JP7260950B2 - low back pain reliever - Google Patents

Description

TECHNICAL FIELD The present invention relates to a lumbago alleviating agent.

Low back pain is a general term for symptoms of pain and inflammation in the lower back, and the causes are broadly classified into five types: spine-derived, nerve-derived, visceral-derived, vascular-derived, and psychogenic. In addition, lumbago (non-specific lumbago) of which the cause is not clear is also observed (Non-Patent Document 1).

Conventionally, techniques such as rest, massage, drug therapy, hyperthermia therapy, physical therapy, brace therapy, exercise therapy, nerve block injection therapy, and surgical therapy have been applied as methods for improving or treating low back pain. As drugs for improving or treating lumbago, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 selective inhibitors, acetaminophen, muscle relaxants, anxiolytics, antidepressants, opioids and the like are used. In addition, topical medicines such as poultices, lotions, creams, and ointments containing antiphlogistic and analgesic ingredients are also used. However, drug therapy, heat therapy, physical therapy, brace therapy, exercise therapy, nerve block injection therapy, or surgical therapy require guidance from doctors and other medical personnel, and low back pain that can occur to anyone. There is a demand for a method for improving the above by a simpler method.

On the other hand, Milk-fat Globule Membrane (MFGM) is a membrane component that covers the milk fat globules secreted from the mammary glands, and is abundant in milk complex lipid-rich fractions such as buttermilk and butter serum. It is known to be included (Non-Patent Document 2). It has been reported that milk fat globule membranes not only have the function of dispersing fat in milk, but also have physiological functions such as improving motor function and improving muscle strength in mice (Patent Document 1). On the other hand, there are no reports of improvement in joint pain or low back pain.

Glucosamine is a kind of natural amino sugar, and is mainly present as an N-acetyl form in glycoconjugates of animals, plants, and microorganisms, especially chitin, proteoglycan, glycoprotein, and glycolipid. Industrially, it is mainly produced by hydrolyzing chitin and crystallizing it in the form of hydrochloride or sulfate.
In recent years, research on the physiological functions of glucosamine has progressed, and it has been reported that it has physiological functions such as improving symptoms of osteoarthritis and joint pain and moisturizing the skin. An oral composition useful for the treatment of lumbago and spondylolisthesis (Patent Document 2), and a herbal drug composition useful for the prevention or treatment of arthralgia such as lumbago comprising glucosamine and pulverized crude drugs have been proposed. (Patent Document 3).
However, there is no report on the effect of the combination of milk fat globule membrane and glucosamine on low back pain.

JP 2010-59155 A Japanese Unexamined Patent Application Publication No. 2001-72582 Japanese Patent Application Laid-Open No. 2006-176460

Supervised by the Japanese Orthopedic Association and the Japanese Society for Low Back Pain, "Low Back Pain Treatment Guidelines 2012" Nankodo, 2012 Susumu Miura, FOOD STYLE21, 2009

The present invention relates to providing pharmaceuticals, quasi-drugs or foods useful for alleviating lumbago, or materials or formulations that can be blended therein.

Means for Solving the Problems In view of the above-mentioned problems, the present inventors conducted intensive studies and found that a combination of milk fat globule membrane and glucosamine is useful for alleviating lumbago.

That is, the present invention provides a lumbago alleviating agent comprising (A) milk fat globule membrane and (B) glucosamine or a salt thereof as active ingredients.
The present invention also provides a lumbago-improving food containing (A) milk fat globule membranes and (B) glucosamine or a salt thereof as active ingredients.

ADVANTAGE OF THE INVENTION According to this invention, the pain of a waist can be reduced and the improvement of a lumbago can be aimed at.

The graph which shows the result of VAS evaluation.

The (A) milk fat globule coating used in the present invention is defined as a film covering the milk fat globules and a mixture of components constituting the film. Milk fat globule membranes have a wealth of food experience and are highly safe.
About half of the dry weight of the milk fat globule membrane is generally composed of lipids, and it is known that the lipids include triglycerides, phospholipids, and glycosphingolipids (Susumu Miura, FOOD STYLE 21, 2009 and Keenan TW, Applied Science Publishers, 1983, pp89-pp130). Phospholipids are known to include sphingophospholipids such as sphingomyelin (SM), glycerophospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS).
In addition, it is known that a glycoprotein called milk mucin is included as a component other than lipids (Mather, Biochim Biophys Acta, 1978).

The (A) milk fat globule membrane used in the present invention has a lipid content of 10% by mass or more, further 20% by mass or more, further 30% by mass or more from the viewpoint of physiological effects. From the viewpoint of flavor and handling, it is preferably 100% by mass or less, more preferably 90% by mass or less, and further preferably 60% by mass or less.

(A) The milk fat globule membrane has a phospholipid content of 5% by mass or more, further 8% by mass or more, further 10% by mass or more, further 15% by mass or more from the viewpoint of physiological effects. From the viewpoint of flavor and handling, it is preferably 100% by mass or less, further 85% by mass or less, further 70% by mass or less, and furthermore preferably 60% by mass or less.

(A) The milk fat globule membrane has a sphingomyelin (SM) content of 1% by mass or more, further 2% by mass or more, further 3% by mass or more from the viewpoint of physiological effects. is preferable, and from the viewpoint of flavor and handling, it is preferably 50% by mass or less, further 30% by mass or less, further 25% by mass or less, and furthermore preferably 20% by mass or less.
From the same point, (A) the sphingomyelin content in the total phospholipids of the milk fat globule membrane is 3% by mass or more, 5% by mass or more, 10% by mass or more, and 15% by mass or more. It is preferably 50% by mass or less, further 40% by mass or less, further 35% by mass or less, further preferably 30% by mass or less.
In the present specification, the content of lipids and phospholipids in the milk fat globule membranes, and the content of sphingomyelin in the total phospholipids of the milk fat globule membranes are the ratio by mass to the dry matter of the milk fat globule membranes. do.

(A) Milk fat globule membranes can be obtained from raw milk by known methods such as centrifugation and organic solvent extraction. For example, a method for preparing a milk fat globule film described in JP-A-3-47192 can be used. Also, the methods described in Japanese Patent No. 3103218 and Japanese Patent Application Laid-Open No. 2007-89535 can be used.
Further, it is also possible to use one whose purity has been increased by purification by techniques such as dialysis, ammonium sulfate fractionation, gel filtration, isoelectric precipitation, ion exchange chromatography, and solvent fractionation.
(A) The form of the milk fat globule film is not particularly limited, and may be liquid, semi-solid (paste, etc.), solid (powder, solid, granule, etc.) at room temperature (15 to 25 ° C.), etc. These may be used alone or in combination of two or more, but are preferably solid (powder).

(A) Examples of raw milk for the milk fat globule membrane include cow's milk and goat's milk. Among them, cow's milk is preferable because it is widely used as a food and is inexpensive. In addition, raw milk includes milk such as raw milk, whole milk powder and processed milk, as well as dairy products. Dairy products include buttermilk, butter oil, butter serum, whey protein concentrate (WPC) and the like. be done.
Buttermilk is obtained when butter grains are produced from cream obtained by centrifuging milk or the like, and since the buttermilk contains a large amount of milk fat globule membranes, it is You can use it as it is. Similarly, butter serum produced in the production of butter oil also contains a large amount of milk fat globule membranes, so butter serum may be used as it is as milk fat globule membranes.

(A) A commercial product can also be used for the milk fat globule film. Examples of such commercially available products include "BSCP" from Megret Japan Co., Ltd., "Milk Ceramide MC-5" from Snow Brand Milk Products Co., Ltd., and "Phospholipid Concentrate Series (500, 700)" from New Zealand Milk Products Co., Ltd.

(B) Glucosamine used in the present invention is a compound represented by the molecular formula C ₆ H ₁₃ NO ₅ . Glucosamine may be a D-isomer, an L-isomer, or a DL-isomer in which both isomers are mixed, but the D-isomer is preferred. Moreover, it may be either α-type or β-type.
Salts of glucosamine include, for example, inorganic salts such as hydrochloride, sulfate, and phosphate; acetate, propionate, tartrate, fumarate, maleate, malate, citrate, methane Organic acid salts such as sulfonates, p-toluenesulfonates and trifluoroacetates are included, and hydrochlorides are preferred.
These glucosamines or salts thereof can be used alone or in combination of two or more.
(B) Glucosamine or a salt thereof may be produced by known methods such as enzymatic treatment, hydrolysis, microbial fermentation, chemical synthesis, etc. of chitin obtained from crustaceans such as crabs and shrimps, or commercially available products may be used. can also

In the present invention, the ratio of (A) milk fat globule membrane and (B) glucosamine or a salt thereof is the content of component (A) relative to the glucosamine equivalent of component (B) (in terms of dry matter) from the viewpoint of physiological effects. The mass ratio [(A) / (B)] is preferably 0.15 or more, more preferably 0.3 or more, still more preferably 0.5 or more, and preferably 10 or less, more preferably 5 1 or less, more preferably 1 or less.

As shown in the examples below, the combination of (A) milk fat globule membrane and (B) glucosamine or a salt thereof has an effect of alleviating lumbago.
Therefore, the combination of (A) milk fat globule membranes and (B) glucosamine or a salt thereof can be a lumbago alleviating agent useful for alleviating lumbago, and can be used for producing a lumbago alleviating agent. That is, a combination of (A) milk fat globule membranes and (B) glucosamine or a salt thereof can be applied to a person who is concerned about lumbago and used to improve lumbago.
Here, "low back pain" is a general term for symptoms of pain and inflammation in the lower back, but generally refers to pain located in the area between the lowest ribs and the gluteal groove that can be felt by humans. It is defined (Japanese Orthopedic Association, Japanese Lumbago Society supervised, "Low back pain treatment guideline 2012" Nankodo 2012).
"Amelioration" refers to amelioration of symptoms or conditions, prevention, inhibition or delay of worsening of symptoms or conditions, or reversal, prevention, inhibition or delay of progression of symptoms or conditions.
"Use" can be administration or ingestion to humans, and can be therapeutic or non-therapeutic use. "Non-therapeutic" means a concept that does not include medical practice, i.e., a concept that does not include methods of surgery, treatment or diagnosis of humans, more specifically, surgical procedures performed on humans by a physician or a person under the direction of a physician. , is a concept that does not include methods of performing therapy or diagnosis.

The lumbago-relieving agent of the present invention comprising a combination of (A) milk fat globule membranes and (B) glucosamine or a salt thereof comprises (A) a milk fat globule membrane component and (B) glucosamine or a salt thereof as a compounding agent. It may be formulated in a mold, or a kit that allows individual formulations to be used simultaneously or separately at intervals. Preferably, it is a single dosage form containing (A) a milk fat globule membrane component and (B) glucosamine or a salt thereof.

The lumbago-relieving agent of the present invention is a drug, quasi-drug, or food that exerts a lumbago-relieving effect when ingested or administered to animals including humans. It can be a material or formulation that is used by blending with food.

Such foods include foods with the concept of alleviating back pain and permitted to label as such (foods for specified health uses, foods with function claims) as necessary. These foods can be distinguished from ordinary foods because they are foods with functional claims.

Examples of dosage forms of the pharmaceuticals (including quasi-drugs, hereinafter the same) include oral administration using tablets, capsules, granules, powders, troches, syrups, and the like.
Such various formulations can be prepared by combining (A) the milk fat globule membrane of the present invention and (B) glucosamine or a salt thereof, or other pharmaceutically acceptable carriers such as excipients, Binders, fillers, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, flavoring agents, coating agents, carriers, diluents, glucosamine or its salts and milk fat globules It can be prepared by appropriately combining medicinal ingredients other than the film.
Among them, preferred dosage forms are solid preparations for oral administration, and tablets are preferred.

The content (A) of the milk fat globule film (in terms of dry matter) in the drug is generally 0.01% by mass or more, preferably 0.1% by mass or more, and more preferably 0.2% by mass or more. , more preferably 1% by mass or more, preferably 90% by mass or less, more preferably 80% by mass or less, still more preferably 70% by mass or less, still more preferably 60% by mass or less.

The content of (B) glucosamine or a salt thereof in the drug is generally 0.8% by mass or more, preferably 8% by mass or more, more preferably 25% by mass, and still more preferably 33% by mass or more in terms of glucosamine. Also, it is preferably 75% by mass or less, more preferably 66% by mass or less, and still more preferably 58% by mass or less.

Examples of the form of the food include beverages such as soft drinks, tea drinks, coffee drinks, fruit juice drinks, carbonated drinks, jellies, wafers, biscuits, breads, noodles, sausages, and various food compositions such as nutritious foods. Furthermore, nutritional supplement compositions in the same form as the oral administration formulations described above (solid formulations such as tablets, capsules, and lozenges) are also included. Among them, solid preparations are preferred, and tablets are more preferred.

Foods in various forms may be combined with (A) milk fat globule membranes and (B) glucosamine or its salts, or other food ingredients, solvents, softeners, oils, emulsifiers, preservatives, acidulants, sweeteners. , a bittering agent, a flavoring agent, a stabilizer, a coloring agent, an antioxidant, a humectant, a thickener, an active ingredient other than the milk fat globule membrane and glucosamine or a salt thereof, and the like.

The content of the (A) milk fat globule membrane in the food (in terms of dry matter) varies depending on the form of use, but in the form of beverages, it is preferably 0.001% by mass or more, more preferably 0.01% by mass or more. , more preferably 0.1% by mass or more, preferably 3% by mass or less, more preferably 2% by mass or less, and even more preferably 1% by mass or less.

The content of (B) glucosamine or a salt thereof in the food varies depending on the form of use. It is preferably 1% by mass or more, preferably 25% by mass or less, more preferably 8% by mass or less, and even more preferably 4% by mass or less.

In the form of solid foods such as tablets and processed foods, the content of (A) the milk fat globule membrane (in terms of dry matter) is preferably 0.05% by mass or more, more preferably 0.1% by mass or more, and even more preferably 0.1% by mass or more. is 0.2% by mass or more, and is preferably 90% by mass or less, more preferably 80% by mass or less, even more preferably 70% by mass or less, and still more preferably 60% by mass or less.

In the form of solid foods such as tablets and processed foods, the content of (B) glucosamine or a salt thereof is 0.8% by mass or more, preferably 8% by mass or more, more preferably 25% by mass, more preferably 25% by mass, in terms of glucosamine. is 33% by mass or more, preferably 75% by mass or less, more preferably 66% by mass or less, and even more preferably 58% by mass or less.

The dosage or intake of the lumbago-relieving agent of the present invention may vary according to the body weight, sex, age, condition, or other factors of the subject of administration or intake. The dose, route, interval of administration, and the amount and interval of intake can be appropriately determined by those skilled in the art, but usually, per day per adult (60 kg), as milk fat globule film (converted to dry matter) , preferably 0.1 g or more, more preferably 0.3 g or more, still more preferably 1 g or more, and preferably 30 g or less, more preferably 20 g or less, still more preferably 10 g or less.
In general, per adult (60 kg) per day, sphingomyelin is preferably 10 mg or more, more preferably 20 mg or more, still more preferably 40 mg or more, and preferably 1500 mg or less, more preferably It is 1000 mg or less, more preferably 500 mg or less, and still more preferably 250 mg or less.
In general, per adult (60 kg) per day, the amount of glucosamine is preferably 10 mg or more, more preferably 400 mg or more, still more preferably 1200 mg or more, and preferably 20 g or less, more preferably 10 g. Below, more preferably 5 g or less.
In the present invention, it is preferable to administer or take such an amount once or several times a day.

The formulations can be administered or taken according to any schedule.
The period of administration or intake is not particularly limited, but it is preferable to administer or intake repeatedly and continuously, more preferably to administer or intake continuously for 5 days or more, and to administer or intake continuously for 15 days or more. More preferred.

Subjects for administration or intake are not particularly limited as long as they require or desire improvement of lumbago, but administration or ingestion to humans who are aware of lumbago is effective.

[Preparation of tablets]
Tablets (Example 1: 330 mg/tablet, Comparative Example 1: 330 mg/tablet) having the composition shown in Table 1 below were prepared according to the Japanese Pharmacopoeia (General Rules for Formulations, "Tablets").

A milk fat globule membrane (MFGM) prepared from cow's milk was used.
The water content of MFGM was 3.6 mass %. The composition of MFGM was carbohydrate: 11.3% by mass, lipid: 25.1% by mass, and protein: 53.6% by mass in terms of dry matter. In MFGM, the phospholipid content was 16.6% by mass and the sphingomyelin content was 3.6% by mass in terms of dry matter.

Analysis of the above MFGM and glucosamine was performed as follows.
(1) Analysis of protein The amount of protein was determined using the Kjeldahl method with a nitrogen/protein conversion factor of 6.38.

(2) Analysis of lipids The amount of lipids was determined by an acidolysis method. After weighing 1 g of a sample and adding hydrochloric acid to decompose it, diethyl ether and petroleum ether were added and mixed with stirring. The ether mixture layer was taken out and washed with water. After distilling off the solvent and drying, the weight was measured to determine the amount of lipid.

(3) Carbohydrate analysis The carbohydrate content was obtained by removing the protein content, lipid content, ash content, and water content in the sample from the mass of the sample. The ash content was determined by a direct incineration method (a sample was incinerated at 550°C and weighed), and the moisture content was determined by a normal pressure drying method (dried at 105°C for 4 hours and weighed).

(4) Analysis of phospholipids Weigh 1 g of the sample, homogenize in 150 mL, 100 mL, and 20 mL of a 2:1 (V/V) mixture of chloroform and methanol, and then 0.88 wt% (W/V) potassium chloride aqueous solution. 93 mL was added and left overnight at room temperature. After dehydration filtration and solvent distillation, chloroform was added to bring the total volume to 50 mL. A 2 mL portion thereof was taken, and after distilling off the solvent, it was incinerated by heat treatment at 550° C. for 16 hours. After dissolving the ash in 5 mL of a 6 M hydrochloric acid aqueous solution, distilled water was added to bring the total volume to 50 mL. A 3 mL portion was taken, 5 mL of molybdenum blue coloring reagent, 1 mL of 5% by mass (W/V) ascorbic acid aqueous solution, and distilled water were added to make the total volume 50 mL, and the absorbance at 710 nm was measured. The amount of phosphorus was obtained from a calibration curve using potassium dihydrogen phosphate, and the amount of phosphorus was multiplied by 25.4 to obtain the amount of phospholipid.

(5) Analysis of sphingomyelin A 1 g sample was weighed and homogenized in 150 mL, 100 mL, and 20 mL of a 2:1 (V/V) mixture of chloroform and methanol, followed by a 0.88 wt% (W/V) potassium chloride aqueous solution. 93 mL was added and left overnight at room temperature. After dehydration filtration and solvent distillation, chloroform was added to bring the total volume to 50 mL. 10 mL of this was taken out and added to a silica cartridge column. After washing the column with 20 mL of chloroform, the phospholipid was eluted with 30 mL of methanol, and after the solvent was distilled off, it was dissolved in 1.88 mL of chloroform. 20 µL was loaded on a silica gel thin layer plate, and tetrahydrofuran:acetone:methanol:water = 50:20:40:8 (V/V) was used as the one-dimensional developing solvent, and chloroform:acetone:methanol:acetic acid:water was used as the two-dimensional developing solvent. =50:20:10:15:5 (V/V) was used for two-dimensional development. A Ditmer reagent was sprayed on the developed thin layer plate, the sphingomyelin spot was scraped off, 2 mL of a perchloric acid solution containing 3% by mass (V/V) nitric acid was added, and heat treatment was performed at 170° C. for 3 hours. After adding 5 mL of distilled water, 5 mL of molybdenum blue coloring reagent, 1 mL of 5% by mass (W/V) ascorbic acid aqueous solution and distilled water were added to bring the total volume to 50 mL, and the absorbance at 710 nm was measured. The amount of phosphorus was determined from a calibration curve using potassium dihydrogen phosphate, and the amount of sphingomyelin was obtained by multiplying the amount of phosphorus by 25.4.

(6) Analysis of Glucosamine 1 g of a sample was weighed, added with water, and subjected to ultrasonic extraction for 30 minutes. After a constant volume of 200 mL, the mixture was filtered with filter paper and then with a membrane filter, and the filtrate was used as a sample for high performance liquid chromatography. The conditions for the high performance liquid chromatographic operation are as follows.
Model: LC-10ADvp (Shimadzu Corporation)
Detector: Differential refractometer RID-10A (Shimadzu Corporation)
Column: YMC-Pack ODS A, φ6.0 mm × 150 mm (YMC Co., Ltd.)
Column temperature: 45°C
Mobile phase: 23 mmol/L citrate buffer (pH 3.5) containing 0.005 mol/L Na octanesulfonate
Flow rate: 0.5mL/min
Injection volume: 20 μL

[Comparative verification study by double-blind randomized parallel]
(1) Subjects and test method 46 healthy men and women in their 50s to 70s who routinely take a commercially available supplement containing 1g or more of glucosamine hydrochloride (5 days or more a week) were divided into two groups ( 23 people in each group), tablets of Example 1 containing MFGM and glucosamine (10 tablets in total) in one group (MFGM + glucosamine group), and tablets of Comparative Example 1 containing glucosamine in the other group (glucosamine group). The tablets (total of 6 tablets) were taken daily for 4 weeks at any time.

(2) Evaluation of Effect of Improving Back Pain Evaluation of the effect of improving back pain was performed according to I. of the lower back pain patient functional evaluation questionnaire (JLEQ: Japan Low Back Pain Evaluation Questionnaire, Japanese Orthopedic Association Musculoskeletal Rehabilitation Committee, etc.). It was performed by a visual analogue scale (VAS) asking "How bad is your lower back pain?" Specifically, before the start of the test (week 0) and 4 weeks after the start of the test, the left end 0 mm of the 100 mm straight line was "no pain" (numerical value 0), and the right end 100 mm was "the most severe pain ever experienced". As a feeling of (numerical value 100), the degree of pain in the lower back felt now was marked on a straight line of 100 mm with reference to the sensations shown on the left and right ends of the straight line.

(3) Statistics Twenty-three subjects in the MFGM+glucosamine group and twenty-one subjects in the glucosamine group, excluding two subjects in the glucosamine group who had taken the test tablets for less than 26 days, were included in the final analysis for a total of 44 subjects. The numerical values obtained for the 44 final analysis subjects are shown as mean ± standard deviation. For statistics, a paired t-test was used with a significance level of 5%.

(4) Results The results are shown in FIG.
In the MFGM+glucosamine group, the degree of low back pain after the end of the study was significantly lower than before the start of the study, confirming an improvement in low back pain (p<0.01).

Claims (15)

(A) milk fat globule membrane and (B) glucosamine or a salt thereof as active ingredients for oral lumbago relief (except for lumbago associated with bone and joint disease). (A) The oral lumbago alleviating agent according to claim 1, wherein the milk fat globule membrane contains 5 to 100% by mass of phospholipid. (A) The oral lumbago ameliorating agent according to claim 1, wherein the milk fat globule coat contains 1 to 50% by mass of sphingomyelin. The oral lumbago alleviating agent according to any one of claims 1 to 3, which is in the form of a solid preparation. The oral lumbago alleviating agent according to claim 4, wherein the solid preparation is a tablet. The oral lumbago alleviating agent according to any one of claims 1 to 5, wherein 10 to 1500 mg of sphingomyelin is orally administered or orally ingested per adult per day. The oral lumbago alleviating agent according to any one of claims 1 to 6, wherein 10 to 20,000 mg of glucosamine is orally administered or ingested per adult per day. (A) milk fat globule membrane and (B) glucosamine or a salt thereof as active ingredients for relieving lumbago (excluding use as a food for relieving lumbago due to bone and joint disease). (A) The food for relieving lumbago according to claim 8, wherein the milk fat globule membrane contains 5 to 100% by mass of phospholipid. (A) The food for relieving lumbago according to claim 8, wherein the milk fat globule membrane contains 1 to 50% by mass of sphingomyelin. The lumbago improvement according to any one of claims 8 to 10, wherein the mass ratio [(A)/(B)] of the content of component (A) to the glucosamine equivalent amount of component (B) is 0.15 to 10. Food for. The food for lumbago relief according to any one of claims 8 to 11, wherein the dosage form is a solid preparation. 13. The food for lumbago relief according to claim 12, wherein the solid preparation is a tablet. 14. The food for relieving lumbago according to any one of claims 8 to 13, wherein 10 to 1500 mg of sphingomyelin is orally administered or ingested per adult per day. The food for relieving lumbago according to any one of claims 8 to 14, wherein 10 to 20,000 mg of glucosamine is orally administered or ingested per adult per day.

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