JP7123205B2 - Oral pharmaceutical composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to an analgesic action, particularly an oral pharmaceutical composition that exhibits excellent action on pain associated with psychogenic factors (irritability, anxiety, depression, etc.).

Pain is defined as ``an unpleasant sensory or emotional experience when some tissue damage actually occurs, is likely to occur, or is expressed during such damage''. (For example, see Non-Patent Document 1). In addition, as a classification according to the cause of pain, 1. pain due to external nociceptive stimulus that occurs when stimulus is applied from the outside, 2. 3. Pain associated with internal noxious stimuli associated with lesions of the living body; 3. Pain due to nervous system abnormalities caused by abnormalities in primary neurons and higher central nerves; 5. Pain due to psychophysical causes triggered by mental factors such as stress; It is classified as pain caused by a psychogenic reaction that occurs when the cause of pain cannot be found in the body at all. Four. 4. Pain due to psychosomatic causes; In relation to pain associated with psychogenic reactions, there have been many reports of psychological symptoms, especially during menstrual pain in women, such as ``irritability,''``depression,'' and ``anxiety'' associated with pain. Mainly symptoms. Thus, pain and psychological symptoms are closely related. However, at present, there is no preventive/therapeutic drug for pain associated with such psychological factors.

Loxoprofen sodium is a phenylpropionic acid-based non-steroidal anti-inflammatory drug, and has excellent analgesic, anti-inflammatory and antipyretic effects. In particular, since it is rapidly absorbed from the gastrointestinal tract, the analgesic, inflammatory, and antipyretic effects are exhibited quickly, and since it is a prodrug type, it has excellent properties that cause relatively few gastrointestinal disorders (for example, non-patented Reference 2).

Allyl isopropyl acetyl urea is a mild sedative ingredient, which is included in SG combination granules, and is used for the relief of colds, earache, sore throat, menstrual pain, headache, toothache, symptomatic neuralgia, and traumatic pain ( For example, see Non-Patent Document 3).

Magnesium aluminometasilicate is an antacid component of gastrointestinal drugs, and is known to have the effect of temporarily alleviating stomach pain by neutralizing gastric acid (see, for example, Non-Patent Document 3).

Caffeine is added to aid the analgesic action of antipyretic analgesic ingredients and to suppress drowsiness by acting on the central nervous system (see, for example, Non-Patent Document 4).

On the other hand, the present inventors have disclosed the following compositions containing these components.
1) The combined use of loxoprofen sodium and ketotifen enhances the antipyretic effect of loxoprofen sodium (see Patent Document 1).
2) When loxoprofen sodium is used in combination with allylisopropylacetylurea, the analgesic action of loxoprofen sodium is further enhanced (see Patent Document 2). Further, the same document discloses a composition containing loxoprofen sodium, allylisopropylacetylurea and caffeine.
3) When loxoprofen sodium is blended with allylisopropylacetylurea and caffeine, storage stability is improved (see Patent Document 3).

However, there is no description that these formulations exhibit excellent effects on pain associated with psychogenic factors (irritability, anxiety, depression, etc.). Furthermore, the combination of loxoprofen sodium, allyl isopropyl acetyl urea, magnesium aluminometasilicate and caffeine is not known, and these compositions have psychogenic factors (irritability, anxiety, depression, etc.). It has not been suggested that an analgesic effect is exhibited.

JP-A-2004-83579 Patent No. 5100619 JP 2012-67095 A

Toyo Miyazaki et al., Pain book for practitioners: Nagai Shoten, 2000 Pharmaceutical interview form “Loxonin tablets 60mg, Loxonin fine granules 10%”, Daiichi Sankyo Co., Ltd. Prescription Drugs 2013 Edition JAPIC 2013 OTC Handbook 2013

The present invention is to provide a novel pharmaceutical composition having a preventive and/or therapeutic effect on pain associated with psychogenic factors (irritability, anxiety, depression, etc.). To provide a composition excellent in prevention and/or treatment of headache and menstrual pain accompanied by irritability, anxiety, depression, etc.

The inventors of the present invention have further conducted extensive research in order to find a composition that is effective against pain associated with psychogenic factors (irritability, anxiety, depression, etc.). As a result, it was found that loxoprofen sodium containing allyl isopropyl acetyl urea, magnesium aluminometasilicate and caffeine caused menstrual cramps and headaches accompanied by significant psychogenic factors (irritability, anxiety, depression, etc.). The inventors have found that it has an improving effect, and have completed the present invention.

That is, the present invention
(1) an antipyretic analgesic composition containing the following (a), (b), (c) and (d);
(a) loxoprofen or a salt thereof (b) allylisopropylacetylurea and bromvalerylurea (c) magnesium aluminometasilicate (d) caffeine or anhydrous caffeine (2) psychogenic factors The analgesic composition according to (1) above, characterized by ameliorating accompanying pain;
(3) The analgesic composition according to (1) or (2) above, wherein the pain associated with psychogenic factors is menstrual pain;
(4) The analgesic composition according to (1) or (2) above, wherein the pain associated with psychogenic factors is headache;
(5) The analgesic composition according to any one of (1) to (4) above, which is in an oral dosage form;
It provides

The pharmaceutical composition of the present invention, which contains loxoprofen sodium and at least one selected from allylisopropylacetylurea, magnesium aluminometasilicate and caffeine, exhibits even better psychogenic factors (irritability, anxiety, Since it has an analgesic effect accompanied by depression, etc.), it is particularly useful for the prevention and/or treatment of headache symptoms and/or menstrual pain symptoms.

Psychogenic factors are those that cause mental imbalance due to stress, such as irritability, anxiety, and depression. Pain associated with psychogenic factors includes (1) pain caused by mental factors (diseases) such as stress diseases and depression, and (2) pain that continues for years in the same way, worsening in the morning and improving in the evening. (3) Those with strong mental factors include mental disorders that require prompt treatment by a psychiatric specialist, such as depression, somatic expression disorder, and schizophrenia. , Different from other chronic pain, it requires treatment and management by a psychiatrist / psychosomatic medicine specialist. say something Specifically, it refers to psychogenic headache, psychogenic menstrual pain, and psychogenic dysmenorrhea.

Loxoprofen sodium and caffeine according to the present invention are listed in the Japanese Pharmacopoeia 2012, 16th Edition.

In addition, magnesium aluminometasilicate and magnesium oxide are listed in Japanese Pharmacopoeia Pharmaceutical Standards 2002, and allylisopropylacetylurea and bromvalerylurea are also commercially available and easily available.

The pharmaceutical composition of the present invention can include dosage forms such as tablets, capsules, powders, granules, fine granules, liquids, troches, and jellies.

Formulation can be performed by known formulation techniques, and suitable formulation additives can be added to the formulation. Formulation additives may be added as appropriate within a range that does not impair the effects of the present invention. Pharmaceutical additives include, for example, excipients, disintegrants, binders, sweeteners, flavoring agents, lubricants, coating agents and the like.

Excipients include, for example, 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, silicic acid. Calcium, magnesium aluminometasilicate, magnesium oxide, aminoacetic acid, synthetic hydrotalcite, synthetic aluminum silicate, sucrose fatty acid ester, hydrogenated oil, lactose, sucrose, D-mannitol, erythritol, trehalose, glucose, fructose, etc. be able to.

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

Binders include, for example, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, povidone, macrogol, gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, aminoalkylmethylcellulose, Acrylate copolymers, pullulan, and the like may be mentioned.

Sweetening agents include, for example, aspartame, sucralose, acesulfame potassium, xylitol, erythritol, sorbitol, mannitol, saccharin and the like.

Examples of flavoring agents include menthol, peppermint water, peppermint oil, ascorbic acid, citric acid, cinnamon oil, clove oil, lactic acid, honey, borneol, and rose oil.

Lubricants include, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, polyethylene glycol, hardened oil and the like. These formulation additives may be used singly or in combination of two or more.

The dosage of the pharmaceutical composition of the present invention to a patient may be appropriately determined according to the patient's sex, age, symptoms, administration method, administration frequency, administration period, and the like.

For example, loxoprofen sodium is preferably administered at 10 to 1000 mg, more preferably 100 to 360 mg, and particularly preferably 180 mg per day as an anhydrate.

Allylisopropylacetylurea is also preferably administered at 10-1000 mg, more preferably 100-360 mg, and particularly preferably 180 mg per day. In addition, bromvalerylurea is preferably administered in an amount of 20 to 2000 mg, more preferably 200 to 2000 mg, and particularly preferably 600 mg per day.

As for caffeine, it is preferable to administer 10 to 1000 mg, more preferably 50 to 500 mg, and particularly preferably 150 mg per day as an anhydrate.

Magnesium aluminometasilicate is preferably administered in an amount of 10 to 2000 mg, more preferably 50 to 500 mg, and particularly preferably 250 mg per day.

That is, the pharmaceutical composition of the present invention contains 10 to 1000 mg of loxoprofen anhydride, 10 to 1000 mg of allylisopropylacetylurea, 10 to 1000 mg of anhydrous caffeine, and 10 to 2000 mg of magnesium aluminometasilicate per day. Formulations to be administered are preferred.

Furthermore, it is more preferable to combine 100 to 360 mg of loxoprofen sodium, 100 to 360 mg of allylisopropylacetylurea, 50 to 500 mg of anhydrous caffeine, and 50 to 500 mg of magnesium aluminometasilicate per day. .

The pharmaceutical composition of the present invention may be prepared as a single formulation containing multiple components of the present invention and administered, or each component of the present invention may be divided into separate formulations and A kit formulation that allows simultaneous or sequential administration of the formulations may also be used.

The pharmaceutical composition of the present invention is used for the prevention or treatment of pain associated with psychogenic factors (irritability, anxiety, depression, etc.), more specifically, psychogenic factors (irritability, anxiety, depression, etc.). It is preferably used for the prevention or treatment of accompanying headache symptoms and/or menstrual pain symptoms.

EXAMPLES The present invention will be described below with reference to Examples, but the present invention should not be limited to these.

(Formulation example 1)
Tablets were produced by a conventional method with the following composition.

(Formulation example 2)
Granules having the following composition were produced by a conventional method.

(Example 1) Administration test for headache with psychogenic factor 1. Test method
A total of 62 subjects diagnosed with headache were examined to see if it was effective for headaches associated with psychogenic factors (irritability, anxiety, depression, etc.). Either the formulation of Formulation Example 1 or Formulation Example 2 containing loxoprofen sodium, allylisopropylacetylurea, magnesium aluminometasilicate and caffeine as main ingredients was taken with water or lukewarm water. When taking the drug, avoid taking it on an empty stomach as much as possible, and when taking it further, take it at an interval of 4 hours or more. Usually, it should be taken up to twice a day, but if the symptoms appear again, take a third dose.
We sought the rate of improvement in headache accompanied by depressive feeling, etc., especially 120 minutes after the first dose.

2. Test Results The results are shown in Table 3. The mild improvement rate for headaches associated with psychogenic reactions was 93.8% for nausea, 83.3% for anxiety, 81.0% for irritability, 77.8% for vomiting, 75.6% for malaise, and 77.1% for eye fatigue, with a mild improvement rate of 70%. It was confirmed that the improvement was as high as 10% or more. In addition, it was confirmed that headache associated with sensitivity to light, sensitivity to sound, and sensitivity to odors was greatly improved.

Therefore, it was found that the pharmaceutical composition of the present invention exhibits excellent effects on pain associated with psychogenic factors (irritability, anxiety, depression, etc.).

(Example 2) Administration test for menstrual pain accompanied by psychogenic factors 1. Test method 57 subjects diagnosed with menstrual cramps were targeted to confirm whether it was effective against menstrual cramps associated with psychogenic factors (irritability, anxiety, depression, etc.). Either the formulation of Formulation Example 1 or Formulation Example 2 containing loxoprofen sodium, allylisopropylacetylurea, magnesium aluminometasilicate and caffeine as main ingredients was taken with water or lukewarm water. When taking the drug, avoid taking it on an empty stomach as much as possible, and when taking it further, take it at an interval of 4 hours or more. Usually, the dose is up to twice a day, but if the symptoms appear again, take a third dose. We sought the improvement rate of menstrual pain associated with menstrual cramps, especially 120 minutes after the first dose.

2. Test Results The results are shown in Table 4. The mild improvement rate for headaches associated with psychogenic reactions was 93.8% for nausea, 83.3% for anxiety, 81.0% for irritability, 77.8% for vomiting, 75.6% for malaise, and 77.1% for eye fatigue, with a mild improvement rate of 70%. It was confirmed that the improvement was as high as 10% or more. In addition, it was confirmed that headache associated with sensitivity to light, sensitivity to sound, and sensitivity to odors was greatly improved.

Therefore, it was found that the pharmaceutical composition of the present invention exhibits excellent effects on pain associated with psychogenic factors (irritability, anxiety, depression, etc.).

The pharmaceutical composition containing loxoprofen sodium, allyl isopropyl acetyl urea, magnesium aluminometasilicate and caffeine of the present invention is more excellent for headache accompanied by psychogenic factors (irritability, anxiety, depression, etc.). - It is useful as a pharmaceutical composition for the prevention and/or treatment of menstrual cramps.

Claims (5)

A pharmaceutical composition for improving psychogenic symptoms of pain associated with psychogenic factors, comprising the following (a) to (d), wherein the pain associated with psychogenic factors is psychogenic headache, A pharmaceutical composition for causative menstrual pain or psychogenic dysmenorrhea, wherein the psychogenic symptom is nausea, vomiting or malaise.
(a) loxoprofen or a salt thereof (b) one or more selected from allylisopropylacetylurea and bromvalerylurea (c) magnesium aluminometasilicate (d) caffeine or anhydrous caffeine 2. The pharmaceutical composition of claim 1, wherein (b) is allylisopropylacetylurea. 3. The pharmaceutical composition according to claim 1 or 2, wherein the pain associated with psychogenic factors is psychogenic menstrual pain . 3. The pharmaceutical composition according to claim 1 or 2, wherein the pain associated with psychogenic factors is psychogenic headache. The pharmaceutical composition according to any one of claims 1 to 4, which is for oral administration.