Pharmaceutical compositions containing alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamidophosphate, tartrate, or a combination thereof and methods for preparing same

Abstract

The present invention relates to a pharmaceutical composition containing an alkylcarbamoylnaphthalenyloxyoctenoylhydroxyamidophosphate (hereinafter referred to as CG200745PPA) compound or a derivative thereof, and can be provided in the form of tablets, granules, powder, capsules, dry syrup, or injections. By providing compositions in various forms, it is possible to easily select an appropriate form for application when oral administration is difficult.

Description

[Technical field]

[0001] The present invention relates to pharmaceutical compositions comprising an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate compound, an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate compound, or a combination thereof.

[0002] The present invention also relates to a method for producing said pharmaceutical composition. [Background technology]

[0003] Histones are basic proteins that bind to DNA in the nucleus of eukaryotic cells, and reversible acetylation occurs at the amino group of lysine residues at specific positions in each histone molecule. This histone acetylation reaction is related to the formation of higher-order structures of chromatin and the cell division cycle, and is involved in the regulation of expression of genetic information, and is stably regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes are known to regulate gene expression at the transcription level by neutralizing the positive charge of lysine residues (four in the case of H4) at the amino terminus of histones through acetylation to induce transcriptional activity, or by deacetylating them and re-adding charges to suppress transcription, thereby inducing equilibrium in the acetylation level of histones.

[0004] HDAC has been recently found to be highly expressed under adverse environmental conditions such as hypoxia, low glucose, and cell carcinogenesis, and plays a role in promoting cell proliferation by inhibiting the expression of cell proliferation inhibitors, and is recognized as an important factor in regulating cell carcinogenesis and differentiation. That is, if a highly acetylated state of chromatin inhibits cell proliferation and promotes differentiation, HDAC plays a crucial role in inducing cell proliferation through deacetylation of histones. This fact is supported by the fact that treatment with HDAC inhibitors inhibits cell proliferation and angiogenesis, and there is a demand for the development of HDAC inhibitors that are more selective and have excellent pharmacological properties. Accordingly, the present inventors have confirmed the possibility of alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamides as HDAC inhibitors, and research on this is in progress.

[0005] However, the alkyl carbamoyl naphthalene yloxy octenoyl hydroxyamide has a property of absorbing moisture from the atmosphere, so there is a possibility that the physicochemical stability is vulnerable. Multiple purification procedures to remove softening substances generated by moisture absorption increase production costs, and since it is difficult to maintain a solid state due to high hygroscopicity, it is difficult to mass-produce solid formulations, so there is a disadvantage that a separate means such as a freezer or packaging is required.

[0006] Therefore, there is a need for pharmaceutical compositions that are stable and have a rapid onset of effect while at the same time being convenient to manufacture as HDAC inhibitors. Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides a pharmaceutical composition in the form of a tablet, granule, powder, capsule, dry syrup or injection comprising an alkylcarbamoylnaphthalenyloxyoctenoylhydroxyamide hydrochloride compound, an alkylcarbamoylnaphthalenyloxyoctenoylhydroxyamide tartrate compound, or a combination thereof.

[0008] Also provided is a method for producing said pharmaceutical composition. [Means for solving the problem]

[0009] In order to solve the above problems, the present invention provides a pharmaceutical composition in the form of a tablet, granule, powder, capsule, dry syrup or injection, comprising a compound of Chemical Formula 1 (alkylcarbamoylnaphthaleneyloxyoctenoyl hydroxyamide phosphate), a compound of Chemical Formula 2 (alkylcarbamoylnaphthaleneyloxyoctenoyl hydroxyamide tartrate), or a combination thereof.

[0010] [ka]

[0011] [ka]

[0012] In the above formula 1 or 2, R1 is halophenyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkyl, cyclohexanyl, furanyl, thiophenyl, imidazole, imidazolidinyl C 1-3 Alkyl, C 1-3 Alkylamino, DiC 1-3 Alkylamino, hydroxyphenyl, tetrahydrofuranyl, cyclohexyl, cyclohexenyl, oxopyrrolidinyl, C 1-3 Alkoxyphenyl, DiC 1-3 Alkylaminophenyl, C 1-3C substituted or unsubstituted with one or more substituents selected from the group consisting of alkylpyrrolidinyl, and trifluoromethoxyphenyl. 1-3 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-3 Alkyl, benzyl, C 1-3 Alkyl or C 3-8 Cycloalkylcarbonyl-substituted or unsubstituted pyrrolidine, C 1-3 Alkyl or C 3-8 Cycloalkyl-substituted piperidine, furan, or C 3-8 is cycloalkyl, However, unsubstituted C 1-2 Alkyl and C 1-2 Alkylpyrrolidinyl substituted C 1-2 Alkyl is excluded.

[0013] According to an embodiment, the coating layer may be included in an amount of 1 to 10% by weight based on 100 parts by weight of the tablet or capsule.

[0014] According to one embodiment, the composition is an injectable pharmaceutical composition in liquid phase or lyophilized form.

[0015] According to an embodiment, there is provided a pharmaceutical composition for anticancer agent comprising a compound of Formula 1, a compound of Formula 2, or a combination thereof.

[0016] According to yet another embodiment, there is provided a method for preparing a pharmaceutical composition in the form of a tablet, granule, powder, capsule, dry syrup or injection, comprising: 1) adding an organic solvent to an alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide compound or a derivative thereof to extract a free base; and 2) adding phosphoric acid or tartaric acid to the free base solution.

[0017] According to an embodiment, the method may further include adding a solvent having a lower solubility than the organic solvent of step 1).

[0018] According to an embodiment, the organic solvent in step 1) may include at least one selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, and ethyl acetate.

[0019] According to an embodiment, the solvent having a lower solubility than the solvent of step 1) may include at least one selected from the group consisting of alcohols including methanol, ethanol, and propanol, tetrahydrofuran, acetonitrile, and acetone.

[0020] According to an embodiment, the method may further include a step of sterilizing the mixture by high temperature vacuum sterilization or sterile filtration.

[0021] Further details of the embodiment of the present invention are included in the following detailed description. Effect of the Invention

[0022] According to the alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide phosphate compound, alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide tartrate compound or a combination thereof of the present invention, it is possible to improve stability against moisture while maintaining properties such as efficacy and effective amount. In addition, by improving hygroscopicity, it is possible to simplify the production and commercialization process of the formulation. In particular, by maintaining stability during the manufacturing process, it is possible to provide a compound and pharmaceutical composition that is safe and easy to manufacture by preventing the generation of softening substances. [Brief description of the drawings]

[0023] [Figure 1] 1 is a graph showing the dissolution pattern of alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide phosphate tablets. [Diagram 2] 1 is a graph showing the dissolution pattern of alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide phosphate capsules. [Diagram 3] 1 is a graph showing the results of measuring the amount of softening substance produced in Example 12. [Figure 4] 1 is a graph showing changes in moisture content. [Diagram 5] 1 is a graph comparing the amounts of softening material produced in Examples and Comparative Examples. [Figure 6] 1 is a graph showing the amount of soft substance produced in Example 13 depending on storage temperature. [Figure 7] 1 is a graph showing the amount of soft substance produced in Example 14 depending on storage temperature. [Figure 8] 1 is a photograph showing the properties of an alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide phosphate freeze-dried injection composition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Since the present invention can be modified in various ways and has various embodiments, specific embodiments are illustrated in the drawings and described in detail in the detailed description. However, this does not limit the present invention to a specific embodiment, and it should be understood that the present invention includes all modifications, equivalents, or alternatives within the spirit and technical scope of the present invention. In describing the present invention, if it is determined that a detailed description of related publicly known technology may obscure the gist of the present invention, the detailed description will be omitted.

[0025] As used herein, the term "pharmaceutical composition" is used interchangeably with "medicinal composition" and "pharmaceutical acceptable composition" and refers to a formulation of any organic or inorganic compound that is relatively non-toxic and has an effective effect that is harmless to the subject to which it is administered, and the side effects resulting from the composition do not reduce the efficacy of the drug, do not induce severe irritation in the subject to which the compound is administered, and do not impair the biological activity and physical properties of the compound.

[0026] The term "subject" as used herein is interchangeably described with "subject," "recipient," and "recipient organism," and refers to any animal, including humans, in need of HDAC inhibition.

[0027] Hereinafter, the pharmaceutical compositions containing alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide phosphate, alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide tartrate, or a combination thereof according to embodiments of the present invention will be described in more detail.

[0028] It has been confirmed that alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide or its derivatives can be used as histone deacetylase (HDACs) inhibitors (Korea Patent Registration No. 0814092). In the present invention, in order to improve the stability against moisture while maintaining the properties such as efficacy and effective dose of alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide or its derivatives, the present invention has studied the form of the salt that is physicochemically most ideal and has a stable form among various acceptable salts.

[0029] Specifically, the present invention provides a pharmaceutical composition comprising a compound of formula 1 (alkylcarbamoylnaphthaleneyloxyoctenoyl hydroxyamide phosphate), a compound of formula 2 (alkylcarbamoylnaphthaleneyloxyoctenoyl hydroxyamide tartrate), or a combination thereof.

[0030] [ka]

[0031] [ka]

[0032] In the above formula 1 or 2, R1 is halophenyl, C 1-3 Alkoxy, C 1-3 Alkoxy C 1-3 Alkyl, cyclohexanyl, furanyl, thiophenyl, imidazole, imidazolidinyl C 1-3 Alkyl, C 1-3 Alkylamino, DiC 1-3 Alkylamino, hydroxyphenyl, tetrahydrofuranyl, cyclohexyl, cyclohexenyl, oxopyrrolidinyl, C 1-3 Alkoxyphenyl, DiC 1-3 Alkylaminophenyl, C 1-3 C substituted or unsubstituted with one or more substituents selected from the group consisting of alkylpyrrolidinyl, and trifluoromethoxyphenyl. 1-3 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-3 Alkyl, benzyl, C 1-3 Alkyl or C 3-8 Cycloalkylcarbonyl-substituted or unsubstituted pyrrolidine, C 1-3 Alkyl or C 3-8 Cycloalkyl-substituted piperidine, furan, or C 3-8 is cycloalkyl, However, unsubstituted C 1-2 Alkyl and C 1-2 Alkylpyrrolidinyl substituted C 1-2 Alkyl is excluded.

[0033] According to a specific embodiment, R1 is N,N-dimethylpropylamine.

[0034] The present invention provides an alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide compound containing a phosphate or tartrate salt, as represented by Chemical Formula 1 or Chemical Formula 2, and a preferred compound as the alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide derivative may be selected from the group consisting of the following compounds:

[0035] 1) (E)-N1-(3-(1H-imidazol-1-yl)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)octenediamide, 2) (E)-N8-hydroxy-N1-(4-hydroxyphenethyl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 3) (E)-N1-(3-(dimethylamino)-2,2-dimethylpropyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)octenediamide, 4) (E)-N1-(2-(diisopropylamino)ethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)octenediamide, 5) (E)-N8-hydroxy-N1-(1-methoxypropan-2-yl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 6) (E)-N8-Hydroxy-N1-(4-methoxybenzyl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 7) (E)-N1-(4-fluorophenethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 8) (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(tetrahydrofuran-2-yl)methyl)-2-octenediamide, 9) (E)-N1-(2-cyclohexenylethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 10) (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(3-(2-oxopyrrolidin-1-yl)propyl)-2-octenediamide, 11) (E)-N1-(furan-2-ylmethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 12) (E)-N1-(4-(dimethylamino)benzyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 13) (E)-N8-Hydroxy-N1-(2-methoxyethyl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 14) (E)-N1-Cyclohexyl-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 15) (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(thiophen-2-ylmethyl)-2-octenediamide, 16) (E)-N8-Hydroxy-N1-(4-methoxyphenethyl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 17) (E)-N8-Hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(4-(trifluoromethoxy)benzyl)-2-octenediamide, 18) (E)-N1-(1-(cyclohexylmethyl)pyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 19) (E)-N1-(1-cyclopentylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 20) (E)-N1-(1-benzylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 21) (E)-N8-Hydroxy-N1-(1-isopropylpyrrolidin-3-yl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 22) (E)-N1-(1-(cyclohexanecarbonyl)pyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 23) (E)-3-(8-(hydroxyamino)-2-((naphthalen-1-yloxy)methyl)-8-oxo-2-octanamido)pyrrolidine-1-carboxylic acid t-butyl ester, 24) (E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(pyrrolidin-3-yl)-2-octenediamide, 25) (E)-N1-(1-cyclohexylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-2-yloxy)methyl)-2-octenediamide, 26) (E)-N1-(1-cyclopropylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 27) (E)-N1-(1-cyclopropylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 28) (E)-N1-(1-ethylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 29) (E)-N1-(1-ethylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 30) (E)-N8-hydroxy-N1-(2-(1-methylpyrrolidin-2-yl)ethyl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, and 31) (E)-N8-Hydroxy-N1-(1-isopropylpiperidin-4-yl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide, 32) (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide.

[0036] According to another embodiment of the present invention, 1) adding an organic solvent to an alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide compound or a derivative thereof to extract a free base; and 2) adding phosphoric acid or tartaric acid to the free base solution.

[0037] According to an embodiment, the alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide or a derivative thereof is in a solid, gel or solution state, and the solution state means a state in which it is completely dissolved in an organic solvent or a state of suspension.

[0038] According to an embodiment, the organic solvent may include at least one selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, and ethyl acetate. For example, the organic solvent may include at least one selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide (DMF), and dimethylsulfoxide (DMSO), which have relatively high solubility.

[0039] According to an embodiment, the method may further include a step of adding a solvent having a lower solubility than the organic solvent in step 1). For example, the solvent having a lower solubility than the solvent in step 1) may include at least one selected from the group consisting of alcohols including methanol, ethanol, and propanol, tetrahydrofuran, acetonitrile, and acetone. For example, after adding an organic solvent to the alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide or its derivative, whether or not precipitation, i.e., the formation of a salt, may be observed, and if necessary, a solvent having a lower solubility than the added organic solvent may be further added to observe whether or not precipitation occurs. The addition of the solvent having a lower solubility may be repeated 2 to 5 times, for example, repeated twice to obtain a salt.

[0040] The pharmaceutical composition of the present invention can be provided in the form of tablets, granules, powders, capsules, dry syrups or injections.Specifically, it can be provided in any convenient form, such as tablets, pellets, granules, capsules, suspensions, emulsions or powders suitable for reconstitution with water or other suitable liquid media.It can also be applied in the form of oral administration or injections.

[0041] The pharmaceutical composition for oral administration may include one or more diluents selected from the group consisting of microcrystalline cellulose, mannitol, lactose, and lactose, one or more lubricants selected from the group consisting of talc, magnesium stearate, sodium stearyl fumarate, and glyceryl behenate, and one or more binders selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethylcellulose, and hydroxypropylcellulose. In addition, the composition may include a coating layer in an amount of 1 to 10% by weight based on 100 parts by weight of the tablet or capsule. Specifically, the coating layer may include a water-soluble coating base, and a commonly used coating base may be used. More specifically, the coating layer may include a coating base containing a polyvinyl alcohol derivative, a methacrylic acid derivative, and a polyacrylic acid derivative, and may include one or more of Opadry®, Kollicoat®, and hydroxypropylmethylcellulose (HPMC), and may include polyvinyl alcohol-containing Opadry®, which has a relatively excellent moisture and light blocking effect.

[0042] When preparing granules of a composition for oral administration, it is preferable not to use purified water as a binding solvent, taking into consideration the unstable water stability, and ethanol, which is easy to remove during the manufacturing process, can be used. Magnesium stearate, a lubricant used in conventional compositions for oral administration, has poor compatibility with the alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide of the present invention, so a substitute can be used.

[0043] According to an embodiment, in addition to the above additives, pharmaceutical excipients having excellent compatibility with the compounds may be added.

[0044] As an injectable composition, the alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide component is provided in the form of a liquid phase since it is a water-soluble substance that dissolves well in water, and it is not essential to use solubilizers and other additives that are generally used for poorly soluble substances, and since compatibility with additives is unstable, it is preferable to use a minimum amount of additives. More specifically, it can be prepared by dissolving in nitrogen-purged water for injection and then lyophilizing.

[0045] According to an embodiment, the method may further include a sterilization step. Sterilization methods may include dry heat sterilization, pressure or vacuum sterilization, filtration sterilization, gas sterilization, radiation sterilization, etc. For filtration sterilization, for example, a nitrocellulose membrane filter may be used, and filters such as 0.45 μm and 0.2 μm may be used. In the present invention, for example, a sterilization step may be further included using high-temperature vacuum sterilization or aseptic filtration.

[0046] According to another embodiment of the present invention, there is provided a pharmaceutical composition for anticancer drug comprising the compound of Formula 1, the compound of Formula 2, or a combination thereof as an active ingredient. EXAMPLES

[0047] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is described in detail below in order to enable those skilled in the art to easily practice the present invention. However, the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[0048] Examples 1 to 4 In order to prepare a tablet composition that is convenient to take and easy to manufacture, a tablet composition was prepared using alkylcarbamoylnaphthaleneyloxyoctenoyl hydroxyamide phosphate and stable additives as shown in Table 1 based on the results of compatibility tests. As the alkylcarbamoylnaphthaleneyloxyoctenoyl hydroxyamide phosphate, (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide phosphate compound (CG200745PPA) was used. The unit of weight shown in the following table is mg.

[0049] Due to the poor fluidity of CG200745PPA, the tablet composition was manufactured by the granulation method using ethanol as a binding solvent rather than the direct compression method. In addition, due to the characteristics of the raw material CG200745PPA, it is difficult to separate the punch and the tablet when subjected to tableting pressure in the tableting process, so the ratio of added excipients was increased to minimize the influence of the main ingredient properties.

[0050] In addition, in Table 2, the degree of mold release is indicated as good or bad depending on the degree to which the composition is pinched by the machine during tablet punching, the degree of sticking to the machine surface is indicated as ○: not sticking, X: sticking, △: good, and the degree of capping is indicated as ○: no capping, X: capping occurred depending on the layer cracking phenomenon of the tablets after tableting. The evaluation was performed by observing the degree of separation and sticking with the naked eye, and the degree of capping was confirmed by applying physical force to the tablets with hands to separate them.

[0051] [Table 1]

[0052] [Table 2]

[0053] As a result of Examples 1 to 4, it was confirmed that even when the ratio of excipient to main ingredient was 2:8, the tablet was pinched by the punch, making it difficult to eject the tablet, and the mixture stuck to the punch surface (sticking) occurred. It was confirmed that this problem was not significantly improved even if the type and amount of lubricant was increased.

[0054] Examples 5 to 8 To improve the sticking phenomenon, tablets were manufactured by increasing the amount of excipients and decreasing the ratio of the main ingredient as shown in Table 3. Tablet compression performance was also evaluated as shown in Table 4.

[0055] [Table 3]

[0056] [Table 4]

[0057] Examples 9 and 10 CG200745PPA is applicable as an anticancer drug, and most of the subjects are patients undergoing anticancer treatment. If the size of the tablet is large, it is very difficult to take and there is a risk of refusal to take it, so we tried to improve it. A capsule-type composition with a simple process that has little physical impact on the production, such as a tableting process, was produced. As shown in the composition of Table 5, for convenience of taking, the minimum number of excipients that can be produced were used, and for process simplification, it was produced by direct mixing. In addition, the flowability was evaluated according to the repose angle measurement standard (General Chapters; 1174, USP) according to Table 6 using a repose angle meter, and the results were shown as good or bad in Table 7, and the degree of sticking was also shown.

[0058] EMBO CAPS (hard capsules, Sofun) were used for capsules No. 0 and No. 1.

[0059] [Table 5]

[0060] [Table 6]

[0061] [Table 7]

[0062] Example 11 and Example 12 To improve the flowability, a mixture was prepared with granules to prepare a composition that can be filled into capsule No. 1 according to Table 8. The flowability, sticking degree, and mass deviation are shown in Table 9.

[0063] [Table 8]

[0064] [Table 9]

[0065] The capsules filled with the granules showed good fluidity and little weight deviation. The total weight of 290 mg was considered to be problematic for No. 1 filling due to the large volume of the mixture, so a composition with a total weight of 260 mg was selected.

[0066] Experimental Example 1: Evaluation of tablet dissolution In vitro dissolution tests were carried out on the formulation of Example 8 according to the Korean Pharmacopoeia Dissolution Test Method 2 (Paddle Method, Apparatus 2). Dissolution tests were carried out using all four solutions, and the results are shown in FIG. 1 and Table 10.

[0067] [Table 10]

[0068] Experimental Example 2: Evaluation of capsule dissolution As in Experimental Example 1, the CG200745PPA capsules were subjected to an in vitro dissolution test for the formulation of Example 12 according to the Korean Pharmacopoeia Dissolution Test Method No. 2 (Paddle Method, Apparatus 2). Dissolution was performed using all four solutions, and the results are shown in FIG. 2 and Table 11.

[0069] [Table 11]

[0070] Experimental Example 3: Evaluation of the softening agent of the capsule composition of Example 12 In order to evaluate the change in softening agent of Example 12, the composition of Example 12 was placed in an accelerated condition chamber (45°C±2, 75%±5) and the amount of softening agent generated was measured for 6 months. The amount of softening agent generated was measured by pretreating the composition of Example 12 and then testing it by liquid chromatography according to the general test method of the Korean Pharmacopoeia, and measuring the peak area of ​​the softening agent generated (softening agent 0.2% or less, total softening agent 1.0%, respectively, measuring equipment: HPLC LC-2030C_Shimadzu). The results are shown in Table 12 and Figure 3. In Table 12, the unit of the amount of softening agent generated is %. Also, Figure 3 shows the result of measuring the softening agent at 28 minutes of accelerated condition, with the reference value being 0.2%.

[0071] [Table 12]

[0072] As shown in Table 12 and FIG. 3, the production amount of the remaining soft materials, except for the peak at RT 28.3 minutes, was insufficient, and it was confirmed that the RT 28.3 soft material peak also met the soft material standard for 6 months of accelerated testing.

[0073] Experimental Example 4: Stability Evaluation In order to evaluate the stability of the compound according to the present invention, an alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide compound was used as Comparative Example 1, an alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide tartrate was used as Example 13, and an alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide phosphate was used as Example 14. As the alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide, an (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalene-1-yloxy)methyl)-2-octenediamide compound was used.

[0074] The stability evaluation proceeded by observing the changes due to storage time under room temperature (20-25°C, below 50%), long-term (25±2°C and 60±5% RH), accelerated (40±2°C and 75±5% RH) and harsh (60±2°C) conditions.

[0075] Experimental Example 4-1: Evaluation of changes in moisture content To evaluate the change in moisture content, the compounds according to the Examples and Comparative Examples were stored in an open state at room temperature (20-25°C, 50% or less), and the change was measured as the difference between the initial moisture content and the moisture content after 3 days, and the results are shown in Figure 4. The moisture content was measured by volumetric titration (Karl Fischer method) according to the general test method of the Korean Pharmacopoeia (measuring equipment: 701KF_Metrohm).

[0076] As shown in FIG. 4, the moisture content increased by about 3% in Comparative Example 1, increased by 2% in Example 13, and increased by about 0.01% in Example 14, and the changes were extremely small.

[0077] Experimental Example 4-2: Evaluation of property changes In order to evaluate changes in the properties of the compounds according to the comparative examples and examples, each compound was opened and stored under the conditions shown in Table 13 below, and then changes were observed.

[0078] [Table 13]

[0079] As shown in Table 13, in the case of Comparative Example 1, after one day (24 hours), the initial sponge-like solid phase (foam) absorbed moisture and its properties changed to a highly viscous liquid or gel structure, while in the case of Example 14, it was confirmed that the properties remained constant regardless of the conditions.

[0080] Experimental Example 4-3: Evaluation of content changes To evaluate the change in compound content according to the examples, each compound was stored in an open state or in a polyethylene bottle (with silica gel added) and the change in content was measured. The content was measured by pretreating the comparative examples and examples, and measuring the CG200745 peak area of ​​each liquid using the liquid chromatography method of the general test method of the Korean Pharmacopoeia (measurement equipment: HPLC LC-2030C_Shimadzu). The content standard is that the product must contain 95.0~105.5% of the labeled amount of CG200745 based on our company's standards and test methods.

[0081] The results of the measurements in the open state are shown in Table 14 below, and the results of the measurements in the bottle-packaged state are shown in Table 15 below.

[0082] [Table 14]

[0083] [Table 15]

[0084] Taking the results of Experimental Example 4 together, it can be seen that in Example 13, the content was maintained at a constant level under room temperature conditions, and in Example 14, the content was maintained at a constant level regardless of the packaging condition, heating, and humidity.

[0085] Experimental Example 5: Comparison of changes in soft materials In order to evaluate the change in softening agent of the compounds according to the comparative examples and examples, each compound was stored in an open state at room temperature for 3 days, and the amount of softening agent generated was measured in the same manner as in Experimental Example 3, and the results are shown in Figure 5. As shown in Figure 5, in the case of Comparative Example 1, the softening agent increased by about 10%, while in Example 13 it was 0.05%, and in Example 14 it was 0.02%, confirming that the increase was relatively small.

[0086] In addition, the change in the amount of softening material produced depending on the temperature and storage time for the compounds of Examples 13 and 14 is shown in Figures 6 and 7. As shown in Figure 6, it can be seen that the amount of softening material produced in Example 13 is maintained within a certain range at a relatively low temperature, and as shown in Figure 7, in the case of Example 14, the amount of softening material produced is not affected by the storage temperature and time and is uniformly maintained within a certain range of about 0.22%.

[0087] Example 15 CG200745PPA is an anticancer drug administered to cancer patients for the purpose of treating cancer, so various administration routes must be considered depending on the patient's condition. That is, routes that can be administered to subjects for whom oral administration is difficult include intravenous and intramuscular injections, and for these, there are liquid-phase injections and freeze-dried injection compositions that are diluted immediately before use. In order to improve stability in the dissolved state and compatibility with other additives, the drug was dissolved in nitrogen-purged water for injection according to the composition shown in Table 16 without using any solubilizer or other additives, and then freeze-dried. A photograph of the prepared composition is shown in FIG. 8.

[0088] [Table 16]

[0089] As can be seen from the above results, the CG200745PPA compound according to the present invention can improve the dissolution rate while maintaining properties such as efficacy and effective amount.

[0090] Therefore, anti-cancer agents related to HDAC inhibition can be easily administered to subjects as oral or injectable agents.

[0091] The above description is merely an illustrative example of the technical idea of ​​the present invention, and those skilled in the art can make various modifications and variations without departing from the essential characteristics of the present invention. Furthermore, the embodiments disclosed in the present invention are for illustrative purposes only, and are not intended to limit the technical idea of ​​the present invention, and the scope of the technical idea of ​​the present invention is not limited by such embodiments. The scope of protection of the present invention should be interpreted according to the following claims, and any technical idea within the scope equivalent thereto should be interpreted as being included in the scope of the present invention.

Claims

1. A pharmaceutical composition for use as an anti-cancer agent in the form of tablets, granules, powders, capsules, or injections, comprising a compound of formula 1, a compound of formula 2, or a combination thereof. [Chemical formula 1] 【Chemistry 1】 [Chemical formula 2] 【Chemistry 2】 [wherein, in the above-mentioned Chemical Formula 1 or Chemical Formula 2, R １ =-CH ２ CH ２ CH ２ N (CH ３ ) ２ It is.

2. The pharmaceutical composition is in the form of a tablet, granule, or capsule, and further comprises a coating layer; The pharmaceutical composition for use as an anticancer agent according to claim 1, wherein the coating layer is contained in an amount of 1 to 10% by weight based on the weight of the tablet, granule, or capsule.

3. 2. The pharmaceutical composition for use as an anticancer agent according to claim 1, which is formulated for injection in the form of a liquid or lyophilized product.

4. A method for preparing a pharmaceutical composition comprising a compound of formula 1, a compound of formula 2, or a combination thereof, comprising: 1) forming a free base solution of the alkylcarbamoylnaphthaleneyloxyoctenoylhydroxyamide of Formula 1 or Formula 2, or a combination thereof, in a first organic solvent; 2) adding phosphoric acid or tartaric acid to the base solution, and a pharmaceutical composition in the form of a tablet, granule, powder, capsule, or injection solution for use as an anti-cancer agent. [Chemical formula 1] 【Chemistry 3】 [Chemical formula 2] 【Chemistry 4】 [wherein, in the above-mentioned Chemical Formula 1 or Chemical Formula 2, R １ =-CH ２ CH ２ CH ２ N (CH ３ ) ２ It is.

5. The method for preparing a pharmaceutical composition for use as an anticancer agent according to claim 4, further comprising the step of adding a second solvent having a lower solubility than the first organic solvent in step 1).

6. 6. The method for producing a pharmaceutical composition for use as an anticancer agent according to claim 4 or 5, wherein the first organic solvent in step 1) comprises one or more solvents selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, and ethyl acetate.

7. 6. The method for producing a pharmaceutical composition for use as an anticancer agent according to claim 5, wherein the second solvent having a lower solubility than the first organic solvent in step 1) comprises one or more solvents selected from the group consisting of alcohols including methanol, ethanol, and propanol, tetrahydrofuran, acetonitrile, and acetone.

8. A method for producing a pharmaceutical composition for use as an anticancer agent according to any one of claims 4 to 7, further comprising a step of sterilizing the composition by high-temperature reduced pressure sterilization or aseptic filtration.

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