JP7557963B2 - Pharmaceutical combination for the prevention and/or treatment of dysmenorrhea - Google Patents

Description

The present invention relates to a combination drug for the prevention and/or treatment of dysmenorrhea that exhibits excellent analgesic effects against bodily pain, particularly pain during menstruation.

Dysmenorrhea is a pathological symptom such as lower abdominal pain, lower back pain, diarrhea, and headache that occurs during menstruation and accompanies menstruation. It has been reported that it occurs in approximately 45-60% of women with an established ovulation/menstrual cycle. It is believed that most of the pain in dysmenorrhea (menstrual pain, period pain) is caused by regular and pathologically strong contractions of the uterus that block blood flow to the uterine muscle, resulting in ischemia of the uterine muscle (see Non-Patent Document 1). In addition, prostaglandins (hereinafter also referred to as PGs) produced in the endometrium are said to migrate into the bloodstream and cause menstrual symptoms such as palpitations, dizziness, and headaches, as well as gastrointestinal symptoms such as nausea, vomiting, and diarrhea (Non-Patent Document 2).

In the endometrium, PGs (PGE2, PGF2α, etc.) are known to be produced by cyclooxygenase (COX) using arachidonic acid, a lipid in the cell membrane, as a substrate, and these PGs cause uterine contractions. There are two types of COX: COX-1 and COX-2. COX-2 in particular is induced in the follicle by luteinizing hormone during ovulation, and is known to be closely involved in reproductive phenomena such as fertilization, implantation, and parturition.

Loxoprofen sodium is a nonsteroidal anti-inflammatory drug of the phenylpropionic acid family, and has excellent analgesic, anti-inflammatory, and antipyretic effects. Antipyretic and analgesic drugs containing loxoprofen sodium as an active ingredient are effective in relieving headaches, menstrual pain (period pain), toothache, pain after tooth extraction, sore throat, lower back pain, joint pain, neuralgia, muscle pain, stiff shoulders, earache, bruises, fracture pain, sprains, and trauma pain, and in reducing fever during chills and fever (see, for example, Non-Patent Document 3).

It has been reported that spontaneous motility in the uterus (excised from rats) was halted at 1 μg/mL or more of loxoprofen sodium hydrate. It is known that PG plays a major role in spontaneous uterine motility, and this effect is thought to be due to the prostaglandin biosynthesis inhibitory effect of loxoprofen sodium hydrate. (See Non-Patent Document 4)

Although loxoprofen sodium inhibits uterine muscle contractions and is expected to have an analgesic effect against menstrual pain (period pain), a drug that combines superior efficacy and safety is desired.

Hesperidin is a type of polyphenol found in mandarin orange peel and is also known as a type of vitamin P. It is an extremely useful substance that has effects such as strengthening capillaries, improving blood lipids, improving blood flow, anti-allergic effects, and inhibiting carcinogenesis (see, for example, Patent Document 1).

However, the effect of hesperidin on uterine muscle is unknown. In addition, although a preparation containing loxoprofen sodium hydrate and hesperidin is known (see Patent Document 2), it is not known that the analgesic effect is enhanced by combining loxoprofen or its salt with hesperidin.

JP 2008-074838 A JP 2018-090549 A

The World of Obstetrics and Gynecology Vol. 58 No. 7 2006 Pages 3-10 Clinical Gynecology and Obstetrics, Vol. 63, No. 8, August 2009, pp. 1076-1081 Loxonin S Package Insert Daiichi Sankyo Healthcare Co., Ltd. Pharmaceutical interview form "Loxonin Tablets 60mg, Loxonin Granules 10%", Daiichi Sankyo Co., Ltd. Medical Drug Collection 2013 Edition JAPIC 2013

The problem to be solved by the present invention is to provide a combination drug for the prevention and/or treatment of dysmenorrhea that has a therapeutic effect on pain associated with dysmenorrhea, i.e., menstrual pain (period pain).

As a result of intensive research, the present inventors have found that the combined use of loxoprofen or its salt or its hydrate with hesperidins suppresses uterine muscle contractions, specifically, reduces the frequency and amplitude of uterine muscle contractions. Furthermore, they have found that the combination of loxoprofen or its salt or its hydrate with hesperidins further suppresses uterine muscle contractions when it is further combined with peony root or its extract, one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea, magnesium aluminometasilicate, and xanthines. As a result, the present inventors have found that a combination drug containing loxoprofen or its salt or its hydrate with hesperidins has an excellent analgesic effect on pain associated with dysmenorrhea, i.e., menstrual pain (period pain), and have completed the present invention.

That is, according to the present invention, the following inventions are provided.
(1) A combination drug for the prevention and/or treatment of dysmenorrhea, comprising loxoprofen or a salt thereof or a hydrate of the same and a hesperidin analogue.
(2) A combination drug for preventing and/or treating menstrual pain, comprising loxoprofen or a salt thereof or a hydrate thereof, and a hesperidin analogue.
(3) The combination medicine according to (1) or (2) above, further comprising one or more selected from the group consisting of peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; xanthines; and magnesium aluminometasilicate.
(4) The combination medicine according to (1) or (2) above, further comprising: peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; xanthines; and magnesium aluminometasilicate.
(5) A combination medicine containing loxoprofen or a salt thereof or a hydrate of the same, hesperidins, and peony root or an extract thereof.
(6) A combination medicine containing loxoprofen or a salt thereof or a hydrate of the same, hesperidin, peony or an extract thereof, and magnesium aluminometasilicate.

(A1) A method for preventing and/or treating dysmenorrhea, comprising administering to a subject loxoprofen or a salt thereof, or a hydrate of the above, and a hesperidin analogue.
(A2) A method for preventing and/or treating menstrual pain, comprising administering to a subject loxoprofen or a salt thereof, or a hydrate of the above, and a hesperidin analogue.
(A3) The method according to (A1) or (A2) above, further comprising administering one or more selected from the group consisting of peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; xanthines; and magnesium aluminometasilicate.
(A4) The method according to (A1) or (A2) above, further comprising administering peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; xanthines; and magnesium aluminometasilicate.
(A5) The method according to (A1) or (A2) above, which comprises administering to a subject loxoprofen or a salt thereof or a hydrate thereof, hesperidins, and peony root or an extract thereof.
(A6) The method according to (A1) or (A2) above, which comprises administering to a subject loxoprofen or a salt thereof or a hydrate thereof, hesperidins, peony root or an extract thereof, and magnesium aluminometasilicate.

(B1) A combination of loxoprofen or a salt thereof or a hydrate of the same and a hesperidin for use in the prevention and/or treatment of dysmenorrhea.
(B2) A combination of loxoprofen or a salt thereof or a hydrate thereof, and a hesperidin-type compound for use in the prevention and/or treatment of menstrual pain.
(B3) The combination according to (B1) or (B2) above, further comprising one or more selected from the group consisting of peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; xanthines; and magnesium aluminometasilicate.
(B4) The combination according to (B1) or (B2) above, further comprising: peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; xanthines; and magnesium aluminometasilicate.
(B5) The combination according to (B1) or (B2) above, comprising loxoprofen or a salt thereof or a hydrate thereof, hesperidins, and peony root or an extract thereof.
(B6) A combination according to (B1) or (B2) above, containing loxoprofen or a salt thereof or a hydrate of the same, hesperidins, peony root or an extract thereof, and magnesium aluminometasilicate.

(C1) Use of loxoprofen or a salt thereof, or a hydrate of the same or a hydrate thereof, and a hesperidin or a similar compound for the manufacture of a combined medicine for the prevention and/or treatment of dysmenorrhea.
(C2) Use of loxoprofen or a salt thereof, or a hydrate of the same or a hydrate thereof, and a hesperidin or a similar compound for the manufacture of a combination medicine for the prevention and/or treatment of menstrual pain.
(C3) The use according to (C1) or (C2) above, further comprising one or more selected from the group consisting of peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; xanthines; and magnesium aluminometasilicate.
(C4) The use according to (C1) or (C2) above, further comprising: peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; xanthines; and magnesium aluminometasilicate.
(C5) The use according to (C1) or (C2) above, which uses loxoprofen or a salt thereof or a hydrate thereof, hesperidins, and peony root or an extract thereof.
(C6) The use according to (C1) or (C2) above, in which loxoprofen or a salt thereof or a hydrate thereof, hesperidins, peony root or an extract thereof, and magnesium aluminometasilicate are used.

The combination drug of the present invention containing loxoprofen or a salt thereof or a hydrate thereof and hesperidins is useful for preventing and/or treating the symptoms of menstrual pain (period pain).

Examples of loxoprofen or a salt thereof or a hydrate thereof in the present invention include loxoprofen, loxoprofen sodium, loxoprofen sodium hydrate (dihydrate), etc. Loxoprofen sodium hydrate in the present invention is listed in the Japanese Pharmacopoeia, 17th Edition, 2016, etc.

Hesperidins in the present invention include hesperidin and hesperidin derivatives such as glycosyl hesperidin. Hesperidin is also called vitamin P and is listed in the Japanese Pharmacopoeia Extracorporeal Pharmaceutical Standards 2002 and other standards.

Peony root is the dried root of the Paeonia lactiflora plant, which belongs to the Paeoniaceae family. The peony or its extract in the present invention is not particularly limited, but examples thereof include dried peony extract (dried peony extract), soft peony extract, and liquid peony extract.

Allylisopropylacetylurea and bromvalerylurea are commercially available as active ingredients in sedatives and are readily available.
Magnesium aluminometasilicate is listed in the Japanese Pharmacopoeia Non-Prescription Drugs Standards 2002. In addition to being used as a pharmaceutical excipient, it is also used as an antacid to improve the symptoms of gastric and duodenal ulcers and gastritis, and to suppress gastrointestinal disorders caused by nonsteroidal anti-inflammatory drugs.

Examples of xanthines in the present invention include caffeine hydrate, anhydrous caffeine, sodium caffeine benzoate, theophylline, and diprophylline. Caffeine hydrate or anhydrous caffeine is preferred as the xanthines in the present invention. These xanthines are listed in the 17th Revised Japanese Pharmacopoeia 2016 and the Japanese Pharmacopoeia Non-Drug Standards 2002, etc.

Dosage forms of the pharmaceutical of the present invention include tablets, capsules, powders, granules, fine granules, liquids, lozenges, jellies, etc.

The formulation can be made by known formulation techniques, and appropriate formulation additives can be added to the formulation. The formulation additives may be added appropriately within a range that does not impair the effects of the present invention. Examples of formulation additives include excipients, disintegrants, binders, sweeteners, flavoring agents, lubricants, coating agents, etc.

Examples of excipients include crystalline cellulose, powdered cellulose, corn starch, potato starch, light anhydrous silicic acid, hydrated silicon dioxide, silicon dioxide, precipitated calcium carbonate, anhydrous calcium hydrogen phosphate, magnesium oxide, calcium lactate, calcium silicate, magnesium aluminometasilicate, magnesium oxide, aminoacetic acid, synthetic hydrotalcite, synthetic aluminum silicate, sucrose fatty acid ester, hardened oil, lactose, white sugar, D-mannitol, erythritol, trehalose, glucose, fructose, etc.

Examples of disintegrants include carmellose, carmellose calcium, croscarmellose sodium, low-substituted hydroxypropylcellulose, crospovidone, alginic acid, partially pregelatinized starch, and bentonite.

Examples of binders include methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, povidone, macrogol, gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, aminoalkyl methacrylate copolymer, pullulan, etc.

Examples of sweeteners include aspartame, sucralose, acesulfame potassium, xylitol, erythritol, sorbitol, mannitol, and saccharin.

Flavors include, for example, menthol, peppermint water, peppermint oil, ascorbic acid, citric acid, cinnamon oil, clove oil, lactic acid, honey, borneol, and rose oil.

Examples of lubricants include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, glycerin fatty acid esters, polyethylene glycol, and hardened oils.

Examples of coating agents include aminoalkyl methacrylate copolymers, gum arabic, ethyl cellulose, carnauba wax, carboxyvinyl polymer, magnesium stearate, talc, shellac, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pullulan, povidone, polyvinyl alcohol, macrogol, etc.

These formulation additives may be used alone or in combination of two or more.

The dosage of the combination drug of the present invention to a patient should be determined appropriately based on the patient's sex, age, symptoms, administration method, number of doses, administration time, etc.

For example, it is preferable to administer 10 to 1,000 mg of loxoprofen sodium per day as an anhydrous form, more preferably 100 to 360 mg, and particularly preferably 180 mg.

As for hesperidins, it is preferable to administer 1 to 1000 mg of hesperidin per day, more preferably 15 to 150 mg, and particularly preferably 50 to 120 mg.

It is preferable to administer 100 to 5,000 mg of peony or its extract per day, calculated as the raw herb of peony, more preferably 150 to 2,000 mg, and particularly preferably 200 to 900 mg.

In this specification, the amount of raw herbal medicine equivalent is the mass (dry mass) of raw herbal medicine required to obtain that amount of ingredient.

If the peony or its extract is, for example, peony root cut or crushed into small pieces or chunks, or crushed into powder, the mass of peony to be added will be the equivalent amount of raw herbal medicine, and in the case of peony extract (dried peony extract, soft peony extract, etc.), the dry mass of raw herbal medicine (peony) required to obtain the amount of peony extract to be added will be the equivalent amount of raw herbal medicine.

The dried peony extract is not particularly limited, but examples of commercially available dried peony extracts include dried peony extract manufactured by Nippon Powder Pharmaceutical Co., Ltd. (product name: dried peony extract-Q, extraction solvent: water, crude drug equivalent ratio 7:1 (peony concentrated 7 times)) and dried peony extract manufactured by Alps Pharmaceutical Co., Ltd. (extraction solvent: water, crude drug equivalent ratio 5:1 (peony concentrated 5 times)).

The peony soft extract is not particularly limited, but examples of commercially available peony soft extracts include peony soft extract manufactured by Nippon Funa Yakuhin Co., Ltd. (product name: Peony Dry Extract-A, extraction solvent: water, crude drug equivalent ratio 4:1 (peony concentrated 4 times)) and peony extract manufactured by Alps Yakuhin Kogyo Co., Ltd. (extraction solvent: water, crude drug equivalent ratio 4:1 (peony concentrated 4 times)).

When the xanthine is anhydrous caffeine, it is preferable to administer 10 to 1000 mg per day, more preferably 50 to 500 mg, and particularly preferably 150 mg.

For magnesium aluminometasilicate, it is preferable to administer 10 to 2000 mg per day, more preferably 50 to 500 mg, and especially preferably 300 mg.

For one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea, it is preferable to administer 10 to 1000 mg per day, more preferably 100 to 360 mg, and particularly preferably 180 mg.

The combination drug of the present invention may be prepared as a single preparation (single pharmaceutical composition) containing multiple components according to the present invention and administered as such, or the components according to the present invention may be separated into separate preparations (multiple pharmaceutical compositions) and these preparations may be administered simultaneously or sequentially as a kit preparation.
When the dosage form of the combination drug formulation of the present invention is a solid formulation, it can be appropriately packaged in a glass bottle, PTP, etc. Furthermore, if necessary, a desiccant can be enclosed together with the pharmaceutical composition of the present invention.

The combination drug for preventing and/or treating dysmenorrhea of the present invention, which contains loxoprofen or a salt thereof or a hydrate thereof, and hesperidins, is preferably used for preventing or treating menstrual pain symptoms.

The uses of the combination medicine of the present invention containing loxoprofen or a salt thereof or a hydrate thereof, hesperidins, and peony or an extract thereof, and the combination medicine of the present invention containing loxoprofen or a salt thereof or a hydrate thereof, hesperidins, peony or an extract thereof, and magnesium aluminometasilicate are not particularly limited. The combination medicine of the present invention described above may be used for the prevention and/or treatment of dysmenorrhea or for the prevention or treatment of menstrual pain symptoms, and may also be used, for example, as a painkiller for the pain relief of headache, toothache/pain after tooth extraction, sore throat, lower back pain, joint pain, neuralgia, muscle pain, stiff shoulders, ear pain, bruise pain, fracture pain, sprain pain, and trauma pain, or for the reduction of fever during chills and fever.

The present invention will be explained below with reference to examples, but the present invention should not be limited to these examples.

(Example 1) Magnus test using rat uterus for test substance 1. Test method Forty-four 9-11 week old female rats (Slc:SD, Japan SLC Co., Ltd.) were acclimated for 6 days or more, and the rats were confirmed to be in the estrus stage of the sexual cycle by vaginal smear examination. The rats were sacrificed by exsanguination, and the abdomen was opened to remove the left and right uterine horns. The removed uterine horns were cut into tubular specimens with a length of 2-3 cm. The organ bath was filled with Locke-Ringer solution with a mixed gas of 95% _O2 + 5% _CO2 , and the specimen was suspended with a load of 0.5 g.

The specimen's response was recorded using an isotonic transducer (TD-111T, Nihon Kohden Corporation), a high-sensitivity DC amplifier (AD-611J, Nihon Kohden Corporation), and PowerLab (PL3516, AD INSTRUMENTS) with data recording and analysis software (LabChartPro, AD INSTRUMENTS).

The specimens were suspended and allowed to stabilize for approximately 30 minutes. After the amplitude of spontaneous movement had stabilized, the vehicle or test solution of each specimen was applied to each specimen at one concentration, and spontaneous movement was recorded for at least 10 minutes after application.

Data analysis was performed as follows.
Amplitude of spontaneous movement (mm): Before application, one waveform obtained immediately before the application of the vehicle or each sample was analyzed. After application, the last waveform obtained 10 minutes after application was analyzed. The minimum and maximum values of each contraction waveform were measured, and the difference between the minimum and maximum values was calculated.
Number of contractions of spontaneous movement (times/10 min): The number of contractions was counted from waveform recordings for 10 min before and after application of the vehicle or each sample.

The percentage of change (%) from the value before application was calculated for all data. The results were expressed as the mean and standard deviation (± SD).

A Student's t-test (significance level 5%) was performed on the obtained data for the medium group and each sample group.

2. Test substance The following test substance components were used: loxoprofen sodium hydrate (hereinafter also referred to as LOX) manufactured by Tokyo Chemical Industry Co., Ltd., dried peony extract (original herb equivalent ratio 7:1, hereinafter also referred to as peony) manufactured by Nippon Funa Yakuhin Co., Ltd., hesperidin manufactured by Fujifilm Wako Pure Chemical Industries Co., Ltd., caffeine monohydrate (hereinafter also referred to as caffeine) manufactured by Nacalai Tesque Co., Ltd., allylisopropylacetylurea (hereinafter also referred to as AIAU) manufactured by Kongo Kagaku Co., Ltd., and magnesium aluminometasilicate manufactured by Fuji Chemical Industry Co., Ltd.

Locke-Ringer solution was prepared by dissolving sodium chloride (154.0 mmol/L), potassium chloride (5.6 mmol/L), calcium chloride (2.2 mmol/L), magnesium chloride (2.1 mmol/L), sodium bicarbonate (5.9 mmol/L), and D-(+)-glucose (2.8 mmol/L) in distilled water.

3. Samples and Test Group Composition Each sample was prepared by suspending or dissolving each test substance in Locke-Ringer solution, and then adding a fixed amount of each test substance to an organ bath so as to achieve the final concentrations shown in Table 1.

4. Test Results The results are shown in Table 2.

Sample 2 from the loxoprofen-only group showed a lower amplitude of spontaneous movement compared to sample 1 from the vehicle group, but no significant difference was observed. The number of contractions was significantly lower compared to the vehicle group. Sample 4 from the 0.8% hesperidin-only group had no effect on the amplitude of spontaneous movement, but showed a significantly lower number of contractions compared to the vehicle group. Sample 5 from the 1.6% hesperidin-only group had no effect on the amplitude of spontaneous movement, but showed a significantly lower number of contractions compared to the vehicle group.

Sample 8, which was administered a combination of loxoprofen and hesperidin 0.8%, showed significantly lower amplitude of spontaneous movement and significantly lower number of contractions compared to the vehicle group.

Furthermore, sample 3, which was 1.0% dried peony extract, showed significantly lower spontaneous movement and number of contractions than the vehicle group.
Sample 6, which was 1.4% caffeine monohydrate, showed a lower amplitude of spontaneous movement compared to the vehicle group, but no significant difference was observed. The number of contractions was significantly lower than that of the vehicle group.

Sample 10, containing 1.9% loxoprofen, 1.0% dried peony extract and 0.8% hesperidin, showed significantly lower values for spontaneous movement and number of contractions compared to the vehicle group.
Sample 11, containing 1.9% ibuprofen, 1.0% dried peony extract, 0.8% hesperidin and 1.4% caffeine monohydrate, showed significantly lower values for spontaneous movement and number of contractions compared to the vehicle group.

Sample 12, which contained 1.9% loxoprofen, 1.0% dried peony extract, 0.8% hesperidin, 1.4% caffeine monohydrate, 1.67% allylisopropylacetylurea, and 0.7% magnesium aluminometasilicate, showed significantly lower spontaneous movement and contraction frequency than the vehicle group.

Therefore, the combination drug of the present invention exhibited an inhibitory effect on uterine muscle contractions, and was therefore found to have an excellent effect on dysmenorrhea and menstrual pain caused by excessive uterine muscle contractions.

(Example 2) Magnus test 2 using rat uterus isolated from test substance
1. Test method Thirty-six 9-11 week old female rats (Slc:SD, Japan SLC Co., Ltd.) were acclimated for 6 days or more, and the rats were confirmed to be in the estrus phase of the sexual cycle by vaginal smear examination. The rats were killed by exsanguination, and the abdomen was opened to remove the left and right uterine horns. The removed uterine horns were made into tubular specimens with a length of 2-3 cm. The organ bath was filled with Locke-Ringer solution containing a mixed gas of 95% _O2 + 5% _CO2 , and the specimens were suspended under a load of 0.5 g.
The subsequent test methods, specimen recording methods, and analysis methods were the same as in Test Example 1.

2. Test substance The following test substance components were used: loxoprofen sodium hydrate (hereinafter also referred to as LOX) manufactured by Tokyo Chemical Industry Co., Ltd., dried peony extract (original herb equivalent ratio 7:1, hereinafter also referred to as peony) manufactured by Nippon Powder Pharmaceutical Co., Ltd., hesperidin manufactured by Tokyo Chemical Industry Co., Ltd., and magnesium aluminometasilicate manufactured by Fuji Chemical Industry Co., Ltd.
3. Samples and Test Group Composition Each sample was prepared by suspending or dissolving each test substance in Locke-Ringer solution, and then adding a fixed amount of each test substance to an organ bath so as to achieve the final concentrations shown in Table 3.

4. Test Results The results are shown in Table 4.

Sample 15 in the loxoprofen-only group showed significantly lower amplitude of spontaneous movement and number of contractions compared to sample 14 in the vehicle group. Sample 16 (1.0% dried peony extract-only group), sample 17 (0.8% hesperidin-only group), and sample 18 (2.78% magnesium aluminometasilicate-only group) did not affect the amplitude of spontaneous movement, but showed significantly lower number of contractions compared to sample 14 in the vehicle group.

Sample 19, containing 1.9% rofecoxib, 1.0% dried peony extract, and 0.8% hesperidin, showed significantly lower amplitude of spontaneous movement and significantly lower number of contractions compared to sample 14, the vehicle group.
In addition, sample 20, containing 1.9% ibuprofen, 1.0% dried peony extract, 0.8% hesperidin, and 2.78% magnesium aluminum silicate, showed significantly lower amplitude of spontaneous movement and significantly lower number of contractions compared to the vehicle group.

These combination drugs therefore demonstrated an inhibitory effect on uterine muscle contractions, and were therefore found to be effective against dysmenorrhea and menstrual pain caused by excessive uterine muscle contractions.

(Formulation Example 1)
Tablets are produced by a conventional method using the composition in Table 5 below.

(Formulation Example 2)
Tablets are produced by a conventional method using the composition in Table 6 below.

The combination drug of the present invention containing loxoprofen sodium and hesperidin improves dysmenorrhea and menstrual pain, and is therefore useful as a combination drug for the prevention and/or treatment thereof.

Claims (4)

A combination drug for the prevention and/or treatment of dysmenorrhea, comprising loxoprofen or a salt thereof or a hydrate of the same, and hesperidin . A combination drug for preventing and/or treating menstrual pain, comprising loxoprofen or a salt thereof or a hydrate thereof, and hesperidin . 3. The combination medicine according to claim 1 or 2, further comprising one or more selected from the group consisting of peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; one or more xanthines selected from caffeine hydrate, caffeine anhydrous, sodium caffeine benzoate, theophylline and diprophylline; and magnesium aluminometasilicate. 3. The combination medicine according to claim 1 or 2, further comprising: peony root or an extract thereof; one or more sedatives selected from allylisopropylacetylurea and bromvalerylurea; one or more xanthines selected from caffeine hydrate, caffeine anhydrous, sodium caffeine benzoate, theophylline and diprophylline ; and magnesium aluminometasilicate.