KR20230149007A - Physiological active substance carrier - Google Patents

Abstract

The present invention provides a bioactive substance carrier comprising capric acid or a physiologically acceptable salt thereof and poloxamer. Specifically, the bioactive substance may be an anti-cancer bioactive substance, and the present invention increases the viscosity through the addition of capric acid to poloxamer, a bioactive substance carrier, to control the sol-gel transition temperature and release the bioactive substance. Time can be effectively delayed.

Description

Physiologically active substance carrier {PHYSIOLOGICAL ACTIVE SUBSTANCE CARRIER}

The present invention provides a bioactive substance carrier with a delayed-release effect and a pharmaceutical composition for preventing or treating cancer using the same, and can be used in the medical and pharmaceutical fields.

Local injection of anticancer drugs for the treatment of malignant tumors has already been attempted in the treatment of various cancers, and local injection of anticancer drugs around tumors to kill stomach cancer has also been studied. Compared to intravenous administration of general anticancer drugs, local injection of anticancer drugs around the tumor can deliver a large amount of drug not only to the submucosa around the tumor but also to the surrounding lymph nodes.

In previous studies, the safety of the anticancer drug fluorouracil (5-FU) was proven as no complications occurred when an excessive amount was injected locally around the tumor. However, the results of animal experiments conducted by the present inventor showed that exposing 5-FU to the tumor for a long period of time, even in small amounts, was not effective. Considering that the tumor killing effect was significantly greater than that of simply exposing a large amount of 5-FU for a short period of time, the short duration of 5-FU action on tumors in previous studies limited the effect of anticancer drugs on tumors. It can be seen as a dot.

A method to overcome this short drug action time is a sustained-release drug manufacturing method using a sol-gel reaction. This is a technique that uses the sol-gel reaction of a vehicle for sustained release to continuously release the drug for several hours or months by mixing the drug with the vehicle and administering it topically to the desired location. Among these sustained-release mediators, there is poloxamer, but poloxamer has the disadvantage that the gelation reaction occurs at a relatively high concentration.

Poloxamer 407, which is used as a representative drug carrier, exhibits a temperature-dependent sol-gel transition phenomenon when the aqueous solution concentration is over 16% and has biocompatibility, so it is used as a sustained-release drug delivery medium to the human eye.

However, in order to increase the sustained-release effect of Poloxamer 407, at least 25% by weight must be included in the drug. In this case, the drug must be maintained below 4℃, and gelation occurs quickly when injected into the tissue, preventing the drug from spreading. There is a problem that appears in a limited way.

Therefore, it can be stored at room temperature, and even after entering the tissue, gelation occurs at a temperature of about human body temperature and can spread in the tissue, and the drug release time can last longer compared to the existing Poloxamer (for effective anticancer action of anticancer drugs). The anticancer drug must be released at a certain concentration over a certain period of time, and for this purpose, a release time of about 10 hours is appropriate.) There is a need for the development of a sustained-release medium.

The purpose of the present invention is to provide a new bioactive material carrier with increased delayed release effect and controlled sol-gel transition temperature.

1. A bioactive substance carrier containing capric acid or its physiologically acceptable salt and poloxamer.

2. In 1 above, the poloxamer is poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184. , Poloxamer 185, Poloxamer 188, Poloxamer 212, Poloxamer 215, Poloxamer 217, Poloxamer 231, Poloxamer 234, Poloxamer 235, Poloxamer 237, Poloxamer 238, Poloxamer 282, Poloxamer 284, Poloxamer Poloxamer 288, Poloxamer 331, Poloxamer 333, Poloxamer 334, Poloxamer 335, Poloxamer 338, Poloxamer 401, Poloxamer 402, Poloxamer 403 and Poloxamer 407, Bioactive substance transporter.

3. The bioactive substance carrier according to 1 above, wherein the capric acid and poloxamer are contained in a weight ratio of 0.25 to 3.25:30.

4. The bioactive substance carrier according to 1 above, wherein the capric acid and poloxamer are contained in a weight ratio of 2.8 to 3.2:30.

5. A pharmaceutical composition for the prevention or treatment of cancer containing an anti-cancer bioactive substance, capric acid or a physiologically acceptable salt thereof, and poloxamer.

6. In item 5 above, the anticancer bioactive substances include fluorouracil, cisplatin, carboplatin, cyclophosphamide, paclitaxel, tamoxifen, toremifene, fulvestrant, diindolimethane, exemestane, raloxifene, of cancer, selected from the group consisting of aromatase inhibitors, doxorubicin, oxaliplatin, vincristine, gemcitabine, anthracyclines, taxanes, irinotecan, docetaxel, eribulin, bevacizumab, tyrosine kinase inhibitors and human epidermal growth factor receptor. Pharmaceutical composition for prevention or treatment.

7. The pharmaceutical composition for preventing or treating cancer according to item 5 above, which is administered by local injection around the tumor.

The release of bioactive substances can be effectively delayed through the delivery vehicle of the present invention.

The delivery vehicle of the present invention can facilitate the administration and diffusion of bioactive substances in the body.

Figure 1 shows the change in viscosity of a mixture of PF-127 and capric acid (C10) according to temperature.
Figure 2 compares the difference in release rates between a drug containing only 30% Pluronic F-407 and a drug containing both 30% Pluronic F-407 and 2.9% Capric acid (C10: capric acid, P407: Pluronic F- 407, * experiment at 37°C).
Figure 3 shows three drugs, a mixture of 30% Pluronic F-127, 30% Pluronic F-127, and 2.9% capric acid, and 30% Pluronic F-127, 2.9% capric acid, and 2.5% 5-FU, an anticancer agent, on mouse skin. The immune response that appears when administered below was confirmed through histological examination (C10: capric acid).
Figure 4 is a schematic diagram of the step (A) of injecting the experimental drug and the step (B) of injecting the drug into the normal tissue around the tumor located on the back in the example of the present application. Drugs are mainly injected toward the bottom of the tumor.
Figure 5 is a photograph taken of the results of an in-vivo experiment using nude mice in an example of the present application.
Figure 6 is a graph comparing the tumor volume before and after drug administration in the examples herein (P < 0.05).

The present invention relates to a bioactive substance carrier comprising capric acid or a physiologically acceptable salt thereof and poloxamer.

The capric acid is a compound represented by the following formula (1) and is a type of saturated fatty acid.

[Formula 1]

As used herein, the term “physiologically acceptable” means that the compound exhibits characteristics that do not cause serious irritation to the subject, cell, or tissue to which it is administered and do not damage the biological activity and physical properties of the compound.

The physiologically acceptable salt may be a salt prepared using capric acid and a relatively non-toxic acid or base. Physiologically acceptable salts may be, for example, metal salts or acid addition salts.

The metal salt may be a sodium, potassium or calcium salt. Metal salts can be prepared using a base, for example, an alkali metal or alkaline earth metal salt by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt and evaporating the filtrate. Alternatively, it can be obtained by drying.

Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, as well as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanes. It can be formed from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. These physiologically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, and iodine. Ide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propylate, oxalate, malonate, succinate, suberate, Sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, methoxy Benzoate, phthalate, terephthalate, benzenesulfonate, rtuenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β_hydroxybutyrate, glycol It may include nitrate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate. For example, the acid addition salt of the compound represented by Formula 1 can be obtained by dissolving the compound in an excess of aqueous acid solution and precipitating the salt using a hydratable organic solvent such as methanol, ethanol, acetone, or acetonitrile. .

The poloxamer refers to a terpolymer composed of a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) structure and can be represented by the following formula (2).

[Formula 2]

For example, the average molecular weight of the poloxamer may be 1,000 to 100,000, 10,000 to 100,000, 10,000 to 20,000, or 1,0000 to 15,000, and can be appropriately selected by a person skilled in the art depending on the substance to be delivered.

Poloxamers are generally designated by a numbering system indicating their approximate molecular weight and percent polyoxyethylene content, and are also referred to by their trade name, pluronic. For example, Poloxamer 407 and its brand name, Pluronic F-127, can be used interchangeably.

For example, the poloxamer is poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, It may include one or more from the group consisting of Poloxamer 331, Poloxamer 333, Poloxamer 334, Poloxamer 335, Poloxamer 338, Poloxamer 401, Poloxamer 402, Poloxamer 403, and Poloxamer 407.

The poloxamer is a type of surfactant, and therefore can load substances by forming micelles in an aqueous environment, and the hydrogel composed of poloxamers forms a matrix and serves as a carrier that releases substances locally and continuously. can be used The poloxamer hydrogel may include crosslinking between poloxamers.

Poloxamers can be manufactured in various molecular weights and ratios and are highly biocompatible materials. The bioactive substances that can be loaded into poloxamers are not particularly limited, such as compounds, peptides, and nucleic acids. For example, a hydrophobic bioactive substance can be loaded into the poloxamer, or a non-hydrophobic bioactive substance can be loaded by adding or treating an appropriate composition to load the poloxamer.

The physiologically active substance is a substance that can be delivered to an individual and exhibit activity, meaning that it affects the function (physiology) of a human or animal organism. The bioactive substance may be a therapeutically active agent capable of providing direct or indirect therapeutic, physiological and/or pharmacological effects.

The therapeutically active agent may be, for example, a general medicine, drug, prodrug or target group, or a drug or prodrug containing a target group. The type is not limited and may be, for example, compounds, peptides, DNA, RNA, proteins, polymers, etc.

Since the bioactive substance carrier of the present invention can carry various bioactive substances and deliver them to the target site, the target disease for which the carrier can be used can be determined by the bioactive substance carried.

For specific examples, bioactive substances are anti-cancer bioactive substances, such as fluorouracil, cisplatin, carboplatin, cyclophosphamide, paclitaxel, tamoxifen, toremifene, fulvestrant, diindolimethane, Mestane, raloxifene, aromatase inhibitors, doxorubicin, oxaliplatin, vincristine, gemcitabine, anthracyclines, taxanes, irinotecan, docetaxel, eribulin, bevacizumab, tyrosine kinase inhibitors, human epidermal growth factor receptor, VEGF (vascular endothelial growth factor) inhibitor, nitrogen mustard, imatinib, rituximab, erlotinib, neratinib, lapatinib, gefitinib, vandetanib, nirotinib, semasanib, bosutinib, axitinib, cediranib, Resta Urtinib, Trastuzumab, Gefitinib, Bortezomib, Sunitinib, Sorafenib, Bevacizumab, Cetuximab, Viscum Album, Asparaginase, Tretinoin, Hydroxycarbamide, Dasatinib, Estramer Steen, gemtuzumab ozogamycin, ibritumomabtuxetan, heptaplatin, methylaminolevulinic acid, amsacrine, alemtuzumab, procarbazine, alprostadil, holmium nitrate chitosan, gemcitabine, doxyfluri. Dean, pemetrexed, tegafur, capecitabine, gimeracin, oteracil, azacitidine, methotrexate, uracil, cytarabine, fluorouracil, fludagabine, enocitabine, flutamide, decitabine , capecitabine, mercaptopurine, thioguanine, cladribine, carmophor, raltitrexed, belotecan, topotecan, vinorelbine, etoposide, vinblastine, teniposide, idarubicin, epirubi. Syndrome, mitoxantrone, mitomycin, bleromycin, daunorubicin, dactinomycin, pyrarubicin, aclarubicin, pepromycin, temsirolimus, temozolomide, busulfan, ifosfamide, cyclo Phosphamide, melphalan, altretmin, dacarbazine, thiotepa, nimustine, chlorambucil, mitolactol, leucovorin, tretonin, aminoglutethimide, anagrelide, navelvin, padra It may be selected from known anticancer agents such as sol, testolactone, anastrozole, letrozole, vorozole, bicalutamide, lomustine, vorinostat, entinostat, and carmustine.

The tyrosine kinase inhibitor may be, for example, Nexavar (sorafenib).

The human epidermal growth factor receptor (EGFR) may be, for example, irresa (gefitinib).

The carrier may further include other carriers, etc., and may be formulated together with the carrier, which can be appropriately selected by a person skilled in the art considering the type of bioactive substance, the route by which the carrier is administered, etc.

For example, acceptable pharmaceutical carriers for formulation as liquid solutions include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline solution, P.B.S., albumin injection solution, dextrose solution, maltodextrin solution, Glycerol, ethanol, and one or more of these components can be mixed and used, and other common additives such as antioxidants, buffers, and bacteriostatic agents can be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.

The carrier can effectively delay the release of the loaded bioactive substance compared to when poloxamer is used alone.

In addition, the carrier can increase viscosity and increase the sol-gel transition temperature of poloxamer by mixing capric acid and poloxamer.

For example, the sol-gel transition temperature of the carrier may be between room temperature and body temperature, for example, 20 to 40°C, 25 to 37°C. In this case, the carrier is convenient to store, transport, and use in a sol state at room temperature, and when it acts in the body, it is in a gel state and is easy to spread in tissues.

The capric acid and poloxamer may be included in a weight ratio of 0.25 to 3.4:30, 1 to 3.4:30, and 2 to 3:30, and specifically, the capric acid and poloxamer may be contained in a weight ratio of 2.75 to 3.3:30, 2.8 to 30. By including it at a weight ratio of 3.2:30, the sol-gel transition of the carrier can occur between 25 and 36°C.

The poloxamer and capric acid have low toxicity and are biocompatible, and when poloxamer and capric acid are mixed as in the above carrier, the in vivo stability is higher than when poloxamer is used alone.

Additionally, the present invention relates to a pharmaceutical composition for the prevention or treatment of cancer containing an anti-cancer bioactive substance, capric acid or a physiologically acceptable salt thereof, and poloxamer.

The specific description of the meaning of capric acid or its physiologically acceptable salt and poloxamer, the operating principle and effect of delayed release through their combination are as described above.

The cancer is not particularly limited and includes, for example, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, penile cancer, urogenital cancer, testicular tumor, esophageal cancer, laryngeal cancer, stomach cancer, gastrointestinal cancer, skin cancer, and keratoacanthoma. , follicular carcinoma, melanoma, lung cancer, small cell lung carcinoma, non-small cell lung carcinoma (NSCLC), lung adenocarcinoma, squamous cell carcinoma of the lung, colon cancer, pancreas cancer, thyroid cancer, papillary cancer, bladder cancer, liver cancer, bile duct cancer, kidney, bone cancer, bone marrow. Disorders, lymphatic disorders, hair cell cancer, oral cavity and pharynx (oral) cancer, lip cancer, tongue cancer, oral cancer, salivary gland cancer, pharynx cancer, small intestine cancer, colon cancer, rectal cancer, kidney cancer, prostate cancer, vulva cancer, thyroid cancer, colon cancer , endometrial cancer, uterine cancer, brain cancer, central nervous system cancer, peritoneal cancer, hepatocellular cancer, head cancer, cervical cancer, Hodgkin's cancer, leukemia, etc.

A detailed description of the anti-cancer bioactive substance is as described above.

Using the composition, the therapeutic effect of the anti-cancer bioactive substance can be increased by delaying the release time of the anti-cancer bioactive substance in the body.

The composition may be formulated with other carriers, as described above.

The composition may be prepared as an oral or parenteral formulation. For example, the formulation may be oral, rectal, nasal, topical (including cheeks and under the tongue), subcutaneous, vaginal, or parenteral (intramuscular, subcutaneous and It includes forms suitable for administration (including intravenous) or administration by inhalation or insufflation.

The composition may be an injectable formulation, and does not form a precipitate in the biological environment, blood, etc., and can be administered even with a thin injection needle, so it can be particularly preferably used in an injectable formulation.

The composition may be administered by local injection around the tumor.

The local injection can deliver a large amount of drug to the submucosa around the tumor as well as the surrounding lymph nodes compared to the intravenous administration of a general anticancer drug, and can reduce the side effects of the anticancer drug compared to systemic administration.

The composition is administered in a pharmaceutically effective amount. The effective dosage level depends on factors including the type and severity of the patient's disease, drug activity, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the field of medicine. can be decided.

The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, the amount that can achieve the maximum effect with the minimum amount without side effects can be administered, and this can be easily determined by a person skilled in the art.

The dosage of the composition varies widely depending on the patient's weight, age, gender, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. The appropriate dosage is, for example, in the patient's body. It may vary depending on the amount of accumulated drug and/or the specific efficacy of the anti-cancer bioactive substance used in the present invention.

The anti-cancer bioactive substance may contain one or more active ingredients that exhibit the same or similar functions, or may additionally contain a compound that maintains/increases the solubility and/or absorption of the active ingredient.

Hereinafter, the present invention will be described in detail with reference to examples.

Example

1. Change in viscosity due to mixing of Pluronic F-127 and capric acid

When 30% Pluronic F-127, 2.9 ~ 3.1% capric acid, and 66.9 ~ 67.1% phosphage buffer saline (PBS) were mixed, the following phenomenon was observed above a certain concentration of capric acid.

First, the mixture maintains a sol state at room temperature (20 ± 5℃) and then clearly gels at normal body temperature (36 ~ 37.4℃).

Second, the viscosity increases significantly compared to that of PF-127 (2000000; blue dotted line) (see Figure 1).

In Figure 1, the blue line (0%) is the viscosity when 30% of Pluronic F-127 is used alone, and the viscosity of the mixture increases by almost two times compared to when 30% of Pluronic F-127 is used alone. I was able to confirm that

Therefore, it was confirmed that a mixture of 30% PF-127 and 2 to 3% capric acid was most appropriate for use as a sustained-release vehicle for anticancer drugs.

2. Drug release experiment

To study the diffusion pattern of the drug, 0.1 ml each of a 30% Pluronic F-407 solution containing 10mM calcein and a solution containing both 30% Pluronic F-407 and 2.9% Capric acid were injected into pig skin. Skin was stored at 37 °C and 90% relative humidity. The degree of drug diffusion was evaluated using a fluorescence microscope 1, 2, 3, 4, 5, and 24 hours after drug administration (see Figure 2).

As a result, when 2.9% Capric acid was added to 30% Pluronic F-407, the drug release rate was significantly reduced.

3. Stability within the organization

A mixture of 30% Pluronic F-127, 30% Pluronic F-127, and 2.9% capric acid, and a mixture of 30% Pluronic F-127, 2.9% capric acid, and 2.5% 5-FU, an anticancer agent, were administered in a certain amount to the tissue. In order to observe the histological changes that occur during treatment, an experiment was conducted in which drugs were administered to mice and the immune response was observed.

As an experimental method, 0.2 cc of each drug was administered under the left dorsal skin of a nude mouse, and 24 hours later, the mouse was sacrificed and the skin at the injection site, including the muscle, was removed. The extracted tissue was subjected to H&E staining (Hematoxylin & eosin stain) and the pathological findings were observed. It was confirmed that the mixture of 30% Pluronic F-127 and 2.9% capric acid resulted in less inflammatory response than the injection of 30% PF-127 alone (see biopsy in Figure 3 and scoring results in Table 1).

Degeneration
& necrosis Inflammation Fibrosis 30% Pluronic F-127 2 2 One 30% Pluronic F-127
+2.9% Capric acid One One 0 30% Pluronic F-127
+2.9% Capric acid
+2.5% 5-FU 3 3 2

Scoring: 0=absent, 1=mild, 2=moderate, 3=severe. As above, the mixture of 30% Pluronic F-127 and 2.9% capric acid causes less inflammatory response than 30% Pluronic F-127 alone. I was able to confirm.

4. In-vivo experiments of anticancer drugs

An in-vivo experiment was conducted to examine the response to anticancer drugs after xenografting human stomach cancer cells into nude mice.

The animals to be used in the experiment are 5 male nude mice (Crj: BALB/c-nu/nu mice, male) produced in Orient, 5 weeks old and weighing about 30 grams on average. After a one-week inspection period in the laboratory, they were used in this study. It was used in . For each nude mouse, 5x10 ⁶ cells / 100ul (PBS) were inoculated into the subcutaneous fat layer on the back, and the inoculation sites were transplanted at two locations on the side of the mouse, just below the front feet. The size of the tumor was measured periodically, and drug administration experiments were conducted when it reached 1 cm in diameter.

30% Pluronic F-127, 2.9% capric acid, and 2.5% 5-FU drugs were injected right next to the tumor at 0.2 cc (5-FU 5 mg) three times at weekly intervals. One month later, the long and short diameters of the tumor growing on the dorsal epidermis were measured, and the size before and after drug administration was measured and compared as mean tumor volume = (longer diameter × shorter diameter ² )/2 (mm ³ ). In Figure 4, the experimental method is schematically shown.

As a result of the experiment, it was confirmed that when a mixture of 30% Pluronic F-127, 2.9% capric acid, and 2.5% 5-FU was administered to the lower part of the stomach cancer tumor, the malignant tumor was almost killed (see Figure 5).

Additionally, when comparing the tumor volume before and after drug administration, it was confirmed that the size of the tumor significantly decreased after drug administration (see Figure 6).

Claims (7)

A bioactive substance carrier containing capric acid or its physiologically acceptable salt and poloxamer.
The method of claim 1, wherein the poloxamer is poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer Poloxamer 185, Poloxamer 188, Poloxamer 212, Poloxamer 215, Poloxamer 217, Poloxamer 231, Poloxamer 234, Poloxamer 235, Poloxamer 237, Poloxamer 238, Poloxamer 282, Poloxamer 284, Poloxamer 288 , Poloxamer 331, Poloxamer 333, Poloxamer 334, Poloxamer 335, Poloxamer 338, Poloxamer 401, Poloxamer 402, Poloxamer 403, and Poloxamer 407. mass carrier.
The bioactive substance carrier according to claim 1, wherein the capric acid and poloxamer are contained in a weight ratio of 0.25 to 3.25:30.
The bioactive substance carrier according to claim 1, wherein the capric acid and poloxamer are contained in a weight ratio of 2.8 to 3.2:30.
A pharmaceutical composition for preventing or treating cancer containing an anticancer bioactive substance, capric acid or a physiologically acceptable salt thereof, and poloxamer.
The method of claim 5, wherein the anticancer bioactive substances include fluorouracil, cisplatin, carboplatin, cyclophosphamide, paclitaxel, tamoxifen, toremifene, fulvestrant, diindolimethane, exemestane, raloxifene, and aromatase. The prevention of cancer or Pharmaceutical composition for therapeutic use.
The pharmaceutical composition for preventing or treating cancer according to claim 5, which is administered by local injection around a tumor.