Europaisches Patentamt 19 European Patent Office
Office europeen des brevets (fi) Publication number: 0 431 663 B1
12 EUROPEAN PATENT SPECIFICATION
@ Date of publication of patent specification © int. ci.5: A61K 31/645, A61K9/08, 12.01.94 Bulletin 94/02 A61K47/18, A61K 47/20
(2j) Application number : 90203064.2
(22) Date of filing : 20.11.90
(54) Stabilized solutions of psychotropic agents.
(30) Priority : 06.12.89 EP 89203092 (73) Proprietor : AKZO N.V. Velperweg 76 NL-6824 BM Am hem (NL) (43) Date of publication of application 12.06.91 Bulletin 91/24 (72) Inventor : Van den Oetelaar, Petrus Johannes Maria Plantsoen 1 @ Publication of the grant of the patent : NL-5384 ET Heesch 12.01.94 Bulletin 94/02 (NL) Inventor : Mentink, Maria Martina Francisca Oude Wei 38 NL-5345 KJ Oss (NL) @ Designated Contracting States : AT BE CH DE DK ES FR GB GR IT LI NL SE (74) Representative : Hermans, Franciscus G.M. et al @ References cited : Organon International BV Postbus 20 EP-A- 0 093 373 NL-5340 BH Oss (NL) EP-A- 0 114 199 GB-A- 2 082 910
CO CO CO CO
CO Note : Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been LU filed until the opposition fee has been paid (Art. 99(1) European patent convention).
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Description and methionine (e.g. L-methionine ("L-MET")). The preparation will contain a sufficient amount of stabil- Field. izer to stabilize these compounds in aqueous solution for a desired time at a desired temperature. This invention relates to pharmaceutical compo- 5 sitions generally, and to stabilized aqueous solutions Description of the Preferred Embodiments of certain antidepressant drugs specifically. Preferred heterocyclic compounds include mirta- State of the Art: zapine (EXAMPLE I), mianserin (EXAMPLE II), ami- 10 triptyline HCI (EXAMPLE III), setipiline or "setiptili- Solutions of certain antidepressants (e.g., ami- num" (EXAMPLE IV), derivatives thereof, acid addi- triptyline) are not very stable. They discolor, form par- tion salts thereof, and mixtures thereof. These com- ticles, and/or suffer a decrease in concentration under pounds are known antidepressant ("thymoleptic") certain conditions. For example, they may discolor or compounds. show a decrease in concentration upon exposure to 15 The heterocyclic compound ("heterocycle") used light; upon the formation of peroxides in, or addition will be present in the aqueous preparations in suffi- of peroxides to, the solutions; or when such solutions cient concentrations to be therapeutically useful, eith- are stored at elevated temperatures. Particles may er parenterally or orally, in the volume of aqueous also form in such solutions under these conditions. preparation contemplated for use. As used herein, an Discoloration, development of opalescence, a de- 20 aqueous preparation is a preparation containing wa- crease in concentration, and particle formation are all ter as a primary, but not necessarily t he only, solvent. tokens of instability. These tokens of instability may Useful doses for the heterocyclic compounds are occur rather rapidly, sometimes within days, forcing well-known to medical practitioners. For example, 20 the dispensing pharmacist to mix new solutions fre- milliliters (ml) of an oral solution containing 5 mill i- quently. 25 grams/milliliter (mg/ml) of amitriptyline hydrochloride An attempt to stabilize dry pharmaceutical prep- administered at bedtime may be sufficient to treat arations containing amitriptyline oxide dihydrate is someone suffering from depression. described in German Patent Application DE 3247676 Especially preferred heterocyclic compounds for A1, published on 28 June '84 (corresponding to U.S. use with the stabilizer L-MET are mirtazapine and Patent No. 4,567,202). That patent application de- 30 mianserin, due to these compounds' ability to be sta- scribes a composition containing amitriptyline oxide bilized with that stabilizer. dihydrate and an organic acid including certain listed Acid addition salts of the heterocycles are prefer- amino acids. The organic acid, especially citric acid, ably used in the aqueous preparations mainly due to is used to stabilize the amitriptyline. solubility considerations. Pharmacologically accept- GB 2,082,91 OA to Berk Pharmaceuticals Ltd. 35 able salts are preferably formed from a pharmacolog- (published on 17 March 1982) describes a pharma- ically acceptable organic or inorganic acid such as hy- ceutical composition (e.g. a syrup) comprising ami- drochloric, hydrobromic, fumaric ascorbic, tartaric, triptyline and L-tryptophan in an inert carrier. The L- citric, lactic, maleic, palmitic, or other known acids. tryptophan reportedly acts to reduce side-effects as- The hydrocloride salt is especially prefered. sociated with the amitriptyline. 40 As used herein, "stabilize" is a relative term. To EP 93,373A (corresponding to U.S. Patent No. stabilize with a stabilizing agent or compound means 4,603,131) to Abbott Laboratories describes a liquid the ability to prevent or delay the onset of tokens of pharmaceutical composition useful for preventing ir- instability. For example, a solution would be deemed ritation of the nasal mucousal membrane. The com- "stabilized" if, with the addition of a stabilizing com- position contains a tri-cyclic antidepressant, certain 45 pound ("stabilizer"), it took longer (e.g. 2 weeks in- buffers, and "preservatives". The preservatives listed stead of 1 week) to discolor in the presence of a de- include: benzalkonium chloride, edetate disodium, stabilizing stimulus (e.g. storage of the solution at an sodium bisulfate, phenylmercuric acetate, cetylpyridi- elevated (40°C) temperature). nium chloride, thimerosal, chlorobutamol, cetyltrime- Preferred stabilizers for use with the particular thyl ammonium bromide, methylparaben, propylpar- so heterocylclic compounds are L-methionine, D-me- aben, and butylparaben. thionine, DL-methionine, and mixtures thereof. Pri- marily due to its relatively low toxicity in man, L-MET Summary of the Invention is especially preferred. The concentration of stabilizer in solution will gen- Generally, the invention includes a stable aqu- 55 erally vary with the amount of time the solution is to eous preparation of mirtazipine, mianserin, amitripty- be stabilized. For example, L-MET will generally be line, setiptiline, derivatives thereof, acid addition salts present in concentrations varying from 0.05 mg/ml of thereof and mixtures thereof in admixture with water solution to 5 mg/ml. A concentration of 0.05 mg/ml is 2 3 EP 0 431 663 B1 4 sufficient to an aqueous solution of mirtazapine at containing 0.25 mg/ml L-MET exhibited no discol- 60°C in the dark for a few days, which may be suffi- oration (
A. Stabilization of 1,2,3,4,10,14beta-hexahydro-2- 45 1,2,3,4,10,14b-hexahydro-2-methyl-dibenzo [c,f] methylpyrazino [2,1-a] pyrido [2,3-c][2] benzazepine pyrazino [1,2-a] azepinemonohydrochloride (mianser- with L-MET. in) is a compound described in United States Patent No. 3,534,041 to van der Burg Mianserin and similar 1, 2,3,4,1 0,14beta-hexahydro-2-methylpyrazino compounds may be made according to the teachings [2,1-a] pyrido (2,3-c][2] ("mirtazapine") and similar so of these patents. compounds may be prepared as disclosed in United Solutions of 3.0 mg/ml mianserin were prepared. States Patent No. 4,062,848 to van der Burg Aqueous The pHs of the solutions were adjusted to 4, and the solutions containing 3 mg/ml of the described anti- solutions were sterilized by filtration through a 0.22 depressant compound (1.1 millimolar) were prepared. micron filter. Aseptic techniques were used through- The solutions were buffered with citric acid to pH 4. 55 out the experiments. To one of the solutions, suffi- The solutions further contained sufficient NaCI to cient L-MET was added to bring the concentration of make them iso-osmotic with blood. L-MET to 0.5 mg/ml of solution. The samples were 1. Two weeks at 60°C in the dark-Solutions of stored at 60°C in the dark, and at room temperature the described antidepressant compound also in daylight. 3 5 EP 0 431 663 B1 6
The sample without L-MET stored at 60°C discol- hibited no discoloration. ored (BY3) within 1 week's time. Both samples stored in daylight discolored, although the sample without EXAMPLES V-VIII added L-MET was more discolored (B4) than the 5 sample with L-MET (B7). The other sample remained Attempts were made to use L-cysteine - 0.587 stable during the first week. After 2 weeks time, all mg/ml (EXAMPLE V), 1,4-dithioerythitol - 0.527 samples discolored, although the samples without L- mg/ml (EXAMPLE VI), L-tryptophan - 0.685 mg/ml MET discolored more (>BY1 @ 60°C and B2 with day- (EXAMPLE VII), and cystine - 0.807 mg/ml (EXAM- light) than the samples containing L-MET (B8 @ 60°C 10 PLE VIII) as stabilizers for mirtazapine by substituting and B5 with daylight). these particular compounds, one at a time, for L-MET, and testing the solutions for clarity and discoloration EXAMPLE III after storage in daylight and at 60°C in the dark. The solutions with these compounds showed more discol- Stabilization of amitriptyline HCI with L-methionine 15 oration than those which contained none of the com- pound. Amitriptyline HCI is readily commercially avail- able from various companies including Merck, Sharpe EXAMPLES IX-XVI & Dohme. Solutions containing 3.14 mg/ ml of amitrip- tyline HCI were prepared. As with the other EXAM- 20 In a similar manner as described in EXAMPLES PLES tested for two weeks, the pH of the solutions l-IV, preparations of mirtazapine mianserin, amitripty- were adjusted to 4 with a citrate buffer, and the solu- line, or setiptiline may be stabilized with 0.5 mg/ml tions were sterilized by filtration through a 0.22 mi- solutions of D-methionine or DL-methionine. cron filter. Aseptic techniques were used throughout the experiments. To one of the solutions, sufficient L- 25 MET was added to bring the concentration of L-MET Claims to 0.5 mg/ml of solution. The samples were stored at 60°C in the dark, and at room temperature in daylight. Claims for the following Contracting The sample containing L-MET displayed better clarity States : AT, BE, CH, DE, DK, FR, GB, IT, LI, than the sample not containing L-MET when exposed 30 NL, SE to daylight ("clear" vs. many particles present respec- tively) over one week's time. After two weeks time, 1. A stable aqueous preparation comprising: the sample containing L-MET also had many particles a stabilizer selected from L-methionine, D- present. All solutions of amitriptyline HCI stored at methionine, DL-methionine, and mixtures there- 60°C in the dark displayed clarity and no discolora- 35 of, said stabilizer being in admixture with water tion. and further in admixture with a therapeutically useful concentration of a EXAMPLE IV pharmaceutical compound selected from mirta- zapine, mianserin, amitriptyline, setipiline, deriv- Stabilization of 2(N)-methyl-1 ,2,3,4-tetrahydro-9H- 40 atives thereof, acid addition salts thereof, and dibenzo[a,e]pyridino[3,4-c]cycloheptatriene maleate mixtures thereof, (setiptiline) with L-methionine wherein the stabilizer is present in a con- centration sufficient to stabilize the pharmaceut- Solutions containing 3.77 mg/ ml of setipiline ical compound. (Chemical Abstracts Service registry number 57262- 45 94-9) maleate were prepared. The pHs of the solu- 2. The stable aqueous preparation of claim 1 where- tions were adjusted to 4, and the solutions were ster- in the pharmaceutical compound is mianserin ilized by filtration through a 0.22 micron filter. Aseptic present at a quantity of 1 to 5 milligrams per mil- techniques were used throughout the experiments. liliter of preparation. To one of the solutions, sufficient L-MET was added 50 to bring the concentration of L-MET to 0.5 mg/ml of 3. The stable aqueous preparation of claim 1 where- solution. The samples were stored at 60°C in the in the pharmaceutical compound is mirtazapine, dark, and at room temperature in daylight. All samples a pharmaceutical^ acceptable acid addition salt remained stable after one week's time. After two thereof, or a pharmaceutical^ acceptable qua- weeks time, the sample without L-MET which was ex- 55 ternary ammonium salt thereof, present in a posed to daylight was no longer clear and contained quantity of 1 to 5 milligrams per milliliter of prep- many particles, while the sample containing L-MET aration. remained clear. All solutions containing setipiline mal- eate stored at 60°C in the dark remained clear and ex- 4. The stable aqueous preparation of claim 1 where- 4 7 EP 0 431 663 B1 8
in said stabilizer is an isomer or racemic mixture stabilized aqueous pharmaceutical preparation. of methionine, and said pharmaceutical com- pound is selected from mirtazapine, mianserin, 2. The process of claim 1 wherein the pharmaceut- amitriptyline, setipiline, and mixtures thereof. 5 ical compound is mianserin present at a quantity of 1 to 5 milligrams per milliliter of stabilized aqu- 5. The stable aqueous preparation of claim 1 where- eous pharmaceutical preparation. in said pharmaceutical compound is mirtazapine. 3. The process of claim 1 wherein the pharmaceut- 6. A method of stabilizing an aqueous admixture of ic10 ical compound is mirtazapine, a pharmaceutical- a pharmaceutical compound selected from mirta- ly acceptable acid addition salt thereof, or a phar- zapine, mianserin, setipiline, amitriptyline, and maceutically acceptable quaternary ammonium mixtures thereof, comprising: dissolving into said salt thereof, present at a quantity of 1 to 5 milli- aqueous admixture a sufficient amount of L-me- grams per milliliter of stabilized aqueous pharma- thionine, D-methionine, DL-methionine, or mix- 15 ceutical preparation. tures thereof to stabilize the pharmaceutical compound in said aqueous admixture. 4. The process of claim 1 wherein said stabilizer is an isomer or racemic mixture of methionine, and 7. A stabilized aqueous solution comprising, in ad- said pharmaceutical compound is selected from mixture, a pharmaceutical compound selected 20 mirtazapine, mianserin, amitriptyline, setipiline, from mirtazapine, mianserin, setipiline, amitripty- and mixtures thereof. line, and mixtures thereof in an amount of 1 to 5 milligrams per milliliter aqueous solution, and a 5. The process of claim 1 wherein said pharmaceut- sufficient amount of L-methionine, D-methio- ical compound is mirtazapine. nine, DL-methionine or mixtures thereof to stabil- 25 ize said pharmaceutical compound in said solu- 6. A method of stabilizing an aqueous admixture of tion. a pharmaceutical compound selected from mirta- zapine, mianserin, setipiline, amitriptyline, and 8. The stabilized aqueous solution of claim 7 where- mixtures thereof, comprising: dissolving into said in the pharmaceutical compound is mirtazepine 30 aqueous admixture a sufficient amount of L-me- and the methionine is present in an amount of thionine, D-methionine, DL-methionine, or mix- 0.05 to 5 milligrams per milliliter aqueous solu- tures thereof to stabilize the pharmaceutical tion. compound in aqueous solution.
9. The stabilized aqueous solution of claim 8 con- 35 7. The method of claim 6 wherein the pharmaceut- taining DL-methionine or L-methionine. ical compound is mirtazepine and the methionine is present in an amount of 0.05 to 5 milligrams per 10. A process of manufacturing a stabilized aqueous milliliter aqueous solution. pharmaceutical preparation comprising: incor- porating (a) a stabilizer selected from L-methio- 40 8. The method of claim 7 containing DL-methionine nine, D-methionine, DL-methionine, and (b) a or L-methionine. pharmaceutical compound selected from mirta- zapine, mianserin, amitriptyline, setipiline, deriv- 9. The process of claim 1 wherein said pharmaceut- atives thereof, acid addition salts thereof, and ical compound is amitriptyline. mixtures thereof, into (c) an aqueous solvent to 45 form said stabilized aqueous pharmaceutical 10. The process of cleclaim 1 wherein said pharmaceut- preparation. ical compound is setiptiline.
Claims for the following Contracting States : GR, ES 50 Patentanspriiche
1 . A process of manufacturing a stabilized aqueous Patentanspriiche fur folgende pharmaceutical preparation comprising: admix- Vertragsstaaten : AT, BE, CH, DE, DK, FR, ing (a) a stabilizer selected from L-methionine, D- GB, IT, LI, NL, SE methionine, DL-methionine, and (b) a pharma- 55 ceutical compound selected from mirtazapine, 1. Stabiles wasseriges Praparat enthaltend : mianserin, amitriptyline, setipiline, derivatives einen Stabilisator ausgewahlt aus L-Me- thereof, acid addition salts thereof, and mixtures thionin, D-Methionin, DL-Methionin und Gemi- thereof, with (c) an aqueous solvent to form said schen davon, wobei dieser Stabilisator gemischt 5 g EP 0 431 663 B1 10
ist mit Wasser und ausserdem gemischt ist mit Losung zugegen ist. einertherapeutisch nutzlichen Konzentra- tion an einer pharmazeutischen Verbindung, aus- 9. Stabilisierte wasserige Losung nach Anspruch 8, gewahlt aus Mirtazepin, Mianserin, Amitriptylin, 5 enthaltend DL-Methionin oder L-Methionin. Setiptilin, Derivaten davon, Saureadditionssal- zen davon und Gemischen davon, 10. Verfahren zur Herstellung eines stabilisierten wobei der Stabilisator in genugender Kon- wasserigen pharmazeutischen Praparates, um- zentration vorhanden ist, um die pharmazeuti- fassend : das Einverleiben (a) eines Stabilisa- sche Verbindung zu stabilisieren. 10 tors, ausgewahlt aus L-Methionin, D-Methionin, DL-Methionin, und (b) eine pharmazeutische 2. Stabiles wasseriges Praparat nach Anspruch 1 , Verbindung, ausgewahlt aus Mirtazapin, in welchem die pharmazeutische Verbindung Mianserin, Amitriptylin, Setiptilin, Derivaten da- Mianserin ist, welche in einer Menge von 1 bis 5 von, Saureadditionssalzen davon und Gemi- Milligramm pro Milliliter Praparat zugegen ist. 15 schen davon, in (c) ein wasseriges Losungsmit- tel, um das stabilisierte wasserige pharmazeuti- 3. Stabiles wasseriges Praparat nach Anspruch 1 , sche Praparat zu bilden. in welchem die pharmazeutische Verbindung Mirtazapin, ein pharmazeutisch annehmbares Patentanspriiche fur folgende Saureadditionssalz davon oder ein pharmazeu- 20 Vertragsstaaten : GR, ES tisch annehmbares quaternares Ammoniumsalz davon ist, zugegen in einer Menge von 1 bis 5 Mil- 1. Verfahren zur Herstellung eines stabilisierten ligramm pro Milliliter Praparat. wasserigen pharmazeutischen Praparates um- fassend : das Vermischen (a) von einem Stabili- 4. Stabiles wasseriges Praparat nach Anspruch 1 , 25 sator, ausgewahlt aus L-Methionin, D-Methionin, in welchem der Stabilisator ein Isomer oder ein DL-Methionin, und (b) einer pharmazeutischen razemisches Gemisch von Methionin ist und die Verbindung, ausgewahlt aus Mirtazapin, pharmazeutische Verbindung ausgewahlt ist aus Mianserin, Amitriptylin, Setiptilin, Derivaten da- Mirtazapin, Mianserin, Amitriptylin, Setiptilin und von, Saureadditionssalzen davon und Gemi- Gemischen davon. 30 schen davon, mit (c) einem wasserigen Losungs- mittel, um das stabilisierte wasserige pharma- 5. Stabiles wasseriges Praparat nach Anspruch 1 , zeutische Praparat zu bilden. in welchem die pharmateutische Verbindung Mirtazapin ist. 2. Verfahren nach Anspruch 1 , in welchem die phar- 35 mazeutische Verbindung Mianserin ist, die in ei- 6. Verfahren zur Stabilisierung eines wasserigen ner Menge von 1 bis 5 Milligramm pro Milliliter des Gemisches einer pharmazeutischen Verbindung stabilisierten wasserigen pharmazeutischen Pra- ausgewahlt aus Mirtazapin, Mianserin, Setiptilin, parates zugegen ist. Amitriptylin und Gemischen davon, umfassend : das Auflosen einer genugenden Menge an L-Me- 40 3. Verfahren nach Anspruch 1 , in welchem die phar- thionin, D-Methionin, DL-Methionin oder Gemi- mazeutische Verbindung Mirtazapin, ein phar- schen davon in dem wasserigen Gemisch, um die mazeutisch annehmbares Saureadditionssalz pharmazeutische Verbindung in dem wasserigen davon oder ein pharmazeutisch annehmbares Gemisch zu stabilisieren. quaternares Ammoniumsalz davon ist, zugegen 45 in einer Menge von 1 bis 5 Milligramm pro Milliliter 7. Stabilisierte wasserige Losung enthaltend, im des stabilisierten wasserigen pharmazeutischen Gemisch, eine pharmazeutische Verbindung Praparates. ausgewahlt aus Mirtazapin, Mianserin, Setiptilin, Amitriptylin und Gemischen davon in einer Men- 4. Verfahren nach Anspruch 1 , in welchem der Sta- ge von 1 bis 5 Milligramm pro Milliliterwasseriger 50 bilisator ein Isomer oder razemisches Gemisch Losung, und eine genugende Menge von L-Me- von Methionin ist, und die pharmazeutische Ver- thionin, D-Methionin, DL-Methionin oder Gemi- bindung ausgewahlt ist aus Mirtazapin, schen davon, um die pharmazeutische Verbin- Mianserin, Amitriptylin, Setiptilin und Gemischen dung in der Losung zu stabilisieren. davon. 55 8. Stabilisierte wasserige Losung nach Anspruch 7, 5. Verfahren nach Anspruch 1 , in welchem die phar- in welcher die pharmazeutische Verbindung mazeutische Verbindung Mirtazapin ist. Mirtazapin ist und das Methionin in einer Menge von 0,05 bis 5 Milligramm pro Milliliter wasserige 6. Verfahren zur Stabilisierung eines wasserigen 6 11 EP 0 431 663 B1 12
Gemisches einer pharmazeutischen Verbindung, un sel d'addition d'acide pharmaceutique accep- ausgewahlt aus Mirtazapin, Mianserin, Setiptilin, table de cette derniere ou a un sel d'ammonium Amitriprylin und Gemischen davon, umfassend : quaternaire pharmaceutiquement acceptable de das Auflosen einer genugenden Menge an L-Me- 5 cette derniere et il est present en une quantite de thionin, D-Methionin, DL-Methionin oder Gemi- 1 a 5 mg/ml de preparation. schen davon in das wasserige Gemisch, um die pharmazeutische Verbindung in wasseriger Lo- La preparation aqueuse stable selon la revendi- sung zu stabilisieren. cation 1, caracterisee en ce que I'agent stabili- 10 sant correspond a un isomere de la methionine 7. Verfahren nach Anspruch 6, in welchem die phar- ou au melange racemique de cette derniere et le mazeutische Verbindung Mirtazepin ist, und das compose pharmaceutique est selection ne parmi: Methionin in einer Menge von 0,05 bis 5 Milli- mirtazapine, mianserine, amitriptyline, setiptiline gramm pro Milliliter wasseriger Losung zugegeh et leurs melanges. ist. 15 La preparation aqueuse stable selon la revendi- 8. Verfahren nach Anspruch 7, enthaltend DL-Me- cation 1, caracterisee en ce que ledit compose thionin oder L-Methionin. pharmaceutique correspond a la mirtazapine.
9. Verfahren nach Anspruch 1 , in welchem die phar- 20 6. Un procede permettant de stabiliser un melange mazeutische Verbindung Amitriptylin ist. aqueux constitue d'un compose pharmaceutique selectionne parmi mirtazapine, mianserine, se- 10. Verfahren nach Anspruch 1, in welchem die phar- tiptiline, amitriptyline et leurs melanges, compre- mazeutische Verbindung Setiptilin ist. nant la dissolution d'une quantite suff isante de L- 25 methionine, de D-methionine, de DL-methionine ou des melanges de ces derniers dans ledit me- Revendications lange aqueux pour stabiliser le compose pharma- ceutique dans ledit melange aqueux. Revendications pour les Etats contractants suivants : AT, BE, CH, DE, DK, FR, GB, IT, LI, 30 7. Une solution aqueuse stabilisee comprenant un NL, SE melange constitue d'un compose pharmaceuti- que selectionne parmi mirtazapine, mianserine, 1. Une preparation aqueuse stable comprenant: setiptiline, amitriptyline et les melanges de ces - un agent stabilisant selectionne parmi L- derniers en une quantite de 1 a 5 mg/ml de solu- methionine, D-methionine, DL-methionine 35 tion aqueuse, et une quantite suff isante de L-me- et leurs melanges, cet agent stabilisant thionine, D-methionine, DL-methionine ou de etant melange avec de I'eau et il est de plus leurs melanges pour stabiliser ledit compose melange avec: pharmaceutique dans ladite solution. - une concentration utile du point de vue the- rapeutique d'un compose pharmaceutique 40 8. La solution aqueuse stabilisee selon la revendi- selectionne parmi mirtazapine, mianserine, cation 7, caracterisee en ce que le compose amitriptyline, setiptiline, les derives de ces pharmaceutique correspond a la mirazepine et la composes, les sels d'addition d'acide de methionine est presents en une quantite de 0,05 ces composes et les melanges de ces a 5 mg/ml de solution aqueuse. composes, 45 caracterisee en ce que I'agent stabilisant 9. La solution aqueuse stabilisee selon la revendi- est present en une concentration suff isante cation 8, qui contient de la DL-methionine ou de pour stabiliser le compose pharmaceuti- la L-methionine. que. 50 10. Un procede de preparation d'une preparation 2. La preparation aqueuse stable selon la revendica pharmaceutique aqueuse stabilisee comprenant: tion 1 , caracterisee en ce que le compose phar- I'incorporation maceutique correspond a la mianserine et il est a) d'un agent stabilisant selectionne parmi L- present en une quantite de 1 a 5 mg/ml de prepa- methionine, D-methionine, DL-methionine; et ration. 55 b) d'un compose pharmaceutique selectionne parmi mirtazapine, mianserine, amitriptyline, 3. La preparation aqueuse stable selon la revendi- setiptiline, les derives de ces composes, les cation 1, caracterisee en ce que le compose sels d'addition d'acide de ces composes et les pharmaceutique correspond a la mirtazapine a melanges de ces composes dans 7 13 EP 0 431 663 B1 14
c) un solvant aqueux pour former lad ite prepa- pond a la mirtazepine et la methionine est pre- ration pharmaceutique aqueuse stabilisee. sents en une quantite de 0,05 a 5 mg/ml de solu- tion aqueuse. Revendications pour les Etats contractants 5 suivants : GR, ES 8. Le procede selon la revendication 7, contenant de la DL-methionine ou de la L-methionine. 1. Un procede de preparation d'une preparation pharmaceutique aqueuse stabilisee comprenant 9. Le procede selon la revendication 1, caracterise le melange de: 10 en ce que ledit compose pharmaceutique corres- a) un agent stabilisant selectionne parmi L- pond a I'amitriptyline. methionine, D-methionine, DL-methionine; et b) un compose pharmaceutique selectionne 10. Le procede selon la revendication 1, caracterise parmi mirtazapine, mianserine, amitriptyline, en ce que ledit compose pharmaceutique corres- setiptiline, les derives de ces composes, les 15 pond a la setiptiline. sels d'addition d'acide de ces composes et les melanges de ces composes avec c) un solvant aqueux pour former lad ite prepa- ration pharmaceutique aqueuse stabilisee. 20 2. Le procede selon la revendication 1, caracterise en ce que le compose pharmaceutique corres- pond a la mianserine et il est present en une quantite de 1 a 5 mg/ml de preparation pharma- ceutique aqueuse stabilisee. 25
3. Le procede selon la revendication 1, caracterise en ce que le compose pharmaceutique corres- pondant a la mirtazapine, a un sel d'addition d'acide pharmaceutiquement acceptable de cet- 30 te derniere ou a un sel d'ammonium quaternaire pharmaceutiquement acceptable de cette der- niere et il est present en une quantite de 1 a 5 mg/ml de preparation pharmaceutique aqueuse stabilisee. 35
4. Le procede selon la revendication 1, caracterise en ce que ledit agent stabilisant correspond a un isomere de la methionine ou au melange racemi- que de cette derniere, et le compose pharmaceu- 40 tique est selectionne parmi: mirtazapine, mianse- rine, amitriptyline, setiptiline et leurs melanges.
5. Le procede selon la revendication 1, caracterise en ce que le compose pharmaceutique est la mir- 45 tazapine.
6. Un procede permettant de stabiliser un melange aqueux constitue d'un compose pharmaceutique selectionne parmi mirtazapine, mianserine, se- so tiptiline, amitriptyline et leurs melanges, compre- nant la dissolution d'une quantite suff isante de L- methionine, de D-methionine, de DL-methionine ou des melanges de ces derniers dans ledit me- lange aqueux pour stabiliser le compose pharma- 55 ceutique dans ledit melange aqueux.
7. Le procede selon la revendication 6, caracterise en ce que le compose pharmaceutique corres- 8