STABLE INJECTABLE PHARMACEUTICAL FORMULATION FOR 1,4-DIHYDROXY-5,8-BIS((2-(HYDROXYETHYLAMINO)-ETHYL)AMINO)ANTHRAQUINONE, DIHYDROCHLORIDE

Abstract: This disclosure describes stable injectable pharmaceuti­ cal formulations of NOVANTRONE®.

Description: Title: STABLE INJECTABLE PHARMACEUTICAL FORMULATION FOR 1,4-DIHYDROXY 5,8-BISl2-(2-HYDROXYETHYLAMINO)- ETHYLAMINO]ANTHRAQUINONE, DIHYDROCHLORIDE DESCRIPTION OF THE INVENTION The compound 1,4-dihydroxy-5,8-bisl2-(2-hydroxy- ethylamino)ethylamino]anthraquinone, dihydrochloride, having the formula: EMI1.1 is described and claimed in U. S. Patent No. 4,197,249 and is sold under the registered trademark NovantroneW in Canada and Europe and is currently under consideration by the United States Food and Drug Administration tor approval as an anti-cancer agent. This compound is known to undergo Oxidative degradation in aqueous solution. This degradation occurs much more rapidly in the presence of metal ions such as cuprous, cupric, ferrous, ferric, etc., even when present in minute quantities (e.g. less than 10 ppm). Since this compound exhibits optimum pharmacological activity in humans when administered parenterally (intramuscularly, intravenously) as opposed to oral administration, it is extremely important that solutions of this compound remain stable for prolonged periods under normal storage conditions. It has now been discovered that the inclusion of a combination of critical factors in an aqueous formulation of 1,4-dihydroxy-5,8-bis[2-(hydroxyethylamino) ethylamino]anthraquinone, dihydrochloride provides a formulation whicb is extremely stable under normal storage conditions. These factors are I) the inclusion of a suitable antioxidant, 2) specific pH range, and 3) the inclusion of a suitable metal ion chelator. With regard to antioxidants the most effective proved to be sodium metabisulfite. The most effective pH range was 2.0-3.5 with 3.0 being optimum. The most effective metal ion chelator was a combination of sodium EDTA and glycine. Since the desired injectable formulation of 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamilno)ethylamino} anthraquinone, dihydrochloride contains 1 to 5 mg of this compound per ml of formulation, this new stable formula would have a pH of 2.0 to 3.5, with 3.0 being optimal, a sodium metabisulfite concentration of 0.01 to 0.10%, with 0.05% being optimal, disodium EDTA at a concentration of 0.01 to 0.11% with 0.10% being optimal, and glycine concentration of 0.05 to 0.2% with 0.1% being optimal. In order to prove the enhanced stability of this new formulation, formulae of the following composition were prepared and stability studies conducted. Formula I 1,4-Dihydroxy-5,8-bis[2-(2-hydroxy ethylamino)ethylamino]anthraquinone, dihydrochloride 2 mg/ml Water for Injection U.S.P. ...................... 100% Headspace Air Formula II i,4-Dihydroxy-5,8-bis[2-(2-hydroxy- ethylamino)ethylamino]anthraquinone, di hydrochloride 2 mg/ml Cupric ions 7 ppm Water for Injection U.S.P. h 100% Headspace Air pH 5.50 Formula III 1,4-Dihydroxy-5,8-bis[2-(2-hydroxy ethylamino)ethylamino]anthraquinone, dihydrochloride Z mg/ml Sodium metabisulfite............................0.01% Sodium acetate..................................0.005% Acetic acid, glacial , O.0467a Sodium chloride.................................0.80% Water for injection U.S.P.......................100% pH 3.5 Headspace......................................Nitrogen Formula IV 1,4-Dihydroxy-5,8-bis-[2-(2-hydroxy ethylamino)ethylamino]anthraquinone, dihydrochloride 2 mg/ml Sodium metabisulfate............................0.05% Disodium EDTA o.1o Glycine..........................................0.10% Sodium chloride (Isotonic Agent).................0.786% Water for injection U.S.P........................100% pH...............................................3.0 Headspace as indicated *One portion filled under nitrogen, two portions tilled under air. The results of these stability studies are given below: EMI5.1 <SEP> %of <SEP> Initional <SEP> Potency <tb> Formula <SEP> Vial <SEP> Size <SEP> Headspace <SEP> Temp. C <SEP> 1 <SEP> Day <SEP> 2 <SEP> Weeks <SEP> 3 <SEP> Weeks <SEP> 4 <SEP> Weeks <SEP> 6 <SEP> Weeks <SEP> 8 <SEP> Weeks <tb> I <SEP> 10 <SEP> ml <SEP> Air <SEP> 56 <SEP> 88 <SEP> 84.5 <SEP> 72 <tb> II <SEP> 10 <SEP> ml <SEP> Air <SEP> 56 <SEP> 13 <tb> III <SEP> 10 <SEP> ml <SEP> Nitrogen <SEP> 56 <SEP> 90 <SEP> 85 <tb> III <SEP> 2 <SEP> ml <SEP> Nitrogen <SEP> 42 <SEP> 96 <SEP> 93 <tb> III <SEP> 2 <SEP> ml <SEP> Nitrogen <SEP> 56 <SEP> 85 <SEP> 72 <tb> IV <SEP> 10 <SEP> ml <SEP> Nitrogen <SEP> 56 <SEP> 99 <tb> IV <SEP> 2 <SEP> ml <SEP> Nitrogen <SEP> 42 <SEP> 98.6 <SEP> 97.9 <tb> IV <SEP> 10 <SEP> ml <SEP> Air <SEP> 56 <SEP> 98 <SEP> 97.6 <tb> IV <SEP> 10 <SEP> ml <SEP> Air <SEP> 42 <SEP> 98 <SEP> 97.5 <tb> V <SEP> 10 <SEP> ml <SEP> Nitrogen <SEP> 56 <SEP> 99 <SEP> 98.4 <tb> The above results show the superiority of the new formulation of this invention over the previous formulation and an aqueous solution of this drug. Like most other anticancer drugs, the dose of Novantronee is based upon the patient's body surface area and disease state. It is highly advantageous from cost and marketing point of views to have Novantrone product available in small size containers like 2 ml vials. However, because of relatively higher headspace to volume ratio of smaller vials as against the larger vials, the stability of this product becomes critical in small 2 ml vials. It is important to note that the new formulation was found to be superior to the previous formulation in both small as well as relatively larger volume vials. To further illustrate the stability of this invention a composition was prepared as follows. Formula V 1,4-Dihydroxy-5,8-bis[2-(2-hydroxy- ethylamino)ethylamino]anthraquinone, dihydrochloride 2 mg/ml Disodium EDTA......................................0.10% Sodium metabisulfite...............................0.04% Glycine............................................0.10% Sodium chloride (Isotonic Agent) 0.60% Water for Injection U.S.P. .................... 100X pH.................................................3.0 This formula (V) and a composition of formula (I) each had cupric ions added to a concentration of 6 ppm and were then placed in a stability study at 560C for 4 weeks. The results at the end of this time showed that formula (I) lost 98% of its potency in 2 days while formula (V) retained 98.6% potency after 4 weeks.

Claims: CLAIMS We claim: 1. A pharmaceutical formulation comprising from 1 to 5 mg per ml of formulation of 1,4-dihydroxy -5,8-bisl2-(2-hydroxyethylamino)ethylamino]anthraquinone, dihydrochloride in an isotonic solution at a pH of from 2.0 to 3.5, containing sodium metabisulfite at a concentration of from 0.01 to 0.10%, disodium EDTA ata concentration of from 0.01 to 0.115 and glycine at a concentration of from 0.05 to 0.20;. 2. A formulation according to Claim 1 where the concentration of 1,4-dihydroxy-5,8-bist2-(2-hydroxy- ethylamino)ethylamino]anthraquinone, dihydrochloride is 2 mg/ml and the concentrations of sodium metabisulfite, disodium EDTA and glycine are 0.05%, 0.10% and 0.10% respectively.

Inventors: DESAI, NARENDRA R., JONES, PAUL N., MOONEY, KIERAN G., NIPHADKAR, PRADEEP V.
Applicants: AMERICAN CYANAMID COMPANY
Application year: 1987
Main classification: A61K31
IPC codes: A61K9, C07C213, A61K47, A61K31, C07C225, C07C67