JP5885972B2 - Pharmaceutical composition containing a PDE5 inhibitor - Google Patents
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- JP5885972B2 JP5885972B2 JP2011196861A JP2011196861A JP5885972B2 JP 5885972 B2 JP5885972 B2 JP 5885972B2 JP 2011196861 A JP2011196861 A JP 2011196861A JP 2011196861 A JP2011196861 A JP 2011196861A JP 5885972 B2 JP5885972 B2 JP 5885972B2
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 26
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 title description 29
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 title description 29
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 68
- 229960003080 taurine Drugs 0.000 claims description 33
- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 claims description 19
- 230000018052 penile erection Effects 0.000 claims description 18
- 229960002639 sildenafil citrate Drugs 0.000 claims description 17
- 230000000694 effects Effects 0.000 claims description 10
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 8
- 201000001881 impotence Diseases 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 3
- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Natural products CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 15
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 12
- 230000009471 action Effects 0.000 description 11
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 10
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 10
- 230000004064 dysfunction Effects 0.000 description 9
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 6
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 6
- 229960003310 sildenafil Drugs 0.000 description 6
- 210000005226 corpus cavernosum Anatomy 0.000 description 5
- 229960000438 udenafil Drugs 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 229960000835 tadalafil Drugs 0.000 description 4
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 4
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 description 4
- FBCDRHDULQYRTB-UHFFFAOYSA-N 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1h-imidazo[5,1-f][1,2,4]triazin-4-one;trihydrate;hydrochloride Chemical compound O.O.O.Cl.CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 FBCDRHDULQYRTB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102000006538 Nitric Oxide Synthase Type I Human genes 0.000 description 3
- 108010008858 Nitric Oxide Synthase Type I Proteins 0.000 description 3
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- 238000000034 method Methods 0.000 description 3
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- 229960001540 vardenafil hydrochloride Drugs 0.000 description 3
- 229940094720 viagra Drugs 0.000 description 3
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 108010078321 Guanylate Cyclase Proteins 0.000 description 2
- 102000014469 Guanylate cyclase Human genes 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- 230000001856 erectile effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000003908 liver function Effects 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
- 239000000203 mixture Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010023129 Jaundice cholestatic Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 201000005267 Obstructive Jaundice Diseases 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- YWXYYJSYQOXTPL-JGWLITMVSA-N [(3r,3ar,6s,6as)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-JGWLITMVSA-N 0.000 description 1
- 239000002160 alpha blocker Substances 0.000 description 1
- 229940124308 alpha-adrenoreceptor antagonist Drugs 0.000 description 1
- 229960003116 amyl nitrite Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 208000027119 bilirubin metabolic disease Diseases 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
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- 230000003222 cGMP degradation Effects 0.000 description 1
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- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 208000036796 hyperbilirubinemia Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002840 nitric oxide donor Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 210000005164 penile vein Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
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- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
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Description
本発明は、ホスホジエステラーゼ５阻害剤とタウリンを含有する、主として陰茎***機能不全治療用又は改善用医薬組成物に関する。 The present invention relates to a pharmaceutical composition mainly for treating or improving penile erection dysfunction, comprising a phosphodiesterase 5 inhibitor and taurine.
ホスホジエステラーゼ（以下、ＰＤＥと称す）はサイクリックＡＭＰ（以下、ｃＡＭＰと称す）やサイクリックＧＭＰ（以下、ｃＧＭＰと称す）のリン酸エステルを加水分解する酵素であり、これまでに１１種のＰＤＥが存在することが判っている。細胞の機能が損なわれた状態では多くの場合、ＰＤＥ活性が亢進しており、結果的にｃＧＭＰやｃＡＭＰが不足した状態になることが推定され、ＰＤＥを阻害する薬剤はこれらを増加させるのに有用である。 Phosphodiesterase (hereinafter referred to as PDE) is an enzyme that hydrolyzes cyclic AMP (hereinafter referred to as cAMP) and cyclic GMP (hereinafter referred to as cGMP) phosphate esters. I know it exists. In many cases, the PDE activity is increased in the state in which the cell function is impaired, and it is estimated that cGMP and cAMP are deficient as a result, and drugs that inhibit PDE increase these. Useful.
ＰＤＥの１種であるＰＤＥ５については陰茎海綿体や肺組織に豊富に存在する酵素であり、陰茎***に関与することが知られている。***の機序は、これまでの公知文献を統合すると、以下のように説明できる。 PDE5, which is a kind of PDE, is an enzyme that is abundant in the corpus cavernosum and lung tissue, and is known to be involved in penile erection. The mechanism of erection can be explained as follows by integrating the known literatures so far.
性的刺激により、陰茎海綿体にある末梢神経の神経型一酸化窒素合成酵素（ｎＮＯＳ）によって生成した一酸化窒素（ＮＯ）が、陰茎海綿体のグアニル酸シクラーゼを活性化してｃＧＭＰが合成される。ｃＧＭＰ濃度上昇とともに陰茎海綿体の平滑筋が弛緩して陰茎動脈から血液が流入してくる。陰茎海綿体への血液流入により陰茎体積・寸法の増大と、内圧上昇による陰茎硬化が惹起される。これに伴い陰茎静脈が圧迫されるようになり陰茎海綿体からの血液流出も抑制され、***が完結する。その後、***の完了又は性的刺激の減弱によってＮＯ供給が途絶えてくると、陰茎海綿体に存在するＰＤＥ５によりｃＧＭＰが分解され、陰茎動脈からの血液流入が止まり、やがて***前の状態に戻る。 By sexual stimulation, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) in peripheral nerves in the penile cavernous body activates guanylate cyclase in the penile cavernous body to synthesize cGMP. . As the cGMP concentration rises, the smooth muscle of the cavernous cavernous body relaxes and blood flows from the penile artery. The blood inflow into the penile cavernous body causes an increase in penis volume and size, and penile hardening due to an increase in internal pressure. As a result, the penile veins are compressed, blood outflow from the cavernous corpus cavernosum is suppressed, and the erection is completed. Thereafter, when the supply of NO is interrupted due to completion of ejaculation or attenuation of sexual stimulation, cGMP is decomposed by PDE5 present in the cavernous corpus cavernosum, blood inflow from the penile artery is stopped, and the state before the erection is eventually restored.
ストレス等による交感神経の緊張による陰茎動脈収縮による海綿体血液流入の遮断、ｎＮＯＳの活性低下、グアニル酸シクラーゼ活性の低下、ＰＤＥ５活性の亢進、等のいずれか又はこれらが複合して起こると、陰茎が***しなかったり、***しても持続しなかったりして、***が行えなくなる。このような病態を***不全、***機能障害あるいは***障害と言うが、心理的な配慮から、最近では、英名Erectile Dysfunctionの略名表示である「ＥＤ」が広く用いられるようになってきた。 When any of these, or a combination of these, such as blockage of cavernous blood inflow due to penile artery contraction due to sympathetic nerve tension due to stress, decrease in nNOS activity, decrease in guanylate cyclase activity, increase in PDE5 activity, etc. Does not erection or does not continue even if erection, sexual intercourse can not be done. Such a pathological condition is called erectile dysfunction, erectile dysfunction, or erectile dysfunction, but recently "ED", which is an abbreviation for the English name Erectile Dysfunction, has been widely used due to psychological considerations.
近年、ＰＤＥ５阻害剤が見いだされ、ＥＤ治療に革命がもたらされた。これは、陰茎海綿体のｃＧＭＰ分解酵素であるＰＤＥ５の活性を阻害し、陰茎の末梢ＮＯ神経によってもたらされる陰茎海綿体内のｃＧＭＰ量を維持・増大させ、陰茎海綿体内圧上昇（***）状態を持続させるものである（例えば、非特許文献１参照）。ＰＤＥ５阻害剤がＥＤに悩む患者の大部分を救った。 In recent years, PDE5 inhibitors have been found and revolutionized ED treatment. This inhibits the activity of PDE5, a cGMP-degrading enzyme in the corpus cavernosum, maintains and increases the amount of cGMP in the corpus cavernosum caused by peripheral NO nerves in the penis, and maintains the increased intracavernosal pressure (erection) state (For example, refer nonpatent literature 1). PDE5 inhibitors saved the majority of patients suffering from ED.
世界初のＰＤＥ５阻害剤（シルデナフィルクエン酸塩、商品名バイアグラ）が発売された当初、ＮＯ供与剤である狭心症治療薬（ニトログリセリン、亜硝酸アミル、硝酸イソソルビド等の硝酸薬）との併用による死亡事故が多数報告されたため、現在では両者は併用禁忌となっている。この理由は、ＮＯ供与剤がｃＧＭＰの産生を刺激し、ＰＤＥ５阻害剤がｃＧＭＰの分解を阻害することにより、ｃＧＭＰの増大を介するＮＯの降圧作用が増強するためとされている。現在では、ｃＧＭＰを増加させる薬剤、降圧剤、α遮断薬等は併用注意喚起がなされている（例えば、非特許文献２参照）。 When the world's first PDE5 inhibitor (sildenafil citrate, trade name Viagra) was released, it was used in combination with an angina treatment drug (nitric acid drugs such as nitroglycerin, amyl nitrite, and isosorbide nitrate) that are NO donors. Due to numerous reports of deaths due to, both are now contraindicated. The reason for this is that NO hypotensive action through the increase of cGMP is enhanced by the NO donor stimulating the production of cGMP and the PDE5 inhibitor inhibiting the degradation of cGMP. At present, concomitant attention has been given to drugs that increase cGMP, antihypertensives, α-blockers, and the like (see, for example, Non-Patent Document 2).
一方、タウリン（アミノエチルスルホン酸）は高ビリルビン血症（閉塞性黄疸を除く）における肝機能の改善や、うっ血性不全に対して投与される（例えば、非特許文献１及び３参照）。ＯＴＣ薬（一般用医薬品）では、肝機能改善作用を有するため、滋養強壮薬やドリンク剤に配合されている（例えば、非特許文献４参照）。
しかし、タウリンの***作用は知られておらず、ＰＤＥ５阻害剤とタウリンの組合せも知られていない。
On the other hand, taurine (aminoethylsulfonic acid) is administered for improvement of liver function in hyperbilirubinemia (excluding obstructive jaundice) and congestive failure (see, for example, Non-Patent Documents 1 and 3). OTC drugs (over-the-counter drugs) have a liver function improving action, and are therefore incorporated in nourishing tonics and drinks (see, for example, Non-Patent Document 4).
However, the erection action of taurine is not known, and the combination of a PDE5 inhibitor and taurine is not known.
ＥＤに悩む人は若年よりも圧倒的に中高年であり、狭心症薬や降圧薬の服用率が高い年代であるため、ＰＤＥ５阻害剤の恩恵に浴せない患者がでてくるという課題があった。そこで、副作用の少ない低用量でのＰＤＥ５阻害剤投与で、充分かつ優れた陰茎***機能を発現する医薬組成物を提供することが、本発明の課題である。 People who are afflicted with ED are overwhelmingly older than younger people, and since the age of taking angina and antihypertensive drugs is high, there is a problem that some patients cannot take advantage of PDE5 inhibitors. It was. Accordingly, it is an object of the present invention to provide a pharmaceutical composition that exhibits sufficient and excellent penile erection function by administration of a PDE5 inhibitor at a low dose with few side effects.
本発明者らはかかる課題を解決するために、数多くの併用成分につき試行錯誤を繰り返しながら、今日まで鋭意研究を進めてきた。その結果、ＰＤＥ５阻害剤にタウリンを併用すると、それぞれ単剤からでは予測しえないＰＤＥ５阻害剤の***作用が著しく増強されることを見出し、本発明を完成するに至った。 In order to solve such a problem, the present inventors have been diligently researching to date while repeating trial and error for a large number of combined components. As a result, it was found that when taurine is used in combination with a PDE5 inhibitor, the erection action of the PDE5 inhibitor which cannot be predicted from each single agent is remarkably enhanced, and the present invention has been completed.
すなわち、本発明は、
（１）ホスホジエステラーゼ５阻害剤とタウリンを含有する医薬組成物
であり、好適には、
（２）陰茎***機能不全治療用又は陰茎***機能不全改善用である上記(１)に記載の医薬組成物、
（３）ホスホジエステラーゼ５阻害剤投与において得られる陰茎***作用を、タウリンを含有させることによって増強させるための上記（１）に記載の医薬組成物、
（４）ホスホジエステラーゼ５阻害剤投与において得られる陰茎***持続時間を、タウリンを含有させることによって持続延長させるための上記（１）に記載の医薬組成物、
（５）ホスホジエステラーゼ５阻害剤が、シルデナフィル、バルデナフィル、タダラフィル、ウデナフィル及びそれらの薬理上許容される塩からなる群から選択される１種以上である、上記（１）−（４）から選択されるいずれか１項に記載の医薬組成物、
（６）ホスホジエステラーゼ５阻害剤が、シルデナフィルクエン酸塩、バルデナフィル塩酸塩水和物、タダラフィル又はウデナフィルである、上記（１）−（４）から選択されるいずれか１項に記載の医薬組成物、
（７）ホスホジエステラーゼ５阻害剤が、シルデナフィルクエン酸塩である、上記（１）−（４）から選択されるいずれか１項に記載の医薬組成物、
（８）ホスホジエステラーゼ５阻害剤とタウリンを、同一の医薬組成物中に含有する上記（１）−（７）から選択されるいずれか１項に記載の医薬組成物の製造方法、
（９）陰茎***機能不全治療用又は陰茎***機能不全改善用医薬組成物を製造するための、ホスホジエステラーゼ５阻害剤とタウリンの使用、
（１０）ホスホジエステラーゼ５阻害剤とタウリンを同時に、順次又は別個に投与する方法、または、
（１１）哺乳動物に上記（１）−（７）から選択されるいずれか１項に記載された医薬組成物の有効量を投与することを特徴とする、陰茎***機能不全治療方法又は陰茎***機能不全改善方法
である。
That is, the present invention
(1) A pharmaceutical composition comprising a phosphodiesterase 5 inhibitor and taurine, preferably
(2) The pharmaceutical composition according to the above (1), which is used for treating penile erection dysfunction or for improving penile erection dysfunction,
(3) The pharmaceutical composition according to the above (1) for enhancing the penile erection action obtained by administration of a phosphodiesterase 5 inhibitor by containing taurine,
(4) The pharmaceutical composition according to (1) above, wherein the duration of penile erection obtained by administration of the phosphodiesterase 5 inhibitor is prolonged by including taurine,
(5) The phosphodiesterase 5 inhibitor is selected from the above (1)-(4), which is one or more selected from the group consisting of sildenafil, vardenafil, tadalafil, udenafil and pharmacologically acceptable salts thereof. The pharmaceutical composition according to any one of the above,
(6) The pharmaceutical composition according to any one of (1) to (4), wherein the phosphodiesterase 5 inhibitor is sildenafil citrate, vardenafil hydrochloride hydrate, tadalafil or udenafil.
(7) The pharmaceutical composition according to any one of (1) to (4), wherein the phosphodiesterase 5 inhibitor is sildenafil citrate,
(8) The method for producing a pharmaceutical composition according to any one of (1) to (7), wherein the phosphodiesterase 5 inhibitor and taurine are contained in the same pharmaceutical composition,
(9) Use of a phosphodiesterase 5 inhibitor and taurine for producing a pharmaceutical composition for treating penile erection dysfunction or for improving penile erection dysfunction;
(10) A method of administering a phosphodiesterase 5 inhibitor and taurine simultaneously, sequentially or separately, or
(11) A method for treating penile erection dysfunction or penile erection, comprising administering an effective amount of the pharmaceutical composition described in any one of (1) to (7) above to a mammal It is a dysfunction improvement method.
本発明の医薬組成物を投与する際は、それぞれのホスホジエステラーゼ５阻害剤を含有する医薬組成物と、タウリンとを同時に又は順次に投与することが出来る。 When administering the pharmaceutical composition of the present invention, the pharmaceutical composition containing each phosphodiesterase 5 inhibitor and taurine can be administered simultaneously or sequentially.
「同時に」投与するとは、全く同時に投与することの他、薬理学上許される程度に相前後した時間に投与することも含むものである。その投与形態は、ほぼ同じ時間に投与できる投与形態であれば特に限定はないが、単一の医薬組成物であることが好ましい。 “Simultaneous” administration includes administration at exactly the same time, as well as administration at a time that is pharmacologically acceptable. The dosage form is not particularly limited as long as it can be administered at approximately the same time, but is preferably a single pharmaceutical composition.
「順次又は別個に」投与するとは、異なった時間に別々に投与できる投与形態であれば特に限定はないが、例えば、１の組成物を投与し、次いで、決められた時間後に、他の組成物を投与する方法がある。 “Sequentially or separately” administration is not particularly limited as long as it can be administered separately at different times. For example, one composition is administered and then another composition is administered after a predetermined time. There are ways to administer things.
「治療」とは、病気又は症状を治癒させること又は改善させること或いは症状を抑制させることを意味する。 “Treatment” means curing or ameliorating a disease or condition or suppressing a symptom.
本発明により、ＰＤＥ５阻害剤とタウリンを含有する医薬組成物を、性行為の約１時間前に、ほぼ同時に併用すれば、陰茎***作用が著しく増強されかつ安全である。これにより、ＰＤＥ５阻害剤の含有量を減量することが可能となるので有用である。 According to the present invention, if a pharmaceutical composition containing a PDE5 inhibitor and taurine is used together approximately 1 hour before sexual activity, the penile erection action is remarkably enhanced and safe. This is useful because the content of the PDE5 inhibitor can be reduced.
「陰茎***機能不全」とは、何らかの原因により、***に必要とされるほどの陰茎***が発現しなかったり、いったん***しても持続せず正常な***渉が行えなかったりする状態を指し、「陰茎***機能不全改善」とは、このような状態を改善することをいう。 `` Penis erection dysfunction '' refers to a condition where, for some reason, penile erection is not enough to be required for sexual intercourse, or it does not persist even after erection and normal sexual intercourse cannot be performed, “Improving penile erection dysfunction” refers to improving such a condition.
本発明の「ＰＤＥ５阻害剤」とは、ホスホジエステラーゼ５（ＰＤＥ５）を阻害する作用があれば特に限定されないが、具体的には、シルデナフィルクエン酸塩、バルデナフィル塩酸塩、タダラフィル、ウデナフィル等を指す。 The “PDE5 inhibitor” of the present invention is not particularly limited as long as it has an action of inhibiting phosphodiesterase 5 (PDE5), and specifically refers to sildenafil citrate, vardenafil hydrochloride, tadalafil, udenafil and the like.
ＰＤＥ５阻害剤として、シルデナフィルクエン酸塩、バルデナフィル塩酸塩、タダラフィル、ウデナフィルは公知の化合物であり市販されているため入手できる。
本発明のタウリン（アミノエチルスルホン酸）は、第１５改正日本薬局方に収載されており容易に入手できる。
Sildenafil citrate, vardenafil hydrochloride, tadalafil, and udenafil are known compounds and are available as PDE5 inhibitors because they are commercially available.
The taurine (aminoethylsulfonic acid) of the present invention is listed in the 15th revised Japanese Pharmacopoeia and can be easily obtained.
本発明の医薬組成物の１日投与量における、ＰＤＥ５阻害剤の含有量は１ｍｇ〜１５０ｍｇであり、好ましくは、５ｍｇ〜１００ｍｇである。 The content of the PDE5 inhibitor in the daily dose of the pharmaceutical composition of the present invention is 1 mg to 150 mg, preferably 5 mg to 100 mg.
タウリンの含有量は、１０ｍｇ〜３０００ｍｇであり、好ましくは、５０ｍｇ〜２０００ｍｇである。 The content of taurine is 10 mg to 3000 mg, preferably 50 mg to 2000 mg.
これらを１日１回、性行為の約１時間前に服用する。また、肺動脈性肺高血圧症の場合は当該量を３回に分けて服用する。 Take these once a day, approximately 1 hour before sexual activity. In the case of pulmonary arterial hypertension, take this amount in three divided doses.
なお、「順次又は別個に」投与する場合には、ＰＤＥ５阻害剤とタウリンを性行為の約１時間前に服用することには変わりないが、別個に服用する場合でも時間間隔は３０分以内が望ましい。 When administered “sequentially or separately”, the PDE5 inhibitor and taurine should be taken about 1 hour before sexual activity, but the time interval is preferably within 30 minutes even when taken separately. .
本発明の実施例を以下に記載するが、これらに限定されるものではない。
（実施例）錠剤
（成分）
（表１）
４錠中（ｍｇ） ａ ｂ ｃ
―――――――――――――――――――――――――――――――――
シルデナフィルクエン酸塩 ２５ − −
バルデナフィル塩酸塩又はタダラフィル − １０ −
ウデナフィル − − １００
タウリン ３００ ３００ ３００
結晶セルロース ８０ ８０ ８０
乳糖 ６０ ６０ ６０
ステアリン酸マグネシウム ２ ２ ２
ヒドロキシプロピルセルロース 適量 適量 適量
――――――――――――――――――――――――――――――――――
（製法）
上記成分および分量をとり、日局製剤総則「錠剤」の項に準じて錠剤を製造する。
Examples of the present invention are described below, but are not limited thereto.
(Example) Tablet (component)
(Table 1)
4 tablets (mg) a b c
―――――――――――――――――――――――――――――――――
Sildenafil citrate 25--
Vardenafil hydrochloride or tadalafil-10-
Udenafil − − 100
Taurine 300 300 300
Crystalline cellulose 80 80 80
Lactose 60 60 60
Magnesium stearate 2 2 2
Hydroxypropylcellulose Suitable amount Suitable amount Suitable amount ――――――――――――――――――――――――――――――――――
(Manufacturing method)
Taking the above ingredients and amounts, tablets are produced according to the section “General Tablet Preparation Guidelines”.
（試験例）陰茎***効果確認試験
（１）被験物質
シルデナフィルクエン酸塩は市販の医療用バイアグラ錠（ファイザー製）を乳鉢ですり潰して使用した。タウリンはＳＩＧＭＡ−ＡＬＤＲＩＣＨ製のものを使用した。
シルデナフィルクエン酸塩は蒸留水で２ｍｇ／ｍＬ濃度に希釈して５ｍＬ／Ｋｇ投与した（１０ｍｇ／Ｋｇ）。同様に調製して、タウリンは１００ｍｇ／Ｋｇ投与した。
シルデナフィルクエン酸塩とタウリンを併用する場合は、シルデナフィルクエン酸塩を１０ｍｇ／Ｋｇ投与した後にタウリンを投与した。
併用投与群は以下に示すとおりである。
(Test example) Penile erection effect confirmation test (1) Test substance Sildenafil citrate was used by grinding commercially available Viagra tablets (manufactured by Pfizer) in a mortar. Taurine used was SIGMA-ALDRICH.
Sildenafil citrate was diluted with distilled water to a concentration of 2 mg / mL and administered at 5 mL / Kg (10 mg / Kg). Similarly prepared, taurine was administered at 100 mg / Kg.
When sildenafil citrate and taurine were used in combination, taurine was administered after 10 mg / Kg of sildenafil citrate was administered.
The combination administration group is as follows.
（実施例１）
シルデナフィルクエン酸塩（１０ｍｇ／Ｋｇ）及びタウリン（１００ｍｇ／Ｋｇ）の併用投与。
Example 1
Combined administration of sildenafil citrate (10 mg / Kg) and taurine (100 mg / Kg).
（２）使用動物
ＪＷ雄性家兎１６週齢を日本ＳＬＣ（株）から購入し、温度２０〜２６℃、湿度３０〜７０％、照明時間６時〜１８時に制御されたウサギ飼育室内でウサギ用ブラケットテーパーケージに入れ、ウサギ飼育用飼料および水フィルターを通した水道水を自由に摂取させた。
(2) Animals used JW male rabbits, 16 weeks old, purchased from Japan SLC Co., Ltd., for rabbits in a rabbit breeding room controlled at a temperature of 20 to 26 ° C., a humidity of 30 to 70%, and a lighting time of 6:00 to 18:00 The animal was placed in a bracket taper cage and freely fed with rabbit feed and tap water through a water filter.
（３）試験方法
被験物質はゾンデまたはネラトンカテーテル１２号を用いて経口投与した。いずれの被験物質も投与液量は５ｍＬ／Ｋｇである。通常、家兎のペニスは露出しておらず、***時に露出してくるので、被験薬投与による***作用は、露出した陰茎長さによって評価できる。
被験薬投与後、５、１５、３０、４５、６０、９０、１２０及び１８０分の間隔にて、陰茎露出長さ（ｍｍ）をノギスによって測定した。
(3) Test method The test substance was orally administered using a sonde or Neraton catheter No. 12. The administration volume of any test substance is 5 mL / Kg. Usually, the rabbit's penis is not exposed and is exposed at the time of erection, so the erection effect by administration of the test drug can be evaluated by the exposed penile length.
The penis exposure length (mm) was measured with calipers at intervals of 5, 15, 30, 45, 60, 90, 120 and 180 minutes after administration of the test drug.
（４）試験結果
被験薬投与後の各時間（経過時間）における家兎ペニス長さの測定結果を表２に示す。各値とも１群３匹の平均値である。
(4) Test results Table 2 shows the measurement results of the rabbit penis length at each time (elapsed time) after administration of the test drug. Each value is the average of 3 animals per group.
（表２）ペニス長さ（ｍｍ）
投与後時間 シルデナフィル タウリン シルデナフィル(10 mg/Kg)
（ｍｉｎ） (10mg/Kg) (100mg/Kg) ＋タウリン(100mg/Kg)
――――――――――――――――――――――――――――――――――――――
５ ０．０ ０．０ ０．０
１５ ０．９ ０．０ ３．２
３０ ５．０ ０．０ ６．８
４５ ４．５ ０．０ １０．０
６０ １．３ ０．０ ７．０
９０ ３．２ ０．０ ８．０
１２０ ２．０ ０．０ ６．２
１８０ ０．７ ０．０ ６．１
――――――――――――――――――――――――――――――――――――――
ＡＵＣ ３８９ ０ １１５２
(Table 2) Penis length (mm)
Time after administration Sildenafil Taurine Sildenafil (10 mg / Kg)
(Min) (10mg / Kg) (100mg / Kg) + Taurine (100mg / Kg)
――――――――――――――――――――――――――――――――――――――
5 0.0 0.0 0.0
15 0.9 0.0 3.2
30 5.0 0.0 6.8
45 4.5 0.0 10.0
60 1.3 0.0 7.0
90 3.2 0.0 8.0
120 2.0 0.0 6.2
180 0.7 0.0 6.1
――――――――――――――――――――――――――――――――――――――
AUC 389 0 1152
表２の結果より、シルデナフィルクエン酸塩単剤の***作用が認められ、タウリン単剤では***作用は認められなかった。一方、シルデナフィルにタウリンが併用された実施例では、シルデナフィルの***作用の増強効果及び持続時間延長作用が顕著に発現した。 From the results in Table 2, the erectile action of sildenafil citrate alone was observed, and the erectile action of taurine alone was not observed. On the other hand, in the Example in which taurine was used in combination with sildenafil, the effect of enhancing the erection action and the action of extending the duration of sildenafil were remarkably exhibited.
すなわち、ＡＵＣ（ｍｍ×ｍｉｎ）で評価するとシルデナフィル単剤と較べて、タウリン併用した実施例１の場合は、驚くべきことに３倍にも達した。 That is, when evaluated by AUC (mm × min), in the case of Example 1 in which taurine was used in combination, surprisingly, it reached 3 times as compared with sildenafil alone.
本発明により、ＰＤＥ５阻害剤とタウリンを含有する医薬組成物を、性行為の約１時間前に、ほぼ同時に併用すれば、陰茎***作用が著しく増強されかつ安全である。これにより、ＰＤＥ５阻害剤の含有量を減量することが可能となるので有用である。 According to the present invention, if a pharmaceutical composition containing a PDE5 inhibitor and taurine is used together approximately 1 hour before sexual activity, the penile erection action is remarkably enhanced and safe. This is useful because the content of the PDE5 inhibitor can be reduced.
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