Pharmaceutical formulation composition and preparation method therefor

Abstract

The present invention relates to a pharmaceutical formulation composition and a preparation method therefor. The composition comprises a kinase inhibitor represented by formula (I). The composition prepared in the present invention has good dissolution and stable quality, and can simultaneously meet various requirements, such as clinical medication and patient compliance.

Description

A pharmaceutical preparation composition and a preparation method thereof

[0001] Cross-reference to related applications

[0002] This application claims priority to Chinese Patent Application No. 202411008187.X entitled "A pharmaceutical preparation composition and a preparation method thereof" filed on July 25, 2024, the entire disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0003] The present application belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical composition containing a RET kinase inhibitor as an active ingredient and a preparation method thereof. BACKGROUND

[0004] The rearranged during transfection (RET) gene is a proto-oncogene that undergoes rearrangement during transfection, which encodes a cell membrane receptor tyrosine kinase, and its abnormality is a rare driver of multiple types of tumors. It is estimated that RET fusion exists in about 2% of non-small cell lung cancer (NSCLC), 10-20% of papillary thyroid cancer (PCT) and other types of thyroid cancer, and other cancer (such as colorectal cancer) subgroups; RET point mutation exists in about 60% of medullary thyroid cancer (MCT). RET fusion and RET point mutation cancer mainly rely on the activation of RET kinase to maintain their proliferation and survival, which is usually referred to as "oncogene addiction", making such tumors highly sensitive to small molecule inhibitors targeting RET.

[0005] Retevmo (selpercatinib) is a selective RET kinase inhibitor that can block RET kinase and prevent cancer cell growth. In May 2020, Retevmo was approved by the US FDA for the treatment of three types of tumor patients with gene changes (mutations or fusions) in the RET gene in tumors: non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and other types of thyroid cancer.

[0006] The compound 6-(3-hydroxy-3-methylmonocyclobutane-1-yl)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile of formula (I) is a highly selective rearranged during transfection (RET) kinase inhibitor that can block RET kinase and prevent cancer cell growth.

[0007] The compound of formula (I) has poor water solubility, which affects the bioavailability of the drug in vivo, and poor thermal stability, which causes significant absorption difference, and it is difficult to design high-dose toxicity climbing experiment in early research and development. How to improve the solubility of poorly soluble drugs has always been one of the hotspots in the field of pharmaceutical sciences today. The preparation of solid dispersion makes it possible to solve the above problems. There are many factors that cause the instability of solid dispersion, such as improper selection of carrier, improper ratio, etc. The interaction parameters between the drug and the polymeric carrier determine the direction of free energy change, and further determine the dissolution behavior. There are various types of polymer carriers, and the drug and the polymer carrier are limited in the free movement of the drug molecules in the polymer carrier through various weak interactions such as hydrogen bonding, van der Waals force, and ionic interaction, thereby determining the stability. Selecting different high molecular materials as carriers has different effects on the dissolution and recrystallization ability of the preparation. Different carriers can affect the interaction force between the drug and the carrier. In addition, different hydrophilic carrier materials have different hygroscopicity, which will affect the water absorption during storage. If the hygroscopicity of the carrier is too strong, not only will it reduce the viscosity of the carrier, thereby increasing the migration rate of the molecules, but also it will eventually lead to the recrystallization trend of amorphous drugs. At the same time, it will also lower the Tg value of the system, reduce its plasticity, accelerate aging, change the properties of the drug, reduce the dissolution rate, and ultimately affect the efficacy.

[0008] There are many methods for preparing solid dispersions at present, including hot melt extrusion, spray drying, freeze drying, anti-solvent precipitation method, etc. The dissolution rate, stability, morphology, particle size, etc. of the solid dispersions prepared by different preparation methods are also quite different. For example, the amorphous simvastatin prepared by freeze grinding crystallizes rapidly within 1 day, while the amorphous prepared by melt cooling method remains stable for 42 days. Therefore, we should select the appropriate preparation method in combination with the high temperature resistance, solubility, melting point, etc. of the drug itself and its use. SUMMARY

[0009] The present application provides a composition containing a RET kinase inhibitor compound of formula (I) and a preparation method thereof. The composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The composition can be prepared into a solid dispersion containing active ingredients by spray drying, and the solid dispersion is dry granulated with a pharmaceutically acceptable excipient to prepare granular capsules or tablets, preferably tablets.

[0010] The excipient in the pharmaceutical composition of the present application contains at least one of a filler, a disintegrant, a glidant and a lubricant.

[0011] The filler includes one or more of microcrystalline cellulose, siliconized microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, calcium dihydrogen phosphate, etc., preferably microcrystalline cellulose and siliconized microcrystalline cellulose. The disintegrant includes one or more of a mixture of cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, etc., preferably cross-linked sodium carboxymethyl cellulose. The glidant includes silicon dioxide, colloidal silicon dioxide, etc. The lubricant includes one or more of a mixture of magnesium stearate, stearic acid, calcium stearate, talc, sodium lauryl sulfate, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate, glycerol monostearate, etc.

[0012] The present application provides a spray-dried solid dispersion of a compound of formula (I) and a preparation method. The weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the polymer carrier is 2:1 to 1:5, preferably 1:3. The polymer carrier is selected from one or more of a mixture of copolyvidone, polyvinylpyrrolidone, polyethylene glycol, hypromellose and / or hypromellose-derivatives, and polyethylene glycol / vinylcaprolactam / vinyl acetate copolymer, and the preferred carrier is copolyvidone. The weight percentage of the solubilizer is 0.1% to 5%, and the solubilizer is selected from one or more of a mixture of poloxamer, sodium lauryl sulfate and vitamin E polyethylene glycol succinate (TPGS), and the preferred solubilizer is sodium lauryl sulfate. The organic solvent is selected from one or more of acetone, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, tetrahydrofuran and dichloromethane.

[0013] The pharmaceutical preparation composition of the present application can be prepared by the following process:

[0014] 1) completely dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymer carrier and a solubilizer in an organic solvent;

[0015] 2) spray-drying to obtain a solid dispersion, and the spray-drying inlet temperature is 80 to 100°C;

[0016] 3) dry granulation after mixing the solid dispersion with other excipients;

[0017] 4) tabletting or encapsulating the dry granulation.

[0018] The purpose of the present application is to provide a composition for clinical use, which has good dissolution, stable quality and can meet various requirements such as clinical medication and patient compliance. The compound of formula (I) has poor water solubility, which affects the in vivo bioavailability of the drug, and has poor thermal stability, so that degradation impurities are generated during hot melt extrusion. The compound of formula (I) and the preparation method thereof of the present application can significantly improve the solubility of the drug and thus improve the in vivo bioavailability, and can also avoid the increase of degradation impurities caused by high-temperature operation.

[0019] The compound of formula (I) has poor water solubility, with a solubility of about 0.14 mg / ml at pH 4.5 and only about 7 ug / ml at pH 6.8. The low water solubility results in low bioavailability in vivo. Solid dispersions can well improve this problem, and hot melt extrusion and spray drying are the two processes most commonly used to prepare solid dispersions. Hot melt extrusion has relatively high efficiency but has a significant disadvantage that it is not suitable for raw materials which are sensitive to heat. After trial and selection, spray drying is used to prepare the solid dispersion, which not only achieves the purpose of increasing solubility and improving bioavailability, but also avoids the occurrence of thermal degradation. The prepared spray-dried solid dispersion of the compound of formula (I) has a solubility of 16 mg / ml at pH 4.5 and 14 mg / ml at pH 6.8, which is significantly improved compared with the compound of formula (I).

[0020] The data in Table 1 show that about 20% of the compound of formula (I) is dissolved in 60 minutes without any solubilizing adjuvant or solubilizing treatment in Examples 1 and 2, and about 40% of the compound of formula (I) is dissolved in 60 minutes after adding the solubilizing agent sodium dodecyl sulfate in Example 3; about 90% of the compound of formula (I) is dissolved in 60 minutes in the solid dispersions prepared in Example 4 and Example 12. The data in Table 5 show that the related substance test finds that the thermal degradation impurities of Example 12 increase significantly compared with other examples.

[0021] The types of polymer carriers are various, and the drug and the polymer carrier are limited in the free movement of the drug molecules in the polymer carrier through various weak interactions such as hydrogen bonds, van der Waals forces, and ionic interactions, thereby affecting the dissolution behavior. Examples 4-7 investigate the solubilizing effect of different polymer carriers, and the data in Table 2 show that the dissolution is increased most significantly when copolyvidone and polyvinylpyrrolidone are used as carriers, with about 90% of the compound of formula (I) being dissolved in 60 minutes. However, the results of the accelerated test (40°C, RH 75%) (Table 4) show that the dissolution with polyvinylpyrrolidone as the carrier has a downward trend, which is presumably due to the crystallization of the solid dispersion caused by the strong hygroscopicity of polyvinylpyrrolidone.

[0022] When the ratio of the drug and the high molecular polymer carrier is not properly selected, the dissolution and storage stability will be affected. Examples 4 and 8-11 investigate the effect of the ratio of API to copolyvidone on the solubilizing effect, and the results in Table 3 show that the dissolution is significantly improved as the ratio of API: polymer carrier increases from 1:1 to 1:3, but there is no significant change as the ratio increases from 1:3 to 1:5. Considering the convenience of the preparation process and the patient's medication compliance, the ratio of API: polymer carrier is finally selected to be 1:3.

[0023] The results of the in vivo PK study in rats are shown in Table 6, and the AUC of Example 1 and Example 3 is 9850 (hr*ng / mL) and 8568 (hr*ng / mL), respectively, while the AUC of Example 4 is 12300 (hr*ng / mL). 0-INF 0-INF ​AUC of the solid dispersion (Example 4) was 25480 (hr*ng / mL), which was 2-3 times that of the conventional formulation (Example 1 and Example 3). The solid dispersion is a compound of formula (I) dispersed in a molecular state in a water-soluble carrier in an amorphous state, which has broken the crystal lattice to enable a significant increase in solubility, thereby improving bioavailability in rats. The hot melt extrusion process at high temperature significantly increases thermal degradation impurities of the compound of formula (I), and the preparation of the solid dispersion by spray drying can avoid thermal degradation. 0-INF is 2-3 times that of the conventional formulation (Example 1 and Example 3). The solid dispersion is a compound of formula (I) dispersed in a molecular state in a water-soluble carrier in an amorphous state, which has broken the crystal lattice to enable a significant increase in solubility, thereby improving bioavailability in rats. The hot melt extrusion process at high temperature significantly increases thermal degradation impurities of the compound of formula (I), and the preparation of the solid dispersion by spray drying can avoid thermal degradation. DETAILED DESCRIPTION

[0024] The present application is further illustrated by the following examples, but is not limited to the following examples.

[0025] Example 1

[0026] The pharmaceutical composition of the present application, preferably the formula composition is as follows (% w / w):

[0027] The preparation process is as follows:

[0028] 1) Mix the compound of formula (I), microcrystalline cellulose PH101, sodium carboxymethyl starch and magnesium stearate uniformly;

[0029] 2) Take the mixed material to a rotary tablet press for tabletting, and perform film coating.

[0030] Example 2

[0031] The pharmaceutical composition of the present application, preferably the formula composition is as follows (% w / w):

[0032] The preparation process is as follows:

[0033] 1) Mix the compound of formula (I), microcrystalline cellulose PH102, lactose F100, croscarmellose sodium, magnesium stearate and silicon dioxide uniformly;

[0034] 2) Take the mixed material to fill the capsule.

[0035] Example 3

[0036] The pharmaceutical composition of the present application, preferably the formula composition is as follows (% w / w):

[0037] The preparation process is as follows:

[0038] 1) Mix the compound of formula (I), microcrystalline cellulose PH101, sodium carboxymethyl starch, sodium dodecyl sulfate and magnesium stearate (internal) uniformly;

[0039] 2) The mixed material is added to the hopper of the dry granulator for granulation. The dry granulation parameters are as follows: feeding frequency 10 Hz, tabletting frequency 13 Hz, granulation frequency 12 Hz, and oil pressure 15-25 kg / cm 2 The first screen is 2.0 mm and the second screen is 0.8 mm.

[0040] 3) The prepared granules are mixed with the additional materials and then fed into a rotary tablet press.

[0041] 4) The granules are coated with Opadry, and the coating weight is 2-4%.

[0042] Examples 4-7

[0043] The pharmaceutical composition of the present application has the following preferred formulation composition (% w / w):

[0044] 1) The compound of formula (I), the polymer carrier and sodium dodecyl sulfate are completely dissolved in a mixed solvent of methanol and dichloromethane (1:1) to obtain a solution with a solid content of 15%.

[0045] 2) The inlet temperature is 80-100°C, and the pump speed is 20%. The solid dispersion is obtained by spray drying.

[0046] 3) The solid dispersion is mixed with the internal material, and dry granulation is performed.

[0047] 4) The dry granulation granules are mixed with the additional excipients, and then fed into a rotary tablet press.

[0048] 5) The granules are coated with Opadry, and the coating weight is 2-4%.

[0049] Examples 8-11

[0050] The pharmaceutical composition of the present application has the following preferred formulation composition (% w / w):

[0051] 1) The compound of formula (I), the polymer carrier and sodium dodecyl sulfate are completely dissolved in a mixed solvent of methanol and dichloromethane (1:1) to obtain a solution with a solid content of 15%.

[0052] 2) The inlet temperature is 80-100°C, and the pump speed is 20%. The solid dispersion is obtained by spray drying.

[0053] 3) The solid dispersion is mixed with the internal material, and dry granulation is performed.

[0054] 4) The dry granulation granules are mixed with the additional excipients, and then fed into a rotary tablet press.

[0055] 5) The granules are coated with Opadry, and the coating weight is 2-4%.

[0056] Example 12

[0057] The pharmaceutical composition of the present application, preferably the formulation composition is as follows (% w / w):

[0058] The preparation process is as follows:

[0059] 1) The compound of formula (I) and Soluplus are hot melt extruded and crushed through an 80 mesh sieve to obtain a solid dispersion

[0060] 2) The solid dispersion is mixed evenly with the remaining excipients, and a rotary tablet press is used to press the tablets;

[0061] 3) Coated with Opadry, with a coating weight increase of 2-4%.

[0062] Experimental Example 1

[0063] Determination of dissolution curve of the present application

[0064] Take the sample of each example, adopt the second method of dissolution and release determination in Chinese Pharmacopoeia 2020 edition volume four general rules 0931 to determine the dissolution curve.

[0065] The dissolution method is: paddle method, pH 4.5 phosphate buffer, 900 mL, 50 rpm, 37 ± 0.5 ℃, sampling time 10 minutes and 60 minutes. The dissolution data is shown in Tables 1-3.

[0066] Table 1 dissolution data of examples 1-4 and example 12

[0067] Table 2 dissolution data of examples 4-7

[0068] Table 3 dissolution data of examples 4 and examples 8-11

[0069] Experimental Example 2

[0070] Determination of accelerated test dissolution curve of the present application

[0071] Take the sample of example 4 and example 5 and place it in the condition of 40℃, RH 75%, respectively take sample in January, February, March and June, adopt the second method of dissolution and release determination in Chinese Pharmacopoeia 2020 edition volume four general rules 0931 to determine the dissolution curve.

[0072] The dissolution method is: paddle method, pH 4.5 phosphate buffer, 900 mL, 50 rpm, 37 ± 0.5 ℃, sampling time 10 minutes and 60 minutes. The dissolution data is shown in Table 4.

[0073] Table 4 dissolution data of examples 4 and example 5 (accelerated test)

[0074] Experimental Example 3

[0075] Determination of Related Substances

[0076] The samples of Example 1, Example 3, Example 4 and Example 12 were taken for determination of related substances by HPLC. The results are shown in Table 5.

[0077] Table 5 Data of Related Substances

[0078] Experimental Example 4

[0079] Study of In Vivo Bioavailability

[0080] The samples of Example 1, Example 3 and Example 4 were taken, and male rats were randomly divided into 3 groups, 3 rats in each group, and orally administered with single dose of 5 mg / kg. The three experimental groups were administered with the crushed product of the tablet of the compound of formula (I) in Example 1, Example 3 and Example 4, respectively. Blood samples were collected into heparin tubes at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, and the plasma samples were stored at -80°C before detection. The drug concentration in the plasma was determined by HPLC-MS / MS method.

[0081] The blood concentration-time data were analyzed by WinNonlin model software. The main pharmacokinetic parameters AUC 0-INF , C max , T max , and T 1 / 2 were fitted and calculated. The experimental data are shown in Table 6.

[0082] Table 6 Pharmacokinetic Data

Claims

1. A solid dispersion comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymeric carrier and a solubilizer; 2. The solid dispersion of claim 1, wherein, The weight ratio of the compound of formula (I) or its pharmaceutically acceptable salt to the polymer carrier is 2:1 to 1:5, preferably 1:

3.

3. The solid dispersion according to claim 1 or 2, characterized in that, The polymer carrier is selected from one or more of copolyvidone, polyvinylpyrrolidone, polyethylene glycol, hypromellose and / or hypromellose-derivatives and polyethylene glycol / vinylcaprolactam / vinylacetate copolymer, preferably copolyvidone.

4. The solid dispersion according to any one of claims 1 to 3, characterized in that, The solubilizer is selected from one or more of poloxamer, sodium lauryl sulfate and vitamin E polyethylene glycol succinate (TPGS), preferably sodium lauryl sulfate.

5. The solid dispersion according to any one of claims 1 to 4, wherein the solid dispersion is a tablet. The weight percentage of the solubilizer is 0.1% to 5%.

6. The solid dispersion according to any one of claims 1 to 5, wherein, The solid dispersion is prepared by spray drying.

7. The solid dispersion according to any one of claims 1 to 6, wherein, The preparation method of the solid dispersion comprises: completely dissolving the compound of formula (I), the polymer carrier and the solubilizer in an organic solvent to obtain a solution with a solid content of 15%; the inlet temperature is 80-100℃, the pump speed is 20%, and the solid dispersion is obtained by spray drying.

8. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises the solid dispersion of any one of claims 1-7 and pharmaceutically acceptable excipients; preferably, the excipients comprise at least one of fillers, disintegrants, glidants and lubricants.

9. The pharmaceutical composition of claim 8, wherein, The dosage form of the pharmaceutical composition is a capsule or a tablet, preferably a tablet.

10. Use of the solid dispersion of claims 1-7 or the pharmaceutical composition of claims 8-9 in the preparation of a medicament for treating a disease mediated by RET kinase.

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