JP2017178813A - Cancer cell proliferation inhibiting composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a highly-safe cancer cell proliferation inhibiting composition (composition for the prevention/treatment of cancer) and a method of inhibiting cancer cell proliferation using the composition.SOLUTION: A cancer cell proliferation inhibiting composition comprises at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate.SELECTED DRAWING: None

Description

  The present invention relates to a cancer cell proliferation inhibiting composition and a method for inhibiting cancer cell proliferation.

  Currently, cancer is the leading cause of death and the number of patients is increasing year by year. Among them, an extract derived from a natural product having a cancer cell growth inhibitory effect has been found, and since it is safer than conventional anticancer agents, it contains a cell growth inhibitor with few side effects and an anti-cancer agent containing these components. It is expected to provide tumor agents (also called anticancer agents and anticancer agents), and health foods for preventing cancer.

  In recent years, pets such as dogs tend to be regarded as members of the family, and in the 2001 survey, 64% of the total population thought that “pets are also part of the family” and the lifestyle was It is close to humans. On the other hand, with increasing life expectancy of pets, neoplastic diseases are increasing. Especially in dogs and cats, the death rate due to cancer is high in elderly people, and the incidence of cancer may be higher than that in humans depending on the breed of dog and cat. However, pets, like humans, rarely show symptoms at an early stage even when they have cancer, and often progress only to symptoms such as loss of appetite and swelling of lymphoma. Cancer treatment methods, like humans, include surgery, chemotherapy, drug therapy, radiation therapy, and immunotherapy. Although these methods are effective if they are early treatments, they cannot be said to be effective treatments at the stage of considerable progress as described above. In addition, all of the above methods put a considerable burden on the pet, which makes it difficult for the pet and the owner.

  For this reason, drugs effective for cancer cell growth inhibition are administered to cancer patients (humans, pets) to treat cancer or alleviate cancer symptoms, or ingest food or pet food containing such substances in advance. There is a need to prevent cancer. For example, Patent Document 1 has found that Hatake shimeji mushroom extract significantly suppresses the decrease in the number of white blood cells, particularly the number of neutrophils, caused by an anticancer drug, and the use of Hatake shimeji mushroom extract to reduce the side effects caused by chemotherapy with an anticancer drug. It is disclosed that it can be used.

JP 2010-173977 A

  The present invention provides a highly safe cancer cell growth inhibitory composition (a composition for preventing or treating cancer) that can replace a conventionally known antitumor agent, and a method for suppressing cancer cell growth using the composition. The purpose is to do.

  In order to solve the above-mentioned problems, the present inventors have intensively studied. As a result, in the previous application (PCT / JP2015 / 085680), it was found that a composition containing a rosemary extract and a green tea extract in a specific mixing ratio has a remarkable inhibitory effect on cancer cell proliferation. As a result of further intensive studies on the composition, the present inventors have discovered a combination of components that are particularly effective in suppressing cancer cell growth in the extract, and completed the present invention.

  That is, the above object can be achieved by a cancer cell growth inhibitory composition comprising at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate.

  In addition, the object is to suppress cancer cell proliferation, comprising administering at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate to a patient in need of inhibiting cancer cell proliferation. It can also be achieved by the method.

  ADVANTAGE OF THE INVENTION According to this invention, the safe cancer cell growth inhibitory composition (composition for the prevention and treatment of cancer) which can replace a conventionally well-known cancer cell growth suppression (cancer prevention and treatment agent) is provided. .

In Examples 1-2 and Comparative Examples 1-5, it is a graph which shows the cell growth inhibitory effect with respect to the colon cancer cell by combined use of the component A and the component B.

  Embodiments of the present invention will be described below. In addition, this invention is not limited only to the following embodiment. In this specification, “X to Y” indicating a range includes X and Y, and means “X or more and Y or less”. Unless otherwise specified, measurement of operation and physical properties is performed under conditions of room temperature (20 to 25 ° C.) / Relative humidity 40 to 50%.

(Cancer cell proliferation inhibiting composition and cancer cell proliferation inhibiting method)
According to one aspect of the present invention, there is provided a cancer cell growth inhibitory composition comprising at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate.

  According to another aspect of the present invention, the method includes administering at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate to a patient in need of suppressing cancer cell growth. Methods for inhibiting cancer cell growth are provided.

  In the present specification, “at least one of carnosic acid and carnosol (carnosic acid and / or carnosol)” is also referred to as “component A”. Similarly, “at least one of epigallocatechin gallate and epicatechin gallate (epigallocatechin gallate and / or epicatechin gallate)” is also referred to as “component B”. In the present specification, “epigallocatechin gallate” is also simply referred to as “EGCG”, and “epicatechin gallate” is also simply referred to as “ECG”.

  In the previous application (PCT / JP2015 / 085680), the inventors of the present invention compared to a case where a composition containing a rosemary extract and a green tea extract in a specific mixing ratio is used alone. The present inventors have found that a remarkable inhibitory effect on cancer cell proliferation is exhibited. The inventors have further studied this composition. As a result, a combination of carnosic acid or carnosol in rosemary extract and epigallocatechin gallate (EGCG) or epicatechin gallate (ECG) in green tea extract is particularly effective in suppressing cancer cell growth I found out. The carnosic acid, carnosol, epigallocatechin gallate and epicatechin gallate are known to have an anticancer effect alone. However, the present inventors combined carnosic acid and / or carnosol with epigallocatechin gallate and / or epicatechin gallate to suppress cancer cell growth compared to when each component was used alone. It has been found that the effect can be synergistically improved. The above-mentioned cancer cell growth inhibitory effect can be significantly achieved particularly when component A is used in combination at a ratio of 0.1 mol or more and 15 mol or less with respect to 1 mol of component B.

  Moreover, these components are used as an antioxidant in foods, and safety is recognized. For this reason, the cancer cell growth inhibitory composition of the present invention is ingested daily for the purpose of preventing cancer, in addition to the purpose of treatment after onset of cancer, as a health food, etc. or mixed with pet food. It is also possible.

  In addition, the composition of the present invention includes components A and B, which are specific substances, rather than in the form of an extract that is a mixture of various substances. For this reason, the composition does not contain substances that induce side effects (eg, tachycardia, tremors / convulsions) when given to pet animals (eg, dogs), such as caffeine. Therefore, the composition of the present invention can be suitably added to pet food because it can suppress side effects when taking pet food.

  Here, the treatment target of the cancer cell growth inhibitory composition (subject who needs to suppress cancer cell growth) is not particularly limited, but is a mammal or a bird, preferably a mammal or a bird suffering from cancer. . Here, mammals include primates such as humans, monkeys, gorillas, chimpanzees, orangutans, and non-humans such as mice, rats, hamsters, guinea pigs, rabbits, dogs, cats, pigs, cows, horses, sheep, camels, and goats. Includes both human mammals. Examples of birds include chickens, quails and pigeons. Of these, humans, hamsters, guinea pigs, rabbits, dogs, cats and pigs are preferred, and humans and pet animals such as dogs, cats and rabbits are more preferred. That is, according to a preferred embodiment of the present invention, the cancer cell growth-suppressing composition of the present invention is used orally for at least one pet animal selected from the group consisting of humans, dogs, cats, and rabbits. According to a more preferred form of the invention, the cancer cell growth inhibitory composition of the invention is used orally for humans, dogs or cats. According to a particularly preferred form of the invention, the cancer cell growth inhibitory composition of the invention is used orally in dogs or cats.

  The cancer cell proliferation-suppressing composition of the present invention is effective for the treatment and / or prevention of cancer (herein, simply referred to as “cancer treatment / prevention”). For this reason, the cancer cell proliferation inhibitory composition of the present invention is also useful as an agent for treating / preventing cancer. In the present specification, “treatment / prevention of cancer” refers to suppressing the progression of cancer in a patient suffering from cancer, eliminating cancer or tumor, suppressing the growth of cancer or tumor, and onset of cancer. It means satisfying at least one of prevention of cancer and prevention of cancer recurrence. Here, “prevention” means preventing or delaying the onset of cancer or tumor, or reducing the risk of onset of cancer or tumor. Therefore, in the present specification, the “cancer treatment / prevention agent” means a drug exhibiting the above-mentioned cancer treatment / prevention effect when used in the treatment of cancer.

  As described above, component A (carnosic acid, carnosol) and component B (epigallocatechin gallate, epicatechin gallate) are components that can be extracted from rosemary and green tea, respectively, and are used as an antioxidant in foods. , Safety is recognized. For this reason, the cancer cell proliferation inhibitory composition of the present invention can be taken on a daily basis for the purpose of preventing cancer, for example, as a health food or mixed with pet food. That is, according to a preferred embodiment of the present invention, the cancer cell growth inhibitory composition of the present invention is a human health food or pet food composition.

  Here, the type of cancer that is the subject of the cancer cell proliferation inhibitory composition (for cancer treatment / prevention) is not particularly limited. For example, cancer of the nervous system (eg, brain tumor, cervical cancer); cancer of the digestive system (eg, oral cancer, pharyngeal cancer, esophageal cancer, stomach cancer, liver cancer, gallbladder cancer, biliary tract cancer, spleen cancer, colon cancer, small intestine cancer) , Duodenal cancer, colon cancer, colon adenocarcinoma, rectal cancer, pancreatic cancer, liver cancer); musculoskeletal cancer (eg sarcoma, osteosarcoma, myeloma); urinary cancer (eg bladder cancer, renal cancer) ); Reproductive cancer (eg, breast cancer, uterine cancer, ovarian cancer, testicular cancer, prostate cancer); Respiratory cancer (eg, lung cancer); Hematopoietic cancer (eg, acute or chronic myeloid leukemia, Acute promyelocytic leukemia, leukemia such as acute or chronic lymphocytic leukemia, malignant lymphoma (lymphosarcoma), angiosarcoma, multiple myeloma, myelodysplastic syndrome, primary myelofibrosis, epivascular cell tumor); thyroid Cancer, parathyroid cancer, tongue cancer, malignant melanoma, mastocytoma, skin tissue Tumor, lipoma, follicular tumor, cutaneous papillomas, sebaceous adenoma, such as basal cell cancer. Among these, the cancer cell proliferation suppressing composition of the present invention is more effective against hematopoietic cancer, digestive cancer, genital cancer, malignant melanoma, mastocytoma, and basal cell carcinoma. Has a high effect. That is, according to a preferred embodiment of the present invention, the composition for inhibiting cancer cell proliferation of the present invention comprises hematopoietic cancer, digestive cancer, genital cancer, melanoma, mastocytoma and basal tumor. It is used for the prevention and / or treatment of at least one disease selected from the group consisting of cell carcinomas. According to a more preferred embodiment of the present invention, the cancer cell growth inhibitory composition of the present invention is used for the prevention and / or treatment of hematopoietic or digestive cancer. According to a particularly preferred form of the present invention, the cancer cell growth inhibitory composition of the present invention is used for the prevention and / or treatment of cancer of the digestive system.

(Component A)
The cancer cell growth inhibitory composition of the present invention contains at least one of carnosic acid and carnosol (component A).

  Here, carnosic acid is a natural benzenediol abietane diterpene having the following structure, and is contained in dried leaves of rosemary (Rosmarinus officinalis). Carnosic acid is an antioxidant and is used as a food preservative and antioxidant and has been recognized as safe.

  Carnosol is a natural polyphenol having the following structure, and is contained in rosemary (Rosmarinus officinalis). It is known that carnosol exhibits an antioxidant action like carnosic acid, and has an action of activating a biological defense mechanism, a detoxification action, and the like. Carnosol is also used as a food preservative and antioxidant and has been recognized as safe.

  Carnosic acid and carnosol may be a commercially available product, or may be extracted and purified from natural products such as rosemary.

  Moreover, although the cancer cell growth inhibitory composition of this invention should just contain at least one of carnosic acid and carnosol, it is preferable that both carnosic acid and carnosol are included. According to the said form, the cancer cell growth inhibitory composition can exhibit a synergistic effect with the component B regarding cancer cell growth suppression more notably. That is, according to a preferred embodiment of the present invention, the cancer cell growth inhibitory composition comprises carnosic acid, carnosol, and at least one of epigallocatechin gallate and epicatechin gallate. The preferred form of the present invention is that the cancer cell growth-suppressing composition comprises (i) three components of carnosic acid, carnosol and epigallocatechin gallate as active ingredients; (ii) carnosic acid, carnosol and epicatechin gallate A form containing three components as active ingredients; or (iii) a form containing four ingredients of carnosic acid, carnosol, epigallocatechin gallate and epicatechin gallate as active ingredients.

(Component B)
The cancer cell growth inhibitory composition of the present invention contains at least one of epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) (component B) in addition to component A.

  Here, epigallocatechin gallate (EGCG) is an ester of epigallocatechin and gallic acid, and is a catechin having the following structure. This epigallocatechin gallate is contained in green tea and is known to have antioxidant and antibacterial properties.

  Epicatechin gallate (ECG) is a catechin having the following structure. This epicatechin gallate is contained in green tea and is known to have antioxidant and antibacterial properties.

  Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) may be commercially available or may be extracted and purified from natural products such as green tea.

  The cancer cell growth inhibitory composition of the present invention only needs to contain at least one of epigallocatechin gallate (EGCG) and epicatechin gallate (ECG), but epigallocatechin gallate (EGCG) or epicatechin gallate (ECG). ) Is preferably included. According to the said form, the cancer cell growth suppression composition can exhibit a synergistic effect with the component A regarding cancer cell growth suppression more notably. That is, according to a particularly preferred form of the present invention, the cancer cell growth inhibitory composition comprises (i) three components of carnosic acid, carnosol and epigallocatechin gallate as active ingredients; or (ii) carnosic acid, carnosol and epi Contains three components of catechin gallate as an active ingredient.

  When caffeine is given to a pet animal (for example, a dog), symptoms such as tachycardia, tremors / convulsions, arrhythmia, excessive excitement, and diarrhea may occur. On the other hand, the composition of the present invention contains specific components A and B, not in the form of a green tea extract. For this reason, since the composition of the present invention is substantially free of caffeine (unless caffeine is intentionally added), a pet animal (eg, a dog) ingests a pet food containing the composition of the present invention. However, the above symptoms do not develop. Therefore, the composition of the present invention can be suitably added to pet food.

  As described above, the cancer cell growth inhibitory composition of the present invention contains carnosic acid and / or carnosol as component A, and epigallocatechin gallate and / or epicatechin gallate as component B as active ingredients. Here, the mixing ratio of component A and component B is not particularly limited. For example, the component A is in a ratio of 0.1 mol to 15 mol, more preferably 0.25 mol to 5 mol, and still more preferably 0.5 mol to 2.5 mol with respect to 1 mol of the component B. Preferably it is present. If it is such a range, the more excellent synergistic effect of the component A and the component B can be achieved. In consideration of a further excellent synergistic effect between component A and component B, it is preferable that component A is more than component B. Specifically, in the composition, the component A is more than 1 mol to 5 mol, 1.1 mol to 4.5 mol, 1.2 mol to 4 mol, relative to 1 mol of the component B, 1.3 to 3.5 mol, 1.4 to 3 mol, 1.5 to 2.8 mol, 1.7 to 2.7 mol, 1.9 to 2.5 It is preferable that they are present in the order of a molar ratio. When component A is a mixture of carnosic acid and carnosol, the content of component A is the total amount (mole) of carnosic acid and carnosol. Similarly, when component B is a mixture of epigallocatechin gallate and epicatechin gallate, the content of component B is the total amount (mol) of epigallocatechin gallate and epicatechin gallate.

(Use of cancer cell growth inhibitory composition)
The cancer cell growth inhibitory composition of the present invention may be used for medical purposes (therapeutic or preventive purposes) or as a health food, except that it contains the cancer cell proliferation inhibitory composition of the present invention as an active ingredient. , And can be used in the same dosage form as before. That is, the cancer cell growth inhibitory composition of the present invention is mixed with a pharmaceutically acceptable additive such as an excipient, and is suitable for parenteral, oral or external administration. It can be used in the form of a thing.

  Here, when the cancer cell proliferation inhibitory composition of the present invention is used in the form of a food composition, the cancer cell proliferation inhibitory composition can be used as a food such as an oil product, an emulsified product, a soft drink, It can be added and used as a health food. Here, the “food composition” means a composition intended for consumption by mammals (including pets) such as humans. For example, a pet food composition is a food composition intended for consumption by a pet. Food compositions are widely known in the art. A pet food composition may or may not be nutritionally balanced, and in addition to supplements (eg, food), it is a nutritionally balanced composition suitable for a daily diet. May be. Here, “nutritionally balanced” means that the composition of the present invention has known nutrients necessary to maintain life in an appropriate amount and proportion in the pet nutrition field. To do.

  Especially when the cancer cell proliferation inhibitory composition of the present invention is added to and used in human health food (health food for humans) and pet food, the amount (content) of the cancer cell proliferation inhibitory composition is particularly limited. Although not, the amount is preferably 0.01 to 30% by weight, more preferably about 0.05 to 20% by weight with respect to health food and pet food (in terms of solid content). Alternatively, the amount is such that the cancer cell growth inhibitory composition of the present invention is administered at a total weight of 0.1 to 1000 mg / kg body weight, more preferably about 1 to 500 mg / kg body weight per day. With such an amount, a sufficient cancer preventive effect can be achieved. In addition, if the amount is as described above, the pet will not disturb the pet's taste and the pet will consume the entire amount of the given pet food.

  As described above, when caffeine is given to a pet animal (for example, a dog), symptoms such as tachycardia, tremors / convulsions, arrhythmia, excessive excitement, and diarrhea may occur. For this reason, when using the composition of this invention for pet food (for example, for dogs), it is preferable that a composition does not contain caffeine as much as possible. Specifically, the content of caffeine in the cancer cell growth inhibitory composition is preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 2% by weight or less, and particularly preferably 1% by weight. The following (lower limit: 0% by weight).

  The pet food contains the same components as in the prior art except that it contains the cancer cell growth inhibitory composition of the present invention. For example, the pet food is a monosaccharide, oligosaccharide, polysaccharide, dietary fiber, starch (for example, waxy corn starch, corn starch, wheat starch, rice starch, glutinous rice, in addition to the cancer cell growth inhibitory composition of the present invention. Starch, potato starch, honeydew starch, tapioca starch, sago starch, chemically treated or chemically modified starch) and cereals (eg, corn, barley, wheat, rye, sorghum, rice, mushroom, awa Carbohydrate sources such as cattle, pigs, sheep, rabbits, kangaroos, by-products and processed products, chicken, turkey, quail, etc. , Fish, white fish, etc., by-products and processed products, meat meal, meat bones, chicken meal, porter meal, fish Animal protein sources such as lettering such as schmir; vegetable protein sources such as soy protein, wheat protein, wheat gluten, corn gluten; α-sitosterol, β-sitosterol, stigmasterol, campesterol, α-sit Plant sterols such as free forms such as stanol, β-sitostanol, stigmasteranol, campestanol, and cycloartenol, and esters such as these fatty acid esters, ferulic acid esters, and cinnamic acid esters; bran such as rice bran and bran And soy bean paste, vegetables such as vegetable extract, vitamins A, B1, B2, D, E, niacin, pantothenic acid, carotene and other vitamins. In addition to the above, other additives such as a gelling agent, a shape-retaining agent, a pH adjuster, a seasoning, an antiseptic, and a nutrient reinforcing agent that are generally used in pet foods may be contained. In addition to or in place of the other additives, an antioxidant such as butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), ethoxyquin, tert-butylhydroquinone (TBHQ), propyl gallate, etc. It can also be used in combination. The addition amount (content) of each component described above is not particularly limited, and the same amount as conventional can be applied.

  Pet food is manufactured by a conventionally well-known method. For example, it can be produced by mixing the cancer cell growth inhibitory composition of the present invention and the above-mentioned necessary components into a desired form. As an example, citric acid or citrate is mixed with the cancer cell growth inhibitory composition of the present invention, cereal, meat meal, and mineral components such as iron and copper, if necessary, and after mixing, Extrude with an extruder while watering with steam. Thereafter, it is preferably dried with hot air until the water content becomes 10% or less, to produce a pet food. In addition, when pet food contains the fats and oils which have the fatty acid which has two or more double bonds, it is desirable to coat after drying with hot air.

The pet food may be in any form such as dry type, wet type, semi-moist type, jerky type, biscuits type, gum type, granular, powdery, soup, etc. It is preferable from the property. Examples of dry-type pet foods include kibble shapes, flat plate shapes, and bone shapes. From the standpoint of obtaining pets that are easy to chew and handle, the bulk density is 100 kg / m ³ or more, preferably 300 kg / m ³ or more, and 900 kg / m ³ or less, preferably 700 kg / m ³ or less. Or 100 to 900 kg / m ³ , particularly 300 to 700 kg / m ³ is preferable. In addition, the pet food can be provided in the form of bagging, boxing, packing, canning, and retort pouch.

  Moreover, the cancer cell proliferation inhibiting composition of the present invention can also be used as a cancer treatment / prevention agent for medical use (for treatment or prevention). That is, the present invention relates to a subject (including a patient suffering from a disease) who needs to suppress cancer cell growth using at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate. The present invention also provides a method for inhibiting cancer cell proliferation, which comprises administering to a cell. Here, component A (carnosic acid and / or carnosol) and component B (epigallocatechin gallate and / or epicatechin gallate) may be administered in the form of one agent containing both of these active ingredients, or These active ingredients may be administered simultaneously in the form of two agents separately. Considering the improvement of synergistic effect by these active ingredients and the ease of administration, it is preferable to administer in the form of one agent containing both components A and B.

  In this embodiment, the cancer cell growth inhibitory composition can be added to oral preparations, external preparations, injections, inhalants, nasal drops, eye drops, etc., and tablets, liquids, injections can be used depending on their usage. , Ointments, creams, lotions, aerosols, suppositories and the like. Moreover, an excipient | filler, a base, an emulsifier, a stabilizer, a solubilizing agent, a corrigent, a preservative, a fragrance | flavor, a coloring agent, a coating agent, etc. can be suitably mix | blended as needed. For quasi-drugs and cosmetics, it can be added to lotions, emulsions, creams, etc., if necessary, oil, moisturizer, UV absorber, water-soluble polymer, antioxidant, surfactant, metal An ion sequestering agent, an antibacterial preservative and the like can be blended. As described above, since the components A and B have an antioxidant action, it is not always necessary to add an antioxidant, but they may be added as needed for the purpose of storing for a longer period of time. May be.

  When the cancer cell growth inhibitory composition of the present invention is used as a pharmaceutical, the dosage is determined by the route of administration; the nature of the patient's disease; the patient's size, weight, surface area, age and sex; other drugs to be administered; It depends on the judgment. A suitable dose (total amount of component A and component B) is 1 to 500 mg / kg body weight per day. Given the different available compositions and the different effectiveness of the different routes of administration, it is expected that the required dosage can vary widely. These dosage level variations can be adjusted using standard empirical procedures for optimality known in the art. In particular for oral delivery, encapsulation of the composition in a suitable delivery vehicle (eg, polymer microparticles or implantable devices) increases delivery efficiency. The dose may be divided once or multiple times a day. Or, in some cases, it may be administered less frequently (eg, weekly or monthly). In addition, even in the same patient, the dose may vary depending on the patient's symptoms and severity.

  For use in pharmaceuticals (cancer treatment / prevention agents), a therapeutically effective amount of a cancer cell growth inhibitory composition is formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The That is, the cancer cell growth inhibitory composition of the present invention can be provided in the form of a pharmaceutical composition further containing a pharmaceutically acceptable additive (eg, excipient, carrier, etc.). The cancer cell proliferation inhibiting composition of the present invention in this form can be specifically formulated for administration in solid or liquid as will be described in detail below. As oral administration, for example, liquid medicine (aqueous solution or non-aqueous solution or suspension), tablet, bolus, powder medicine, granule, paste for application to the tongue can be exemplified. For parenteral administration, for example, as a sterile solution or suspension, for example, a formulation for subcutaneous, intramuscular or intravenous injection, or as a topical, for example as a cream, ointment or spray applied to the skin, or It can be formulated in the vagina or rectum, for example, as a vaginal suppository, cream or foam.

  As used herein, “therapeutically effective amount” as used herein is effective to produce any desired therapeutic effect at a reasonable benefit / risk ratio applicable to any medical treatment. Means the amount of the active agent or composition. For example, although the dose of the cancer cell growth inhibitory composition of the present invention varies depending on the target disease, administration subject, administration route, etc., the cancer cell growth inhibitory composition of the present invention is orally administered for the purpose of cancer treatment / prevention. In this case, the dose can be easily selected by those skilled in the art because it can easily vary depending on conditions such as the weight of the subject. In the end, the attending physician will make an appropriate selection in consideration of the patient's symptoms and severity.

  As used herein, “pharmaceutically acceptable” means that within a reasonable medical judgment, commensurate with a reasonable benefit / risk ratio, without problems or complications such as excessive toxicity, irritation, and allergic reaction, Used to refer to compounds, materials, compositions, and / or dosage forms suitable for use in contact with tissue of a subject to be treated (human, mammal, etc.).

  A pharmaceutically acceptable carrier is a liquid or solid filler involved in transporting or transporting the cancer cell growth-inhibiting composition of the present invention from one organ or part of the body to another organ or part of the body, By a pharmaceutically acceptable material, composition or excipient, such as a diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the dosage form and not injurious to the patient. Pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; Polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; magnesium hydroxide and water Buffers such as aluminum; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other adaptations non-toxic substance which is used in the drug formulation and the like. In some embodiments, the drug formulation is non-pyrogenic. That is, the thing which does not raise a patient's body temperature is desirable. In addition, wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants, as well as colorants, release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants are cancer cells of the present invention. It may be contained in a growth inhibitory composition (cancer treatment / prevention agent).

  Pharmaceutically acceptable antioxidants include, but are not limited to, water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite and the like; ascorbyl palmitate, butylhydroxyanisole ( Oil-soluble antioxidants such as BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like A metal chelating agent is mentioned.

  The cancer cell growth inhibitory composition of the present invention can be used in various dosage forms such as oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The dosage form may be conveniently presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally that amount of the compound that produces a therapeutic effect, but generally the amount of active ingredient (the total amount of component A and component B) is And about 0.1 to about 99% by weight, preferably about 1 to about 70% by weight, and more preferably about 5 to about 50% by weight, based on the cancer cell growth inhibitory composition.

  Methods for preparing these dosage forms or compositions comprise the step of combining the cancer cell growth inhibitory composition of the present invention with a carrier and optionally one or more accessory ingredients. In general, dosage forms are prepared by uniformly and intimately bringing into association one or more agents of the present invention with liquid carriers or finely divided solid carriers or both and, if necessary, shaping the product.

  For example, dosage forms of the invention suitable for oral administration are in the form of capsules, cachets, pills, tablets, lozenges (with seasoned active ingredients, usually sucrose and gum arabic or tragacanth), powders, granules Or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, or pastilles (such as gelatin and glycerin, or sucrose and gum arabic) And / or a gargle and the like, each containing a predetermined amount of the compound of the present invention as an active ingredient. The agent of the present invention may be administered as a bolus, electuary or paste.

  In solid dosage forms of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredients (component A and component B) are as sodium citrate or dicalcium phosphate. One or more pharmaceutically acceptable carriers and / or mixed with any of the following: a filler or bulking agent such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; Binders such as methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; humectants such as glycerol; agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and Disintegrants such as sodium carbonate; paraffinic Such absorption retardants as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; talc, calcium stearate, magnesium stearate, solid polyethylene Lubricants such as glycols, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets and pills, the cancer cell growth inhibitory composition may include a buffer. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules with excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

  A tablet may also be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be binders (eg, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium glycolate starch or crosslinked sodium carboxymethylcellulose), surfactants Alternatively, it can be prepared using a dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Solid dosage forms such as tablets of the cancer cell growth-inhibiting composition of the present invention, such as sugar-coated tablets, capsules, pills and granules, are optionally nicked or such as enteric coatings well known in the pharmaceutical dispensing arts. It may be prepared using a coating and shell. They are controlled or controlled release of the internal active ingredient using, for example, hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres in various ratios to provide the desired release profile. It may be formulated to provide release. They may be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating a sterilant in the form of a sterile solid composition that can be dissolved in a sterile injectable medium such as sterile water immediately before use. . These compositions may optionally contain opacifiers, in compositions that release one or more active ingredients only in certain parts of the gastrointestinal tract or preferentially there, optionally in a delayed manner. There may be. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient may be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

  Liquid dosage forms for oral administration of the cancer cell growth inhibitory composition of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms include, in addition to the active ingredient, inert diluents commonly used in the art, such as water and other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Like fatty acids esters of benzyl, propylene glycol, 1,3-butadiene glycol, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan Solubilizers and emulsifiers, and mixtures thereof. In addition to inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, flavoring and preserving agents. Suspensions may be suspended in addition to the active compound, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. A turbidity agent may be included.

  The dosage form of the cancer cell growth inhibitory composition of the present invention for rectal or vaginal administration may be presented as a suppository. This suppository comprises mixing one or more agents of the present invention with one or more suitable nonirritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository waxes or salicylates. Which is solid at room temperature but liquid at body temperature, it will melt in the rectum or vaginal cavity and release the active compound. Dosage forms suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray dosage forms containing carriers as known to be suitable in the art.

  Dosage forms for topical or transdermal administration of one or more cancer cell growth inhibitory compositions of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredients (component A and component B) may be mixed under sterile conditions with a pharmaceutically acceptable base material and, if necessary, preservatives, buffers, or propellants. Ointments, pastes, creams and gels contain, in addition to the active ingredients (component A and component B), animal or vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids And excipients such as talc and zinc oxide, or mixtures thereof.

  Powders and sprays contain, in addition to the active ingredient (component A and component B), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. But you can. The spray may further comprise customary high pressure gases such as chlorofluorinated hydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

  Transdermal patches have the additional advantage of delivering the cancer cell growth inhibitory composition of the present invention to the body in a controlled manner. Such a dosage form can be obtained by dissolving or dispersing the cancer cell growth inhibitory composition of the present invention in an appropriate medium. It is also possible to increase the flux of the substance containing the cancer cell proliferation inhibiting composition of the present invention across the skin using an absorption enhancer. The speed of such flux can be controlled by either providing a speed control membrane or by dispersing the compound in a polymer matrix or gel.

  The cancer cell growth inhibitory composition of the present invention suitable for parenteral administration is used with one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or uses with the composition. Includes sterile powders that can be reconstituted in sterile injectable solutions or dispersions immediately before, for example, solutes or suspensions that make the antioxidants, buffers, bacteriostats, preparations isotonic with the blood of the intended recipient. Can include turbidity or thickening agents.

  Examples of suitable aqueous and non-aqueous carriers that can be used in the cancer cell growth inhibitory composition of the present invention include water, ethanol, polyol (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof. There are vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. The inherent fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersants and by the use of surfactants.

  The cancer cell growth inhibitory composition of the present invention may contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the activity of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol and phenol sorbate. It may be desirable to include isotonic agents such as sugars, sodium chloride in the composition. In addition, prolonged absorption of the injectable drug form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

  Moreover, the cancer cell proliferation inhibitory composition of this invention can be utilized also as a foodstuff (foodstuff composition). At this time, the cancer cell proliferation inhibiting composition of the present invention may be used as it is, and it may be used as a liquid, gel or solid food such as juice, soft drink, tea, soup, soy milk, salad oil, dressing, yogurt, jelly, pudding. , Sprinkles, infant formula, cake mix, powdered or liquid dairy products, bread, cookies, etc., pellets, tablets with excipients such as dextrin, lactose, starch, flavorings, pigments, etc. It can be processed into granules, etc., or coated with gelatin and molded into capsules for use as health foods or dietary supplements. The amount of the cancer cell proliferation-suppressing composition of the present invention in these foods or edible compositions is difficult to define uniformly depending on the type or state of the food or composition, but with respect to the total weight of the food, 0.01 to 90% by weight, more preferably 0.1 to 80% by weight. If it is such a compounding quantity, the effect by the cancer cell proliferation inhibitory composition can fully be exhibited, without impairing flavor. Moreover, food can be easily prepared.

  Furthermore, the cancer cell growth inhibitory composition of the present invention can also be used as a cosmetic (cosmetic composition). In this case, the form of the cosmetic (cosmetic composition) includes lotion, milky lotion, cream, powder and the like, but is not particularly limited thereto. Such a cosmetic (cosmetic composition) containing the cancer cell growth-inhibiting composition of the present invention can be produced using techniques known to those skilled in the art. Examples of the form in which the cancer cell growth inhibitory composition of the present invention is used as a cosmetic (cosmetic composition) include lotions, emulsions, creams, powders and the like, but are not particularly limited thereto. Such a cosmetic composition containing the cancer cell proliferation-inhibiting composition of the present invention can be produced using techniques known to those skilled in the art.

  The effects of the present invention will be described using the following examples and comparative examples. However, the technical scope of the present invention is not limited only to the following examples. In the following examples, the operation was performed at room temperature (25 ° C.) unless otherwise specified. Unless otherwise specified, “%” and “part” mean “% by weight” and “part by weight”, respectively.

Examples 1-2 and Comparative Examples 1-5: Evaluation of cell growth inhibitory effect on colon cancer cells (Sample preparation)
Carnosic acid (manufactured by Wako Pure Chemical Industries), carnosol (manufactured by Wako Pure Chemical Industries), epigallocatechin gallate (EGCG) (manufactured by Sigma Aldrich) and epicatechin gallate (ECG) (manufactured by Wako Pure Chemical Industries) The 6.7 mM carnosic acid solution (sample 3), the 6.7 mM carnosol solution (sample 4), and the 6.7 mM EGCG solution (sample) were respectively added to dimethyl sulfoxide (DMSO) to a concentration of 6.7 mM. 5) and 6.7 mM ECG solution (sample 6) were prepared. Further, using the solution thus prepared, a solution (total concentration: 20 mM, sample 1) containing carnosic acid, carnosol and EGCG at a 1: 1: 1 mixing ratio (molar ratio), carnosic acid, carnosol and A solution (total concentration: 20 mM, sample 2) containing ECG at a mixing ratio (molar ratio) of 1: 1: 1 was prepared.

(Evaluation of cancer cell growth inhibitory effect)
Human colon adenocarcinoma-derived DLD-1 cells were cultured at 37 ° C. in a 5% by volume CO ₂ atmosphere using 10 (v / v)% FBS-containing RPMI1640 medium. 1 ml of this cultured cell was seeded on a 12-well plate so that the number of cells was 1 × 10 ⁴ per well. After culturing DLD-1 cells for 24 hours at 37 ° C. in an atmosphere of 5% by volume CO ₂ , the above-mentioned samples 1 to 6 were subjected to final concentrations of 6.7 μM (sample 3 (comparative example 1), sample 4 (comparative example) 2), sample 5 (Comparative Example 3), sample 6 (Comparative Example 4)) or 20 μM (Sample 1 (Example 1), Sample 2 (Example 2)) was added to each medium in an amount of 1 μl. . In addition, 1 μl of only DMSO as a solvent was added as a control (Sample 7, Comparative Example 5).

Forty-eight hours after adding each sample or DMSO, DLD-1 cells were cultured at 37 ° C. in a 5% by volume CO ₂ atmosphere. After culturing for a predetermined time, the number of viable cells was measured by trypan blue staining, and the cell growth inhibition rate (%) of each sample was calculated by the following formula (1). The results are shown in Table 1 below and FIG. In the following formula (1), “the number of viable cells of each sample” indicates the number of viable cells of DLD-1 cells when each sample is added and cultured, and “the number of viable cells of control” is added with DMSO. -The number of viable cells of DLD-1 cells when cultured is shown.

  As apparent from Table 1 and FIG. 1, the compositions of Examples 1 and 2 were prepared using each component alone (carnosic acid (Comparative Example 1), carnosol (Comparative Example 2), EGCG (Comparative Example 3) and ECG ( It can be seen that the inhibition rate of cancer cell proliferation is significantly higher as compared with Comparative Example 4)) and without addition (Comparative Example 5). Moreover, according to the composition of Examples 1-2, it turns out that the cancer cell proliferation suppression rate significantly higher than the sum total of the cancer cell proliferation suppression rate by each component single can be achieved. From the results, it is considered that the cancer cell proliferation inhibitory effect can be synergistically improved by using the composition of the present invention.

  In this example, the cancer cell proliferation inhibitory effect was evaluated for human cells, but it is presumed that similar results can be obtained for pet animals such as dogs and cats.

Claims (6)

  A cancer cell growth inhibitory composition comprising at least one of carnosic acid and carnosol, and at least one of epigallocatechin gallate and epicatechin gallate.   The cancer according to claim 1, wherein the total amount (mol) of carnosic acid and carnosol is 0.1 mol or more and 15 mol or less with respect to the total amount (mol) of epigallocatechin gallate and epicatechin gallate. A cytostatic composition.   The cancer cell proliferation inhibitory composition according to claim 1 or 2, comprising carnosic acid, carnosol, and at least one of epigallocatechin gallate and epicatechin gallate.   For the prevention and / or treatment of at least one disease selected from the group consisting of hematopoietic cancer, digestive cancer, genital cancer, malignant melanoma, mastocytoma, and basal cell carcinoma The cancer cell proliferation inhibitory composition of any one of Claims 1-3 used.   The cancer cell proliferation inhibitory composition according to any one of claims 1 to 4, which is used orally for at least one kind of pet animal selected from the group consisting of humans, dogs, cats and rabbits.   The cancer cell growth inhibitory composition according to any one of claims 1 to 5, which is a human health food or pet food composition.