Patent CA-3127906-A1 (CA)
Title: Pharmaceutical composition comprising amide derivative or pharmaceutically acceptable salt thereof
Inventor: KIM YONG IL
IPC: A61P35/00
Filed: 2011-06-10
Abstract: The present invention relates to a pharmaceutical composition comprising an amide derivative or a pharmaceutically acceptable salt thereof, and an acidic additive. This composition, owing to improved stability even after a long-term storage, is suitable for inhibiting the growth of cancer cells.        comprising 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en- 1-on of formula (I) disclosed in Korea Patent Laid-open Publication No. 2008-0107294 as an active ingredient. However, the formulation prepared by using the conventional pharmaceutical acceptable additives caused a lowered amount of the compound and facilitated the formation of a compound of formula (II) (Impurity E) during a storage period. ci HN                                               CI O N N) (I) o õ11,ci N F                                             N-Th CI CI NH r..m, "-N N) CI                               r)or NN) o (11) A purity of the active ingredient is an important factor for preparing a safe and effective pharmaceutical composition. Especially, anticancer drugs applied to the patients suffering from cancer having very weak immune system are required to comprise an active ingredient with a maximum purity. Impurities of a drug such as degraded products from the final drug product induced by various environmental factors such as temperature, humidity and light in addition to impurities capable of being removed in the preparation process of the active ingredient may cause various side effects to the patients who are being treated.  Hence, the present inventors have endeavored to improve the stabilities of the compound of formula (I) by inhibiting the formation of any impurities, and found that an acidic additive is effective in improving the stabilities of the inventive active ingredient.   Date Recue/Date Received 2021-08-12 It is an object of the present invention to provide a pharmaceutical composition comprising an amide derivative or a pharmaceutically acceptable salt thereof with improved stability. According to one particular aspect, the invention relates to a pharmaceutical composition comprising: a compound of formula (I) or a pharmaceutically acceptable salt thereof   an acidic additive that is (1) a C2-20-organic acid or fatty acid having a COOH or SO3H group; (2) an inorganic acid selected from the group consisting of phosphoric acid, sulfuric acid, boric acid and a mixture thereof; or (3) any material showing pH 1 to 6 when dissolved or dispersed in water at a concentration of 1 to 5% (w/v) as a pharmaceutically acceptable excipient; and a diluent comprising microcrystalline cellulose, lactose, mannitol, calcium phosphate, or a mixture thereof; a binder comprising povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, sodium carboxymethyl cellulose, or a mixture thereof; or a disintegrant comprising crospovidone, sodium croscarmellose, sodium starch glycolate, or a mixture thereof. According to another particular aspect, the invention relates to the use of a pharmaceutical composition as defined herein for the treatment of cancer According to another particular aspect, the invention relates to the use of a pharmaceutical composition as defined herein for inhibiting growth of cancer cells. According to another particular aspect, the invention relates to the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for the treatment of cancer.   According to another particular aspect, the invention relates to a medicament for the treatment of cancer comprising: a unit dose of about 8 mg of the compound of formula (I) or pharmaceutically acceptable salt thereof   an acidic additive that is (1) a C2-20-organic acid or fatty acid having a COOH or SO3H group; (2) an inorganic acid selected from the group consisting of phosphoric acid, sulfuric acid, boric acid and a mixture thereof; or (3) any material showing pH 1 to 6 when dissolved or dispersed in water at a concentration of 1 to 5% (w/v) as a pharmaceutically acceptable excipient; and a diluent comprising microcrystalline cellulose, lactose, mannitol, calcium phosphate, or a mixture thereof; a binder comprising povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, sodium carboxymethyl cellulose, or a mixture thereof; or a disintegrant comprising crospovidone, sodium croscarmellose, sodium starch glycolate, or a mixture thereof. BRIEF DESCRIPTION OF THE DRAWINGS  The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawings, which respectively show: Fig. 1: the stabilities at 60 C of the formulations prepared in accordance with Examples 1 to 7, and Comparative Example 1; Fig. 2: the stabilities of the formulations according to the amount of acidic additive; Fig. 3: the stabilities at 60 C of the formulations prepared in accordance with Example 1, and Comparative Examples 2 to 5; and Fig. 4: the stabilities at 60 C of the formulations prepared in accordance with Examples 11 and 12, and Comparative Example 6. 4a