KR20210026640A - Anti-cancer adjuvant comprising tetrahydrouridine epimer beta form and use thereof - Google Patents

Abstract

The present invention relates to an anti-cancer adjuvant comprising epimer beta type (β-type) of tetrahydrouridine and a use thereof. The epimer β-type of tetrahydrouridine (THU) of the present invention has a substantially cytidine deaminase (CDA) inhibitory effect unlike an alpha type (α-type), so as to obtain a sufficient CDA inhibitory effect even with a significantly reduced amount compared to the amount of THU used for CDA inhibition in the past. In addition, in the case of preparing an enteric-soluble formulation, the anti-cancer adjuvant is not exposed to gastric acid and can prevent transformation into an inactive epimer structure, thereby more effectively enhancing the anticancer effect of an anticancer agent having a CDA analog structure.

Description

[Anti-cancer adjuvant comprising tetrahydrouridine epimer beta form and use thereof]

The present invention relates to an anticancer adjuvant comprising a tetrahydrouridine epimer β type and a use thereof.

Cytidine Deaminase (CDA) is an enzyme that hydrolyzes cytidine or other derivatives in the body and converts them into uridine or uridine derivatives. Cytidine and its analogs are rapidly metabolized by CDA.In particular, anticancer drugs having various cytidine analog structures such as decitabine, azacytidine, gemcitabine, or cytarabine are used. The compound of uridine structure, which is metabolized by CDA, has a very short half-life of about 15 minutes, and it is difficult to distribute ideally in each tissue of the body, so that it does not have the desired anticancer effect. In addition, when the anticancer drugs are administered orally, metabolism occurs first in the liver through the first pass effect of drugs after they are absorbed through the intestine.The CDA is widely distributed in the liver and kidneys in addition to blood in the body. The oral absorption rate is further lowered by hydrolyzing them. In addition, the existence of differences in the level of expression and activity of CDA for each individual causes problems in the use of these anticancer agents. In other words, even if a standardized dose is administered, the metabolic rate is different for each patient, and in some patients, metabolism occurs rapidly and an amount that does not reach the effective dose is administered. In another patient, metabolism occurs slowly, and the exposure of the drug after administration. There are cases where the toxic dose is exceeded. Therefore, in order to more effectively utilize these cytidine-like anticancer drugs, by pre-administering a CDA inhibitor, the problem arising from the difference in the drug first pass effect and metabolic rate in the liver is solved. Efforts have been made to minimize side effects and ultimately administer these cytidine-like structural anticancer drugs orally, but there are still several technical problems.

Tetrahydrouridine (THU) is a CDA inhibitor developed by Upjohn and is known to be a safe substance that can be administered by injection and orally. It was confirmed that THU can inhibit CDA activity very excellently in various in vitro and in vivo experiments. It is known that if THU is administered 2 hours before administration of a cytidine analog drug and the blood concentration of THU is maintained at 1 μg/ml or more until 4 hours after administration of the drug, CDA activity in vivo can be almost completely inhibited. It has been confirmed that administration of the drug in the concentration range does not show serious side effects in animals and humans. However, THU can easily achieve blood concentrations of 1 ㎍/㎖ or more when administered orally in in vivo experiments in rodents or beagle dogs. , Rhesus monkey (Rhesus monkey), or when administered orally in humans, it is difficult to achieve a significant blood concentration, and clinical use is remarkably limited. This phenomenon is due to the phenomenon that the THU compound is easily and spontaneously changed into an inactive β-ribopyranosylhydroxyuridine compound by acid. Although this was not a big problem in rodents with a short drug retention time, it is because apes and humans have a severe gastric acid pH of 1-2, which corresponds to severe conditions and the drug retention time in the stomach is long. In addition, THU has two types of epimers according to the configuration of the hydroxyl group at position 4 of the uracil ring in up (beta form) or down (alpha form). Epimers in the form are also easily converted to each other by acid.

Republic of Korea Patent Registration No. 10-1543049 relates to specific tetrahydrouridine derivative compounds, pharmaceutical compositions and kits containing these compounds, and methods of preparing and using these compounds, and derivatives derived based on tetrahydrouradine are It is disclosed that it has an inhibitory effect on cytidine deaminoase.

However, among the epimers of tetrahydrouridine, there has not been disclosed a study or description of an enterolytic formulation of an epimer having an effect of substantially inhibiting cytidine deaminase.

Accordingly, the present inventors have made diligent efforts to isolate and provide an epimer having a substantially cytidine deaminoase (CDA) inhibitory effect among the epimers of tetrahydrouridine (THU). As a result, the THU epimer β type of the present invention (beta form) was confirmed to have a substantially CDA inhibitory effect, and the present invention was completed.

Accordingly, it is an object of the present invention to provide an anticancer adjuvant comprising a tetrahydrouridine epimer β type and a use thereof.

In order to achieve the object of the present invention, the present invention is an anticancer adjuvant comprising a compound represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for preventing or treating cancer comprising all of the anticancer agent Provides:

[Formula 1]

Each of R1 to R4 is independently selected from the group consisting of hydrogen, halogen, and C1 to C6 linear or branched alkyl groups.

According to a preferred embodiment of the present invention, all of R1 to R4 may be hydrogen.

According to a preferred embodiment of the present invention, the anticancer adjuvant may be an oral formulation.

According to a preferred embodiment of the present invention, the oral administration formulation may additionally include any one or more selected from the group consisting of excipients, disintegrants, sustained release agents, and lubricants.

According to a preferred embodiment of the present invention, the oral formulation may be an enteric soluble oral formulation.

According to a preferred embodiment of the present invention, the anticancer agent may be an anticancer agent having a cytidine analog structure.

According to a preferred embodiment of the present invention, the cancer is selected from the group consisting of gastric cancer, liver cancer, kidney cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, lung cancer, colon cancer, breast cancer, melanoma, hematologic cancer, and pancreatic cancer. It may be any one or more.

The present invention also includes a) a compound represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof; And excipients; Mixing the mixture to form a mixture;

b) encapsulating the mixture of step a) in a capsule; And

c) coating the enclosed capsule of step b);

It provides a method for preparing an anticancer adjuvant for oral administration comprising:

[Formula 1]

Each of R1 to R4 is independently selected from the group consisting of hydrogen, halogen, and C1 to C6 linear or branched alkyl groups.

According to a preferred embodiment of the present invention, all of R1 to R4 may be hydrogen.

According to a preferred embodiment of the present invention, the mixture of step a) may additionally include any one or more selected from the group consisting of a disintegrant, a sustained-release agent, and a lubricant.

According to a preferred embodiment of the present invention, the mixture of step b) may be included in an amount of 1 mg to 1000 mg per capsule.

According to a preferred embodiment of the present invention, the coating in step c) may be an enteric coating.

The present invention also includes a) a compound represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof; And excipients; Mixing the mixture to form a mixture;

b) coating the mixture of step a); And

c) encapsulating the coated mixture of step b) in a capsule;

It provides a method for preparing an anticancer adjuvant for oral administration comprising:

[Formula 1]

Each of R1 to R4 is independently selected from the group consisting of hydrogen, halogen, and C1 to C6 linear or branched alkyl groups.

According to a preferred embodiment of the present invention, all of R1 to R4 may be hydrogen.

According to a preferred embodiment of the present invention, the mixture of step a) may additionally include any one or more selected from the group consisting of a disintegrant, a sustained-release agent, and a lubricant.

According to a preferred embodiment of the present invention, the coating in step b) may be an enteric coating.

According to a preferred embodiment of the present invention, the mixture of step c) may be included in an amount of 1 mg to 1000 mg per capsule.

The beta form of the tetrahydrouridine (THU) of the present invention has a substantially inhibitory effect on cytidine deaminase (CDA), unlike the alpha form, so it has been previously used for CDA inhibition. Sufficient CDA inhibitory effect can be obtained even with a significantly reduced amount of THU used. In addition, when it is formulated into an enteric soluble formulation, it is possible to prevent it from being transformed into an inactive structure that does not have a CDA inhibitory effect because it is not exposed to the acid of the stomach, so that the anticancer effect of an anticancer drug having a CDA analog structure can be more effectively enhanced.

Hereinafter, the present invention will be described in more detail.

As described above, tetrahydrouridine (THU) has an effect of inhibiting cytidine deaminase (CDA), but only some of the epimers of THU have a CDA inhibitory effect, so an unnecessarily large amount of THU is used to inhibit CDA. When THU is exposed to stomach acid through oral administration, etc., there is a problem that the CDA inhibitory activity is transformed into an inactive structure, so that the clinical use of anticancer drugs similar to CDA is increasing. There is a need for research on a method that can be controlled.

The epimer β type (beta form) of THU of the present invention has a CDA inhibitory effect of about 10 times more than that of the α type (alpha form). Can be reached, so that the anticancer effects of anticancer drugs having a CDA analog structure can be more effectively enhanced.

The “epimer β form of tetrahydrouridine (THU)” of the present invention refers to a compound in which all of R1 to R4 are hydrogen among compounds that can be represented by the following [Chemical Formula 1]. In other words, it means an epimer type of THU in which the hydroxyl group at position 4 of the uracil ring of THU is up.

The'enteric soluble formulation' of the present invention is a kind of drug delivery system that performs an enteric coating on the surface of a drug formulation so that the active ingredients (functional ingredients, drugs, etc.) of the formulation are not released from the stomach but from the intestine. In other words, as the formulation passes through the stomach and disintegrates in the intestine, the active ingredients contained in the formulation are not affected by stomach acid, and at the same time, it does not affect the stomach wall, and as a result, the decomposition of components affected by stomach acid is prevented. It refers to a formulation capable of increasing bioavailability.

Accordingly, the present invention can provide an anticancer adjuvant comprising a compound represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof:

[Formula 1]

The R1 to R4 may each independently be any one selected from the group consisting of hydrogen, a halogen and a C1 to C6 linear or branched alkyl group, and preferably all of R1 to R4 may be hydrogen.

The anticancer adjuvant of the present invention may be an oral formulation.

The oral administration formulation of the present invention may additionally include any one or more selected from the group consisting of excipients, disintegrants, sustained-release agents, and lubricants.

The excipients are starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol. , Cellulose, microcrystalline cellulose, methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, sodium hydrogen phosphate or gelatin are mixed and prepared. For example, tablets or dragees can be obtained by blending the active ingredient with a solid excipient, pulverizing it, adding a suitable auxiliary, and processing it into a granule mixture. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions or syrups, and various excipients, such as wetting agents, sweeteners, fragrances or preservatives, are included in addition to water and liquid paraffin, which are commonly used simple diluents. I can. In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and anti-aggregating agents, flavoring agents, emulsifying agents, solubilizing agents, dispersing agents, flavoring agents, antioxidants, packaging agents. , Pigments and preservatives, etc. may additionally be included.

The oral administration formulation of the present invention may be an enteric soluble oral administration formulation. The enteric-soluble oral formulation is a formulation that is coated with an oral formulation with an enteric film, etc., so that the formulation withstands the above acidic conditions (pH 1 to 2) and dissolves in the intestinal conditions (pH 6 to 8). Means.

The present invention also includes a) a compound represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof; And excipients; Mixing the mixture to form a mixture;

b) encapsulating the mixture of step a) in a capsule; And

c) coating the enclosed capsule of step b);

It can provide a method for preparing an anticancer adjuvant for oral administration comprising:

[Formula 1]

The R1 to R4 may each independently be any one selected from the group consisting of hydrogen, a halogen and a C1 to C6 linear or branched alkyl group, and preferably all of R1 to R4 may be hydrogen.

The excipient in step a) is the same as the excipient that may be additionally included in the anticancer adjuvant, so the description is replaced with the description.

The mixture of step a) of the present invention may additionally contain at least one selected from the group consisting of a disintegrant, a sustained-release agent, and a lubricant.

The mixture of step b) of the present invention may be included in an amount of 1 mg to 1000 mg per capsule.

The capsules are gelatin (e.g., type A, type B), carrageenan (e.g., kappa, iota, lambda) and/or modified cellulose (e.g., hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose acetate succinate). Nate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate), and optionally one or more excipients, such as oils (e.g. fish oil, olive oil, corn oil, soybean oil, coconut oil, tri-, di- and monoglycerides), plasticizers ( Examples: glycerol, glycerin, sorbitol, polyethylene glycol, citric acid, citric acid esters such as triethylcitrate, polyhydric alcohols), co-solvents such as triacetin, propylene carbonate, ethyl lactate, propylene glycol, oleic acid, Dimethylisosorbide, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, glyceryl behenate, glyceryl palmitostearate), surfactants, buffers, lubricants, moisturizers, preservatives, colorants and fragrances. Capsules can be hard or soft. Examples of hard capsules include Coni-Snap®, DRcaps ^™ , OceanCaps®, Pearlcaps®, Plantcaps®, DUOCAP ^™ , Eudragit®, Vcaps® and Vcaps® as well as capsules commercially available from Capsugel. Hard capsules are prepared, for example, by forming two sandwiched capsule halves, filling one half of them with a compound of [Chemical Formula 1] or a pharmaceutically acceptable salt thereof, and sealing the capsule halves together. Can be. The filler can be in any suitable form, such as dry powder, granule, suspension or liquid. Examples of soft capsules include soft gelatin (also called soft gel, or soft elastic), such as SGcaps. Soft capsules can be manufactured, for example, by a rotary die, plate, reciprocating die or Accogel machine method. In addition, the capsules may be liquid-filled hard capsules or soft-gelatin capsules.

The coating of step c) of the present invention may be an enteric coating.

The enteric-soluble coating means that the capsule is coated with a coating agent so that it withstands the above acidic conditions (pH 1 to 2) and dissolves in the intestinal conditions (pH 6 to 8). The coating agent is a methacrylic acid copolymer, a methacrylic acid-methyl methacrylate copolymer (e.g., EUDRAGIT L100 (type A), EUDRAGIT S100 (type B), Rohm GmbH, Germany), methacrylic acid-ethyl acrylate copolymer Coalescence (eg EUDRAGIT L100-55 (Type C) and EUDRAGIT L30D-55 copolymer dispersion, Rohm GmbH, Germany); A copolymer of methacrylic acid-methyl methacrylate and methyl methacrylate (EUDRAGIT FS); Terpolymers of methacrylic acid, methacrylate and ethyl acrylate; Cellulose acetate phthalate (CAP); Hydroxypropyl methylcellulose phthalate (HPMCP) (eg, HP-55, HP-50, HP-55S, Shinetsu Chemical, Japan); Polyvinyl acetate phthalate (PVAP) (eg, COATERIC, OPADRY enteric white OY-P-7171); Cellulose acetate succinate (CAS); HF Grade including hydroxypropyl methylcellulose acetate succinate (HPMCAS), such as HPMCAS LFGrade, MF Grade, AQOAT LF and AQOAT MF (Shinetsu Chemical, Japan); Carboxymethyl ethylcellulose (CMEC, Freund Corporation, Japan) and cellulose acetate phthalate (CAP) (eg, AQUATERIC); It may be any one or more selected from the group consisting of cellulose acetate trimellitate (CAT).

The present invention also includes a) a compound represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof; And excipients; Mixing the mixture to form a mixture;

b) coating the mixture of step a); And

c) encapsulating the coated mixture of step b) in a capsule;

It can provide a method for preparing an anticancer adjuvant for oral administration comprising:

[Formula 1]

The R1 to R4 may each independently be any one selected from the group consisting of hydrogen, a halogen and a C1 to C6 linear or branched alkyl group, and preferably all of R1 to R4 may be hydrogen.

The excipient in step a) is the same as the excipient that may be additionally included in the anticancer adjuvant, so the description is replaced with the description.

The mixture of step a) of the present invention may additionally contain at least one selected from the group consisting of a disintegrant, a sustained-release agent, and a lubricant.

The coating in step b) of the present invention may be an enteric coating. Since the enteric-soluble coating is performed in the same manner as coating the capsule, the description is replaced with the substrate.

The mixture of step c) of the present invention may be included in an amount of 1 mg to 1000 mg per capsule. The capsules are the same as those for encapsulating a mixture that is not preceded by the enteric-soluble coating, so the description is replaced with the description.

The present invention can also provide a pharmaceutical composition for preventing or treating cancer comprising both the anticancer adjuvant and the anticancer agent.

The anticancer agent of the present invention may be an anticancer agent having a cytidine analog structure. Specifically, decitabine, azacytidine, gemcitabine, cytarabine (ara-C), troxacitabine, tezacitabine, and thai arabine (Thiarabine), 5-Aza-4'-thiodeoxycytidine or 4'-ThioFAC.

The cancer of the present invention is any one selected from the group consisting of gastric cancer, liver cancer, kidney cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, lung cancer, colon cancer, breast cancer, melanoma, leukemia, bladder cancer, hematologic cancer, and pancreatic cancer. It may be more than that. The hematologic cancer may be non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, leukemia, lymphoma, myelodysplastic syndrome (MDS), acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia or isolated myeloma.

The pharmaceutical composition of the present invention may be in an oral dosage form. When formulating the composition, one or more buffers (e.g., saline or PBS), antioxidants, bacteriostatic agents, chelating agents (e.g., EDTA or glutathione), fillers, bulking agents, binders, adjuvants (e.g., Aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrants or surfactants, diluents or excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient in one or more compounds, such as starch (corn starch, wheat starch, rice starch, potato Starch), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, microcrystalline cellulose, methyl cellulose, sodium carboxymethylcellulose and It is prepared by mixing hydroxypropylmethyl-cellulose, sodium hydrogen phosphate or gelatin. For example, tablets or dragees can be obtained by blending the active ingredient with a solid excipient, pulverizing it, adding a suitable auxiliary, and processing it into a granule mixture.

In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions or syrups, and various excipients, such as wetting agents, sweeteners, fragrances or preservatives, are included in addition to water and liquid paraffin, which are commonly used simple diluents. I can. In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and anti-aggregating agents, flavoring agents, emulsifying agents, solubilizing agents, dispersing agents, flavoring agents, antioxidants, packaging agents. , Pigments and preservatives, etc. may additionally be included.

The composition of the present invention is administered in a pharmaceutically effective amount. A pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type of disease, severity, drug activity, drug sensitivity, administration time of the patient. , Route of administration and rate of excretion, duration of treatment, factors including concurrent drugs and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. That is, the total effective amount of the composition of the present invention may be administered to a patient in a single dose, and may be administered by a fractionated treatment protocol that is administered for a long time in multiple doses. . It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.

The dosage of the pharmaceutical composition of the present invention varies according to the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity. However, it may increase or decrease depending on the route of administration, the severity of obesity, sex, weight, and age.

The composition of the present invention may be used alone or in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and methods using biological response modifiers.

Hereinafter, the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and it is apparent to those of ordinary skill in the art that the scope of the present invention is not construed as being limited by these examples.

Isolation of THU epimer

A mixed THU (1g) containing both the epimers of THU α type (alpha form) and THU β type (beta form) was separated by preparative HPLC and 300 mg of pure THU α type and THU β type each Was obtained.

Rodent PK measurement of THU epimers

Pure THU α type (alpha form) or THU β type (beta form) was administered intravenously (IV) to mice in an amount of 100 mg/kg, respectively, and it was confirmed that these compounds were not mutually converted and maintained in the blood. .

Next, it was confirmed that these compounds were easily exposed in the blood when these THU α type or THU β type were administered orally to mice in an amount of 100 mg/kg, respectively, but about 20% of the amount compared to the amount at the time of IV administration. It was confirmed that the drug exposure was shown and converted to a mixture of THU α type and THU β type.

In addition, when these THU α type or THU β type were administered rectally to mice in an amount of 100 mg/kg, respectively, it was confirmed that significantly larger amounts of drugs were exposed to the body of these compounds than when administered IV or oral. In addition, it was confirmed that these pure compounds of THU α type and THU β type can hardly be inhibited from being converted into a mixed type.

Preparation of THU enteric soluble capsule

For the evaluation of PK in large animals such as apes, which were a problem in the use of existing THU, THU α type or THU β type was mixed with excipients in an amount of 10 mg per capsule. After encapsulation in soluble DRcaps® capsules, enteric soluble capsules were prepared by surface coating with Eudragit® L100-55 coating four times.

In addition, THU α type (alpha form) or THU β type (beta form) is mixed with an excipient in an amount of 10 mg per capsule, and the mixture is coated with an enteric soluble substance and then enclosed in a capsule. Also prepared together.

As an excipient, an appropriate amount of a buffer compound (such as sodium hydrogenphosphate) was mixed with microcrystalline cellulose and used.

PK evaluation in apes using THU enteric-soluble capsule

First, pure THU α type (alpha form) or THU β type (beta form) was administered intravenously (IV) to a rhesus monkey in an amount of 10 mg/kg, respectively, so that these compounds were not converted to each other in the blood. It could be confirmed that it was maintained.

Next, it was confirmed that these compounds were easily exposed in the blood when a suspension was prepared in an amount of 10 mg/kg each of these THU α type or THU β type and administered orally to Rhesus monkey, but compared to the amount at the time of IV administration. It was confirmed that the drug exposure level was less than about 10% and converted to a mixture of THU α type and THU β type. In addition, it was confirmed that sufficient drug exposure was difficult because the blood concentration in Rhesus monkey was far below 1 ㎍/㎖.

In addition, when 3 enteric-soluble capsules prepared in <Example 2> were administered orally to Rhesus monkey, respectively, a suspension of THU α type or THU β type compound was administered to the body by IV administration or oral administration of a significantly larger amount of the drug. It was confirmed that exposure to THU α type or THU β type can be almost inhibited from conversion of pure compounds of the THU α type or the THU β type. In addition, it was confirmed that sufficient drug exposure was easily achieved because the blood concentration in Rhesus monkey exceeded 1 ㎍/㎖ for about 4 hours or more.

Evaluation of the pharmacological effect of enteric soluble capsules

It was attempted to confirm the pharmacodynamic effect of the enteric soluble capsule prepared in <Example 2> in apes.

First, decitabine was put in a gelatin capsule at a dose of 10 mg/kg, and then the PK profile was measured after oral administration in a rhesus monkey. At this time, Cmax (maximum drug plasma level) was 50-100 ng/ml. It can be seen that the AUC (area under the curve) was also low in the amount of the level, resulting in very low drug exposure.

Next, 3 enteric-soluble capsules prepared in <Example 2> were orally administered to Rhesus monkey, 2 hours later, decitabine was put in a gelatin capsule at a dose of 10 mg/kg, and then PK profile after oral administration in Rhesus monkey. Was measured. At this time, in the subjects administered enterolytic properties containing the active THU β type (beta form) compound, the Cmax of decitabine was at the level of about 1000 ng/ml and the AUC was also high, compared to the fact that it was confirmed that the drug exposure was significantly improved. It was confirmed that the drug exposure of decitabine hardly increased in the subjects administered enterolytic properties containing the compound.

Claims (18)

Anticancer adjuvant comprising a compound represented by the following [Chemical Formula 1] or a pharmaceutically acceptable salt thereof:
[Formula 1]

Each of R1 to R4 is independently selected from the group consisting of hydrogen, halogen, and C1 to C6 linear or branched alkyl groups.
The anticancer adjuvant according to claim 1, wherein all of R1 to R4 are hydrogen.
The anticancer adjuvant according to claim 1, wherein the anticancer adjuvant is an oral administration agent.
The anticancer adjuvant according to claim 3, wherein the oral administration formulation further comprises at least one selected from the group consisting of excipients, disintegrants, sustained-release agents, and lubricants.
The anticancer adjuvant according to claim 3, wherein the oral administration preparation is an enteric soluble oral administration preparation.
a) a compound represented by the following [Formula 1] or a pharmaceutically acceptable salt thereof; And excipients; Mixing the mixture to form a mixture;
b) encapsulating the mixture of step a) in a capsule; And
c) coating the encapsulated capsule of step b);
A method for preparing an anticancer adjuvant for oral administration comprising:
[Formula 1]

Each of R1 to R4 is independently selected from the group consisting of hydrogen, halogen, and C1 to C6 linear or branched alkyl groups.
The method of claim 6, wherein all of R1 to R4 are hydrogen.
The method of claim 6, wherein the mixture of step a) further comprises at least one selected from the group consisting of a disintegrant, a sustained-release agent, and a lubricant.
The method of claim 6, wherein the mixture of step b) is contained in an amount of 1 mg to 1000 mg per capsule.
The method of claim 6, wherein the coating in step c) is an enteric coating.
a) a compound represented by the following [Formula 1] or a pharmaceutically acceptable salt thereof; And excipients; Mixing the mixture to form a mixture;
b) coating the mixture of step a); And
c) encapsulating the coated mixture of step b) in a capsule;
A method for preparing an anticancer adjuvant for oral administration comprising:
[Formula 1]

Each of R1 to R4 is independently selected from the group consisting of hydrogen, halogen, and C1 to C6 linear or branched alkyl groups.
The method of claim 11, wherein all of R1 to R4 are hydrogen.
The method of claim 11, wherein the mixture of step a) further comprises at least one selected from the group consisting of a disintegrant, a sustained-release agent, and a lubricant.
The method of claim 11, wherein the coating in step b) is an enteric coating.
The method according to claim 11, wherein the coated mixture of step c) is contained in an amount of 1 mg to 1000 mg per capsule.
A pharmaceutical composition for cancer treatment comprising all of the anticancer adjuvant and anticancer agent of claim 1.
The pharmaceutical composition of claim 16, wherein the anticancer agent is an anticancer agent having a cytidine analog structure.
The method of claim 16, wherein the cancer is selected from the group consisting of gastric cancer, liver cancer, kidney cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, lung cancer, colon cancer, breast cancer, melanoma, leukemia, bladder cancer, blood cancer, and pancreatic cancer. Pharmaceutical composition, characterized in that any one or more.