阅读说明：本技术 预防或治疗抗癌药引起的痛觉超敏的药物组合物 (Pharmaceutical composition for preventing or treating allodynia caused by anticancer drugs ) 是由 金善光 李知桓 张大植 金佑镇 李景镇 于 2019-06-07 设计创作，主要内容包括：本公开涉及一种用于预防、减轻或治疗由抗癌剂引起的痛觉超敏的组合物,其包含肉桂酸或其药学上可接受的盐作为活性成分。本发明的组合物可通过施用于计划接受抗癌药或已接受抗癌药的受试者来预防、减轻或治疗痛觉超敏。(The present disclosure relates to a composition for preventing, alleviating or treating allodynia caused by an anticancer agent, comprising cinnamic acid or a pharmaceutically acceptable salt thereof as an active ingredient. The compositions of the invention can be used to prevent, alleviate or treat allodynia by administration to a subject who is scheduled to receive an anti-cancer agent or who has received an anti-cancer agent.)

1. A pharmaceutical composition for preventing or treating allodynia caused by an anticancer agent, comprising cinnamic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The pharmaceutical composition of claim 1, wherein the allodynia is cold allodynia or mechanical allodynia.

3. The pharmaceutical composition of claim 1, wherein the anticancer agent is a platinum anticancer agent.

4. The pharmaceutical composition of claim 3, wherein the anticancer agent is oxaliplatin.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered orally or by intraperitoneal injection in an amount of 5mg/kg to 100 mg/kg.

6. A food composition for preventing or improving allodynia caused by an anticancer agent, comprising cinnamic acid or a food acceptable salt thereof as an active ingredient.

7. The food composition of claim 6, wherein the allodynia is cold allodynia or mechanical allodynia.

8. A pharmaceutical composition for preventing or treating allodynia caused by an anticancer agent, comprising a cinnamon extract as an active ingredient.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises cinnamic acid or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is administered orally in an amount of 50mg/kg to 500 mg/kg.

11. The pharmaceutical composition of claim 8, wherein the allodynia is cold allodynia or mechanical allodynia.

12. The pharmaceutical composition of claim 8, wherein the extract is a cinnamon hot water extract.

13. The pharmaceutical composition of claim 8, wherein the anticancer agent is a taxane anticancer agent.

14. The pharmaceutical composition of claim 13, wherein the anticancer agent is paclitaxel.

15. A food composition for preventing or improving allodynia caused by an anticancer agent, comprising a cinnamon extract as an effective ingredient.

16. The food composition of claim 15, wherein the food composition comprises cinnamic acid or a pharmaceutically acceptable salt thereof.

17. The food composition of claim 15, wherein the allodynia is cold allodynia or mechanical allodynia.

18. The food composition of claim 15, wherein the extract is a cinnamon hot water extract.

19. A method for preventing or treating allodynia caused by an anticancer agent, the method comprising administering a composition comprising cinnamic acid or a pharmaceutically acceptable salt thereof to a subject other than a human.

20. The method for preventing or treating allodynia caused by an anticancer agent according to claim 19, wherein the composition is cinnamon extract.

21. The pharmaceutical composition for preventing or treating allodynia caused by an anticancer agent according to claim 20, wherein the extract is hot water extract of cinnamon.

22. The method for preventing or treating allodynia caused by an anticancer agent, as claimed in claim 19, wherein the composition is administered orally or intraperitoneally in an amount of 5mg/kg to 500 mg/kg.

23. A kit for preventing or treating cancer, the kit comprising a first component comprising cinnamic acid or a pharmaceutically acceptable salt thereof; a second component containing an anticancer agent as an active ingredient.

24. The kit for preventing or treating cancer according to claim 23, wherein the first component is a cinnamon extract.

25. The pharmaceutical composition for preventing or treating allodynia caused by an anticancer agent according to claim 24, wherein the extract is hot water extract of cinnamon.

26. The kit for preventing or treating cancer according to claim 23, wherein the administration route and frequency of the first and second compositions are independent of each other.

Technical Field

The present disclosure relates to a pharmaceutical composition for preventing or treating allodynia (allodynia) caused by an anticancer agent, comprising cinnamic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

Background

Pain perceived by humans can be broadly classified into acute pain and chronic pain. According to the international pain institute's parlance, pain is defined as "unpleasant sensations and emotional experiences with actual or potential tissue damage", and if such pain symptoms are classified by features and duration, pain can be classified as acute and chronic pain.

Acute pain caused by noxious stimulation due to tissue damage resulting from disease or trauma includes childbirth pain, post-operative pain, post-tissue injury pain, and the like. Usually disappear within 3 to 6 months and can be effectively treated by various medicines (narcotic analgesics, non-steroidal anti-inflammatory drugs).

Chronic pain is caused by nerve damage of unknown origin and subsequent changes in the nervous system, lasting longer than the healing period of the disease or the resulting damage, unclear boundaries of the pain area, exhibiting persistent dull and deep pain, lasting longer than 6 months, and limited in the use of narcotic analgesics or non-steroidal anti-inflammatory drugs. For example, chronic pain includes migraine, rheumatic pain, diabetic pain, and cancer pain, which greatly reduce the quality of life of patients, and may be accompanied by depression and the like. Narcotic analgesics have moderate effects, but strong side effects, making their continuous use difficult, and non-steroidal anti-inflammatory drugs have weak effects (JoshiSK et al, Neuroscience, 2006, 12/1/143 (2): 587-96; LaBudaCJ et al, J.Neurosci methods, 2005, 6/15/144 (2): 175-81). At present, tricyclic antidepressants or antiepileptics are clinically used, but the effects are known to be weak, and therefore, development of new drugs is required.

In chronic pain diseases, cancer pain can be classified into pain caused by tumor itself, bone pain caused by cancer metastasizing to bone, and pain caused by therapy related to treatment (i.e., anticancer drugs).

Among these pains, the pain caused by anticancer drugs is neuropathic pain, which includes spontaneous pain (spontaneous pain that occurs spontaneously without external stimulation), hyperalgesia (a stimulus that usually causes more pain), and allodynia (severe pain is caused even by a mild stimulus that usually does not cause pain).

There are several types of allodynia, such as pain caused by mechanical stimuli (mechanical allodynia) and cold stimuli (cold allodynia). The degree of mechanical and cold allodynia caused may vary depending on the anti-cancer drug.

Meanwhile, allodynia caused by anticancer agents is difficult to treat after it occurs, and even if the use of the drug is stopped, pain lasts for weeks to months, sometimes years.

Therefore, in the case of cancer treatment using an anticancer drug, sufficient suppression of hyperalgesia has become a very important point in the application of strong anticancer effects to the drug.

For example, in korean patent application No. 697212, a hematopoietic enhancer for the treatment of side effects caused by the administration of anticancer agents is disclosed, which contains an extract of a herbal mixture of astragalus and angelica as an effective ingredient. In korean patent application No. 1133837, there is disclosed a composition for inhibiting nephrotoxicity caused by administration of an anticancer agent, which comprises pulsatilla chinensis extract as an active ingredient. In korean patent application No. 1350143, a composition for reducing side effects caused by anticancer agents is disclosed, which comprises extracts of pinellia ternata and scutellaria baicalensis as active ingredients. However, there is a problem in that most of the effects of these inhibition side effects interfere with the anticancer activity of the anticancer agent, thereby reducing the anticancer activity to some extent.

Meanwhile, cinnamic acid is a component of cinnamon, and cinnamic acid or its derivatives are known to have excellent physiological effects such as anti-inflammatory, anticancer, antibacterial and antiviral effects. Furthermore, it is known to be effective even for mental diseases acting on the Central Nervous System (CNS), such as ischemia, parkinson's disease, alzheimer's disease and huntington's disease. However, there is no known application for preventing, ameliorating or treating allodynia caused by administration of an anticancer agent.

Disclosure of Invention

Technical problem

The present inventors have made many efforts to develop a method capable of promoting safer cancer treatment by preventing or treating allodynia caused by anticancer agents, and as a result, found that cinnamic acid can prevent or treat allodynia caused by anticancer agents, thereby completing the present disclosure.

Technical solution

An object of the present disclosure is to provide a pharmaceutical composition for preventing or treating allodynia caused by an anticancer agent, comprising cinnamic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

It is another object of the present disclosure to provide a food composition for preventing or improving allodynia caused by an anticancer agent, comprising cinnamic acid or a food acceptable salt thereof as an active ingredient.

It is another object of the present disclosure to provide a pharmaceutical composition for preventing or treating allodynia caused by an anticancer agent, comprising cinnamon (Cinnamomi Cortex) extract as an active ingredient.

It is another object of the present disclosure to provide a food composition for preventing or improving allodynia caused by an anticancer agent, comprising a cinnamon extract as an active ingredient.

It is another object of the present disclosure to provide a method for preventing or treating allodynia caused by an anticancer agent, comprising administering to a subject a composition comprising cinnamic acid or a pharmaceutically acceptable salt thereof.

It is another object of the present disclosure to provide a kit for preventing or treating cancer, which comprises a first composition comprising cinnamic acid or a pharmaceutically acceptable salt thereof; a second composition containing an anticancer agent as an active ingredient.

Advantageous effects

According to the present invention, a composition comprising cinnamic acid or a pharmaceutically acceptable salt thereof is administered to a subject scheduled to administer an anti-cancer agent or who has received an anti-cancer agent, thereby preventing, ameliorating or treating allodynia.

Drawings

Fig. 1 is a graph showing the results of oral administration of cinnamic acid to a group of experimental animals in which oxaliplatin anticancer agent causes neuropathic pain.

Fig. 2 is a graph showing the results of orally administering cinnamic acid to a group of experimental animals that caused neuropathic pain to a paclitaxel anticancer agent.

Fig. 3 is a graph showing the results of orally administering cinnamic acid to a group of experimental animals that caused neuropathic pain to a vincristine anticancer agent.

Figure 4 is a chart showing oxaliplatin-induced neuropathic pain behavior and spinal neuronal hyperexcitability in a single injection. Mice developed significant allodynia 4 days after a single injection of oxaliplatin. (A) Cold allodynia; n is 34. (B) Mechanical allodynia; n is 31. (C to F) injection of 5% glucose (control, n-7) or oxaliplatin (n-7) was followed by brushing, pressing, and kneading with acetone at the excitation frequency of spinal cord WDR neurons. (G) In the control and oxaliplatin groups, WDR neurons were kneaded with the typical primary stimulus traces of acetone stimulation and the data are presented as mean ± s.e.m. By paired t-test (a, B), p <0.05, # p <0.01, # p < 0.001; and p <0.05, p <0.01, p <0.001, as compared to control; by unpaired t-test (C-F).

Figure 5 shows a graph of the intraperitoneal administration of cinnamic acid delaying oxaliplatin-induced cold allodynia and mechanical allodynia. When mice treated with oxaliplatin exhibited signs of significant allodynia, cinnamic acid was injected intraperitoneally at three different concentrations (10mg/kg, 20mg/kg and 40mg/kg) on day 4 (time point of 0 minutes). Behavioral tests for (a) cold allodynia and (B) mechanical allodynia were performed before injection of cinnamic acid (time point 0 min) and 30 min, 60 min and 120 min post-injection. Vehicle groups were administered 10% DMSO as a control. Data are expressed as mean ± s.e.m. P <0.05, p <0.01, p <0.001 compared to 0 min; post-hoc assays of bonveroni (Bonferroni) were performed after one-way analysis of variance (ANOVA) (a, B).

Figure 6 shows that intraperitoneal administration of cinnamaldehyde had no effect on the delay of oxaliplatin-induced cold allodynia and mechanical allodynia. When oxaliplatin-treated mice showed signs of significant allodynia, cinnamaldehyde was injected intraperitoneally at three different concentrations (10mg/kg, 20mg/kg and 40mg/kg) on day 4 (time point 0 min). Behavioral tests for (a) cold allodynia and (B) mechanical allodynia were performed before cinnamaldehyde injection and after 30, 60 and 120 minutes post injection. The vehicle group was administered 1% Tween20 as a control. Data are expressed as mean ± s.e.m. P <0.05, p <0.01, p <0.001 compared to 0 min; post hoc assays of bonveroni (Bonferroni) were performed after one-way anova (a, B).

Figure 7 shows that cinnamic acid inhibits spinal cord WDR neuron hyperexcitability in oxaliplatin-treated mice. Changes in the firing frequency of WDR neurons to cold and mechanical allodynia were measured by in vivo extracellular recordings after intraperitoneal injection of cinnamic acid (20mg/kg, i.p.) in olsalazine-treated mice (n-6). WDR neurons were applied to (a) brushing, (B) pressing, (C) kneading, (D) change in excitation frequency of drop acetone stimulation. Control mice (n ═ 6) were given the same volume of 10% DMSO. Data are expressed as mean ± s.e.m. P <0.05, p <0.001 compared to 0 min; dunnetts multiple comparison test was performed in a two-factor differential analysis (a-D), n.s.: and (4) non-significance. (E) Typical original stimulus traces of WDR neurons in response to pinching or dropping acetone stimuli before and after injection of cinnamic acid.

Fig. 8 shows the results of orally administering a hot water extract of cinnamon containing cinnamic acid to experimental herds of neuropathic pain induced by paclitaxel-based anticancer agents according to the production area. YB1, IN and CN represent cinnamon from vietnam, indonesia and china, respectively.

Best mode for carrying out the invention

The present invention will be specifically described below. Meanwhile, each description and embodiment disclosed in the present invention may also be applied to each other description and embodiment. That is, all combinations of the parts disclosed in the present invention are within the scope of the present disclosure. In addition, the specific description described below does not limit the scope of the present disclosure.

As one aspect of the present disclosure to solve the problems, the present disclosure provides a pharmaceutical composition for preventing or treating allodynia caused by an anticancer agent, comprising cinnamic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present disclosure, "cinnamic acid" is a compound represented by the following chemical formula 1, and is a component of cinnamon.

[ chemical formula 1]

Cinnamon, the raw material for cinnamic acid, refers to the bark of cinnamon of the family lauraceae or other closely related plants. Conventionally, in oriental medicine, there are known effects such as sanhanhaepyo (effect of dispelling cold from the surface by sweating), ongyeontgtongmaek (effect of promoting tie of stagnant meridians using a thermal drug) and tongyanghwagi effect of transferring and enhancing energy), and the like. Cinnamon has been studied for its nerve, immune and anticancer effects and antibacterial effects, and has been conventionally used as a prescription for the pharmacotherapeutic hall (onyyengtang), the cinnamomi hall (gyejitaang), the cinnamomi military hall (gyejakyenghwan), the sinomenian hall (sogeongjungtang) and the chongqing hall (soceongnyonngtang).

Cinnamon having the above characteristics is a widely used herbal medicine, and there is almost no side effect after applying cinnamon to a human body. Cinnamic acid as a cinnamon ingredient can also be used without side effects.

Cinnamic acid can be purchased and used in a form that is already commercially available, and can be extracted and purified from herbs such as cinnamon by methods known in the art, or can be chemically synthesized.

In the present disclosure, cinnamic acid is used for preventing or treating allodynia caused by an anticancer agent. Cinnamic acid that may be used includes any pharmaceutically acceptable form such as, but not limited to, salts, isomers, esters, amides, thioesters and solvates.

Pharmaceutically acceptable salts of cinnamic acid refer to salts prepared according to methods common in the art and such methods of preparation are known to those skilled in the art. Specifically, the pharmaceutically acceptable salt includes pharmaceutically or physiologically acceptable salts formed from the following inorganic and organic acids and bases, but is not limited thereto.

Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of compound and acid or alcohol (e.g. ethylene glycol monomethyl ether) in water is heated and the mixture is then evaporated and dried, or the precipitated salt is suction filtered. Here, as the free acid, an organic acid or an inorganic acid can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, or the like can be used. As the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, hemilactobionic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, and the like can be used, but the free acid is not limited thereto.

Bases may also be used to prepare pharmaceutically acceptable metal salts. The alkali metal salt or alkaline earth metal salt can be obtained, for example, by dissolving the compound in a large amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, the metal salts are pharmaceutically suitable, but not limited to, salts prepared in particular from sodium, potassium or calcium salts. Further, a silver salt corresponding thereto can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

The term "anticancer agent" in the present disclosure refers to prophylactic and therapeutic agents for cancer. Examples of the anticancer agent include therapeutic agents for preventing and treating cancers that cause side effects of peripheral nerve diseases, such as lung cancer (e.g., non-small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), duodenal cancer, small intestinal cancer, colon cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colon cancer, hereditary rhinopolypus, gastrointestinal stromal tumor), breast cancer (e.g., invasive ductal cancer, non-invasive ductal cancer, inflammatory breast cancer), ovarian cancer (e.g., epithelial ovarian cancer, extratesticular germ cell tumor, ovarian malignant tumor), testicular tumor, tumor of the stomach, and/or colon cancer, Prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), liver cancer (e.g., hepatocellular cancer, primary liver cancer, extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid cancer), kidney cancer (e.g., renal cell carcinoma, transitional epithelium of renal pelvis and ureter), cervical cancer (e.g., cervical cancer, uterine corpus carcinoma, uterine sarcoma), brain tumor (e.g., medulloblastoma, glioma, pineal fibroblast, globular gonatoma, diffuse gonablastoma, degenerative gonablastic tumor, pituitary adenoma), retinoblastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma), malignant bone tumor, bladder cancer, blood cancer (e.g., multiple myeloma, leukemia, liver cancer, extrahepatic bile duct cancer), and thyroid cancer, Malignant lymphoma, hodgkin's disease, chronic granulocytic disease), primary unknown cancer, etc.

Examples of such anticancer agents include taxane anticancer agents (e.g., paclitaxel and docetaxel), vinblastine alkaloid anticancer agents (e.g., vincristine), platinum drugs (e.g., cisplatin, carboplatin, oxaliplatin), molecularly targeted drugs (e.g., bortezomib), and the like.

Among the above anticancer drugs, paclitaxel, vincristine, oxaliplatin, cisplatin, carboplatin and bortezomib are known as drugs having allodynia, which is neuropathic pain with significant side effects (J.Clinonocol.24): 1633-.

The term "allodynia" as used herein refers to a condition, symptom or disease that causes severe pain even under weak stimuli that do not normally cause pain, and is one of neuropathic pain. Allodynia includes several types of allodynia, such as pain caused by mechanical stimuli (mechanical allodynia) and pain caused by cold stimuli (cold allodynia).

The degrees of mechanical and cold allodynia may differ from each other depending on the anti-Cancer drug (J.Immunol. 249: 9-17,2002.) oxaliplatin is known to specifically induce a high frequency of cold allodynia (Toxicology) 234: 176-184, 2007; Cancer chemistry (Cancer Chemother Pharmacol.) 25: 299-303, 1990).

In one embodiment of the present disclosure, by administering cinnamic acid to an animal model to which an anticancer agent is administered, it can be confirmed that allodynia is alleviated, and as a result, it can be confirmed that cinnamic acid can be effectively used for preventing or treating allodynia caused by the anticancer agent.

Specifically, it was confirmed that cinnamic acid shows an excellent effect on cold allodynia when administered orally, and it was confirmed that a significant reduction in cold allodynia was observed in the oxaliplatin-administered group. In addition, when cinnamic acid was injected intraperitoneally, cinnamic acid had an excellent effect of alleviating cold hyperalgesia and mechanical allodynia in the oxaliplatin-administered group. That is, cinnamic acid or a pharmaceutically acceptable salt thereof of the present disclosure may be used in combination with a platinum-based anticancer agent that causes cold allodynia or mechanical allodynia to alleviate pain.

Meanwhile, cinnamic acid not only minimizes side effects by alleviating hyperalgesia, but also maximizes anticancer activity by being administered in combination with anticancer agents. That is, the anticancer activity can be improved as compared with the case of single administration of the anticancer agent.

The pharmaceutical compositions of the present disclosure have utility in the "prevention" and/or "treatment" of allodynia caused by anti-cancer agents. For prophylactic use, the pharmaceutical compositions of the present disclosure are administered to a subject having a disease, disorder, or condition described herein or suspected of being at risk of developing a disease. That is, the pharmaceutical compositions of the present disclosure can be administered to a subject who is scheduled to receive an anti-cancer drug or who is at risk of developing allodynia as a result of administration of an anti-cancer drug. For therapeutic use, a pharmaceutical composition of the present disclosure is administered to a subject (e.g., a patient already suffering from a disorder described herein) in an amount sufficient to treat or at least partially arrest a symptom of the disease, disorder, or condition described herein. The amount effective for such use will vary depending upon the severity and course of the disease, disorder or condition, previous treatments, the health and responsiveness of the subject to the drug, and the judgment of the physician or veterinarian.

Suitable carriers, excipients or diluents commonly used may be further included in the preparation of the pharmaceutical compositions of the present disclosure. At this time, the content of the compound 1 contained in the composition is not particularly limited thereto, but may be 0.0001 wt% to 10 wt%, preferably 0.001 wt% to 1 wt%, based on the total weight of the composition.

The pharmaceutical composition may have at least one formulation selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, oral liquids, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizates and suppositories, and may be various oral or parenteral formulations. When formulating a pharmaceutical composition, the preparation may be prepared by using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules and the like, and the solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin and the like with at least one compound. In addition, lubricants such as magnesium stearate, talc, and the like may be used in addition to simple excipients. Liquid preparations for oral administration may correspond to suspensions, oral liquids, emulsions, syrups and the like, and may include various excipients such as wetting agents, sweetening agents, flavoring agents, preservatives, which are generally used as simple diluents in addition to water and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizates and suppositories. As the nonaqueous solution or suspension, vegetable oils such as propylene glycol, polyethylene glycol, olive oil, and the like, injectable esters such as ethyl oleate, and the like can be used. As the base of the suppository, there can be used vicisol (witepsol), polyethylene glycol, tween 61, cacao butter, lauric acid, glycerogelatin, and the like.

The compositions of the present disclosure may be administered to a subject in a pharmaceutically effective amount.

In the present disclosure, the term "pharmaceutically effective dose" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and may be determined according to factors including the kind, severity, age, sex, type of disease, activity of a drug, sensitivity to a drug, administration time, administration route, excretion rate, duration of treatment, and concomitant use of a drug, and other factors well known in the medical field. The compositions of the present disclosure may be administered as a sole therapeutic agent or in combination with other therapeutic agents, and sequentially or simultaneously with conventional therapeutic agents. In addition, the composition of the present invention may be applied once or several times. In view of all factors, it is important to administer it in an amount capable of obtaining the maximum effect in the minimum amount without side effects, and the amount thereof can be easily determined by those skilled in the art. The preferred dosage of the composition of the present disclosure varies depending on the condition and body weight of the patient, the severity of the disease, the form of the drug, and the administration route and duration, and the dosage may be administered once or more times per day. The composition is not particularly limited as long as it is a subject for preventing or treating allodynia caused by an anticancer agent, and any composition can be used. Methods of administration include, but are not limited to, as long as the method is conventional in the art. For example, the compositions may be administered by oral, intraperitoneal, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

The pharmaceutical composition of the present disclosure may be orally or intraperitoneally injected in an amount of 5mg/kg to 100mg/kg, and specifically, may be orally administered in an amount of 10mg/kg to 100mg/kg or intraperitoneally administered in an amount of 10mg/kg to 40mg/kg, but is not limited thereto. Specifically, according to an embodiment of the present disclosure, it was confirmed that cold allodynia caused by oxaliplatin was alleviated by orally administering 10mg/kg cinnamic acid to an experimental animal in which allodynia was induced by oxaliplatin. In addition, it was confirmed that the alleviation of cold allodynia caused by paclitaxel and vincristine was alleviated by the results of orally administering 100mg/kg cinnamic acid to experimental animals of paclitaxel and vincristine-induced allodynia. According to another embodiment of the present disclosure, mechanical allodynia and cold allodynia caused by oxaliplatin were confirmed to be alleviated by intraperitoneal administration of 20mg/kg cinnamic acid to an experimental animal in which allodynia was induced by oxaliplatin.

The pharmaceutical compositions of the present disclosure may be administered to a subject scheduled to receive an anti-cancer agent or a subject receiving an anti-cancer agent to prevent the onset or reduce the extent of the onset of allodynia.

As another aspect of the present disclosure for solving the problems, the present disclosure provides a food composition for preventing or improving allodynia caused by an anticancer agent, comprising cinnamic acid or a food acceptable salt thereof as an active ingredient.

The terms used herein are the same as the above terms.

In the present disclosure, the term "improve" means to improve or contribute to all the effects of the symptoms of a subject suspected of or having developed allodynia caused by an anticancer agent by using a composition comprising cinnamic acid or a food acceptable salt thereof as an active ingredient.

As the food acceptable salt of the present disclosure, an acid addition salt formed from a food acceptable free acid or a metal salt formed from a base is useful. For example, inorganic and organic acids may be used as the free acid. As the inorganic acid, hydrochloric acid, sulfuric acid, bromic acid, sulfurous acid, or phosphoric acid can be used, and as the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, or methanesulfonic acid can be used. In addition, as the metal salt, an alkali metal salt or an alkaline earth metal salt, such as a sodium salt, a potassium salt or a calcium salt, may be used. However, the present disclosure is not necessarily limited thereto.

The food composition for preventing or improving allodynia caused by the anticancer agent of the present disclosure includes the form of a pill, powder, granule, infusion, tablet, capsule or liquid, and the food to which the composition of the present disclosure is added includes various foods such as beverages, chewing gums, tea, vitamin complexes, health care products, and the like.

As essential ingredients that can be contained in the food composition of the present invention, other ingredients than the ingredients containing the compound represented by the above chemical formula 1 are not particularly limited, and various herbal extracts, food supplements or natural carbohydrates can be contained as other ingredients such as general foods. In the food composition, the mixing amount of the essential ingredient may be appropriately determined depending on the purpose of use (prevention, improvement, health or treatment).

In addition, food supplements include food additives conventional in the art, such as, for example, flavoring agents, coloring agents, bulking agents, stabilizers, and the like.

Examples of natural carbohydrates may include common sugars, such as monosaccharides, such as glucose, fructose, and the like; disaccharides such as maltose, sucrose, and the like; polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol, erythritol and the like. In addition to those described above, natural flavoring agents (e.g., rebaudioside a, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used as the flavoring agent.

In addition, the food compositions of the present disclosure may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents (e.g., synthetic and natural flavoring agents), coloring agents and enhancers (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonic acid agents used in carbonated beverages, and the like. Additionally, the food compositions of the present disclosure may comprise pulp for the preparation of natural fruit juices and juice beverages, as well as vegetable beverages. These components may be used alone or in combination.

In the present disclosure, health foods include health functional foods and health foods. Health functional food is the same term as special health food (FoSHU), and refers to food with high medical/health care effects, which can effectively exert biological regulation function in addition to providing nutrition after being processed. Herein, "functional" means to regulate nutrition to the structure and function of the human body or to obtain useful effects for health applications, such as physiological effects. The food products of the present disclosure may be prepared by methods commonly used in the art, and may be prepared by adding raw materials and ingredients commonly added in the art in preparation. In addition, the preparation of food may be prepared without limitation as long as the preparation is considered to be food. The food composition of the present disclosure can be prepared in various forms of preparations, and unlike general medicines, the food composition has the following advantages: the medicine prepared from food as raw material has no side effect and good portability.

The allodynia can be cold allodynia or mechanical allodynia, but is not limited thereto.

As another aspect of the present disclosure to solve the problems, the present disclosure provides a pharmaceutical composition for preventing or treating allodynia caused by an anticancer agent, comprising a cinnamon extract as an active ingredient.

The terms used herein are the same as the above terms.

The term cinnamon in this disclosure is the stem bark of the lauraceae plant cinnamon (cinnamon casia Presl), which is used directly or with a slight peel removal, and has a unique odor with a slight sweet and pungent taste. Cinnamon may vary in quality from region to region and is produced in vietnam, china, indonesia, taiwan, turkey, thailand, etc. In the present disclosure, the term "cinnamon" may be used interchangeably with "cinnamon bark".

The extraction method used for preparing the extract can be preferably, but not limited to, boiling water extraction, hot water extraction, cold needle extraction, reflux cooling extraction, ultrasonic extraction or the like.

The extract may be prepared by extracting with an extraction solvent or adding a fractionation solvent to an extract prepared by extracting with an extraction solvent and fractionating. The extraction solvent is not limited thereto, but water, an organic solvent or a mixed solvent thereof may be used, and the organic solvent may use a polar solvent such as alcohol having 1 to 4 carbon atoms, ethyl acetate or acetone, a polar solvent such as hexane or dichloromethane, or a mixed solvent thereof. In addition, the extract may be more preferably a hot water extract, but is not limited thereto. The content of the extract may be 0.001 wt% to 100 wt%, more preferably 0.1 wt% to 80 wt%, based on the total weight of the pharmaceutical composition.

The pharmaceutical composition may comprise cinnamic acid or a pharmaceutically acceptable salt thereof.

The term "cinnamic acid" and pharmaceutically acceptable salts are as described above.

In one embodiment of the present disclosure, it can be confirmed that the hypersensitivity of pain is alleviated by administering the hot water extract of cinnamon to an animal model to which an anticancer agent is administered, and the result confirms that the hot water extract of cinnamon can be effectively used for preventing or treating the hypersensitivity of pain caused by the anticancer agent.

In particular, when the hot water extract of cinnamon is orally taken, the hot water extract of cinnamon in the paclitaxel group shows good effects of relieving cold allodynia and mechanical allodynia. That is, the extract of cinnamomum cassia presl of the present disclosure may be used in combination with a taxane-based anticancer agent, so that the taxane anticancer agent causes pain relief from cold pain hypersensitivity or mechanical pain hypersensitivity.

Meanwhile, the cinnamon extract not only minimizes side effects by alleviating hyperalgesia, but also maximizes anticancer activity by being administered in combination with anticancer agents. That is, the anticancer activity can be improved as compared with single administration of the anticancer agent.

The effect of the extract of cinnamon may be that cinnamic acid or a pharmaceutically acceptable salt thereof contained in the hot water extract of cinnamon plays a role. Specifically, when the hot water extract of cinnamon was orally administered, in the hot water extract of cinnamomum cassia presl having a high cinnamic acid content, a better effect of alleviating cold allodynia and mechanical allodynia was shown compared to the hot water extract of cinnamomum cassia presl or cinnamomum indonesii having a lower cinnamic acid content than that of cinnamomum cassia presl, but it is considered that cinnamic acid plays an important role in reducing allodynia induced by anticancer agents. That is, cinnamic acid or a pharmaceutically acceptable salt thereof, and a cinnamon extract comprising cinnamic acid of the present disclosure may be used in combination with a taxane anticancer agent, such that the taxane anticancer agent causes pain relief of cold allodynia or mechanical allodynia.

The pharmaceutical composition may be orally administered in an amount of 50mg/kg to 500mg/kg, and specifically, may be orally administered in an amount of 200mg/kg to 500 mg/kg. According to one embodiment of the present invention, the results of oral administration of 200mg/kg of cinnamon hot water extract to experimental animals with paclitaxel-induced allodynia confirm that cold allodynia and mechanical allodynia caused by paclitaxel are alleviated.

The pharmaceutical composition may be administered to a subject scheduled to receive an anti-cancer agent or a subject receiving an anti-cancer agent to prevent the onset or reduce the extent of the onset of allodynia.

As another aspect of the present disclosure to solve the problems, the present disclosure provides a food composition for preventing or improving allodynia caused by an anticancer agent, comprising a cinnamon extract as an active ingredient.

The terms used herein are the same as the above terms.

There is no particular limitation on other ingredients except that the cinnamon hot water extract is contained as an essential ingredient that can be contained in the food composition.

The cinnamon extract may comprise cinnamic acid or a food acceptable salt thereof.

The cinnamon extract may be a cinnamon hot water extract, but is not limited thereto.

The allodynia can be cold allodynia or mechanical allodynia, but is not limited thereto.

As a further aspect of the present disclosure to solve the problem, the present disclosure provides a method for preventing or treating allodynia caused by an anti-cancer agent, the method comprising administering to a subject a composition comprising cinnamic acid or a pharmaceutically acceptable salt thereof.

The terms used herein are the same as the above terms.

In the present disclosure, the term "subject" refers to all animals, including humans who are scheduled to receive an anticancer agent or have developed or may develop allodynia by administration of an anticancer agent, and the pharmaceutical composition of the present invention can be administered to a subject suspected of allodynia caused by an anticancer agent, effectively treating the subject.

The term "administering" in the present disclosure means introducing the pharmaceutical composition of the present disclosure into a subject suspected of suffering from allodynia caused by an anticancer agent by any suitable method, and the pharmaceutical composition of the present disclosure can be administered by various oral or parenteral routes to the target tissue.

The pharmaceutical compositions of the present disclosure may be administered in a pharmaceutically effective dose.

In the present disclosure, the term "pharmaceutically effective dose" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and may be determined according to factors including the kind, severity, age, sex, type of disease, activity of a drug, sensitivity to a drug, administration time, administration route, excretion rate, duration of treatment, and concomitant use of a drug, and other factors well known in the medical field. The compositions of the present disclosure may be administered as a sole therapeutic agent or in combination with other therapeutic agents, and sequentially or simultaneously with conventional therapeutic agents. In addition, the composition of the present invention may be applied once or several times. In view of all factors, it is important to administer it in an amount capable of obtaining the maximum effect in the minimum amount without side effects, and the amount thereof can be easily determined by those skilled in the art.

The pharmaceutical composition of the present disclosure is not particularly limited as long as it is a subject for preventing or treating allodynia caused by an anticancer agent, and any composition can be used. For example, in addition to humans, non-human animals such as monkeys, dogs, cats, rabbits, woodchucks, rats, mice, cows, sheep, pigs, goats, birds, fish, and the like may be used. The pharmaceutical compositions may be administered parenterally, subcutaneously, intraperitoneally, intrapulmonary, and intranasally, and for topical treatment, if desired, the pharmaceutical compositions may be administered by any suitable method, including intralesional administration. The preferred dosage of the pharmaceutical composition of the present disclosure varies depending on the condition and body weight of the patient, the degree of disease, the type of the drug, and the route and time of administration, but may be appropriately selected by those skilled in the art. For example, the pharmaceutical composition may be administered by oral, intraperitoneal, rectal or intravenous, intramuscular, subcutaneous, intrauterine dura mater or intracerebral vascular injection, but is not limited thereto.

The physician will be able to determine, within the scope of sound medical judgment, a suitable total daily amount to be used, usually in an amount of from 0.001mg/kg to 1000mg/kg, especially from 0.05mg/kg to 1000mg/kg, more particularly an amount of from 5mg/kg to 500mg/kg which can be administered once to several times per day.

The composition comprising cinnamic acid or a pharmaceutically acceptable salt thereof may be a cinnamon extract, but is not limited thereto.

The cinnamon extract may be a cinnamon hot water extract, but is not limited thereto.

As still another aspect of the present disclosure for solving the problems, the present disclosure provides a kit for preventing or treating cancer, comprising a first component containing cinnamic acid or a pharmaceutically acceptable salt thereof; a second component containing an anticancer agent as an active ingredient.

The terms used herein are the same as the above terms.

The first component may include a cinnamic acid extract comprising, but not limited to, cinnamic acid or a pharmaceutically acceptable salt thereof.

The cinnamon extract may be a cinnamon hot water extract, but is not limited thereto.

The kit of the present disclosure refers to a tool useful for preventing or treating cancer, comprising a first component and a second component. The type of the kit is not particularly limited, and a kit generally used in the art may be used.

The kits of the present disclosure are packaged in the following form: the first and second components are each contained in separate containers or in one container divided into one or more compartments, and each of the first and second compositions may be packaged in unit dosage form as a single dose.

The first composition and the second composition in the kit may be administered in combination at an appropriate time according to the health condition of the subject to be administered.

That is, the route of administration and frequency of administration of the first and second compositions may be independent of each other.

The kits of the present disclosure may further comprise an instruction manual describing the respective dosages, methods of administration, and frequency of administration of the first and second compositions.

According to still another aspect of the present disclosure, there is provided a method for preventing or treating cancer using the kit.

[ modes for the invention ]

Hereinafter, the configuration and effect of the present disclosure will be described in more detail by way of examples. The following examples are provided only to illustrate the present disclosure, and the scope of the present disclosure is not limited by the following examples.

EXAMPLE 1 preparation of an intraperitoneal administration composition containing cinnamic acid

Cinnamic acid (Wako) was dissolved in Tween80 solvent to prepare a composition at a concentration of 2 mg/mL.

Experimental example 1-pain relief test with cinnamic acid administration in anticancer agent pain model

Construction of animal models

Mice six weeks old (c57/bl6 mice)Construction ofIs an experimental animal.

(1) Oxaliplatin animal model

Oxaliplatin (Sigma-Aldrich) in a 5% glucose solution at a concentration of 2mg/mL was administered alone intraperitoneally to experimental animals in an amount of 6 mg/kg. Significant pain was observed about 3 days after intraperitoneal administration.

(2) Taxol animal model

Mixing polyoxyethylene castor oil EL and ethanol in a ratio of 1: paclitaxel (Sigma-Aldrich) dissolved at a concentration of 6mg/mL in solution 1 was diluted to a concentration of 2mg/mL and injected intraperitoneally 4 times at 2 mg/kg. The administration was once every other day on days 0, 2, 4 and 6. Significant pain was observed starting from about 10 days after the first dose.

(3) Vincristine animal model

Vincristine was injected at a concentration of 1mg/mL intraperitoneally (i.p.) at 0.1mg/kg for 7 consecutive days. Significant pain was observed starting from about 10 days after the first injection.

Method for evaluating cold allodynia and mechanical allodynia

(1) Method for evaluating cold allodynia

The reaction that occurred by applying about 20 μ L of acetone to the paw bottom of both hind paws of the experimental animals was observed and recorded for about 15 s.

The behaviors as recording criteria were avoidance response, behavior of shaking the sole of the paw, and behavior of licking the sole of the paw. The evaluation was repeated three times in total, and the average of the number of recorded behaviors.

(2) Evaluation method of mechanical allodynia

The number of responses was recorded by stimulating the soles of both hind paws of the experimental animals 10 times with von Frey filaments under a pressure of 0.4 g.

The behaviors as the recording criteria were avoidance response and behavior of licking the sole of the paw. The recordings of both paws were averaged and confirmed.

Experiment timeWatch (A)

(1) Oxaliplatin administration group

Experimental animals inducing allodynia were selected by pre-behavioral experiments and effects were confirmed 2h after oral administration of 10mg/kg of cinnamic acid.

(2) Paclitaxel administration group

As a pre-behavioral experiment, cinnamic acid was orally administered at 50mg/kg and 100mg/kg to experimental animals induced by allodynia, and the effects after 1 hour and 2 hours were confirmed.

(3) Vincristine administration group

Experimental animals inducing allodynia were selected by pre-behavioral experiments, administered with 50mg/kg and 100mg/kg cinnamic acid orally, and effects after 1 hour and 2 hours were confirmed.

Results of the experiment

(1) Oxaliplatin treatment group

Fig. 1 shows the results of oral administration of cinnamic acid to an experimental animal group in which oxsulbactam anticancer agent caused neuropathic pain. For mechanical allodynia, no significant analgesic effect was observed compared to the control group (vehicle), but for cold allodynia, a significant analgesic effect was observed 2 hours after administration compared to the control group.

(2) Paclitaxel treatment group

Fig. 2 shows the results of cinnamic acid oral administration to experimental animal groups, in which paclitaxel anticancer agent caused neuropathic pain. The results show that no significant analgesic effect was observed in both mechanical and cold allodynia with 50mg/kg cinnamic acid administered orally. When 100mg/kg cinnamic acid was orally administered, no significant analgesic effect was observed compared with the control group for mechanical allodynia, but a significant analgesic effect was shown after 1 hour compared with the control group for cold allodynia.

(3) Vincristine administration group

Fig. 3 shows the results of cinnamic acid oral administration to a group of experimental animals, in which vincristine anticancer agent caused neuropathic pain. The results show that no significant analgesic effect was observed in both mechanical and cold allodynia with oral administration of 50mg/kg cinnamic acid. When 100mg/kg cinnamic acid was orally administered, no significant analgesic effect was observed compared with the control group for mechanical allodynia, but a significant analgesic effect was shown after 1 hour compared with the control group for cold allodynia.

Therefore, when cinnamic acid is orally administered to an experimental group of animals suffering from pain caused by three anticancer agents, it can be seen that there is no significant inhibition of mechanical allodynia, but the analgesic effect against cold allodynia is significant. In particular, in the case of cold allodynia induced by oxaliplatin, an analgesic effect was shown within 2 hours after the administration of a low dose (10mg/kg, oral), whereas in the case of cold allodynia caused by other anticancer drugs (paclitaxel and vincristine), an analgesic effect was not shown until 1 hour after the administration of a high dose (100mg/kg, oral). In other words, it can be seen that the analgesic effect on cold allodynia is particularly pronounced in the oxaliplatin anticancer agent model, and weaker in the cold allodynia model caused by the other anticancer agents (paclitaxel and vincristine).

Example 2-preparation of a composition for intraperitoneal administration comprising cinnamic acid or cinnamaldehyde

Cinnamic acid (trans-cinnamic acid, osaka, japan and Wako Pure Chemical Industries) and cinnamaldehyde (Wako Pure Chemical Industries, osaka, japan) were dissolved in 10% dimethyl sulfoxide (DMSO, Sigma) (adjusted to pH 7 with 2M HCl and 5M NaOH) and 1% Tween20(Sigma), respectively. The final volume of 10% DMSO and 1% Tween20 used in the experiment was 2L/g rat. Different concentrations of cinnamic acid and cinnamaldehyde (10mg/kg, 20mg/kg and 40mg/kg) were administered to rats with cold allodynia and mechanical allodynia.