EP0596970A1 - Prostaglandin-e 1? formulation - Google Patents
Prostaglandin-e 1? formulationInfo
- Publication number
- EP0596970A1 EP0596970A1 EP92916379A EP92916379A EP0596970A1 EP 0596970 A1 EP0596970 A1 EP 0596970A1 EP 92916379 A EP92916379 A EP 92916379A EP 92916379 A EP92916379 A EP 92916379A EP 0596970 A1 EP0596970 A1 EP 0596970A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- liposomes
- prostaglandin
- active ingredient
- formulation
- pgei
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 15
- 238000009472 formulation Methods 0.000 title claims description 13
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 title abstract 3
- 229960000711 alprostadil Drugs 0.000 title abstract 3
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 title abstract 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 title abstract 3
- 239000002502 liposome Substances 0.000 claims abstract description 40
- 239000003708 ampul Substances 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims abstract description 4
- 150000003180 prostaglandins Chemical class 0.000 claims description 8
- 239000000243 solution Substances 0.000 description 19
- 239000004480 active ingredient Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 9
- 239000013543 active substance Substances 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- 238000003860 storage Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005538 encapsulation Methods 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000008344 egg yolk phospholipid Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000003311 flocculating effect Effects 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000000304 vasodilatating effect Effects 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
- A61K9/1278—Post-loading, e.g. by ion or pH gradient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Definitions
- the present invention relates to a new formulation for prostaglandin egg.
- Liposomes consist of spherical lipid membranes that can be formed in water by dispersing suitable lipids.
- the lipid membrane of the liposomes separates an inner aqueous lumen encapsulated by the liposomes from the water phase surrounding the liposomes.
- Water-soluble active substances can be encapsulated in the aqueous interior of the liposomes, lipophilic active substances can be integrated ("built-in") into the membrane of the liposomes.
- Liposomal active ingredient formulations often have clear advantages over purely aqueous active ingredient solutions, e.g. with intravenous administration.
- the liposomal formulation of hydrolysis-sensitive active substances e.g. PGEi.
- This active ingredient decomposes in an aqueous medium to form prostaglandin Ai.
- a storage-stable formulation should therefore contain as little water as possible.
- Liposomal formulations with e.g. PGEi must therefore be lyophilized, corresponding methods are known (e.g. US 4,370,349 and
- the active ingredient cannot be brought into the aqueous interior of the liposomes with this method; it is then largely in the water phase surrounding the liposomes.
- PGEi is known to have a very short half-life after intravenous injection due to a pulmonary first-pass effect. It is known that a considerable proportion of the dose of active substance applied is already metabolized during the first passage of the lung and thus inactivated.
- the effectiveness could be significantly improved (see EP 150 732).
- the storage stability of the active ingredient in the aqueous formulation is, however, limited even in cool storage.
- the active ingredient (PGEi) can subsequently be added to an already formed liposome solution without the liposomes flocculating.
- the effectiveness of the PGEi after intravenous administration of the liposome formulation is independent of whether the active substance was encapsulated in liposomes (transmembrane loading technique) or whether it was subsequently added to liposomes (without transmembrane loading technique).
- the invention therefore relates to a formulation for prostaglandin egg consisting of an ampoule with a liposome solution and an ampoule which contains the prostaglandin E in solid or dissolved form.
- the liposome solution is prepared in a known manner (cf. for example US 4,737,323).
- Phospholipids possibly in a mixture with cholesterol
- synthetic lipids cf. EP 331 091
- the PGEi can be added to the liposome formulation in solid form (addition of the active ingredient powder), but also in the form of e.g. ethanolic PGEi solution, provided the amount of ethanol added remains small (maximum 1% [volume] of the liposome solution.
- the dosage form according to this procedure therefore consists of 2 parts, which are combined immediately before application and mixed by briefly shaking.
- the first part consists of the "empty" lipid formulation (liposome solution), the second part of the active ingredient, for example in powdered form or in the form of a concentrated solution in for example ethanol
- Solvents are conceivable in which the active ingredient is stable in storage and can be applied parenterally.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Une composition de prostaglandine E1 comprend une ampoule contenant une solution de liposomes. L'invention concerne en outre une ampoule contenant la prostaglandine E1 à l'état solide ou dissous.A prostaglandin E1 composition includes an ampule containing a solution of liposomes. The invention further relates to an ampule containing prostaglandin E1 in a solid or dissolved state.
Description
Prostaglandin Ei-Formulierung Prostaglandin egg formulation
Beschreibungdescription
Gegenstand der vorliegenden Erfindung ist eine neue Formu¬ lierung für Prostaglandin Ei.The present invention relates to a new formulation for prostaglandin egg.
Prostaglandin Ei (= PGE ) ist ein bekannter Wirkstoff mit u.a. vasodilatierender Wirkung. Da der Wirkstoff nicht sehr stabil ist, muß er stabilisiert werden.Prostaglandin egg (= PGE) is a known active ingredient with i.a. vasodilating effect. Since the active ingredient is not very stable, it has to be stabilized.
Hierzu bietet sich sein Einbau in Liposomen oder Emulsionen an.For this purpose, its incorporation into liposomes or emulsions lends itself.
Liposomen bestehen aus kugelförmigen Lipidmembranen, die sich in Wasser durch Dispergieren geeigneter Lipide bilden lassen. Die Lipidmembran der Liposomen trennt ein inneres von den Liposomen verkapseltes wäßriges Lumen von der die Liposomen umgebenden Wasserphase ab.Liposomes consist of spherical lipid membranes that can be formed in water by dispersing suitable lipids. The lipid membrane of the liposomes separates an inner aqueous lumen encapsulated by the liposomes from the water phase surrounding the liposomes.
In den wäßrigen Innenraum der Liposomen können wasserlösli¬ che Wirkstoffe verkapselt werden, lipophile Wirkstoffe kön¬ nen in die Membran der Liposomen integriert ("eingebaut") werden. Liposomale Wirkstoff-Formulierungen besitzen oft deutliche Vorteile gegenüber rein wäßrigen Wirkstofflösun¬ gen, z.B. bei der intravenösen Applikation.Water-soluble active substances can be encapsulated in the aqueous interior of the liposomes, lipophilic active substances can be integrated ("built-in") into the membrane of the liposomes. Liposomal active ingredient formulations often have clear advantages over purely aqueous active ingredient solutions, e.g. with intravenous administration.
Problematisch wird die liposomale Formulierung hydroly- seeempfindlicher Wirkstoffe, wie z.B. PGEi. Dieser Wirkstoff zersetzt sich im wäßrigen Milieu unter Bildung von Prostag¬ landin Ai. Eine lagerstabile Formulierung darf daher mög¬ lichst kein Wasser enthalten. Liposomale Formulierungen mit z.B. PGEi, müssen daher lyophilisiert werden, entsprechende Verfahren sind bekannt (z.B. US 4 370 349 sowieThe liposomal formulation of hydrolysis-sensitive active substances, e.g. PGEi. This active ingredient decomposes in an aqueous medium to form prostaglandin Ai. A storage-stable formulation should therefore contain as little water as possible. Liposomal formulations with e.g. PGEi must therefore be lyophilized, corresponding methods are known (e.g. US 4,370,349 and
US 4 229 360) . Das Lyophilisat muß dann kurz vor der Verwen¬ dung mit Wasser rehydratisiert werden. Lyophilisationsver- fahren sind allerdings aufwendig und kostenintensiv, insbe¬ sondere bei der Herstellung von Arzneimitteln, die für eine parenterale Applikation vorgesehen sind (Keimfreiheit) .
Es ist bekannt, daß leere, nicht mit Wirkstoffen beladene Liposo enlösungen über lange Zeiträume stabil sind (> 1 Jahr, evtl. bei Kühllagerung) , d.h. eine Lyophilisation der Liposomen ist nicht in jedem Fall zur Erreichung einer guten Lagerstabilität notwendig. Vereinzelt wurde auch, ins¬ besondere bei Verwendung synthetischer Lipide zur Bildung der Liposomen von Präparationen berichtet, die über lange Zeiträume bei Raumtemperatur stabil sind. Die Lagerstabili¬ tät von Liposomenlösungen ist daher oft, insbesondere bei hydrolysee pfindlichen Stoffen wie PGEi, oder Peptiden/ Proteinen einzig durch den Wirkstoff limitiert. Es wäre daher zur Erreichung maximaler Lagerstabilität wünschens¬ wert, den Wirkstoff erst kurz vor der Applikation der Liposomenlösungen oder der Emulsion zuzusetzen, um ihn so kurz wie möglich dem wäßrigen Milieu auszusetzen. Dieses Verfahren ist allerdings kaum praktisch anwendbar, weilUS 4,229,360). The lyophilisate must then be rehydrated with water shortly before use. However, lyophilization processes are complex and costly, in particular in the manufacture of medicaments which are intended for parenteral administration (sterility). It is known that empty liposome solutions which are not loaded with active substances are stable over long periods (> 1 year, possibly in cold storage), ie lyophilization of the liposomes is not always necessary in order to achieve good storage stability. There have also been isolated reports, particularly when using synthetic lipids to form the liposomes, of preparations which are stable over long periods at room temperature. The storage stability of liposome solutions is therefore often limited only by the active ingredient, particularly in the case of substances sensitive to hydrolysis such as PGEi or peptides / proteins. To achieve maximum storage stability, it would therefore be desirable to add the active ingredient shortly before the application of the liposome solutions or the emulsion, in order to expose it to the aqueous environment as shortly as possible. However, this method is hardly practical because
a) durch die nachträgliche Wirkstoffzugabe die Liposomen- lösung im allgemeinen sofort ausflockt (infolge des Aus- salzeffektes der im allgemeinen ionischen Wirkstoffe, aber auch durch andere Effekte)a) the subsequent addition of active ingredient generally flocculates the liposome solution immediately (due to the salting-out effect of the generally ionic active ingredients, but also due to other effects)
b) der Wirkstoff mit dieser Methode nicht in den wäßrigen Innenraum der Liposomen gebracht werden kann, er befin- det sich dann weitestgehend in der die Liposomen umge¬ benden Wasserphase.b) the active ingredient cannot be brought into the aqueous interior of the liposomes with this method; it is then largely in the water phase surrounding the liposomes.
Große Anstrengungen sind unternommen worden, um Verfahren zu finden, Wirkstoffe in den Innenraum von Liposomen zu verkap- sein. Aus der sehr umfangreichen Literatur sei nur ein Bei¬ spiel erwähnt: Mit Hil e von pH-Gradienten (transmembrane loading Technik) gelingt es, das PGEi, i wäßrigen Innenraum der Liposomen zu verkapseln (WO 88/09170) . Bei diesem Ver¬ fahren wird die wirkstoffhaltige Liposomenlösung mit Hilfe einer sauren Pufferlösung von pH 7 auf pH 4 acidifiziert, durch den dadurch aufgebauten Ionengradienten erfolgt eine effiziente Verkapselung des PGEi in άsn Liposomen. Diese Verkapselung bleibt aber nur aufrecht erhalten, wenn der pH- Wert der Liposomenlösung im Sauren belassen wird, da letz- tendlich nur der pH-Gradient (Innenraum der Liposomen pH 7, äußere Wasserphase pH 4) die Verkapselung bewirkt. Wird der pH-Wert wieder neutral gestellt (pH 7) , fließt der Wirkstoff wieder aus den Liposomen heraus. Genau dies geschieht bei
der Verabreichung derartiger Präparationen, beispielsweise bei der intravenösen Applikation durch die Verdünnung mit Blut (pH des Vollblutes ca. 7,2-7,4) . Es ist allerdings theoretisch auch möglich, den transmembranen pH-Gradienten durch Acidifizieren einer bei alkalischen pH-Werten (z.B. 9-10) hergestellten Liposomlösung auch auf pH 7 herzustel¬ len. Damit wäre die Verkapselungsstabilität auch im biologi¬ schen Milieu (z.B. Vollblut) gewährleistet. Allerdings sind bekanntermaßen weder die eingesetzten Liposomen bildenden Hilfsstoffe (z.B. Phospholipide) noch PGEi, bei derart alka¬ lischen pH-Werten stabil. Diese Methode ist daher nicht an¬ wendbar.Great efforts have been made to find processes for encapsulating active substances in the interior of liposomes. Only one example from the very extensive literature should be mentioned: With the aid of pH gradients (transmembrane loading technique) it is possible to encapsulate the PGEi, i aqueous interior of the liposomes (WO 88/09170). In this driving compounds according to the active substance-containing liposome solution with the aid of an acidic buffer solution of pH is acidified to pH 4 7, characterized by the established ion gradients occurs efficient encapsulation of the PGEi i n n άs liposomes. However, this encapsulation is only maintained if the pH of the liposome solution is left in the acid, since ultimately only the pH gradient (inside of the liposomes pH 7, outer water phase pH 4) effects the encapsulation. If the pH is reset to neutral (pH 7), the active ingredient flows out of the liposomes again. This is exactly what happens at the administration of such preparations, for example in the case of intravenous application by dilution with blood (pH of the whole blood approx. 7.2-7.4). However, it is theoretically also possible to produce the transmembrane pH gradient to pH 7 by acidifying a liposome solution prepared at alkaline pH values (eg 9-10). This would ensure encapsulation stability even in a biological environment (eg whole blood). However, it is known that neither the liposome-forming auxiliaries used (for example phospholipids) nor PGEi are stable at such alkaline pH values. This method is therefore not applicable.
PGEi besitzt bekanntermaßen infolge eines pulmonalen first- pass-Effektes eine sehr kurze Halbwertszeit nach intravenö¬ ser Injektion. Ein erheblicher Anteil der applizierten Wirk¬ stoffdosis wird bekanntermaßen bereits bei der ersten Lun¬ genpassage metabolisiert und damit inaktiviert. Durch Einbau des Wirkstoffs in Lipidformulierungen konnte die Wirksamkeit deutlich verbessert werden (siehe EP 150 732) . Die Lagersta¬ bilität des Wirkstoffs in der wäßrigen Formulierung ist al¬ lerdings auch bei kühler Lagerung limitiert.PGEi is known to have a very short half-life after intravenous injection due to a pulmonary first-pass effect. It is known that a considerable proportion of the dose of active substance applied is already metabolized during the first passage of the lung and thus inactivated. By incorporating the active ingredient in lipid formulations, the effectiveness could be significantly improved (see EP 150 732). The storage stability of the active ingredient in the aqueous formulation is, however, limited even in cool storage.
Überraschenderweise wurde nun gefunden, daßSurprisingly, it has now been found that
a) der Wirkstoff (PGEi) nachträglich zu einer bereits ge¬ bildeten Liposomenlösung gegeben werden kann, ohne daß es dabei zum Ausflocken der Liposomen kommt.a) the active ingredient (PGEi) can subsequently be added to an already formed liposome solution without the liposomes flocculating.
b) die Wirksamkeit des PGEi nach intravenöser Verabreichung der Liposomenfor ulierung unabhängig davon ist, ob der Wirkstoff in Liposomen verkapselt wurde (transmembrane loading Technik) oder ob er nachträglich Liposomen zuge¬ setzt wurde (ohne transmembrane loading Technik) .b) the effectiveness of the PGEi after intravenous administration of the liposome formulation is independent of whether the active substance was encapsulated in liposomes (transmembrane loading technique) or whether it was subsequently added to liposomes (without transmembrane loading technique).
Entscheidend für die verbesserte Wirksamkeit des PGEi mit Hilfe von Liposomen ist demnach nicht eine Verkapselung des PGEi in das Liposomeninnere, sondern lediglich die Anwesen¬ heit kolloidaler Lipidpartikel bei der Injektion. Diese Vor- aussetzung ist bereits durch einfaches Mischen des Wirk¬ stoffs mit einer wäßrigen Liposomenlösung erfüllt, da die
Zugabe von PGEi nicht zu einem Ausflocken der Liposomen führt.Critical to the improved effectiveness of the PGEi by means of liposomes is therefore not an encapsulation of the PGEi i n the interior of liposomes, but only the Anwesen¬ uniform colloidal lipid particles in the injection. This requirement is already met by simply mixing the active ingredient with an aqueous liposome solution, since the Adding PGEi does not lead to flocculation of the liposomes.
Gegenstand der Erfindung ist daher eine Formulierung für Prostaglandin Ei bestehend aus einer Ampulle mit einer Lipo¬ somen-Lösung und einer Ampulle, die das Prostaglandin E in fester oder gelöster Form enthält.The invention therefore relates to a formulation for prostaglandin egg consisting of an ampoule with a liposome solution and an ampoule which contains the prostaglandin E in solid or dissolved form.
Die Liposomen-Lösung wird in bekannter Weise hergestellt (vgl. beispielsweise US 4 737 323) . Zur Herstellung der Li¬ posomen können Phospholipide (evtl. in Mischung mit Chole- sterin) , aber auch synthetische Lipide (vgl. EP 331 091) eingesetzt werden.The liposome solution is prepared in a known manner (cf. for example US 4,737,323). Phospholipids (possibly in a mixture with cholesterol), but also synthetic lipids (cf. EP 331 091) can be used to produce the liposomes.
Die Zugabe des PGEi zur Liposomenformulierung kann in fester Form erfolgen (Zugabe des Wirkstoffpulvers) , aber auch in Form einer z.B. ethanolischen PGEi-Lösung, sofern die Menge des zugegebenen Ethanols klein bleibt (maximal 1 % [Volumen] der Liposomenlösung. Die Arzneiform nach diesem Verfahren besteht daher aus 2 Teilen, die direkt vor der Applikation vereinigt und durch kurzes Schütteln gemischt werden. Der erste Teil besteht aus der "leeren" Lipidformulierung (Lipo¬ somenlösung) , der zweite Teil aus dem Wirkstoff, z.B. in pulverisierter Form oder in Form einer konzentrierten Lösung in z.B. Ethanol. Statt Ethanol sind dabei auch andereThe PGEi can be added to the liposome formulation in solid form (addition of the active ingredient powder), but also in the form of e.g. ethanolic PGEi solution, provided the amount of ethanol added remains small (maximum 1% [volume] of the liposome solution. The dosage form according to this procedure therefore consists of 2 parts, which are combined immediately before application and mixed by briefly shaking. The first part consists of the "empty" lipid formulation (liposome solution), the second part of the active ingredient, for example in powdered form or in the form of a concentrated solution in for example ethanol
Lösungsmittel denkbar, in denen der Wirkstoff lagerstabil ist und die parenteral applizierbar sind.Solvents are conceivable in which the active ingredient is stable in storage and can be applied parenterally.
Die folgenden Beispiele veranschaulichen die Erfindung.The following examples illustrate the invention.
Beispiel 1example 1
a) 1670 mg Eierlecithin (Lecithin E100, Fa. Lipoid KG, BRD) und 346 mg Cholesterin wurden in wenig Dichlormethan in einem Rundkolben gelöst. Das Lösungsmittel wurde anfangs am Rotationsverdampfer, anschließend über Nacht an einer Hochvakuumpumpe restlos entfernt. Von dem Rückstand wur¬ den 1622 mg in ein mit einem Kühlmantel versehenes Be¬ cherglas eingefüllt, das mit Hilfe eines ümwälzthermo- staten auf 45CC thermostatisiert wurde. Nach Zugabe von 18 ml Saccharoselösung (eingestellt mit 1,0 N Natronlau¬ ge auf pH 7,4) wurde 45 min mit 50 Watt ultrabeschallt (Branson Sonifier, Standardhorn) . Die beschallte Liposo-
menlösung wurde quantitativ über ein Sterilfilter in ei¬ ne 25 ml Ampulle gefüllt. Anschließend wurde die Ampulle verschlossen.a) 1670 mg of egg lecithin (lecithin E100, from Lipoid KG, FRG) and 346 mg of cholesterol were dissolved in a little dichloromethane in a round bottom flask. The solvent was initially removed completely on a rotary evaporator, then overnight on a high vacuum pump. 1622 mg of the residue were poured into a beaker provided with a cooling jacket, which was thermostatted to 45 ° C. with the aid of a circulating thermostat. After the addition of 18 ml of sucrose solution (adjusted to pH 7.4 with 1.0 N sodium hydroxide solution), the system was sonicated with 50 watts for 45 min (Branson Sonifier, Standardhorn). The sonicated liposo- The solution was filled quantitatively into a 25 ml ampoule using a sterile filter. The ampoule was then closed.
b) 0,2 ml Ethanol enthaltend 0,25 mg Prostaglandin Ei wurde unter sterilen Bedingungen in eine Ampulle gefüllt.b) 0.2 ml of ethanol containing 0.25 mg of prostaglandin egg was filled into an ampoule under sterile conditions.
c) Die gemäß a) und b) erhaltenen Ampullen wurden zusammen verpackt.
c) The ampoules obtained according to a) and b) were packed together.
Claims
PatentanspruchClaim
Formulierung für Prostaglandin Ei bestehend aus einer .Ampul¬ le mit einer Liposomen-Lösung und einer Ampulle, die das Prostaglandin Ei in fester oder gelöster Form enthält.
Formulation for prostaglandin egg consisting of an ampoule with a liposome solution and an ampoule which contains the prostaglandin egg in solid or dissolved form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19914125255 DE4125255A1 (en) | 1991-07-31 | 1991-07-31 | PROSTAGLANDIN E (DOWN ARROW) 1 (DOWN ARROW) FORMULATION |
| DE4125255 | 1991-07-31 | ||
| PCT/EP1992/001684 WO1993002681A1 (en) | 1991-07-31 | 1992-07-23 | Prostaglandin-e1 formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0596970A1 true EP0596970A1 (en) | 1994-05-18 |
Family
ID=6437340
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP92916379A Withdrawn EP0596970A1 (en) | 1991-07-31 | 1992-07-23 | Prostaglandin-e 1? formulation |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0596970A1 (en) |
| JP (1) | JPH06509568A (en) |
| CA (1) | CA2113443A1 (en) |
| DE (1) | DE4125255A1 (en) |
| MX (1) | MX9204183A (en) |
| WO (1) | WO1993002681A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015155716A1 (en) | 2014-04-08 | 2015-10-15 | Pantex International S.P.A. | Multilayer material and absorbent sanitary article comprising the same |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4309579C3 (en) * | 1993-03-24 | 2000-01-27 | Sanol Arznei Schwarz Gmbh | Pharmaceutical composition in the form of a pack |
| US5840328A (en) * | 1994-01-11 | 1998-11-24 | The Liposome Company, Inc. | Treatment using arachidonic acid metabolite and particulate formulations |
| CA2179986A1 (en) * | 1994-01-11 | 1995-07-13 | Andrew S. Janoff | Treatment using arachidonic acid metabolite and particulate formulations |
| DK0722323T3 (en) * | 1994-08-05 | 2000-04-03 | Inpharma Sa | Compositions containing troxerutin complexed with phosphatidylcholine for topical treatment of erectile impotence |
| EP1013269A4 (en) * | 1997-06-06 | 2002-02-20 | Shionogi & Co | Improvement in medicament administration system |
| US6682758B1 (en) | 1998-12-22 | 2004-01-27 | The United States Of America As Represented By The Department Of Health And Human Services | Water-insoluble drug delivery system |
| JP2002532535A (en) * | 1998-12-22 | 2002-10-02 | アメリカ合衆国 | Water-insoluble drug delivery system |
| DK3512495T3 (en) | 2016-09-15 | 2022-12-05 | Camurus Ab | FORMULATIONS OF PROSTACYCLIN ANALOGUES |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2515001C2 (en) * | 1975-04-04 | 1986-10-02 | Schering AG, 1000 Berlin und 4709 Bergkamen | Freeze-dried powders containing prostaglandin |
| US4814270A (en) * | 1984-09-13 | 1989-03-21 | Becton Dickinson And Company | Production of loaded vesicles |
| US5082664A (en) * | 1987-05-22 | 1992-01-21 | The Liposome Company, Inc. | Prostaglandin-lipid formulations |
-
1991
- 1991-07-31 DE DE19914125255 patent/DE4125255A1/en not_active Withdrawn
-
1992
- 1992-07-16 MX MX9204183A patent/MX9204183A/en unknown
- 1992-07-23 WO PCT/EP1992/001684 patent/WO1993002681A1/en not_active Application Discontinuation
- 1992-07-23 CA CA 2113443 patent/CA2113443A1/en not_active Abandoned
- 1992-07-23 EP EP92916379A patent/EP0596970A1/en not_active Withdrawn
- 1992-07-23 JP JP5503231A patent/JPH06509568A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9302681A1 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015155716A1 (en) | 2014-04-08 | 2015-10-15 | Pantex International S.P.A. | Multilayer material and absorbent sanitary article comprising the same |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993002681A1 (en) | 1993-02-18 |
| DE4125255A1 (en) | 1993-02-04 |
| MX9204183A (en) | 1993-01-01 |
| CA2113443A1 (en) | 1993-02-18 |
| JPH06509568A (en) | 1994-10-27 |
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