KR20250044972A - Solid formulations for oral administration containing idelalisib and preparation method thereof - Google Patents

Abstract

The present invention relates to a solid oral dosage form comprising idelalisib and its pharmaceutically acceptable salt, an acidifying agent and a disintegrating agent, and a method for producing the same.

Description

Solid formulations for oral administration containing idelalisib and preparation method thereof {Solid formulations for oral administration containing idelalisib and preparation method thereof}

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.

The chemical name of Idelalisib is 5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4-one, and the compound and its preparation method are described in International Publication No. WO 2012/152210.

Idelalisib was developed as a PI3Kδ (phosphoinositide-3-kinaseδ) inhibitor and was approved by the US FDA in 2014. It was launched by Gilead under the trade name ^Zydelig® . It is prescribed in combination with rituximab for the treatment of relapsed chronic lymphocytic leukemia (CLL) and as a monotherapy for the treatment of relapsed follicular B-cell non-Hodgkin lymphoma (FL) in many countries, including the US, Europe, the UK, Canada, Australia, New Zealand, and Switzerland. In addition, idelalisib has been reported to exhibit anticancer effects in hepatocellular carcinoma with overexpression of PI3Kδ by specifically inhibiting PI3Kδ activity and inactivating the ROS→PI3Kδ→pAKT→TERT signaling pathway.

A key issue in drug development is to provide high bioavailability of the active pharmaceutical ingredient and predictable and reproducible pharmacokinetic properties. The active pharmaceutical ingredient can exist in various solid forms. More than seven polymorphs of idelalisib have been reported. Idelalisib Form I is known to be partially converted to Form II under typical pressure conditions of tablet manufacturing, and both Idelalisib Forms I and II have very low solubility of about 70 mg/L at pH 6.8 and poor overall solubility. The commercially available idelalisib, ^Zydelig® , contains a mixture of Forms I and II.

Different polymorphs of an active pharmaceutical ingredient may have different solubility. If the active pharmaceutical ingredient of a drug product contains polymorphs or is converted into different forms during the formulation process or storage, the in vivo profile of the drug product may become unpredictable and the bioavailability may not be reproducible.

Therefore, there is a need to develop a novel idelalisib tablet that has predictable and reproducible pharmacokinetic properties while also having improved dissolution characteristics to enhance in vivo absorption without being affected by gastrointestinal pH.

International Publication No. WO2012/152210 Republic of Korea Patent No. 10-1662975

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

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

To achieve the above-mentioned purpose, the oral solid preparation of the present invention comprises idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent, and a disintegrating agent.

Among the above oral administration solid formulations, idelalisib may exist in an amorphous form.

The above solid oral administration preparation 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 idelalisib or a pharmaceutically acceptable salt thereof.

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.

The above disintegrant may be at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose.

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

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

The above solid oral administration preparation may further contain 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.

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

When the above oral solid preparation is tested using pH 1.2 dissolution test solution, pH 4.0 dissolution test solution, pH 6.8 dissolution test solution and 900 ml of purified water according to Method 2 (paddle method) of the dissolution test items of the United States Pharmacopoeia (USP) or the Korean Pharmacopoeia (KP), at 37±0.5℃ conditions and rotating at 50 rpm, at least 80% of idelalisib or a pharmaceutically acceptable salt thereof can be dissolved in all of the test solutions within 45 minutes.

In addition, the method for manufacturing the oral solid dosage form of the present invention for achieving the other purposes 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 slurry; 3) a lubricating step of mixing a lubricant into the slurry; and 4) a tableting step of compressing the slurry mixture into tablets.

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

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

The oral solid preparation of the present invention improves the dissolution characteristics by including idelalisib, an acidifying agent, and a disintegrating agent, so that idelalisib can be dissolved by 80% or more 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.

In addition, the solid oral dosage form of the present invention shows 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 longer, and exhibits excellent stability even under harsh conditions of high humidity and temperature.

Figure 1 is a graph measuring the particle size distribution of idelalisib used as an active pharmaceutical ingredient of the present invention.
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.
Figure 3 is a graph showing the results of a dissolution test performed on 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 2nd method of the dissolution test method of the Korean Pharmacopoeia (paddle method).
Figure 4 shows the results of evaluating the dissolution rate by adding the tablet of Example 11 of the present invention and Zydelic ^® to 900 mL of a dissolution test solution according to the 2nd method of the dissolution test method of the Korean Pharmacopoeia (paddle method) and rotating it 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.
FIG. 5a is a graph of the mean plasma concentration-time curve of the tablet of Example 11 of the present invention and ^idelalisib in Zydelik® in male beagle dogs (n=12), and FIG. 5b is a graph of the mean plasma concentration-time log-linear of the tablet of Example 11 of the present invention and idelalisib in ^Zydelik® in male beagle dogs (n=12).

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.

Hereinafter, the present invention will be described in detail.

The oral solid preparation 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.

Idelalisib, the active pharmaceutical ingredient of the present invention, has poor flowability and solubility, so it dissolves smoothly only in a strongly acidic environment, and its crystal form may change due to pressure, heat, and moisture. Therefore, the physical properties of idelalisib should be improved to increase the bioavailability and long-term stability of idelalisib and to enable prediction and reproduction of the in vivo profile.

According to the present invention, idelalisib in the solid oral dosage form exists in an amorphous state and may have a volume weighted median diameter (D50) of 10 to 50 ㎛, preferably 15 to 20 ㎛, a D10 (10% cumulative particle size distribution) of 0.5 to 5 ㎛, and a D90 (90% cumulative particle size distribution) of 150 to 210 ㎛. When idelalisib and a pharmaceutically acceptable salt thereof are formulated into a solid dosage form, if the particle size is within the above range, the dissolution rate is improved and the area under the blood concentration-time curve (AUC) and the maximum blood concentration (C _max ) can be improved, which is preferable, and if it is finer than the above range, process failure may be caused during tableting.

In addition, the acidifying agent is used in an amount of 6 to 25 parts by weight, preferably 9 to 20 parts by weight, per 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof. When 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 when it exceeds the upper limit, it may interfere with the function of a 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.

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 80% or more of idelalisib or a pharmaceutically acceptable salt thereof in all test solutions at 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 in accordance with 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. The test results showed that the oral solid preparation 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 also showed improved dissolution characteristics, area under the blood concentration-time curve (AUC), and maximum blood concentration (C _max ) compared to Zydelik ^® tablets.

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

The solid oral dosage form 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 dosage form not including an acidifying agent, it was observed in the XRD examination that some of the amorphous idelalisib was converted to crystalline Form I after a 3-month accelerated test (40±2℃, 75±5%RH; RH: relative humidity, sealed, stored for 3 months) in the solid dosage form, but it was confirmed that the solid dosage form including the acidifying agent according to the present invention had excellent long-term stability since the conversion rate from the amorphous form to the crystalline form was almost zero.

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, the acidifying agent 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 a pKa value within the above ranges did not produce any soluble substances during long-term storage, and was particularly excellent in improving the dissolution rate.

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.

In addition, the disintegrant may be at least one selected from the group consisting of croscarmellose sodium, sodium starch glycolate, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose; 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.

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

The oral solid preparation of the present invention may further contain, in addition to idelalisib, an acidifying agent, and a disintegrating agent, a pharmaceutically acceptable excipient, binder, or lubricant.

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

The above excipients can 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.

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, per 100 parts by weight of idelalisib or a pharmaceutically acceptable salt thereof.

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, per 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.

The solid oral dosage form of the present invention can be used as a drug for treating or improving a disease or condition caused by phosphatidylinositol-3-kinase δ (PI3Kδ) hyperactivation. The disease or condition caused by PI3Kδ hyperactivation can be selected from the group consisting of, but not limited to, activated PI3Kδ syndrome, liver cancer, hepatocellular carcinoma, B-cell benign tumor, hematological cancer, asthma, allergic rhinitis, chronic obstructive pulmonary disease, rheumatism, inflammatory diseases, lupus erythematosus, multiple sclerosis, psoriasis, eczema, and combinations thereof.

The oral solid formulation 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 formulation 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 formulation 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 formulation of the present invention contains 25, 50, 75, 100, and 150 mg.

In addition, in order to achieve the other objects mentioned above, 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 slurry; 3) a lubricating step of mixing a lubricant into the slurry; and 4) a tableting step of compressing the slurry mixture.

In addition, the step 1) above can manufacture granules by further including one or more pharmaceutical additives selected from the group consisting of excipients and binders.

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, for example, purified water is added thereto to knead the mixture, thereby preparing granules (granulation).

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 with 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.

Next, add a lubricant to make it lubricated and then press it into a tablet.

The types and contents of the above idelalisib, acidifying agent, disintegrating agent, excipient, binder and lubricant are the same as defined above.

The terms “have,” “can have,” “contains,” “includes,” or “may include” indicate the presence of a feature (e.g., a numerical value, or a component such as an ingredient) but do not exclude the presence of additional features.

Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are only illustrative of the present invention, and it will be apparent 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 natural that such changes and modifications fall within the scope of the appended patent claims.

Examples 1 to 11 and Comparative Examples 1 to 3

Idelalisib (Zhejiang Lepu Pharmaaceurical co. LTD; China), an acidifier (fumaric acid: Fumaric acid EMPROVE, Merck), a disintegrant (croscarmellose sodium: VIVASOL, JRS Pharma; sodium starch glycolate: Explotab, JRS Pharma), an excipient (microcrystalline cellulose: VIVAPUR 101, JRS Pharma), and a binder (hydroxypropyl cellulose: NISSO HPC-L, Nippon Soda) were weighed according to the following [Table 2] and [Table 3], sieved to 20 mesh, mixed, then a binder (purified water) was added and kneaded to form a granule. The granule was 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. The suspension was mixed with a lubricant (magnesium stearate, Merck; 40 mesh) 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 dosage form 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.

Since the idelalisib used as a raw material in the present invention was confirmed to contain 4.5% moisture in a moisture content test according to the moisture measurement method (Karl Fischer method), it was added by increasing the amount by 4% by weight to correct the moisture content during the manufacture of tablets.

standard Diameter (mm) Mass (mg) Thickness (mm) Hardness (kp) 1 6.0 77.0±1.0 2.5-2.8 6.0-8.0 2 7.0 120.0±2.0 3.3-3.6 6.0-8.0 3 9.0 200.0±2.0 3.5-4.0 6.0-8.0 4 9.0 240.0±2.0 4.1-4.6 6.0-8.0 5 10.0 360.0±3.0 4.9-5.2 8.0-10.0

division Content (mg) Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Example 3 Example 4 Idelariship 104 104 104 104 104 104 104 Microcrystalline cellulose 76 71 86 58 78 98 88 Hydroxypropyl cellulose 6 6 6 6 6 6 6 Fumaric acid - 5 10 10 10 10 20 Croscarmellose sodium 6 6 6 10 10 10 10 Sodium starch glycolate 6 6 6 10 10 10 10 Magnesium stearate 2 2 2 2 2 2 2 Total weight (mg/tablet) 200 200 220 200 220 240 240

division Content (mg) Example 5 Example 6 Example 7 Example 8 Example Example 10 Example 11 Idelariship 104 104 104 104 26 52 156 Microcrystalline Cellulose 88 88 88 88 35.7 44 132 Hydroxypropyl cellulose 6 6 6 6 1.9 3 9 Fumaric acid 10 10 10 10 3.2 5 15 Croscarmellose sodium 10 30 15 - 3.2 5 15 Sodium starch glycolate 20 - 15 30 6.4 10 30 Magnesium stearate 2 2 2 2 0.6 1 3 Total weight (mg/tablet) 240 240 240 240 77 120 360

<Example of an exam>

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 by one-way ANOVA, and statistical significance was tested at the P < 0.05 level using Duncan's test.

Test Example 1. Evaluation of raw material properties

The appearance, moisture content, particle size, and crystallographic properties of idelalisib raw material were evaluated. Idelalisib is an odorless white powder, and was evaluated to contain 4.5% moisture in the moisture content test according to the moisture measurement method of the Korean Pharmacopoeia (Karl Fischer method). 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/°).

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

Figure 2a shows the results of analyzing the raw material of idelalisib by X-ray diffraction (XRD) 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.

Test Example 2. Mixing Compatibility

The compounding compatibility of idelalisib and five kinds of excipients (microcrystalline cellulose, isomalt, mannitol, lactose, and lactose monohydrate), three kinds of binders (hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone), three kinds of acidifiers (citric acid, fumaric acid, and tartaric acid), three kinds of disintegrants (croscarmellose sodium, crospovidone, and sodium starch glycolate), and three kinds of lubricants (magnesium stearate, sodium stearyl fumarate, and glyceryl behenate) was evaluated. 150 mg of each of the 17 kinds of additives was weighed and placed into each brown vial. Then, 150 mg of idelalisib was added to each vial so that each additive and idelalisib were in a 1:1 weight ratio, and the mixture was mixed in a vortex mixer for 5 minutes. Brown vials containing the idelalisib-additive mixture and brown vials containing only idelalisib were stored under long-term sealed (25±2℃, 60±5%RH, sealed), long-term opened (25±2℃, 60±5%RH, opened), accelerated sealed (40±2℃, 75±5%RH, sealed), and accelerated 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 compounding suitability and storage stability.

2-1. Visual evaluation

No changes in color, properties, or phase were observed for idelalisib and idelalisib-additive mixtures at the time of preparation and at 4 weeks for each condition.

2-2. Evaluation of flexible substances (impurities)

The standard solution was prepared by putting 25 mg of idelalisib in a vial and diluting it to a concentration of 500 ppm. The test solution was prepared by putting 200 mg of idelalisib-additive mixture (1:1 weight ratio) in a vial and diluting it to a concentration of 4000 ppm. The dilution solution used was acetonitrile: purified water = 1:1 (v/v), and the high-performance liquid chromatography (HPLC) conditions are as shown in [Table 4] below. 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.

item detail note Detector UV spectrophotometer Measurement wavelength 270 nm column USP L11, 4.6 mm ×150 mm, 3.5 ㎛ ZORBAX SB-Phenyl Column temperature 40℃ Specimen temperature 4℃ Injection amount 5 ㎕ Moving Mobile phase A: 20 mM KH ₂ PO ₄ :ACN(95:5 v/v) (pH7.0)
Mobile phase B: ACN (Acetonitrile)
<Moving gradient fraction>
flux 1.0 mL/min

Analysis of flexible substances was performed using HPLC and calculated according to the following [Mathematical Formula 1].

[Mathematical formula 1]

A _t : Peak area of the flexible substance in the test solution A _s : Peak area of idelalisib in the standard solution

W _t : Sample collection amount (mg) W _s : Idelalisib collection amount (mg)

D _t : Test solution dilution factor D _s : Standard solution dilution factor

P: Idelariship Purity (%)

F: Relative reaction coefficient of the specified flexible substance

Idelariship : 1.00 (Relative Hold Time 1.00)

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

Flexible Material B(Desfluoro) : 1.00 (relative retention time 0.96)

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

Flexible Material D(IDL-03) : 2.10 (relative retention time 0.75)

As a result of confirming the amount of flexible substances produced, the production of flexible substances A, B, C, and D was not observed in idelalisib and idelalisib-additive mixtures. Meanwhile, unknown flexible 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 additives were evaluated to have compatibility with idelalisib.

2-3. Differential scanning calorimetry (DSC) evaluation

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 at 4 weeks were placed in an aluminum pan for measurement, covered with an aluminum lid, compressed, and then measured at a temperature increase rate of 5 ℃ per minute in the range of 40-300 ℃.

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 showed cross-reactivity with idelalisib, confirming poor compounding compatibility.

The Idelalisib/additive mixture not mentioned above showed no significant difference after 4 weeks compared to the time of preparation, confirming the mixing suitability and storage stability.

Test Example 3. Safety Evaluation

3-1. Evaluation of flexible material production amount

For the tablets of Examples 5 and 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.

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

division Example 5 Example 9 Example 10 Example 11 beginning long time acceleration beginning long time acceleration beginning long time acceleration beginning long time acceleration
flexible material
(%) A BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD B BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD C BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD D BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD BLOD Unknown 0.08 0.10 0.08 0.10 0.11 0.10 0.08 0.10 0.10 0.08 0.10 0.10 gun 0.08 0.10 0.08 0.10 0.11 0.10 0.08 0.10 0.10 0.08 0.10 0.10

BLOD: Below the Limit of detection

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.

3-2. Evaluation of X-ray diffraction analysis

The phase change from an amorphous to a 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.

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 (not compressed) 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 for the tablet of Example 5; FIG. 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 FIG. 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.

In Figs. 2a to 2d, idelalisib maintained an amorphous pattern, and no new peaks were observed, indicating that there was little change in the crystal form. On the other hand, in Fig. 2e, peaks were observed to be generated with a 2Theta value of singlet at 12° and doublet at 18°. The two newly observed peaks were confirmed to be typical XRD characteristic peaks appearing in idelalisib crystal form I.

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 prediction of the in vivo profile and reproduction of bioavailability are possible.

Test Example 4. Evaluation of dissolution characteristics of solid preparations

4-1. Dissolution characteristics test method

(1) Preparation of test solution

For each purified sample, add 900 mL of dissolution test solution (pH 1.2, 4.0, 6.8, and purified water) according to the Standards for Pharmaceutical Equivalence Tests (Notification No. 2021-91 of the Ministry of Food and Drug Safety) and the 2nd method of the Dissolution Test 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.

(2) Preparation of standard solution for calibration curve of elution test

Dissolve 100 mg of the idelalisib raw material 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 a calibration curve at five concentrations.

(3) Dissolution test analysis method

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

[Mathematical formula 2]

4-2. Evaluation of elution characteristics

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

The results of the dissolution rates of tablets according to Example 1-11 and Comparative Example 1-3 in purified water (water), which was 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.

division Idelalisib dissolution rate (%) (dissolution solution: purified water) 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes Comparative Example 1 20.3±0.01 37.1±0.01 46.9±0.01 55.5±0.01 61.1±0.01 67.4±0.01 71.0±0.01 Comparative Example 2 25.4±0.01 38.9±0.02 50.9±0.02 62.9±0.01 72.1±0.01 84.4±0.00 92.1±0.00 Comparative Example 3 36.5±0.01 55.5±0.00 63.0±0.01 75.5±0.02 81.8±0.01 92.9±0.01 97.5±0.01 Example 1 42.5±0.01 57.1±0.01 69.0±0.02 80.0±0.00 83.7±0.01 91.7±0.01 96.5±0.01 Example 2 44.1±0.01 61.7±0.02 72.2±0.01 82.8±0.01 88.8±0.02 97.1±0.02 98.1±0.00 Example 3 47.4±0.01 66.5±0.03 75.2±0.02 84.1±0.01 91.1±0.01 99.1±0.01 98.2±0.01 Example 4 45.8±0.01 62.4±0.01 72.5±0.01 83.7±0.03 87.8±0.02 95.6±0.04 99.1±0.02 Example 5 58.8±0.04 73.4±0.01 80.0±0.01 87.6±0.02 93.8±0.01 100.3±0.01 100.8±0.01 Example 6 47.1±0.02 63.4±0.02 72.6±0.03 83.3±0.01 87.8±0.02 95.6±0.01 96.8±0.01 Example 7 54.5±0.01 66.1±0.01 75.6±0.01 84.3±0.02 91.9±0.03 99.4±0.02 99.5±0.01 Example 8 51.3±0.02 67.7±0.01 74.9±0.01 83.1±0.01 90.5±0.01 97.7±0.01 98.8±0.01 Example 9 56.6±0.01 75.4±0.00 85.7±0.01 90.4±0.00 94.6±0.02 98.8±0.02 101.1±0.00 Example 10 49.7±0.03 63.9±0.03 74.0±0.04 82.3±0.03 89.5±0.04 96.2±0.04 98.6±0.06 Example 11 47.5±0.02 64.8±0.01 75.4±0.00 83.9±0.01 88.8±0.01 97.4±0.03 100.6±0.03

As shown in Table 6 above, the tablets of Examples 1 to 8 were confirmed to achieve the dissolution rate targeted by the present invention (80% or more within 45 minutes).

The tablets that did not contain 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 agent had a minimal effect on improving the dissolution rate or could even reduce the dissolution rate (compare Examples 3 and 4).

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 particularly when the content of starch glycolate was contained in a greater 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).

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

The oral solid preparation of the present invention was developed as a standard dose containing 100 mg of idelalisib, and Example 5 was selected as the final finished drug product. Oral solid preparations 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 in the pharmaceutical equivalence test standards for general preparations (Notice of the Ministry of Food and Drug Safety No. 2021-91) (Examples 9 to 11). The similarity of dissolution profiles is compared using the similarity factor (f ₂ ), and must be 50 or higher. The similarity factor (f ₂ ) was calculated according to [Mathematical Formula 3].

[Mathematical formula 3]

In the above mathematical expression 3, n is the number of comparison time points, R _t is the average dissolution rate of the control drug, and T _t is the average dissolution rate of the test drug.

The comparative dissolution tests of the tablets of Examples 5 and 9 to 11 were performed in 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 Examples 9 to 11 were dissolved by 80% or more within 45 minutes in all dissolution test solutions, and the comparative dissolution test similarity factor (f ₂ ) values were confirmed to be 50 or higher (>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.

division Formulation name Idelariship content Volume change level Similarity factor (f ₂ ) Example 5 Standard dosage form 100 mg - - Example 9 Lowest dose formulation 25 mg A >50 Example 10 low dose preparation 50 mg A >50 Example 11 High dose preparation 150 mg C >50

Test Example 5. Comparative Elution Test

The tablets (MMT-IDL 150 mg tablets) of Example 11 of the present invention and the commercially available idelalisibin Zydelig ^® (Zydelig ^® 150 mg tablets) as a control drug were placed in 900 mL of a dissolution test solution (pH 1.2, pH 4.0, and pH 6.8) in accordance with the Standards for Pharmaceutical Equivalence Tests (Notification No. 2021-91 of the Ministry of Food and Drug Safety) and the Dissolution Test Method of the Korean Pharmacopoeia, Method 2 (Paddle Method), and the comparative dissolution equivalence was evaluated by rotating the test solution 50 times per minute (50 rpm) at 37±0.5℃. 5 mL of the dissolution solution was collected at a total of 9 time points (10, 15, 30, 45, 60, 90, 120, 240, and 360 minutes) and used as test solutions, and the dissolution characteristics were evaluated by the method of Test Example 4. The similarity factor (f ₂ ) was calculated using the above [Mathematical Formula 3].

Figure 4 and Table 8 show the results of a comparative dissolution test performed on the tablet of Example 11 of the present invention and the control drug Zydelic ^® in dissolution test solutions of pH 1.2, pH 4.0, and pH 6.8.

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 11 10 72±0.05 95±0.01 17±0.02 51±0.01 21±0.03 52±0.00 15 95±0.02 101±0.01 30±0.02 62±0.01 27±0.03 62±0.01 30 98±0.01 102±0.01 35±0.01 74±0.01 33±0.01 74±0.01 45 100±0.01 101±0.03 34±0.01 81±0.02 33±0.01 81±0.01 60 100±0.01 100±0.02 34±0.00 84±0.02 34±0.01 86±0.01 90 100±0.01 99±0.01 35±0.01 88±0.02 34±0.01 92±0.01 120 100±0.01 99±0.01 36±0.00 90±0.01 35±0.01 95±0.01 240 101±0.00 100±0.01 38±0.01 99±0.05 38±0.01 98±0.01 360 101±0.00 101±0.01 39±0.01 98±0.03 36±0.02 100±0.01

As shown in Table 8 and Fig. 4(a), in the pH 1.2 dissolution test solution, Example 11 showed a similarity factor (f ₂ ) of 50 or more (f ₂ = 69) with Zydelic ^® , confirming that there was comparative dissolution equivalence, and Example 11 showed a pattern of dissolution faster than Zydelic ^® . Meanwhile, in the pH 4.0 and pH 6.8 dissolution test solutions, as shown in Table 8 and Fig. 4(b) and Fig. 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 ^® was evaluated to have a dissolution rate of no more than 40% even after 360 minutes from the start of dissolution.

These results suggest that the oral solid formulation according to the present invention, unlike commercially available ^Zydelic® , exhibits smooth dissolution without being affected by gastrointestinal pH, thereby providing not only improved bioavailability but also a predictable and reproducible in vivo profile.

Test Example 6. Bioavailability Evaluation

Pharmacokinetic studies (PK studies) were performed to evaluate the bioavailability of the tablets of Example 11 of the present invention (MMT-IDL 150 mg tablets) and Zydelig ^® (Zydelig ^® 150 mg tablets).

Twelve male beagle dogs were divided into two groups of six dogs each. Group 1 was orally administered the tablet of Example 11 and Group 2 was orally administered Zydelik ^® at a dose of 1 mg/kg each in a single cross-over manner. 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 AUC and C _max of idelalisib were calculated using Phoenix WinNonlin (Ver 835, Pharsight-A Certara company, USA) when administering the test drug (tablet of Example 11) and the control drug (Zydelik ^® ), and the pharmacokinetic parameters were evaluated, which are shown in Table 9 and Figure 5.

division AUC _0-24 (ng·hr/mL) C _max (ng/mL) T _max (hr) t _1/2 (hr) Example 11 1902.52±727.63 744.02±368.38 1.2±0.6 2.4±3.0 Zydelic ^® 1402.95±546.98 439.48±153.80 1.5±0.7 1.4±0.2

Figure 5a is a graph of the mean plasma concentration-time curve of idelalisib in the tablet of Example 11 of the present invention and ^Zydelic® in a male beagle dog, and Figure 5b is a graph of the mean plasma concentration-time log-linear graph of idelalisib.

As shown in Table 9 and Figure 5, the relative bioavailability of the tablet of Example 11 to ^Zydelic® was 135.6%, indicating an increased bioavailability.

Claims (14)

An oral solid dosage form comprising idelalisib or a pharmaceutically acceptable salt thereof, an acidifying agent and a disintegrating agent. A solid formulation in claim 1, wherein idelalisib in the solid formulation exists in an amorphous form. A solid preparation comprising, in claim 1, 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. A solid preparation in claim 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. A solid preparation in claim 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. In claim 1, the disintegrant is a solid preparation comprising croscarmellose sodium and starch glycolate sodium mixed in a weight ratio of 1:0.5-5. A solid preparation in 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. In claim 1, the idelalisib or a pharmaceutically acceptable salt thereof is a solid preparation having a volume weighted median diameter (D50) of 10 to 50 ㎛. In the first paragraph, the solid preparation is a solid preparation that is an immediate-release tablet or an enteric-coated tablet. In claim 1, a solid preparation, wherein when a test is performed by rotating the solid preparation at 50 rpm 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 preparation dissolves at least 80% of idelalisib or a pharmaceutically acceptable salt thereof in all test solutions within 45 minutes. 1) A 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 above-mentioned granules to produce a granulated product;
3) A lubricating step of mixing a lubricant into the above-mentioned established material; and
4) A method for producing a solid preparation for oral administration, comprising a tableting step of tableting the above-mentioned activated mixture. In claim 11, step 1) is a method for producing a solid preparation for producing granules by further including at least one pharmaceutical additive selected from the group consisting of excipients and binders. A method for producing 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 claim 11. In claim 11, a method for producing a solid formulation in which idelalisib among the solid formulations is in an amorphous form.