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). Jouve, 18, rue Saint-Denis, 75001 PARIS 1 EP 0 431 663 B1 2 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 (<B9 expressed in Pharmacopoeia Eur. cient for use in a hospital which compounds parenter- standards) after storage for two weeks at 60°C in al admixtures of the compound at or near the time of 5 the dark. In contrast, solutions of the described administration. A concentration of 0.1 mg/ml of L-MET compound without the addition of L-MET dis- is sufficient to stabilize a solution of mirtazapine at played significant discoloration (B6) under iden- 60°C in the darkfor a little over one week. 0.25 mg/ ml tical conditions. of L-MET is sufficient to stabilize a solution of mirta- 2. Six months at 40°C in the dark-Solutions of zapine for 2 weeks at 60°C in the dark. While, 0.5 10 the described antidepressant compound also mg/ml of L-MET is sufficient to stabilize a solution of containing 0.50 mg/ml L-MET were physically mirtazapine for at least 4 weeks at 60°C, and for 6 and chemically stable after storage for 6 months months at40°C (106°F) in the darkand for 12 months at up to 40°C in the dark. In contrast, solutions of at 30 °C. At the same time, 0.5 mg/ml of L-MET sta- the described compound without the addition of bilizes an aqueous solution of amitriptyline HCI for 15 L-MET after 6 months at 30°C and 40°C dis- only a little over one week in the presence of daylight. played severe discoloration (BY5-6 and BY1-3 Furthermore, L-MET does not appear to stabilize the respectively), and some diminishment of concen- light induced degradation of another antidepressant tration when stored at 40°C in the dark. compound, imipramine HCI, at least at the concentra- 3. 12 months at40°C in the dark-Solutions con- tions used. 20 taining mirtazapine (3 mg/ml) were stabilized for Concentrations of D-methionine and DL-methio- 1 year at 40 °C in the dark, with 0.5 mg/ml of L- nine will be similar to those of L-MET. The addition of MET, while, as described in EXAMPLE I A.2., a non-reducing sugar, such as sucrose, to the prepa- samples without the stabilizer displayed severe rations may be useful in oral formulations to improve discoloration and diminishment of concentration the flavor of the formulation. Sugars such as glucose 25 after 6 months. or invert sugar should be avoided. 4. Destabilization with hydrogen peroxide at60°C Methods for making aqueous formulations are in the dark— 1.5ml of 0.001% hydrogen peroxide well-known. Methods for making oral solutions, emul- was added to two solutions of 3.0 mg/ml mirtaza- sions, and suspensions are described in Chase, et al, pine, one containing L-Met (0.5 mg/ml) and the Remington's Pharmaceutical Sciences, pp. 1438- 30 other not. After one week, the solution not con- 1462 (16th ed. 1980, Mack Publ.