STABILISED ANTHRACYCLINE PREPARATION

Abstract: A stabilized preparation, particularly, freeze-drying injection, of anthracycline, for example, (7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-­ pentopyranosyl)oxy] -7,8,9,10-tetrahydro-6,11-dihydroxy-­ naphthacene-5,12-dione or salts thereof which comprises L-cysteine or salts thereof.

Description: The present invention relates to a preparation of (7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-naphthacene-5,12-dione (hereinafter referred to as compound A) or salts thereof stabilized with L-cysteine or salts thereof. Anthracyclines including the compound A or salts thereof (Japanese patent Kokai Sho 58-194846) are unstable in solution. Liquefying injection before using, e.g., powder filling or a freeze-drying product, is familiar to the skilled when such a pharmaceutical preparation as injection is prepared from such compounds ("Recent technique in preparation and application thereof" III, IV. 1, p. 135, 1986, published by Iyaku Journal Co., Ltd.). GB-A-2165751 describes compositions of Daunorubicin and Doxorubicin containing cosolubilising agents including cysteine. Sufficient stabilization of the compound A or salts thereof is hardly expected even after freeze-drying. Storage at room temperature for a long period of time or ill-treat storage causes degradation in potency, formation of hardly soluble deposition substances and/or turbidity in re-dissolution. It is beyond expectation to have found that addition of L-cysteine or salts thereof dissolves such difficulties as mentioned above. The present invention is to provide a stabilized freeze-drying preparation of compound A by having L-cysteine or salts thereof added thereto. Any amount and any method of addition may be employed, with respect to L-cysteine or salts thereof. Preferred amount of L-cysteine or salts thereof in the case of hydrochloride of the compound A is 0.1-50 mg, more preferably 0.6-9 mg every 20 mg potency of said hydrochloride, taking into account of stabilization degree or pharmacological activity of L-cysteine or salts thereof. pH should be 2-5, more preferably 2.5-3.5, taking into consideration of properties of the compound A. For instance, sodium hydroxide and hydrochloric acid may be added as a pH adjustment agent. Furthermore, a pharmaceutical composition of public, for example, fillers may be added, if desired. Freeze-drying injection is prepared by dissolving the compound A or salts thereof with L-cysteine or salts thereof in distillated water for injection, adding a small amount each of sodium hydroxide and hydrochloric acid in order to adjust pH, making sterile filtration, filling the sterile filtrate in vials and subjecting to freeze-drying to prepare powdery preparation for injection. Injection is stored as it is and water is added thereto just before it is applied to. Acids which are utilized for salts of the compound A are, for example, hydrochloric acid, hydrobromic acid, citric acid, tartaric acid, lactic acid, fumaric acid, maleic acid, and methanesulfonic acid. Salts of L-cysteine are usually in the hydrochloride form. Alternatively, they may be sulfate. The following examples will be helpful to understand the nature of the present invention. Example 1 To hydrochloride of the compound A (20 mg potency) containing lactose, a filler, (50 mg), were added L-cysteine hydrochloride, citric acid, sodium dihydrogenphosphate, maleic acid or glycine hydrochloride, respectively, until pH was adjusted to 2.5-3.5. The mixtures were dissolved in distilled water for injection and then a small amount each of sodium hydroxide and hydrochloric acid was added thereto until pH was adjusted to about 3. The solution was filtered under sterilization and was filled in vials (18 ml each) and subjected to freeze-drying. Stability of the products stored at 60°C for 3 days and 7 days is shown in Table 1 together with that of a product prepared in the same procedure as above without L-cysteine hydrochloride. Example 2 To hydrochloride of the compound A (20 mg potency) were added L-cysteine hydrochloride (12 mg) and lactose, a filler, (50 mg). The mixture was dissolved in distilled water for injection (10 ml) and then a small amount each of sodium hydroxide and hydrochloric acid was added thereto until pH was adjusted to about 2.5. The mixture was filtered under sterilization and filled in vials (18 ml each) which were then subjected to freeze-drying and sealed with rubber stoppers to obtain stabilized freeze-drying injection. Example 3 To hydrochloride of the compound A (20 mg potency) were added L-cysteine hydrochloride (3 mg) and lactose, a filler, (50 mg). The mixture was dissolved in distilled water for injection (10 ml) and then a small amount each of sodium hydroxide and hydrochloric acid was added thereto until pH was adjusted to about 3.0. The mixture was filtered under sterilization and filled in vials (18 ml each) which were then subjected to freeze-drying and sealed with rubber stoppers to obtain stabilized freeze-drying injection. Example 4 To hydrochloride of the compound A (20 mg potency) were added L-cysteine hydrochloride (0.5 mg) and maltose, a filler, (50 mg). The mixture was dissolved in distilled water for injection (10 ml) and then a small amount each of sodium hydroxide and hydrochloric acid was added thereto until pH was adjusted to about 3.5. The mixture was filtered under sterilization and filled in vials (18 ml each) which were then subjected to freeze-drying and sealed with rubber stoppers to obtain stabilized freeze-drying injection. Example 5 To hydrochloride of the compound A (10 mg potency) were added L-cysteine hydrochloride (2 mg) and sodium chloride, a filler, (90 mg). The mixture was dissolved in distilled water for injection (10 ml) and then a small amount each of sodium hydroxide and hydrochloric acid was added thereto until pH was adjusted to about 3.0. The mixture was filtered under sterilization and filled in vials (18 ml each) which were then subjected to freeze-drying and sealed with rubber stoppers to obtain stabilized freeze-drying injection. Example 6 To hydrochloride of the compound A (100 mg potency) were added L-cysteine hydrochloride (15 mg) and lactose, a filler, (250 mg). The mixture was dissolved in distilled water for injection (50 ml) and then a small amount each of sodium hydroxide and hydrochloric acid was added thereto until pH was adjusted to about 3.0. The mixture was filtered under sterilization and filled in vials (100 ml each) which were then subjected to freeze-drying and sealed with rubber stoppers to obtain stabilized freeze-drying injection.

Claims: 1. A preparation comprising (7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-naphthacene-5,12-dione or a salt thereof and L-cysteine or a salt thereof. 2. A preparation according to claim 1 comprising L-cysteine or a salt thereof in an amount of 0.1 to 50 mg per 20 mg of (7S, 9S)-9-acetyl-9-amino-7[2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-naphthacene-5,12-dione or equivalent amount of a salt thereof. 3. A preparation according to claim 2, wherein an amount of L-cysteine or salts is 0.6 to 9 mg. 4. A preparation according to any one of claims 1 to 3 wherein the pH is kept at 2 to 5. 5. A preparation according to claim 4 wherein the pH is 2.5 to 3.5. 6. A preparation according to any one of claims 1 to 6, comprising a hydrochloride, hydrobromide, citrate, tartrate, lactate, fumarate, maleate or methanesulfonate salt of (7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxynaphthacene-5,12-dione. 7. A preparation according to any one of claims 1 to 6 comprising a hydrochloride or sulphate salt of L-cysteine. 8. A process for producing a preparation of (7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl) oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-naphthacene-5,12-dione or a salt thereof which comprises adding L-cysteine or a salt thereof to (7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl) oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-naphthacene-5,12 dione or salt thereof and adjusting the pH to 2 to 5. 9. A process for preparing freeze-dried injection of (7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl) oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-naphthacene-5,12-dione or a salt thereof which comprises adding from 0.1 to 50 parts of L-cysteine or a salt thereof to 20 parts by weight of (7S, 9S)-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl) oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-naphthacene-5,12-dione or equivalent amount of a salt thereof, dissolving the resulting mixture in distilled water for injection, adjusting the pH to 2 to 5 and sterile filtering and freeze-drying the solution. 10. A process according to claim 8 or claim 9 for producing a preparation according to any one of claims 2 to 7.

Inventors: NORIHIKO, TANNO, OZAKI, YUKIO, SAKAMAKI, YASUHISA
Applicants: SUMITOMO PHARMACEUTICALS COMPANY, LIMITED
Application year: 1988
Main classification: A61K31
IPC codes: A61K47, C07H15, A61K31