TWI810543B - Process for stabilizing moisture-sensitive substances for pharmaceutical use and stable preparations - Google Patents

Abstract

The object of the present invention is to provide a method and a stable preparation for stabilizing DFP-11207, which is a substance sensitive to humidity and unstable under high humidity, and to provide a method comprising DFP-11207 or a pharmaceutically acceptable salt thereof, and Capsules for the treatment of cancer as hygroscopic agents.

Description

Process for stabilizing moisture-sensitive substances for pharmaceutical use and stable preparations

The present invention relates to a kind of 5-chloro-2-(3-(3-(ethoxymethyl)-5-fluoro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-1 -Carbonyl)benzoyloxy)pyridin-4-yl-2,6-bis(propionyloxy)isonicotinate) (hereinafter referred to as "DFP-11207") pharmaceutically stabilized method and In the stabilized preparation, the above-mentioned DFP-11207 is a medical substance that has multiple ester bonds in its molecule and is therefore easily hydrolyzed under the influence of humidity.

DFP-11207 is a novel derivative of 5-fluorouracil (5-FU), and is a candidate substance for an anticancer agent for oral administration (Patent Document 1, Non-Patent Document 1, and Non-Patent Document 2). 5-FU is mainly applied clinically by intravenous infusion for 1 week (Non-Patent Document 3). Thereafter, oral agents such as Xeloda (Non-Patent Document 4) and S-1 (Non-Patent Document 5) were used clinically.

S-1 is a composite agent containing the following three components: Tegafur (FT) as a 5-FU derivative, Gymast (CDHP) that inhibits the metabolic breakdown caused by dihydropyrimidine dehydrogenase in vivo, Oteracil potassium (OXO), which inhibits the activity of orotate phosphoribosyltransferase. S-1 shows excellent therapeutic effects, but on the other hand, each component is absorbed separately from the intestinal wall, so there is still room for improvement of side effects such as bone marrow toxicity represented by platelet count reduction toxicity.

DFP-11207 is a single compound consisting of 1-ethoxymethyl-5-fluorouracil (EMFU) as a derivative of 5-FU, 5-chloro- 2,4-dihydroxypyridine (CDHP), and citrazinic acid (CTA), which inhibits the activity of orotate phosphoribosyltransferase.

In an experiment using cancer-bearing nude rats as an animal model for predicting the effect of cancer patients, when DFP-11207 and S-11207 were orally administered, the 5-FU derived from DFP-11207 The area under the time curve (AUC) of drug concentration is equal to the AUC of 5-FU derived from S-1, but the maximum concentration (Cmax) of 5-FU derived from DFP-11207 in blood is significantly lower than that derived from S-1 Austrian 5-FU Cmax. Generally speaking, the AUC of 5-FU in the blood is likely to reflect the efficacy of 5-FU, and the Cmax of 5-FU in the blood is likely to reflect side effects (especially bone marrow toxicity such as decreased platelet count). DFP-11207 is a substance with an excellent balance of effects and side effects compared to S-1, which is an existing drug. In an experiment using cancer-bearing nude rats as the best animal model for predicting the effect in cancer patients, DFP-11207 and S-1 were orally administered respectively to compare the therapeutic effects. The results showed that DFP-11207 Better than S-1 (non-patent literature 1). In the phase I clinical trial of DFP-11207 conducted by the M.D. Anderson Cancer Center in the United States, it was also found that it has high safety (no severe gastrointestinal disease such as diarrhea) for patients with solid cancers such as colorectal cancer, gastric cancer, and pancreatic cancer. Toxicity; no toxicity of decreased platelet count) (Non-Patent Document 2). Regarding S-1, it is necessary to stop the drug for a period of time in order to recover from side effects, but DFP-11207 does not require a drug withdrawal time at all, and does not need to adjust the dosage according to the body surface area of cancer patients (Non-Patent Document 2). [Prior Art Literature] [Patent Document]

[Patent Document 1] Japanese Patent No. 5008778 [Non-patent literature]

[Non-Patent Document 1] M. Fukushima et al., Drug Design, Development and Therapy (2017): 1693 - 1705 [Non-Patent Document 2] J. Ajani et al., Investigational New Drugs (2020): 1763 - 1773 [Non-Patent Document 3] Heidelbelger et al., Cancer Research (1963): 1226 - 1243 [Non-Patent Document 4] H. Ishitsuka et al., Biochemical Pharmacology (1998): 1091 - 1097 [Non-Patent Document 5] M. Fukushima et al., Cancer Research (1996): 2602 - 2606

[Problem to be solved by the invention]

The present inventors found that although DFP-11207 is a clinically excellent candidate substance for anticancer agents, it has many ester bonds in the molecule, so it is sensitive to humidity (that is, its stability will decrease due to humidity), and sometimes it is difficult to maintain it for a long time. save.

DFP-11207 is EMFU as a slow-release substance of 5-FU, CDHP that inhibits the metabolic decomposition of 5-FU in vivo, and CTA that can inhibit the severe toxicity (diarrhea, etc.) of the digestive tract caused by 5-FU. When DFP-11207 is orally administered to a single compound formed by three substances bonded by ester bonds, DFP-11207 is metabolized into EMFU, CDHP, and CTA in intestinal tissues. EMFU releases 5-FU slowly in the blood, and CDHP inhibits the metabolic decomposition of 5-FU in the blood, so the concentration of 5-FU in the blood is maintained, so the anti-tumor effect of 5-FU is improved. On the other hand, most of the CTA will stay in the intestinal tissue, thereby reducing the digestive tract toxicity caused by 5-FU.

As mentioned above, DFP-11207 is a functional substance that releases 5-FU into the molecule (EMFU), a functional substance that inhibits the decomposing enzyme of 5-FU (CDHP), and relieves 5-FU in the digestive tract tissue. Highly functional substance (CTA) that causes toxicity in the interior, but it is sensitive to humidity.

The object of the present invention is to provide a method and a stable preparation for stabilizing DFP-11207, which is a substance sensitive to humidity and unstable at high humidity. [Technical means to solve the problem]

The inventors of the present invention conducted earnest research in order to solve the above problems, and as a result, found that by making DFP-11207 into a capsule form together with a hygroscopic agent, and by storing the capsule in a container together with a desiccant , which can improve the stability of DFP-11207 as a substance sensitive to humidity, and can be stored indoors or in the refrigerator for a long time.

The present invention is based on these novel findings and includes the following inventions. [1] A capsule for treating cancer, comprising DFP-11207 or a pharmaceutically acceptable salt thereof, and a hygroscopic agent. [2] The capsule of [1], wherein the hygroscopic agent is colloidal silicon dioxide and microcrystalline cellulose. [3] The capsule according to [1] or [2], which contains 25 to 65% by weight of DFP-11207 or a pharmaceutically acceptable salt thereof, 35 to 75% by weight of microcrystalline cellulose, and colloidal silicon dioxide 2 to 5% by weight. [4] The capsule according to any one of [1] to [3], which contains 100 mg of DFP-11207 or a pharmaceutically acceptable salt thereof. [5] The capsule according to any one of [1] to [4], wherein the film-coating base of the capsule contains hydroxypropylmethylcellulose. [6] The capsule according to any one of [1] to [5], which is in the size of No. 2 capsule to No. 00 capsule. [7] The capsule according to any one of [1] to [6], which is in a form contained in a container together with a desiccant. [8] A method for producing a capsule for treating cancer, comprising the step of filling a capsule with DFP-11207 or a pharmaceutically acceptable salt thereof, and a hygroscopic agent. [9] The production method according to [8], wherein the hygroscopic agent is colloidal silica and microcrystalline cellulose. [10] The production method according to [8] or [9], comprising filling DFP-11207 or a pharmaceutically acceptable salt thereof with 25 to 65% by weight, microcrystalline cellulose with 35 to 75% by weight, and colloidal dioxide The step of 2-5% by weight of silicon. [11] The production method according to any one of [8] to [10], which includes the step of filling 100 mg of DFP-11207 or a pharmaceutically acceptable salt thereof. [12] The production method according to any one of [8] to [11], wherein the coating base of the capsule contains hydroxypropylmethylcellulose. [13] The production method according to any one of [8] to [12], wherein the capsule has a size of No. 2 capsule to No. 00 capsule. [14] The production method according to any one of [8] to [13], which further includes the step of housing the produced capsules together with a desiccant in a container. [Effect of Invention]

According to the present invention, a method and a stable formulation for stabilizing DFP-11207, which is a substance sensitive to humidity and unstable at high humidity, can be provided. According to the present invention, since there are 5-FU slow-release functional substances (EMFU), 5-FU decomposing enzyme inhibitory functional substances (CDHP) in the intramolecular ester bond and active amide bond, and the inhibition is derived from 5 - The high-functional substance DFP-11207, which is made of the functional substance (CTA) of gastrointestinal toxicity of FU, is a substance that is sensitive to humidity and unstable. Therefore, a substance that inhibits the movement of water molecules and makes the substance sensitive to humidity and unstable The method for stabilizing DFP-11207 can provide a pharmaceutical preparation in which the preparation of DFP-11207 can be stored stably for a long time and there is no problem in transportation.

The present invention relates to a capsule for treating cancer, which comprises DFP-11207 or a pharmaceutically acceptable salt thereof, and a hygroscopic agent.

In the present invention, "DFP-11207" is represented by the following formula 1:

[chemical 1] The compound represented by the chemical structural formula is 1-ethoxymethyl-5-fluorouracil (EMFU), which is a derivative of 5-FU, and 5-chloro-2, which inhibits the enzymatic decomposition caused by dihydropyrimidine dehydrogenase, 4-Dihydroxypyridine (CDHP) and citrazinic acid (CTA) which inhibits the activity of orotate phosphoribosyltransferase are linked by an ester bond and an active amide bond. In the present invention, "DFP-11207" can use a previously known method (for example, Japanese Patent No. 5008778, the above-mentioned M. Fukushima et al., (2017), J. Ajani et al., (2020), etc.) manufacturer, or a commercially available one can also be used.

In the present invention, "its pharmaceutically acceptable salt" means a salt that can be administered to a living body, for example, hydrochloride, sulfate, nitrate, phosphate, hydrobromide, carbonate , acetate, trifluoroacetate, p-toluenesulfonate, propionate, tartrate, fumarate, malate, maleate, citrate, methanesulfonate, alkali metal salt (sodium Salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, etc.), magnesium salt, ammonium salt, etc., but are not limited to these.

In the present invention, the "hygroscopic agent" is not particularly limited, as long as it is pharmaceutically acceptable (that is, can be administered to a living body) and exhibits hygroscopicity, for example, microcrystalline Cellulose, colloidal silicon dioxide, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, carboxy polyethylene, methyl cellulose, Ethyl cellulose, dextran, carboxymethyl starch, starch, calcium silicate, magnesium silicate, talc, polyvinylpyrrolidone, polyvinyl alcohol, thaumatin, sodium polyphosphate, phthalic anhydride, Maleic anhydride, anhydrous sodium dihydrogen phosphate, sodium metaphosphate, etc., one or more selected from these can be used. In the present invention, the "hygroscopic agent" preferably includes microcrystalline cellulose and/or colloidal silicon dioxide, more preferably microcrystalline cellulose and colloidal silicon dioxide. By including the "hygroscopic agent" in the present invention, the movement of water molecules can be reduced, and the stability of DFP-11207 or its pharmaceutically acceptable salt to humidity can be improved.

In one aspect, the capsule of the present invention may contain 25-65% by weight of DFP-11207 or a pharmaceutically acceptable salt thereof, and 35-75% by weight of a hygroscopic agent.

In another aspect, the capsule of the present invention may contain 25-65% by weight of DFP-11207 or a pharmaceutically acceptable salt thereof, 35-75% by weight of microcrystalline cellulose, and 2-2% by weight of colloidal silicon dioxide. 5% by weight. For example, the capsule of the present invention may contain 100 mg of DFP-11207 or a pharmaceutically acceptable salt thereof, 56.8 mg to 292 mg of microcrystalline cellulose, and 3.2 mg to 8 mg of colloidal silicon dioxide.

In the capsule of the present invention, if necessary, excipients, binders, disintegrants, lubricants, diluents, stabilizers, isotonic agents, pH adjusters, Buffers, solubilizers, suspending agents, colorants, preservatives, preservatives, antioxidants and other ingredients. The DFP-11207 or its pharmaceutically acceptable salt and the hygroscopic agent filled into the capsules can be made into powder, granule, etc. form alone, or together with these other ingredients into powder, granule, etc. form.

In the present invention, the coating of the capsule contains, or consists of, one or more bases generally used in the manufacture of the coating. As such a capsule coating base, for example, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, agar, carrageenan, Alginic acid, Indian gum, Arabic gum, triglucose, Brunei gum, sanxian gum, gellan gum, tragacanth gum, pectin, glucomannan, starch, polydextrose, dextrin, maltodextrin, Cyclodextrin, indigestible dextrin, guar gum, tara gum, tamarind gum, locust bean gum, psyllium seed gum, flaxseed gum, gelatin, casein, zein, sorbitol, maltitol , lactitol, batitol, xylitol, mannitol, galactitol, erythritol, etc., but are not limited to these. In the present invention, the coating of the capsule preferably contains or consists of HPMC.

The size of the capsule is not particularly limited, as long as it can contain the above-mentioned DFP-11207 or a pharmaceutically acceptable salt thereof, a hygroscopic agent, and other ingredients added as needed, and is suitable for oral administration, for example Follow the definition of Japanese Pharmacopoeia Capsule Specifications, the size of No. 000 (standard content 1 g) ~ 5 (standard content 0.03 g), preferably No. 00 (standard content 0.5 g) ~ 4 (standard content 0.06 g), for example, the size of No. 00 (standard content 0.5 g) to No. 3 (standard content 0.12 g), more preferably No. 00 (standard content 0.5 g) ~ 2 (standard content 0.2 g) g) size.

Capsules can be in any form of hard capsules, soft capsules, or seamless capsules, preferably hard capsules. The capsules are colored or colorless, and transparent, translucent or opaque, preferably colored opaque capsules.

The capsules of the present invention can be produced according to previously known capsule production methods. That is, it can be carried out by filling and encapsulating the above-mentioned DFP-11207 or a pharmaceutically acceptable salt thereof, a hygroscopic agent, and other components added as necessary, into a capsule.

The manufactured capsules may be in a form accommodated in a container together with a desiccant, and can be provided, transported, sold, stored, etc. in this form.

In the present invention, the "container" can be any of "airtight container", "airtight container" and "airtight container" (defined by the General Principles of the Seventeenth Revised Edition of the Japanese Pharmacopoeia), and it is preferable to prevent moisture Ingress moisture-proof container. Also, the container preferably has a child resistant lid.

The container may be in any form, and examples thereof include, but are not limited to, bottle-shaped containers, bag containers, and box containers. Containers can be made of high moisture-proof materials such as glass, metal, resin (polyethylene, polypropylene, etc.). The container is colored or colorless, and transparent, translucent or opaque, preferably a colored opaque container. The capacity of the container is not particularly limited, for example, it can be 50-500 mL (typically 50 mL, 100 mL, 150 mL, 180 mL, 200 mL, 250 mL, 300 mL, 350 mL, 400 mL, 450 mL or 500 mL ), preferably 100-200 mL.

In the present invention, "drying agent" can be exemplified: silica gel, alumina gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, calcium chloride, lithium chloride, magnesium chloride, lime, clay, zeolite, talc , diatomaceous earth, clay, carbon black, superabsorbent resin, synthetic resin powder, sulfate, carbonate, hydroxide, oxide, chloride, and phosphate, etc., and one or more of them can be used . The form of the desiccant is not particularly limited, and it can be packaged in a sachet, pouch, pack, etc., and stored in a container together with the capsule.

The amount of desiccant contained in the container can be properly adjusted according to the amount or size of the capsule, the size, shape or material of the container, and the type of desiccant. For example, the capacity of the container can contain 0.5 g to 10 g, such as about 1 g to 8 g, 2 g to 5 g of desiccant. In one aspect, 50 capsules of the present invention and 3 g of silica gel can be accommodated in a high-density polyethylene white bottle container (capacity 150 mL).

Compared with a single component of DFP-11207 or a pharmaceutically acceptable salt thereof, the capsules of the present invention have high stability. In particular, by storing the capsule of the present invention in a container together with a desiccant, higher stability can be obtained, and it can be stored at room temperature (25°C/humidity 50%) or in a refrigerator (5°C). In particular, it can be stored for a long time (for example, 1 month or more, 2 months or more, 3 months or more, 4 months or more, 5 months or more, or 6 months) under low temperature conditions (such as 1 to 5°C) in a refrigerator. More than one month, more than 7 months, more than 8 months or more than 9 months, the upper limit is not particularly limited, it is less than 84 months, less than 72 months, less than 60 months, less than 48 months, less than 36 months , less than 24 months, less than 18 months or less than 12 months) have high stability. In the present invention, "having high stability" means that there is little or no modification or decomposition of the compound, which means that it can maintain more than 90%, such as more than 91%, More than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98% or more than 99% purity.

The capsules of the present invention are administered to cancer patients by oral administration. Although the dose may vary depending on factors such as the patient's age, body weight, state, type and severity of cancer, it is an arbitrary amount sufficient to treat cancer. For example, the capsules of the present invention can be administered once or divided into 2-3 times, and can be administered every day, once every 2-3 days, once a week or once every 1-3 weeks. Based on the amount of DFP-11207 or its pharmaceutically acceptable salt as the active ingredient, the daily dose is 50 mg to 500 mg, preferably 100 mg to 400 mg, more preferably 200 mg to 300 mg.

In the present invention, "treating cancer" means not only a state where the cancer has completely disappeared, but also a state where the cancer shrinks or disappears temporarily or permanently, or a state where the cancer is stable without deterioration. For example, it includes one or more of the following conditions: reduction in cancer size, reduction in tumor marker levels, improvement in symptoms associated with cancer, extension of overall survival, progression-free survival, and median survival.

Orally administered DFP-11207 or its pharmaceutically acceptable salts are metabolized into 5-FU slow-release substance EMFU, 5-FU decomposition inhibitor CDHP in the lower digestive tract tissues, and inhibit lower digestion such as severe diarrhea. CTA with intestinal toxicity, after passing through the lower digestive tract, EMFU slowly releases the anticancer active substance 5-FU, CDHP inhibits the enzymatic decomposition of 5-FU caused by dihydropyrimidine dehydrogenase, and CTA stays in the lower digestive tract tissue, inhibiting this The activity of orotic acid phosphoribosyltransferase in the tissue can reduce the toxicity of the lower digestive tract (severe diarrhea, etc.) caused by 5-FU, and show the maximum therapeutic effect of 5-FU, surpassing the existing 5-FU anticancer agent.

In the present invention, regarding the type of cancer to be treated, since DFP-11207 is the same 5-FU anticancer agent as 5-FU, S-1, and Xeloda, examples include: colorectal cancer, Gastric cancer, esophageal cancer, pancreatic cancer, hepatocellular carcinoma, gallbladder cancer, gallbladder cancer, biliary tract cancer, breast cancer, ovarian cancer, breast cancer, cervical cancer, uterine body cancer, cervical cancer, head and neck cancer, etc. In addition, DFP-11207 has CDHP in the molecule that inhibits the decomposition caused by dihydropyrimidine dehydrogenase (DPD), so non-small cell lung cancer with strong DPD activity can also be included in the treatment objects.

In addition, the capsule of the present invention is characterized in that the side effects such as severe diarrhea, decreased leukocyte count, neutrophil count, and platelet count that are easily accompanied by 5-FU anticancer agents are small.

Hereinafter, examples are given to describe the present invention in more detail, but the technical scope of the present invention is not limited by these examples. [Example]

(Example 1) 100 mg capsule preparation of DFP-11207 of the first formulation Table 1 shows the constituents, amount and packaging form of 100 mg capsules of DFP-11207 in the first formulation.

According to the first formulation, 100 mg capsule preparation of DFP-11207 was prepared. Fill 100 mg of DFP-11207, 56.8 mg of microcrystalline cellulose, and 3.2 mg of colloidal silicon dioxide into white opaque hard capsules made of HMPC of size 2, and put 50 capsule preparations into 3 silicone bags for drying ( 1 g) in a 150 cc high-density polyethylene (HDPE) bottle with a diameter of 38 mm and closed with a cap that cannot be opened by children.

[Table 1] The composition, quantity and packaging form of the 100 mg capsule of DFP-11207 of the first formula Element Purchasing place 100 mg capsule of DFP-11207 mg/ capsule %w/w DFP-11207 - 100.0 62.5 Microcrystalline Cellulose PH112, NF/EP/JP FMC 56.8 35.5 Colloidal silica, NF/EP/JP Evonik 3.2 2.0 Filling quantity / capsule 160.0 100.0 capsule Qualicaps No. 2 (white opaque hard capsule made by HMPC) capsule filled bottle Drug & PlasticsCompany 150 cc high-density polyethylene (HDPE) bottle of 38 mm diameter in child-resistant packaging Texas TechnologyCompany Bag containing silicone gel for drying (1 g) Package 50 100 mg capsules (3 g silica gel for drying)/bottle

Table 2 shows the long-term stability of the 100 mg capsule preparation of DFP-11207 of the first formulation at 5°C, under accelerated conditions (25°C/humidity 60%), under severe conditions (30°C/humidity 65%) The sampling time (analysis time) of the samples used in the stability test.

[Table 2] Analysis time of samples used in stability test of 100 mg capsules of DFP-11207 of the first formulation condition Analysis time ( month ) Number of test bottles 0 1 2 3 6 9 12 18 twenty four 36 48 ^60c Number of trials keep quantity The total amount 5°C A A A A A A A A A 8 5 13 25℃/60%RH A A A A A A A A 8 4 12 30℃/65%RH A A A A A A 6 3 9 Total number of test bottles 34

Table 3 shows the specification, stability test method (appearance (white, off-white or cream) and purity (90%-110%)) and definition of test groups of the 100 mg capsule preparation of DFP-11207 of the first formulation. The purity was measured by high performance liquid chromatography (the same applies to the tests described below).

[Table 3] Specifications, Stability Test Methods and Definition of Test Groups of 100 mg Capsules of DFP-11207 of the First Formula Number of test bottles characteristic method specification Test group A Exterior ATM-1095 Capsules in white, off-white, creamy pink 1 purity ATM-1349 90.0～110.0% similar substance ATM-1349 Individual: ≥0.1% (% area) Overall: Measured value moisture content USP <921> Ia measured value disintegration time USP<701> 6 individual decomposition times and average Total number of test bottles 1

Table 4-1 and Table 4-2 show the long-term stability test data at 5° C. of the 100 mg capsule preparation of DFP-11207 of the first formulation.

Furthermore, in the following, "similar substance 1" is represented by the following formula 2:

[Chem 2] Compounds represented by the chemical structural formula;

"Similar substance 2" is represented by the following formula 3:

[Chem 3] Compounds represented by the chemical structural formula;

"Impurity 1" is represented by the following formula 4:

[chemical 4] Compounds represented by the chemical structural formula;

"Impurity 2" is represented by the following formula 5:

[chemical 5] Compounds represented by the chemical structural formula;

"Impurity 3" is represented by the following formula 6:

[chemical 6] The compound represented by the chemical structural formula.

As shown in the results, the purity after 48 months at 5°C was 94.8% (within the specification range of 90.0 to 110.0), and the stability for 48 months was confirmed.

[Table 4-1] Instant stability of 100 mg capsules of DFP-11207 of the first formulation at 5°C test method specifications 0 months 3 months 6 months 9 months 12 months 18 months Analysis date 2016/11/09 2017/02/02 2017/05/10 2017/08/10 2018/02/12 Exterior ATM-1095 white, off-white or cream off-white off-white off-white off-white off-white off-white purity ATM-1349 90.0～110.0% 99.3% 99.4% 97.4% 100.4% 98.4% 99.0% similar substance ATM-1349 Measured value ≥ 0.1% (individual): % area Overall: Measured value Similar substance 1: 0.1% RRT 0.47: 0.1% Impurity 1: 0.1% RRT 0.61: 0.1% Impurity 2: 0.4% Impurity 3: 0.4% RRT 0.88: 0.2% RRT 0.90: 0.1% RRT 0.92: 0.2% RRT 0.94: 0.2 % RRT 1.03: 0.2% Impurity 4: 0.3% Total: 2.4% Similar substance 2: 0.1% Similar substance 1: 0.1% RRT 0.46: 0.1% Impurity 1: 0.2% Impurity 2: 0.5% RRT 0.79: 0.2% Impurity 3: 0.5% RRT 0.87: 0.2% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.1% Impurity 4: 0.3% Total: 2.5% Similar substance 2: 0.1% Similar substance 1: 0.1% RRT 0.48: 0.1% Impurity 1: 0.1% RRT 0.61: 0.1% Impurity 2: 0.5% RRT 0.80: 0.1% Impurity 3: 0.4% RRT 0.88: 0.2% RRT 0.91: 0.1% RRT 0.92: 0.1% RRT 0.94: 0.1% RRT 1.03: 0.2% Impurity 4: 0.3% Total: 2.5% Similar substance 2: 0.1% Similar substance 1: 0.1% Impurity 1: 0.1% Impurity 2: 0.5% RRT 0.79: 0.1% Impurity 3: 0.4% RRT 0.87: 0.2% RRT 0.88: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.03: 0.1% Impurity 4: 0.3% Total: 2.2% Similar substance 2: 0.1% Similar substance 1: 0.1% RRT 0.46: 0.1% Impurity 1: 0.1% RRT 0.60: 0.1% Impurity 2: 0.5% RRT 0.79: 0.1% Impurity 3: 0.5% RRT 0.87: 0.2% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.1% Impurity 4: 0.3% Total: 2.5% Similar substance 2: 0.1% Similar substance 1: 0.1% RRT 0.46: 0.1% Impurity 1: 0.2% Impurity 2: 0.5% RRT 0.79: 0.1% Impurity 3: 0.4% RRT 0.87: 0.2% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.2% RRT 1.04: 0.2% Impurity 4: 0.3% Total: 2.6% moisture content USP <921> Ia measured value 1.6% 1.1% 1.2% 1.3% 1.5% 1.2% disintegration time USP<701> measured value 1:59, 1:51, 1:38, 1:51, 1:59, 2:14 Average: 1:55 1:34, 1:31, 1:34, 1:32, 1:28, 1:37 Average: 1:33 1:37, 2:15, 2:23, 2:26, 2:26, 2:41 Average: 2:18 1:25, 1:30, 1:32, 1:33, 1:35, 1:40 Average: 1:33 1:40, 1:50, 1:57, 2:04, 2:08, 2:2 Average: 2:00 1:30, 1:33, 1:40, 1:42, 1:45, 1:50 Average: 1:40 Note) RRT: Relative Retention Time of HPLC (high performance liquid chromatography)

[Table 4-2] The immediate stability of 100 mg capsules of DFP-11207 of the first formulation at 5°C test project method specifications 24 months 36 months 48 months 60 months analysis day 2018/08/10 2019/08/12 2020/08/10 Exterior ATM-1095 off-white off-white off-white purity ATM-1349 90.0～110.0% 102.9% 100.5% 94.8% similar substances ATM-1349 Measured value ≥ 0.1% (individual): % area Overall: Measured value Similar substance 2: 0.1% Similar substance 1: 0.1% RRT 0.46: 0.1% Impurity 1: 0.2% RRT 0.61: 0.1% Impurity 2: 0.6% RRT 0.79: 0.1% Impurity 3: 0.4% RRT 0.87: 0.2% RRT 0.89: 0.1% RRT 0.90: 0.2% RRT 0.91: 0.2% RRT 0.93: 0.2% RRT 1.04: 0.2% Impurity 4: 0.3% Total: 3.1% Similar substance 2: 0.1% Similar substance 1: 0.1% RRT 0.46: 0.1% Impurity 1: 0.2% RRT 0.61: 0.1% Impurity 2: 0.6% RRT 0.79: 0.2% Impurity 3: 0.5% RRT 0.87: 0.2% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.1% RRT 1.06: 0.1% Impurity 4: 0.3% RRT 1.24: 0.1% Total: 3.0% Similar substance 2: 0.2% Similar substance 1: 0.2% RRT 0.46: 0.1% Impurity 1: 0.4% RRT 0.61: 0.1% Impurity 2: 1.5% RRT 0.79: 0.2% Impurity 3: 0.4% RRT 0.87: 0.3% RRT 0.88: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.1% RRT 1.06: 0.1% Impurity 4: 0.3% RRT 1.24: 0.1% Total: 4.4% moisture content USP <921> Ia measured value 1.5% 1.7% 2.0% disintegration time USP<701> measured value 1:15, 1:18, 1:20, 1:30, 1:40, 1:45 Average: 1:28 1:40, 1:20, 1:24, 1:27, 1:30, 1:15 Average: 1:26 1:29, 1:31, 1:40, 1:46, 1:47, 1:56 Average: 1:42

Also, Table 5 shows the stability test data under accelerated conditions (25° C./humidity 60%) for a 100 mg capsule preparation of DFP-11207 of the first formulation.

As shown in the results, stability was confirmed for 6 months, but after 9 months and 12 months, both were lower than the specification value (90% to 110%), and stability was not confirmed.

[Table 5] Stability of 100 mg capsules of DFP-11207 of the first formulation under accelerated conditions (25°C/60RH) test method specification 0 months 1 month 2 months 3 months 6 months 9 months 12 months 18 months 24 months Analysis date 2016/9/12 2016/10/10 2016/11/19 _ 2017/2/8 2017/5/10 2017/8/10 Exterior ATM-1095 white, off-white or cream off-white off-white off-white off-white off-white off-white cream color purity ATM-1349 90.0～110.0% 99.3% 98.6% 98.5% 93.7% ** 97.4% 85.8%, 89.7%, 83.5%, 88.9% 76.9% similar substances ATM-1349 Measured value ≥ 0.1% (individual): % area Overall: Measured value Similar substance 1: 0.1% RRT 0.47: 0.1% Impurity 1: 0.1% RRT 0.61: 0.1% Impurity 2: 0.4% Impurity 3: 0.4% RRT 0.88: 0.2% RRT 0.90: 0.1% RRT 0.92: 0.2% RRT 0.94: 0.2 % RRT 1.03: 0.2% Impurity 4: 0.3% Total: 2.4% Similar substance 2: 0.2% RRT 0.37: 0.1% Similar substance 1: 0.1% RRT 0.45: 0.1% Impurity 1: 0.2% RRT 0.59: 0.1% Impurity 2: 0.6% RRT 0.79: 0.1% Impurity 3: 0.4% RRT 0.87: 0.3% RRT 0.89: 0.1% RRT 0.91: 0.2% RRT 0.93: 0.2% RRT 1.04: 0.2% RRT 1.06: 0.1% Impurity 4: 0.3% Total: 3.3% Similar substance 2: 0.2% Similar substance 1: 0.2% RRT 0.45: 0.1% Impurity 1: 0.3% RRT 0.59: 0.1% Impurity 2: 0.8% RRT 0.79: 0.1% Impurity 3: 0.4% RRT 0.87: 0.2% RRT 0.89: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.2% Impurity 4: 0.3% Total: 3.2% Similar substance 2: 0.3% Similar substance 1: 0.2% RRT 0.46: 0.1% Impurity 1: 0.3% Impurity 2: 1.1% RRT 0.79: 0.1% Impurity 3: 0.4% RRT 0.87: 0.2% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.2% Impurity 4: 0.3% Total: 3.4% Similar substance 2: 0.4% RRT 0.37: 0.1% Similar substance 1: 0.4% RRT 0.48: 0.1% Impurity 1: 0.5% RRT 0.61: 0.1% Impurity 2: 1.8% RRT 0.80: 0.3% Impurity 3: 0.4% RRT 0.88: 0.2% RRT 0.91: 0.1% RRT 0.92: 0.1% RRT 0.94: 0.2% RRT 1.03: 0.2% Impurity 4: 0.3% Total: 5.2% Similar substance 2: 1.9% RRT 0.31: 0.3% RRT 0.33: 0.1% RRT 0.36: 0.2% Similar substance 1: 1.0% Impurity 1: 1.4% RRT 0.55: 0.1% Impurity 2: 4.0% RRT 0.79: 0.5% Impurity 3: 0.7% RRT 0.83: 0.3% RRT 0.87: 0.2% RRT 0.88: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.2% RRT 1.03: 0.3% Impurity 4: 0.4% Total: 11.8% Similar substance 2: 4.5% RRT 0.31: 1.0% RRT 0.33: 0.2% RRT 0.36: 0.3% Similar substance 1: 1.8% Impurity 1: 1.5% RRT 0.49: 0.1% RRT 0.55: 0.4% RRT 0.60: 0.1% RRT 0.67: 0.1% Impurity 2: 6.0% RRT 0.79: 0.6% Impurity 3: 0.6% RRT 0.84: 0.9% RRT 0.87: 0.2% RRT 0.89: 0.2% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.3% RRT 1.04: 0.6% Impurity 4: 0.2% Total: 19.8% moisture content USP <921> Ia measured value 1.6% 1.3% 1.5% 1.3% 1.1% 1.3% 1.5% disintegration time USP<701> measured value 1:59, 1:51, 1:38, 1:51, 1:59, 2:14 Average: 1:55 1:40, 1:40, 1:46, 1:52, 1:57, 1:58 Average: 1:49 1:23, 1:43, 1:29, 1:35, 1:38, 1:45 Average: 1:36 1:25, 1:29, 1:36, 1:22, 1:27, 1:30 Average: 1:29 1:43, 2:19, 2:20, 2:22, 2:23, 2:24 Average: 2:15 1:21, 1:32, 1:36, 1:43, 1:49, 1:55 Average: 1:39 1:59, 2:06, 2:15, 2:18, 2:30, 2:42 Average: 2:18

Furthermore, Table 6 shows the data of the stability test under severe conditions (30° C./humidity 65%) of the 100 mg capsule preparation of DFP-11207 of the first formulation.

As shown in the results, stability was confirmed for 3 months, but stability was not confirmed thereafter. After 6 months, the appearance also changed from off-white to slightly brown.

[Table 6] Stability of 100 mg capsules of DFP-11207 of the first formulation under severe conditions (30°C/65RH) test method specifications 0 months 1 month 2 months 3 months 6 months 9 months 12 months Analysis date 2016/9/12 2016/10/10 2016/11/9 2017/2/8 Exterior ATM-1095 white, off-white or cream off-white off-white off-white off-white slightly brown purity ATM-1349 90.0～110.0% 99.3% 95.8% 95.3% 92.7% similar substance ATM-1349 Individual: Measured value ≥ 0.1% (% area) Overall: Measured value Similar substance 1: 0.1% RRT 0.47: 0.1% Impurity 1: 0.1% RRT 0.61: 0.1% Impurity 2: 0.4% Impurity 3: 0.4% RRT 0.88: 0.2% RRT 0.90: 0.1% RRT 0.92: 0.2% RRT 0.94: 0.2 % RRT 1.03: 0.2% Impurity 4: 0.3% Total: 2.4% Similar substance 2: 0.3% Similar substance 1: 0.2% RRT 0.45: 0.1% Impurity 1: 0.3% RRT 0.59: 0.1% Impurity 2: 0.8% RRT 0.79: 0.1% Impurity 3: 0.4% RRT 0.87: 0.2% RRT 0.89: 0.1% RRT 0.91: 0.2% RRT 0.93: 0.2% RRT 1.04: 0.2% RRT 1.06: 0.1% Impurity 4: 0.3% Total: 3.6% Similar substance 2: 0.4% Similar substance 1: 0.3% RRT 0.45: 0.1% Impurity 1: 0.5% RRT 0.59: 0.1% Impurity 2: 1.6% RRT 0.79: 0.2% Impurity 3: 0.4% RRT 0.87: 0.2% RRT 0.89: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.2% Impurity 4: 0.3% Total: 4.6% Similar substance 2: 0.7% RRT 0.36: 0.1% Similar substance 1: 0.5% Impurity 1: 1.0% Impurity 2: 2.3% RRT 0.79: 0.2% Impurity 3: 0.5% RRT 0.84: 0.1% RRT 0.87: 0.2% RRT 0.91: 0.1% RRT 0.93: 0.2% RRT 1.04: 0.3% Impurity 4: 0.3% Total: 6.5% moisture content USP <921> Ia measured value 1.6% 1.2% 1.5% 1.1% disintegration time USP<701> measured value 1:59, 1:51, 1:38, 1:51, 1:59, 2:14 Average: 1:55 2:02, 2:10, 2:16, 2:16, 2:30, 2:31 Average: 2:18 1:43, 1:31, 1:39, 1:35, 1:44, 1:22 Average: 1:36 1:40, 1:37, 1:32, 1:18, 1:26, 1:28 Average: 1:30

(Example 2) 100 mg capsule preparation of DFP-11207 of the second formulation Table 7 shows the constituents, amount and packaging form of the 100 mg capsule preparation of DFP-11207 of the second formulation.

According to the second formulation, 100 mg capsule preparation of DFP-11207 was prepared. Fill white opaque hard capsules made of HMPC No. 00 with 100 mg of DFP-11207, 292.0 mg of microcrystalline cellulose, and 8.0 mg of colloidal silicon dioxide, and put 50 capsule preparations into 3 silicone bags for drying (1 g) in a 150 cc high-density polyethylene (HDPE) bottle with a diameter of 38 mm and closed with a cap that cannot be opened by children.

[Table 7] The composition, quantity and packaging form of 100 mg capsules of DFP-11207 of the second formulation Element Purchasing place 100 mg capsule of DFP-11207 mg/ capsule %w/w DFP-11207 - 100.0 25.0 Microcrystalline Cellulose PH112, NF/EP/JP FMC 292.0 73.0 Colloidal silica, NF/EP/JP Evonik 8.000 2.0 Filling quantity/capsule 400.0 100.0 capsule Qualicaps No. 00 (white opaque hard capsule made by HMPC) capsule filled bottle Drug & PlasticsCompany 150 cc high-density polyethylene (HDPE) bottle of 38 mm diameter in child-resistant packaging Texas TechnologyCompany Bag containing silicone gel for drying (1 g) Package 50 100 mg capsules (3 g silica gel for drying)/bottle

Table 8 shows the long-term stability of the 100 mg capsule preparation of DFP-11207 of the second formulation at 5°C, under accelerated conditions (25°C/humidity 60%), under severe conditions (30°C/humidity 65%) The sampling time (analysis time) of the samples used in the stability test.

[Table 8] The analysis time of the samples used in the stability test of the 100 mg capsules of DFP-11207 of the second formulation condition Analysis time (month) Number of test bottles 0 1 2 3 6 9 12 18 twenty four 36 48 60 72 84 Number of trials keep quantity The total amount 5°C A B A B A A A A A A A A 20 ^10c 30 25℃/60%RH B B B A B A A A 12 6 18 30℃/65%RH B B B A B A 8 4 12 Total number of test bottles 60

Table 9 shows the specification, stability test method and definition of test groups of the 100 mg capsule preparation of DFP-11207 of the second formulation.

[Table 9] Specifications, Stability Test Methods and Definition of Test Groups of 100 mg Capsules of DFP-11207 of the Second Formulation characteristic method specifications Number of test bottles Test group A Test group B Exterior ATM-1095 Capsules in white, off-white, creamy pink 1 1 purity ATM-1349 90.0～110.0% similar substance ATM-1349 Individual: ≥0.1% (% area) Overall: Measured value moisture content USP <921> Ia measured value disintegration time USP<701> 6 individual decomposition times and average microbial content USP<61>USP<62> Total aerobic bacteria count (TAMC) ≤ 10 ³ cfu/g Total yeast and mold count (TYMC) ≤ 10 ² cfu/g Escherichia coli: None 1 Total number of test bottles 2 1

Table 10 shows the interim data of the long-term stability test (immediate stability test) at 5° C. for the 100 mg capsule formulation of DFP-11207 of the second formulation.

As shown in the results, the purity after 9 months at 5°C is 103.7% (within the specification range of 90.0-110.0), which can predict the long-term stability at 5°C.

[Table 10] Instant stability of 100 mg capsules of DFP-11207 of the second formulation at 5°C test method specifications 0 months 3 months 6 months 9 months 12 months 18 months Analysis date 2020/07/01 2020/10/02 2021/01/04 _ Exterior ATM-1095 white, off-white or cream off-white off-white off-white off-white purity ATM-1349 90.0～110.0% 100.3% 103.3% 101.9% 103.7% similar substance ATM-1349 Individual: Measured value ≥ 0.1% (% area) Overall: Measured value Impurity 1: 0.1% Impurity 2: 0.3% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.2% RRT 0.93: 0.2% RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% RRT 1.53: 0.1% Total: 2.3% Similar substance 2: 0.1% Impurity 1: 0.1% Impurity 2: 0.3% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.88: 0.1% RRT 0.90: 0.2% RRT 0.91: 0.2% RRT 0.93: 0.1% RRT 1.04: 0.1 % Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% Total: 2.4% Similar substance 2: 0.1% Impurity 1: 0.1% Impurity 2: 0.4% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1 % RRT 1.32: 0.1% Total: 2.1% Similar substance 2: 0.1% Impurity 1: 0.4% Impurity 2: 0.3% RRT 0.81: 0.1% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.2 % Impurity 4: 0.4% Total: 2.4% moisture content USP <921> Ia measured value 1.4% 2.0% 1.7% 1.7% disintegration time USP<701> Determining the mean 1:56, 2:18, 1:58, 1:46, 1:54, 2:29 Average: 2:04 1:33, 1:42, 1:45, 2:00, 2:10, 2:18 Average: 1:55 1:14, 1:35, 1:38, 1:45, 1:53, 2:03 Average: 1:41 1:23, 1:31, 1:37, 1:46, 1:52, 2:16 Average: 1:44 microbial content USP<61>USP<62> Total aerobic bacteria count (TAMC) ≤ 10 ³ cfu/g Total yeast and mold count (TYMC) ≤ 10 ² cfu/g Escherichia coli: None Total aerobic bacteria count (TAMC) ≤ 10 cfu/g Total yeast and mold count (TYMC) ≤ 10 cfu/g Escherichia coli: None Total aerobic bacteria count (TAMC) ≤ 10 cfu/g Total yeast and mold count (TYMC) ≤ 10 cfu/g Escherichia coli: None

In addition, Table 11-1 and Table 11-2 show the interim data of the stability test under accelerated conditions (25° C./humidity 60%) of the 100 mg capsule preparation of DFP-11207 of the second formulation.

As the results show, long-term stability over 9 months can be predicted. A significant improvement was confirmed compared to the stability time (6 months) of the 100 mg capsule formulation of DFP-11207 of the first formulation under accelerated conditions (25°C/humidity 60%).

[Table 11-1] Stability of 100 mg capsules of DFP-11207 in the second formulation under accelerated conditions (25°C/60RH) test method specifications 0 months 1 month 2 months 3 months 6 months Analysis date 2020/05/01 2020/06/01 2020/06/01 2020/10/02 Exterior ATM-1095 white, off-white or cream off-white off-white off-white off-white off-white purity ATM-1349 90.0～110.0% 100.3% 100.6% 102.8% 103.7% 104.5% similar substances ATM-1349 Individual: Measured value ≥ 0.1% (% area) Overall: Measured value Impurity 1: 0.1% Impurity 2: 0.3% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.2% RRT 0.93: 0.2% RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% RRT 1.53: 0.1% Overall: 2.3% Similar substance 2: 0.1% RRT 0.50: 0.1% Impurity 1: 0.1% Impurity 2: 0.4% RRT 0.81: 0.1% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.2% RRT 0.93: 0.1 % RRT 0.94: 0.1% RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% RRT 1.41: 0.1% Overall: 2.7% Similar substance 2: 0.1% Impurity 1: 0.1% Impurity 2: 0.5% RRT 0.81: 0.1% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.88: 0.1% RRT 0.90: 0.2% RRT 0.91: 0.2% RRT 0.93: 0.1 % RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% Overall: 2.7% Similar substance 2: 0.1% Impurity 1: 0.3% Impurity 2: 0.4% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.88: 0.1% RRT 0.90: 0.2% RRT 0.91: 0.2% RRT 0.93: 0.1% RRT 1.04: 0.1 % Impurity 4: 0.5% RRT 1.31: 0.1% RRT 1.32: 0.1% Overall: 2.8% Similar substance 2: 0.1% Similar substance 1: 0.1% Impurity 1: 0.1% Impurity 2: 0.9% RRT 0.81: 0.1% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.2% Impurity 4: 0.4% RRT 1.24: 0.1% RRT 1.31: 0.1% RRT 1.32: 0.1% Overall: 3.1% moisture content USP <921> Ia measured value 1.4% 1.6% 2.4% 1.7% 2.4% disintegration time USP<701> Determining the mean 1:56, 2:18, 1:58, 1:46, 1:54, 2:29 Average: 2:04 1:58, 1:41, 1:45, 1:50, 2:00, 2:25 Average: 1:57 2:08, 1:38, 1:48, 2:15, 1:30, 2:01 Average: 1:53 1:07, 1:14, 1:26, 1:40, 1:48, 2:02 Average: 1:33 1:08, 1:20, 1:31, 1:44, 1:51, 1:59 Average: 1:36 microbial content USP<61>USP<62> Total aerobic bacteria count (TAMC) ≤ 10 ³ cfu/g Total yeast and mold count (TYMC) ≤ 10 ² cfu/g Escherichia coli: None Total aerobic bacteria count (TAMC) ≤ 10 cfu/g Total yeast and mold count (TYMC) ≤ 10 cfu/g Escherichia coli: None Total aerobic bacteria count (TAMC) ≤ 10 cfu/g Total yeast and mold count (TYMC) ≤ 10 cfu/g Escherichia coli: None

[Table 11-2] Stability of 100 mg capsules of DFP-11207 in the second formulation under accelerated conditions (25°C/60RH) test method specifications 8 months 9 months 12 months 18 months 24 months Analysis date 2020/12/04 2021/01/04 Exterior ATM-1095 white, off-white or cream off-white off-white purity ATM-1349 90.0～110.0% 101.9% 104.3% similar substances ATM-1349 Individual: Measured value ≥ 0.1% (% area) Overall: Measured value Similar substance 2: 0.1% Similar substance 1: 0.1% Impurity 1: 0.4% Impurity 2: 0.9% RRT 0.81: 0.2% Impurity 3: 1.0% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.94: 0.1% RRT 1.04: 0.2% Impurity 4: 0.4% RRT 1.32: 0.2% Overall: 3.9% Similar substance 2: 0.2% Similar substance 1: 0.1% Impurity 1: 0.6% Impurity 2: 1.0% RRT 0.81: 0.2% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.1% RRT 1.04: 0.2% Impurity 4: 0.4% Overall: 3.6% moisture content USP <921> Ia measured value 1.5% 1.7% disintegration time USP<701> Determining the mean 1:50, 1:46, 1:52, 1:58, 2:10, 2:15 Average: 1:59 1:19, 1:29, 1:41, 1:50, 1:59, 2:19 Average: 1:46 microbial content USP<61>USP<62> Total aerobic bacteria count (TAMC) ≤ 10 ³ cfu/g Total yeast and mold count (TYMC) ≤ 10 ² cfu/g Escherichia coli: None

Furthermore, Table 12-1 and Table 12-2 show the interim data of the stability test under severe conditions (30° C./humidity 65%) of the 100 mg capsule preparation of DFP-11207 of the second formulation.

As shown in the results, the stability over 9 months can be predicted at least. Significant improvement was confirmed compared to the stability time (3 months) of the 100 mg capsule formulation of DFP-11207 of the first formulation under severe conditions (30°C/humidity 65%).

[Table 12-1] Stability of 100 mg capsules of DFP-11207 in the second formulation under severe conditions (30°C/65%RH) test method specification 0 months 1 month 2 months 3 months 6 months Analysis date 2020/05/01 2020/06/01 2020/06/01 2020/10/02 Exterior ATM-1095 white, off-white or cream off-white off-white off-white off-white off-white purity ATM-1349 90.0～110.0% 100.3% 101.7% 102.2% 104.1% 99.8% similar substance ATM-1349 Individual: Measured value ≥ 0.1% (% area) Overall: Measured value Impurity 1: 0.1% Impurity 2: 0.3% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.2% RRT 0.93: 0.2% RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% RRT 1.53: 0.1% Overall: 2.3% Similar substance 2: 0.1% RRT 0.50: 0.1% Impurity 1: 0.2% Impurity 2: 0.5% RRT 0.81: 0.1% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.90: 0.1% RRT 0.91: 0.2% RRT 0.93: 0.1 % RRT 0.94: 0.1% RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% RRT 1.48: 0.1% Overall: 2.9% Similar substance 2: 0.2% Similar substance 1: 0.1% Impurity 1: 0.1% Impurity 2: 0.7% RRT 0.81: 0.2% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.88: 0.1% RRT 0.90: 0.2% RRT 0.91: 0.2% RRT 0.93: 0.1% RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% Overall: 3.2% Similar substance 2: 0.1% Similar substance 1: 0.1% Impurity 1: 0.2% Impurity 2: 0.8% RRT 0.81: 0.1% Impurity 3: 0.5% RRT 0.87: 0.1% RRT 0.88: 0.1% RRT 0.90: 0.2% RRT 0.91: 0.2% RRT 0.93: 0.1% RRT 1.04: 0.1% Impurity 4: 0.4% RRT 1.31: 0.1% RRT 1.32: 0.1% Overall: 3.2% Similar substance 2: 0.3% Similar substance 1: 0.2% Impurity 1: 0.4% Impurity 2: 1.8% RRT 0.81: 0.3% Impurity 3: 0.5% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.2% RRT 1.04: 0.2% Impurity 4: 0.4% RRT 1.32: 0.1% Overall: 4.6% moisture content USP <921> Ia measured value 1.4% 1.6% 2.2% 1.8% 1.9% disintegration time USP<701> Determining the mean 1:56, 2:18, 1:58, 1:46, 1:54, 2:29 Average: 2:04 1:50, 2:26, 2:38, 2:02, 1:58, 2:10 Average: 2:11 1:47, 1:56, 1:25, 2:08, 1:37, 2:14 Average: 1:51 2:09, 1:32, 1:38, 1:50, 2:06, 2:13 Average: 1:55 0:59, 1:16, 1:21, 1:28, 1:34, 1:41 Average: 1:23 microbial content USP<61>USP<62> Total aerobic bacteria count (TAMC) ≤ 10 ³ cfu/g Total yeast and mold count (TYMC) ≤ 10 ² cfu/g Escherichia coli: None Total aerobic bacteria count (TAMC) ≤ 10 cfu/g Total yeast and mold count (TYMC) ≤ 10 cfu/g Escherichia coli: None Total aerobic bacteria count (TAMC) ≤ 10 cfu/g Total yeast and mold count (TYMC) ≤ 10 cfu/g Escherichia coli: None

[Table 12-2] Stability of 100 mg capsules of the second formulation of DFP-11207 under severe conditions (30°C/65%RH) test method specifications 9 months 12 months Analysis date 2021/01/04 Exterior ATM-1095 white, off-white or cream off-white purity ATM-1349 90.0～110.0% 98.4% similar substance ATM-1349 Individual: Measured value ≥ 0.1% (% area) Overall: Measured value Similar substance 2: 0.6% RRT 0.35: 0.1% Similar substance 1: 0.3% Impurity 1: 1.1% Impurity 2: 2.9% RRT 0.74: 0.1% RRT 0.81: 0.3% Impurity 3: 0.5% RRT 0.90: 0.1% RRT 0.91: 0.1% RRT 0.93: 0.2% RRT 1.04: 0.3% Impurity 4: 0.4% RRT 1.31: 0.1% Overall: 7.1% moisture content USP <921> Ia measured value 1.7% disintegration time USP<701> Determining the mean 1:13, 1:28, 1:36, 1:46, 1:59, 2:08 Average: 1:41 microbial content USP<61>USP<62> Total aerobic bacteria count (TAMC) ≤ 10 ³ cfu/g Total yeast and mold count (TYMC) ≤ 10 ² cfu/g Escherichia coli: None

On the other hand, Table 13 shows the results of the stability test of the DFP-11207 bulk drug which does not have a capsule preparation form. The drug substance of DFP-11207 meets the specifications of the drug substance with a stability time of less than 3 months under accelerated conditions (25°C/humidity 60%). The stability time to meet the specifications of the preparation under accelerated conditions (25°C/humidity 60%) is 6 months, and the stability time of the second formulation of the capsule preparation of DFP-11207 to meet the specifications of the preparation is For more than 9 months, the drug substance of DFP-11207 is not stable compared with the preparation of the first formulation of the capsule formulation of DFP-11207 and the formulation of the second formulation of the capsule formulation of DFP-11207.

[Table 13] The results of the stability test of the API of DFP-11207 at 25°C/60% humidity test project specifications Result ( after 3 months ) Qualified or not Exterior off-white to light yellow off-white qualified Purity (% area) ≥96.0% 94.0% unqualified Similar substances (% area) Individual impurities: ≤1.0% relative dissolution time %area unqualified 0.30 0.27% Similar substance-1 (RRT 0.42) 0.18% Impurity 1 (RRT 0.49) 0.73% Impurity 2 (RRT 0.74) 2.13% 0.80 0.21% Impurity 3 (RRT 0.83) 0.49% 0.88 0.07% 0.89 0.05% 0.90 0.10% 0.92 0.15% 0.93 0.13% 0.94 0.05% 1.03 0.22% Impurity 4 (RRT 1.13) 0.86% 1.29 0.06% 1.30 0.09% All impurities: ≦4.0% 5.8% unqualified moisture content ≤0.5% 0.2% qualified [Industrial availability]

According to the present invention, DFP-11207, which is sensitive to humidity and has concerns about long-term stable storage at room temperature and humidity, can be stored stably by a previously unknown novel formulation method. As a result, DFP-11207 products are expected to be stably supplied to the pharmaceutical market after they are approved to be manufactured and sold as pharmaceuticals. In addition, it can be stored for a long time in general hospitals treating cancer patients, and there is no concern about transportation. Furthermore, excellent stability is achieved, and cancer patients can be stored at room temperature (25°C/humidity 50%) or in a refrigerator (5°C) at home, etc. , observe the status of cancer patients, and prescribe medicines every 1 month). The present invention can provide excellent products of DFP-11207, so it is of great benefit in the pharmaceutical industry.

Claims (9)

A capsule for treating cancer comprising 5-chloro-2-(3-(3-(ethoxymethyl)-5-fluoro-2,6-dioxo-1,2,3,6- Tetrahydropyrimidine-1-carbonyl)benzoyloxy)pyridin-4-yl-2,6-bis(propionyloxy)isonicotinate (DFP-11207) or a pharmaceutically acceptable salt thereof, and Hygroscopic agent. As the capsule of claim 1, wherein the hygroscopic agent is colloidal silicon dioxide and microcrystalline cellulose. The capsule of claim 1, which contains 25-65% by weight of DFP-11207 or its pharmaceutically acceptable salt, 35-75% by weight of microcrystalline cellulose, and 2-5% by weight of colloidal silicon dioxide. The capsule according to claim 1, which contains 100 mg of DFP-11207 or a pharmaceutically acceptable salt thereof. The capsule as claimed in item 1, wherein the film-coating base of the capsule comprises hydroxypropylmethylcellulose. As the capsule of claim 1, it is the size of No. 2 capsules to No. 00 capsules. The capsule according to any one of claims 1 to 6, which is in the form of being housed in a container together with a desiccant. A method for manufacturing capsules for treating cancer, comprising filling capsules with 5-chloro-2-(3-(3-(ethoxymethyl)-5-fluoro-2,6-dioxo-1 ,2,3,6-tetrahydropyrimidine-1-carbonyl)benzoyloxy base) pyridin-4-yl-2,6-bis(propionyloxy)isonicotinate (DFP-11207) or a pharmaceutically acceptable salt thereof, and a hygroscopic agent. The manufacturing method according to claim 8, which further includes the step of storing the manufactured capsules together with a desiccant in a container.