JP2021020953A - Pharmaceutical combinations comprising hdac inhibitor and proteasome inhibitor or immunomodulatory drug for the treatment of hematological cancer - Google Patents

Abstract

To provide formulations that are useful for treating a hematological cancer such as multiple myeloma, with reduced toxicity.SOLUTION: A combination for treating a hematological cancer comprising, 1) a compound of the following chemical formula 1 or its pharmaceutically acceptable salt as the first active ingredient, 2) a proteasome inhibitor or an immunomodulatory drug as the second active ingredient and 3) a steroidal anti-cancer agent as the third active ingredient.SELECTED DRAWING: Figure 1a

Description

The present invention relates to pharmaceutical formulations for the treatment of hematological malignancies, more specifically multiple myeloma, in particular hematological malignancies that are resistant to conventional therapies, and specifically histone deacetylases. It relates to a pharmaceutical formulation for the treatment of myeloma containing both an acetylase (HDAC) inhibitor, an immunomodulatory drug and a steroidal anticancer drug.

Myeloma, a hematological malignancies, refers to a tumor composed of cells of the type normally found in the bone marrow. In addition, multiple myeloma (MM) is associated with widespread osteolytic lesions that induce bone pain, pathological fractures, hypercalcemia and normochromic anemia. It means a disseminated malignant neoplasm of plasma cells characterized by bone marrow tumor lesions and secretion of M component (monoclonal immunoglobulin fragment). Multiple myeloma is untreatable with conventional, high-dose chemotherapy use.

On the other hand, the acetylated state of nucleosome histones plays an important role in the regulation of gene expression. Deacetylation of nucleosome histones is facilitated by a group of enzymes known as histone deacetylases (HDACs), which have 11 known isoforms. Histone deacetylation induces chromatin condensation, which leads to transcriptional suppression, while acetylation is a transcriptional mechanism that induces localized relaxation within specific chromosomal sites to facilitate transcription. Allows closer access to (transcriptional machinery). In tumor cells, selective inhibitors of HDAC enzymes lead to hyperacetylation of histones. It is known to alter transcriptional regulation of a subset of genes (subsets), including many tumor suppressor genes involved in cell cycle regulation, cell division and apoptosis. In addition, HDAC inhibitors have been reported to suppress tumor growth in vivo. Inhibition of tumor growth is accompanied by histone and tubulin hyperacetylation and can include a number of mechanisms. HDAC inhibitors block cancer cell growth both in vitro (in vitro) and in vivo (in vivo). Thus, it has been known that HDAC inhibitors effectively suppress cancer growth in multiple myeloma, but the problem with previously developed drugs is that their use is limited due to their severe toxicity. Had.

On the other hand, proteasome inhibitors and immunomodulatory drugs are well known as major preparations for the treatment of multiple myeloma.

On the other hand, immunomodulatory (IMiD) drugs have been shown to show prominent anti-myeloma properties in a variety of multiple myeloma models and have significant clinical activity in patients with multiple myeloma. Of these, bortezomib (also known as Velcade or PS-341) is a small molecule proteasome inhibitor recently approved by the FDA in the treatment of refractory multiple myeloma and is active in NSCLC cell lines. It has been reported to have, where it was discovered to induce concentration and time-dependent G2 / M cell cycle arrest.

Due to various problems including the toxicity of such therapies, there is a strong demand for more effective and less toxic compositions and methods for the treatment of multiple myeloma. ..

Against this background, the present inventors have repeated diligent studies on preparations for more effective and less toxic hematological cancers, specifically multiple myeloma, and as a result, as HDAC inhibitors, compounds of chemical formula 1 and proteasome inhibition When a drug or immunomodulatory drug is combined with a steroidal anticancer drug, it is at the same level as existing HDAC inhibitors in multiple myeloma, which has been difficult to treat effectively due to various problems such as hematological cancer, especially conventional toxicity. The present invention has been completed after confirming that it is possible to secure an ascending anticancer effect that can greatly reduce the toxicity while showing the medicinal effect of.

Therefore, an object of the present invention is to provide a therapeutic formulation for myeloma containing a compound of the following chemical formula 1 as a histone deacetylase inhibitor, a proteasome inhibitor or an immunomodulatory drug, and a steroidal anticancer agent. There is.

As one aspect for achieving the above object, the present invention is:
(1) As the first active ingredient, a hydroxamic acid derivative represented by the following chemical formula 1, N- (7- (hydroxyamino) -7-oxoheptyl) -4-methyl-N- (4- ( 1-Methyl-1H-Indazole-6-yl) phenyl) Piperazin-1-Carboxamide Methanesulfonate (N- (7- (hydroxynamio) -7-oxoheptyl) -4-methyl-N- (4- (1-methyl-) 1H-indazole-6-yl) phenyl) piperazine-1-carboxamide methylfone) or a pharmaceutically acceptable salt thereof;
(2) A proteasome inhibitor or immunomodulatory drug is included as the second active ingredient; and (3) a steroidal anti-cancer agent is included as the third active ingredient.
It relates to a pharmaceutical formulation for the treatment of hematological cancer. Preferably, the hematological malignancies are multiple myeloma.

The improved efficacy of the formulations according to the invention can be substantiated by measuring the therapeutically elevated efficacy. The formulation of the present invention exhibits an increasing effect when the first active ingredient, which is an HDAC inhibitor, is administered in combination with the second active ingredient and the third active ingredient, and has an anticancer activity against hematological cancers, particularly multiple myeloma. Excellent.

MM. It is a cancer growth graph of a control group and each experimental group in a 1s xenograft mouse model. MM. The 1s xenograft mouse model showed individual tumor size changes in each experimental group on the last day of the experiment (day 57). MM. It is a cancer growth graph of a control group and each experimental group in a 1s xenograft mouse model. MM. The 1s xenograft mouse model showed individual tumor size changes in each experimental group on the last day of the experiment (day70).

It will be described in more detail below.
The first active ingredient of the pharmaceutical formulation according to the present invention is the compound of Chemical Formula 1, which has activity as a histone deacetylase (HDAC) inhibitor. The description and manufacturing method of the compound of Chemical Formula 1 are described in detail in International Patent Publication No. WO2010-110545, which is included as a reference for the present invention. In the present invention, the compound of the chemical formula 1 can be produced by the production method disclosed in the above-mentioned literature. In general, the amount of the compound of Chemical Formula 1 administered to humans varies depending on various administration factors including factors specific to the individual patient, and it is known that the compound can be administered at, for example, 10 to 210 mg / m2. ing.

On the other hand, the second active ingredient of the pharmaceutical formulation according to the present invention is a proteasome inhibitor or an immunomodulatory drug, and the proteasome inhibitor is a proteasome that degrades a cell division-regulating protein (proteasome; that is, a cell complex that degrades a protein). It is a preparation that reversibly suppresses the activity of the body), and while normal cells recover the cell division ability even if the activity of the proteasome is suppressed for a while, various cancer cells suppress the activity of the proteasome even for a while. It is used to immediately enter the death process. The proteasome inhibitor that may be included in the pharmaceutical composition of the present invention may be known various grades of proteasome inhibitor. For example, the peptide boronate grade includes bortezomib (INN, PS0341; Velcade), a compound approved in the United States for the treatment of recurrent multiple myeloma. In addition, as another peptide boronate, there is CEP-18770. Other grades of proteasome inhibitors include peptide aldehydes (eg MG132), peptide vinyl sulfones, peptide epoxy ketones (eg epoxomicin, calfilzomib), β lactone inhibitors (eg lactacystin, MLN519, NPI-0052). , Salinosporamide A), compounds that form dithiocarbamate complexes with metals (eg, disulfiram, a drug that is also used to treat chronic alcohol intoxication), and specific antioxidants (eg, epigalocatechin-3-gallate) catechins. There are -3-gallate, and salinosporamide A. The proteasome inhibitor contained in the pharmaceutical composition of the present invention is preferably bortezomib represented by the following chemical formula 2 or a pharmaceutically acceptable salt thereof. Bortezomib can generally be administered intravenously or subcutaneously in doses of 0.3 to 1.5 mg / m ² once or twice weekly, depending on the dosing regimen, but is not limited.

On the other hand, immunomodulatory drugs have effects such as promoting the expansion of immune cells and the death of tumor cells. Specifically, they are substances that improve ADCC (antibody-dependent cell-mediated cytotoxicity) and regulate immunity. Is. Specifically, the immunomodulatory drug contained in the pharmaceutical composition of the present invention may be thalidomide, lenalidomide, pomalidomide or a pharmaceutically acceptable salt thereof, and is preferably represented by the following chemical formula 3. Lenalidomide or a pharmaceutically acceptable salt thereof. Lenalidomide is generally given orally in doses of 10 mg to 30 mg, depending on the dosing regimen, but is not limited.

The third active ingredient of the pharmaceutical formulation according to the invention is a steroidal anti-cancer agent, which may be, for example, prednisone or dexamethasone, but is not limited thereto. Preferably, the dexamethasone represented by the following chemical formula 4, that is, (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R) -9-fluoro-11,17-dihydroxy-17- (2-hydroxyacetyl). -10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentane [a] phenanthrene-3-one or isotope mutation The body; or a pharmaceutically acceptable salt, hydrate or solvate thereof. In one embodiment, the dexamethasone is (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R) -9-fluoro-11,17-dihydroxy-17- (2-hydroxyacetyl) -10,13,16. -Trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentane [a] phenanthrene-3-one. In another embodiment, the dexamethasone is deuterated (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R) -9-fluoro-11,17-dihydroxy-17. -(2-Hydroxyacetyl) -10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentane [a] phenanthrene- It is 3-d on.

In the present invention, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, an inorganic ionic salt produced from calcium, potassium, sodium and magnesium, hydrochloric acid, nitrate, phosphoric acid, brom. Inorganic acid salts, acetic acid, trifluoroacetic acid, citric acid, maleic acid, amber acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, etc. made from acids, iodoic acid, perchloric acid, tartaric acid and sulfuric acid, etc. Organic acid acid, methanesulfonic acid produced from propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbon acid, vanillic acid, hydroiodoic acid, etc. Sulfonates made from acids, ethanesulfonic acids, benzenesulfonic acids, p-toluenesulfonic acids, naphthalenesulfonic acids, etc., amino acid salts made from glycine, arginine, lysine, etc. and trimethylamine, triethylamine, ammonia, pyridine, picolin Although there are amine salts produced from the above, the types of salts meant in the present invention are not limited by these listed salts.

In one specific embodiment, the first active ingredient, the second active ingredient and the third active ingredient are in the case of a proteasome inhibitor such as bortezomib as the second active ingredient with respect to 100 parts by weight of the total pharmaceutical formulation. , The first active ingredient may be contained in 28.55 to 85.60 parts by weight, the second active ingredient 1.28 to 8.63 parts by weight, and the third active ingredient 2.71 to 69.55 parts by weight. 2 When an immunomodulatory drug such as renalidemid is contained as an active ingredient, the first active ingredient is 19.54 to 94.69 parts by weight, the second active ingredient is 2.46 to 52.63 parts by weight, and the third active ingredient is 2. It may be contained in parts of .52 to 59.70 parts by weight.

The pharmaceutical formulations of the present invention may comprise three separate formulations and may consist of two or one formulation.

The formulations of the present invention can be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to the method of interest. In the present invention, the first active ingredient and the second active ingredient may be administered parenterally or orally, preferably parenterally. In addition, the third active ingredient may be administered parenterally or orally, preferably orally.

In the formulation of the present invention, suitable doses of the first to third active ingredients are the weight, age, sex, health condition, diet, administration time, administration method, disposition rate and disease severity of the patient. The range varies depending on the degree. The daily dose of the first active ingredient of the present invention is about 10 to 80 mg / kg, preferably 20 to 60 mg / kg. The daily dose of the second active ingredient of the present invention is about 0.1 to 5 mg / kg, preferably 0.5 to 2 mg / kg.

In the formulation of the present invention, the suitable dosing cycle of the first active ingredient, the second active ingredient and the third active ingredient may be determined by the dose. For example, when the second active ingredient of the present invention is a proteasome inhibitor, the first active ingredient of the present invention may be administered once a day to once every two weeks, preferably once a week. It can be administered once. In addition, the second active ingredient of the present invention may be administered once a day to once a week, and preferably twice a week. The third active ingredient of the present invention may be administered once a day to once a week, and preferably four times a week. When the second active ingredient of the present invention is an immunomodulatory drug, the first active ingredient of the present invention may be administered once a day to once every two weeks, preferably for one week. The second active ingredient may be administered once a day to once a week, and preferably once a day. The third active ingredient may be administered once a day to once a week, and preferably once a week.

The pharmaceutical formulation of the present invention has an increasing complementary effect of the first active ingredient which is an HDAC inhibitor, the second active ingredient which is a proteasome inhibitor or an immunomodulatory drug, and the third active ingredient which is a steroidal anticancer agent. It was confirmed, and as a result, it shows excellent anticancer activity.

Therefore, the anti-cancer formulation of the present invention can be usefully used as an anti-cancer treatment strategy, and is particularly preferable for the treatment of hematological cancer. The hematological malignancies can preferably be multiple myeloma.

In the present invention, the first active ingredient, the second active ingredient and the third active ingredient contained in the formulation of the present invention may be contained in separate pharmaceutical compositions, and the pharmaceutical composition is the invention. Manufactured in unit volume form or placed in a multidose container by formulation with a pharmaceutically acceptable carrier by a method readily practiced by those with conventional knowledge in the art to which it belongs. May be manufactured.

The pharmaceutically acceptable carriers are usually used in preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone. , But not limited to, such as, but not limited to, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may additionally contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative and the like. Suitable pharmacologically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).

In yet another aspect, the present invention provides a method of treating cancer that comprises administering the pharmaceutical formulation to an individual in need thereof. In the present invention, the term "individual" includes mammals, especially humans.

Hereinafter, the configuration and effect of the present invention will be described in more detail through Examples. These examples are merely for exemplifying the present invention, and the scope of the present invention is not limited by these examples.

<Example 1: MM. Confirmation of anticancer effect of the formulation according to the present invention using bortezomib as the second active ingredient in a 1s xenograft model>
1-1) Experimental method a. Animal tumor model preparation MM., A human multiple myeloma cell line. 1s was purchased at ATCC (USA). MM. The 1s cell line was maintained at RPMI 1640 (Gibco, USA) containing 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA).

NOD. MM.M. CB17-Prkdcscid / NCRHsd male mice mixed with matrigel. The 1s cells were subcutaneously administered (2 × 10 ⁷ cell / head) to form a group so that the tumor size was evenly distributed, and then used in the experiment.

b. Preparation of Active Ingredient The compound of Chemical Formula 1 was dissolved in physiological saline and prepared at a concentration of 4 mg / ml.
Bortezomib was dissolved in physiological saline and prepared at a concentration of 0.005 mg / ml.
Dexamethasone was prepared by diluting a 5 mg / mL stock solution with physiological saline to a concentration of 0.05 mg / ml.
The solution to be used was prepared on the day of use, and the remaining solution was discarded.

c. Confirmation of antitumor activity The anticancer effect of the compound of Chemical Formula 1 and bortezomib and dexamethasone was described in MM. It was evaluated in a 1s xenograft model. The experimental group was divided into the following other administration groups.
-Control group: vehicle
-Compound alone administration group of the chemical formula 1: The compound of the chemical formula 1 (40 mg / kg, once a week, injection)
-Bortezomib plus dexamethasone group: bortezomib (0.05 mg / kg, twice a week, injection), dexamethasone (0.5 mg / kg, four times a week, injection)
-Chemical formula 1 compound, bortezomib and dexamethasone combined administration group: The compound of chemical formula 1 (40 mg / kg, once a week, injection), bortezomib (0.05 mg / kg, twice a week, injection), dexamethasone (0) .5 mg / kg, 4 times a week, injection)

All experimental groups were administered peritoneally for 57 days. Toxicity was observed by body weight measurement in mice and tumor growth was measured using calipers during the experimental period. Tumor volume was calculated by Equation 1 below.
[Formula 1]
Tumor volume = (length) x width ² ) / 2

d. Quantitative analysis (Statistical analysis)
Assuming the normality of the data for all the results of this experiment, comparison between test groups was performed through population parameter multiple comparison or non-parameter multiple comparison, and the statistical analysis was Prism 5.03 (GraphPad). It was carried out using Software Inc., San Diego, CA, USA), and when the p value was less than 0.05, it was judged to be statistically significant.

1-2) Experimental Results In order to evaluate the antitumor effect of the combined administration of the compound of Chemical Formula 1 and bortezomib and dexamethasone, xenograft mice were administered with each substance, and body weight and tumor growth were observed for 57 days.

In terms of tumor growth inhibitory effect, the tumor size of the compound-administered group of Chemical Formula 1 and the combined administration of bortezomib and dexamethasone, and the combined administration of the compound of Chemical Formula 1 + bortezomib + dexamethasone was the same as that of the excipient-administered group during the administration period. In comparison, tumor growth was greatly suppressed.

The combination of bortezomib and dexamethasone tended to be slightly smaller than the initial cancer size, but only one mouse reached complete remission, and most mice had a cancer reduction effect within 50%. On the other hand, complete remission was observed in 3 mice in the combined administration group of the compound of Chemical Formula 1 + bortezomib + dexamethasone, and most of the mice showed an effect of reducing cancer by 50% or more. Reaching complete remission of cancer is a very surprising effect, and an increased rate of complete remission suggests that the combination of these drugs is very beneficial.

Such a result suggests that the anticancer effect of the compound of Chemical Formula 1 and the triple therapy of bortezomib and dexamethasone is very large.

<Example 2: MM. Confirmation of anticancer effect of the formulation according to the present invention using lenalidomide as the second active ingredient in the 1s xenograft model>
2-1) Experimental method a. Animal tumor model preparation MM., A human multiple myeloma cell line. 1s was purchased at ATCC (USA). MM. The 1s cell line was maintained at RPMI 1640 (Gibco, USA) containing 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA).

NOD. MM.M. CB17-Prkdcscid / NCRHsd male mice mixed with matrigel. The 1s cells were subcutaneously administered (2 × 10 ⁷ cell / head) to form a group so that the tumor size was evenly distributed, and then used in the experiment.

b. Preparation of Active Ingredient The compound of Chemical Formula 1 was dissolved in physiological saline and prepared at a concentration of 6 mg / ml.
Lenalidomide is dissolved in 1% HCl in PBS and then titrated at neutral pH to 1 mg.
Prepared at / ml concentration.
0.2 mg / ml by diluting 0.5 mg / ml dexamethasone with saline.
Dexamethasone was prepared at a ml concentration.
The solution to be used was prepared on the day of use, and the remaining solution was discarded.

c. Confirmation of antitumor activity The anticancer effect of the compound of Chemical Formula 1 and lenalidomide and dexamethasone was described in MM. It was evaluated in a 1s xenograft model. The experimental group was divided into the following other administration groups.
-Control group: vehicle
-Compound alone administration group of the chemical formula 1: The compound of the chemical formula 1 (60 mg / kg, once a week, injection)
-Lenalidomide and dexamethasone combination administration group: lenalidomide (10 mg / kg, 7 times a week, injection), dexamethasone (2 mg / kg, once a week, injection)
-Combined administration group: Compound of Chemical Formula 1 (60 mg / kg, once a week, injection), lenalidomide (10 mg / kg, 7 times a week, injection), dexamethasone (2 mg / kg, once a week, injection)

All experimental groups were administered peritoneally for 70 days. Toxicity was observed by body weight measurement in mice and tumor growth was measured using calipers during the experimental period. Tumor volume was calculated by Equation 1 of Example 1.

d. Quantitative analysis (Statistical analysis)
Assuming the normality of the data for all the results of this experiment, comparison between test groups was performed through population parameter multiple comparison or non-parameter multiple comparison, and the statistical analysis was Prism 5.03 (GraphPad). It was carried out using Software Inc., San Diego, CA, USA), and when the p value was less than 0.05, it was judged to be statistically significant.

2-2) Experimental Results In order to evaluate the antitumor effect of the combined administration of the compound of Chemical Formula 1 and lenalidomide and dexamethasone, xenograft mice were administered with each substance, and body weight and tumor growth were observed for 70 days.

In terms of tumor growth inhibitory effect, the tumor size of the compound administration group of the chemical formula 1, the lenalidomide and dexamethasone combination administration group, and the compound of the chemical formula 1 + lenalidomide + dexamethasone combination administration group was the same as that of the excipient administration group during the administration period. In comparison, tumor growth was greatly suppressed.

While the combination group of lenalidomide and dexamethasone tended to be slightly larger than the initial cancer size, 80% of the mice in the combination administration group of the compound of Chemical Formula 1 + lenalidomide + dexamethasone showed the effect of eliminating cancer.

Such a result suggests that the anticancer effect of the triple therapy of the compound of Chemical Formula 1 with lenalidomide and dexamethasone is very large.

Claims (13)

1) As the first active ingredient, the compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof;
2) Proteasome inhibitor or immunomodulatory drug as the second active ingredient; and 3) Steroidal anti-cancer drug as the third active ingredient.
Formulations for the treatment of blood cancer:

.. The formulation of claim 1, wherein the proteasome inhibitor is bortezomib of formula 2 below or a pharmaceutically acceptable salt thereof:

.. The formulation according to claim 1, wherein the immunomodulatory drug is lenalidomide of Chemical Formula 3 or a pharmaceutically acceptable salt thereof.

.. The formulation according to claim 1, wherein the steroidal anti-cancer agent is dexamethasone of the following chemical formula 4 or a pharmaceutically acceptable salt thereof.

.. The formulation according to claim 1, wherein the pharmaceutically acceptable salt of the compound of Chemical Formula 1 is methanesulfonate. The formulation according to claim 3, wherein the lenalidomide is a lenalidomide free base. The second active ingredient is a proteasome inhibitor, and the first active ingredient, the second active ingredient and the third active ingredient are 28.55 to 85. The first active ingredient with respect to 100 parts by weight of the whole pharmaceutical formulation. The formulation according to claim 1, which comprises 60 parts by weight of the second active ingredient 1.28 to 8.63 parts by weight of the second active ingredient and 2.71 to 69.55 parts by weight of the third active ingredient. The second active ingredient is an immunomodulatory drug, and the first active ingredient, the second active ingredient and the third active ingredient are 19.54 to 94 of the first active ingredient with respect to 100 parts by weight of the whole pharmaceutical formulation. The formulation according to claim 1, which comprises .69 parts by weight of the second active ingredient 2.46 to 52.63 parts by weight of the second active ingredient and 2.52 to 59.70 parts by weight of the third active ingredient. The formulation according to claim 1, wherein the hematological malignancies are multiple myeloma. The formulation according to claim 1, wherein the first active ingredient, the second active ingredient, and the third active ingredient are contained in separate preparation forms. The formulation according to claim 1, wherein the first active ingredient, the second active ingredient, and the third active ingredient are combined and contained in one formulation form. The formulation according to claim 10, wherein the first active ingredient and the second active ingredient are contained as a preparation in a parenteral administration form, and the third active ingredient is contained as a preparation in an oral administration form. The preparation containing the first active ingredient, the preparation containing the second active ingredient, and the preparation containing the third active ingredient in the preparation can be administered simultaneously or sequentially. The formulation according to claim 10 or 12, which is a formulation form.