KR-20260062790-A - Pharmaceutical preparation containing nintedanib or pharmaceutically acceptable salt thereof and a methacrylic acid copolymer

Abstract

The present invention relates to a tablet comprising nintedanib or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer, wherein the tablet provides an excellent dissolution rate of 90% or more at 180 minutes in a pH 4.5 test solution under the Korean Pharmacopoeia Dissolution Method 2 (Paddle Method) conditions of 50 rpm.

Inventors

• 이정은
• 전다은
• 김상현
• 허보라
• 안정아

Assignees

• 일동제약(주)

Dates

Publication Date

20260507

Application Date

20250327

Priority Date

20241029

Claims (12)

1. A tablet comprising nintedanib or a pharmaceutically acceptable salt thereof, and a methacrylic acid copolymer, The above tablet is a tablet having a dissolution rate of 90% or higher in a pH 4.5 test solution at 50 rpm under the Korean Pharmacopoeia Dissolution Method 2 (Paddle Method) conditions after 180 minutes.
2. In claim 1, the above dissolution rate is a tablet having a dissolution rate of 90% or more at 180 minutes in a pH 4.5 test solution under the Korean Pharmacopoeia Dissolution Method 2 (Paddle Method) conditions of 50 rpm.
3. In claim 1, the above dissolution rate is a tablet having a 60-minute dissolution rate of 45% or more, a 120-minute dissolution rate of 70% or more, and a 180-minute dissolution rate of 90% or more under the Korean Pharmacopoeia Dissolution Method 2 (Paddle Method) at 50 rpm.
4. A tablet according to claim 1, wherein the methacrylic acid copolymer comprises one or more selected from the group consisting of Eudrajit L100 (methacrylic acid/methyl methacrylate copolymer), Eudrajit L100-55 (methacrylic acid/ethyl acrylate copolymer), Eudrajit E100, and Eudrajit EPO (dimethylaminoethyl methacrylate/methyl methacrylate copolymer).
5. In paragraph 3, the methacrylic acid copolymer is a tablet comprising dimethylaminoethyl methacrylate/methyl methacrylate copolymer.
6. In claim 1, the tablet comprises 15 to 35 weight percent of the methacrylic acid copolymer relative to the total weight of the tablet.
7. In claim 1, the tablet comprises a coating layer, and the coating layer is a coated tablet that does not contain Eudrajit.
8. In claim 7, the tablet wherein the weight of the coating layer of the coated tablet is 1 to 15 weight percent relative to the weight of the core part,
9. In claim 1, the nintedanib is a tablet which is nintedanib esylate.
10. In claim 1, the tablet is a tablet that does not contain an acidifying agent.
11. In claim 10, the above acidifying agent comprises one or more selected from the group consisting of ascorbic acid, benzoic acid, succinic acid, citric acid, glutamic acid, phosphoric acid, acetic acid, propionic acid, tartaric acid, carbonic acid, lactic acid, boric acid, maleic acid, fumaric acid, malic acid, adipic acid, hydrochloric acid, and sulfuric acid.
12. In paragraph 1, the above tablet is A tablet comprising 18 to 40 weight% of nintedanib or a pharmaceutically acceptable salt thereof based on the total weight of the tablet, and 15 to 35 weight% of a methacrylic acid copolymer based on the total weight of the tablet.

Description

Pharmaceutical preparation containing nintedanib or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer The present invention relates to a pharmaceutical formulation comprising nintedanib or a pharmaceutically acceptable salt thereof, and more specifically, to a pharmaceutical formulation comprising nintedanib or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer. Nintedanib is a compound represented by the chemical formula 1 below , having the empirical formula C31H33N5O4 , and is a drug that competitively inhibits non-receptor tyrosine kinase (nRTK) and receptor tyrosine kinase (RTK) , and is used in combination with other drugs for the treatment of idiopathic pulmonary fibrosis and some non-small cell lung cancers. <Chemical Formula 1> An oral formulation containing nintedanib is sold under the brand name “ Ofev® Soft Capsules,” and its formulation is a soft capsule containing a suspension. Nintedanib, the active ingredient of Ofev® , is a poorly soluble drug in the form of a light yellow powder with a melting point of 305±5°C. Additionally, nintedanib is known to undergo hydrolysis as a general metabolic reaction and is sensitive to extreme oxidative conditions (EMA Nintedanib Assessment report). Ofev® is a drug in which the active ingredient nintedanib is suspended in triglycerides; the triglycerides serve to stabilize the drug by blocking water and oxygen, while simultaneously facilitating absorption within the gastrointestinal tract upon oral administration. It is also marketed in soft gelatin capsules composed of gelatin, hydrogenated oil acting as a thickening agent, and lecithin used as a dispersant. However, due to the sensitivity of gelatin, the main component of the soft capsule, to heat and moisture, Ofev® may experience difficulties in handling by patients, as phenomena such as 1) deformation of appearance due to softening and hardening of the capsule film, 2) adhesion between capsules due to increased adhesiveness of the capsule film, 3) leakage of contents due to rupture of the capsule film, and 4) delayed disintegration due to cross-linking of gelatin caused by the reaction between the contents and the film may occur during storage. Accordingly, there is a case in which a study was conducted to change the formulation to a solid formulation containing nintedanib to overcome the disadvantages of Ofev® , a soft capsule formulation. One of the major challenges faced in developing nintedanib as a tablet rather than a conventional capsule is that, in addition to its low solubility, its viscosity increases significantly when it comes into contact with water. This results in delayed disintegration and dissolution in in vitro dissolution evaluations, making it very difficult to achieve bioequivalence for the soft capsule formulation of Ofev® . Accordingly, the inventors developed a new oral formulation with an improved dissolution rate and confirmed bioequivalence in a bioequivalence test with Ofev soft capsules. The following drawings attached to this specification illustrate preferred embodiments of the present invention and serve to further enhance understanding of the technical concept of the present invention together with the aforementioned description; therefore, the present invention should not be interpreted as being limited only to the matters described in such drawings. Figure 1 is a photograph confirming the degree of gelation of the tablet remaining after the dissolution experiment. The image shows the appearance inside the dissolution port after a 180-minute dissolution experiment using manufacturing number 112 (left). When the remaining tablet is broken open, it can be seen that the dry tablet remains intact because water could not penetrate to the inside due to the gelation of the active ingredient on the surface (right). Figure 2 is a graph showing the results of confirming the equivalence between the tablet of the present invention and Ofev soft capsules. Figure 3a is a graph showing the dissolution rate results of RU5001, and Figure 3b is a graph showing the dissolution rate results of the control drug Ofev. The present invention aims to provide a pharmaceutical formulation comprising nintedanib or a pharmaceutically acceptable salt thereof (hereinafter referred to as nintedanib) and a methacrylic acid copolymer, preferably a tablet, and more preferably a coated tablet. The coated tablet can be understood to mean a tablet comprising a core portion and a coating layer surrounding said core portion. The core portion refers to the part of the tablet excluding the coating layer formed by the coating base. The inventors of the present invention sought to improve the problem in which the tablet gels in an aqueous solution, thereby inhibiting the release of the active ingredient and failing to provide an appropriate dissolution rate. A tablet according to one embodiment of the present invention may have a dissolution rate of 90% or more a