DD252539A1 - METHOD FOR ORAL APPLICATION OF BIOLOGICALLY ACTIVE PEPTIDES WITH DELAYED EFFECT - Google Patents

METHOD FOR ORAL APPLICATION OF BIOLOGICALLY ACTIVE PEPTIDES WITH DELAYED EFFECT Download PDF

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Publication number
DD252539A1
DD252539A1 DD29447386A DD29447386A DD252539A1 DD 252539 A1 DD252539 A1 DD 252539A1 DD 29447386 A DD29447386 A DD 29447386A DD 29447386 A DD29447386 A DD 29447386A DD 252539 A1 DD252539 A1 DD 252539A1
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German Democratic Republic
Prior art keywords
biologically active
active peptides
peptides
protease inhibitor
peptide
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Application number
DD29447386A
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German (de)
Inventor
Guenter Losse
Iris Kirste
Elke Hacker
Joachim Kossowicz
Karl Milde
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Berlin Chemie Veb
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Priority to DD29447386A priority Critical patent/DD252539A1/en
Publication of DD252539A1 publication Critical patent/DD252539A1/en

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Abstract

Die Erfindung betrifft ein Verfahren zur oralen Anwendung biologisch aktiver Peptide mit verzoegerter und langandauernder Wirkung. Die Wirkung beruht darauf, dass der Wirkstoff auf einen Traeger fixiert und mit einem Resorptionsvermittler und einem Proteaseinhibitor eingesetzt wird. Der Vorteil beruht darauf, dass die gemeinsame Anwendung von drei an sich bekannten Verfahren die bisher nicht als moeglich gehaltene orale Anwendung biologisch aktiver Peptide nunmehr mit hoher Wirksamkeit gestattet.The invention relates to a method for the oral administration of biologically active peptides with delayed and long-lasting action. The effect is based on the fact that the active ingredient is fixed on a Traeger and used with a Resorptionsvermittler and a protease inhibitor. The advantage stems from the fact that the joint application of three methods known per se now allows the previously not considered possible oral application of biologically active peptides now with high efficiency.

Description

Anwendungsgebiet der Erfindung —Field of application of the invention

Die Erfindung betrifft die Anwendung biologisch aktiver Substanzen mit Peptidstruktur, wie z. B. Insulin, Substanz P, GnRH, GnRH-Analoga, atriales Natrium-diuretisches Peptid, in Form geeigneter Zubereitungen in der Human- und Veterinärmedizin durch orale Applikation, wobei ihre Einsatzmöglichkeit dadurch erreicht wird, daß drei an sich bekannte Verfahren angewendet werden.The invention relates to the use of biologically active substances having a peptide structure, such as. B. Insulin, substance P, GnRH, GnRH analogs, atrial sodium diuretic peptide, in the form of suitable preparations in human and veterinary medicine by oral administration, their use is achieved by using three known methods.

Charakteristik der bekannten technischen LösungenCharacteristic of the known technical solutions

Für die Anwendung biologisch aktiver Substanzen in der Human- und Veterinärmedizin müssen verschiedentlich Formen gewählt werden, die die Umgehung der Magen-Darm-Passagen zum Gegenstand haben. Grund dafür ist, daß viele dieser Substanzen unter den im Magen-Darm-Trakt herrschenden Bedingungen irreversibel inaktiviert werden, nicht resorbierbar sind und/oder eine zu kurze Verweilzeit aufweisen.For the application of biologically active substances in human and veterinary medicine must be selected various forms that have the circumvention of the gastrointestinal passages to the object. The reason for this is that many of these substances are irreversibly inactivated under the conditions prevailing in the gastrointestinal tract, are not absorbable and / or have too short a residence time.

Die bekannteste Form zur Überwindung dieser Schwierigkeiten ist nach wie vor die parenterale Applikation der biologisch aktiven Substanzen. Daneben spielt die nasale und die rektale Resorption aus entsprechenden pharmazeutischen Zubereitungen eine Rolle. Durch den Einsatz von Resorptionsvermittlern ist es gelungen, biologisch aktive Peptide über Schleimhäute resorbierbar zu machen. Besonders haben sich dabei Eiweiß-Fettsäure-Kondensate (EFK) bewährt, da Vertreter dieser Verbindungsklasse neben ihrer ausgeprägten Wirksamkeit beim Stofftransport auch absolut untoxisch und hoch schleimhautverträglich sind. Die Erkenntnis führt zu Verfahren, die es ermöglichen, biologisch aktive Peptide, insbesondere Insulin, in Form von Suppositorien und Nasensprays mittels EFK in eine hochwirksame und voll verträglich Anwendungsform zu bringen. Die orale Applikation biologisch aktiver Peptide, wie z. B. Insulin, wurde schon vielfach erprobt, hat aber bisher dagegen zu keinem verwertbaren Ergebnis geführt.The best known form for overcoming these difficulties is still the parenteral application of the biologically active substances. In addition, nasal and rectal absorption from corresponding pharmaceutical preparations plays a role. Through the use of absorption mediators it has been possible to make biologically active peptides absorbable via mucous membranes. In particular, protein-fatty acid condensates (EFK) have proven to be effective, since representatives of this class of compounds are not only highly effective in mass transport but also absolutely nontoxic and highly mucous membrane compatible. The finding leads to methods that make it possible to bring biologically active peptides, in particular insulin, in the form of suppositories and nasal sprays by means of EFK in a highly effective and fully compatible form of application. The oral administration of biologically active peptides, such as. As insulin, has been tested many times, but so far, however, has led to no usable result.

Ziel der ErfindungObject of the invention

Ziel der Erfindung ist ein Verfahren zu entwickeln, daß es ermöglicht, biologisch aktive Peptide oral applizieren zu können und dabei eine lang anhaltende Wirkung zu erreichen.The aim of the invention is to develop a process that makes it possible to be able to apply biologically active peptides orally and thereby achieve a long-lasting effect.

Darlegung des Wesens der ErfindungExplanation of the essence of the invention

Die Erfindung beinhaltet ein Verfahren, nach dem es möglich ist, biologisch aktive Peptide oral zu verabreichen und zur Langzeitwirkung zu bringen. Dies wird dadurch erreicht, daß das biologisch aktive Peptid kombiniert mit einem Resorptionsvermittler vom Typ EFK, einem Proteaseinhibitor vom Typ Aprotenin oder EAC und an einem hochmolekularen Träger fixiert, zur Anwendung gelangt.The invention includes a method according to which it is possible to administer biologically active peptides orally and bring to long-term effect. This is achieved by using the biologically active peptide in combination with an EFK-type absorption promoter, an Aprotenin or EAC type protease inhibitor and fixed on a high molecular carrier.

Nebenwirkungen, wie Schleimhautreinigungen und allergische Reaktionen, treten nich auf.Side effects, such as mucous membrane cleansing and allergic reactions, do not occur.

Die Herstellung des EFK erfolgt nach bekannten Verfahren wie z.B. in den Patentschriften DD 106783 und 117681 dargelegtThe production of the EFK is carried out by known methods, e.g. in patents DD 106783 and 117681 set forth

Die Fixierung des biologisch aktiven Peptids kann, wie am Beispiel der Peptide Insulin und GnRH in der Erfindungsbeschreibung DD 219673 beschrieben, erfolgen.The fixation of the biologically active peptide can, as described for the example of the peptides insulin and GnRH in the description of the invention DD 219673 done.

Es war überraschend, daß die Anwendung der drei an sich bekannten Verfahren die bisher als nicht möglich gehaltene orale Anwendung biologisch aktiver Peptide mit hoher Wirksamkeit gestattet.It was surprising that the use of the three methods known per se, the previously considered impossible oral use of biologically active peptides with high efficiency.

Wie das Ausführungsbeispiel zeigt, konnte im Tierexperiment durch die Verabreichung der erfindungsgemäßen Präparation eine deutlich Blutglukose-Senkung mit zeitverzögerter und lang anhaltender Wirkung bei Einsatz von Insulin als biologisch aktivem Peptid erreicht werden.As the exemplary embodiment shows, it was possible in the animal experiment to achieve a marked reduction in blood glucose with a time-delayed and long-lasting action by the administration of the preparation according to the invention when using insulin as the biologically active peptide.

Beispielexample

An acht Stoffwechsel-gesunden männlichen, nüchternen Kaninchen des mittleren Körpergewichts von 3,0 kg (2,85-3,1 Okg) wurden mit einem Lacküberzug versehene Insulin-haltige Kapseln verabreicht. Jede Kapsel enthielt 1OJE Insulin, zu 15% auf Agar-Agar als polymeren Träger fixiert, 5 mg Resorptionsvermittler EFK und 60 mg Proteaseinhibitor EAC. Die Anzahl der verabreichten Kapseln belief sich auf 1 Stück/kg Körpergewicht. DieGlucose-Bestimmung erfolgte spektrometrisch mittels Fermognost-Testbesteck. Die Tabelle macht die Signifikanz der retardierten Insulinwirkung deutlich.Coated insulin-containing capsules were given to eight metabolically healthy male fasting medium weight 3.0 kg (2.85-3.1 ounce) rabbits. Each capsule contained 10J of insulin, 15% fixed on agar-agar as a polymeric carrier, 5 mg of absorption enhancer EFK and 60 mg of protease inhibitor EAC. The number of capsules administered was 1 piece / kg body weight. Glucose was determined spectrometrically using Fermognost test kit. The table shows the significance of the delayed insulin action.

Tier Nr. 0,5Animal No. 0.5

1,01.0

1,51.5

2,52.5

3,03.0

3,53.5

4,04.0

5,05.0

6,06.0

11 103,0103.0 96,596.5 98,598.5 96,596.5 101,0101.0 108,0108.0 103,0103.0 89,089.0 91,591.5 91,591.5 81,581.5 88,088.0 22 102,0102.0 95,595.5 104,0104.0 95,5 .95.5. 106,0.106.0. 114,0114.0 101,0101.0 111,0111.0 99,599.5 98,098.0 88,088.0 82,582.5 33 93,593.5 89,089.0 84,584.5 85,585.5 98,098.0 111,0111.0 87,587.5 91,591.5 95,095.0 96,596.5 87,087.0 81,581.5 44 97,097.0 103,0103.0 85,585.5 82,582.5 111,5111.5 97,097.0 86,586.5 103,0103.0 92,592.5 86,586.5 -79,5-79.5 88,588.5 55 101,5101.5 106,0106.0 125,0125.0 94,594.5 113,0113.0 106,0106.0 97,097.0 108,5108.5 97,097.0 94,594.5 86,086.0 85,085.0 66 102,0102.0 98,598.5 104,5104.5 107,0107.0 107,5107.5 104,5104.5 95,395.3 98,098.0 88,088.0 86,086.0 85,585.5 77 99,599.5 99,599.5 99,099.0 109,0109.0 93,593.5 109,0109.0 93,093.0 93,093.0 96,096.0 92,092.0 83,583.5 83,583.5 88th 101,0101.0 98,098.0 98,098.0 90,590.5 99,099.0 98,598.5 99,099.0 94,094.0 94,594.5 84,584.5 80,080.0 86,086.0 99,499.4 98,3898.38 99,7599.75 95,1395.13 103,56103.56 106,0106.0 95,2995.29 98,5798.57 95,595.5 91,4491.44 83,983.9 85,085.0 ± 3,2± 3.2 5,015.01 12,712.7 9,339.33 6,976.97 5,875.87 6,06.0 8,818.81 2,72.7 4,824.82 3,293.29 2,492.49 Tier Nr.Animal no. 8,08.0 9,09.0 10,010.0 11,011.0 12,012.0 13,013.0 14,014.0 15,015.0 11 74,074.0 90,090.0 94,594.5 79,079.0 78,078.0 76,576.5 22 74,574.5 91,091.0 89,589.5 91,091.0 96,096.0 86,086.0 99,099.0 33 75,575.5 82,082.0 89,089.0 87,087.0 89,089.0 74,574.5 72,072.0 84,084.0 44 80,580.5 74,574.5 88,588.5 77,577.5 83,083.0 88,588.5 93,093.0 55 80,080.0 64,064.0 88,088.0 84,584.5 87,087.0 89,089.0 98,598.5 66 79,579.5 83,583.5 82,082.0 89,589.5 95,595.5 82,082.0 97,097.0 94,594.5 77 75,575.5 70,070.0 87,587.5 88,588.5 93,593.5 85,085.0 92,092.0 99,599.5 88th 75,575.5 75,075.0 86,586.5 87,087.0 93,593.5 87,087.0 88,588.5 92,092.0 76,8876.88 75,575.5 87,8187.81 87,2587.25 90,7990.79 85,1285,12 85,5885.58 92,1392.13 ± 2,66± 2.66 7,967.96 7,797.79 4,884.88 4,574.57 6,646.64 9,199.19 8,108.10

Angaben in mg Glukose/% des Ausgangswertes Zeit in StundenData in mg glucose /% of initial value time in hours

Claims (5)

1. Verfahren zur oralen Anwendung biologisch aktiver Peptide mit verzögerter und langandauernder Wirkung, gekennzeichnet dadurch, daß das biologisch aktive Peptid auf einen Träger fixiert und mit einem Resorptionsvermittler sowie einem Proteaseninhibitor eingesetzt wird.1. A method for the oral administration of biologically active peptides with delayed and long-lasting effect, characterized in that the biologically active peptide is fixed on a support and used with a absorption promoter and a protease inhibitor. 2. Verfahren nach Anspruch 1, gekennzeichnet dadurch, daß als Resorptionsvermittler ein Eiweiß-Fettsäure-Kondensat zur Anwendung gelangt.2. The method according to claim 1, characterized in that a protein-fatty acid condensate is used as absorption promoter. 3. Verfahren nach Anspruch 1 und 2, gekennzeichnet dadurch, daß als Proteaseninhibitor Epsilon-Aminokapronsäure (EAC), Derivate der EAC oder Aprotenin Verwendung findet.3. The method according to claim 1 and 2, characterized in that as protease inhibitor epsilon-aminocaproic acid (EAC), derivatives of EAC or Aprotenin finds use. 4. Verfahren nach Anspruch 1 bis 3, gekennzeichnet dadurch, daß die Retardierung des biologisch aktiven Peptids durch seine Fixierung an einem polymeren Träger erreicht wird.4. The method according to claim 1 to 3, characterized in that the retardation of the biologically active peptide is achieved by its fixation on a polymeric carrier. 5. Verfahren nach Anspruch 1 bis 4, gekennzeichnet dadurch, daß als biologisch aktive Peptide Insulin, Substanz P, GnRH, GnRH-Analoga, atriales Natrium-diuretisches Peptid, synthetische Thymuspeptide, peptidische Angiotensin-Converting-Enzym- und Renin-Inihibitoren sowie Neuropeptide gemeint sind.5. The method according to claim 1 to 4, characterized in that as biologically active peptides insulin, substance P, GnRH, GnRH analogues, atrial sodium diuretic peptide, synthetic thymus peptides, peptidic angiotensin converting enzyme and renin inhibitors and neuropeptides are meant.
DD29447386A 1986-09-17 1986-09-17 METHOD FOR ORAL APPLICATION OF BIOLOGICALLY ACTIVE PEPTIDES WITH DELAYED EFFECT DD252539A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0371195A1 (en) * 1988-07-12 1990-06-06 BERLIN-CHEMIE Aktiengesellschaft Process for producing preparations containing acitve peptides suited for rectal and vaginal application
EP0533938A1 (en) * 1991-02-19 1993-03-31 TSUMURA & CO. Composition for rectal administration of difficultly absorbable peptide
DE4140186A1 (en) * 1991-12-05 1993-06-09 Alfatec-Pharma Gmbh, 6900 Heidelberg, De Oral dosage forms for peptide drugs - esp. insulin, contg. drug in gelatin matrix
WO1995034294A1 (en) * 1994-06-15 1995-12-21 Yissum Research Development Company Of The Hebrew University Of Jerusalem Controlled release oral drug delivery system
EP1591453A1 (en) * 1999-05-17 2005-11-02 ConjuChem Inc. Modified peptides yy and conjugates thereof
US7601691B2 (en) 1999-05-17 2009-10-13 Conjuchem Biotechnologies Inc. Anti-obesity agents

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0371195A1 (en) * 1988-07-12 1990-06-06 BERLIN-CHEMIE Aktiengesellschaft Process for producing preparations containing acitve peptides suited for rectal and vaginal application
EP0533938A1 (en) * 1991-02-19 1993-03-31 TSUMURA & CO. Composition for rectal administration of difficultly absorbable peptide
DE4140186A1 (en) * 1991-12-05 1993-06-09 Alfatec-Pharma Gmbh, 6900 Heidelberg, De Oral dosage forms for peptide drugs - esp. insulin, contg. drug in gelatin matrix
WO1995034294A1 (en) * 1994-06-15 1995-12-21 Yissum Research Development Company Of The Hebrew University Of Jerusalem Controlled release oral drug delivery system
EP1591453A1 (en) * 1999-05-17 2005-11-02 ConjuChem Inc. Modified peptides yy and conjugates thereof
US7601691B2 (en) 1999-05-17 2009-10-13 Conjuchem Biotechnologies Inc. Anti-obesity agents
US7906482B2 (en) 1999-05-17 2011-03-15 Advanced Diagnostics And Discovery Anti-obesity agents

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