JP6325036B2 - Composition for improving peripheral neuropathy caused by anticancer agent - Google Patents

Description

  Today, the number of cancer deaths continues to increase worldwide, and research into effective treatments continues. There are three main types of cancer treatment methods: surgical treatment, chemotherapy, and radiation therapy, and methods using anticancer drugs are often used as chemotherapy. In recent years, platinum preparations (platinum preparations), vinca alkaloid preparations, and taxane preparations are frequently used in treatments using anticancer agents.

  On the other hand, anticancer agents such as platinum preparations, vinca alkaloid preparations and taxane preparations may develop peripheral neuropathy such as numbness, pain in the limbs and sensory abnormalities as side effects when used (non-patented) Reference 1). Peripheral neuropathy caused by anticancer drugs takes a long time to recover after stopping the use of anticancer drugs, and appetite may be greatly reduced, significantly reducing the patient's quality of life (QOL) There is a fear. Furthermore, when peripheral neuropathy develops, in order to prevent its seriousness, it is often necessary to reduce the dose or discontinue the administration of anticancer drugs, and peripheral nerves caused by anticancer drugs are often required. Disorders are recognized as a serious problem in treating cancer (Non-Patent Document 2). In particular, when anticancer drug treatment is effective or when it is performed as postoperative adjuvant therapy, it is desired to continue treatment while controlling the symptoms of peripheral neuropathy (Non-patent Document 1). Therefore, establishment of a method for improving peripheral neuropathy is an extremely important issue in continuing anticancer drug treatment. It is also required to maintain the nutritional status of patients with reduced appetite during anticancer drug treatment. However, there is no effective method yet.

  In such a present situation, methods attempted to prevent the seriousness of peripheral neuropathy are roughly classified into two (Non-patent Document 2). One is a method of preventing peripheral neuropathy from becoming serious by reducing the dose of anticancer drugs, discontinuing the administration, or extending the drug withdrawal period. Discontinuing administration of anticancer drugs is the only reliable way to stop peripheral neuropathy, but peripheral neuropathy may persist or worsen after discontinuation. The other is a method of reducing peripheral neuropathy by combining with pharmacotherapy for preventing the onset and progression of peripheral neuropathy and by practice of self-care (Non-patent Document 2). Drug therapy to alleviate peripheral neuropathy includes antidepressants (amitriptyline hydrochloride), antiepileptic drugs (carbamazepine), antiarrhythmic drugs (mexiletine), intravenous administration of electrolytes (magnesium and calcium), vitamin B12 preparation (mecobalamin) ), Amino acids (acetyl L-carnitine), Kampo medicine Kyugan (goshkin cancer) and the like are often used (Non-patent Documents 1 and 2). However, these drug therapies are only trying to alleviate symptoms empirically and their effects are limited. Further, in the treatment of peripheral neuropathy, the use of drugs as described above is considered as non-insurance use, and it is preferable to suppress the use of drugs from the viewpoint of reducing the burden on patients.

Ryozo Oishi et al., Fukuoka Medical Journal, 104 (5), 171-180, 2013 Arakawa Kazuhiko et al., Japanese Journal of Palliative Medicine, 4, 1-13, 2011

  The present invention has now found that peripheral neuropathy caused by administration of an anticancer drug is effectively improved when a patient administered with the anticancer drug is ingested with a specific composition. Furthermore, it discovered that the nutrition supply with respect to the patient under treatment with an anticancer agent can be effectively performed with the improvement of a peripheral neuropathy by using the said composition. The present invention is based on such knowledge.

  Therefore, an object of the present invention is to provide means for effectively improving peripheral neuropathy caused by administration of an anticancer agent. Another object of the present invention is to effectively supply nutrients to a patient who is being treated with an anticancer drug as well as to improve peripheral neuropathy.

According to the present invention, the following inventions are provided.
(1) An anticancer comprising a milk protein hydrolyzate and a fermented milk-derived protein as a protein component; a medium chain fatty acid or a triglyceride thereof and an n-3 fatty acid as a fat component; and isomaltulose as a carbohydrate component A composition for improving peripheral neuropathy caused by administration of an agent.
(2) The milk protein is selected from the group consisting of casein, milk protein concentrate (MPC), whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin. The composition according to (1), which is at least one of
(3) The composition according to (1) or (2), wherein the milk protein hydrolyzate is a whey protein hydrolyzate.
(4) The composition according to any one of (1) to (3), wherein the milk protein hydrolyzate content is 0.5 to 3.0 g per 100 kcal of the composition.
(5) The composition according to any one of (1) to (4), wherein the fermented milk-derived protein is derived from fresh cheese.
(6) The protein derived from fermented milk is derived from fermented milk obtained by fermenting skim milk using Lactobacillus Bulgaricus ( Lactobacillus Bulgaricus ), Streptococcus thermophilus ( Streptococcus Thermophilus ), or a combination thereof. The composition according to any one of (5).
(7) The composition according to any one of (1) to (6), wherein the content of the fermented milk-derived protein is 0.5 to 6 g per 100 kcal of the composition.
(8) The composition according to any one of (1) to (7), wherein the medium chain fatty acid is a medium chain fatty acid having 8 to 14 carbon atoms.
(9) The composition according to any one of (1) to (8), wherein the content of the medium chain fatty acid or triglyceride thereof is 0.01 to 2 g per 100 kcal of the composition.
(10) The composition according to any one of (1) to (9), wherein the n-3 fatty acid includes one or more fatty acids selected from docosahexaenoic acid and eicosapentaenoic acid.
(11) The composition according to any one of (1) to (10), wherein the content of the n-3 fatty acid is 0.05 to 2.2 g per 100 kcal of the composition.
(12) The composition according to any one of (1) to (11), wherein the content of isomaltulose is 1 to 15 g per 100 kcal of the composition.
(13) Any one of (1) to (12), further including an n-6 fatty acid as a lipid component, wherein a weight ratio of the n-6 fatty acid to the n-3 fatty acid is 1 to 3. A composition according to 1.
(14) The composition according to any one of (1) to (13), further comprising at least one component selected from dietary fiber, a vitamin component, and a mineral component.
(15) The composition according to any one of (1) to (14), which is a beverage.

  According to the present invention, peripheral neuropathy caused by administration of an anticancer agent can be remarkably improved. Furthermore, according to the present invention, it is possible to effectively perform nutritional supplementation for patients together with improvement of peripheral neuropathy. According to the present invention, it is possible to continue anticancer drug treatment while maintaining and improving QOL in patients who receive anticancer drug treatment.

It is a figure which shows the change of the adverse event Grade of the peripheral neuropathy in the cancer patient (1 person) who is ingesting the anticancer agent treatment which took the composition of this invention. It is a figure which shows the change of the adverse event Grade of the peripheral neuropathy in another cancer patient (1 person) who is ingesting the anticancer agent treatment which took the composition of this invention.

Detailed description of the invention

  The composition of the present invention comprises a milk protein hydrolyzate and a fermented milk-derived protein as a protein component; a medium chain fatty acid or a triglyceride thereof and an n-3 fatty acid as a fat component; and isomaltulose as a carbohydrate component. . It is a surprising fact that an excellent improvement effect on peripheral neuropathy caused by administration of an anticancer agent can be realized when the above components are blended in the composition.

Protein component The protein component of the present invention comprises a milk protein hydrolyzate and a protein derived from fermented milk.
The milk protein of the present invention is not particularly limited as long as it does not interfere with the effects of the present invention, but it is also referred to as casein, milk protein concentrate (MPC), and total milk protein (TMP). ), Whey, α-lactalbumin (α-La) and β-lactoglobulin (β-Lg) and other whey proteins, whey protein concentrates (Whey Protein Concentrate: WPC), whey protein isolates (Whey Protein Isolate: WPI) ), And lactoferrin. These hydrolysates of milk proteins may be modified with amino acid residues as necessary to achieve physical and physiological properties such as solubility, viscosity, gelation, thermal stability, and emulsion stability. It may be changed. Moreover, the milk protein hydrolyzate in this invention can also be fractionated below to a predetermined molecular weight as needed. The molecular weight of the milk protein hydrolyzate is preferably 50,000 or less, more preferably 30,000 or less, and even more preferably 10,000 or less.

  As the milk protein hydrolyzate of the present invention, for example, a product obtained by hydrolyzing each of the above milk proteins with an enzyme is used. The enzyme that hydrolyzes the milk protein is not particularly limited as long as it does not interfere with the effects of the present invention. Various proteases such as endoprotease and exoprotease, crude purified products containing these proteases, and disruption of the cells containing these proteases A thing etc. can be used. These can be used alone or in combination of two or more. Examples of the various proteases include animal-derived proteases pepsin, trypsin, chymotrypsin and pancreatin, plant-derived proteases papain, bromelain and actinidine, and microorganism-derived proteases. These proteases may be commercially available. Examples of commercially available endoproteases include Alcalase (registered trademark) derived from Bacillus licheniformus and Esperase derived from Bacillus lentus (both sold by Novozymes). (Registered trademark), Neutase (registered trademark) derived from Bacillus subtilis, Protamex (registered trademark) derived from Bacillus amyloliquefaciens, trypsin derived from porcine pancreas (PTN (registered trademark)), and the like It is done. Examples of commercially available exoproteases include Flavorzyme (registered trademark) derived from Aspergillus oryzae, and carboxypeptidase derived from porcine or bovine viscera. When hydrolyzing the milk protein of the present invention, it is preferable to use a combination of Alcalase derived from Bacillus licheniformus and trypsin (PTN) derived from porcine pancreas.

The whey protein hydrolyzate, which is one embodiment of the milk protein hydrolyzate of the present invention, can be prepared, for example, by the following method.
A whey protein isolate (WPI) containing about 90% by weight dry protein is dissolved in water to contain 8% by weight protein. The obtained WPI aqueous solution is heated at 85 ° C. for 2 minutes to denature the whey protein. To the aqueous solution after the denaturation treatment, 2.4 L of Alcalase derived from Bacillus licheniformus is added so as to be 2% by weight based on the weight of the whey protein, and reacted at 55 ° C. for 3 hours. Thereafter, trypsin derived from porcine pancreas (PTN 6.0S) is further added so as to be 3% by weight with respect to the weight of the whey protein and reacted at 55 ° C. for 3 hours. The obtained reaction solution was centrifuged at 20,000 × g for 10 minutes, the supernatant was applied to an ultrafiltration membrane with a molecular weight cut off of 10,000, and the fraction that passed through the ultrafiltration membrane was hydrolyzed with whey protein. It is a thing.

  A commercially available product may be used as the milk protein hydrolyzate of the present invention. Examples of commercially available milk protein hydrolysates include, for example, Peptigen IF-3080, Peptigen IF-3090, PeptigenIF-3091 and Lacprodan DI-3065 (all manufactured by Aria Foods Ingredients), WE80BG (manufactured by Friesland Campina Domo), Hyprol 3301, Hyprol 8361 and Hyprol 8034 (all manufactured by Kerry), Tatua2016 and HMP406 (all manufactured by Tatua), Whey Hydrolysate 7050 (manufactured by Fonterra), Biozate3 (manufactured by Davisco), and the like.

  The content of the milk protein hydrolyzate in the composition of the present invention can be appropriately adjusted depending on the content of other components, the pathology of the subject of administration of the composition, the medical condition, age, body weight, use and the like. Specifically, the content of the milk protein hydrolyzate in the composition of the present invention is not particularly limited as long as the effect of the present invention is not hindered, but it is 0.5 to 3.0 g per 100 kcal of the composition. Yes, preferably 0.9-3.0 g, more preferably 1.2-2.0 g.

As the fermented milk-derived protein of the present invention, a protein contained in fermented milk can be used. As fermented milk, for example, livestock milk such as cow's milk, buffalo milk, goat's milk, sheep milk and horse milk, skim milk of these livestock milk, partially skim milk, reduced whole milk, reduced skim milk, reduced partially skim milk, And fermented milk raw materials prepared by combining one or two or more fermented milk raw materials such as butter and cream produced from livestock milk, and fermented with bacteria such as lactic acid bacteria and bifidobacteria. The lactic acid bacteria and bifidobacteria used in the fermentation, for example, Lactobacillus bulgaricus, Streptococcus thermophilus, Streptococcus lactis, Streptococcus cremoris, Streptococcus diacetilactis, Enterococcus faecium, Enterococcus fecalis, Lactobacillus casei, Lactobacillus helveticus, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus Examples include murinus , Lactobacillus reuteri , Lactobacillus brevis , Lactobacillus gasseri , Bifidobacterium longum , Bifidobacterium bifidum , Bifidobacterium bifidum , Bifidobacterium breve and the like. Moreover, when manufacturing fermented milk, in addition to the said lactic acid bacteria and bifidobacteria, bacteria of the Propionibacterium (Propionibacterium) genus can also be used together.

  Examples of fermented milk used in the present invention include yogurt and cheese. Fresh cheese that has not been ripened is preferable as the cheese, and examples of the fresh cheese include cottage, quark, string, nucharte, cream cheese, mozzarella, ricotta, and mascarpone.

The protein derived from fermented milk in the present invention may be a protein prepared using any fermented milk as long as the effects of the present invention are not hindered, but preferably skim milk is obtained from quark or Lactobacillus bulgaricus and Streptococcus thermophilus alone or in combination. It is a protein prepared using fermented milk obtained by fermentation, and more preferably a protein prepared using fermented milk obtained by fermenting skim milk by a combination of Lactobacillus bulgaricus and Streptococcus thermophilus .

The quark which is one embodiment of the fermented milk for obtaining the fermented milk-derived protein in the present invention can be produced, for example, by the following method.
Bovine skim milk is heat-sterilized and then inoculated with lactic acid bacteria (mixture of Lactobacillus bulgaricus and Streptococcus thermophilus ) serving as a fermentation starter so as to be 0.5 to 5% (W / W) and fermented. When the pH of bovine skim milk reaches about 4.6 by fermentation, bovine skim milk is separated into curd and whey. The card obtained by separating the whey is cooled to obtain a quark. The composition of the quark thus obtained has, for example, a total solid content of 17 to 19% (w / w), a protein of 11 to 13% (w / w), a fat of less than 1% (w / w), a carbohydrate of 2 ~ 8% (w / w), less than 2% (w / w) lactose. The quark can also be obtained by inoculating and fermenting a lactic acid bacterium serving as a starter, adding rennet and coagulating it. Further, as lactic acid bacteria as a starter, it can also be used a mixture of Leuconostoc bacteria such as Lactococcus lactis and / or Lactococcus cremoris and Leuconostoc mesenteroides.

  The content of the protein derived from fermented milk in the composition of the present invention can be appropriately adjusted depending on the content of other components, the pathology of the subject to be administered with the composition, the medical condition, age, weight, use, and the like. Specifically, the content of the protein derived from fermented milk in the composition of the present invention is 0.5 to 6.0 g, preferably 2.0 to 6.0 g, more preferably 2 per 100 kcal of the composition. .5 to 4.5 g. The method for adding the fermented milk-derived protein of the present invention to the composition is not particularly limited as long as the effects of the present invention are not hindered, and the fermented milk such as yogurt and quark is directly contained in the composition. Alternatively, a fermented milk-derived protein separated from fermented milk may be included in the composition.

Fat Component The fat component of the present invention comprises a medium chain fatty acid or a triglyceride thereof and an n-3 fatty acid.
The medium chain fatty acid of the present invention is preferably a medium chain fatty acid having 8 to 14 carbon atoms. Moreover, it is preferable that a part or all of the medium chain fatty acid of the present invention is contained in the form of medium chain fatty acid triglyceride (MCT). MCT is characterized in that it is quickly absorbed in the body and easily becomes energy, and the body is hard to get fat. Examples of the fats and oils containing MCT include fats and oils obtained from palmaceous plants such as palm oil, palm kernel oil and coconut oil, and medium chain fatty acid-containing fats and oils. The composition of the present invention may contain a medium chain fatty acid or a triglyceride thereof as it is, or may contain it in the form of the oil or fat.

  Examples of the n-3 fatty acid of the present invention include docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), α-linolenic acid, docosapentaenoic acid (DPA), and preferably α-linolenic acid, DHA and EPA, more preferably DHA and EPA. Examples of the fats and oils containing n-3 fatty acids include fish oil, perilla oil, linseed oil (flux oil), sesame oil, rapeseed oil, soybean oil and canola oil (salad oil). The composition of this invention may contain the n-3 type fatty acid as it is, and may contain in the form of the said fats and oils.

  The composition of the present invention may contain other fatty acids in addition to the medium chain fatty acids or triglycerides thereof and n-3 fatty acids.

  Examples of other fatty acids include oleic acid, palmitic acid, palmitoleic acid, linoleic acid, stearic acid, linolenic acid, and arachidonic acid, with n-6 fatty acids such as linoleic acid being preferred. Examples of fats and oils containing other fatty acids include edible oils such as high oleic sunflower oil, rapeseed oil, olive oil, high oleic safflower oil, soybean oil, corn oil and palm oil. The composition of this invention may contain the other fatty acid as it is, and may contain in the form of the said fats and oils.

  According to a preferred embodiment of the present invention, the weight ratio of the n-6 fatty acid and the n-3 fatty acid in the composition of the present invention is preferably 1 to 3, more preferably 1.5 to 2. 0.5, more preferably 1.8 to 2.2, and even more preferably 1.9 to 2.1.

  The composition of the present invention may contain one or more known phospholipids such as milk phospholipid, soybean-derived lecithin, and egg yolk lecithin. The phospholipid of the present invention can be fractionated and purified from raw materials derived from milk, soybeans, eggs and the like. Moreover, as long as the effect of this invention is acquired, you may use commercially available phospholipid.

  Milk phospholipid is preferred as the phospholipid of the present invention. Milk phospholipid (also called milk lecithin) is composed of sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), lysophosphatidylcholine (LPC), Localized only in milk fat globule membrane (MFGM). The component composition of the MFGM phospholipid fraction is described, for example, in the Bulletin of Japan Dairy Technical Association, Vol. 50: pp. 58-91, 2000.

  The content of the phospholipid in the composition of the present invention can be adjusted as appropriate depending on the content of other components, the pathology of the subject to be administered with the composition, the disease state, age, weight, use, and the like. Suitable phospholipid content is 1-15 g, 1-10 g, 2-10 g, 3-10 g, 4-10 g, 5-10 g, 6-10 g, 7-10 g or 7-9 g per 100 kcal composition. .

Sugar component The composition of the present invention comprises isomaltulose as a carbohydrate component. Isomaltulose is a substance represented by CAS Registry Number 13718-94-0 and chemical formula C12H22O11.

  Isomaltulose is commercially available as Palatinose (registered trademark), and is contained in products such as commercially available palatinose syrup, reduced palatinose, and palatinose starch candy. In the composition of the present invention, isomaltulose itself may be added, or the above-mentioned product containing isomaltulose may be added.

  In addition, the composition of the present invention may contain a saccharide other than isomaltulose. Examples of carbohydrates other than isomaltulose include sucrose, glucose, fructose, honey, and dextrin.

  The content of the saccharide in the composition of the present invention can be appropriately adjusted depending on the content of other components, the pathological condition of the subject to be ingested, the medical condition, age, weight, use and the like. Suitable carbohydrate content is 1 to 25 g, 1 to 22 g, 2 to 20 g, 4 to 18 g, 4 to 16 g, 6 to 16 g, 6 to 16 g, 8 to 14 g, 10 to 14 g, -15g, 1.5-12g, 2-10g, 3-9g, 4-8g or 5-7g.

  Moreover, in the composition of this invention, the weight ratio of a protein component and a lipid component becomes like this. Preferably it is 0.3: 1-3: 1, More preferably, it is 1.4: 1-2: 1.

  In the composition of the present invention, the weight ratio of the protein component to the saccharide component is preferably 1: 2 to 1:20, more preferably 1: 2 to 1: 4.

  In the composition of the present invention, the weight ratio between the lipid component and the carbohydrate component is preferably 1: 3 to 1: 7, more preferably 1: 4 to 1: 6.

Additional nutritional components The composition of the present invention adjusts its nutritional composition, flavor, form, pH, osmotic pressure, etc. by blending at least one additional nutrient or a combination of two or more. can do. Additional nutrients in the present invention are not particularly limited as long as they do not interfere with the effects of the present invention, but amino acids, dietary fibers, vitamins, minerals, organic acids, organic bases, fruit juices, flavors, artificial sweeteners (for example, Aspartame), moisture and the like.

  Dietary fiber is divided into water-soluble dietary fiber and insoluble dietary fiber, and both can be used. Examples of the water-soluble dietary fiber include indigestible oligosaccharides, indigestible dextrin, lactitol, raffinose, pectin, guar gum and the like. Examples of the insoluble dietary fiber include cellulose, hemicellulose, lignin, chitin, chitosan, soy dietary fiber, wheat bran, pine fiber, corn fiber, beet fiber and the like.

  The content of dietary fiber in the composition of the present invention is not particularly limited, and can be appropriately adjusted depending on the content of other components, the pathology of the subject to be ingested, the medical condition, age, weight, use, and the like. Suitable dietary fiber content is 0.5-10 g, 0.5-8 g, 0.5-6 g, 0.5-4 g, 0.5-2 g or 1-2 g per 100 kcal composition.

  Suitable examples of vitamins include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, niacin, folic acid, biotin, pantothenic acid, or a part thereof. All combinations and the like can be mentioned, but biotin is more preferable.

  The content of vitamins in the composition of the present invention can be appropriately adjusted depending on the content of other components, the pathological condition of the subject to be ingested, the medical condition, age, weight, use, and the like. The content of a suitable vitamin component is 1 to 200 μg, 10 to 200 μg, 20 to 100 μg, 30 to 100 μg, 40 to 100 μg, or 40 to 60 μg per 100 kcal of the composition. Suitable biotin content is 0.5-20 μg, 0.5-10 μg, 1-10 μg, 2-10 μg, 4-10 μg, 5-9 μg, 6.5-8 μg or 7-8 μg per 100 kcal of the composition. 8 μg.

  Preferable examples of minerals include sodium, chlorine, potassium, sulfur, magnesium, calcium, phosphorus, iron, iodine, manganese, copper, zinc, selenium, chromium, molybdenum, or a combination of parts or all thereof. Is more preferably sodium, zinc or copper or a combination thereof.

  The content of minerals in the composition of the present invention can be appropriately adjusted depending on the content of other components, the pathological condition of the subject to be ingested, the medical condition, age, weight, use and the like. Suitable mineral content is 10-900 mg, 30-800 mg, 40-700 mg, 100-600 mg, 150-550 mg, 200-500 mg, 250-500 mg or 300-500 mg per 100 kcal of the composition. Moreover, suitable sodium content is 10-150 mg per 100 kcal of compositions, 20-130 mg, 30-110 mg, 40-100 mg, 50-90 mg, 60-80 mg, or 65-75 mg. Moreover, suitable zinc content is 0.01-30 mg, 0.05-15 mg, 0.05-10 mg, 0.1-7 mg, 0.3-5 mg, 0.5-2. 5 mg or 0.5-1.5 mg. Moreover, suitable copper content is 0.002-20 mg, 0.004-15 mg, 0.006-10 mg, 0.008-5 mg, 0.01-1 mg or 0.03-0. 07 mg.

  The water content in the composition of the present invention is 1 to 99 g, 10 to 99 g, 30 to 99 g, 50 to 99 g, 70 to 99 g, 75 to 99 g, 80 to 99 g, or 80 to 90 g per 100 kcal of the composition. is there.

  The form of the composition of the present invention is not particularly limited as long as the effect of the present invention is not hindered, and may be liquid, pasty, solid, powder or the like, but is preferably liquid.

  Although the pH of the composition of this invention is not specifically limited, For example, the pH can be pH2-pH6, Preferably it can be pH3-pH5.

  The osmotic pressure of the composition of the present invention is not particularly limited, and is, for example, about 300 to 1000 mOsm / L, preferably about 300 to 750 mOsm / L.

  When measured at room temperature, the viscosity of the composition of the present invention is, for example, about 5 to 100 cp (1 cp = 0.001 Pa · s), preferably less than 80.

  Moreover, although the calorie of the composition of this invention is not specifically limited, For example, it is about 0.5-2 kcal / mL, Preferably it is 1-1.5 kcal / mL.

  The method for preparing the composition of the present invention is not particularly limited, and can be carried out by blending and homogenizing the above-described components by a known method. Moreover, in the preparation method of this invention, it is preferable to perform well-known sterilization (heating etc.) processing with respect to the composition or each component of this invention. Therefore, according to an aspect of the present invention, milk protein hydrolyzate and fermented milk-derived protein as protein components; medium chain fatty acids or triglycerides thereof and n-3 fatty acids as fat components; and isomaltulose as carbohydrate components There is provided a method for producing a composition for improving peripheral neuropathy resulting from administration of an anticancer agent, comprising the steps of blending in a composition and optionally homogenizing and heating the composition. The number of times of the sterilization step and the homogenization step is not particularly limited, and may be performed a plurality of times as described later. Although the order of a mixing process, a homogenization process, and a sterilization process is not specifically limited, It is preferable to perform a homogenization process after a sterilization process. Further, when the usage form of the composition is powder, the homogenized product may be spray-dried or freeze-dried, for example.

Hereinafter, the preparation method of the present invention will be described with more specific examples.
First, in a preferred example of the preparation method of the present invention, warm water is stirred in a tank, and components other than vitamins are added and mixed and stirred sequentially in consideration of the ease of mixing and diffusing, A mixed solution is used. The order in which raw materials are easily mixed and diffused varies depending on the amount and characteristics of the raw materials, and they are charged at once or in various orders. For example, a method in which sugars, proteins, fats, and minerals are charged in this order. There is. As another example, there is a method in which some carbohydrates, proteins, other carbohydrates, minerals, and fat are added in this order. As yet another example, there is a method in which fat, protein, sugar, and minerals are added in this order. The mixture is sterilized by heating with a steam injection method, and then homogenized with a homogenizer (homogenized with two-stage pressure) to obtain a homogenized solution. Vitamins and flavors (fragrances) are added to and mixed with this homogenized liquid to obtain the final mixed liquid. This final mixed solution can be further heat sterilized (two-stage sterilization) using a steam infusion method, and then homogenized (homogenized with two-stage pressure) using a homogenizer to obtain the composition of the present invention.

  The mixing conditions in the preparation method of the present invention may be appropriately set according to the types, ratios, properties, and the like of the components and the composition, but the mixing temperature when mixing the proteins is, for example, 2 ° C to 70 ° C, preferably Is 55 ° C. or lower, more preferably 5 to 55 ° C., further preferably 40 to 55 ° C., further preferably 40 to 53 ° C., and further preferably 40 to 50 ° C. When the protein is used, the mixing temperature is preferably in the range of 2 ° C. to 70 ° C. in order to prevent the coagulation (curd formation) of the protein and to dissolve or disperse the protein in water or the like.

  Moreover, it is preferable to perform a known high temperature sterilization process in the sterilization process of the present invention. In the sterilization step, for example, the temperature is 100 to 150 ° C., the holding time is 1 to 30 seconds, preferably 115 to 145 ° C., 1 to 20 seconds, more preferably 120 to 145 ° C., 1 to 10 seconds, and still more preferably 125. It can be set to ˜140 ° C. for 1 to 5 seconds.

Moreover, when sterilizing at a high temperature, the pressure may be adjusted (pressurized or depressurized) to the mixed solution. At this time, normally, for the purpose of preventing the mixture from boiling, for example, the sterilization pressure is set to about 1 to 10 kg / cm ² . That is, in the high temperature sterilization of the present invention, such pressure may be applied in addition to temperature (heating). Examples of the high-temperature sterilizer include a plate heat exchanger, a tube heat exchanger, a steam injection sterilizer, a steam infusion sterilizer, and an electric heating sterilizer.

  Moreover, in this invention, it is preferable to homogenize, after disinfecting a liquid mixture. Homogenization after sterilization is preferable for reducing the degree of thickening accompanying heating during sterilization. Here, the number of times of homogenization after sterilization may be one or more times. For example, when the mixture is sterilized for the second time and then sterilized for the second time, the first homogenization may be performed after the second sterilization. Further, when the mixture is sterilized after the first sterilization and further sterilized for the second time, it may be homogenized for the second time after the second sterilization. Further, when the mixture is sterilized and then homogenized and the second sterilization is not performed, the second homogenization may be performed as it is.

  A homogenization process can be implemented using a well-known homogenizer. Suitable conditions for the homogenization step are not particularly limited as long as the effects of the present invention are not hindered. For example, when the temperature is set to about 10 to 60 ° C. and the flow rate is set to about 100 to 10,000 L / h, the pressure is set to 10 to 100 MPa. The pressure is preferably 20 to 80 MPa, more preferably 30 to 70 MPa, and still more preferably 20 to 50 MPa.

  In addition, in the preparation method of this invention, you may sterilize again the homogenization thing (what homogenized the sterilization liquid) before filling to a container or after filling. Specifically, if necessary, the homogenized product is heat-sterilized and then cooled and then aseptically filled (for example, a method using a combination of the UHT sterilization method and the aseptic packaging method), filling can containers and soft bags. Then, a method of sterilizing by retort (for example, a retort method or an autoclave method) can be applied.

  In addition, the composition of the present invention obtained as described above may be further formulated with a pharmaceutically acceptable additive as desired, and the present invention includes such an embodiment. Examples of pharmaceutically acceptable additives include excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspending agents, coating agents, solvents, and isotonic agents.

  The composition of the present invention is suitably used in any form such as pharmaceuticals, foods and drinks, nutritional compositions, supplements, special purpose foods, nutritional functional foods, health foods, pharmaceutical additives, functional indication foods or food additives. can do.

  According to the present invention, peripheral neuropathy caused by administration of an anticancer drug can be effectively improved by ingesting the above composition into a subject. Therefore, according to another aspect of the present invention, there is provided a method for ameliorating peripheral neuropathy caused by administration of an anticancer agent, wherein a subject in need thereof is ingested an effective amount of the composition of the present invention. Is provided. Here, the “amelioration” of the present invention includes not only treating an established disease state or symptom, but also preventing a disease state or symptom that may be established in the future.

  The “subject” of the present invention is not particularly limited, but is preferably a mammal, more preferably a human, a domestic animal species or a wild animal, more preferably a human, still more preferably. A human cancer patient.

  The anticancer agent of the present invention is not particularly limited as long as it can cause peripheral neuropathy, and a known anticancer agent may be applied, for example, leukemia, malignant lymphoma, myeloma, lung cancer, breast cancer. Anticancer agents for colon cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, renal cell carcinoma and the like. More specifically, the anticancer agent of the present invention includes an anticancer agent that damages microtubules and causes peripheral neuropathy. Preferable examples of such drugs include taxane drugs such as paclitaxel and docetaxel, and vinca alkaloid drugs such as vincristine, vinplastin, vindesine and vinorelbine. In addition, anti-cancer agents that cause peripheral neuropathy by causing axonal damage due to nerve cell injury can be mentioned. Preferable examples of such agents include platinum preparations such as oxaliplatin, carboplatin, cisplatin, nedaplatin and the like.

  Suitable examples of peripheral neuropathy caused by anticancer agents include pain such as tingling and burning pain, numbness of the extremities of the extremities, sensory abnormalities such as burning sensation, hypersensitivity such as hypersensitivity to cold stimulation, Examples include sensory abnormalities such as loss of sensation, paralysis and discomfort, sensory ataxia, and weakness of muscles. Peripheral neuropathy caused by the anticancer agent of the present invention is not only peripheral neuropathy caused by monotherapy using one kind of anticancer agent, but also multiple agents administered in combination with a plurality of drugs having different action mechanisms It includes peripheral neuropathy that occurs in combination therapy and biochemical modulation therapy that devise the combination and administration method of drugs so that drugs with different mechanisms of action can exert their maximum effectiveness.

  The method of ingesting the composition of the present invention into the subject may be either oral or parenteral, and the ingestion form may be a pharmaceutical form or a non-pharmaceutical form such as food or drink. .

  In the case of taking the composition of the present invention as a pharmaceutical, for example, enteral or oral administration by a nasal tube, gastrostomy, intestinal fistula etc. by enteral nutrition, liquid, etc. can be mentioned. The dosage form may be processed into a preparation such as an agent, granule, powder, syrup and the like.

  When the composition of the present invention is ingested as a food or drink, milk, soft drinks (fruit juice drinks, milk shake drinks, etc.), fermented milk, yogurt, cheese, bread, biscuits, crackers, pizza crusts, Examples include prepared powdered milk, liquid food, food for the sick, nutritional food, frozen food, food composition, processed food, and other commercially available foods. The composition can also be a soluble powder that can be reconstituted before use.

  The timing of ingesting the composition of the present invention is not particularly limited as long as the effect of the present invention is not hindered, but the composition of the present invention is used before administration of the anticancer agent, during the administration period of the anticancer agent and / or Or it is preferable to ingest after administration of an anticancer agent. Further, the composition of the present invention may be appropriately taken before meals, after meals, between meals and / or before going to bed. Moreover, the composition of this invention can be used instead of a meal, and can be utilized also as a meal assistance.

  The effective amount of the composition of the present invention can be adjusted as appropriate according to the sex, symptoms, condition, weight, etc. of the subject, and a suitable effective amount is 10 to 3000 kcal per day in terms of calories, 50 to 50 It is 2500 kcal, 50-2000 kcal, 100-2000 kcal, 100-1500 kcal, 100-1250 kcal, 100-1000 kcal, 150-850 kcal, 150-650 kcal, or 200-600 kcal. The preferred effective amount of the composition of the present invention is 2 to 665 g, 11 to 555 g, 11 to 445 g, 22 to 445 g, 22 to 335 g, 22 to 335 g, 22 to 280 g, 22 in terms of solid content weight. -280g, 33-190g, 33-145g or 45-135g. Moreover, the suitable effective amount of the composition of this invention can be suitably adjusted in the range of 0.5-135g per patient once converted into solid content weight. Further, the composition of the present invention may be taken about 1 to 3 times a day for 1 week or more (preferably about 1 to 12 months).

  According to another aspect of the present invention, a milk protein hydrolyzate and a protein derived from fermented milk as a protein component for improving peripheral neuropathy caused by administration of an anticancer agent; a medium chain fatty acid as a fat component Also provided is the use of a composition comprising triglycerides and n-3 fatty acids thereof; and isomaltulose as a carbohydrate component. According to still another aspect of the present invention, a milk protein hydrolyzate and a protein derived from fermented milk as a protein component in the manufacture of a composition for improving peripheral neuropathy caused by administration of an anticancer agent; a fat component; There is provided the use of a composition comprising as a medium chain fatty acid or triglycerides thereof and n-3 fatty acids; and isomaltulose as a carbohydrate component. According to still another aspect of the present invention, a milk protein hydrolyzate and a fermented milk-derived protein as a protein component and a medium chain as a fat component for improving peripheral neuropathy caused by administration of an anticancer agent A combination of fatty acids or their triglycerides and n-3 fatty acids; and isomaltulose as a carbohydrate component is provided. Any of the above embodiments can be carried out based on the description of the composition and method of the present invention.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. In the following examples, “%” means “% by weight” unless otherwise specified. In addition, unless otherwise specified, the units and measurement methods in the present specification follow the rules of Japanese Industrial Standard (JIS).

Example 1: Preparation of test composition
A whey protein isolate (WPI, Davisco) having a protein content of about 90% as a dried milk protein hydrolyzate was dissolved in distilled water at a protein content of 8% (w / v). The solution was denatured by heating at 85 ° C. for 2 minutes. The pH of the heated solution was about 7.5. In the hydrolysis, 2.4 L of Alcalase (enzyme, Novozymes) was added at a concentration of 2.0% with respect to the substrate and reacted at 55 ° C. for 3 hours. Next, PTN 6.0S (Novozymes Japan), which is a trypsin derived from pigs, was added at a concentration of 3.0% with respect to the substrate and reacted at 55 ° C. for 3 hours. Total hydrolysis time was 6 hours. The pH at the end of the reaction was about 7.0. The obtained reaction solution is centrifuged (20,000 × g, 10 minutes), further subjected to a UF membrane treatment (Millipore Ultrafree-MC) with a molecular weight cut off of 10,000, and a milk protein hydrolyzate (whey protein hydrolyzate). Decomposition product).

The protein skim milk derived from fermented milk was sterilized (120 ° C., 30 seconds) and then inoculated with about 5% (w / w) of lactic acid bacteria starters (Lactobacillus bulgaricus and Streptococcus thermophilus) and fermented. After the pH of the obtained fermentation broth reached about 4.6 and a curd was formed, the whey was centrifuged using a separator, and the obtained curd was cooled to obtain a protein derived from fermented milk.

Assuming that 100 L of the test composition is obtained, warm water at 55 ° C. is stirred in the tank, the protein component (containing 2 kg of milk protein hydrolyzate, 3 kg of fermented milk-derived protein), fat component ( Medium chain fatty acid triglyceride 0.59kg, refined fish oil 0.2kg, edible oil 1.91kg), sugar component (isomalulose 7kg included), dietary fiber 1.2kg, minerals 71g (containing sodium, zinc, copper) ) Was added and mixed. The obtained mixture was sterilized by heating with a steam injection method (135 ° C., 5 seconds) and then homogenized (15 MPa) with a homogenizer to obtain a homogenized solution. To this homogenized solution, 7.5 mg of biotin and the like were added and mixed to obtain a mixed solution again. The obtained mixed solution was adjusted to pH 3.8 with citric acid, further sterilized by heating with a steam infusion method (135 ° C., 5 seconds), and then homogenized (15 MPa) with a homogenizer. 100 L of the test composition (100 kcal / 100 mL) shown in 2 was obtained. The total content of docosahexaneenoic acid and eicosapentaenoic acid in the test composition was 0.06 g, and the weight ratio of n-6 fatty acid and n-3 fatty acid in the test composition (n- 6 / n-3) was 2.0. The n-6 fatty acid is linoleic acid, and the n-3 fatty acid is a combination of α-linolenic acid, docosahexaneenoic acid and eicosapentaenoic acid.

Example 2: Confirmation test of improvement effect of peripheral neuropathy caused by anticancer drug Chemotherapy is being carried out, 2 cancer patients who can be outpatient and can continue their own research (case 1-female, 43 years old, malignant lymphoma patient, stage IV; case 2-female, 47 years old, colon cancer patient, stage IV) were selected as subjects. Chemotherapy was performed by instilling an anticancer drug into the subject on the first day of each cycle, with about 20 days as one cycle.
As for the anticancer drug administration regimen, for the patients with malignant lymphoma, R-CHOP therapy (rituximab 520 mg, cyclophosphamide 1040 mg, adriamycin 69 mg, vincristine 1.9 mg) was used in the second half of the anticancer drug administration. R-CVP therapy (rituximab 520 mg, cyclophosphamide 1040 mg, vincristine 1.9 mg) was used for the administration of the anticancer drug at one time.
As for colon cancer patients, the first four anticancer drug administrations used CapeOX therapy (capecitabine 1200 mg, oxaliplatin (L-OHP 100 mg), and the last one anticancer drug administration was R-CVP. Cape / Bev therapy (capecitabine 1200 mg, bevacizumab 270 mg) was used.

  Further, during the chemotherapy, a course A for ingesting the test composition and a course B for ingesting only the normal meal were provided, and each of the A and B courses was repeated alternately for each subject. Specifically, in course A, subjects ingested 3 test compositions (equivalent to 600 kcal) per day from 3 days prior to the implementation of chemotherapy (infusion therapy) to the day before the implementation, and further from the day of chemotherapy. During the four days up to the third day after the therapy, one day (corresponding to 200 kcal) was orally ingested, and then a normal meal was ingested. On the other hand, in the case of B course, the subject orally ingested the meal before and after chemotherapy.

  During the study, subjects evaluated the peripheral neuropathy (numbness, etc.) associated with chemotherapy with a four-step evaluation based on the patient's own description, referring to the adverse events of version 4 of Common Terminology Criteria for Adverse Events (CTCAE). Grade 0 is normal, Grade 1: light numbness or pain, Grade 2: numbness or pain is difficult but life is not troubled, Grade 3: numbness or pain is bad, life is difficult .

The results were as shown in FIG. 1 and FIG. Peripheral neuropathy, which is a side effect of anticancer drugs, is accumulated every time chemotherapy is performed, and the grade of adverse events of peripheral neuropathy usually does not decrease. However, as a result of this study, it was confirmed that in any subject, the grade of adverse events of peripheral neuropathy was reduced when the test composition was ingested. Specifically, in the malignant lymphoma patient of FIG. 1, the adverse event decreased from Grade 2 to Grade 1 by the third infusion of the anticancer drug (Day 60) by using the test composition together. In addition, in the colorectal cancer patient in FIG. 2, regarding the period up to the 60th day, an increase in adverse events occurred when the anticancer drug was instilled (25th day) without taking the test composition. In contrast to Grade 0 to Grade 2, the increase in adverse events was suppressed from Grade 0 to Grade 1 when the anticancer drug was infused (Days 4 and 46) together with the intake of the test composition. It was.
In addition, none of the subjects became difficult to take the test composition due to a decrease in appetite, and nutritional supplementation with the test composition was continued along with improvement of peripheral neuropathy.

Claims (15)

  Administration of an anticancer drug comprising milk protein hydrolyzate and fermented milk-derived protein as protein component; medium chain fatty acid or triglyceride thereof and n-3 fatty acid as fat component; and isomaltulose as carbohydrate component A composition for improving peripheral neuropathy caused by the disease.   The milk protein is at least selected from the group consisting of casein, milk protein concentrate (MPC), whey protein concentrate (WPC), whey protein isolate (WPI), α-lactalbumin, β-lactoglobulin and lactoferrin. The composition of claim 1, which is one.   The composition according to claim 1 or 2, wherein the milk protein hydrolyzate is a whey protein hydrolysate.   The composition according to any one of claims 1 to 3, wherein a content of the milk protein hydrolyzate is 0.5 to 3 g per 100 kcal of the composition.   The composition according to any one of claims 1 to 4, wherein the fermented milk-derived protein is derived from fresh cheese.   The protein derived from fermented milk is a protein of fermented milk obtained by fermenting skim milk using Lactobacillus Bulgaricus, Streptococcus thermophilus or a combination thereof. The composition as described in any one of -5.   The composition according to any one of claims 1 to 6, wherein the content of the fermented milk-derived protein is 0.5 to 6 g per 100 kcal of the composition.   The composition according to any one of claims 1 to 7, wherein the medium chain fatty acid is a medium chain fatty acid having 8 to 14 carbon atoms.   The composition according to any one of claims 1 to 8, wherein a content of the medium chain fatty acid or a triglyceride thereof is 0.01 to 2 g per 100 kcal of the composition.   The composition according to any one of claims 1 to 9, wherein the n-3 fatty acid comprises one or more fatty acids selected from docosahexaenoic acid and eicosapentaenoic acid.   The composition according to any one of claims 1 to 10, wherein the content of the n-3 fatty acid is 0.05 to 2.2 g per 100 kcal of the composition.   The composition according to any one of claims 1 to 11, wherein the content of isomaltulose is 1 to 15 g per 100 kcal of the composition.   The composition according to any one of claims 1 to 12, further comprising an n-6 fatty acid as a lipid component, wherein a weight ratio of the n-6 fatty acid to the n-3 fatty acid is 1 to 3. .   The composition according to any one of claims 1 to 13, further comprising at least one component selected from the group consisting of dietary fiber, vitamins and minerals.   The composition according to any one of claims 1 to 14, which is a beverage or a liquid food.