Pharmaceutical formulation containing nintedanib or pharmaceutically acceptable salt thereof and methacrylic acid copolymer

Abstract

The present invention relates to a pharmaceutical formulation containing nintedanib or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer, wherein the formulation provides an excellent dissolution rate of 90% or more after 180 minutes under the conditions of the Korean Pharmacopoeia dissolution method II (paddle method) at 50 rpm in a test solution of pH 4.5.

Description

Pharmaceutical preparations comprising nintedanib or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer

[0001] The present application claims priority based on Korean Patent Application No. 10-2024-0149733 filed on October 29, 2024 and Korean Patent Application No. 10-2025-0039882 filed on March 27, 2025, and all contents disclosed in the specification and drawings of said application are incorporated by reference into the present application. 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.

[0002] Nintedanib is a compound represented by the following chemical formula 1, C 31 H 33 It has the empirical formula N5O4 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.

[0003]

[0004] <Chemical Formula 1>

[0005]

[0006] An oral formulation containing nintedanib, brand name "Ofev" ® A product called "soft capsule" is being sold, and its formulation is a soft capsule containing a suspension.

[0007] Offev ® Nintedanib, the active ingredient, is a light yellow powder with a melting point of 305±5°C and is a poorly soluble drug. In addition, nintedanib is known to undergo hydrolysis as a general metabolic reaction and is sensitive to extreme oxidative conditions (EMA Nintedanib Assessment report). Ofev ®It is a pharmaceutical product in which the active ingredient, nintedanib, is suspended in triglycerides. The triglycerides provide stabilization by blocking water and oxygen, while also facilitating absorption within the gastrointestinal tract upon oral administration. Additionally, it is marketed in soft gelatin capsules composed of gelatin, hydrogenated oil acting as a thickening agent, and lecithin used as a dispersing agent.

[0008] However, Ofev ® Due to the sensitivity of gelatin, the main component of soft capsules, to heat and moisture, there is a high risk that the stability required for the medicine during storage will be compromised and patients may experience difficulties in handling it, 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.

[0009] Accordingly, Ofev, a soft capsule formulation ® There is a case where a study was conducted to change the formulation to a solid dosage form containing nintedanib to overcome the disadvantages of the product.

[0010] One of the major challenges faced in developing nintedanib as a tablet rather than an existing capsule is that its viscosity increases significantly upon contact with water, in addition to its low solubility. As a result, disintegration and dissolution were delayed in in vitro dissolution evaluations, leading to the soft capsule formulation Ofev ® It becomes very difficult to secure biological equivalence for .

[0011] Accordingly, the inventors developed a new oral formulation with an improved dissolution rate and confirmed bioequivalence in a bioequivalence test with Ofev soft capsules.

[0012] The technical problem that the present invention aims to solve is to provide a new pharmaceutical formulation containing nintedanib or a pharmaceutically acceptable salt thereof that can be provided in tablet form while being recognized as bioequivalent to Ofev soft capsules. One objective of the present invention is to provide a new composition that can solve the problem of inhibited release experienced when a formulation containing nintedanib or a pharmaceutically acceptable salt thereof is made into a tablet form. The present invention aims to provide a tablet that exhibits small individual variation upon dissolution in a weak acid (pH 4.0–4.5), which is a biocompatible environment, and can minimize variation in efficacy for patients.

[0013] The present invention aims to provide a pharmaceutical formulation comprising nintedanib or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer, preferably a tablet, more preferably a coated tablet. The dissolution rate of the said pharmaceutical formulation may be 90% or higher in a pH 4.5 test solution at 50 rpm under the Korean Pharmacopoeia Dissolution Method 2 (Paddle Method) conditions for 180 minutes.

[0014] The dissolution rate of the pharmaceutical formulation of the present invention, preferably a tablet, may be 90% or higher in a pH 4.5 test solution at 50 rpm under the Korean Pharmacopoeia Dissolution Method 2 (Paddle Method).

[0015] The methacrylic acid copolymer included in the above pharmaceutical formulation is Eudragit ®It includes polymers of the ) series, wherein the polymers of the Eudrajit series may include one or more selected from the group consisting of Eudrajit L, S, RS, RL, NE, and E, and one or more selected from Eudrajit E and L. More specifically, the Eudrajit may include 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). For the purposes of the present invention, the reference drug (Ofev) ® To improve the in vivo behavior pattern, bioavailability, or dissolution rate of the tablet similar to ), one or more selected from Eudrajit E, Eudrajit E PO, and mixtures thereof may be more preferably used as the formulation.

[0016] The above methacrylic acid copolymer may be included in an amount of 15 to 35 weight% relative to the total weight of the pharmaceutical formulation, preferably in an amount of 15.5 to 33 weight%. In the above content range, the dissolution rate of nintedanib or a pharmaceutically acceptable salt thereof is excellent.

[0017] Although the above Eudrajit is generally used as an enteric coating agent, the inventors of the present invention do not use the above Eudrajit as a coating agent. The inventors of the present invention confirmed that when mixed with the active ingredient and formulated, the release of the active ingredient is excellent and the main ingredient does not gel. Furthermore, they were able to confirm in vivo behavior patterns and bioavailability similar to those of Ofev capsule formulations.

[0018] The above nintedanib or pharmaceutically acceptable salt thereof may include both organic and inorganic salts of nintedanib, and preferably may include nintedanib esylate.

[0019] In one embodiment, the pharmaceutical formulation may not include an acidifying agent 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. An acidifying agent refers to an excipient that lowers the pH of a substance or solution by increasing acidity, as it possesses the property of having a higher concentration of hydrogen ions than the concentration of hydroxide ions when ionized in an aqueous solution. Specifically, in the present invention, an acidifying agent refers to an excipient that has an acidifying effect or enhances acidity, and is capable of imparting a pH not exceeding 7 to an aqueous solution or dispersion. If such an acidifying agent is included in a nintedanib formulation, it may have an adverse effect on the stability of the raw material, such as an increase in impurities.

[0020] The above pharmaceutical formulation is preferably provided as a tablet. The formulation may consist only of a core portion and may include a coating layer as needed. In one embodiment, the tablet may be provided as a coated tablet comprising a core portion and a coating layer. The formulation may contain nintedanib or a pharmaceutically acceptable salt thereof in an amount of 18 to 40 weight% relative to the total weight of the tablet and a methacrylic acid copolymer in an amount of 15 to 35 weight% relative to the total weight of the tablet in the core portion. For the purposes of the present invention, when the content of the methacrylic acid copolymer and nintedanib is as described above, the reduction in dissolution of nintedanib due to gelation of the tablet may be reduced. Therefore, to ensure excellent dissolution rate and prevention of gelation, nintedanib and the methacrylic acid copolymer may have the above content ranges. The weight of the coating layer of the coated tablet may be included in an amount of 1 to 15 weight% relative to the weight of the core portion.

[0021] The formulation of the present invention has an excellent dissolution rate. The formulation of the present invention is recognized as bioequivalent to Ofev soft capsules and can be taken conveniently. The formulation of the present invention can improve the problem of reduced release rate of active ingredients due to gelation of the formulation, which occurred when the formulation was developed in tablet form.

[0022] 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.

[0023] 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).

[0024] Figure 2 is a graph showing the results of confirming the equivalence between the tablet of the present invention and Ofev soft capsules.

[0025] 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.

[0026] 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 solid formulation, more preferably a tablet, and even 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.

[0027] 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 at 180 minutes in a pH 4.5 test solution under the conditions of the Korean Pharmacopoeia Dissolution Method No. 2 (Paddle Method) at 37±0.5℃ and 50 rpm; more specifically, the dissolution rate at 60 minutes may be 45% or more, the dissolution rate at 120 minutes may be 70% or more, and the dissolution rate at 180 minutes may be 90% or more.

[0028] In one embodiment of the present invention, the formulation comprises nintedanib or a pharmaceutically acceptable salt thereof, and is not particularly limited to any nintedanib salt capable of achieving the purpose of the present invention. The nintedanib or a pharmaceutically acceptable salt thereof may include both organic and inorganic salts of nintedanib, and preferably may include nintedanib esylate. For example, the above pharmaceutically acceptable salt may comprise one or more selected from esylates, acetates, acetonides, alanine, aluminum, arginine, ascorbate, asparagine, aspartic acid, benzathine, benzoate, besylates, bisulfates, bisulfites, bitartrates, diallycylates, edethates, diethylsylates, estolates, ethylenediamine, ethanedisulfonates, esylates hydroxides, gluteptates, gluconates, glucuronates, glutamic acid, glutamine, glycine, hypochlorites, histidine, hydrobromides, hydrochlorides, and hydroxides, and preferably may comprise esylates. Unless otherwise indicated herein, crystalline or amorphous forms of the above compounds may also be included within the scope of the present invention.

[0029] The formulation of the present invention comprises a methacrylic acid copolymer as an additive that forms a formulation, preferably a tablet, together with nintedanib. The methacrylic acid copolymer preferably comprises a polymer of the EUDRAGIT® series, and may include EUDRAGIT L, S, RS, RL, NE, E, etc. Preferably, the polymer of the EUDRAGIT series may include one or more selected from the group consisting of EUDRAGIT L, S, RS, RL, NE, and E, and preferably one or more selected from EUDRAGIT E and L. More specifically, the above-mentioned Eudrajit may comprise 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). For the purposes of the present invention, it is more preferable to select from Eudrajit E, Eudrajit EPO, and mixtures thereof to improve the dissolution rate. When the above-mentioned Eudrajit is used together with nintedanib to form a core portion, a particularly improved dissolution rate improvement effect can be exhibited, and the reference drug (Ofev) ® Similar in vivo behavior patterns and bioavailability to that of ) can be expected. The methacrylic acid copolymer may be included in an amount of 15 to 35 weight% relative to the total weight of the tablet, and preferably in an amount of 15.5 to 33 weight%. Within the above content range, the dissolution rate of nintedanib or its pharmaceutically acceptable salt is excellent.

[0030] The tablet of the present invention may preferably be provided as a coated tablet comprising a coating layer. In this case, the coating layer of the coated tablet does not contain Eudrajit. Although Eudrajit is generally used as an enteric coating agent, the inventors of the present invention have confirmed that when Eudrajit is not included in the coating layer and is mixed with the active ingredient to form a tablet, the dissolution of the active ingredient is excellent and the active ingredient does not gel. If Eudrajit is included in the coating layer, the variation in content between individual tablets may be more severe than when it is included in the tablet core. This variation in content is largely caused by individual variations due to differences in the rate at which the coating film peels off in the body, which can lead to variations in drug efficacy. Furthermore, even if Eudrajit is included in the coating layer, it cannot prevent the gelation of the tablet, and a reduction in the release of the active ingredient may still occur. Therefore, the coated tablet containing nintedanib does not contain Eudrajit in the coating layer.

[0031] In one embodiment, the formulation does not include an acidifying agent 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. An acidifying agent refers to an excipient that lowers the pH of a substance or solution by increasing acidity, as it possesses the property of having a higher concentration of hydrogen ions than the concentration of hydroxide ions when ionized in an aqueous solution. Specifically, in the present invention, an acidifying agent refers to an excipient that has an acidifying effect or enhances acidity, and is capable of imparting a pH not exceeding 7 to an aqueous solution or dispersion. If such an acidifying agent is included in a nintedanib formulation, problems may arise such as reduced stability of nintedanib and increased generation of impurities. To resolve these problems, the nintedanib tablet of the present invention was completed as a result of research to improve the dissolution rate without containing an acidifying agent.

[0032] The formulation of the present invention may be prepared by adding pharmaceutically usable excipients, binders, lubricants, disintegrants, etc., which are generally used in the pharmaceutical field when manufacturing tablets, and may be prepared into a tablet according to a method well known to those skilled in the art to which the present invention belongs.

[0033] For example, as excipients, ingredients that are inexpensive and have no pharmacological activity, such as starch, sorbitol, mannitol, sucrose, colloidal silica, spray-dried lactose, anhydrous lactose, calcium dihydrogen phosphate, anhydrous dibasic calcium phosphate, and microcrystalline cellulose, may be used alone or in combination; as disintegrants, potassium polyacrylinate, lactose, starch, sodium starch glycolate, crospovidone, sodium croscarmellose, maltodextrin, and microcrystalline cellulose may be used alone or in combination. Lubricants are used to ensure smooth flowability during the feeding of granules to the tablet press and the movement of manufactured tablets, or to prevent phenomena such as sticking and capping during tablet compression; suitable lubricants may include colloidal silicon dioxide, talc, and magnesium stearate. Polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc. may be used as binders. The excipient may be included together with the granules during granulation or mixed after the granules are prepared. Preferably, it may be provided after being mixed following the preparation of the granules.

[0034] In one embodiment, the nintedanib tablet of the present invention may be provided as a coated tablet. The coated tablet may be provided including a coating layer surrounding a core portion. The coating layer is provided in an amount of 1 to 15 weight% or 1.5 to 10 weight% relative to the weight of the core portion, and the coating layer may be coated within a range that does not inhibit the dissolution of the active ingredient of the core portion. The coating layer may use a component generally used for tablet coating, and, for example, coating components such as Opadry®, Tabshield®, etc. may be used.

[0035] The above tablet may contain nintedanib or a pharmaceutically acceptable salt thereof in an amount of 18 to 40 weight%, more preferably 19 to 38 weight%, relative to the total weight of the tablet, and the tablet may be provided with a methacrylic acid copolymer in an amount of 15 to 35 weight%, preferably 15.5 to 33 weight%, relative to the total weight of the tablet. Preferably, the tablet may contain nintedanib as nintedanib esylate in an amount of 20 to 40 weight%, preferably 22 to 38 weight%, relative to the total weight of the tablet. When having the above content range, it provides excellent dissolution rates under acidic conditions (pH 4±0.5) while having a small variation in the dissolution rate of nintedanib. In addition, it can reduce the generation of impurities by maintaining the stability of nintedanib.

[0036] The tablets of the present invention may be manufactured by conventional methods, but preferably by a wet granulation method. One embodiment of manufacturing the tablets of the present invention may include the steps of mixing a wet portion containing nintedanib with a solvent, drying the mixture obtained in the mixing step, granulating after drying, and mixing the granulated material obtained in the granulation process with a post-mixing portion to manufacture the tablets. The wet portion preferably comprises nintedanib or a pharmaceutically acceptable salt thereof, and may also include the methacrylic acid copolymer of the present invention to improve the dissolution of nintedanib. Preferably, the solvent comprises water, a lower alcohol, or a mixture thereof, and preferably may comprise ethanol. The wet portion may include general excipients, and preferably may include mannitol, microcrystalline cellulose, colloidal silicon dioxide, etc. A person skilled in the art will understand that the post-mixing portion may include conventional ingredients for manufacturing tablets. In one embodiment, colloidal silicon dioxide may be included in both the wet section and the post-mixing section, which may be advantageous for achieving the objective of the present invention.

[0037] A person skilled in the art can easily understand that the dosage level may be appropriately changed. A preferred dosage can be easily determined by a person skilled in the art by various means.

[0038] "Effective dose" or "effective amount" may be understood to mean an amount suitable for use in the therapeutic use of nintedanib for lung diseases, such as idiopathic pulmonary fibrosis, some non-small cell lung cancers, and chronic fibrotic interstitial lung disease, which can produce the desired effect, for example, by improving or delaying the progression of a disease or disease state. The effective dose may be determined on an individual basis and will be determined by considering the symptoms to be treated and the desired outcome. "Therapeutic effective dose" or "therapeutic amount" or "therapeutic amount" is an amount sufficient to achieve the desired clinical outcome (i.e., to achieve therapeutic efficacy).

[0039] An effective dose (e.g., a therapeutically effective dose) may be administered in the range of about 0.001 to about 100 mg / kg body weight (for humans), about 0.1 to about 50 mg / kg body weight, about 1 to about 50 mg / kg body weight, or about 5 to about 40 mg / kg body weight per day.

[0040] The course of treatment may be less than about 12 weeks, less than about 8 weeks, or less than about 4 weeks, for example, 1-12 weeks, 2-12 weeks, 4-12 weeks, 4-8 weeks, etc. Administration may be once a week, twice a week, every other day, daily, twice a day, every 2 weeks, etc.

[0041] The tablets of the present invention may be administered orally alone or in combination with other agents designed to assist in the treatment of an individual, but are not limited thereto, to an individual by any route of administration understood in the art.

[0042] The above nintedanib is administered in a unit dosage form; for example, each unit dosage form contains 10 to 10,000 mg, 15 to 1,000 mg, 20 to 500 mg, 25 to 200 mg, or 30 to 180 mg, 50 to 160 mg of nintedanib.

[0043] The above nintedanib can be provided as a single daily dose.

[0044] Preferably, the tablets of the present invention are administered as a constant dose of 150 mg / dose of nintedanib twice daily, and the dissolution rate at 180 minutes is 90% or higher in a pH 4.5 test solution under the Korean Pharmacopoeia Dissolution Method 2 (Paddle Method) conditions of 37±0.5℃ and 50 rpm. For the calculation of pharmacokinetic variables, Phoenix TM WinNonlin ® 8.0 (CERTARA USA. Inc.) was used.

[0045]

[0046] One embodiment of the present invention may provide a formulation comprising: a wet portion comprising nintedanib or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer; and a post-mixing portion mixed after the preparation of the wet portion. The wet portion and the post-mixing portion may include disintegrants, lubricants, and / or binders as described herein, and the same excipient may be included in the wet portion and the post-mixing portion, or different excipients may be included. To achieve the objectives of the present invention, excipients such as colloidal silicon dioxide, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate may be included in the wet portion and / or the post-mixing portion. The colloidal silicon dioxide has excellent compatibility with nintedanib or its salt as well as with Eudrazit.

[0047] The tablets of the present invention may be provided for the prevention, improvement, or treatment of idiopathic pulmonary fibrosis (IPF), systemic sclerosis-associated interstitial lung disease (SSc-ILD), and chronic fibrosing interstitial lung disease with a progressive phenotype.

[0048]

[0049] Examples

[0050] Hereinafter, the present invention will be described in detail with reference to examples to aid in understanding. However, the embodiments according to the present invention may be modified in various different forms, and the scope of the present invention should not be interpreted as being limited to the following embodiments. The embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the field to which the present invention pertains. Unless otherwise specified, % in this specification may be understood to mean weight %.

[0051]

[0052] The experiment was conducted as follows. The dissolution rate of the original drug, Boehringer Ingelheim’s Ofev soft capsules, was verified; the issue of reduced dissolution rate during tablet manufacturing was identified; and optimal additives for improving dissolution rate were screened. Subsequently, the results of dissolution experiments and bioequivalence tests using the manufactured tablets were confirmed.

[0053] Through this, a nintedanib tablet with excellent dissolution rate and recognized bioequivalence to Ofev soft capsules was completed.

[0054]

[0055] The following explains this in detail.

[0056] 1. Dissolution test

[0057] A dissolution test was conducted to verify whether the formulation tested in a pH 4.5 environment could overcome the inhibition of release due to gelation of the active ingredient and release more than 90% of the active ingredient.

[0058] Experimental method: Using a pH 4.5 test solution as a medium, a dissolution test is performed on 1 tablet / capsule of this drug according to the paddle method of the Korean Pharmacopoeia dissolution test method at a paddle rotation speed of 50 rpm and 37℃, and the dissolution rate of nintedanib is calculated by HPLC.

[0059] pH 4.5 test solution: Use a buffer solution made by dissolving 2.99 g of sodium acetate trihydrate and 1.66 g of glacial acetic acid in water to make 1 L.

[0060]

[0061] (1) Evaluation of original drugs

[0062] A dissolution test was conducted to determine whether the original drug formulation could overcome the release inhibition caused by gelation of the active ingredient and release more than 90% of the active ingredient in a pH 4.5 environment.

[0063] Original drug: Ofev soft capsules 150 mg (Boehringer Ingelheim Korea Co., Ltd.) was tested on 3 batches with different manufacturing numbers.

[0064] Results: As confirmed in Table 1 below, it was confirmed that 96–102% was released in 180 minutes.

[0065] Dissolution Rate (%) 5 min 10 min 15 min 30 min 45 min 60 min 90 min 120 min 180 min Ofev Soft Capsules 150 mg (Manufacturing No. 205268) 0382946587687101 Ofev Soft Capsules 150 mg (Manufacturing No. 107020) 1511304557758696 Ofev Soft Capsules 150 mg (Manufacturing No. 103594) 15112946608093102

[0066]

[0067] Based on the above results, it was determined that the inhibition of release due to gelation of the active ingredient was overcome when the dissolution rate after 180 minutes of preparation of the example tablet was checked and 90% or more was released.

[0068] (2) Preparation and evaluation of tablets using conventional additives

[0069] To produce a tablet formulation, tablets were manufactured using conventional additives and a wet granulation method. A high proportion of strong disintegrants was added to prevent release inhibition.

[0070]

[0071] Manufacturing Method

[0072] The wet-mixture ingredients in Table 2 below were mixed. An appropriate amount of purified water or ethanol was added to the mixture as a mixing liquid and mixed. The mixture was dried in a tray dryer, and the dried material was sieved using a sieve. The mixture of the sieved material and the post-mixture ingredients in the table below was compressed into tablets using a tablet press to contain 180.6 milligrams of nintedanib esylate (150.0 milligrams as nintedanib).

[0073]

[0074] <Result>

[0075] The dissolution rate of nintedanib was low in the pH 4.5 test solution. Even with the use of high proportions of potent disintegrants (potassium polacrylin and sodium croscarmellose), the formulation could not inhibit the gelation and release of the active ingredient.

[0076] A dissolution experiment was conducted using the tablet labeled manufacturing number 112 in Table 2 below. As a result, as can be seen in Figure 1, when the tablet remaining inside the dissolution port (left) was broken after a 180-minute dissolution experiment, a dry tablet was confirmed as it was because water could not penetrate to the inside due to the gelation of the main ingredient on the surface (right).

[0077] mg / 1 tablet Manufacturing No. 112115125126127 Wet Bunintedanib Esylate 180.6180.6180.6180.6180.6 Microcrystalline Cellulose 135.0135.0135.0135.0135.0 Povidone 20.020.020.020.020.0 Potassium Polyacrylate 25.025.025.025.025.0 Post-mixing D-Mannitol 109.4109.4 Microcrystalline Cellulose 109.4 Lactose Monohydrate 109.4 Pregelatinized Starch 109.4 Potassium Polyacrylate 25.015.015.015.0 Sodium Croscarmellose 50.0 Magnesium Stearate 5.05.05.05.05.0 Tablet Core Weight 500.0525.0490.0490.0490.0 pH 4.5 Dissolution Rate (%) (180 min) 2912393830

[0078]

[0079] From these results, it can be seen that it is difficult to prevent gelation of nintedanib tablets and improve dissolution rate with commonly used disintegrants.

[0080] (3) Additive screening

[0081] Manufacturing method: Nintedanib esylate was added to an ethanol solution in which Eudrajit was dissolved while stirring to suspend the suspension, and the resulting dried product was sieved using a sieve. A mixture of the sieved product and the raw materials for the post-mixing section shown in the table below was compressed into tablets using a tablet press to contain 180.6 milligrams of nintedanib esylate (150.0 milligrams as nintedanib).

[0082] Results: Among the Eudrajit grades, the tablet containing Eudrajit E specifically showed 96% dissolution after 180 minutes. The tablet containing Eudrajit E was able to inhibit the gelation of the active ingredient and release it.

[0083] mg / tablet %w / w Manufacturing No. 017018019 017018019 Wet Bunintedanib Esylate 180.6 180.6 180.6 24.1 24.1 24.1 D-Mannitol 329.4 329.4 329.4 43.9 43.9 43.9 Eudragit L100-551 50.0 20.0 Eudragit L1001 50.0 20.0 Eudragit E1001 50.0 20.0 Subsequent Mixture Sodium Glycolate 75.0 75.0 75.0 10.0 10.0 10.0 Colloidal Silicon Dioxide 7.5 7.5 7.5 1.0 1.0 1.0 Magnesium Stearate 7.5 7.5 7.5 1.0 1.0 1.0 Tablet Core Weight 750.0750.0750.0100.0100.0100.0100.0 pH 4.5 Dissolution Rate (%) (180 min) 535396---

[0084]

[0085] (4) Preparation & Evaluation of Tablets

[0086] Tablets containing Eudrajit E were prepared, and the dissolution rate was verified.

[0087]

[0088] Manufacturing method: The wet ingredients in the table below were mixed. An appropriate amount of ethanol was added to the mixture as a blending agent and blended. The blended product was dried in a tray dryer, and the dried product was sieved using a sieve. The mixture of the sieved product and the post-mixing ingredients in the table below was compressed into tablets using a tablet press to contain 180.6 milligrams of nintedanib esylate (150.0 milligrams as nintedanib).

[0089]

[0090] Results: The 180-minute dissolution rate was poor when Eudrajit E was contained at 12.5–15.6% w / w per tablet, but it was over 90% when Eudrajit E was contained at 16.7% w / w or more per tablet. Experiments confirmed that containing 16.7% w / w or more of Eudrajit E per tablet is desirable, and tablets containing 16.7% w / w or more of Eudrajit E inhibited the gelation of the active ingredient and had no difficulty releasing nintedanib.

[0091]

[0092]

[0093] (7) Preparation & Evaluation of Coated Tablets

[0094] A coated tablet containing Eudrajit E was prepared by the following method.

[0095]

[0096] Manufacturing method: The wet component raw materials in Table 6 below were mixed. An appropriate amount of ethanol was added to the mixture as a blending agent and blended. The blended product was dried in a tray dryer, and the dried product was sieved using a sieve. The mixture of the sieved product and the post-mixing component raw materials in the table below was compressed into tablets using a tablet press to contain 180.6 mg of nintedanib esylate (150.0 mg as nintedanib) or 120.4 mg of nintedanib esylate (100.0 mg as nintedanib). The compressed tablet cores were coated using a coating machine to produce nintedanib-coated tablets.

[0097]

[0098] mg / tablet %w / w Manufacturing Number RU5001EX40801 RU5001EX40801 Wet Bunintedanib Esylate 180.6 120.4 29.6 29.6 D-Mannitol 215.4 143.6 35.3 35.3 Eudrajit EPO 104.0 69.3 331 7.0 17.0 Colloidal Silicon Dioxide 3.0 2.0 0.5 0.5 Subsequently Mixed Microcrystalline Cellulose 59.0 39.3 339.7 9.7 Sodium Starch Glycolate 36.0 24.0 5.9 5.9 Colloidal Silicon Dioxide 3.0 2.0 0.5 0.5 Magnesium Stearate 9.0 6.0 1.5 1.5 Tablet Core Weight 610.0 406.6 66100.0 100.0 Coating Buopadry Red (03B650006)18.3--Tab Shield Pink (11P1528)17.89--Coated Tablet Weight 628.3424.556--

[0099] RU5001 is manufactured in a 150mg dose, and EX40801 is manufactured in a 100mg dose. It was confirmed that tablets can also be manufactured in the dose of commercially available Ofev soft capsules.

[0100]

[0101] 2. Bioequivalence test

[0102] Objective: An experiment was conducted to ensure bioequivalence between the original drug Ofev soft capsules 150 mg and the example (RU5001).

[0103]

[0104] Experimental Methods: A bioequivalence study was conducted in healthy adult male subjects as an open-label, randomized, two-group, two-period, postprandial, single-dose, oral crossover study. Depending on the assigned group, subjects maintained a fasting state for at least 10 hours and consumed a high-fat breakfast (at least 900 kcal, at least 35% fat) within 20 minutes starting around 7:30 AM on the day of the study. At around 8:00 AM, one tablet of the test drug or one capsule of the control drug (150.0 mg as nintedanib) was orally administered with 150 mL of room-temperature water. Blood was collected at predetermined time intervals, and the plasma concentration of nintedanib was analyzed to confirm the pharmacokinetic profile.

[0105]

[0106] Reference drug: Ofev soft capsules 150 mg (Boehringer Ingelheim Korea Co., Ltd.)

[0107] Test drug: Example manufacturing number RU5001

[0108]

[0109] Decision criteria: After analyzing drug concentrations, pharmacokinetic parameters are calculated, and for the primary evaluation items Cmax and AUCt, if the 90% confidence interval of the geometric mean ratio between the reference drug and the test drug is within 80.00% to 125.00%, the test drug and the reference drug are determined to be equivalent.

[0110]

[0111] Experimental results: Equivalence was confirmed. The results are shown in Table 7 and Figure 2.

[0112] Pharmacokinetic Parameters (Units) Ofev Soft Capsules 150 mg Preliminary Rate (%) Lower 90% Confidence Interval (%) Upper 90% Confidence Interval (%) n6767---Cmax (ng / mL)32.67535.32108.1100.04116.8AUC last (hr*ng / mL)207.318215.517103.9599.44108.67

[0113] Through the contents of such experiments, it can be seen that the nintedanib tablet of the present invention can overcome dissolution inhibition and secure bioequivalence.

[0114]

[0115] 3. Octanol Transfer Test

[0116] (1) Experimental Objective: An octanol transfer test was conducted to determine the extent to which the active ingredient is transferred into the oil phase, octanol, while dissolving the test drug and the control drug in a pH 4.0 environment. This allows for the prediction of how easily the active ingredient can be absorbed within the organism.

[0117] The absorption characteristics of the drug were evaluated by creating a biphasic environment by adding an octanol layer during in vitro dissolution to the pattern of absorption from the gastrointestinal tract into the bloodstream, and the in vivo behavior of the drug was predicted.

[0118] (2) Experimental method: In a bi-phasic medium in which a pH 4.0 test solution is the water phase and octanol is the oil phase, one tablet / capsule of this drug is added to the water phase, and a dissolution test is performed according to the paddle method of the Korean Pharmacopoeia dissolution test method at 50 rpm and 37°C. The dissolution rate of nintedanib in the oil phase is calculated by HPLC.

[0119]

[0120] pH 4.0 test solution: Prepare a mixture of 0.05 mol / L acetic acid solution and 0.05 mol / L sodium acetate solution (41:9) and adjust the pH to 4.0.

[0121]

[0122] Reference drug: Ofev soft capsules 150 mg (Boehringer Ingelheim Korea Co., Ltd.)

[0123] Test drug: Example manufacturing number RU5001

[0124]

[0125] (3) Experimental results: Similar levels of absorption patterns were observed between the control drug and the test drug. From these results, it can be seen that the test drug exhibits behavior similar to that of the control drug in vivo.

[0126]

[0127] Sample / Time 30 min 60 min 90 min 120 min 150 min 180 min Test drug (oil phase) 0.19 1.16 2.65 4.48 6.37 8.08 Control drug (oil phase) 0.36 1.60 3.07 5.06 6.8 48.54

[0128]

[0129] 4. Dissolution deviation

[0130] (1) Experimental objective: To determine the individual variation of the formulations tested in a pH 4.0 / 4.5 environment. For each test solution, 6 tablets of the test drug and 6 capsules of the control drug were tested.

[0131] (2) Experimental method: Using a pH 4.0 / 4.5 test solution as a medium, a dissolution test was performed on 1 tablet / capsule of this drug according to the paddle method of the Korean Pharmacopoeia dissolution test method at 50 rpm and 37°C, and the dissolution rate of nintedanib was calculated by HPLC.

[0132]

[0133] pH 4.5 test solution: Use a buffer solution made by dissolving 2.99 g of sodium acetate trihydrate and 1.66 g of glacial acetic acid in water to make 1 L.

[0134] pH 4.0 test solution: Prepare a mixture of 0.05 mol / L acetic acid solution and 0.05 mol / L sodium acetate solution (41:9) and adjust the pH to 4.0.

[0135]

[0136] Reference drug: Ofev soft capsules 150 mg (Boehringer Ingelheim Korea Co., Ltd.)

[0137] Test drug: Example manufacturing number RU5001

[0138]

[0139] (3) Results: The dissolution rate of the test drug tablets was less individual variation than that of Ofev. The results are shown in Figures 3a and 3b. The test drug in Figure 3a showed significantly less individual variation in dissolution rate compared to the control drug in Figure 3b.

[0140]

[0141] 5. Confirmation of dissolution of coated tablets

[0142] (1) Experimental Objective: An experiment was conducted to confirm the release power of nintedanib-coated tablets containing Eudrajit E.

[0143] (2) Manufacturing method: The wet ingredients in the table below were mixed. An appropriate amount of ethanol was added to the mixture as a mixing solution and mixed. The mixture was dried in a tray dryer, and the dried material was sieved using a sieve. The mixture of the sieved material and the post-mixing ingredients in the table below was compressed into tablets using a tablet press to contain 180.6 milligrams of nintedanib esylate (150.0 milligrams as nintedanib). The compressed tablet cores were coated using a coating machine.

[0144] mg / 1 tablet Manufacturing No. 067A067B067C077AEX40201A Wet Bunintedanib Esylate 180.6180.6180.6180.6180.6180.6D-Mannitol 206.9206.9206.9215.4215.4 Eudrajit EPO 112.5112.5112.5104.0104.0 Colloidal Silicon Dioxide 3.03.03.03.03.0 Post-mixed Microcrystalline Cellulose 000059.0 Sodium Starch Glycolate 36.036.036.036.036.0 Colloidal Silicon Dioxide 3.03.03.03.03.0 Magnesium Stearate 6.06.06.06.09.0 Tablet Core Weight 548.0548.0548.0548.0610.0 Coated by Opadry Red (03B650006) 16.443 2.884 9.321 6.4418.3 Coated Tablet Weight 564.4458 0.8859 7.32564.44628.3 pH 4.5 Dissolution Rate (%) (180 min) 10010110199103

[0145] (3) Result: It was confirmed that the release power of nintedanib is maintained even when the outside of the tablet is coated.

[0146]

[0147] 6. Stability Test

[0148] Content and impurity tests were conducted after 6 months of storage under accelerated conditions (40℃, 75%RH). As a result, the tablets remained stable under accelerated conditions for 6 months. The results are shown in Table 10.

[0149] Manufacturing Number Content (Standard: 95.0 ~ 105.0%) Imperfying Standard: Other individual impurities 0.2% or less, Total impurities sum 1.0% or less Accelerated Start 6 Months Accelerated Start 6 Months RU500 199.5% 100.5% Other individual impurities: ND Total impurities sum: ND Other individual impurities: 0.06% or less Total impurities sum: 0.06%

[0150]

[0151] The present invention provides a tablet comprising nintedanib or a pharmaceutically acceptable salt thereof and a methacrylic acid copolymer. The present invention provides a tablet that is recognized as bioequivalent to Ofev.

Claims

A preparation comprising nintedanib or a pharmaceutically acceptable salt thereof, and a methacrylic acid copolymer, The above preparation is a preparation having a dissolution rate of 90% or higher in a pH 4.5 test solution under the Korean Pharmacopoeia Dissolution Method 2 (Paddle Method) conditions of 50 rpm after 180 minutes. In claim 1, the above dissolution rate is a preparation 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. In claim 1, the above dissolution rate is a preparation 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. The formulation 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). In paragraph 3, the methacrylic acid copolymer is a formulation comprising dimethylaminoethyl methacrylate / methyl methacrylate copolymer. In claim 1, the methacrylic acid copolymer is included in an amount of 15 to 35 weight percent relative to the total weight of the formulation. In paragraph 1, the above preparation is a tablet preparation. In claim 7, the above tablet comprises a coating layer, and the coating layer is a coated tablet that does not contain Eudrajit. A formulation according to claim 8, wherein the weight of the coating layer of the coated tablet is 1 to 15 weight percent relative to the weight of the core portion. In claim 1, the nintedanib is a preparation that is nintedanib esylate. In claim 1, the above formulation is a formulation that does not contain an acidifying agent. In claim 11, the 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. In paragraph 1, the above preparation is A formulation comprising 18 to 40 weight% of nintedanib or a pharmaceutically acceptable salt thereof based on the total weight of the formulation, and 15 to 35 weight% of a methacrylic acid copolymer based on the total weight of the formulation.

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