Idelalisib-containing solid preparation for oral administration, and preparation method therefor

Abstract

The present invention relates to a solid preparation for oral administration, and a preparation method therefor, the solid preparation comprising Idelalisib, a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrant.

Description

Solid oral dosage form containing idelalisib and method for manufacturing the same

[0001] The present invention relates to a solid oral dosage form containing idelalisib or a pharmaceutically acceptable salt thereof and a method for producing the same.

[0002] The chemical name of Idelalisib is 5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4(3H)-one, and the compound and its preparation method are described in International Publication No. WO2005 / 113556.

[0003] Idelalisib was developed as a PI3Kδ (phosphoinositide-3-kinaseδ) inhibitor and was approved by the US FDA in 2014 and is marketed as Zydelig by Gilead. ® It was launched under the trade name idelalisib and is prescribed in several countries, including the United States, Europe, the United Kingdom, Canada, Australia, New Zealand, and Switzerland, as a treatment for relapsed chronic lymphocytic leukemia (CLL) in combination with rituximab, and as a treatment for relapsed follicular B-cell non-Hodgkin lymphoma (FL) as a single agent. In addition, it has been reported that idelalisib exhibits an anticancer effect in hepatocellular carcinoma with overexpression of PI3Kδ by specifically inhibiting PI3Kδ activity and inactivating the ROS→PI3Kδ→pAKT→TERT signaling pathway.

[0004] A key aspect of drug development is to provide high bioavailability of the active pharmaceutical ingredient and predictable and reproducible pharmacokinetic properties. Active pharmaceutical ingredients can exist in various solid forms. At least seven polymorphs of idelalisib have been reported. Idelalisib Form I is known to be partially and readily converted to Form II under the pressure conditions typical of tablet manufacturing. Both Idelalisib Forms I and II have very low solubility (approximately 70 mg / L at pH 6.8) and poor overall solubility. The commercially available idelalisib, Zydelic, is a ® It contains a mixture of types I and II.

[0005] Different polymorphs of an active pharmaceutical ingredient can have different solubilities. If the active pharmaceutical ingredient in a pharmaceutical product contains polymorphs or is converted to different forms during the formulation process or storage, the in vivo profile of the drug substance becomes unpredictable, and bioavailability becomes unreproducible.

[0006] Therefore, there is a need to develop a novel idelalisib tablet that has predictable and reproducible pharmacokinetic properties, improved dissolution characteristics, and enhanced in vivo absorption without being affected by gastrointestinal pH.

[0007] An object of the present invention is to provide a solid oral dosage form comprising idelalisib or a pharmaceutically acceptable salt thereof, which has a predictable and reproducible dissolution rate and an improved dissolution rate.

[0008] Another object of the present invention is to provide a composition comprising a solid preparation for oral administration comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrating agent.

[0009] Another object of the present invention is to provide a treatment method comprising a step of administering to a subject in need thereof a solid oral dosage form comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrating agent.

[0010] Another object of the present invention is to provide a therapeutic use of a solid oral dosage form comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrating agent.

[0011] In addition, another object of the present invention is to provide a method for producing the above solid preparation for oral administration.

[0012] The solid oral dosage form of the present invention for achieving the above-mentioned purpose comprises idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a disintegrating agent.

[0013] Among the above oral solid formulations, idelalisib may exist in an amorphous form.

[0014] The above solid preparation for oral administration may contain 6 to 25 parts by weight of an acidifying agent and 15 to 70 parts by weight of a disintegrating agent per 100 parts by weight of the idelalisib or a pharmaceutically acceptable salt thereof.

[0015] The above acidifying agent may be at least one selected from the group consisting of fumaric acid, acetic acid, lactic acid, malic acid, maleic acid, formic acid, propionic acid, butyric acid, oxalic acid, succinic acid, pyruvic acid, sorbic acid, salicylic acid, carbonic acid, adipic acid, ascorbic acid, citric acid, and tartaric acid.

[0016] The above disintegrant may be at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, calcium carboxymethylcellulose, and sodium carboxymethylcellulose.

[0017] The above disintegrant may be a mixture of croscarmellose sodium and sodium starch glycolate in a weight ratio of 1:0.5-5.

[0018] The above idelalisib or a pharmaceutically acceptable salt thereof may have a volume weighted median diameter (D50) of 10 to 50 μm.

[0019] The above solid preparation for oral administration may further comprise 50 to 140 parts by weight of an excipient, 3 to 15 parts by weight of a binder, or 0.5 to 5 parts by weight of a lubricant, per 100 parts by weight of the idelalisib or a pharmaceutically acceptable salt thereof.

[0020] The above solid preparation for oral administration may be an immediate-release tablet or an enteric-coated tablet.

[0021] When the above oral solid preparation is tested by rotating the tablet at 50 revolutions per minute under conditions of 37±0.5℃ using a pH 1.2 dissolution test solution, a pH 4.0 dissolution test solution, a pH 6.8 dissolution test solution, and 900 ml of purified water according to the second method (paddle method) of the dissolution test items of the United States Pharmacopoeia (USP) or the Korean Pharmacopoeia (KP), idelalisib or its pharmaceutically acceptable salt can be dissolved by 80% or more in all of the test solutions within 45 minutes.

[0022] In addition, the composition of the present invention for achieving the other purposes mentioned above may include a solid preparation for oral administration containing idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a disintegrating agent.

[0023] The above composition may be a pharmaceutical composition for treating or improving a disease or condition caused by PI3Kδ overexpression or overactivation.

[0024] In addition, the treatment method of the present invention for achieving another purpose mentioned above may include a step of administering to a subject in need thereof a solid oral dosage form comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a disintegrating agent.

[0025] In addition, the therapeutic use of the present invention to achieve another purpose described above may be the therapeutic use of an oral solid formulation comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a disintegrating agent.

[0026] In addition, the method for manufacturing a solid preparation for oral administration of the present invention for achieving another object mentioned above may include 1) a granulation step of mixing idelalisib or a pharmaceutically acceptable salt thereof; an acidifying agent; and a disintegrating agent to manufacture granules; 2) a sizing step of drying and milling the granulated granules to manufacture a spheroid; 3) a lubricating step of mixing a lubricant into the spheroid; and 4) a tableting step of compressing the spheroid mixture into tablets.

[0027] The above step 1) can manufacture granules by further including one or more pharmaceutical additives selected from the group consisting of excipients and binders.

[0028] The types and contents of idelalisib, acidifying agent, disintegrating agent, excipient, binder or lubricant in the above oral administration solid formulation are as defined above.

[0029] The oral solid dosage form of the present invention improves dissolution characteristics by including idelalisib, an acidifying agent, and a disintegrating agent, thereby dissolving idelalisib by more than 80% within 45 minutes in both dissolution test solutions of pH 1.2, pH 4.0, and pH 6.8 and purified water. Therefore, it can be provided as an enteric-coated tablet as well as an immediate-release tablet, can increase bioavailability, and can provide a predictable and reproducible in vivo profile.

[0030] In addition, the solid oral dosage form of the present invention exhibits almost no phase change of idelalisib or production of volatile substances even when stored for a long period of time, for example, 12 weeks or more, and exhibits excellent stability even under harsh conditions of high humidity and temperature.

[0031] Figure 1 is a graph measuring the particle size distribution of idelalisib used as an active pharmaceutical ingredient of the present invention.

[0032] FIG. 2a is an X-ray diffraction (XRD) result of idelalisib, an active pharmaceutical ingredient of the present invention; FIG. 2b is an XRD result of a mixture in which each component included in the tablet is mixed in the content ratio of Example 5; FIG. 2c is an XRD result of an initial product of the tablet of Example 5 of the present invention; FIG. 2d is an XRD result of a 3-month accelerated test (40±2°C, 75±5%RH, sealed, stored for 3 months) for the tablet of Example 5 of the present invention; and FIG. 2e is an XRD result of a 3-month accelerated test (40±2°C, 75±5%RH, sealed, stored for 3 months) for the tablet of Comparative Example 1.

[0033] Figure 3 is a graph showing the results of a dissolution test performed on the tablets of Example 5 and Examples 9 to 11 of the present invention in a dissolution test solution (pH 1.2, 4.0, 6.8, and purified water) according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia.

[0034] Figure 4 shows the tablet and Zydelic of Example 11 of the present invention. ® This is the result of evaluating the dissolution rate by adding 900 mL of dissolution test solution according to the 2nd method of the dissolution test method of the Korean Pharmacopoeia (paddle method) and rotating 50 times per minute (50 rpm) at 37±0.5℃; (a) pH 1.2 dissolution test solution, (b) pH 4.0 dissolution test solution, and (c) pH 6.8 dissolution test solution.

[0035] Figure 5a shows the results of the treatment of Example 11 of the present invention with Zydelic in a male beagle dog. ® This is a graph of the mean plasma concentration-time curve of Idelalisib (n=12), and Fig. 5b shows the results of the tablet of Example 11 of the present invention and Zydelic in a male beagle dog. ® This is a log-linear graph of the mean plasma concentration versus time of idelalisib (n=12).

[0036] The present invention relates to a solid oral dosage form containing idelalisib or a pharmaceutically acceptable salt thereof and a method for producing the same.

[0037] Hereinafter, the present invention will be described in detail.

[0038] The solid oral dosage form of the present invention comprises idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a disintegrating agent, thereby improving dissolution characteristics and long-term stability, enhancing bioavailability, and providing a predictable and reproducible in vivo profile.

[0039] Idelalisib, the active pharmaceutical ingredient of the present invention, has poor flowability and solubility, dissolving only in strongly acidic environments. Furthermore, its crystalline form can change under pressure, heat, and moisture. Therefore, its physical properties must be improved to increase idelalisib's bioavailability and long-term stability, and to enable prediction and reproduction of its in vivo profile.

[0040] According to the present invention, idelalisib in the solid formulation for oral administration exists in an amorphous state, and the volume weighted median diameter (D50) of the particles may be 10 to 50 ㎛, preferably 15 to 20 ㎛, the D10 (10% cumulative particle size distribution) may be 0.5 to 5 ㎛, and the D90 (90% cumulative particle size distribution) may be 150 to 210 ㎛. When idelalisib and a pharmaceutically acceptable salt thereof are formulated into a solid formulation, when the particle size is in the above range, the dissolution rate is improved, and the area under the blood concentration-time curve (AUC) and the peak blood concentration (C) are improved. max ) is desirable because it can improve the fineness, and if it is finer than the above range, it can cause process failure during tableting.

[0041] In addition, the acidifying agent is used in an amount of 6 to 25 parts by weight, preferably 9 to 20 parts by weight, based on 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof. If the content of the acidifying agent is less than the lower limit, it is difficult to dissolve idelalisib by 80% or more even 60 minutes after the start of dissolution in an environment exceeding pH 2, and if it exceeds the upper limit, it may interfere with the function of the disintegrant or excipient, thereby lowering the dissolution rate, and a sticking phenomenon (a phenomenon in which the composition sticks to the machine) may occur in the solid dosage form production process, which is undesirable.

[0042] The solid preparation for oral administration according to the present invention can significantly increase the dissolution rate of idelalisib, a poorly soluble drug, due to the inclusion of an acidifying agent, thereby increasing bioavailability. In one embodiment, the solid preparation for oral administration is a solid preparation that dissolves idelalisib or a pharmaceutically acceptable salt thereof by 80% or more in all test solutions within 45 minutes when a test is performed using a pH 1.2 dissolution test solution, a pH 4.0 dissolution test solution, a pH 6.8 dissolution test solution, and 900 ml of purified water according to the second method (paddle method) of the dissolution test items of the United States Pharmacopoeia (USP) or the Korean Pharmacopoeia (KP) at 50 rotations per minute under conditions of 37±0.5°C. As a result of the test, the oral solid dosage form containing an acidifying agent showed a significantly increased dissolution rate of the active ingredient in the dissolution test solutions of pH 1.2, pH 4.0 and pH 6.8 compared to the case without an acidifying agent, and Zydelic ® Compared to the original, improved dissolution characteristics, area under the blood concentration-time curve (AUC) and peak blood concentration (C) max ) was shown.

[0043] The solid preparation for oral administration according to the present invention can be provided as an enteric-coated tablet as well as an immediate-release tablet because it exhibits a dissolution rate of idelalisib of 80% or more within 45 minutes in both pH 1.2, 4.0, and 6.8 dissolution test solutions and distilled water.

[0044] The solid preparation for oral administration according to the present invention can significantly increase the long-term stability of idelalisib due to the inclusion of an acidifying agent. According to one embodiment of the present invention, in the solid preparation not including an acidifying agent, after a 3-month accelerated test (40±2℃, 75±5%RH; RH: Relative Humidity, sealed, stored for 3 months), it was observed in an XRD examination that some of the amorphous idelalisib was converted to crystalline Form I. However, in the solid preparation including an acidifying agent according to the present invention, the conversion rate from amorphous to crystalline form was almost zero, and thus it was confirmed that the long-term stability was excellent.

[0045] The acidifying agent may be an organic or inorganic acid having a molecular weight of 40-200 g / mol and a pKa value of 1.0-5.0 at 25°C; preferably, it may be an organic or inorganic acid having a molecular weight of 45-150 g / mol and a pKa value of 2.0-4.0 at 25°C. A solid preparation containing an acidifying agent having a molecular weight and pKa value within the above range did not produce any volatile substances during long-term storage and was particularly excellent in improving dissolution rate.

[0046] Such acidifying agents include at least one selected from the group consisting of fumaric acid, acetic acid, lactic acid, malic acid, maleic acid, formic acid, propionic acid, butyric acid, oxalic acid, succinic acid, pyruvic acid, sorbic acid, salicylic acid, carbonic acid, adipic acid, ascorbic acid, citric acid and tartaric acid; preferably, at least one selected from the group consisting of fumaric acid, lactic acid, malic acid, formic acid, pyruvic acid, salicylic acid and carbonic acid.

[0047] In addition, the disintegrant may be at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, calcium carboxymethylcellulose, and sodium carboxymethylcellulose; preferably, it may be a mixture of croscarmellose sodium and sodium starch glycolate; more preferably, it may be a mixture of croscarmellose sodium and sodium starch glycolate in a weight ratio of 1:0.5-5; and even more preferably, it may be a mixture of croscarmellose sodium and sodium starch glycolate in a weight ratio of 1:1.5-2.5.

[0048] In one embodiment, a solid dosage form comprising both croscarmellose sodium and sodium starch glycolate as disintegrants exhibits particularly excellent dissolution rates. The disintegrant may be included in an amount of 15 to 70 parts by weight, preferably 25 to 60 parts by weight, relative to 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof. When included within the above range, it is particularly easy to achieve the dissolution rate targeted by the present invention.

[0049] The solid oral dosage form of the present invention may further include, in addition to idelalisib, an acidifying agent, and a disintegrating agent, a pharmaceutically acceptable excipient, binder, or lubricant.

[0050] The above excipient is particularly preferable for not reacting with idelalisib, improving the flowability of the solid dosage form, and achieving the desired dissolution rate, and specifically includes at least one selected from the group consisting of microcrystaline cellulose, corn starch, potato starch, lactose hydrate, calcium orthophosphate, and potassium phosphate.

[0051] The above excipient may be used in an amount of 50 to 140 parts by weight, preferably 80 to 140 parts by weight, per 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof.

[0052] In addition, the binder may be at least one selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, carbomer, carrageenan, xanthan gum, and guar gum, and may be included in an amount of 3 to 15 parts by weight, preferably 5 to 12 parts by weight, based on 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof.

[0053] In addition, the lubricant may be at least one selected from the group consisting of magnesium stearate, sodium stearate, sodium stearyl fumarate, glyceryl behenate, talc, and silicon dioxide, and may be included in an amount of 0.5 to 5 parts by weight, preferably 1 to 4 parts by weight, based on 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof. If the content of the lubricant is less than the above range, it may cause tableting problems, which may not be suitable for productivity, and if it exceeds the upper limit, a delay in dissolution may occur.

[0054] In addition, in order to achieve the other objects mentioned above, the present invention provides a composition comprising an oral solid preparation comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrating agent as an active ingredient.

[0055] The above composition may be a pharmaceutical composition for treating or improving a disease or condition caused by overexpression or overactivation of phosphatidylinositol-3-kinase δ (PI3Kδ).

[0056] In addition, to achieve another object mentioned above, the present invention provides a method for treating a disease or condition caused by PI3Kδ overexpression or overactivation, comprising the step of administering to a subject in need thereof a solid oral dosage form comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrating agent.

[0057] The term "subject" refers to a mammal, preferably a human, that is the object of prevention, treatment, observation or experiment.

[0058] In addition, in order to achieve another object mentioned above, the present invention provides a therapeutic use of a solid oral dosage form comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrating agent.

[0059] The above therapeutic use may be for the treatment of a disease or condition caused by PI3Kδ overexpression or overactivation.

[0060] The solid oral dosage form of the present invention can be used as a drug for preventing, treating, or improving a disease or condition caused by overexpression or overactivation of phosphatidylinositol-3-kinase δ (PI3Kδ). PI3Kδ has been suggested to be involved in proliferation or survival signaling in cancer, inflammatory, or autoimmune diseases, and PI3Kδ has been utilized as a target for treating such diseases (U.S. Patent Nos. 6,800,620; 8,435,988; 8,673,906; 9,133,168).

[0061] In some embodiments, the disease or condition caused by PI3Kδ overexpression or overactivation is selected from the group consisting of activated PI3Kδ syndrome, rheumatism, osteoarthritis, atherosclerosis, psoriasis, eczema, rhinitis, systemic lupus erythematosus, multiple sclerosis, inflammatory diseases, asthma, chronic obstructive airway disease, pneumonitis, dermatitis, alopecia, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, hepatitis, primary biliary cirrhosis, sclerosing cholangitis, diabetes (including type I diabetes), acute rejection of a transplanted organ, lymphoma, multiple myeloma, hematological malignancies, tumors and combinations thereof, preferably activated PI3Kδ syndrome, liver cancer, hepatocellular carcinoma, B-cell positive tumor, chronic lymphocytic leukemia, asthma, allergic rhinitis, chronic obstructive pulmonary disease, rheumatism, inflammatory diseases, lupus erythematosus, multiple sclerosis, May be selected from the group consisting of, but not limited to, psoriasis, eczema and combinations thereof.

[0062] The term "inhibition of PI3Kδ hyperactivation" refers to a decrease in PI3Kδ activity, either directly or indirectly, in the presence of a compound described herein, compared to the activity of PI3Kδ in the absence of such compound. In some embodiments, the inhibition of PI3Kδ activity can be compared to the same subject prior to treatment, or to another subject who has not received the treatment.

[0063] The oral solid dosage form of the present invention may contain idelalisib or a pharmaceutically acceptable salt thereof in a dosage of 5 to 300 mg / tablet. In one embodiment, the oral solid dosage form of the present invention contains idelalisib or a pharmaceutically acceptable salt thereof in a dosage of 10 to 250 mg / tablet. In another embodiment, the oral solid dosage form of the present invention contains idelalisib or a pharmaceutically acceptable salt thereof in a dosage of 20 to 200 mg / tablet. In yet another embodiment, the oral solid dosage form of the present invention contains 25, 50, 75, 100, and 150 mg.

[0064] As used herein, "pharmaceutically acceptable salt" means a formulation of a compound that does not cause serious irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound, unless otherwise defined. The pharmaceutically acceptable salt includes acid addition salts formed by acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid; organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts such as lysine, arginine, guanidine, etc.; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine, etc. Idelalisib according to the present invention can also be converted into its salt by conventional methods.

[0065] In addition, the above pharmaceutical composition may be prepared as a pharmaceutical composition by additionally including one or more pharmaceutically acceptable carriers in addition to the above-described effective ingredients for administration.

[0066] Pharmaceutically acceptable carriers that can be used in the present disclosure are those commonly used in formulations. Examples of such pharmaceutically acceptable carriers include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. The pharmaceutical compositions of the present disclosure may further comprise one or more additives selected from the group consisting of lubricants, wetting agents, sweetening agents, flavoring agents, emulsifying agents, suspending agents, and preservatives. Details of suitable pharmaceutically acceptable carriers and formulations can be found in Remington's Pharmaceutical Sciences (19th ed., 1995).

[0067] In addition, in order to achieve the above-mentioned another object, the present invention provides a method for producing a solid preparation for oral administration, comprising: 1) a granulation step of mixing idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a disintegrating agent to produce granules; 2) a sizing step of drying and milling the granulated granules to produce a spheroid; 3) a lubricating step of mixing a lubricant into the spheroid; and 4) a tableting step of compressing the spheroid mixture into tablets.

[0068] In addition, the step 1) above may further include one or more pharmaceutical additives selected from the group consisting of excipients and binders to manufacture granules.

[0069] Specifically, idelalisib or a pharmaceutically acceptable salt thereof; an acidifying agent; a disintegrating agent; and optionally one or more pharmaceutical additives selected from excipients and binders are weighed and sieved to 10 to 30 mesh, preferably 15 to 25 mesh. The sieved components are mixed and a binder, such as purified water, is added to knead the mixture to prepare granules (granulation).

[0070] Next, the granulated granules are dried, and it is preferable that the drying loss is less than 1.5%. Next, the dried material is milled using a conical mill to produce a granulated material. The size of the granulated material may be 10 to 30 mesh, preferably 15 to 25 mesh, and a size within the above range is preferable because the dissolution rate is fast and the dissolution is easy.

[0071] Next, add a lubricant to make it lubricant and then press it into a tablet.

[0072] The types and contents of the above idelalisib, acidifier, disintegrant, excipient, binder and lubricant are the same as defined above.

[0073] The terms "have", "may have", "contains", "includes" or "may include" indicate the presence of a feature (e.g., a numerical value, or a component such as an ingredient) and do not exclude the presence of additional features.

[0074] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only illustrative of the present invention, and it is obvious to those skilled in the art that various changes and modifications are possible within the scope and technical idea of ​​the present invention, and it is also natural that such changes and modifications fall within the scope of the appended patent claims.

[0075] Examples 1 to 11 and Comparative Examples 1 to 3

[0076] Idelalisib (Zhejiang Lepu Pharmaaceurical co. LTD; China), acidifier (fumaric acid: Fumaric acid EMPROVE, Merck), disintegrant (croscarmellose sodium: VIVASOL, JRS Pharma; sodium starch glycolate: Explotab, JRS Pharma), excipient (microcrystalline cellulose: VIVAPUR 101, JRS Pharma), and binder (hydroxypropyl cellulose: NISSO HPC-L, Nippon Soda) were weighed according to [Table 2] and [Table 3], sieved to 20 mesh, mixed, and then a binder (purified water) was added and kneaded to form granules. The granules were dried in an oven at 70°C to a loss on drying of 2% or less, and then sieved to 20 mesh using a conical mill. A lubricant (magnesium stearate, Merck; 40 mesh) was mixed into the suspension and lubricated for 5 minutes. The lubricant was compressed into tablets using a rotary tablet press equipped with a concave punch to produce wet granule tablets (uncoated tablets, solid preparations). The specifications of the compressed tablets are as shown in [Table 1] below. Film-coated tablets were manufactured by coating uncoated tablets using a coating agent (Opadry II 85F18422) and purified water in a tablet coater.

[0077] Since the idelalisib used as a raw material in the present invention was confirmed to contain 4.5% moisture in a moisture content test using a moisture measurement method (Karl Fischer method), it was added by increasing the amount by 4% by weight to correct the moisture content during tablet manufacturing.

[0078] Specification Diameter (mm) Mass (mg) Thickness (mm) Hardness (kp) 16.07 7.0±1.0 2.5-2.8 6.0-8.0 27.0 120.0±2.0 3.3-3.6 6.0-8.0 39.0 200.0±2.0 3.5-4.0 6.0-8.0 49.0 240.0±2.0 4.1-4.6 6.0-8.0 510.0 360.0±3.0 4.9-5.2 8.0-10.0

[0079] Content (mg) Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Example 3 Example 4 Idelalisib 104 104 104 104 104 104 104 104 Microcrystalline Cellulose 76 71 86 58 789 888 Hydroxypropyl Cellulose 66 66 666 Fumaric Acid-5 10 10 10 10 20 Croscarmellose Sodium 66 6 10 10 10 10 Sodium Starch Glycolate 66 6 10 10 10 10 Magnesium Stearate 2 2 2 2 2 Total Weight (mg / Tablet) 20 0 20 0 22 0 20 0 22 0 24 0 24 0

[0080] Content (mg) Example 5 Example 6 Example 7 Example 8 Example 10 Example 11 Idelalisib 104 104 104 104 104 26 5 2 1 5 6 Microcrystalline cellulose 8 8 8 8 8 8 8 3 5.7 4 4 1 3 2 Hydroxypropyl cellulose 6 6 6 1.9 3 9 Fumaric acid 10 10 10 10 3.2 5 1 5 Croscarmellose sodium 10 3 0 15-3.2 5 1 5 Sodium starch glycolate 20-15 3 0 6.4 1 0 3 0 Magnesium stearate 22 2 20.6 1 3 Total weight (mg / tablet) 240 240 240 240 77 120 360

[0081] <Example of an exam>

[0082] The results of this experiment were analyzed using the statistical program SPSS (Statistical package for social science version 25.0, SPSS Inc., Chicago, IL, USA), and the measurement results of each experimental item were expressed as the mean ± standard deviation (mean ± SD). The mean difference between groups was confirmed using one-way ANOVA, and statistical significance was tested using Duncan's test at the P < 0.05 level.

[0083] Test Example 1. Evaluation of raw material properties

[0084] The appearance, moisture content, particle size, and crystallographic properties of idelalisib raw material were evaluated. Idelalisib is an odorless white powder, and the moisture content test according to the Korean Pharmacopoeia moisture measurement method (Karl Fischer method) was evaluated to contain 4.5% moisture. The spectroscopic properties were confirmed by a UV-Vis spectrometer and it was confirmed to have a maximum absorption wavelength at 270 nm. The particle size was analyzed by laser diffraction, and the crystallographic properties were analyzed by X-ray diffraction (XRD) in the range of 0-60 (2-theta / °).

[0085] Figure 1 is a graph measuring the particle size distribution of idelalisib used as the active pharmaceutical ingredient of the present invention. It was confirmed that idelalisib had a particle size distribution of D50 (50% cumulative particle size, volume weighted median diameter) of 16.87 ㎛, D10 (10% cumulative particle size) of 2.06 ㎛, and D90 (90% cumulative particle size) of 201.12 ㎛.

[0086] Figure 2a shows the results of X-ray diffraction (XRD) analysis of the idelalisib raw material in the range of 0-60 (2-theta / °). Only a typical amorphous pattern was observed, and it was evaluated that no crystalline form was included.

[0087]

[0088] Test Example 2. Mixing Compatibility

[0089] The compatibility of idelalisib and five excipients (microcrystalline cellulose, isomalt, mannitol, lactose, and lactose monohydrate), three binders (hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone), three acidifiers (citric acid, fumaric acid, and tartaric acid), three disintegrants (croscarmellose sodium, crospovidone, and sodium starch glycolate), and three lubricants (magnesium stearate, sodium stearyl fumarate, and glyceryl behenate) was evaluated. 150 mg of each of the 17 additives was weighed and placed in a brown vial. 150 mg of idelalisib was added to each vial so that each additive and idelalisib were in a 1:1 weight ratio, and mixed for 5 minutes using a vortex mixer. Brown vials containing the idelalisib-additive mixture and brown vials containing only idelalisib were stored under long-term storage sealed (25±2℃, 60±5%RH, sealed), long-term storage opened (25±2℃, 60±5%RH, opened), accelerated storage sealed (40±2℃, 75±5%RH, sealed), and accelerated storage opened (40±2℃, 75±5%RH, opened) conditions, and after 4 weeks (28 days), the appearance, amount of flexible substances produced, and differential scanning calorimetry were evaluated compared to the time of preparation to confirm the compatibility and storage stability.

[0090] 2-1. Visual evaluation

[0091] No changes in color, appearance, or phase were observed in idelalisib and idelalisib-additive mixtures at the time of preparation or after 4 weeks under each condition.

[0092] 2-2. Evaluation of Impurities

[0093] The standard solution was prepared by placing 25 mg of idelalisib in a vial and diluting it to 500 ppm. The test solution was prepared by placing 200 mg of idelalisib-additive mixture (1:1 weight ratio) in a vial and diluting it to 4000 ppm. The dilution solution used was acetonitrile: purified water = 1:1 (v / v), and the high-performance liquid chromatography (HPLC) conditions are as follows [Table 4]. The criteria for flexible substances are that individual flexible substances should be 0.15% or less and total flexible substances should be 1.00% or less.

[0094]

[0095] The analysis of flexible substances was performed by HPLC and calculated according to the following [Mathematical Formula 1]. [Mathematical Formula 1]

[0096]

[0097] A t : Peak area A of flexible substances in the test solution s : Peak area of ​​idelalisib in the standard solution

[0098] W t : Sample amount (mg) W s : Idelalisib harvested dose (mg)

[0099] D t : Test solution dilution factor D s : Standard solution dilution factor

[0100] P: Idelalisib purity (%)

[0101] F: Relative reaction coefficient of the designated flexible substance

[0102] Idelariship: 1.00 (Relative Hold Time 1.00)

[0103] Flexible Material A (IDL-05): 1.00 (relative retention time 1.72)

[0104] Flexible substance B (Desfluoro): 1.00 (relative retention time 0.96)

[0105] Flexible Material C (IDL-04): 1.66 (relative retention time 0.39)

[0106] Flexible material D (IDL-03): 2.10 (relative retention time 0.75)

[0107]

[0108] As a result of checking the amount of generated reactive substances, the generation of reactive substances A, B, C, and D was not observed in idelalisib and idelalisib-additive mixtures. Meanwhile, unknown reactive substances were detected from all idelalisib and idelalisib-additive mixtures at a relative retention time (RRT) of 1.30, but the maximum detection amount was below the standard (0.15% or less). Therefore, the above-mentioned additives were evaluated to be compatible with idelalisib.

[0109]

[0110] 2-3. Differential scanning calorimetry (DSC) evaluation

[0111] The thermodynamic behavior of the mixture was evaluated using a differential scanning calorimeter (RCS40, TA Instrument). 3.0 mg of the sample at the time of preparation and after 4 weeks were placed in an aluminum pan for measurement, covered with an aluminum lid, compressed, and measured at a temperature ranging from 40 to 300°C at a rate of 5°C / min.

[0112] As a result, the idelalisib-povidone mixture and the idelalisib-crospovidone mixture showed changes in the endothermic peak after 4 weeks, and the idelalisib-mannitol, idelalisib-isomalt, and idelalisib-lactose mixtures were confirmed to have poor compatibility due to cross-reactivity with idelalisib.

[0113] The Idelalisib / additive mixture not mentioned above showed no significant difference after 4 weeks compared to the time of preparation, confirming its compatibility and storage stability.

[0114]

[0115] Test Example 3. Safety Evaluation

[0116] 3-1. Evaluation of flexible material production

[0117] For the tablets of Example 5 and Examples 9 to 11, the long-term stability was evaluated by measuring the amount of flexible substances produced after 6 months under the initial, long-term storage (25±2℃, 60±5%RH, sealed) and accelerated (40±2℃, 75±5%RH, sealed) conditions.

[0118] As a test solution, 10 tablets each of Example 5 and Examples 9 to 11 were taken, powdered, 200 mg of idelalisib was weighed, placed in a vial, and then diluted to a mark to prepare 2000 ppm, and a flexible substance test was conducted using the same method as the flexible substance evaluation method of Test Example 2.

[0119] Classification Example 5 Example 9 Example 10 11 Early long-term acceleration Early long-term acceleration Early long-term acceleration Flexible substances (%) ABLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODDBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLODBLOD Unknown 0.08 0.100 080 100 110 100 080 10 ...

[0120] BLOD: Below the Limit of Detection

[0121] As shown in [Table 5], the tablets of Examples 5 and 9 to 11 of the present invention showed long-term stability as almost no flexible substances were produced even after 6 months compared to the initial state.

[0122]

[0123] 3-2. X-ray diffraction analysis evaluation

[0124] The phase change from an amorphous form to another crystalline form of Idelalisib during the manufacturing process or storage was evaluated using an X-ray diffractometer (XRD), and the results are shown in Figure 2.

[0125] Figure 2a is an X-ray diffraction (XRD) result of idelalisib, an active pharmaceutical ingredient of the present invention; Figure 2b is an XRD result of a mixture (not compressed) in which each component included in the tablet is mixed in the content ratio of Example 5; Figure 2c is an XRD result of an initial product for the tablet of Example 5; Figure 2d is an XRD result of a 3-month accelerated test (40±2°C, 75±5%RH, 3-month storage) for the tablet of Example 5; and Figure 2e is an XRD result of a 3-month accelerated test (40±2°C, 75±5%RH, 3-month storage) for the tablet of Comparative Example 1.

[0126] In Figures 2a to 2d, idelalisib maintained an amorphous pattern, and no new peaks were observed, indicating that there was little change in the crystalline form. In contrast, in Figure 2e, peaks with 2Theta values ​​of singlet at 12° and doublet at 18° were observed to be generated. The two newly observed peaks were confirmed to be typical XRD characteristic peaks appearing in idelalisib crystalline Form I.

[0127] These results suggest that the solid formulation of the present invention has excellent long-term stability without changing its crystal form during the manufacturing process or storage, and that it is possible to predict the in vivo profile and reproduce bioavailability.

[0128]

[0129] Test Example 4. Evaluation of dissolution characteristics of solid preparations

[0130] 4-1. Dissolution characteristics test method

[0131] (1) Preparation of test solution

[0132] For each purified sample, add 900 mL of dissolution test solution (pH 1.2, 4.0, 6.8, and purified water) according to the Pharmaceutical Equivalence Test Standards (MFDS ​​Notice No. 2021-91) and the 2nd method of the Korean Pharmacopoeia (paddle method) and evaluate the dissolution rate by rotating 50 times per minute (50 rpm) at 37±0.5℃. Collect 5 mL of the dissolution solution at a total of 7 time points (10, 20, 30, 45, 60, 90, and 120 minutes) and use it as the test solution.

[0133] (2) Preparation of standard solution for calibration curve of dissolution test

[0134] Dissolve 100 mg of the raw material of idelalisib in 100 mL of methanol to prepare a standard stock solution, and dilute the standard stock solution with the elution test solution to prepare a standard solution for the calibration curve at five concentrations.

[0135] (3) Dissolution test analysis method

[0136] The absorbance of the standard solution and test solution for the calibration curve is measured using a 2 mm layer quartz cell at a wavelength of 270 nm according to the ultraviolet-visible spectrophotometry method, and then the dissolution rate of idelalisib is calculated according to the following [Mathematical Formula 2].

[0137] [Equation 2]

[0138]

[0139]

[0140] 4-2. Evaluation of elution characteristics

[0141] (1) Evaluation of dissolution characteristics of tablets of Test Example 1-11 and Comparative Example 1-3 (purified water)

[0142] The results of the dissolution rates of tablets according to Example 1-11 and Comparative Example 1-3 in purified water (water), which is the test solution with the lowest dissolution rate of idelalisib among the dissolution test solutions (pH 1.2, 4.0, 6.8 and purified water), are shown in [Table 6] below.

[0143] The dissolution rate of the idelalisib (%) (dissolution amount: Purified water) 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes Comparative example 1 20.3 ± 0.01 3 7.1 ± 0.01 4 6.9 ± 0.01 5 5.5 ± 0.01 6 1.1 ± 0.01 6 7.4 ± 0.01 7 1.0 ± 0.01 Comparative example 2 25.4 ± 0.01 3 8.9 ± 0.02 5 0.9 ± 0.02 6 2.9 ± 0.01 7 2.1 ± 0.01 8 4.4 ± 0.00 9 2.1 ± 0.00 Comparative example 3 36.5 ± 0.01 5 5.5 ± 0.00 6 3.0 ± 0.01 7 5.5 ± 0.02 8 1.8 ± 0.01 9 2.9 ± 0.01 9 7.5 ± 0.01 Example 1 42.5 ± 0.01 5 7 .1±0.0169.0±0.0280.0±0.0083.7±0.0191.7±0.0196.5±0.01Example 244.1±0.0161.7±0.0272.2±0.0182.8±0.0188.8±0.0297.1±0.0298.1±0.00Example 347.4±0.0166.5±0.0375.2±0.0284.1±0.0191.1±0.0199.1±0.0198.2±0.01Example 445.8±0.0162.4±0.0172.5±0.0183.7±0.0387.8±0.0295.6±0.0 499.1±0.02Example 558.8±0.0473.4±0.0180.0±0.0187.6±0.0293.8±0.01100.3±0.01100.8±0.01Example 647.1±0.0263.4±0.0272.6±0.0383.3±0.0187.8±0.0295.6±0.0196.8±0.01Example 754.5±0.0166.1±0.0175.6±0.0184.3±0.0291.9±0.0399.4±0.0299.5±0.01Example 851.3±0.0267.7±0.0174.9±0. 0183.1±0.0190.5±0.0197.7±0.0198.8±0.01Example 956.6±0.0175.4±0.0085.7±0.0190.4±0.0094.6±0.0298.8±0.02101.1±0.00Example 1049.7±0.0363.9±0.0374.0±0.0482.3±0.0389.5±0.0496.2±0.0498.6±0.06Example 1147.5±0.0264.8±0.0175.4±0.0083.9±0.0188.8±0.0197.4±0.03100.6±0.03

[0144] As shown in Table 6 above, the tablets of Examples 1 to 8 were confirmed to achieve the dissolution rate (80% or more within 45 minutes) targeted by the present invention. The tablets not containing an acidifying agent did not reach a dissolution rate of 80% even after 360 minutes from the start of dissolution (Comparative Example 1), and it was evaluated that the use of excessive acidifying agents had a minimal effect on improving the dissolution rate or may even lower the dissolution rate (compare Examples 3 and 4).

[0145] Tablets that did not use the disintegrant in the content of the present invention did not achieve the desired dissolution rate (Comparative Examples 2 and 3), and tablets containing both croscarmellose sodium and sodium starch glycolate as disintegrants had a better dissolution rate than tablets containing a single component of disintegrant, and in particular, when the content of starch glycolate was contained in a larger amount than that of croscarmellose sodium, specifically, when croscarmellose sodium and sodium starch glycolate were contained in a weight ratio of 1:2, the dissolution rate was particularly improved (compare Examples 5 to 8).

[0146]

[0147] (2) Evaluation of pharmaceutical equivalence of finished products with different contents

[0148] The oral solid dosage form of the present invention was developed with a standard dose of 100 mg of idelalisib, and Example 5 was selected as the final finished drug product. Oral solid dosage forms with different contents were developed at the AC level, which is the allowable range, according to the level of change in raw materials and dosage of the Pharmaceutical Equivalence Test Standards for General Preparations (Ministry of Food and Drug Safety Notice No. 2021-91) (Examples 9 to 11). The similarity of dissolution profiles is determined by comparing using the similarity factor (f2), which must be 50 or higher. The similarity factor (f2) was calculated according to [Mathematical Formula 3].

[0149] [Equation 3]

[0150]

[0151] In the above mathematical expression 3, n is the number of comparison points, and R t is the average dissolution rate of the control drug, T t is the average dissolution rate of the test drug.

[0152] The comparative dissolution tests of the tablets of Examples 5 and 9 to 11 were performed in the dissolution test solutions of pH 1.2, pH 4.0, pH 6.8 and water according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia, and the results are shown in Fig. 3 and [Table 7]. The tablets of Examples 5 and 9 to 11 were dissolved by more than 80% within 45 minutes in all dissolution test solutions, and the comparative dissolution test similarity factor (f2) values ​​were confirmed to be 50 or more (>50) in the dissolution test solutions of pH 1.2, pH 4.0, pH 6.8 and water, and thus were evaluated to have pharmaceutical equivalence.

[0153] Classification Formulation Name Idelalisib Content Amount Change Level Similarity Factor (f2) Example 5 Standard Dose Formulation 100 mg -- Example 9 Lowest Dose Formulation 25 mg A > 50 Example 10 Low Dose Formulation 50 mg A > 50 Example 11 High Dose Formulation 150 mg C > 50

[0154] Test Example 5. Comparative Dissolution Test

[0155] Tablets (MMT-IDL 150 mg tablets) of Example 11 of the present invention and commercially available idelalisibin Zydelic as a control drug ® (Zydelig ® (150 mg tablet) was added to 900 mL of dissolution test solution (pH 1.2, pH 4.0, and pH 6.8) according to the Pharmaceutical Equivalence Test Standards (MFDS ​​Notice No. 2021-91) and the 2nd method of the Korean Pharmacopoeia (paddle method) and the comparative dissolution equivalence was evaluated by rotating the solution 50 times per minute (50 rpm) at 37±0.5℃. 5 mL of the dissolution solution was collected at 9 time points (10, 15, 30, 45, 60, 90, 120, 240, and 360 minutes) and used as a test solution, and the dissolution characteristics were evaluated by the method of Test Example 4. The similarity factor (f2) was calculated by the above [Mathematical Formula 3].

[0156] Figure 4 and Table 8 show the tablets of Example 11 of the present invention and the control drug Zydelic. ® It shows the results of comparative dissolution tests performed in dissolution test solutions of pH 1.2, pH 4.0, and pH 6.8.

[0157] Time (minutes) pH 1.2 Dissolution test solution pH 4.0 Dissolution test solution pH 6.8 Dissolution test solution Zydelic ® Example 11 Zydelic ® Example 11 Zydelic ® Example 111072±0.0595±0.0117±0.0251±0.0121±0.0352±0.001595±0.02101±0.0130±0.0262±0.0127±0.0362±0.013098±0.01102±0.0135±0.0174±0.0133±0.0174±0.0145100±0.01101±0.0334±0.0181±0.0233±0.0181±0.0160100±0.01100±0.0234±0.00 84±0.0234±0.0186±0.0190100±0.0199±0.0135±0.0188±0.0234±0.0192±0.01120100±0.0199±0.0136±0.0090±0.0135±0.0195±0.01240101±0.00100±0.0138±0.0199±0.0538±0.0198±0.01360101±0.00101±0.0139±0.0198±0.0336±0.02100±0.01

[0158] As shown in Table 8 and Figure 4(a), Example 11 showed Zydelic in the pH 1.2 dissolution test solution. ® It was confirmed that there was comparative dissolution equivalence as the similarity factor (f2) was 50 or more (f2=69), and Example 11 is Zydelic ® It showed a dissolution pattern that was more rapid. Meanwhile, in the dissolution test solutions of pH 4.0 and pH 6.8, as shown in Table 8, Figure 4(b) and Figure 4(c), the tablet of Example 11 of the present invention showed a dissolution rate of 80% or more within 45 minutes from the start of dissolution, whereas Zydelic ®It was evaluated that the dissolution rate did not exceed 40% even 360 minutes after the start of dissolution. This result is similar to that of the commercially available Zydelic solid formulation for oral administration according to the present invention. ® Unlike other compounds, it is not affected by gastrointestinal pH and is released smoothly, suggesting that it can provide not only improved bioavailability but also a predictable and reproducible in vivo profile.

[0159]

[0160] Test Example 6. Bioavailability Evaluation

[0161] A pharmacokinetic test (PK test) was performed to compare the tablets of Example 11 of the present invention (MMT-IDL 150 mg tablets) with Zydelic ® (Zydelig ® The bioavailability of 150 mg tablets was evaluated.

[0162] Twelve male beagles were divided into two groups of six each. Group 1 received the tablets of Example 11, and Group 2 received Zydelic. ® Each was administered orally in a single cross-over manner at a dose of 1 mg / kg. After administration, blood samples were collected at 0, 0.25, 0.5, 1, 2, 3, 5, 8, 10, and 24 hours, and the blood concentration of idelalisib was quantified using LC-MS / MS (Waters Xevo TQ-XS with ACQUITY UPLC). After quantification, the test drug (tablet of Example 11) and the control drug (Zydelic ® ) AUC and C of idelalisib when administered max Pharmacokinetic parameters were evaluated by calculating the dose using Phoenix WinNonlin (Ver 835, Pharsight-A Certara company, USA) and are shown in Table 9 and Figure 5.

[0163] Distinction AUC 0-24 (ng·hr / mL)C max (ng / mL)T max (hr)t 1 / 2(hr) Example 111902.52±727.63744.02±368.381.2±0.62.4±3.0 Zydelic ® 1402.95±546.98439.48±153.801.5±0.71.4±0.2

[0164] Figure 5a shows the results of the tablet of Example 11 of the present invention and Zydelic in a male beagle dog. ® Table 9 and Figure 5 show the mean plasma concentration-time curve graph of idelalisib, and Figure 5b shows the mean plasma concentration-time log-linear graph of idelalisib. As shown in Table 9 and Figure 5, Zydelic ® The relative bioavailability of the purified product of Example 11 was 135.6%, indicating an increased bioavailability.

Claims

1. A solid preparation for oral administration containing idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a disintegrating agent.

2. A solid formulation in which idelalisib in the solid formulation exists in an amorphous form in the first paragraph.

3. A solid preparation comprising 6 to 25 parts by weight of an acidifying agent and 15 to 70 parts by weight of a disintegrating agent per 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof in the first paragraph.

4. A solid preparation in paragraph 1, wherein the acidifying agent is at least one selected from the group consisting of fumaric acid, acetic acid, lactic acid, malic acid, formic acid, propionic acid, butyric acid, oxalic acid, succinic acid, pyruvic acid, sorbic acid, salicylic acid, carbonic acid, adipic acid, maleic acid, ascorbic acid, citric acid, and tartaric acid.

5. A solid preparation in paragraph 1, wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose.

6. In the first paragraph, the disintegrant is a solid preparation in which croscarmellose sodium and starch glycolate sodium are mixed in a weight ratio of 1:0.5-5.

7. A solid preparation according to claim 1, further comprising 50 to 140 parts by weight of an excipient, 3 to 10 parts by weight of a binder, or 0.5 to 5 parts by weight of a lubricant per 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof.

8. In the first paragraph, the idelalisib or a pharmaceutically acceptable salt thereof is a solid preparation having a volume weighted median diameter (D50) of 10 to 50 μm.

9. In the first paragraph, the solid preparation is a solid preparation that is an immediate-release tablet or an enteric-coated tablet.

10. A solid formulation according to paragraph 1, wherein when the solid formulation is tested by rotating the solid formulation at 50 revolutions per minute under conditions of 37±0.5℃ using a pH 1.2 dissolution test solution, a pH 4.0 dissolution test solution, a pH 6.8 dissolution test solution, and 900 ml of purified water according to the second method (paddle method) of the dissolution test items of the United States Pharmacopoeia (USP) or the Korean Pharmacopoeia (KP), the solid formulation dissolves at least 80% of idelalisib or its pharmaceutically acceptable salt within 45 minutes in all test solutions.

11. A pharmaceutical composition for treating or improving a disease or condition caused by overexpression or overactivation of phosphatidylinositol-3-kinase δ (PI3Kδ), comprising the solid preparation of paragraph 1.

12. A method for treating a disease or condition caused by PI3Kδ overexpression or overactivation, comprising administering the solid formulation of paragraph 1 to a subject in need thereof.

13. Therapeutic use of the solid preparation of paragraph 1. 14.1) Granulation step of preparing granules by mixing idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrating agent; 2) A granulation step of drying and milling the granulated granules to produce a granulated product; 3) A lubricating step of mixing a lubricant into the above-mentioned material; and 4) A method for manufacturing a solid preparation for oral administration, comprising a tableting step of tableting the above-mentioned activated mixture.

15. A method for producing a solid preparation in which, in the 14th paragraph, step 1) further comprises at least one pharmaceutical additive selected from the group consisting of excipients and binders to produce granules.

16. A method for producing a solid formulation comprising 6 to 25 parts by weight of an acidifying agent and 15 to 70 parts by weight of a disintegrating agent per 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof in paragraph 14.

17. A method for producing a solid formulation in which idelalisib among the solid formulations is in an amorphous form in the 14th paragraph.

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