DE1617880A1 - Process for the production of organotropic, bioactive agents, in particular drugs - Google Patents
Process for the production of organotropic, bioactive agents, in particular drugsInfo
- Publication number
- DE1617880A1 DE1617880A1 DE19661617880 DE1617880A DE1617880A1 DE 1617880 A1 DE1617880 A1 DE 1617880A1 DE 19661617880 DE19661617880 DE 19661617880 DE 1617880 A DE1617880 A DE 1617880A DE 1617880 A1 DE1617880 A1 DE 1617880A1
- Authority
- DE
- Germany
- Prior art keywords
- organotropic
- production
- bioactive agents
- particular drugs
- cells
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 16
- 230000003372 organotropic effect Effects 0.000 title description 9
- 239000003814 drug Substances 0.000 title description 6
- 229940079593 drug Drugs 0.000 title description 3
- 238000004519 manufacturing process Methods 0.000 title description 3
- 239000012867 bioactive agent Substances 0.000 title description 2
- 239000013543 active substance Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000000126 substance Substances 0.000 description 5
- 229940001470 psychoactive drug Drugs 0.000 description 4
- 239000004089 psychotropic agent Substances 0.000 description 4
- 230000010415 tropism Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 210000002451 diencephalon Anatomy 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 239000003124 biologic agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 210000003850 cellular structure Anatomy 0.000 description 2
- 210000004720 cerebrum Anatomy 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 210000004884 grey matter Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- ZAGRKAFMISFKIO-QMTHXVAHSA-N lysergic acid Chemical class C1=CC(C2=C[C@H](CN([C@@H]2C2)C)C(O)=O)=C3C2=CNC3=C1 ZAGRKAFMISFKIO-QMTHXVAHSA-N 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Verfahren zur Gewinnung von organotropen, bioaktiven Wirkstoffen, insbesondere von Arzneimitteln. Process for the production of organotropic, bioactive agents, especially of pharmaceuticals.
Die biologische Wirkung, sowohl eines Pharmakons, einer Nukleinsäure, wie auch eines Giftes, laßt sich durch Selektion des Wirkungsortes an Organen, Zellen oder Zellbestandteilen verstärken. Dadurch wird die Belastung des Gesamtorganismus auch bezüglich von etwaigen Nebenwirkungen1 verringert und es lä#t sich andererseits eine beträchtlich höhere lokale Konzentration des Wirkstoffes erreichen. Dadurch werden z.T. ganz neuartige pharmakodynamische Wirkungen ermöglicht.The biological effect of both a drug, a nucleic acid, as well as a poison, can be determined by selecting the place of action on organs, cells or strengthen cell components. This increases the burden on the whole organism also with regard to possible side effects1 and it can be reduced on the other hand achieve a considerably higher local concentration of the active ingredient. Through this some completely new pharmacodynamic effects are made possible.
Die meisten biologischen Wirkstoffe besitzen keinen solchen selektiven Organotropismus. Dieser kann jedoch durch Ankopplung an bestimmte Schlepperstoffe, die einen selektiven Tropismus besitzen, erreicht werden. So ist z.B. bekannt, daß zytotrope bzw. organotrope Antikörper als Schlepper für Fluoreszin benützt werden, das chemisch an die entsprechenden Antikörper gebunden wird. In ähnlicher Weise können auch andere biologische Stoffe, wie z.B. Zellmernbranen, Viruseiweiß und Fermente als Schlepper zu bestimmten Zellen bzw. Gewebebestandteilen verwendet werden.Most biological agents do not have such a selective one Organotropism. However, this can be achieved by coupling to certain that have a selective tropism can be achieved. For example, it is known that cytotropic or organotropic antibodies are used to transport fluorescein, which is chemically bound to the corresponding antibodies. In a similar way can also contain other biological substances such as cell membranes, virus proteins and Ferments are used as a tractor to certain cells or tissue components.
Piich ist es möglich, andere Wirkstoffe als das Jr. Fluoreszin mit den Schloppern ?.U konjugieren und auf diese Weise biologische Wirkungen zu lokalisieren.Piich it is possible to use other active ingredients than the Jr. fluorescein conjugate the tractors? .U and in this way localize biological effects.
Durch die Konjugation von einem Wirkstoff mit einem körperfremden oder auch körpereigenen Schleppermolekül entsteht gewöhnlich ein konjugiertes Antigen, das im Organismus Antikörperbildung auslöst. Diese Antikörper führen dann zu einer Antigen-Antikörperreaktion mit dem Konjugat und blockieren dieses funktionell bzw. f;ihren zu dessen Abbau iind Beseitigung aus dem Organismus (vergl. Science 129, Seite 564/1959). Andererseits wird ein Konjugat aus einem hochmolekularen Trägerstoff und einem niedermoleklllaren Wirkstoff durch haut- oder Schleimhäute nicht, bzw. schlecht resorbiert und dann entkoppelt oder denaturiert.By conjugating an active ingredient with an alien one or the body's own tug molecule usually creates a conjugated antigen, which triggers the formation of antibodies in the organism. These antibodies then lead to a Antigen-antibody reaction with the conjugate and block it functionally or f; their removal from the organism in order to break it down (cf. Science 129, Page 564/1959). On the other hand, a conjugate is made from a high molecular weight carrier and a low-molecular-weight active ingredient through skin or mucous membranes, or bad reabsorbed and then decoupled or denatured.
Das vorliegende Verfahren überwindet diese Nachteile, die durch Verwendung biologisch nativer, hochmolekularer Schlepperstoffe entstehen. Es hat sich nämlthgezeigt, daß für den Tropismus an Organzellen nicht-der gesamte hochmolekulare Schlepperstoff verantwortlich ist, sondern gewisse Teile der Molekiile. Diese reaktiven Gruppen, die sich an die Rezeptoren von Zellen binden können, lassen sich durch bekannte Verfahren physikalisch, z.B. mit Ultraschall (DBP 940 316) wie auch chemisch (DBP 1 o29 984) durch Hydrolyse oder auch fermentativ in Bruchstücke spalten, deren Tropismus erhalten bleibt. Solche relativ niedermolekiilaren reaktiven Gruppen können nun in gleicher Weise als Schlepper von biologschen Wirkstoffen verwendet werden. Auch können ie selbst nach bekannten Verfahren radioaktiv markiert werden (Patent Nr. 1 209 699), so da# auf diese Weise die Radioaktivitit lokal an Zellen angereichert werden kann.The present method overcomes these disadvantages inherent in using Biologically native, high molecular weight haulage substances are created. It has been shown that for the tropism of organ cells not all of the high molecular weight carrier substance is responsible, but rather certain parts of the molecules. These reactive groups, which can bind to the receptors of cells can be identified by known Process physically, e.g. with ultrasound (DBP 940 316) as well as chemically (DBP 1 o29 984) split into fragments by hydrolysis or fermentation, their tropism preserved. Such relatively low-molecular reactive groups can now can be used in the same way as a tractor for biological agents. Even they can be radioactively labeled using known methods (patent no. 1 209 699), so that the radioactivity is locally enriched in cells in this way can be.
Als Verfahren zur Konjugation mit biologischen Wirlstoffen eignen sich alle Methoden, die auch zur Konjugation von biologisch na- tiven, nicht frakturierten, organotropen Schlepperstofren @werden, ebenso auch solche Verfahren, die zur Herstellung von konjungierten Antigenen verwendet werden (vergl. II. Schmidt - Fortschritte der Serologie), z.13. die Diazotierung, Behandlung mit Isocyanaten, Umsetzung mit Karbobenzoxy-Verbindungen, das Azid- oder Oxaæolon-Verfahren, wie auch die Adsorption an Kolloide.All methods that are also suitable for conjugation of biologically na- tive, non-fractured, organotropic transport substances, as well as processes that are used to produce conjugated antigens (see II. Schmidt - Advances in Serology), z.13. diazotization, treatment with isocyanates, reaction with carbobenzoxy compounds, the azide or oxaæolon process, as well as adsorption on colloids.
Die Überprüfung des Organotropismus der Schlepper kann in vitro mit den entsprechenden Organbestandteilen erfolgen, an denen dann die Konjugat gebunden werden. Dies ist auch histochemisch durch bekannte Mark i eru ngsm ethoden mit der Autoradiographie bzw. durch Markierung mit Farbstoffen möglich.The organotropism of the tug can be checked in vitro with the corresponding organ components to which the conjugate is then bound will. This is also histochemically by known marking methods with the Autoradiography or marking with dyes is possible.
Als Ausgangsst offe zur Herstellung der Schleppermoleküle können alle nativen Moleküle mit einem entsprechenden Tropismus dienen @lso auch gewisse hochmolekulare Zellbestandteile. Unter biolozwischen Wirkstoffen sind sowohl Pharmaka, wia auch bioaktive gewebeektrakte, insbesondere Nukleinsäuren und deren Abbauprodukte, ebenso aber auch Gifte und Toxine zu verstehen.Any of them can be used as the starting material for the production of the tractor molecules native molecules with a corresponding tropism are also used by certain high-molecular ones Cell components. Among bio-intermediate active ingredients are both pharmaceuticals, wia as well bioactive tissue tracts, in particular nucleic acids and their degradation products, as well but also to understand poisons and toxins.
Da das Verfahren eine allgemeine Anwendungsmöglichkeit erschlie#t, wird in den Beispielen auf detaillierte angaben verzichtet, znmal die Methoden der Frakturierung von organotropen Mclekülen, wie auch der Ankoppltong an andere Stoffe bekannt sind.Since the process opens up a general application, detailed information is not given in the examples, sometimes the methods of Fracturing of organotropic molecules, as well as the coupling to other substances are known.
Ueispiel 1: Es soll ein Vitaminpräparat aus Vitamin A (Axerophtholpalmitat) mit selektiver Wirkung auf die Schilddr se gewonnen werden.Example 1: A vitamin preparation made from vitamin A (axerophthol palmitate) obtained with a selective effect on the thyroid gland.
Dini wird dieses Vitamin mit orgotropen Fragmenten von Schilddrüsenzellen durch Umsetzung mit Karbobenzoxy-Verbindungen konjugiert. Dieses Konjugat kann direkt zur Anwendung gelanger oder aber zur Trockrumg gebracht werden und unmittelbar vor der Anwendung in einem lipoidlöslichen Mittel aufgeschwemmt und gelöst worden. Es ist auch möglich, ein Emulgiermittel, wie z.B. Natrium-Laurylsulfat, zli verwenden und das Konjugat in wässriger Lösung 7u emulgieren.Dini gets this vitamin with orgotropic fragments of thyroid cells conjugated by reaction with carbobenzoxy compounds. This conjugate can be used directly for use or brought to the dry and immediately before upon application, it has been suspended and dissolved in a lipoid soluble agent. It it is also possible to use an emulsifying agent such as sodium lauryl sulfate and emulsify the conjugate in aqueous solution 7u.
Beispiel 2: Es sollen fiir Ganglienzellen des Großhirns vom Menschen spezifische Arzneimittel aus einem Psychopharmakon, einem Lysergsäure-Derivat hergestellt werden. Dazu werden Abwehrfermente nach Abderhalden gegen menschliches Großhirn gewonnen und diese durch tryptische Fermente in organotrope, niedermolekulare Fraktionen gespalten.Example 2: It should be used for ganglion cells of the human cerebrum specific drugs made from a psychotropic drug, a lysergic acid derivative will. For this purpose, defense ferments are used after Abderhalden against the human cerebrum obtained and this by tryptic ferments in organotropic, low molecular weight fractions split.
Diese werden nun mit dem Psychopharmakon durch Behandlung mit Isocyanaten konjugiert.These are now treated with the psychotropic drug through treatment with isocyanates conjugated.
Beispiel 3: Es soll ein gegen Zwischenhirn selektiv gerichtetes Psychopharmakon hergestellt werden Dazu werden gegen die graue Hirnsubstanz von Zwischenhirnzentren Antikörper gewonnen und nach dem Verfahren des DBP 1 o29 984 zu organotropen Fragmenten hydrolysiert.Example 3: A psychotropic drug directed selectively against the diencephalon should be used To be prepared are against the gray matter of the brain of the diencephalon centers Antibodies obtained and according to the method of DBP 1 o29 984 to organotropic fragments hydrolyzed.
Es wird n1n das Psychopharmakon zusammen mit Nukleotiden aus menschlichem Zwischenhirn'durch Diazotierung mit den Antikörper fragmenten verbunden und nach bekannten Verfahren weiterverarbeitet.It will n1n the psychotropic drug along with nucleotides from human Diencephalon connected with the antibody fragments by diazotization and after known method further processed.
P a t e n t a n s p r u c h Verfahren zur Gewinnung von organotropen,
bioaktiven Wirkstoffen, insbesondere von Arzneimitteln, dadurch gekennzeichnet,
daß die nach bekanntem Verfahren gewonnenen rexeptiven,organotropen Wir-
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DET0032198 | 1966-10-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1617880A1 true DE1617880A1 (en) | 1971-07-22 |
Family
ID=7556873
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19661617880 Pending DE1617880A1 (en) | 1966-10-06 | 1966-10-06 | Process for the production of organotropic, bioactive agents, in particular drugs |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1617880A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2470773A1 (en) * | 1979-11-28 | 1981-06-12 | Pasteur Institut | |
| FR2498192A2 (en) * | 1981-01-22 | 1982-07-23 | Pasteur Institut | NOVEL POLYPEPTIDE THIOLE COMPOUND FROM A FRAGMENT OF TETANIC TOXIN, PROCESS FOR OBTAINING SAME AND APPLICATIONS THEREOF |
-
1966
- 1966-10-06 DE DE19661617880 patent/DE1617880A1/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2470773A1 (en) * | 1979-11-28 | 1981-06-12 | Pasteur Institut | |
| EP0030496A1 (en) * | 1979-11-28 | 1981-06-17 | Institut Pasteur | Thiolated polypeptidic compound coming from a fragment of tetanic toxine, process for obtaining it and its applications |
| FR2498192A2 (en) * | 1981-01-22 | 1982-07-23 | Pasteur Institut | NOVEL POLYPEPTIDE THIOLE COMPOUND FROM A FRAGMENT OF TETANIC TOXIN, PROCESS FOR OBTAINING SAME AND APPLICATIONS THEREOF |
| EP0057140A2 (en) * | 1981-01-22 | 1982-08-04 | Pasteur Institut | Thiolated polypeptidic compound from a tetanic toxin fragment, process for its production and its applications |
| EP0057140A3 (en) * | 1981-01-22 | 1982-08-25 | Pasteur Institut | Thiolated polypeptidic compound from a tetanic toxin fragment, process for its production and its applications |
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