eg insulin, GAD) to prediabetic experimental animals can prevent the manifestation of the IDDM (Nat. Med. (1997) 7: 793-796; Diabetologica (1997) 40: 902-909). These substances have to be highly purified or ingested as genetically modified organisms (GMOs) in a certain processing stage.
Aufgabe der Erfindung war es deshalb, Substanzen zu finden und sie durch geeignete Verfahren so zu verpacken, daß sie vor der abbauenden Wirkung der Verdauungsenzyme geschützt sind. Dadurch soll es möglich sein, mit geringen Mengen, ohne gentechnische Bearbeitung und/oder deren aufwendigen Reinigung, diese Stoffe, insbesondere als Nahrungsbestandteil, für eine Prävention von Autoimmunerkrankungen einzusetzen.The object of the invention was therefore to find substances and to package them by suitable methods so that they are protected against the degrading action of the digestive enzymes. This should make it possible to use these substances, in particular as a food component, for the prevention of autoimmune diseases in small quantities, without genetic engineering and / or their elaborate purification.
Im Gegensatz zu den vorherrschenden Arbeitshypothesen geht die Erfindung davon aus, daß auch die selektive Abnahme äußerer Reize für den Ausbruch von Autoimmunerkrankungen von vorrangiger Bedeutung ist. Alle Säugetiere einschließlich des Menschen haben in ihrer phylogenetischen Entwicklung Mechanismen entwickelt, die eine Wirkung der aufgenommenen Nahrungsmittel als antigenen Reiz verhindern, so daß die zugeführte Nahrung als Energiequelle und nicht als potentielle Antigenbelastung wirkt. Säugetiere sind immunologisch tolerant gegenüber den Nahrungsbestandteilen, die infolge ihrer intermittierenden Zufuhr diese Toleranz lebenslang aufrecht erhalten. Bei langandauernden drastischen Veränderungen der Ernährungsgewohnheiten besteht die Möglichkeit einer fehlenden oder mangelhaften Antigenzufuhr, so daß sich konsekutiv eine partielle oder totale Intoleranz gegenüber gegenüber den Nahrungsmitteln entwickeln kann.In contrast to the prevailing working hypotheses, the invention assumes that the selective decrease in external stimuli is of primary importance for the onset of autoimmune diseases. All mammals including the In their phylogenetic development, humans have developed mechanisms which prevent the ingested food from acting as an antigenic stimulus, so that the food supplied acts as an energy source and not as a potential antigen load. Mammals are immunologically tolerant of the food components that, due to their intermittent intake, maintain this tolerance for life. In the event of long-lasting drastic changes in eating habits, there is a possibility of an inadequate or insufficient antigen supply, so that a partial or total intolerance to the food can develop consecutively.
So wurde festgestellt, daß, vorrangig durch den zunehmenden Wohlstand bedingt, sich die Ernährungsgewohnheiten in den letzten 50 Jahren markant dahingehend änderten, daß "minderwertige Nahrung" (Gehirn, Pankreas, Knorpel, Innereien) weitgehend aus dem Ernährungsprogramm verschwunden ist.It was found that, primarily due to increasing prosperity, eating habits have changed markedly over the past 50 years so that "low-quality food" (brain, pancreas, cartilage, offal) has largely disappeared from the nutritional program.
Erfindungsgemäß wurde nun gefunden, daß unverdaute und/oder partiell angedaute Proteine der Nahrung für die Induktion und das Aufrechterhalten der Immuntoleranz des Körpers gegenüber den Nahrungsmitteln von ausschlaggebender Bedeutung sind, und die Zufuhr essentieller Mischproteine, die in den letzten fünf Dekaden aus dem menschlichen Ernährungprogramm weitgehend verschwunden sind, in Form von Kapseln, vorzugsweise in Form von Mikrokapseln, insbesondere als Nahrungsmittelbestandteil, hervorragend geeignet sind, den Zustand der Immuntoleranz in Säugetier-Organismen aufrechtzuerhalten.According to the invention, it has now been found that undigested and / or partially digested proteins of food are of crucial importance for the induction and maintenance of the body's immune tolerance to food, and the supply of essential mixed proteins, which have largely been used in the human diet for the past five decades disappeared, in the form of capsules, preferably in the form of microcapsules, in particular as a food component, are outstandingly suitable for maintaining the state of immune tolerance in mammalian organisms.
Da die Wirksamkeit der applizierten Antigene speziesunabhängig ist, sind keinerlei Probleme in der Antigenbereitstellung bei der Anwendung am Menschen zu erwarten.Since the effectiveness of the applied antigens is species-independent, no problems in the provision of antigens when used in humans are to be expected.
Mit an sich bekannten Verfahren werden Nahrungsmittelbestandteile, die für die Aufrechterhaltung einer notwendigen Immuntoleranz zur Prävention von Autoimmunkrankheiten bedeutsam seien können, in trockener Form oder als Lösung verkapselt.With methods known per se, food components are necessary for the maintenance of a necessary immune tolerance for the prevention of Autoimmune diseases can be significant, in dry form or encapsulated as a solution.
Vorzugsweise als Lebensmittelzusatzstoff werden die Kapseln, bevorzugt Mikrokapseln, mit den darin enthaltenen Mischantigen üblichen Lebensmitteln wie Fleisch-, Milch-, Getreide-, Feinkost- und/oder Saftprodukten so zugemischt, daß die Bestandteile geschmacks- und geruchsneutral verabfolgt werden können.The capsules, preferably microcapsules, are preferably mixed as a food additive with the mixed antigen contained therein, the usual foods such as meat, milk, cereals, delicatessen and / or juice products so that the components can be administered in a tasteless and odorless manner.
Diese werden durch die Lebensmittelproduzenten verschiedenen Milchprodukten und/oder Getreideerzeugnissen zugesetzt, um somit die lebenslange und kontinuierliche Aufnahme zu gewährleisten und den Erhalt der Nahrungsmitteltoleranz zu ermöglichen. Die Verkapselung der zugesetzten Antigene bewirkt nicht nur die Geschmacks- und Geruchsneutralität, sondern erlaubt auch die gezielte Applikation einer definierten Dosis der zu applizierenden Mischproteine in den Dünndarm, der für die Nahrungsmitteltoleranz von entscheidender Bedeutung ist.These are added by the food producers to various dairy products and / or cereal products in order to ensure lifelong and continuous consumption and to maintain food tolerance. The encapsulation of the added antigens not only results in neutral taste and smell, but also allows the targeted application of a defined dose of the mixed proteins to be administered into the small intestine, which is of crucial importance for food tolerance.
Die so hergestellten Lebensmittel rufen durch kontinuierliche und lebenslange Aufnahme einen Zustand der Immuntoleranz gegen die verabreichten Antigengemische hervor und helfen dadurch, das Entstehen einer Autoimmunkrankheit zu verhindern.The food produced in this way causes a state of immune tolerance to the administered antigen mixtures through continuous and lifelong intake and thereby helps to prevent the development of an autoimmune disease.
Eine tägliche Aufnahme derart verkapselter Lebensmittel reduzierte die Häufigkeit das Risiko des Erkrankens an Diabetes nachweisbar.Daily intake of such encapsulated foods demonstrably reduced the frequency of the risk of developing diabetes.
Weiterhin beinhaltet die Erfindung den Vorteil, daß durch die intermittierende, aber lebenslange kontinuierliche Zufuhr der angereicherten Antigene, eine Wirksamkeit auch ohne Diagnostik akuter Autoimmunitätsschübe zu erwarten ist.The invention furthermore has the advantage that the intermittent but lifelong continuous supply of the enriched antigens means that effectiveness can be expected even without the diagnosis of acute autoimmunity flare-ups.
Die gezielte Applikation der Nahrungsmittelmischproteine in den Dünndarm via bevorzugter alginatmodifizierter Mikrokapseln erschwert die proteolytische Verdauung der Antigene, so daß geringere Dosen effizient sind, wobei der Applikationsort dem Wirkort entspricht. Die gleiche Wirkung tritt ein, wenn das Mischantigen in Arzneitransportsysteme mit an sich üblichen pharmazeutischen Trägerstoffen für die orale Verabreichung eingeschlossen wird.The targeted application of the mixed food proteins in the small intestine via preferred alginate-modified microcapsules complicates the proteolytic digestion of the antigens, so that smaller doses are efficient, the application site being the Place of action corresponds. The same effect occurs when the mixed antigen is encased in drug delivery systems with conventional pharmaceutical carriers for oral administration.
Da bisher kein ähnliches Produkt am Markt vorhanden ist, können die Vorteile der Erfindung ausschließlich im Vergleich zu Ergebnissen tierexperimenteller Untersuchungen gezogen werden.Since no similar product has so far been available on the market, the advantages of the invention can only be drawn in comparison with results from animal experiments.
Zusammenfassend wird festgestellt:In summary it is stated:
Die Erfindung betrifft die Verwendung von geschmacksneutralen Kapseln, in denen eine oder mehrere antigene Substanzen eingeschlossen sind zur Aufrechterhaltung des Zustandes einer Immuntoleranz in Säugetier-Organismen, zur Prophylaxe und/oder Behandlung von Autoimmunkrankheiten, wie z.B. insulinabhängiger Diabetes (IDDM), Multipler Sklerose und/oder Rheumatoider Arthritis, wobei als Hüllmaterial der Kapseln an sich übliche Polysaccharide, Polyester und Polyamide alleine oder in Kombinationen verwendet werden.The invention relates to the use of taste-neutral capsules, in which one or more antigenic substances are included, for maintaining the state of an immune tolerance in mammalian organisms, for the prophylaxis and / or treatment of autoimmune diseases, such as e.g. insulin-dependent diabetes (IDDM), multiple sclerosis and / or rheumatoid arthritis, polysaccharides, polyesters and polyamides which are customary per se being used as the shell material of the capsules, alone or in combinations.
Vorzugsweise werden als Hüllmaterial im Verdauungstrakt an sich unverdauliche Oligo- und/oder Polysaccharide, z.B. Alginsäure, Polymere der Alginsäure, Alginate, Pectine und/oder Xanthane ggf. zusammen mit einem physiologisch tolerierbaren Metallsalz, wie z.B. einem Calciumsalz, verwendet, die zusätzlich verdauliche Bestandteile in der Kapselwand mit einem Verhältnisanteil von 30 % bis zu 80 % enthalten, vorzugsweise Mono-, Oligo- und/oder Polysaccharide, (poly)Hydroxycarbon- säuren, Fettsäuren sowie deren Salze und Derivate sowie Aminosäuren, deren Salze und deren Derivate.Preferably digestible oligosaccharides and / or polysaccharides, e.g. Alginic acid, polymers of alginic acid, alginates, pectins and / or xanthans, optionally together with a physiologically tolerable metal salt, such as e.g. a calcium salt used, which additionally contain digestible constituents in the capsule wall with a ratio of 30% to 80%, preferably mono-, oligo- and / or polysaccharides, (poly) hydroxycarboxylic acids, fatty acids and their salts and derivatives and amino acids , their salts and their derivatives.
Zu verkapselnde antigene Substanzen sind bevorzugt Organe, Gewebe, Zellen oder Zellinhaltstoffe von tierischen oder pflanzlichen Organismen in behandelter oder unbehandelter Form, deren humane Equivalente durch eine Autoimmunreaktion geschädigt oder zerstört werden können, besonders bevorzugt sogenannte minderwertige Nahrung, wie z.B. Gehirn, Pankreas, Knorpelmasse und/oder Innereien.Antigenic substances to be encapsulated are preferably organs, tissues, cells or cell contents of animal or plant organisms in treated or untreated form, the human equivalents of which can be damaged or destroyed by an autoimmune reaction so-called inferior food, such as the brain, pancreas, cartilage and / or offal.
In einer bevorzugten Ausführungsvariante der Erfindung werden in Alginat verkapselter Schweine-Pankreas oder verkapselte Schweine-Pankreasinseln zur Prophylaxe und/oder Behandlung von insulinabhängiger Diabetes (IDDM) verwendet, ggf. ist dem Alginat Stärke beigemischt.In a preferred embodiment variant of the invention, encapsulated porcine pancreas or encapsulated porcine pancreatic islets are used for the prophylaxis and / or treatment of insulin-dependent diabetes (IDDM), starch is optionally added to the alginate.
Dabei werden zur Anwendung die Kapseln zur Erhaltung des Zustandes der Immuntoleranz zu einer beliebigen Substanz, vorzugsweise zu einem Lebensmittel zugegeben, vorzugsweise zu Fleisch-, Milch-, Getreide-, Feinkost- und/oder Saftprodukten, während oder nach Herstellung, ohne die sensorischen Eigenschaften des Endproduktes nachhaltig zu beeinflussen.For use, the capsules for maintaining the state of immune tolerance are added to any substance, preferably to a food, preferably to meat, milk, cereals, delicatessen and / or juice products, during or after manufacture, without the sensory properties to influence the end product sustainably.
Die Erfindung betrifft auch geschmacksneutrale Kapseln, umfassend ein an sich übliches Hüllmaterial, in dem eine oder mehrere antigene Substanzen, vorzugsweise in Form von Mischproteinen, verkapselt sind, zur Prophylaxe und/oder Behandlung von Autoimmunerkrankungen, vorzugsweise von IDDM, Multipler Sklerose und/oder Rheumatoider Arthritis, wobei die antigenen Substanzen essentielle Mischproteine aller natürlich vorkommender Antigene bzw. ein Teil davon sind, wie sie in sogenannter minderwertiger Nahrung vorkommen, und die Kapseln vorzugsweise eine Größe von 0,2 μm bis 500 μm, bei Mikrokapseln vorzugsweise 0,5 μm bis 20 μm aufweisen.The invention also relates to taste-neutral capsules, comprising a casing material which is conventional per se and in which one or more antigenic substances, preferably in the form of mixed proteins, are encapsulated for the prophylaxis and / or treatment of autoimmune diseases, preferably IDDM, multiple sclerosis and / or rheumatoid Arthritis, where the antigenic substances are essential mixed proteins of all naturally occurring antigens or a part thereof, as they occur in so-called inferior food, and the capsules preferably have a size of 0.2 μm to 500 μm, for microcapsules preferably 0.5 μm to 20 μm.
AusführungsbeispielEmbodiment
Am Beispiel des insulinabhängigen Diabetes (IDDM) wurde tierexperimentell die erfindungsgemäße Strategie überprüft.Using the example of insulin-dependent diabetes (IDDM), the strategy according to the invention was checked in animal experiments.
Durch Untersuchungen an BB-Ratten und NOD-Mäuse, Tieren die einen IDDM entwickeln, wurde die Wirksamkeit des "designer foods" nachgewiesen. Der entscheidende Vorteil des erfindungsgenäßen Vorgehens liegt im Einsatz aller natürlich vorkommenden Antigene (Applikation als angereichertes Mischantigene) , da einerseits der Nachweis von Autoantikörpern (und damit einer partiellen Intoleranz) gegen >15 Proteine bei IDDM die Bedeutung eines einzelnen Proteins deutlich relativierte, so daß die singuläre Proteinapplikation die präventive Effizienz deutlich limitiert.The effectiveness of the "designer food" was demonstrated by tests on BB rats and NOD mice, animals that develop an IDDM. The decisive advantage of the procedure according to the invention lies in the use of all naturally occurring antigens (application as enriched mixed antigens), since on the one hand the detection of autoantibodies (and thus a partial intolerance) against> 15 proteins with IDDM clearly relativized the importance of a single protein, so that the singular protein application clearly limits the preventive efficiency.
Bei einer Inzidenz von 0,03 % erkranken in den USA, der EU und in Japan 250.000 Kinder und Jugendliche jährlich an IDDM. Ausgehend von der begründeten Annahme, daß ca. 5-7 Jahre vor der Manifestation Hinweise für eine beginnende Autoimmunerkrankung diagnostiziert werden können, dürfte die Zielgruppe 1,5 Mill. Probanden betragen, die sich jährlich um 250.000 "Prädiabetiker" erweitert. With an incidence of 0.03%, 250,000 children and adolescents develop IDDM annually in the USA, the EU and Japan. Based on the well-founded assumption that approx. 5-7 years before the manifestation, indications for an beginning autoimmune disease can be diagnosed, the target group is likely to be 1.5 million test persons, which is expanded by 250,000 "prediabetic patients" annually.

Claims

Patentansprüche claims
1. Verwendung von geschmacksneutralen Kapseln, in denen eine oder mehrere antigene Substanzen eingeschlossen sind zur Aufrechterhaltung des Zustandes einer Immuntoleranz in Säugetier-Organismen, zur Prophylaxe und/oder Behandlung von Autoimmunkrankheiten.1. Use of taste-neutral capsules in which one or more antigenic substances are included to maintain the state of an immune tolerance in mammalian organisms, for the prophylaxis and / or treatment of autoimmune diseases.
2. Verwendung nach Anspruch 1 , dadurch gekennzeichnet, daß als Hüllmaterial der Kapseln an sich übliche Polysaccharide, Polyester und Polyamide alleine oder in Kombinationen verwendet werden.2. Use according to claim 1, characterized in that conventional polysaccharides, polyesters and polyamides are used alone or in combinations as the shell material of the capsules.
3. Verwendung nach Anspruch 1 oder 2 , dadurch gekennzeichnet, daß als Hüllmaterial im Verdauungstrakt an sich unverdauliche Oligo- und/oder Polysaccharide, vorzugsweise Alginsäure, Polymere der Alginsäure, Alginate, Pectine und/oder Xanthane ggf. zusammen mit einem physiologisch tolerierbaren Metallsalz, wie z.B. einem Calciumsalz, verwendet werden, die zusätzlich verdauliche Bestandteile in der Kapselwand mit einem Verhältnisanteil von 30 % bis zu 80 % enthalten, vorzugsweise Mono-, Oligo- und/oder Polysaccharide, (poly)Hydroxycarbon- säuren, Fettsäuren sowie deren Salze und Derivate sowie Aminosäuren, deren Salze und deren Derivate.3. Use according to claim 1 or 2, characterized in that indigestible oligo- and / or polysaccharides, preferably alginic acid, polymers of alginic acid, alginates, pectins and / or xanthans, if appropriate together with a physiologically tolerable metal salt, as the covering material in the digestive tract such as a calcium salt can be used, which additionally contain digestible constituents in the capsule wall in a ratio of 30% to 80%, preferably mono-, oligo- and / or polysaccharides, (poly) hydroxycarboxylic acids, fatty acids and their salts and derivatives as well Amino acids, their salts and their derivatives.
4. Verwendung nach den Ansprüchen 1 bis 3, dadurch gekennzeichnet, daß als zu verkapselnde antigene Substanzen Organe, Gewebe, Zellen oder Zellinhaltstoffe von tierischen oder pflanzlichen Organismen in behandelter oder unbehandelter Form verwendet werden, deren humane Equivalente durch eine Autoimmunreaktion geschädigt oder zerstört werden können.4. Use according to claims 1 to 3, characterized in that organs, tissues, cells or cell contents of animal or plant organisms in treated or untreated form are used as the antigenic substances to be encapsulated, the human equivalents of which can be damaged or destroyed by an autoimmune reaction .
5. Verwendung nach Anspruch 4, dadurch gekennzeichnet, daß Gehirn, Pankreaε, Knorpelmasse und/oder Innereien verwendet werden.5. Use according to claim 4, characterized in that Brain, pancreas, cartilage and / or giblets are used.
6. Verwendung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, daß in Alginat verkapselter Schweine-Pankreas oder verkapselte Schweine-Pankreasinseln zur Prophylaxe und/oder Behandlung von insulinabhängiger Diabetes (IDDM) verwendet werden.6. Use according to one of claims 1 to 5, characterized in that encapsulated porcine pancreas or encapsulated porcine pancreatic islets are used for the prophylaxis and / or treatment of insulin-dependent diabetes (IDDM) in alginate.
7. Verwendung nach Anspruch 6 , dadurch gekennzeichnet, daß dem Alginat Stärke beigemischt ist.7. Use according to claim 6, characterized in that starch is added to the alginate.
8. Verwendung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, daß die Kapseln zur Erhaltung des Zustandes der Immuntoleranz zu jeder Substanz, vorzugsweise zu einem Lebensmittel, vorzugsweise zu Fleisch-, Milch-, Getreide-, Feinkost- und/oder Saftprodukten, während oder nach Herstellung zugesetzt werden, ohne die sensorischen Eigenschaften des Endproduktes nachhaltig zu beeinflussen.8. Use according to one of claims 1 to 7, characterized in that the capsules for maintaining the state of immune tolerance to any substance, preferably to a food, preferably to meat, milk, cereals, delicatessen and / or juice products, can be added during or after production without permanently influencing the sensory properties of the end product.
9. Verwendung nach einem der Ansprüche 1 bis 7 , dadurch gekennzeichnet, daß die Kapseln zur Prophylaxe und/oder Behandlung von insulinabhängiger Diabetes (IDDM), Multipler Sklerose und/oder Rheumatoider Arthritis verwendet werden.9. Use according to one of claims 1 to 7, characterized in that the capsules for the prophylaxis and / or treatment of insulin-dependent diabetes (IDDM), multiple sclerosis and / or rheumatoid arthritis are used.
10. Geschmacksneutrale Kapseln, umfassend ein an sich übliches Hüllmaterial, in dem eine oder mehrere antigene Substanzen, vorzugsweise in Form von Mischproteinen, verkapselt sind, zur Prophylaxe und/oder Behandlung von Autoimmunerkrankungen, vorzugsweise von insulinabhängiger Diabetes (IDDM), Multipler Sklerose und/oder Rheumatoider Arthritis.10. Flavor-neutral capsules, comprising a conventional envelope material in which one or more antigenic substances, preferably in the form of mixed proteins, are encapsulated for the prophylaxis and / or treatment of autoimmune diseases, preferably insulin-dependent diabetes (IDDM), multiple sclerosis and / or rheumatoid arthritis.
11. Geschmacksneutrale Kapseln nach Anspruch 10, dadurch gekennzeichnet, daß die antigenen Substanzen essentielle Mischproteine aller natürlich vorkommender Antigene bzw. ein Teil davon sind, wie sie in sogenannter minderwertiger Nahrung vorkommen.11. Taste-neutral capsules according to claim 10, characterized in that the antigenic substances are essential mixed proteins of all naturally occurring antigens or part of it, as they occur in so-called inferior food.
12. Geschmacksneutrale Kapseln nach Anspruch 10 und 11, dadurch gekennzeichnet, daß die antigenen Substanzen aus Gehirn, Pankreas, Knorpelmasse und/oder Innereien stammen.12. Neutral taste capsules according to claim 10 and 11, characterized in that the antigenic substances come from the brain, pancreas, cartilage and / or offal.
13. Geschmacksneutrale Kapseln nach Anspruch 10 bis 12, dadurch gekennzeichnet, daß sie eine Größe von 0,2 μm bis 500 μm aufweisen.13. Neutral taste capsules according to claim 10 to 12, characterized in that they have a size of 0.2 microns to 500 microns.
14. Geschmacksneutrale Kapseln nach Anspruch 13, dadurch gekennzeichnet, daß sie als Mikrokapseln eine Größe von 0,5 μm bis 20 μm aufweisen. 14. Taste-neutral capsules according to claim 13, characterized in that they have a size of 0.5 microns to 20 microns as microcapsules.
PCT/DE1999/003687 1998-11-27 1999-11-19 Utilisation of capsules containing one or more antigenic substances for the prevention and/or treatment of autoimmune diseases WO2000032168A1 (en)

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JP2000584864A JP2002531391A (en) 1998-11-27 1999-11-19 Use of a capsule containing one or more antigenic substances for the prevention and / or treatment of autoimmune diseases
EP99962060A EP1135107A1 (en) 1998-11-27 1999-11-19 Utilisation of capsules containing one or more antigenic substances for the prevention and/or treatment of autoimmune diseases
AU18562/00A AU1856200A (en) 1998-11-27 1999-11-19 Utilisation of capsules containing one or more antigenic substances for the prevention and/or treatment of autoimmune diseases
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