JP2023019148A - General pharmaceutical - Google Patents
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- JP2023019148A JP2023019148A JP2021123650A JP2021123650A JP2023019148A JP 2023019148 A JP2023019148 A JP 2023019148A JP 2021123650 A JP2021123650 A JP 2021123650A JP 2021123650 A JP2021123650 A JP 2021123650A JP 2023019148 A JP2023019148 A JP 2023019148A
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- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims abstract description 77
- 229960001929 meloxicam Drugs 0.000 claims abstract description 64
- 238000009472 formulation Methods 0.000 claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 239000000820 nonprescription drug Substances 0.000 claims description 46
- 208000008035 Back Pain Diseases 0.000 claims description 19
- 208000008930 Low Back Pain Diseases 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 17
- 208000002193 Pain Diseases 0.000 claims description 10
- 208000006820 Arthralgia Diseases 0.000 claims description 6
- 206010028391 Musculoskeletal Pain Diseases 0.000 claims description 6
- 208000007613 Shoulder Pain Diseases 0.000 claims description 6
- 235000012054 meals Nutrition 0.000 claims description 5
- 238000004806 packaging method and process Methods 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 3
- 239000007902 hard capsule Substances 0.000 claims description 3
- 239000007901 soft capsule Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 229940105781 meloxicam 10 mg Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 description 34
- 229940079593 drug Drugs 0.000 description 32
- 206010034464 Periarthritis Diseases 0.000 description 13
- 208000011580 syndromic disease Diseases 0.000 description 13
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical group CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 8
- 239000002775 capsule Substances 0.000 description 6
- 201000008482 osteoarthritis Diseases 0.000 description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 description 6
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 5
- 231100000636 lethal dose Toxicity 0.000 description 5
- 231100000614 poison Toxicity 0.000 description 5
- 230000000202 analgesic effect Effects 0.000 description 4
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical group [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 4
- 231100000820 toxicity test Toxicity 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
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- 230000007096 poisonous effect Effects 0.000 description 3
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- 206010037660 Pyrexia Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010014020 Ear pain Diseases 0.000 description 1
- 206010072132 Fracture pain Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 208000010040 Sprains and Strains Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 208000034526 bruise Diseases 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
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- 229960000913 crospovidone Drugs 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940100853 diclofenac sodium 25 mg Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 208000007176 earache Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229940082061 indomethacin 25 mg Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229960002373 loxoprofen Drugs 0.000 description 1
- YMBXTVYHTMGZDW-UHFFFAOYSA-N loxoprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1CC1C(=O)CCC1 YMBXTVYHTMGZDW-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007391 self-medication Methods 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
Images
Abstract
Description
本発明は、メロキシカムを含有する一般用医薬品に関する。 The present invention relates to an over-the-counter drug containing meloxicam.
メロキシカムは、医療用医薬品として「関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、頸肩腕症候群」に広く使用されてきた非ステロイド性消炎鎮痛剤（ＮＳＡＩＤｓ）であり、本邦では２００４年１２月に薬価収載され、２００５年１月から市場に提供されてきた。現在も医療用医薬品として広く用いられている。 Meloxicam is a nonsteroidal anti-inflammatory analgesic (NSAIDs) that has been widely used as a medical drug for "rheumatoid arthritis, osteoarthritis, lumbago, shoulder periarthritis, cervico-omo-brachial syndrome". It was listed on the drug price list in December and has been available on the market since January 2005. It is still widely used as a medical drug.
医療用医薬品としてのメロキシカムの有効性・安全性は非常に優れており、このメロキシカムを一般用医薬品として転用すれば、その有用性はさらに向上し、セルフメディケーションの選択肢を広げるうえでも非常に意義のあることと考えられる。しかし、医療用医薬品であるメロキシカムを単にそのままスイッチＯＴＣ化すると、効能・効果がわかりにくい、用法用量が煩雑である、適切な包装単位の設定が困難などの問題がある。かかる観点から、メロキシカムは、本邦では一般用医薬品としては提供されていない。 The efficacy and safety of meloxicam as an ethical drug are extremely excellent, and if this meloxicam is converted to an over-the-counter drug, its usefulness will be further improved, and it is very significant in terms of expanding self-medication options. It is considered that there is However, if meloxicam, which is a medical drug, is simply switched OTC as it is, there are problems such as difficulty in understanding efficacy and effects, complicated dosage and administration, and difficulty in setting appropriate packaging units. From this point of view, meloxicam is not provided as an over-the-counter drug in Japan.
本発明の課題は、医療用医薬品の有効成分であるメロキシカムを含有する一般用医薬品を提供することにある。 An object of the present invention is to provide an over-the-counter drug containing meloxicam, which is an active ingredient of ethical drugs.
そこで、本発明者らは、上記課題を解決するために鋭意検討した結果、必要に応じて薬局などで薬剤師や登録販売者からの適切な情報提供を受け、消費者が自らの健康状態に基づいて購入・服用できるようにすることが重要であると考え、メロキシカムの一般用医薬品としての効能・効果、用法・用量、製剤の形態などについて種々工夫をすることにより、消費者が自らの健康状態に対して、安全に有効に正しくメロキシカムを使用できるようになることを見出し、本発明を完成した。 Therefore, as a result of intensive studies to solve the above problems, the present inventors received appropriate information from pharmacists and registered sellers at pharmacies etc. as necessary, and consumers can use it based on their own health conditions. We believe that it is important for consumers to be able to purchase and take meloxicam as an over-the-counter drug. The inventors have found that it is possible to use meloxicam safely, effectively, and correctly, and completed the present invention.
すなわち、本発明は、次の発明［１］～［７］を提供するものである。
［１］１経口投与単位製剤にメロキシカム１０ｍｇを含有する一般用医薬品。
［２］効能効果が、関節痛、腰痛又は肩こり痛の鎮痛である［１］記載の一般用医薬品。
［３］１経口投与単位製剤にメロキシカム１０ｍｇを含有する分割できない製剤である［１］又は［２］記載の一般用医薬品。
［４］１経口投与単位製剤が、錠剤、硬カプセル剤、軟カプセル剤、分包液剤又は分包顆粒剤である［１］～［３］のいずれかに記載の一般用医薬品。
［５］１５歳以上の成人にメロキシカム１０ｍｇを、１日１回、毎回同じ時間帯に食後に服用するものである［１］～［４］のいずれかに記載の一般用医薬品。
［６］1包装単位が２４日分以下である［１］～［５］のいずれかに記載の一般用医薬品。
［７］メロキシカム１０ｍｇを含む１経口単位投与製剤の質量が１８０ｍｇ以上である［１］～［６］のいずれかに記載の一般用医薬品
That is, the present invention provides the following inventions [1] to [7].
[1] An over-the-counter drug containing 10 mg of meloxicam in one oral dosage unit formulation.
[2] The over-the-counter drug according to [1], wherein the indication is pain relief for arthralgia, lumbago or stiff shoulder pain.
[3] The over-the-counter drug according to [1] or [2], which is an indivisible preparation containing 10 mg of meloxicam per oral dosage unit preparation.
[4] The over-the-counter drug according to any one of [1] to [3], wherein one oral dosage unit formulation is a tablet, hard capsule, soft capsule, divided liquid formulation, or divided granule formulation.
[5] The over-the-counter drug according to any one of [1] to [4], wherein 10 mg of meloxicam is administered to adults aged 15 and over once a day at the same time each time after meals.
[6] The over-the-counter drug according to any one of [1] to [5], wherein one packaging unit is for 24 days or less.
[7] The over-the-counter drug according to any one of [1] to [6], wherein the mass of one oral unit dosage formulation containing 10 mg of meloxicam is 180 mg or more.
本発明の一般用医薬品は、関節痛、腰痛又は肩こり痛の鎮痛という消費者に分かりやすい効能効果を有するメロキシカム含有製剤を、１日１回、１投与単位のみ服用するという簡便な用法用量で使用することができる。 The over-the-counter drug of the present invention is a meloxicam-containing preparation that has an effect and effect that is easy for consumers to understand, such as pain relief for arthralgia, low back pain, or stiff shoulder pain, and is used in a simple dosage and administration of taking only one dosage unit once a day. can do.
本発明の有効成分であるメロキシカム（一般名）は、化学名：４－ｈｙｄｒｏｘｙ－２－ｍｅｔｈｙｌ－Ｎ－（５－ｍｅｔｈｙｌ－２－ｔｈｉａｚｏｌｙｌ）－２Ｈ－１，２－ｂｅｎｚｏｔｈｉａｚｉｎｅ－３－ｃａｒｂｏｘａｍｉｄｅ－１，１－ｄｉｏｘｉｄｅ、分子式：Ｃ14Ｈ13Ｎ3Ｏ4Ｓ2のＮＳＡＩＤｓである。
メロキシカム含有医療用医薬品では「関節リウマチ、変形性関節症、腰痛症、肩関節周囲炎、頸肩腕症候群の疾患並びに症状の消炎・鎮痛」を効能効果とするが、医師の疾患の観察が必要な関節リウマチが含まれ、一般用医薬品としての有用性を正しく評価できないと考えられた。そこで、慢性関節リウマチ患者を除く、変形性膝関節症、腰痛症、肩関節周囲炎及び頸肩腕症候群の患者を対象とした医療用医薬品の第III相試験における臨床試験結果（後述の試験例１）から、一般用医薬品としての有効性及び安全性を検討した。
その結果、メロキシカムは、１０ｍｇ含有製剤の１日１回投与で、変形性膝関節症、腰痛症、肩関節周囲炎及び頸肩腕症候群に対して優れた鎮痛作用を示し、安全性も有することが明らかとなった。
Meloxicam (common name), the active ingredient of the present invention, has the chemical name: 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1 , 1-dioxide, molecular formula: C 14 H 13 N 3 O 4 S 2 .
Ethical drugs containing meloxicam are indicated for "anti-inflammatory and pain relief of diseases and symptoms of rheumatoid arthritis, osteoarthritis, lumbago, shoulder periarthritis, cervico-omo-brachial syndrome", but the disease must be observed by a doctor. Rheumatoid arthritis was included, and it was thought that the usefulness as an over-the-counter drug could not be evaluated correctly. Therefore, except for patients with rheumatoid arthritis, clinical trial results in phase III trials of ethical drugs for patients with knee osteoarthritis, low back pain, shoulder periarthritis and cervico-omo-brachial syndrome (Test Example 1 described later) ), the efficacy and safety as an over-the-counter drug were investigated.
As a result, once-daily administration of a formulation containing 10 mg of meloxicam showed excellent analgesic effects on osteoarthritis of the knee, low back pain, shoulder periarthritis, and cervico-omo-brachial syndrome, and was also safe. It became clear.
一方で、一般用医薬品ではイブプロフェンやロキソプロフェンナトリウムなどのＮＳＡＩＤｓの経口剤の効能効果は、一般用医薬品の製造販売承認基準の解熱鎮痛薬の効能効果と同じであり、「頭痛・月経痛（生理痛）・歯痛・抜歯後の疼痛・咽喉痛・腰痛・関節痛・神経痛・筋肉痛・肩こり痛・耳痛・打撲痛・骨折痛・ねんざ痛・外傷痛の鎮痛」「悪寒・発熱時の解熱」と多岐に渡っているため、これらの効能効果の一部はメロキシカムの医療用の処方実態と合致しない。
そこで、本発明者らは、鋭意検討した結果、メロキシカムの一般用医薬品の効能効果としては、解熱鎮痛薬の製造販売承認基準に記載の効能効果ではなく、「関節痛、腰痛、肩こり痛の鎮痛」とさらに対象を絞ったほうが、安全に有効的に効能効果を発現し得ると判断した。
従って、本発明は、１経口投与単位製剤にメロキシカム１０ｍｇを含有する一般用医薬品であり、その効能効果は「関節痛、腰痛、肩こり痛の鎮痛」とするのが好ましい。
ここで、１経口投与単位製剤とは、経口投与用の１投与単位製剤を意味し、錠剤であれば１錠であり、カプセルであれば１カプセルであり、分包剤であれば１分包剤を意味する。従って、本発明の一般用医薬品は、錠剤であれば、１錠中にメロキシカムを１０ｍｇ含有する錠剤であり、カプセル剤であれば１カプセル中にメロキシカムを１０ｍｇ含有するカプセル剤であり、分包剤であれば、１分包剤中にメロキシカムを１０ｍｇ含有する分包剤である。
On the other hand, among over-the-counter drugs, the efficacy and effects of oral NSAIDs such as ibuprofen and loxoprofen sodium are the same as those of antipyretic analgesics in the manufacturing and marketing approval standards for over-the-counter drugs. ), pain after tooth extraction, sore throat, back pain, arthralgia, neuralgia, muscle pain, stiff shoulder pain, earache, bruise pain, fracture pain, sprain pain, trauma pain relief, and fever relief during chills and fever , some of these indications do not match the actual medical prescription of meloxicam.
Therefore, as a result of intensive studies, the present inventors found that the efficacy and effect of meloxicam over-the-counter drugs is not the efficacy and effect described in the manufacturing and marketing approval standards for antipyretic analgesics, but "pain relief for arthralgia, lumbago, and stiff shoulder pain. It was judged that further narrowing down the target would allow safe and effective effects to be expressed.
Therefore, the present invention is an over-the-counter drug containing 10 mg of meloxicam in one oral dosage unit preparation, and its efficacy is preferably "pain relief for arthralgia, lumbago and stiff shoulder pain".
Here, 1 oral dosage unit preparation means 1 dosage unit preparation for oral administration, and if it is a tablet, it is 1 tablet, if it is a capsule, it is 1 capsule, and if it is a divided package, it is 1 package. means drug. Therefore, if the over-the-counter drug of the present invention is a tablet, it is a tablet containing 10 mg of meloxicam per tablet, and if it is a capsule, it is a capsule containing 10 mg of meloxicam per capsule. Then, it is a sachet containing 10 mg of meloxicam per sachet.
メロキシカムの医療用医薬の用法・用量は、「通常、成人にはメロキシカムとして１０ｍｇを１日１回食後に経口投与する。なお、年齢、症状により適宜増減するが、１日最高用量は１５ｍｇとする。」と記載され、用法は１日１回食後服用で分りやすいが、１回の用量は、メロキシカムとして５～１５ｍｇの範囲で疾患の状態に合わせて処方されてきた。
しかしながら、一般用医薬品として１回の容量を適宜増減するのは困難と考え、２０１０年（平成２２年）～２０１９年（令和元年）の関節リウマチ患者を除く適応症の外来患者における医療用医薬のメロキシカム製剤の処方実態（１回用量別処方件数）を調査した（試験例２）。
１回用量別にみると、1回１０ｍｇが最も多く、全処方件数の９割以上を占め、次いで１回５ｍｇが約２～５％とその割合は少なかった（表１０）。同様に、１日用量別にみても１日１０ｍｇが毎年９割以上であったことが確認された（表１１）。これらの結果から、１０ｍｇでの処方が大部分である結果となり、１０ｍｇに固定することが一般用医薬品として最適であると考えられた。
さらに、本発明者らは、成人の具体的な年齢も具体的に記した方が明確になると考えた。すなわち、本発明は、１経口投与単位製剤にメロキシカム１０ｍｇを含有する一般用医薬品であり、その用法用量が「１５歳以上の成人にメロキシカム１０ｍｇを、１日１回、毎回同じ時間帯に食後に服用する」一般用医薬品であるのがより好ましい。
The dosage and administration of meloxicam is as follows: "Generally, for adults, 10 mg of meloxicam is orally administered once a day after a meal. The dose may be adjusted according to age and symptoms, but the maximum daily dose is 15 mg. The dosage is easy to understand as it is taken once a day after meals, but the dose range of 5 to 15 mg as meloxicam per dose has been prescribed according to the condition of the disease.
However, it is considered difficult to appropriately increase or decrease the dosage as an over-the-counter drug. A survey was conducted on the actual prescription of meloxicam preparations (the number of prescriptions by dosage) (Test Example 2).
By dosage, 10 mg was the most common, accounting for more than 90% of all prescriptions, followed by 5 mg at a low rate of about 2-5% (Table 10). Similarly, it was confirmed that 10 mg per day accounted for more than 90% every year (Table 11). Based on these results, the majority of prescriptions were at 10 mg, and it was considered that a fixed dose of 10 mg would be optimal as an over-the-counter drug.
Furthermore, the present inventors thought that it would be clearer to specifically describe the specific age of an adult. That is, the present invention is an over-the-counter drug containing 10 mg of meloxicam in one oral dosage unit preparation, and the dosage and administration is "10 mg of meloxicam for adults aged 15 years or older, once a day at the same time each time after meals. More preferably, it is an over-the-counter drug.
医療用医薬品では１回の用量は、メロキシカムとして５～１５ｍｇの範囲で疾患の状態に合わせて処方される。そこで、本邦では、メロキシカム１０ｍｇを含有する割線入り裸錠及び速崩錠、メロキシカム５ｍｇを含有する割線入りの速崩錠、メロキシカム５ｍｇを含有する割線無しの裸錠が市場に供され汎用されている。これらの医療用医薬品は、分割できるように設計され、５～１５ｍｇの範囲で容量を様々な組み合わせで調節できる為、医療用医薬品としては、利便性が高く、対応性も広い。しかしながら、用量が異なる製剤が存在し、さらに分割などで用量が調節できる製剤は、過剰投与或いは過少投与になる恐れがあり、安全性や有効性からも一般用医薬品としては相応しくないと考えられる。そこで、本発明者らは鋭意検討した結果、投与単位製剤にメロキシカム１０ｍｇを含有する分割できない製剤とすることでこの問題を解決できることを見出した。
すなわち、本発明は、１経口投与単位製剤にメロキシカム１０ｍｇを含有する分割できない製剤である一般用医薬品であるのが好ましい。
A single dose of meloxicam is prescribed in the range of 5 to 15 mg as meloxicam according to the condition of the disease. Therefore, in Japan, scored unscored tablets and fast-disintegrating tablets containing 10 mg of meloxicam, scored fast-disintegrating tablets containing 5 mg of meloxicam, and non-scored unscored tablets containing 5 mg of meloxicam are marketed and widely used. . These ethical drugs are designed so that they can be divided, and the dose can be adjusted in various combinations within the range of 5 to 15 mg. However, there are formulations with different dosages, and formulations that can be adjusted by dividing the dosage, etc., may result in over- or under-dosage, and are considered unsuitable as over-the-counter drugs in terms of safety and efficacy. As a result of intensive studies, the present inventors have found that this problem can be solved by an indivisible formulation containing 10 mg of meloxicam in a dosage unit formulation.
Thus, the present invention is preferably an over-the-counter drug that is an indivisible formulation containing 10 mg of meloxicam in one oral dosage unit formulation.
本発明の製剤の剤形としては、第十七改正日本薬局方の製剤総則の経口投与に適応する製剤であれば適用でき、１経口投与単位製剤にメロキシカム１０ｍｇを含有する製剤であればよい。例えば、１経口投与単位製剤としては、錠剤、硬カプセル剤、軟カプセル剤、分包液剤、分包顆粒剤を例示することができ、それぞれ、１経口投与単位製剤、例えば、１錠、１カプセル、１分包中にメロキシカム１０ｍｇを含有させることにより、本発明の一般用医薬品とするのが好ましい。 The dosage form of the preparation of the present invention is applicable as long as it is compatible with oral administration in the General Rules for Preparations of the 17th Edition of the Japanese Pharmacopoeia, and may be a preparation containing 10 mg of meloxicam per oral dosage unit preparation. For example, 1 oral dosage unit formulation includes tablets, hard capsules, soft capsules, divided liquid formulations, and divided granules, and 1 oral dosage unit formulation, for example, 1 tablet and 1 capsule, respectively. , 10 mg of meloxicam is preferably contained in one sachet to make the over-the-counter drug of the present invention.
また、医療用医薬品のメロキシカムは、毒薬劇薬指定基準で「劇薬」に分類されている。「劇薬は経口致死量が３００ｍｇ／ｋｇ（体重）以下のもの」に該当し、「毒薬」より毒性は低いものの、危険な医薬品とされ、他の医薬品と区別し、厳重に管理することが求められる。そのため、「劇薬」である医療用医薬品のメロキシカムはそのままでは、一般用医薬品として販売することはできなかった。
この問題に対し、本発明者らは、鋭意研究を行ったところ、医療用医薬品のメロキシカムの「劇薬」指定は、メロキシカム原薬に基づくものであり、賦形剤などで原薬が希釈された製剤は、該当しない可能性が出てきた。そこで、医療用医薬品のメロキシカムの初回申請時の単回経口投与毒性試験で感受性の高かったラットを用いて、医療用として市販されているメロキシカム１０ｍｇ錠（質量１８０ｍｇ／錠）を用いた単回経口投与による毒性試験を実施した（試験例３）。
その結果、製剤での概略の致死量は、雄で１０００ｍｇ／ｋｇ、雌で１０００ｍｇ／ｋｇを超える量であり、概略の致死量が毒薬劇薬指定基準を上回っていることが確認された。この結果から、メロキシカム１０ｍｇを含む製剤の質量が１８０ｍｇ以上であれば、劇薬指定の見直しを行え、一般用医薬品として販売することができることがわかった。
すなわち、本発明は、メロキシカム１０ｍｇを含む単位投与製剤の質量が１８０ｍｇ以上である一般用医薬品であり、毒薬劇薬指定基準で「劇薬」に分類されない一般用医薬品であるのが好ましい。
このメロキシカム１０ｍｇを含む単位投与製剤の質量が１８０ｍｇ以上である一般用医薬品のうち、当該製剤の質量は、１８０ｍｇ以上５００ｍｇ以下がより好ましく、１８０ｍｇ以上３００ｍｇ以下がさらに好ましく、１８０ｍｇ以上２５０ｍｇ以下がさらに好ましく、１８０ｍｇがよりさらに好ましい。
１８０ｍｇ以上の製剤中には、メロキシカム１０ｍｇ以外に、可溶剤、賦形剤、結合剤、崩壊剤及び滑沢剤から選ばれる１種又は２種以上が含まれる。この製剤は、製剤全質量に対し、可溶剤を１～２５質量％、賦形剤を５０～９５質量％、結合剤を０．５～１０質量％、崩壊剤を０．１～５質量％、滑沢剤を０．１～３質量％含有する錠剤であるのが好ましい。
In addition, meloxicam, an ethical drug, is classified as a "dangerous drug" under the Poisonous and Deleterious Drug Designation Standards. "Powerful drugs are those with an oral lethal dose of 300 mg/kg (body weight) or less," and although they are less toxic than "poisonous drugs," they are regarded as dangerous drugs, and must be distinguished from other drugs and strictly managed. be done. Therefore, the ethical meloxicam, which is a powerful drug, could not be sold as an over-the-counter drug.
In response to this problem, the present inventors conducted intensive research and found that the designation of meloxicam as a "dangerous drug" for ethical drugs is based on the drug substance of meloxicam, which was diluted with excipients and the like. There is a possibility that the formulation may not be applicable. Therefore, using rats that were highly sensitive in the single oral dose toxicity test at the time of the initial application for meloxicam, a ethical drug, a single oral dose using meloxicam 10 mg tablets (mass 180 mg / tablet) commercially available for medical use A toxicity test by administration was carried out (Test Example 3).
As a result, the approximate lethal dose of the preparation was 1000 mg/kg for males and more than 1000 mg/kg for females, and it was confirmed that the approximate lethal dose exceeded the poison and powerful drug designation criteria. From this result, it was found that if the mass of the formulation containing 10 mg of meloxicam is 180 mg or more, the powerful drug designation can be reviewed and it can be sold as an over-the-counter drug.
That is, the present invention is an over-the-counter drug in which the mass of a unit dosage formulation containing 10 mg of meloxicam is 180 mg or more, and is preferably an over-the-counter drug that is not classified as a "dangerous drug" according to the poison and powerful drug designation standards.
Among over-the-counter drugs in which the mass of a unit dosage formulation containing 10 mg of meloxicam is 180 mg or more, the mass of the formulation is more preferably 180 mg or more and 500 mg or less, more preferably 180 mg or more and 300 mg or less, and even more preferably 180 mg or more and 250 mg or less. , 180 mg is even more preferred.
A preparation of 180 mg or more contains, in addition to 10 mg of meloxicam, one or more selected from solubilizers, excipients, binders, disintegrants and lubricants. This formulation contains 1 to 25% by mass of soluble solvent, 50 to 95% by mass of excipient, 0.5 to 10% by mass of binder, and 0.1 to 5% by mass of disintegrant based on the total mass of the formulation. , preferably a tablet containing 0.1 to 3% by mass of a lubricant.
医療用医薬品のメロキシカムは、調剤薬局での調剤のし易さ、在庫管理のし易さなどから、１００錠（１０錠×１０）ＰＴＰ単位、或いは７００錠（１４錠×５０）ＰＴＰ単位で紙箱に包装され、そこから、調剤され、患者に提供されている。
しかし、一般用医薬品としては、万全と長期間にわたり服用することは安全性や疾患の管理の点からも好ましいことではない。このことを防止する手段としては、薬局で販売される一包装単位に含まれる製剤の数を工夫することが重要であると考えられた。本発明者らが鋭意研究調査したところ、医療用では投与１週間目で十分な鎮痛効果が表れ、過去５年間の処方日数を調査した結果は、図１の様であった（試験例４）。
このことから、一般用医薬品として、安全性と有効性を最大限に発揮するには、１包装単位が２４日分以下であればよく、さらに１２日分以下であることが望ましく、７日分以下であることがさらに望ましいことがわかった。
すなわち、本発明は、１包装単位が２４日分以下であり、好ましくは１２日分以下であり、さらに好ましくは７日分以下であるメロキシカムを含有する一般用医薬品であるのが好ましい。
Meloxicam, an ethical drug, is packed in paper boxes in units of 100 tablets (10 tablets x 10) or 700 tablets (14 tablets x 50) in PTP units because of ease of dispensing and inventory management at dispensing pharmacies. from where it is dispensed and provided to patients.
However, as an over-the-counter drug, taking all possible measures for a long period of time is not preferable from the viewpoint of safety and disease management. As a means to prevent this, it is considered important to devise the number of formulations contained in one package unit sold at pharmacies. As a result of intensive research and investigation by the present inventors, sufficient analgesic effect appeared in the first week of administration for medical use, and the results of investigating the number of prescription days over the past 5 years were as shown in Fig. 1 (Test Example 4). .
From this, in order to maximize safety and efficacy as an over-the-counter drug, one packaging unit should be 24 days or less, preferably 12 days or less, and 7 days. It has been found that the following is more desirable.
That is, the present invention is preferably an over-the-counter drug containing meloxicam in which one package unit is for 24 days or less, preferably for 12 days or less, and more preferably for 7 days or less.
次に実施例を挙げて本発明をさらに詳細に説明するが、本発明はこれら実施例に何ら限定されるものではない。 EXAMPLES Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
試験例１
慢性関節リウマチ患者を除く、変形性膝関節症、腰痛症、肩関節周囲炎及び頸肩腕症候群の患者を対象とした医療用医薬品の第III相試験における臨床試験結果から、メロキシカムの一般用医薬品としての有効性及び安全性を検討した。
Test example 1
Meloxicam has been approved as an over-the-counter (OTC) drug based on the results of a phase III clinical trial of an ethical drug in patients with knee osteoarthritis, low back pain, shoulder periarthritis, and cervico-omo-brachial syndrome, excluding patients with rheumatoid arthritis. We investigated the efficacy and safety of
（１）変形性膝関節症
変形性膝関節症に対する最終全般改善度の検討結果を表１に、概括安全度を表２に、有用度を表３に示した。メロキシカム１０ｍｇ（１日１回）又はジクロフェナクナトリウム２５ｍｇ（１日３回）を４週間投与した二重盲検群間比較法の結果である。
最終全般改善度は、「中等度改善」以上の患者の割合はメロキシカム群で６９．７％、ジクロフェナクナトリウム群で６４．６％であり、メロキシカム群はジクロフェナクナトリウム群と同等の有効性を有していた。概括安全度では、メロキシカム群はジクロフェナクナトリウム群に比し、有意に優れており、「安全」の患者の割合はメロキシカム群で７７．５％、ジクロフェナクナトリウム群で６１．７％であった。有用度では、メロキシカム群はジクロフェナクナトリウム群に比し有意に優れており、「有用」以上の患者の割合は、メロキシカム群で５６．０％、ジクロフェナクナトリウム群で４４．９％であった。
(1) Knee osteoarthritis Table 1 shows the results of the examination of the final overall improvement in knee osteoarthritis, Table 2 shows the overall safety, and Table 3 shows the usefulness. Results of a double-blind between-group comparison of meloxicam 10 mg (once daily) or
The percentage of patients with a final overall improvement of "moderate improvement" or better was 69.7% in the meloxicam group and 64.6% in the diclofenac sodium group. was In terms of overall safety, the meloxicam group was significantly superior to the diclofenac sodium group, and the percentage of patients who were "safe" was 77.5% in the meloxicam group and 61.7% in the diclofenac sodium group. In terms of usefulness, the meloxicam group was significantly superior to the diclofenac sodium group.
（２）腰痛症、肩関節周囲炎及び頸肩腕症候群
腰痛症、肩関節周囲炎及び頸肩腕症候群の患者を対象に二重盲検群間比較法により、メロキシカム１０ｍｇ（１日１回）又はインドメタシン２５ｍｇ（１日３回）を４週間投与し、有効性及び安全性を検討した。最終全般改善度の検討結果を表４に、概括安全度を表５に、有用度を表６に示した。
３疾患全体の全般改善度では、メロキシカム群がインドメタシン群に比し有意に優れ、「中等度改善」以上の患者の割合はメロキシカム群で７７．７％、インドメタシン群で６１．２％であった。また、３疾患別では、頸肩腕症候群でメロキシカム群がインドメタシン群に比し有意に優れていた。なお、腰痛症、肩関節周囲炎及び頸肩腕症候群の「中等度改善」以上の患者の割合は、メロキシカム群でそれぞれ８７．８％、６２．９％、８０．６％、インドメタシン群でそれぞれ７４．５％、５０．０％、５７．５％であり、腰痛症、肩関節周囲炎でもメロキシカム群はインドメタシン群と同等の有効性を有することが示された。概括安全度では、両群間に有意差は認められなかった。「安全性に問題なし」の患者の割合は、メロキシカム群で６８．８％、インドメタシン群で５８．２％であり、メロキシカム群の安全性はインドメタシン群と同等であった。有用度では、メロキシカム群がインドメタシン群に比し有意に優れており、「有用」以上の患者の割合はメロキシカム群で６２．８％、インドメタシン群で５０．５％であった。
(2) Low back pain, scapulohumeral periarthritis and cervico-omo-brachial syndrome By a double-blind comparison method for patients with low back pain, scapulohumeral periarthritis and cervico-omo-brachial syndrome, meloxicam 10 mg (once a day) or
The meloxicam group was significantly superior to the indomethacin group in terms of overall improvement in all three diseases, and the percentage of patients who achieved "moderate improvement" or better was 77.7% in the meloxicam group and 61.2% in the indomethacin group. . In addition, the meloxicam group was significantly superior to the indomethacin group in cervico-omo-brachial syndrome. The percentage of patients with "moderate improvement" or higher in low back pain, shoulder periarthritis and cervico-omo-brachial syndrome was 87.8%, 62.9% and 80.6% in the meloxicam group, respectively, and 74 in the indomethacin group. 0.5%, 50.0%, and 57.5%, indicating that the meloxicam group had efficacy equivalent to that of the indomethacin group for low back pain and shoulder periarthritis. There was no significant difference between the two groups in general safety. The percentage of patients with "no problems with safety" was 68.8% in the meloxicam group and 58.2% in the indomethacin group, and the safety of the meloxicam group was comparable to that of the indomethacin group. In terms of usefulness, the meloxicam group was significantly superior to the indomethacin group.
（３）一般臨床試験
腰痛症、肩関節周囲炎及び頸肩腕症候群の患者について、第III相一般臨床試験により、メロキシカム１０又は１５ｍｇ、１日１回を４週間投与し、有効性及び安全性を検討した。症状改善度を表７に、概括安全度を表８に、有用度を表９に示した。
全般改善度の「中等度改善」以上の患者の割合は、３疾患全体で７５．０％、腰痛症で７６．５％、肩関節周囲炎で６８．２％、頸肩腕症候群で８２．４％であった。概括安全度では「安全性に問題なし」の割合は８０．７％であった。「有用」以上の割合は３疾患全体で６９．１％、腰痛症で７６．５％、肩関節周囲炎で５７．１％、頸肩腕症候群で７６．５％であった。概括安全度では「安全性に問題なし」の割合は８０．７％であった。「有用」以上の割合は３疾患全体で６９．１％、腰痛症で７６．５％、肩関節周囲炎で５７．１％、頸肩腕症候群で７６．５％（１３／１７例）であった。
(3) General clinical study A phase III general clinical study was conducted on patients with low back pain, shoulder periarthritis, and cervico-omo-brachial syndrome. investigated. Table 7 shows symptom improvement, Table 8 shows general safety, and Table 9 shows usefulness.
The percentage of patients with "moderate improvement" or higher in the general improvement rate was 75.0% for all three diseases, 76.5% for low back pain, 68.2% for shoulder periarthritis, and 82.4 for cervico-omo-brachial syndrome. %Met. In terms of overall safety, 80.7% responded that there were no problems with safety. The rate of "useful" or higher was 69.1% for all three diseases, 76.5% for low back pain, 57.1% for shoulder periarthritis, and 76.5% for cervico-omo-brachial syndrome. In terms of overall safety, 80.7% responded that there were no problems with safety. The rate of “useful” or better was 69.1% for all three diseases, 76.5% for low back pain, 57.1% for shoulder periarthritis, and 76.5% (13/17 cases) for cervico-omo-brachial syndrome. rice field.
以上の結果から、一般用医薬品に転用した場合もメロキシカムの有効性・安全性は非常に優れていることが明らかになった。 From the above results, it was clarified that meloxicam has excellent efficacy and safety even when it is converted to over-the-counter drugs.
試験例２
２０１０年（平成２２年）～２０１９年（令和元年）の関節リウマチ患者を除く適応症の外来患者における医療用医薬のメロキシカム製剤の処方実態：１回用量別処方件数を調査した。結果を表１０及び表１１に示す。
1回用量別にみると、１回１０ｍｇが最も多く、全処方件数の９割以上を占め、次いで１回５ｍｇが約２～５％とその割合は少なかった（表1０）。同様に、１日用量別にみても１日１０ｍｇが毎年９割以上であったことが確認された（表１１）。これらの結果から、１０ｍｇでの処方が大部分である結果となり、１０ｍｇに固定することが一般用医薬品として最適であると考えられた。
Test example 2
2010 (Heisei 22) to 2019 (Reiwa 1) actual prescription of meloxicam formulations of ethical drugs in outpatients with indications other than rheumatoid arthritis patients: The number of prescriptions by single dose was investigated. The results are shown in Tables 10 and 11.
By dosage, 10 mg was the most common, accounting for more than 90% of all prescriptions, followed by 5 mg at a low rate of about 2-5% (Table 10). Similarly, it was confirmed that 10 mg per day accounted for more than 90% every year (Table 11). Based on these results, the majority of prescriptions were at 10 mg, and it was considered that a fixed dose of 10 mg would be optimal as an over-the-counter drug.
試験例３
医療用医薬品のメロキシカムの初回申請時の単回経口投与毒性試験で感受性の高かったラットを用いて、医療用として市販されているメロキシカム１０ｍｇ錠（質量１８０ｍｇ／錠）を用いた単回経口投与による毒性試験を実施した。その結果を表１２に示す。
３００ｍｇ／ｋｇ群では、死亡や瀕死はみられず、観察期間中の一般状態、体重及び剖検において被験物質に起因した変化はみられなかった。１０００ｍｇ／ｋｇ群の雄で消化管障害作用に起因する瀕死がみられた。製剤での概略の致死量は、雄で１０００ｍｇ／ｋｇ、雌で１０００ｍｇ／ｋｇを超える量であり、概略の致死量が毒薬劇薬指定基準を上回っていることが確認された。この結果から、メロキシカム１０ｍｇを含む製剤の質量が１８０ｍｇ以上であれば、劇薬指定の見直しを行え、一般用医薬品として販売することはできることがわかった。
Test example 3
A single oral dose of meloxicam 10mg tablets (mass 180mg/tablet) marketed for medical use in rats that were highly susceptible in the single oral dose toxicity test at the time of the initial application for meloxicam, a ethical drug. A toxicity test was performed. The results are shown in Table 12.
In the 300 mg/kg group, no death or moribundity was observed, and no test substance-related changes were observed in general condition, body weight, or autopsy during the observation period. Moribundity due to gastrointestinal disturbances was observed in males in the 1000 mg/kg group. The approximate lethal dose of the preparation was 1000 mg/kg for males and over 1000 mg/kg for females, and it was confirmed that the approximate lethal dose exceeded the criteria for poisonous and powerful drug designation. From this result, it was found that if the mass of the formulation containing 10 mg of meloxicam is 180 mg or more, the powerful drug designation can be reviewed and it can be sold as an over-the-counter drug.
試験例４
過去５年間のメロキシカム含有医療用医薬品の処方日数を調査した結果を図１に示す。図１から、メロキシカム含有医療用医薬品は、投与１週間目で十分な鎮痛効果が表れていることがわかった。
このことから、一般用医薬品として、安全性と有効性を最大限に発揮するには、１包装単位が２４日分以下であればよく、さらに１２日分以下であることが望ましく、７日分以下であることが極めて望ましいことがわかった。
Test example 4
Fig. 1 shows the results of a survey on the number of prescription days for prescription drugs containing meloxicam over the past five years. From FIG. 1, it was found that meloxicam-containing medicaments exhibited a sufficient analgesic effect in the first week of administration.
From this, in order to maximize safety and efficacy as an over-the-counter drug, one packaging unit should be 24 days or less, preferably 12 days or less, and 7 days. It has been found to be highly desirable that:
製造例１
メロキシカム５０ｇ、クエン酸ナトリウム水和物１００ｇ、乳糖水和物４４５ｇ、トウモロコシデンプン９０ｇ、結晶セルロース１７０ｇ、ヒドロキシプロピルセルロース２５ｇ、クロスポビドン１５ｇ、ステアリン酸マグネシウム５ｇを含有する打錠用粉末を常法により製した。次に、割線のない直径８ｍｍの平型の臼杵とロータリー打錠機（ＶＩＲＧ０５１２Ｍ：菊水製作所社製）にて１錠１８０ｍｇになるように１８ｋＰａ～２２ｋＰａの圧力で圧縮成形を行い、平型円形錠として本発明のメロキシカム１０ｍｇを含有する分割線のない錠剤を得た。
Production example 1
A tableting powder containing 50 g of meloxicam, 100 g of sodium citrate hydrate, 445 g of lactose hydrate, 90 g of corn starch, 170 g of crystalline cellulose, 25 g of hydroxypropyl cellulose, 15 g of crospovidone and 5 g of magnesium stearate was prepared by a conventional method. bottom. Next, compression molding is performed at a pressure of 18 kPa to 22 kPa so that each tablet is 180 mg using a flat mortar with a diameter of 8 mm without a score line and a rotary tableting machine (VIRG0512M: manufactured by Kikusui Seisakusho Co., Ltd.) to form flat round tablets. was obtained as a tablet without a split line containing 10 mg of meloxicam of the present invention.
Claims (7)
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