Pharmaceutical compositions containing axitinib

Abstract

To provide immediate release tablet compositions containing axitinib.SOLUTION: The invention relates to an immediate release tablet composition comprising axitinib form IV characterized by an XRPD pattern comprising the peaks at about 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.1, 20.6, 21.6, 23.2, 24.2, 24.9, 26.1 and 27.5±0.1 degrees of 2θ when measured with Cu Kα1 radiation, and one or more pharmaceutically acceptable additives, where the composition comprises an intragranular layer comprising axitinib, an excipient and 20-30 w / w% of a binder relative to the total tablet weight without coating, where the binder is crystalline cellulose, and the composition exhibits a dissolution rate between 40% and 65% in 30 minutes when tested in 900 ml of 0.01 N hydrochloric acid with pH 2.0 at 37°C, 75 rpm in a USP apparatus II.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an immediate release tablet pharmaceutical composition containing axitinib Form IV. [Background technology]

[0002] formula: [ka]

[0003] Axitinib, represented by the formula: N-methyl-2-({3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl}sulfanyl)benzamide, is an inhibitor of tyrosine kinases involved in angiogenesis, in particular VEGFR tyrosine kinase.

[0004] Axitinib, alone and in combination with other chemotherapy agents, has shown clinical activity against several tumors, including non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma (mRCC), metastatic breast cancer, pancreatic cancer, and thyroid cancer, and is undergoing clinical investigation.

[0005] Axitinib is sold by Pfizer under the trade name Inlyta® and is disclosed in WO 2001 / 002369. Pharmaceutical compositions containing axitinib have also been disclosed (e.g. WO 2013 / 046133). Inlyta® is available as immediate release film-coated tablets with various active ingredient doses (1, 3, 5 and 7 mg). Crystalline forms of axitinib characterized by different stability and solubility have also been disclosed (e.g. WO 2006 / 048751, WO 2008 / 122858).

[0006] In developing a formulation of form IV axitinib, it proved to be very difficult to achieve bioequivalence with the commercially available Inlyta®. Prototypes containing form IV axitinib showed similar dissolution behavior to Inlyta® in the FDA dissolution assay, but were more bioavailable in vivo than Inlyta® and were not bioequivalent to Inlyta®.

[0007] Therefore, it is desirable to have a tablet composition containing Form IV axitinib that is stable, suitable for manufacture on a commercial scale, exhibits suitable dissolution, and is bioequivalent to Inlyta®. Summary of the Invention

[0008] The present invention is based on the discovery that an immediate release tablet composition containing axitinib Form IV is bioequivalent to Inlyta® if it exhibits a dissolution rate of 40-70% in 30 minutes when tested using USP Apparatus II containing 900 ml of 0.01 N hydrochloric acid (pH 2.0) at 37°C and 75 rpm.

[0009] Accordingly, the present invention relates to an immediate release tablet composition comprising axitinib Form IV characterized by an XRPD pattern comprising peaks at about 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.1, 20.6, 21.6, 23.2, 24.2, 24.9, 26.1 and 27.5±0.1 degrees 2θ when measured with CuKα1 radiation, and one or more pharma- ceutically acceptable excipients, wherein said composition exhibits a dissolution rate of 40-70% in 30 minutes when tested at 37° C. and 75 rpm using USP Apparatus II containing 900 ml of 0.01N hydrochloric acid, pH 2.0. [Brief description of the drawings]

[0010] [Figure 1] Figure 1 shows the full XRPD pattern of axitinib Form IV. Measurement conditions see Examples. [Diagram 2]FIG. 2 shows a flow chart of the wet granulation process used to manufacture the tablets of Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present invention relates to an immediate release tablet composition comprising axitinib Form IV characterized by an XRPD pattern comprising peaks at about 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.1, 20.6, 21.6, 23.2, 24.2, 24.9, 26.1, and 27.5±0.1 degrees 2θ when measured with CuKα1 radiation, and one or more pharma- ceutically acceptable excipients, wherein the composition exhibits a dissolution rate of 40-70% in 30 minutes when tested at 37° C. and 75 rpm using USP Apparatus II containing 900 ml of 0.01N hydrochloric acid (pH 2.0).

[0012] Axitinib is a BCS class II compound with low solubility; it is only well soluble in the stomach at pH 1.7. Inlyta® contains axitinib in form XLI, which is crystalline (see European Medicines Agency CHMP assessment report). Form XLI is the thermodynamically most stable form among the polymorphs.

[0013] Other forms of axitinib have been disclosed in the prior art. The immediate release tablets of the present invention contain form IV axitinib, which is less photostable but 2-3 times more water soluble than form XLI axitinib, which is crystalline.

[0014] The XRPD pattern of Form IV axitinib is shown in Figure 1. The XRPD pattern includes peaks at about 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.1, 20.6, 21.6, 23.2, 24.2, 24.9, 26.1, and 27.5±0.1 degrees 2θ when measured with CuKα1 radiation. The XRPD pattern of Form IV axitinib may further include characteristic peaks at the following angles 2θ (±0.1) when measured using CuKα1 radiation: 9.5, 14.9, 16.5, 17.3, 19.3, 20.3, 24.6, and 26.4.

[0015] Although different polymorphic forms are known to affect the stability, dissolution and bioequivalence of a formulation, problems were encountered when preparing an immediate release tablet composition using axitinib form IV, possibly due to the higher solubility of axitinib form IV compared to form XLI. In particular, a prototype containing axitinib form IV had a dissolution behavior similar to Inlyta® using the dissolution method shown in the FDA database (USP II (paddle), 75 rpm, 900 ml 0.01 N hydrochloric acid), but the bioavailability was much higher and it was not bioequivalent to Inlyta®.

[0016] Surprisingly, the inventors have found that an immediate release tablet composition containing axitinib Form IV and one or more pharma- ceutically acceptable excipients, which shows a dissolution rate of 40-70% in 30 minutes, preferably 45-65% in 30 minutes, when tested using USP Apparatus II with 900 ml of 0.01 N hydrochloric acid (pH 2.0) at 37°C and 75 rpm, is bioequivalent to Inlyta®.

[0017] The tablet composition of the present invention is highly stable even after storage under high temperature or humidity conditions, without conversion of Form IV axitinib to Form XIL or other crystalline forms of axitinib, or increase in impurities.

[0018] The tablet composition of the present invention is an immediate release tablet composition. As used herein, the term "immediate release tablet" refers to a tablet that disintegrates, dissolves and releases drug rapidly (within 30 minutes, preferably within 5 minutes).

[0019] In the present invention, a dissolution rate of more than 70% is defined as the in vivo C max and AUC t Compared with C for tablets containing axitinib form IV max Value and AUC t Increase the value.

[0020] As used herein, the term “C max " refers to the maximum plasma concentration reached after a drug is administered, and the term "AUC t " refers to the area under the plasma concentration curve from the time of administration to time t.

[0021] C of immediate release tablets containing axitinib form IV with dissolution rates of 40-70% max and AUC t However, Inlighter (registered trademark) C max and AUC t It is the same as:

[0022] Typically, drug dissolution is assessed by dissolution methods known to those skilled in the art. The dissolution method used in the present invention involves dissolving the axitinib formulation in 900 ml of 0.01 N hydrochloric acid (pH 2.0) at 37° C. and stirring at 75 rpm using a USP Apparatus II with paddles.

[0023] Typically, the total weight of the tablet of the present invention (excluding the coating) is 50 to 900 mg, preferably 90 to 800 mg, and even more preferably 100 mg, 300 mg, 500 mg or 700 mg.

[0024] The tablet composition of the present invention contains 0.5 to 5 w / w% axitinib based on the total weight of the tablet excluding the coating.

[0025] Thus, although the amount of Form IV axitinib contained in the tablet composition of the present invention was low, the use of polymorphic Form IV axitinib had a significant impact on the bioavailability of the immediate release tablets.

[0026] The tablet composition of the present invention may further comprise a pharma- ceutically acceptable additive. The additives used in the present invention are well known and are additives that are conventionally used by those skilled in the art. The pharma-ceutically acceptable additives can be selected from one or more excipients, binders, disintegrants, glidants or lubricants. The additives balance the properties of axitinib form IV in immediate release formulations without interacting with axitinib form IV.

[0027] The excipient used in the present invention may be any excipient known to those skilled in the art. Typically, the excipient used in the present invention is lactose, sucrose, calcium carbonate, mannitol, cellulose, maltose, sorbitol, starch or a mixture thereof. Preferably, it is lactose monohydrate.

[0028] The binder used in the present invention can be any binder known to those skilled in the art.Suitable binders are microcrystalline cellulose (MCC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), copovidone, polyvinylpyrrolidone-vinyl acetate (PVP / VA) copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, hypromellose or their mixtures.Microcrystalline cellulose is a particularly preferred binder.

[0029] In some cases, a disintegrant may be used. The disintegrant may be any disintegrant known to those skilled in the art. Suitable disintegrants for use in the present invention include croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, or mixtures thereof. Croscarmellose sodium is a particularly preferred disintegrant. The disintegrant may be incorporated intragranularly or extragranularly, and in a preferred embodiment, the formulation of the present invention has a disintegrant present extragranularly.

[0030] Optionally, a flow agent may be used in the present invention. The flow agent may be any flow agent known to those skilled in the art. Colloidal silicon dioxide is a particularly preferred flow agent.

[0031] The lubricant used in the present invention may be any lubricant known to those skilled in the art. Magnesium stearate is a particularly preferred lubricant.

[0032] Preferably, the tablet composition of the present invention comprises: Intra-particle: Form IV axitinib 0.5-5% One or more excipients, preferably lactose 25-35 w / w% One or more binders, preferably MCC 20-30 w / w% Outside the particle: One or more binders, preferably MCC 30-50 w / w% One or more disintegrants, preferably croscarmellose sodium 0.1-10 w / w%, and One or more lubricants, preferably magnesium stearate 0.1-10 w / w% (All percentages are based on total tablet weight excluding coating) Contains:

[0033] The inventors have demonstrated that in this particular embodiment, the absence of a disintegrant within the particles enhances the C value of the immediate release tablet composition containing axitinib Form IV. max and AUC t It has been found to be useful in reducing the creatinine concentration and promoting bioequivalence with Inlyta®.

[0034] The immediate release tablet composition of the present invention is manufactured by wet granulation, which includes an inner particle layer and an outer particle layer. The method used is robust and cost-effective. The wet granulation method uses a granulation solvent (wetting agent) selected from the group consisting of water, acetone, ethanol, isopropanol or mixtures thereof. Usually, water is used as a wetting agent, which has the advantage of being safe to handle. The wet mass obtained by adding the liquid to the powder mixture is granulated and dried.

[0035] The granulation method may be low shear wet granulation, high shear wet granulation or fluid bed granulation. Preferably, the granulation method is high shear wet granulation.

[0036] The inner layer of the particle contains axitinib form IV and one or more pharma- ceutically acceptable excipients, and improves the flowability and uniform distribution of axitinib form IV in the formulation.Furthermore, in the present invention, the inner layer of the particle also adjusts the dissolution behavior of the tablet composition containing axitinib form IV when prepared by wet granulation.

[0037] Typically, the outer particle layer improves the compression properties of the final blend. In the present invention, the outer particle layer does not contain Form IV axitinib.

[0038] If necessary, the tablet can be further coated with a film coat. Coating is generally performed to decorate the surface. Coating can be selected from one or more suitable coating materials known in the art.

[0039] Coating can be carried out by applying one or more film-forming polymers as a solution / suspension with or without other pharma- ceutically inert additives by coating techniques known in the art, such as spray coating or dip coating in a coating pan or fluidized bed.

[0040] The tablet composition of the present invention is packaged in a primary packaging material, for example a blister. The tablet composition of the present invention is preferably packaged in a PVC / PE / PVDC blister (triplex) or Alu-Alu blister.

[0041] In one embodiment of the invention, the inner particle layer contains axitinib, excipients and a binder.

[0042] Axitinib is present in an amount of 0.5-5 w / w%, more preferably 0.5-3 w / w%, and most preferably 0.5-1.5 w / w%, based on the total tablet weight excluding coating; excipients are present in an amount of 16-42 w / w%, more preferably 21-37 w / w%, based on the total tablet weight excluding coating; and binders are present in an amount of 0.5-38 w / w%, more preferably 0.5-33 w / w%, and even more preferably 15-25 w / w%, based on the total tablet weight excluding coating.

[0043] In a preferred embodiment of the present invention, the particle inner layer contains 0.5 to 5 w / w%, more preferably 0.5 to 3 w / w%, and most preferably 0.5 to 1.5 w / w% of Form IV axitinib, based on the total weight of the tablet excluding the coating, 16 to 42 w / w%, more preferably 21 to 37 w / w% of lactose monohydrate, based on the total weight of the tablet excluding the coating, and 0.5 to 38 w / w%, more preferably 0.5 to 33 w / w%, and even more preferably 15 to 25 w / w% of crystalline cellulose, based on the total weight of the tablet excluding the coating.

[0044] The outer layer of the particles of the immediate release tablet composition of the present invention contains one or more pharmaceutical additives. The additives used in the present invention are well known and are additives that are conventionally used by those skilled in the art. The pharma-ceutically acceptable additives can be selected from binders, disintegrants, or lubricants. In a preferred embodiment of the present invention, the inner layer of the particles contains 30-50 w / w% (percentage relative to the total weight of the tablet excluding the coating, the same applies below) of one or more binders, preferably MCC, 0.1-10 w / w% of one or more disintegrants, preferably croscarmellose sodium, and 0.1-10 w / w% of one or more lubricants, preferably magnesium stearate.

[0045] The invention is illustrated by the following examples. EXAMPLES

[0046] The complete XRPD pattern of Form IV axitinib shown in FIG. 1 was acquired using a Bruker-AXS D8 Vario diffractometer in θ / 2θ geometry (reflection mode) equipped with a Lynxeye detector with the following measurement conditions: Starting angle (2θ): 2.0° End angle (2θ): 35.0° Scan step size: 0.02° Scanning interval: 0.2 to 2.0 seconds Radiation species: Cu Emission wavelength: 1.5406 Å (Kα1), using a primary monochromator Exit slit: 6.0mm Focus slit: 0.2mm Divergence slit: variable (V20) Scattered radiation removal slit: 11.8 mm Receiving slit: 20.7 mm

[0047] Example 1 Pharmaceutical Compositions Containing Axitinib Form IV Tablets containing Form IV axitinib were prepared by wet granulation and the composition is shown in Table 1 below.

[0048] [Table 1]

[0049] Example 2 The composition of Example 1 is film-coated with 39% HPMC, 28% lactose monohydrate, 16% titanium dioxide, 9% iron oxide red, and 8% triacetin to obtain a film-coated tablet.

[0050] Example 3 The stability of the film-coated tablets of Example 2 in Alu-Alu was evaluated.

[0051] [Table 2] The invention as originally claimed is set forth below. [1] An immediate release tablet composition comprising Form IV axitinib and one or more pharma- ceutically acceptable excipients, wherein said Form IV axitinib is characterized by an XRPD pattern comprising peaks at about 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.1, 20.6, 21.6, 23.2, 24.2, 24.9, 26.1, and 27.5±0.1 degrees 2θ when measured with CuKα1 radiation, and wherein said composition exhibits a dissolution rate of 40-70% in 30 minutes when tested at 37° C. and 75 rpm using USP Apparatus II containing 900 ml of 0.01 N hydrochloric acid, pH 2.0. [2] The immediate release tablet composition according to [1], comprising an inner particle layer and an outer particle layer. [3] The immediate release tablet composition of [2], wherein the inner particle layer contains axitinib, an excipient and a binder. [4] The immediate release tablet composition according to [3], wherein axitinib is present in an amount of 0.5 to 5 w / w% based on the total weight of the tablet excluding the coating. [5] The immediate release tablet composition according to [3] or [4], wherein the excipient is present in an amount of 25 to 35 w / w% based on the total weight of the tablet excluding the coating. [6] The immediate release tablet composition according to any one of [3] to [5], wherein the binder is 20 to 30 w / w% based on the total weight of the tablet excluding the coating. [7] The immediate-release tablet composition according to any one of [3] to [6], wherein the excipient is lactose, sucrose, calcium carbonate, mannitol, cellulose, maltose, sorbitol, starch, or a mixture thereof, and the binder is crystalline cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, copovidone, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hypromellose, or a mixture thereof. [8] The immediate release tablet composition of [7], wherein the excipient is lactose monohydrate and the binder is microcrystalline cellulose. [9] The immediate release tablet composition according to any one of [2] to [8], wherein the outer layer of the particle contains a binder, a disintegrant and a lubricant.

[10] The immediate release tablet composition according to [9], wherein the binder is 30 to 50 w / w% based on the total weight of the tablet excluding the coating.

[11] The immediate release tablet composition according to any one of [9] or

[10] , wherein the disintegrant is 0.1 to 10 w / w% based on the total weight of the tablet excluding the coating.

[12] The immediate release tablet composition according to any one of [9] to

[11] , wherein the disintegrant is croscarmellose sodium and the binder is microcrystalline cellulose.

[13] Intraparticle: Form IV axitinib 0.5~5% One or more excipients, preferably lactose 25~35w / w% One or more binders, preferably MCC 20~30w / w% Outside the particle: One or more binders, preferably MCC 30~50w / w% One or more disintegrants, preferably croscarmellose sodium 0.1 to 10 w / w%, and One or more lubricants, preferably magnesium stearate 0.1~10w / w% (All percentages are based on total tablet weight excluding coating) The immediate release tablet composition according to any one of [1] to

[12] ,

[14] The immediate-release tablet according to any one of [1] to

[13] , further comprising a film coating.

[15] The immediate release tablet composition according to any one of [1] to

[14] , which is produced by wet granulation.

Claims

1. 1. An immediate release tablet composition comprising Form IV axitinib and one or more pharma- ceutically acceptable excipients, said Form IV axitinib characterized by an XRPD pattern comprising peaks at 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.1, 20.6, 21.6, 23.2, 24.2, 24.9, 26.1, and 27.5±0.1 degrees 2θ when measured with CuKα1 radiation; 1. An immediate release tablet composition comprising an inner particle layer containing 20-30 w / w% of a binder based on the total weight of the tablet excluding axitinib, excipients, and coating, said binder being crystalline cellulose, said inner particle layer not containing a disintegrant, said composition exhibiting a dissolution rate of 40-65% in 30 minutes when tested at 37°C and 75 rpm using USP Apparatus II containing 900 ml of 0.01 N hydrochloric acid (pH 2.0).

2. 10. The immediate release tablet composition of claim 1, comprising an inner particle layer and an outer particle layer.

3. 3. The immediate release tablet composition of claim 2, wherein axitinib is present at 0.5-5 w / w% based on the total weight of the tablet excluding coating.

4. The immediate release tablet composition according to claim 2 or 3, wherein the excipients are present in an amount of 25-35 w / w% based on the total weight of the tablet excluding coating.

5. The immediate release tablet composition according to any one of claims 2 to 4, wherein the excipient is lactose, sucrose, calcium carbonate, mannitol, cellulose, maltose, sorbitol, starch or a mixture thereof.

6. 6. The immediate release tablet composition of claim 5, wherein said excipient is lactose monohydrate.

7. The immediate release tablet composition according to any one of claims 2 to 6, wherein the particle outer layer contains a binder, a disintegrant and a lubricant.

8. The immediate release tablet composition according to claim 7, wherein the binder in the outer layer of the particles is 30-50 w / w% based on the total weight of the tablet excluding the coating.

9. The immediate release tablet composition according to any one of claims 7 or 8, wherein the disintegrant in the outer layer of the particles is 0.1 to 10 w / w% based on the total weight of the tablet excluding the coating.

10. The immediate release tablet composition of any one of claims 7 to 9, wherein the disintegrant is croscarmellose sodium and the binder is microcrystalline cellulose.

11. Intra-particle: Form IV axitinib 0.5-5% One or more excipients, lactose 25-35 w / w% One or more binders, crystalline cellulose 20-30 w / w% Outside the particle: One or more binders, crystalline cellulose 30-50 w / w% 0.1-10 w / w% of one or more disintegrants, and One or more lubricants: 0.1-10 w / w% (All percentages are based on total tablet weight excluding coating) The immediate release tablet composition according to any one of claims 1 to 10, comprising:

12. The immediate release tablet composition of claim 11, wherein the disintegrant is croscarmellose sodium.

13. The immediate release tablet composition of claim 11, wherein the lubricant is magnesium stearate.

14. The immediate release tablet composition according to any one of claims 1 to 13, further comprising a film coating.

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