Pharmaceutical formulation comprising osimertinib or pharmaceutically acceptable salts thereof

Abstract

The present invention discloses a pharmaceutical formulation comprising osimertinib or a pharmaceutically acceptable salt thereof.

Description

PHARMACEUTICAL FORMULATION COMPRISING OSIMERTINIB OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

[0001] The present invention relates to a pharmaceutical formulation comprising osimertinib or a pharmaceutically acceptable salt thereof. The pharmaceutical formulation according to the present invention is a pharmaceutical formulation capable of achieving excellent effects in both disintegration and dissolution by adopting hydroxypropyl cellulose as a binder so that the pharmaceutical formulation can be manufactured by a direct compression method, even though it does not contain microcrystalline cellulose (MCC), which is known to be essential for manufacturing a formulation comprising osimertinib or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient.

[0002] Osimertinib or a salt thereof (e.g., mesylate) is a targeted anticancer agent used for the treatment of non-small cell lung cancer. It selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and thereby suppresses cancer cell proliferation. It is effective even in patients resistant to existing therapeutic agents and is used to treat patients with non-small cell lung cancer with EGFR gene mutations or patients who are EGFR T790M mutation-positive.

[0003] The chemical name for osimertinib is N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide, and it is represented by the chemical formula shown below (see International Patent Publication No. 2013 / 014448).

[0004] [Chemical Formula 1]

[0005]

[0006] Osimertinib, developed under the brand name Tagrisso™, is used alone (i) as an adjuvant treatment in patients with EGFR exon 19 deletion or exon 21 (L858R) substitution mutated non-small cell lung cancer after complete tumor resection, (ii) as a first-line treatment in patients with EGFR exon 19 deletion or exon 21 (L858R) substitution mutated locally advanced or metastatic non-small cell lung cancer, and (iii) as a treatment in patients with EGFR T790M mutation-positive locally advanced or metastatic non-small cell lung cancer who have been previously treated with EGFR-tyrosine kinase inhibitor (TKI), or in combination with pemetrexed and platinum-based chemotherapy in the first-line treatment of patients with EGFR exon 19 deletion or exon 21 (L858R) substitution mutated locally advanced or metastatic non-squamous non-small cell lung cancer. Osimertinib has been used in Korea since it was approved by the Ministry of Food and Drug Safety in 2016.

[0007] Generally, when manufacturing an oral solid formulation containing a specific active pharmaceutical ingredient, additives are inevitably included, and once the active pharmaceutical ingredient is determined, a miscibility test with various additives necessary for formulation is performed, and among the additives with the same function, one with good miscibility is selected. In the case of osimertinib, as oral solid formulations containing osimertinib as an active pharmaceutical ingredient, capsule dosage forms and tablet dosage forms are disclosed in Korean Patent Publication No. 10-2336378. The document discloses microcrystalline cellulose as an optimal diluent to be combined with osimertinib and discloses a capsule dosage form containing osimertinib and microcrystalline cellulose. Furthermore, considering delayed dissolution associated with the rupture of the capsule shell, the document discloses that when osimertinib is formulated as a tablet, another type of diluent must be included at a specific content together with microcrystalline cellulose.

[0008] However, the document does not disclose a tablet that is manufactured by a direct compression method without using microcrystalline cellulose and that meets both disintegration and dissolution standards.

[0009] [Prior art documents]

[0010] [Patent documents]

[0011] (Patent document 1) International Patent Publication No. 2013 / 014448

[0012] (Patent document 2) Korean Patent Publication No. 10-2336378

[0013] Accordingly, the present inventors sought to provide a tablet that may be manufactured by the direct compression method and achieves excellent effects in both dissolution and disintegration without containing microcrystalline cellulose, which was considered essential when formulating osimertinib, among pharmaceutically acceptable additives. Specifically, the present inventors confirmed that by including hydroxypropyl cellulose as a binder instead of using microcrystalline cellulose as a diluent and a combination of the type and content of pharmaceutical additives optimized for this is used, it is possible to manufacture a pharmaceutical formulation without tableting problems even by the direct compression method (mixed tableting) without using a solvent or forming granules and to provide a pharmaceutical formulation exhibiting rapid disintegration and a high dissolution rate with guaranteed safety and efficacy by securing bioequivalence to the control drug, Tagrisso™ tablet, thereby completing the present invention.

[0014] In order to achieve the above-described objects, the present invention discloses the following.

[0015] In one aspect, the present invention discloses a pharmaceutical formulation comprising osimertinib or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose as a binder, wherein the pharmaceutical formulation does not contain microcrystalline cellulose.

[0016] In another aspect, the present invention discloses a pharmaceutical formulation comprising osimertinib or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose as a binder, wherein the pharmaceutical formulation does not contain microcrystalline cellulose, and is manufactured by a direct compression method.

[0017] Furthermore, as one specific aspect, the present invention discloses a pharmaceutical composition in a tablet form manufactured by a direct compression method, the pharmaceutical composition comprising osimertinib mesylate as an active pharmaceutical ingredient, D-mannitol as an excipient, hydroxypropyl cellulose as a binder, low-substituted hydroxypropyl cellulose as a disintegrant, and sodium stearyl fumarate and light anhydrous silicic acid as lubricants.

[0018] The pharmaceutical formulation of the present invention has the advantage of being manufactured without tableting problems even by a direct compression method (mixed tableting), since it does not contain microcrystalline cellulose but contains hydroxypropyl cellulose as a binder.

[0019] In addition, the present invention provides a pharmaceutical formulation that disintegrates more quickly than the control drug, Tagrisso™ tablet, shows rapid dissolution in a liquid at pH 1.2, and exhibits bioequivalence to Tagrisso™ tablet thereby guaranteeing its safety and efficacy.

[0020] The effects of the present invention are not limited to the above-mentioned effects, and various other effects may be comprised within a scope obvious to those skilled in the art based on the description below.

[0021] FIG. 1 shows the results of a comparative dissolution test for a coated tablet comprising osimertinib mesylate according to Example 6 of the present invention, which is a test drug, and an 80 mg Tagrisso™ tablet, which is a control drug, in a dissolution medium at pH 4.0.

[0022] FIG. 2 shows the results of a comparative dissolution test for a coated tablet comprising osimertinib mesylate according to Example 6 of the present invention, which is a test drug, and an 80 mg Tagrisso™ tablet, which is a control drug, in a pharmacopoeial solution of pH 1.2.

[0023] FIG. 3 shows the results of a comparative dissolution test for a coated tablet comprising osimertinib mesylate according to Example 6 of the present invention, which is a test drug, and an 80 mg Tagrisso™ tablet, which is a control drug, in a pharmacopoeial solution of pH 6.8.

[0024] Hereinafter, the present specification will be described in more detail.

[0025] The present specification is described in more detail as follows. The terms used herein are selected as general terms that are currently widely used as much as possible while considering the functions in the present invention, but they may vary depending on the intention or precedent of those of ordinary skill in the art, the emergence of new technology, or the like. In addition, in certain cases, there are terms arbitrarily selected by the applicant, and in this case, the meaning will be described in the corresponding part of the detailed description of the invention. Therefore, the terms used in the present invention should be defined based on the meaning of the terms and the overall content of the present invention, rather than simply the names of the terms.

[0026] Unless otherwise defined, all terms, comprising technical and scientific terms used herein, have the same meaning as generally understood by one of ordinary skill in the art to which the present invention pertains. Terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and are not interpreted in an idealized or overly formal sense unless clearly so defined in the present invention.

[0027] Numerical ranges are inclusive of the values defined therein. Every maximum numerical limitation given throughout the present specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written. Every minimum numerical limitation given throughout the present specification includes every higher numerical limitation, as if such higher numerical limitations were expressly written. Every numerical limitation given throughout the present specification will include every better numerical range within the broader numerical range, as if the narrower numerical limitations were expressly written.

[0028] Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments for each. In other words, all combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention may not be considered as being limited by the specific description described below.

[0029] Expressions such as "comprising" as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included.

[0030] As used herein, the term "osimertinib" may refer to osimertinib or a pharmaceutically acceptable salt thereof, and more specifically, may refer to osimertinib mesylate.

[0031] Therefore, a pharmaceutical formulation / tablet / coated tablet comprising osimertinib as used herein, may refer to a pharmaceutical formulation / tablet / coated tablet comprising osimertinib or a pharmaceutically acceptable salt thereof.

[0032] Hereinafter, the present invention will be described in detail.

[0033] Pharmaceutical formulation comprising osimertinib or a pharmaceutically acceptable salt thereof

[0034] The present invention discloses a pharmaceutical formulation comprising osimertinib or a pharmaceutically acceptable salt thereof.

[0035] Specifically, the present invention provides a pharmaceutical formulation comprising osimertinib or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose as a binder, and wherein the pharmaceutical formulation does not contain microcrystalline cellulose.

[0036] In the present invention, osimertinib is an example of a 2-(2,4,5-substituted-anilino)pyrimidine derivative, and its chemical name is N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide.

[0037] The osimertinib of the present invention may be present in the form of a pharmaceutically acceptable salt. An acid addition salt formed with a pharmaceutically acceptable free acid is a useful form. In the present invention, the term "pharmaceutically acceptable salt" refers to any organic or inorganic acid addition salt of osimertinib which is relatively non-toxic and harmless to patients at a therapeutically effective concentration, and whose side effects do not diminish the beneficial efficacy of osimertinib.

[0038] Specifically, the pharmaceutically acceptable salt of osimertinib may be osimertinib mesylate (N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide mesylate) but is not limited thereto.

[0039] [Chemical Formula 2]

[0040]

[0041] In the present invention, the pharmaceutical formulation may comprise 15% to 30% by weight of osimertinib or a pharmaceutically acceptable salt thereof based on the total weight of the pharmaceutical formulation, but is not limited thereto.

[0042] In the present invention, the pharmaceutically acceptable salt of osimertinib may be comprised in an amount of 30 mg to 90 mg as osimertinib, specifically 40 mg or 80 mg, but is not limited thereto. When the active pharmaceutical ingredient is osimertinib mesylate, it may be comprised in an amount of 15% to 30% by weight based on the total weight of the pharmaceutical formulation.

[0043] In the present invention, the pharmaceutical formulation may further comprise one or more pharmaceutical additives selected from the group consisting of an excipient, a disintegrant, and a lubricant but is not limited thereto.

[0044] In the present invention, the excipient may be D-mannitol but is not limited thereto.

[0045] In the present invention, the disintegrant may be low-substituted hydroxypropyl cellulose but is not limited thereto.

[0046] In the present invention, the lubricant may be a combination of sodium stearyl fumarate and light anhydrous silicic acid but is not limited thereto.

[0047] In the present invention, the pharmaceutical formulation may comprise an excipient in an amount of 60% to 80% by weight, a disintegrant in an amount of 2% to 6% by weight, and a lubricant in an amount of 1% to 6% by weight, based on the total weight of the pharmaceutical formulation, but is not limited thereto.

[0048] In the present invention, the pharmaceutical formulation may comprise hydroxypropyl cellulose in an amount of 1% to 6% by weight based on the total weight of the pharmaceutical formulation, but is not limited thereto.

[0049] In the present invention, the pharmaceutical formulation may be formulated as a solid oral formulation, but is not limited to this.

[0050] In the present invention, the solid oral formulation may be a tablet or a film-coated tablet, specifically a film-coated tablet, but is not limited thereto.

[0051] In particular, in the case of a film-coated tablet, any coating agent widely known in the art may be used, and the present invention is not limited to thereto.

[0052] Specifically, the pharmaceutical formulation may comprise osimertinib or a pharmaceutically acceptable salt thereof in an amount of 15% to 30% by weight, an excipient in an amount of 60% to 80% by weight, hydroxypropyl cellulose as a binder in an amount of 1% to 6% by weight, a disintegrant in an amount of 2% to 6% by weight, a lubricant in an amount of 1% to 6% by weight, and a coating agent in an amount of 1% to 5% by weight.

[0053] Hereinafter, the present invention will be described in more detail using examples and comparative examples. It will be obvious to those skilled in the art that these examples and comparative examples are intended solely to illustrate the present invention more specifically and are not intended to limit the scope of the present invention.

[0054] Examples and Comparative Examples. Manufacture of coated tablets comprising osimertinib mesylate as an active pharmaceutical ingredient

[0055] Examples 1 to 3 and Comparative Examples 1 and 2. Formulation with varying proportion of binder

[0056] Example 1.

[0057] The active pharmaceutical ingredient osimertinib mesylate, the excipient D-mannitol, the binder hydroxypropyl cellulose, and the disintegrant low-substituted hydroxypropyl cellulose were placed in a bin mixer and mixed at 10 rpm for 15 minutes. Thereafter, the lubricants, sodium stearyl fumarate and light anhydrous silicic acid, were then added and further mixed at 10 rpm for 7 minutes. The resulting mixture was compressed into tablets (uncoated tablets).

[0058] Thereafter, a film-coating solution (coating solvent: purified water) including the coating agent, Tabshield Orange (21O1512), was sprayed onto the compressed tablets (uncoated tablets) to produce coated tablets. A polishing process was performed using carnauba wax.

[0059] Example 2.

[0060] A coated tablet according to Example 2 was manufactured in the same manner as in Example 1, using the ingredients and contents shown in Table 1 below.

[0061] Example 3.

[0062] A coated tablet according to Example 3 was manufactured in the same manner as in Example 1, using the ingredients and contents shown in Table 1 below.

[0063] Comparative Example 1.

[0064] A coated tablet according to Comparative Example 1 was manufactured in the same manner as in Example 1, using the ingredients and contents in Table 1 below.

[0065] Comparative Example 2.

[0066] A coated tablet according to Comparative Example 2 was manufactured in the same manner as in Example 1, using the ingredients and contents shown in Table 1 below.

[0067] Formulation purposeIngredient nameComparative Example 1Example 1Example 2Example 3Comparative Example 2Active pharmaceutical ingredientOsimertinib mesylate(as osimertinib)95.40(80)95.40(80)95.40(80)95.40(80)95.40(80)ExcipientD-mannitol339.00334.00329.00324.00319.00BinderHydroxypropyl cellulose5.0010.0015.0020.0025.00DisintegrantLow-substituted hydroxypropyl cellulose12.0012.0012.0012.0012.00LubricantSodium stearyl fumarate6.006.006.006.006.00LubricantLight anhydrous silicic acid2.602.602.602.602.60Sum total as an uncoated tablet460.00460.00460.00460.00460.00Coating agentTabshield Orange (21O1512)20.0020.0020.0020.0020.00Sum total as a coated tablet480.00480.00480.00480.00480.00

[0068] Examples 2, 4, and 5 and Comparative Example 3. Formulations with varying proportion of disintegrant

[0069] Example 4.

[0070] A coated tablet according to Example 4 was manufactured in the same manner as in Example 1, using the ingredients and contents shown in Table 2 below.

[0071] Example 5.

[0072] A coated tablet according to Example 5 was manufactured in the same manner as in Example 1, using the ingredients and contents shown in Table 2 below.

[0073] Comparative Example 3.

[0074] A coated tablet according to Comparative Example 3 was manufactured in the same manner as in Example 1, using the ingredients and contents shown in Table 2 below.

[0075] Formulation purposeIngredient nameComparative Example 3Example 2Example 4Example 5Active pharmaceutical ingredientOsimertinib mesylate(as osimertinib)95.40(80)95.40(80)95.40(80)95.40(80)ExcipientD-mannitol333.00329.00325.00321.00BinderHydroxypropyl cellulose15.0015.0015.0015.00DisintegrantLow-substituted hydroxypropyl cellulose8.0012.0016.0020.00LubricantSodium stearyl fumarate6.006.006.006.00LubricantLight anhydrous silicic acid2.602.602.602.60Sum total as an uncoated tablet460.00460.00460.00460.00Coating agentTabshield Orange (21O1512)20.0020.0020.0020.00Sum total as a coated tablet480.00480.00480.00480.00

[0076] Control drug

[0077] Tagrisso™ tablet 80 mg (containing 80 mg as osimertinib, AstraZeneca Korea)

[0078] Hereinafter, the present invention will be described in more detail using experimental examples. These experimental examples are intended solely to illustrate the present invention more specifically, and it will be obvious to those skilled in the art that the scope of the present invention is not limited by them.

[0079] Experimental Examples.

[0080] Experimental Example 1. Derivation of an optimal formulation

[0081] Hereinafter, to demonstrate that the exemplary formulations of the present invention are optimal formulation, the effects of the proportion of hydroxypropyl cellulose (amount contained per tablet) as a binder and the proportion of low-substituted hydroxypropyl cellulose (amount contained per tablet) as a disintegrant will be examined.

[0082] 1. Effect of binder proportion on disintegration time and tabletability

[0083] A. Purpose

[0084] Binders are used to provide binding strength to granules. However, since varying the proportion (content) of the binder may result in delayed disintegration or tableting difficulties, disintegration and tabletability were evaluated using tablets prepared according to Examples 1 to 3 and Comparative Examples 1 to 2 in which the proportion of hydroxypropyl cellulose binder was varied.

[0085] B. Evaluation method

[0086] To evaluate disintegration time, the tablets (uncoated tablets) according to Examples 1 to 3 and Comparative Examples 1 to 2 were subjected to a disintegration test (37±2 ℃, in water) in accordance with the General Test Methods of the Korean Pharmacopoeia. The disintegration time was defined as the time it took for the tablets (uncoated tablets) according to Examples 1 to 3 and Comparative Examples 1 to 2 to completely disappear from the bottom of the disintegrator. The results are shown in Table 3.

[0087] To evaluate tabletability, the tablets (uncoated tablets) manufactured in Examples 1 to 3 and Comparative Examples 1 to 2 were used. Tabletability was evaluated by checking for tableting defects such as sticking, where the mixture adheres to the punch surface of the tablet, and capping, where the top of the tablet peels off, when the tablets were compressed at the same compression pressure. The results are shown in Table 3.

[0088] C. Evaluation results

[0089] Referring to Table 3, the disintegration time increased as the proportion of the binder hydroxypropyl cellulose increased.

[0090] In Comparative Example 1, where 5 mg of hydroxypropyl cellulose was added per tablet, sticking occurred during tableting, while no noticeable tableting problems occurred in other formulations.

[0091] Through the disintegration time and tabletability evaluations, it was confirmed that the amount of hydroxypropyl cellulose that met the criteria was 10 to 20 mg per tablet.

[0092] ClassificationComparative Example 1Example 1Example 2Example 3Comparative Example 2Disintegration time2 minutes and 12 seconds4 minutes and 8 seconds5 minutes and 17 seconds9 minutes and 22 seconds11 minutes and 35 secondsTabletabilityStickingNo abnormalityNo abnormalityNo abnormalityNo abnormality

[0093] 2. Effect of proportion of disintegrant on disintegration time, tabletability, and dissolution rate

[0094] A. Purpose

[0095] Disintegrants are used to control the disintegration rate of tablets, and the disintegration rate and dissolution rate may vary depending on the amount of disintegrant. Therefore, among the amounts of hydroxypropyl cellulose confirmed in the above-described experiment (10 to 20 mg), the amount of hydroxypropyl cellulose was fixed at the median value of 15 mg. Tablets (uncoated tablets) of Comparative Example 3 and Examples 2, 4, and 5, in which the proportion of the disintegrant low-substituted hydroxypropyl cellulose was varied, were used to evaluate tabletability, disintegration time, and dissolution rate.

[0096] B. Evaluation method

[0097] Disintegration time and tabletability were evaluated using the same methods described above. The dissolution rate was evaluated using the Dissolution Test Method 2 (paddle method) of the Korean Pharmacopoeia. The tablets were rotated at 50 rpm in 900 mL of solution at pH 4.0 (dissolution medium), pH 1.2 (pharmacopoeial solution), and pH 6.8 (pharmacopoeial solution). The dissolution rate of osimertinib was checked at 5, 10, 15, and 30 minutes. The results are shown in Table 4.

[0098] C. Evaluation results

[0099] Referring to Table 4, as the proportion of low-substituted hydroxypropyl cellulose increased, the disintegration time shortened, and the dissolution rate also gradually increased. Furthermore, no noticeable tableting problems occurred in the tablets (uncoated tablets) of Comparative Example 3 and Examples 2, 4, and 5.

[0100] Based on the disintegration time, dissolution rate, and tabletability, the amount of low-substituted hydroxypropyl cellulose that met the criteria was confirmed to be 12 to 20 mg per tablet. Among these, the amount of low-substituted hydroxypropyl cellulose was set to 12 mg, which showed the most similar dissolution rate to the control drug (Tagrisso™ tablet 80 mg).

[0101] ClassificationComparative Example 3Example 2Example 4Example 5Disintegration time9 minutes and 43 seconds4 minutes and 47 seconds3 minutes and 24 seconds3 minutes and 12 secondsTabletabilityNo abnormalityNo abnormalityNo abnormalityNo abnormalityDissolution rate (15 minutes)66.4%84.7%90.6%92.1%

[0102] 3. Derivation of an optimal formulation considering scale-up

[0103] The formulations of Example 2 and Example 6 (see Table 5 below), in which the amounts of the lubricant and the coating agent were adjusted based on the formulation of Example 2, were evaluated for tableting problems during the actual product production process (scale-up: inputting raw materials for production of 12,000 tablets).

[0104] Formulation purposeIngredient nameExample 2Example 6Active pharmaceutical ingredientOsimertinib mesylate(as osimertinib)95.40(80)95.40(80)ExcipientD-mannitol329.00329.00BinderHydroxypropyl cellulose15.0015.00DisintegrantLow-substituted hydroxypropyl cellulose12.0012.00LubricantSodium stearyl fumarate6.0010.00LubricantLight anhydrous silicic acid2.602.60Sum total as an uncoated tablet460.00464.00Coating agentTabshield Orange (21O1512)20.0014.00Sum total as a coated tablet480.00478.00

[0105] (The coated tablet according to Example 6 was manufactured using the same method as Example 1 according to the ingredients and contents in Table 5 above.)

[0106] As a result of the evaluation, the formulation of Example 6 was superior in terms of the occurrence of tableting defects such as sticking, where the mixture adheres to the punch surface of the tablet, and capping where the top of the tablet peels off, when the tablets were compressed at the same compression pressure in the actual product production process. Thereafter, a finished product evaluation test and a bioequivalence test were performed using the formulation of Example 6.

[0107] Experimental Example 2. Finished product evaluation test

[0108] Test method

[0109] To evaluate the finished product of the coated tablet comprising osimertinib mesylate of Example 6, a content test, a dissolution test, and a content uniformity test were performed. The test methods for each are as follow.

[0110] <Content test>

[0111] - Detector: Ultraviolet spectrophotometer (measurement wavelength: 210 nm)

[0112] - Column: C18, 4.6 mm × 150 mm, 5 μm or equivalent

[0113] - Column temperature: 40 ℃

[0114] - Flow rate: 1.0 mL / min

[0115] - Injection volume: 10 μL

[0116] - Mobile phase: *pH 3.0 buffer: acetonitrile: methanol (700:240:60)

[0117] *pH 3.0 buffer: Approximately 1.36 g of KH2PO4was dissolved in 1,000 mL of water, and 2 mL of triethylamine was added and mixed. The pH was adjusted to 3.0 ± 0.05 with H3PO4.

[0118] <Dissolution test>

[0119] A. Dissolution test conditions

[0120] 1) Dissolution method: Dissolution test method 2 (paddle method) of the Korean Pharmacopoeia

[0121] 2) Dissolution solution: pH 4.0 solution, 900 mL

[0122] 3) Temperature: 37 ± 0.5 ℃

[0123] 4) Rotation speed: 50 rpm

[0124] 5) Test time: 30 minutes

[0125] B. Instrument operating conditions

[0126] 1) Detector: UV spectrophotometer (measurement wavelength: 210 nm)

[0127] 2) Column: C18, 4.6 mm × 150 mm, 5 μm or equivalent

[0128] 3) Column temperature: 40 ℃

[0129] 4) Flow rate: 1.0 mL / min

[0130] 5) Injection volume: 10 μL

[0131] 6) Mobile phase: *pH 3.0 buffer: acetonitrile: methanol (700:240:60)

[0132] *pH 3.0 buffer: Approximately 1.36 g of KH2PO4was dissolved in 1,000 mL of water, and 2 mL of triethylamine was added and mixed. The pH was adjusted to 3.0 ± 0.05 with H3PO4.

[0133] Test results

[0134] Referring to Tables 6 to 9, the coated tablet comprising osimertinib mesylate according to Example 6 of the present invention was confirmed to meet all specified criteria and test methods.

[0135] No.123AverageContent (%)100.6100.3100.6100.5

[0136] No.123AverageDissolution (%)939295No.45693Dissolution (%)939592

[0137] No.12345AverageContent (%)103.198.798.6102.098.1No.678910100.2Content (%)100.2100.998.7101.0100.4Average mass (mg)Average content (x)Standard deviation (s)Acceptance coefficient (k)478.1100.181.652.4Acceptance value (AV, %)| 100.18 - 100.18 | + 2.4 x 1.65 =4.0%

[0138] ClassificationTargetResult valueAcceptanceContent test95.0 ~ 105.0%100.5%AcceptedDissolution test80% or more at 30 minutes92% to 95%AcceptedContent uniformity test15% or less4.0%Accepted

[0139] Experimental Example 3. Bioequivalence test

[0140] A comparative dissolution test and a comparative disintegration test were performed to confirm that the coated tablet (test drug) comprising osimertinib mesylate according to Example 6 of the present invention is bioequivalent to the control drug, Tagrisso™ tablet (80 mg).

[0141] 1. Comparative dissolution test

[0142] Test method

[0143] <Dissolution test conditions>

[0144] <Dissolution test>

[0145] A. Dissolution test conditions

[0146] 1) Dissolution method: Dissolution test method 2 (paddle method) of the Korean Pharmacopoeia

[0147] 2) Dissolution solution: 900 mL of pH 4.0 solution (dissolution medium), pH 1.2 solution (pharmacopoeial solution), pH 6.8solution (pharmacopoeial solution)

[0148] 3) Temperature: 37 ± 0.5 ℃

[0149] 4) Rotation Speed: 50 rpm

[0150] 5) Analysis Time: 5 min, 10 min, 15 min, 30 min, (45 min)

[0151] B. Instrument operating conditions

[0152] 1) Detector: UV spectrophotometer (measurement wavelength: 210 nm)

[0153] 2) Column: C18, 4.6 mm × 150 mm, 5 μm or equivalent

[0154] 3) Column temperature: 40 ℃

[0155] 4) Flow rate: 1.0 mL / min

[0156] 5) Injection volume: 10 μL

[0157] 6) Mobile phase: *pH 3.0 buffer: acetonitrile: methanol (700:240:60)

[0158] *pH 3.0 buffer: Approximately 1.36 g of KH2PO4was dissolved in 1,000 mL of water, and 2 mL of triethylamine was added and mixed. The pH was adjusted to 3.0 ± 0.05 with H3PO4.

[0159] Test results

[0160] The results of the comparative dissolution test in the dissolution medium at pH 4.0 are shown in FIG. 1. Referring to FIG. 1, although the dissolution test criteria (80% or more at 30 minutes) were met, the dissolution rate of the coated tablet comprising osimertinib mesylate according to Example 6, the test drug, was lower than that of the control drug, Tagrisso™ tablet 80 mg.

[0161] The results of the comparative dissolution test in the pharmacopoeial solution at pH 1.2, are shown in FIG. 2. Referring to FIG. 2, the coated tablet comprising osimertinib mesylate according to Example 6, the test drug, exhibited a dissolution rate of 90% or more in 10 minutes.

[0162] The results of the comparative dissolution test in the pharmacopoeial solution at pH 6.8, are shown in FIG. 3. Referring to FIG. 3, the coated tablet comprising osimertinib mesylate according to Example 6, the test drug, exhibited a lower dissolution rate than the control drug, Tagrisso™ tablet 80 mg. However, it was confirmed that both the test drug and the control drug reached a plateau around 30 minutes.

[0163] Through the above-described results, the coated tablet comprising osimertinib mesylate according to Example 6 of the present invention was confirmed to exhibit a dissolution rate suitable for the dissolution test criteria (80% or more at 30 minutes).

[0164] In addition, the coated tablet (test drug) comprising osimertinib mesylate according to Example 6 of the present invention showed delayed dissolution compared to the control drug in the dissolution medium at pH 4.0 and the pharmacopoeial solution at pH 6.8, but it exhibited a faster dissolution rate than the control drug at pH 1.2, which is similar to gastric juice, with a dissolution rate of 90% or more within 10 minutes.

[0165] 2. Comparative disintegration test

[0166] Test method

[0167] The coated tablet comprising osimertinib mesylate according to Example 6, the test drug, and the control drug, Tagrisso™ tablet 80 mg, were subjected to a disintegration test according to the disintegration test method of the General Test Methods of the Korean Pharmacopoeia (37 ± 2 ℃, in water). The disintegration time was defined as the time it took for the tablets to completely disappear from the bottom of the disintegrator. The results are shown in Table 10.

[0168] Test results

[0169] Referring to Table 10, the coated tablet comprising osimertinib mesylate according to Example 6, the test drug, exhibited faster disintegration than the control drug, Tagrisso™ tablet 80 mg.

[0170] ClassificationDisintegration timeTest drug5 minutes and 27 seconds (5 minutes and 3 seconds to 5 minutes and 50 seconds)Control drug8 minutes (7 minutes and 34 seconds to 8 minutes and 29 seconds)

[0171] 3. Conclusion

[0172] When in vivo absorption was predicted based on the results of the bioequivalence test, based on the faster disintegration time than that of the control drug, Tagrisso™ 80 mg tablet, and the dissolution results at pH 1.2 solution, it was predicted that the tablet would be fully dissolved in the stomach before passing into the small intestine, confirming that the dissolution pattern at pH 1.2 is more important than that at pH 4.0 and pH 6.8. Furthermore, the Tmaxof the control drug, Tagrisso™ 80 mg tablet, was six hours (3 to 24 hours), suggesting that dissolution within 30 minutes at pH 4.0 and pH 6.8 would not significantly affect drug absorption. Therefore, the coated tablet comprising osimertinib mesylate according to Example 6 ensured bioequivalence with the control drug, Tagrisso™ 80 mg tablet, thereby confirming the potential for providing a pharmaceutical formulation with guaranteed safety and efficacy.

[0173] While the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that these specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereto. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1.A pharmaceutical formulation comprising osimertinib or a pharmaceutically acceptable salt thereof and hydroxypropyl cellulose as a binder, wherein the pharmaceutical formulation does not contain microcrystalline cellulose.2.The pharmaceutical formulation of claim 1, further comprising one or more pharmaceutical additives selected from the group consisting of an excipient, a disintegrant, and a lubricant.3.The pharmaceutical formulation of claim 2, wherein the excipient is D-mannitol.4.The pharmaceutical formulation of claim 2, wherein the disintegrant is low-substituted hydroxypropyl cellulose.5.The pharmaceutical formulation of claim 2, wherein the lubricant is a combination of sodium stearyl fumarate and light anhydrous silicic acid.6.The pharmaceutical formulation of claim 2, wherein the excipient is in an amount of 60% to 80% by weight, the disintegrant is in an amount of 2% to 6% by weight, and the lubricant is in an amount of 1% to 6% by weight, based on the total weight of the pharmaceutical formulation.7.The pharmaceutical formulation of claim 1, wherein the hydroxypropyl cellulose is in an amount of 1% to 6% by weight based on the total weight of the pharmaceutical formulation.8.The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is formulated into a solid oral formulation.9.The pharmaceutical formulation of claim 8, wherein the solid oral formulation is a tablet or a film-coated tablet.

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