Novel solid dispersion and method for producing the same

Abstract

The present invention relates to a solid dispersion of a triazolopyrimidinone derivative having tankyrase inhibitory activity and a method for producing the same. The solid dispersion of the triazolopyrimidinone derivative represented by formula I according to the present invention has high solubility and excellent bioavailability, and can be usefully used as a pharmaceutical raw material.

Description

[Technical Field]

[0001] The present invention relates to a solid dispersion of a compound of formula I, which has significantly improved solubility and bioavailability, a pharmaceutical formulation containing the same, and a process for preparing the same.

[0002] [ka] [Background technology]

[0003] Tankyrase belongs to the poly(ADP-ribose)polymerase (PARP) protein family, which consists of 17 members that share the catalytic PARP domain. Recently, it has been reported that intracellular actin levels are affected by tankyrase-1 and tankyrase-2 (also known as PARP5a and PARP5b, respectively), members of the PARP enzyme family (Huang et al., 2009, Nature, 461(7264):614-620).

[0004] Inhibitors of tankyrase-1 and tankyrase-2 are known to have therapeutic potential for a variety of cancer diseases, including solid cancers such as colorectal carcinoma, colon cancer, gastric cancer, hepatocellular carcinoma, breast cancer, medulloblastoma, melanoma, non-small cell lung cancer, pancreas adenocarcinoma, and prostate cancer. In addition, inhibitors of tankyrase-1 and tankyrase-2 have therapeutic potential for other diseases in addition to the aforementioned cancer diseases, including osteoporosis, osteoarthritis, polycystic kidney disease, pulmonary fibrosis, diabetes, schizophrenia, vascular disease, cardiac disease, non-oncogenic proliferative diseases, and neurodegenerative diseases such as Alzheimer's disease.

[0005] There is a continuing need for novel therapeutic agents that can be used for the above-mentioned cancers and hyperproliferative conditions, and attempts have been made to develop novel pharmaceutical compounds that can selectively inhibit the tankyrase enzyme. In particular, triazolopyrimidinone derivatives of the following formula I are known as selective tankyrase inhibitors (International Publication No. WO2016 / 006974), and are being developed as therapeutic agents for colon cancer in patients with a colon cancer-causing gene (KRAS) mutation genotype or in patients who are non-responsive to Erbitux.

[0006] [ka]

[0007] However, the triazolopyrimidinone derivative of formula I is a crystalline substance belonging to class II of the Biopharmaceutics Classification System (BCS), and has physicochemical properties of high permeability but very low solubility.

[0008] Therefore, in order to solve the problem of low solubility of the triazolopyrimidinone derivatives of formula I and improve their bioavailability, it is necessary to develop new dosage forms. Summary of the Invention [Problem to be solved by the invention]

[0009] The object of the present invention is to provide novel solid dispersions of triazolopyrimidinone derivatives of formula I with significantly improved solubility and bioavailability.

[0010] Another object of the present invention is to provide a pharmaceutical preparation containing the solid dispersion.

[0011] Another object of the present invention is to provide a novel method for producing the solid dispersion. [Means for solving the problem]

[0012] In order to achieve the above object, the present inventors have conducted extensive research and development to develop novel solid dispersions containing compounds represented by the following formula I, and a method for preparing the same. The present invention has been completed by confirming that the solid dispersions have significantly improved solubility and bioavailability:

[0013] [ka]

[0014] Solid dispersions of compounds of formula I The solid dispersion of the compound of formula I according to the present invention is characterized by significantly improved solubility and bioavailability relative to the compound of formula I.

[0015] The solid dispersion of the compound of formula I of the present invention comprises a compound of formula I and a pH-dependent polymer.

[0016] Specifically, the present invention provides a solid dispersion comprising a compound represented by Formula I below and a pH-dependent polymer:

[0017] [ka]

[0018] In the present invention, the pH-dependent polymeric substance refers to a polymeric substance whose charge state changes under typical pH conditions in the digestive tract, specifically under conditions of pH 1 to 8. The pH-dependent polymer may be a polymeric substance having a functional group whose charge state changes depending on pH conditions, such as a basic functional group such as an amino group or an acidic functional group such as a carboxylic acid.

[0019] The pH-dependent polymer of the present invention may be contained singly or in combination in the solid dispersion of the present invention.

[0020] According to an embodiment of the present invention, the pH-dependent polymer may be methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), carboxymethylethylcellulose (CMEC), cellulose acetate phthalate (CAP), or a combination thereof.

[0021] Specifically, the methacrylic acid-methyl methacrylate copolymer may be Eudragit L100 or Eudragit S100, and the methacrylic acid-ethyl acrylate copolymer may be Eudragit L100-55 or Eudragit L30D-55.

[0022] Preferably, the pH-dependent polymer in the solid dispersion of the present invention may be hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0023] According to a specific example of the present invention, the weight ratio of the compound represented by formula I to the pH-dependent polymer may be 1:1 to 1:10, preferably 1:2 to 1:4, and more preferably 1:4.

[0024] Preferably, in the solid dispersion of the present invention, the weight ratio of the compound represented by formula I to hydroxypropyl methylcellulose acetate succinate (HPMCAS) may be 1:1 to 1:10, more preferably 1:2 to 1:4.

[0025] According to an embodiment of the present invention, the weight ratio of the compound represented by formula I and hydroxypropyl methylcellulose acetate succinate (HPMCAS) may be 1:4.

[0026] According to a specific example of the present invention, the content percentage of the compound represented by formula I may be 1 to 50 w / w %, and the content percentage may preferably be 10 to 40 w / w %.

[0027] In the present invention, in the solid dispersion containing the compound represented by formula I and the pH-dependent polymer, the compound represented by formula I in the solid dispersion may be amorphous.

[0028] In the present invention, the solid dispersion containing the compound represented by formula I and the pH-dependent polymer may be such that the compound represented by formula I in the solid dispersion is partially amorphous or partially crystalline.

[0029] Pharmaceutical Formulations Comprising Solid Dispersions of Compounds of Formula I The present invention provides a pharmaceutical formulation comprising a solid dispersion comprising a compound of Formula I described above and a pH-dependent polymer.

[0030] In the present invention, the pharmaceutical formulation may further contain pharmaceutically acceptable additives within the scope of not impairing the effects of the present invention. The pharmaceutically acceptable additives may be excipients, binders, disintegrants, lubricants, coating agents, solubilizers, stabilizers, or combinations thereof.

[0031] The excipient may be any excipient known in the art, for example, selected from the group consisting of lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, calcium phosphate, light anhydrous silicic acid, colloidal silicon dioxide, magnesium aluminometasilicate, pregelatinized starch, corn starch, potato starch, sucrose, mannitol, dextrin, precipitated calcium carbonate, and any combination thereof.

[0032] The disintegrant may be any disintegrant known in the art, and may, for example, be selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, starch, alginic acid, sodium alginate, and combinations thereof.

[0033] The binder may be any binder known in the art, for example, any one or more selected from the group consisting of polyvinylpyrrolidone, povidone, and copovidone.

[0034] The lubricant may be any lubricant known in the art, and may be selected from the group consisting of, for example, stearic acid, metal stearates, talc, sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glyceryl fatty acid esters, glyceryl dibehenate, and any combination thereof.

[0035] The coating agent may be any coating base known in the art, and may be selected from the group consisting of, for example, polyvinyl alcohol, talc, hydroxypropyl methylcellulose, ethyl cellulose, polyvinyl acetate, titanium dioxide, iron oxide, and combinations thereof.

[0036] The solubilizer may be any solubilizer known in the art, for example, any one or more selected from the group consisting of sodium lauryl sulfate and polysorbate.

[0037] The stabilizer may be any stabilizer known in the art, for example, any one or more selected from the group consisting of citric acid, fumaric acid, hydrochloric acid, benzoic acid, sodium bicarbonate, sodium hydroxide, calcium carbonate, and meglumine.

[0038] The pharmaceutical formulation of the present invention can be prepared using a formulation method commonly used in the art, and the pharmaceutical formulation can be administered orally or parenterally. The pharmaceutical formulation containing the solid dispersion of the present invention may be in the form of, for example, granules, powders, tablets, coated tablets, capsules, syrups, suspensions, emulsions, ointments, creams, gels, infusions, aerosols, or injectable solutions, but is not limited to these. The effective daily dose of the pharmaceutical formulation can be appropriately adjusted depending on the patient's age, weight, sex, dosage form, health condition, or disease severity. The present invention does not particularly limit this, but it may be 1 mg to 1000 mg for an adult, and may be administered once or several times a day in divided doses.

[0039] Method for preparing solid dispersions of compounds of formula I The present invention provides a method for producing a solid dispersion of the compound represented by formula I above.

[0040] The solid dispersions of the present invention can be prepared using any known method for preparing solid dispersions, including, for example, spray drying, hot melt extrusion, or precipitation from solution by the addition of an antisolvent.

[0041] Preferably, the solid dispersion of the present invention can be prepared using micro-precipitated bulk powder (MBP) technology.

[0042] Specifically, the preparation method includes the following steps (S-1) to (S-3): (S-1) preparing a solution by dissolving a compound represented by the following formula I and a pH-dependent polymer in an organic solvent; (S-2) adding the solution dropwise to an acidic anti-solvent or distilled water to precipitate a solid; and (S-3) filtering the solid, washing with an acidic anti-solvent or distilled water, and then drying;

[0043] [ka]

[0044] The details of the method for producing the solid dispersion are the same as those for the solid dispersion of the present invention. Specifically, the compound represented by Formula I, the pH-dependent polymer, and the weight ratio thereof are as described above.

[0045] The steps (S-1) to (S-3) will be described in detail below.

[0046] (S-1) Stage Step (S-1) of the present invention is a step of dissolving the compound represented by formula I and a pH-dependent polymer in an organic solvent to prepare a homogeneous solution.

[0047] According to an embodiment of the present invention, the organic solvent may be dimethylformamide (DMF), dimethylacetamide (DMA), dichloromethane (DCM), chloroform, or N-methylpyrrolidone (NMP). Preferably, the organic solvent is dimethylacetamide (DMA).

[0048] According to a specific example of the present invention, the percent concentration of the solution may be 1 to 50 w / v %. Preferably, a 10 to 30 w / v % solution can be prepared and used, and more preferably, a 10 w / v % solution can be prepared and used.

[0049] (S-2) Stage Step (S-2) of the present invention is a step of slowly adding the solution prepared in step (S-1) dropwise to a poor solvent to precipitate a solid.

[0050] In the present invention, the anti-solvent refers to a solvent that can reduce the solubility of a solute dissolved in a solution and induce a supersaturated state of the solution, thereby precipitating the solute. Specifically, the anti-solvent in step (S-2) of the present invention may be an acidic anti-solvent or distilled water.

[0051] According to an embodiment of the present invention, the acidic anti-solvent may be an aqueous solution of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, citric acid or lactic acid.

[0052] Preferably, the anti-solvent in step (S-2) may be an aqueous hydrochloric acid solution or distilled water, more preferably a 0.01N aqueous hydrochloric acid solution or distilled water.

[0053] According to an embodiment of the present invention, the dropwise addition temperature in step (S-2) may be 0 to 10°C. The dropwise addition temperature means that the temperature of the acidic anti-solvent or distilled water is maintained at 0 to 10°C from the start of dropwise addition until the complete completion of dropwise addition. The dropwise addition temperature may be preferably 0 to 5°C, and more preferably 0°C.

[0054] According to a specific example of the present invention, the step (S-2) may further include a step of stirring the mixture at room temperature after the dropwise addition. Specifically, the stirring step is a step of stirring the mixture after the dropwise addition at 15 to 25°C. Preferably, the stirring step may be carried out for 30 minutes.

[0055] (S-3) Stage Step (S-3) of the present invention is a step of filtering the solid precipitated in step (S-2), washing it with an acidic anti-solvent or distilled water, and then drying it.

[0056] According to an embodiment of the present invention, the acidic anti-solvent may be an aqueous solution of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, citric acid, or lactic acid. Preferably, an aqueous solution of hydrochloric acid may be used, and more preferably, an aqueous solution of 0.01N hydrochloric acid may be used.

[0057] The washing in step (S-3) can be carried out one or more times, for example, washing with 0.01N aqueous hydrochloric acid or distilled water once, and then washing with distilled water two more times.

[0058] In the production method of the present invention, stirring, filtration, washing and drying can be carried out by any method known in the art without any restrictions.

[0059] The present invention also provides a solid dispersion of the compound represented by formula I, prepared according to the preparation method described in steps (S-1) to (S-3). [Effects of the Invention]

[0060] The solid dispersion of the compound represented by formula I according to the present invention has high solubility and excellent bioavailability, and can be usefully used as a pharmaceutical ingredient. DETAILED DESCRIPTION OF THE INVENTION

[0061] The present invention will be described in detail below with reference to examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0062] Example 1: Preparation of a solid dispersion of the compound of formula I 1 g of the compound of Formula I and 4 g of hydroxypropyl methylcellulose acetate succinate (HPMCAS) were mixed and completely dissolved in 50 ml of dimethylacetamide (DMA). 500 ml of 0.01 N HCl or distilled water was cooled to 0°C, and the previously prepared solution was slowly added dropwise. After stirring at room temperature for 30 minutes, the mixture was filtered and washed once with 0.01 N HCl or distilled water. The mixture was then washed twice more with distilled water and vacuum dried to obtain a solid dispersion of the compound of Formula I.

[0063] Examples 2 to 5: Preparation of solid dispersions of compounds of formula I Each solid dispersion was prepared in the same manner as in Example 1, except that Eudragit L100-55, Eudragit L100, Eudragit S100, or hydroxypropyl methylcellulose phthalate (HPMCP) was used instead of hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0064] Experimental Example 1: Confirmation of drug content and purity in Examples 1 to 5 The content and purity of the drug (compound represented by formula I) in the solid dispersions produced in Examples 1 to 5 were confirmed by HPLC (high performance liquid chromatography, manufacturer: Agilent Technologies, model name: 1260 Infinity II), and the results are shown in Table 1.

[0065] Experimental Example 2: Confirmation of the solubility of Examples 1 to 5 in FaSSIF The solubilities of the solid dispersions produced in Examples 1 to 5 in FaSSIF (Fast state simulated intestinal fluid) were confirmed, and the results are shown in Table 1.

[0066] [Table 1]

[0067] As a result, as can be seen from Table 1, it was confirmed that the solid dispersions of the Examples all had increased solubility compared to the compound represented by Formula I. In particular, the solid dispersion of Example 1 containing hydroxypropyl methylcellulose acetate succinate (HPMCAS) had approximately 10-fold increased solubility compared to the compound represented by Formula I.

[0068] Examples 6-7: Preparation of solid dispersions of compounds of formula I Hydroxypropylmethylcellulose acetate succinate (HPMCAS), a pH-dependent polymer that showed the best solubility in solid dispersions, was mixed with the drug (compound of Formula I) in various ratios to prepare solid dispersions.

[0069] Specifically, each solid dispersion was prepared in the same manner as in Example 1, except that 2 g or 2.5 g of hydroxypropyl methylcellulose acetate succinate (HPMCAS) was used per 1 g of the compound represented by formula I.

[0070] Experimental Example 3: Confirmation of drug content and purity in Examples 6 and 7 The content and purity of the drug (compound represented by formula I) in the solid dispersions produced in Examples 6 and 7 were confirmed in the same manner as in Experimental Example 1, and the results are shown in Table 2.

[0071] Experimental Example 4: Confirmation of solubility in FaSSIF of Examples 6 and 7 The solubilities of the solid dispersions produced in Examples 6 and 7 in FaSSIF (Fast state simulated intestinal fluid) were confirmed in the same manner as in Experimental Example 2, and the results are shown in Table 2.

[0072] [Table 2]

[0073] As a result, as can be seen from Table 2, it was confirmed that the solid dispersions of the Examples all had increased solubility compared to the compound represented by formula I. In particular, the solid dispersion of Example 1, which contained the compound represented by formula I and hydroxypropyl methylcellulose acetate succinate (HPMCAS) in a weight ratio of 1:4, had an approximately 11-fold increased solubility compared to the compound represented by formula I.

[0074] Experimental Example 5: Confirmation of bioavailability of Examples 1 and 6 In order to confirm the bioavailability of the solid dispersions of Examples 1 and 6, which were shown to have the best solubility, a pharmacokinetic study (in vivo) was carried out in a mouse model.

[0075] Specifically, after administering drugs orally to rats, blood samples were collected intravenously at specified times. The collected blood was centrifuged to separate the plasma, which was then pretreated and analyzed for concentration by LC-MS / MS. Non-compartmental pharmacokinetic parameters were calculated from the analyzed blood concentration-time data using WinNonlin (Phoenix™, version 6.1), and the results are shown in Table 3.

[0076] [Table 3]

[0077] As a result, as can be seen from Table 3, the solid dispersions of Examples 1 and 6 both had higher C maxIt was confirmed that the solid dispersion of Example 1, which contained the compound of formula I and hydroxypropyl methylcellulose acetate succinate (HPMCAS) in a weight ratio of 1:4, exhibited excellent bioavailability in terms of the AUC value and the AUC value. In particular, the solid dispersion of Example 1, which contained the compound of formula I and hydroxypropyl methylcellulose acetate succinate (HPMCAS) in a weight ratio of 1:4, exhibited an AUC that was approximately 7 times higher than that of the compound of formula I.

[0078] Although the present invention has been described in detail through preferred embodiments, the scope of the present invention is not limited to the specific embodiments, but should be interpreted by the appended claims. It should be understood that many modifications and variations are possible for those skilled in the art without departing from the scope of the present invention.

Claims

1. A solid dispersion comprising a compound of formula I and a pH-dependent polymer: 【Chemistry 1】

2. 2. The solid dispersion of claim 1, wherein the pH-dependent polymer is methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), carboxymethyl ethyl cellulose (CMEC), cellulose acetate phthalate (CAP), or a combination thereof.

3. 2. The solid dispersion according to claim 1, wherein the weight ratio of the compound represented by formula I and the pH-dependent polymer is 1:1 to 1:

10.

4. 2. The solid dispersion according to claim 1, wherein the weight ratio of the compound represented by formula I and the pH-dependent polymer is 1:2 to 1:

4.

5. 2. The solid dispersion according to claim 1, wherein the content of the compound represented by formula I is 1 to 50 w / w%.

6. A pharmaceutical formulation comprising the solid dispersion according to any one of claims 1 to 5.

7. (S-1) preparing a solution by dissolving a compound represented by the following formula I and a pH-dependent polymer in an organic solvent; (S-2) adding the solution dropwise to an acidic anti-solvent or distilled water to precipitate a solid; and (S-3) filtering the solid, washing it with an acidic anti-solvent or distilled water, and then drying it; A method for producing a solid dispersion of a compound of formula I according to any one of claims 1 to 5: 【Chemistry 2】

8. 8. The method of claim 7, wherein the organic solvent is dimethylformamide (DMF), dimethylacetamide (DMA), dichloromethane (DCM), chloroform, or N-methylpyrrolidone (NMP).

9. The method according to claim 7, wherein the percent concentration of the solution is 1 to 50 w / v%.

10. The method according to claim 7, wherein the acidic anti-solvent is an aqueous solution of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, citric acid, or lactic acid.

11. The method of claim 7, wherein the temperature of the dropwise addition in step (S-2) is 0 to 10°C.

12. The method of claim 7, wherein step (S-2) further comprises stirring at room temperature after the dropwise addition.

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