DD291668A7 - METHOD FOR PRODUCING AN ORAL APPLICABLE GNRH PREPARATION - Google Patents
METHOD FOR PRODUCING AN ORAL APPLICABLE GNRH PREPARATION Download PDFInfo
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- DD291668A7 DD291668A7 DD28742286A DD28742286A DD291668A7 DD 291668 A7 DD291668 A7 DD 291668A7 DD 28742286 A DD28742286 A DD 28742286A DD 28742286 A DD28742286 A DD 28742286A DD 291668 A7 DD291668 A7 DD 291668A7
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- German Democratic Republic
- Prior art keywords
- gnrh
- preparation
- surfactants
- tablets
- substances
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 title 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- NMJREATYWWNIKX-UHFFFAOYSA-N GnRH Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CC(C)C)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 NMJREATYWWNIKX-UHFFFAOYSA-N 0.000 claims abstract description 17
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- -1 alginine Polymers 0.000 claims abstract description 6
- 210000001072 colon Anatomy 0.000 claims abstract description 6
- 239000008298 dragée Substances 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 5
- 239000001814 pectin Substances 0.000 claims abstract description 5
- 235000010987 pectin Nutrition 0.000 claims abstract description 5
- 229920001277 pectin Polymers 0.000 claims abstract description 5
- 241000894006 Bacteria Species 0.000 claims abstract description 4
- 239000002775 capsule Substances 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims abstract 3
- 230000002255 enzymatic effect Effects 0.000 claims abstract 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 claims abstract 2
- 239000008187 granular material Substances 0.000 claims abstract 2
- 239000003094 microcapsule Substances 0.000 claims abstract 2
- 238000000576 coating method Methods 0.000 claims description 8
- 239000011248 coating agent Substances 0.000 claims description 7
- 239000003613 bile acid Substances 0.000 claims description 5
- 239000001913 cellulose Substances 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 150000001447 alkali salts Chemical class 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 239000003093 cationic surfactant Substances 0.000 claims description 3
- 239000002563 ionic surfactant Substances 0.000 claims description 3
- 229920000642 polymer Polymers 0.000 claims description 3
- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims description 2
- 239000002736 nonionic surfactant Substances 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims 1
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 210000002429 large intestine Anatomy 0.000 abstract description 3
- 239000004094 surface-active agent Substances 0.000 abstract description 2
- 239000008188 pellet Substances 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000003599 detergent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 230000001380 anti-conceptive effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- GVIRAXRGZUXHCI-UHFFFAOYSA-N 2-acetyloxycarbonylbenzoic acid Chemical compound CC(=O)OC(=O)C1=CC=CC=C1C(O)=O GVIRAXRGZUXHCI-UHFFFAOYSA-N 0.000 description 1
- UHYMCGZSUOMOPR-UHFFFAOYSA-N 2-naphthalen-1-yloxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC1=CC=CC2=CC=CC=C12 UHYMCGZSUOMOPR-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 244000005706 microflora Species 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
Classifications
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- 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
- A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung von oral anwendbaren Praeparaten, die GnRH und/oder GnRH-Analoga als Wirkstoff enthalten, in Form von Tabletten, Dragees, Granulaten, Kapseln, Mehrschichttabletten und Saft in Mikrokapseln, bei dem der Zubereitung resorptionsfoerdernde Stoffe wie Tenside zugemischt werden und die Zubereitung mit einer aeuszeren, vor den zersetzenden Einfluessen des Magen-Darm-Traktes schuetzenden Umhuellung und einer inneren, erst im Dickdarm durch die enzymatische Taetigkeit der Dickdarmbakterien aufloesbaren Umhuellung aus Pektin, Alginin, mikrokristalliner Cellulose und/oder gleichwirkenden Stoffen versehen wird.The invention relates to a process for the preparation of orally applicable preparations containing GnRH and / or GnRH analogues as active ingredient in the form of tablets, dragees, granules, capsules, multi-layer tablets and juice in microcapsules, in which the preparation contains resorptionsfoerdernde substances such as surfactants and the preparation with a aeuszeren, protecting against the corrosive effects of the gastrointestinal tract envelope and an inner, only in the large intestine by the enzymatic activity of the colon bacteria aufloesbaren envelope of pectin, alginine, microcrystalline cellulose and / or equivalent substances is provided.
Description
AntikonzeptivumAntikonzeptivum
Therapeutikum zur Behandlung von Zyklusstörungen,Therapeutic for the treatment of cycle disorders,
Kanzerostatikum wie auch alsKanzerostatikum as well as
Diagnostikumdiagnostic
vor allem in der Humanmedizin zum Einsatz kommen kann.especially in human medicine can be used.
Formulierungen mit GnRH oder davon abgeleiteten Derivaten sind dadurch gekennzeichnet, daß sie als Injektion oder als Infusion bzw. in einer nasal anwendbaren Formulierung (Spray, Tropfen) Verabreicht werden müssen, um ihre Wirkung entfalten zu können. Eine perorale Anwendung ist unökonomisch, da nur ein äußerst geringer Anteil (< 0,1 %) resorbiert wird, da ein proteolytischer Abbau im Magen-Darm-Trakt erfolgt und auf Grund der physikalisch-chemischen Beschaffenheit eine Resorption ohne Hilfsmittel nicht erfolgen kann.Formulations with GnRH or derivative derivatives thereof are characterized in that they must be administered as an injection or as an infusion or in a nasally applicable formulation (spray, drops) in order to be able to exert their effect. A peroral application is uneconomical, since only a very small proportion (<0.1%) is absorbed, since a proteolytic degradation in the gastrointestinal tract takes place and due to the physicochemical nature of a resorption can not be done without aids.
Weiterhin ist es bekannt, Wirkstoffe zur oralen Verabreichung durch Umhüllung mit anionischen filmbildenden Polymeren vor zersetzenden Einflüssen des Magen-Darm-Traktes zu schützen. Es ist ebenfalls bekannt, zur Erhöhung der Resorption von Peptidwirkstoffen im Darm dem Wirkstoff resorptionsfördemde Stoffe, wie nichtionogene oberflächenaktive Mittel vo.^ Ethertyp des Polyoxyethylens, anionische oberflächenaktive Mittel, kationische oberflächenaktive Mittel, ampholytische oberflächenaktive Mittel, Gallensäuren und Alkalisalze der Gallensäure zuzusetzen.Furthermore, it is known to protect active ingredients for oral administration by encasing with anionic film-forming polymers from decomposing influences of the gastrointestinal tract. It is also known to add resorptive substances such as polyoxyethylene nonionic surfactants, anionic surfactants, cationic surfactants, ampholytic surfactants, bile acids and alkali salts to bile acid to enhance the absorption of peptide active ingredients in the gut.
Das Ziel der Erfindung besteht darin, ein Verfahren zur Herstellung eines oral anwendbaren GnRH-Präparates aufzuzeigen und damit die bisher erforderliche Injektion' 1er Infusion bzw. die zur Erzielung eines antikonzeptiven Effektes hauptsächli ,h angewendete Applikation als Nasensprr.y, die mit Unverträglichkeitsreaktionen durch das zur Anwendung kommende Treibgas behaftet ist, zu ersetzen und damit die Anwendung als Antikonzeptivum wesentlich zu vereinfachen.The object of the invention is to provide a method for the preparation of an orally applicable GnRH preparation and thus the previously required injection '1er infusion or applied to achieve an anticonceptive effect Hauptsächli h application as Nasensprr.y, with incompatibility reactions by the to the application of propellant gas is subject to replace, and thus to simplify the use as an anticonceptive essential.
Der Erfindung liegt die Aufgabe zugrunde, ein Verfahren zur Herstellung von Formulierungen mit GnRH und GnRH-Derivaten zu erarbeiten, d'e oral ausreichend wirksam sind.The object of the invention is to develop a process for the preparation of formulations with GnRH and GnRH derivatives which are orally effective.
GnRH, das sowohl diagnostisch als auch therapeutisch und antikonzeptionell Anwendung findet, kann bisher nur injiziert oder mit geringerem Wirkungsgrad nasal verabreicht werden, da as im oberen Magen-Darm-Trakt durch körpereigene Enzyme abgebaut wird.GnRH, which is used both diagnostically and therapeutically and as an anticonceptor, can only be injected or administered nasally with less efficiency, since it is broken down in the upper gastrointestinal tract by endogenous enzymes.
Durch Umhüllung der oralen Zubereitung mit mindestens 2 Schichten kann erreicht werden, daß das GnRH erst in den unteren Darmabschnitten freigesetzt wird, in denen proteolytische Enzyme kaum noch vorhanden sind.By enclosing the oral preparation with at least 2 layers can be achieved that the GnRH is released only in the lower intestine sections in which proteolytic enzymes are barely present.
Dies ist dann gegeben, wenn eine erste Hülle den darunterliegenden Kern vor zersetzenden Einflüssen des Magen-Darm-Traktes schützt. Dafür sind anionische filmbildende Polymere bekannt wie z. B. Celluloseacetylphthalat oder Polymethacrylsäurederivate. Die zweite Hülle muß dann aus einem Material bestehen, das von den Enzymen des Organismus nicht angegriffen, jedoch von den Dickdarmbakterien zerlegt werden.This is the case when a first shell protects the underlying core from the disintegrating effects of the gastrointestinal tract. For anionic film-forming polymers are known, such. As cellulose acetyl phthalate or polymethacrylic acid derivatives. The second shell must then consist of a material that is not attacked by the enzymes of the organism, but are decomposed by the colon bacteria.
Diese Eigenschaften besitzen Pektine, Alginate und vor allem Cellulose und seine Derivate.These properties have pectins, alginates and especially cellulose and its derivatives.
Dieser zweite (innere) Überzug, der erst durch die im Dickdarm vorhandene Bakterienflora zersetzt wird, stellt denThis second (inner) coating, which is only decomposed by the bacteria flora present in the large intestine, represents the
eifindungswesentlichenTeil der Erfindung dar. Dieser Überzug sichert nach der Auflösung des ersten Überzuges im Magen, daß die Freigabe des Wirkstoffes erst im Dickdarm erfolgt.This coating ensures after the dissolution of the first coating in the stomach, that the release of the drug takes place only in the large intestine.
Erfindungsgemäß erhalten die Zubereitungen einen Überzug aus Pektin, Alginin, mikrokristalliner Cellulose, Cellulosederivaten wie Ceiluloseacetylphthalat, Hydroxypropylmethylcellulosephthalat und Celluloseacetosuccir at, aus Benzophenylsalicylat und/oder Styrol-Maleinsäure-Copolymeren, Auch andere gleichwirkende Überzugsstoffe können Anwendung finden.According to the invention, the formulations obtain a coating of pectin, alginine, microcrystalline cellulose, cellulose derivatives such as Ceiluloseacetylphthalat, Hydroxypropylmethylcellulosephthalat and Celluloseacetosuccir at least, from Benzophenylsalicylat and / or styrene-maleic acid copolymers, Other equally effective coating materials can apply.
Um das im Dickdarm freigesetzte GnRH zur ausreichenden Resorption zu bringen, ist die Zugabe eines geeigneten Detergens erforderlich. Ohne einen solchen Zusatz findet keine ausreichende Resorption des GnRH statt.In order to bring the released in the colon GnRH sufficient absorption, the addition of a suitable detergent is required. Without such an addition, there is no adequate absorption of GnRH.
Hierfür geeignete Detergenzien sind unter anderem nichtionogene oberflächenaktive Mittel vom Ethertyp des Polyoxyethylens, anionische oberflächenaktive Mittel, insbesondere Eiweiß-Fettsäure-Kondensate und Laurylsulfonat, kationische oberflächenaktive Mittel, ampholytische oberflächenaktive Mittel, Gallensäuren und deren Alkalisalze.Detergents suitable for this purpose include nonionic ether type surfactants of polyoxyethylene, anionic surfactants, especially protein fatty acid condensates and lauryl sulfonate, cationic surfactants, ampholytic surfactants, bile acids and their alkali salts.
Erfindungsgemäß kann auch so verfahren werden, daß das GnRH und der Resorptionsvermittler in Pellets verarbeitet werden, die duroh eine Substanz umhüllt werden, die durch die Mikroflora des Darms entfernt wird. Damit die Pellets jedoch vom sauren Mageninhalt nicht beschädigt werden, ist eine Einbringung in Hartgelatinekapseln möglich, die nach der Füllung magensaft- und verdauungsenzymresistant dragiert werden.The process according to the invention may also be such that the GnRH and the absorption promoter are processed into pellets, which are enveloped by a substance which is removed by the microflora of the intestine. However, so that the pellets are not damaged by the acidic gastric contents, it is possible to introduce them into hard gelatine capsules which are coated with gastric juices and digestive enzymes after filling.
Durch die kombinierte Anwendung dieser beiden PrinzipienThrough the combined application of these two principles
- Umhüllung des Präparates mit mindestens 2 Überzügen, durch die gewährleistet wird, daß der Wirkstoff erst im Dickdarm freigegeben und somit eine proteolytische Inaktivierung verhindert wird;- Envelopment of the preparation with at least 2 coatings, which ensures that the drug is released only in the colon and thus prevents proteolytic inactivation;
- Zusatz von Detergenzien zur Förderung der Resorption von GnRH durch die Schleimhäute des Dickdarms ist es möglich, GnRH oral zur Anwendung zu bringen.- Addition of detergents to promote the absorption of GnRH through the mucous membranes of the colon, it is possible to apply GnRH orally.
Ausführungsbeispieleembodiments
Drageekerne von 200mg, die nebst Bindemittel 500pg D-Phee-GnRH und 10mg Eiweiß-Fettsäure-Kondensat Mi 105BC enthalten, werden nach beiliegendem Verfahren hergestellt.Dragee kernels of 200 mg, which in addition to binders contain 500 μg of D-Phe e -GnRH and 10 mg of protein-fatty acid condensate Mi 105BC, are prepared according to the enclosed method.
Etwa 1000 dieser Drageekerne werden im Luftsuspensionsverfahren nach WURSTER mit einer Flüssigkeit besprüht, dieAbout 1000 of these dragee cores are sprayed in the air suspension process according to WURSTER with a liquid that
Nach Trocknung im Vakuum erfolgt eine erneute Behandlung der Dragees im Luftsuspensionsverfahren mit einer Lösung ausAfter drying in vacuo, the dragees are re-treated in the air suspension process with a solution
Hydroxypropylmethylcellulosephthalat (HP 55) 30 gHydroxypropylmethylcellulose phthalate (HP 55) 30 g
Isopropanol 250 mlIsopropanol 250 ml
Ethylaceiat 250 ml,Ethyl acetate 250 ml,
Die Zeitdauer der Besprühung ist so gewählt, daß nach Trocknung der Dragees diese ein durchschnittliches Gewicht von 250 mg aufweisen.The duration of the spraying is chosen so that after drying of the dragees they have an average weight of 250 mg.
Pellets von einem Durchmesser von etwa 1 mm werden nach üblichen Verfahren unter Zusatz von Bindemitteln so hergestellt, daß sie pro Pellet etwa 250ng D-Phee-GnRH und 0,01 mg Eiweiß-Fettsäure-Kondensat Mi 105BC enthalten. Diese Pellets werden im Luftsuspensionsverfahren nach WURSTER mit einer Flüssigkeit besprüht, diePellets of about 1 mm in diameter are prepared by conventional methods with the addition of binders so as to contain, per pellet, about 250 ng of D-Phe e -GnRH and 0.01 mg of egg white fatty acid condensate Mi 105BC. These pellets are sprayed in the air suspension process according to WURSTER with a liquid that
mikrokristalline Cellulose 1gmicrocrystalline cellulose 1g
Pektion 6gPection 6g
Ethylcellulose 6gEthyl cellulose 6g
Diethylphthalat 4 gDiethyl phthalate 4 g
Isopropanol 130 mlIsopropanol 130 ml
Ethanol 130 ml enthält.Ethanol contains 130 ml.
Nach Trocknung im Vakuum erfolgt eine erneute Behandlung der Pellets im Luftsuspensionsverfahren mit einer Lösung ausAfter drying in vacuo, the pellets are re-treated in the air suspension process with a solution
Hydroxypropylmethylcellulosephthalat (HP 55) 30 gHydroxypropylmethylcellulose phthalate (HP 55) 30 g
Isopropanol 250 mlIsopropanol 250 ml
Ethylacetat 250 ml.Ethyl acetate 250 ml.
Die Zeitdauer der Bosprühung ist so gewählt, daß nach Trocknung der Pellets diese eine Gewichtszunahme von etwa 10% aufweisen.The duration of the Bosprühung is chosen so that after drying of the pellets they have an increase in weight of about 10%.
Unreife männliche Ratten im Alter von 25 Tagen erhalten 50 oder 250ng D-Phe'-GnRH subcutan bzw. nach beschriebenem Verfahren hergestellte Pellets in den Dosierungen von 250 ng und 1,000Mg, oral appliziert. Einer Kontrollgruppe von 5 Tieren wurde 0,5ml einer physiologischen Kochsalzlösung oral verabreicht. Die orale Applikation der Pellets (1 bzw. 4 pro Tier) erfolgte durch eine starre Schlundsonde und anschließenden Nachspülung mit physiologischer Kochsalzlösung.Immature male rats at 25 days of age receive 50 or 250 ng of D-Phe'-GnRH subcutaneously or pellets prepared by the method described above at the dosages of 250 ng and 1,000 mg, administered orally. In a control group of 5 animals, 0.5 ml of a physiological saline solution was orally administered. The oral application of the pellets (1 or 4 per animal) was carried out by a rigid gavage and subsequent rinsing with physiological saline.
1,1,5,2,3 und 5 Stunden nach Applikation wurden jeweils 6 Tiere pro Dosisgruppe durch Dekapitation getötet und ihr Blut gewonnen. Die Blutproben wurden nach Bildung des Blutkuchens zentrifugiert und die Seren bei -3O0C bis zur radioimmunologisierten LH-Bestimmung aufbewahrt. Die Testung der LH-Spiegel erfolgte im Radioimmunoassay mittels eines Schaf-Anti-LH/Schaf LH-Systems. Als Standard diente die Referenzpräparation NIAMDO-Rat-LH-RP 1. Die Ergebnisse sind in der Tabelle-1 dargestellt.1,1,5,2,3 and 5 hours after administration, 6 animals per dose group were killed by decapitation and their blood collected. The blood samples were centrifuged after formation of the blood cake and the sera stored at -3O 0 C until radioimmunologized LH determination. The LH levels were tested by radioimmunoassay using a sheep anti-LH / sheep LH system. The reference preparation was NIAMDO-Rat-LH-RP 1. The results are shown in Table-1.
LH-Spiegel nach D-Phee-GnRH an unreifen männlichen RattenLH levels after D-Phe e -GnRH in immature male rats
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD28742286A DD291668A7 (en) | 1986-02-28 | 1986-02-28 | METHOD FOR PRODUCING AN ORAL APPLICABLE GNRH PREPARATION |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD28742286A DD291668A7 (en) | 1986-02-28 | 1986-02-28 | METHOD FOR PRODUCING AN ORAL APPLICABLE GNRH PREPARATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DD291668A7 true DD291668A7 (en) | 1991-07-11 |
Family
ID=5576822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD28742286A DD291668A7 (en) | 1986-02-28 | 1986-02-28 | METHOD FOR PRODUCING AN ORAL APPLICABLE GNRH PREPARATION |
Country Status (1)
| Country | Link |
|---|---|
| DD (1) | DD291668A7 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997025980A1 (en) * | 1996-01-16 | 1997-07-24 | Advanced Polymer Systems, Inc. | Topical delivery of drugs to the lower gastrointestinal tract |
| WO1997027843A3 (en) * | 1996-01-30 | 1997-09-18 | Advanced Polymer Systems Inc | Targeted delivery of drugs to the lower gastrointestinal tract |
| US5849327A (en) * | 1994-07-29 | 1998-12-15 | Advanced Polymer Systems, Inc. | Delivery of drugs to the lower gastrointestinal tract |
-
1986
- 1986-02-28 DD DD28742286A patent/DD291668A7/en not_active IP Right Cessation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5849327A (en) * | 1994-07-29 | 1998-12-15 | Advanced Polymer Systems, Inc. | Delivery of drugs to the lower gastrointestinal tract |
| WO1997025980A1 (en) * | 1996-01-16 | 1997-07-24 | Advanced Polymer Systems, Inc. | Topical delivery of drugs to the lower gastrointestinal tract |
| WO1997027843A3 (en) * | 1996-01-30 | 1997-09-18 | Advanced Polymer Systems Inc | Targeted delivery of drugs to the lower gastrointestinal tract |
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