TWI236906B - Therapeutic use of melatonin - Google Patents
Therapeutic use of melatonin Download PDFInfo
- Publication number
- TWI236906B TWI236906B TW089110619A TW89110619A TWI236906B TW I236906 B TWI236906 B TW I236906B TW 089110619 A TW089110619 A TW 089110619A TW 89110619 A TW89110619 A TW 89110619A TW I236906 B TWI236906 B TW I236906B
- Authority
- TW
- Taiwan
- Prior art keywords
- melatonin
- patent application
- scope
- neuroleptic
- intellectual property
- Prior art date
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- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 title claims abstract description 37
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229960003987 melatonin Drugs 0.000 title claims abstract description 37
- 230000001225 therapeutic effect Effects 0.000 title description 2
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- 238000000034 method Methods 0.000 claims abstract description 5
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- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 claims description 6
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- 230000002079 cooperative effect Effects 0.000 claims description 5
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Classifications
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
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1236906 A7 __B7 _ 五、發明說明（1 ) 發明背景和領域 (請先閱讀背面之注音？事項再填寫本頁) 本發明係有關一種用於治療遲發性運動障礙的方法及 藥學調合物。 遲發性運動障礙（T D )是爲一種不自主的運動失調 症，其高比率地發生於曾經精神安定藥物治療過的患者。 科學期刊中已有多篇文獻暗示褪黑激素的分泌和T D症狀 的發生二者之間存在有相反的關係。然而，就此而論，根 據吾人所知，只有少數幾個例子嘗試投服外源性褪黑激素 ，然而以哈泊度（halopendol )治療經松果體切除術處理 的老鼠顯著地導致比未經手術的老鼠更嚴重的運動失調症 ，接著投服褪黑激素（4 m g，i . p ·)在1小時內產 生非顯著地降低運動失調症的嚴重程度（Sabdyk，R.，et al •，Int. J. Neurosci·，1 989，48 (3 — 4) :303 - 8 )。此非顯著的結果中所用的褪黑激素的量對於7 0 k g的人類而言相當於1 0 0 Omg以上，因此其在TD 的後續治療中避免使用外源性褪黑激素並不令人驚訝。例 如，在3&11(1#，尺.之美國專利案5，691，324中， 經濟部智慧財產局員工消費合作社印製 T D是與血淸素傳遞不足和褪黑激素功能不良有關的許多 症狀之一，其治療方法包含投服患者以可增進血淸素神經 傳遞的組成物及繼之於大腦施加磁場。美國專利案 5，6 9 1 ，3 2 4的全部內容倂入本發明中以供參考。 目前驚人地發現，外源性褪黑激素於人類之遲發性運 動障礙產生顯著的治療效果，且其劑量比上述之Int. J. Neurosci.所報導的劑量低至少1 〇倍（以相對於實驗動物 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -4- 1236906 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（2 ) 之平均人的體重計）。 發明總論 本發明一方面提供一種藥學調合物，其含有除了至少 一種載體、稀釋劑或助劑之外，至少一種精神安定性化合 物，而其量足以於需要此治療的患者產生精神安定的功效 ，及褪黑激素，而其量足以改善或預防患者之遲發性運動 障礙病症的發展。 本發明之另一方面提供使用褪黑激素於製備供預防或 治療患者之遲發性運動障礙病症的藥物之用途。該藥物宜 爲含有至少一種下列額外的成份（a )和（b )之藥學調 合物的形式：（a )至少一種載體、稀釋劑或助劑，（b )至少一種精神安定性化合物，而其量足以於需要此治療 的患者產生精神安定的功效。此外，本發明亦提供一種預 防或治療患者之遲發性運動障礙病症的方法，其包含予表 現此病症或易發展成此病症之患者投服以褪黑激素，而其 量足以有效改善或預防患者之遲發性運動障礙病症的發展 發明之詳細說明 本發明之藥物/藥學調合物可以任何傳統的形式投服 ，例如適合經口、直腸、非經腸或皮膚的形式投服。其可 爲例如單位劑型。於一特別體系中，褪黑激素係爲控釋型 調合物，其中褪黑激素宜根據預先設定的速率釋放出。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------------訂--------- (請先閱讀背面之注咅？事項再填寫本頁) -5- 經濟部智慧財產局員工消費合作社印製 1236906 A7 ___B7___ 五、發明說明（3 ) 目前用於預防或治療遲發性運動障礙之褪黑激素的量 係爲可有效達到所欲目的者。目前相信，當用於口服時， 其每日劑量高於〇 · 5mg但不超過l〇〇mg，例如 〇· 5 — 50mg ，宜爲2 · 5 — 20mg ;用於非經腸 或經皮投服時，其劑量介於0 · 1至5 0 m g間。根據本 發明，有效劑量的褪黑激素可與例如有效劑量的精神安定 性藥物一起調配。本發明之藥物/藥學調合物亦可含有至 少一種褪黑激素受體改良劑及/或褪黑激素作用改良劑。 一旦本發明之使用褪黑激素於治療或預防T D的槪念 經由本發明而爲人所知，則將無任何熟悉此項技術人士要 求確定供本治療目的及各種不同投服途徑所需之褪黑激素 的有效劑量。當藥學調合物包含至少一種精神安定性化合 物時，其可爲例如含有至少一種下列環系統之該類化合物 :哌啶、哌嗪、嗎啉、5，6 ，7，8 —四氫吲哚、吩噻 嗪和噻噸。精神安定性化合物的例子是氯丙嗪（ chlorpromazine )、三氟丙嗪（triflupromazine )、米索噠 嗪（mesoridazine )、哌乙醯嗪（piperacetazine )、甲硫 噠嗪（thioridazine )、乙醯芬乃靜（acetophenazine )、 氟芬乃靜（fluphenazine )、皮芬乃靜（perphenazine )、 三氟拉嗪（trifluoperazine )、泰爾登（chlorprothixene ) 、氨硕噻噸（thiothixene )、哈泊度（haloperidol )、羅 塞平（loxapine )、莫林冬（molindone )(參見表1 )及 氯塞平（clothiapine )、克塞平（clozapine )、歐拉塞平 (olanzapine )、利斯普冬（risperidone )和反克維米分醋 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------訂--------- (請先閱讀背面之注咅？事項再填寫本頁) -6- 1236906 A7 _B7_ 五、發明說明（4 ) 酸鹽（zuclopenthixol acetate )，及其藥學上可接受之鹽。 表1 :精神安定性化合物 化合物 每日劑量* 可能劑量常用劑量 投服模式 肌內投服單 位劑量* 氯丙11 秦+(chlorpromazine) 25-2000 300-800 口服;非經腸，經 直腸,SR 20-50 三氟丙嗪+(triflupromazine) 25-300 100-150 口服，非經腸 20-60 米索噠嗪貝斯酸鹽(mesoridazine besylate) 25-300 75-300 口服，非經腸 25 哌乙醯嗪(piperacetazine) 5-200 20-160 口服 — 甲硫噠嘻+(thioridazine) 20-800 200-600 口服 — 乙醯芬乃靜順丁烯二酸鹽(acetophenazine maleate) 20-600 60-120 口服 — 氟芬乃靜+(fluphenazine) 0.5-30 1-20 口服，非經腸 1.25-2.5 皮芬乃靜(perphenazine) 4-64 8-32 口服，非經腸，SR 5-10 三氟拉嗪+(trifluoperazine) 2-60 6-20 口服，非經腸 1-2 泰爾登(chlorprothixene) 30-600 50-400 口服，非經腸 25-50 氨石風噻噸+(thiothixene) 6-60 6-30 口服,非經腸 2-4 哈泊度(haloperidol) 1-100 6-20 口服，非經腸 2-5 羅塞平號拍酸鹽(loxapine succinate) 20-250 60-100 口服，非經腸 12.5-50 莫林冬+(molindone) 12-225 50-100 口服 —- mg+鹽酸鹽SR=控釋型（口服） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 請先閱讀背面之注意事項再填寫本頁) - 1_1 ϋ tmem mamt 1 ϋ 1 一一0, I 1·— ϋ 1 經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 1236906 A7 _____B7 _ 五、發明說明（5 ) 本發明將由下列實例詳細說明之。 實例1 混合下列成份並將混合物置於7 m m圓柱形沖壓機中 在2 · 5噸壓力下壓製以製得控釋型錠劑··氯丙嗪（ chlorpromazine )鹽酸鹽（2 7 5 m g / 錠）、褪黑激素（ 5 mg /錠）、及約1 : 1重量比之EudragitTM R S 1 0 0丙烯酸樹脂載體（Rohm Pharma )和乳糖。雖然此 調合物應根據醫師的指示投服，但在本實驗中，宜在睡覺 前2小時服用二個錠劑。 實例2 混合下列成份並將混合物置於7 m m圓柱形沖壓機中 在2 · 5噸壓力下壓製以製得控釋型錠劑：皮芬乃靜（ perphenazine ) (l〇mg/錠）、褪黑激素（5mg /錠 )、及約2 : 1 : 2 · 5重量比之EudragitTM R S P〇丙 烯酸樹脂載體（Rohm Pharma )、乳糖和磷酸氫鈣。雖然 此調合物應根據醫師的指示投服，但在本實驗中，宜在睡 覺前2小時服用二個錠劑。 實例3 褪黑激素對遲發性運動障礙的功效係以含有2 2名患 者的試驗組進行試驗，其中的6名患者患有分裂情感型精 神分裂症，而其餘1 6名患者患有偏執型精神分裂症。所 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注咅？事項再填寫本頁) ----- 訂— -8- 經濟部智慧財產局員工消費合作社印製 1236906 Α7 Β7 五、發明說明（6) 有的患者均已接受長期的精神安定劑治療，並根據D S Μ I V標準診斷。試驗組中有1 1名男性和1 1名女性， 年齡自1 7 — 6 1歲，平均爲3 9 土1 5歲，其中1 9名完 成實驗及得到結果。以隨機雙盲交叉的方式’每日二次在 睡覺前2小時給予患者含有5 m g褪黑激素之控釋型調合 物（CircadinTM，Neurim Pharmaceuticals，Israel )或者具相 同外觀的安慰藥，歷時6週，且在二個治療週期之間給予 患者4週的安慰藥以沖淡藥物。除了褪黑激素或安慰藥以 外，亦每日分別給予每名患者下列劑量的精神安定劑（ mg) ••氯丙 11 秦（chlorpromazine ) ( 2 5 0 )、氯塞平（ clothiapine ) (2〇、80或160)、克塞平（ clozapine ) (2〇〇、4〇0或550)、哈泊度（ ]^1〇?61^(1〇1)(5、15或20)、歐拉塞平（〇1&1123口1116 )(10 或 15)、皮芬乃靜（perphenazine )( 4、8、 1 2、3 2 或 3 2 )、利斯普冬（nsperidone ) ( 4 )或 反克羅米芬醋酸鹽（zuclopenthixol acetate ) ( 4或2〇） ，或者其中二例未給予精神安定劑。在各治療組的最後一 週，T D嚴重程度係使用不正常的不自主運動等級（ A I M S )加以分析並比較安慰藥組或褪黑激素治療組與 基準線間的差異。結果示於表2和表3。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) ---------訂— -9- 1236906 A7 --_B7 五、發明說明（8 ) 舞黑激素於遲發性運動障礙里結果 AIMS 次 運動的強度(標準誤差） 等級 基準線 安慰藥 基準線 褪黑激素 1 2.14 (0.89) 2.00 (0.82) 2.18 (〇.8〇) 1.91 (0.87) 2 3.27 (0.70) 3.27 (0.70) 3.50 (0.74) 3.00 (0.98) 3 3.00 (1.07) 2.73 (1.12) 3.09 (Ml) 2.68 (1.13) 4 3.55 (0.67) 3.32 (0.65) 3.50 (0-67) 3.18 (0.80) 5 1.73 (0.83) 1.64 (0.79) 1.91 (0.92) 1.50 (0.74) 6 1.23 (0.53) 1.23 (0.53) 1.55 (0.91) 1.27 (0.63) 7 1.18 (0.50) 1.14 (0.47) 1.55 (1.06) 1.27 (0.70) 8 3.36 (0.73) 3.27 (0.70) 3.50 (0.74) 3.27 (0.88) 9 3.09 (0.81) 2.95 (0.79) 3.00 (0.87) 2.73 (0.88) 10 1.73 (0.70) 1.73 (0.70) 1.73 (0.70) 1.73 (0.70) 11 1.91 (0.29) 1.91 (0.29) 1.91 (0.29) 1.91 (0.29) (請先閱讀背面之注咅？事項再填寫本頁) ---------訂— 經濟部智慧財產局員工消費合作社印製 結論：此項硏究顯示高度有效的降低（p < Ο · Ο Ο Ο 1 ，Μ A Ν〇V A )，即在投服褪黑激素之後，與安慰藥相 比較，得到改良功效（分別爲一 3 ± 2 · 1及一 1 ± 1 · 3 雖然本發明已由上述一些特定的體系加以說明，但是 熟悉此項技術人士均知仍可以進行各種改良及變化，因此 本發明並不只限於上述的特定體系，本發明之槪念可由下 列申請專利範圍之精神及範圍加以說明。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -11 -
Claims (1)
- [236906 A8 B8 C8 D8 申請專利範圍 22 附件2A 第89 1 1061 9號專利申請案 中文申請專利範圍替換本 民國94年3月22日修正 1 . 一種用於治療病患遲發性運動障礙或預防遲發性 運動障礙病症之發展的藥學組成物，其包含0 · 1 mg至 1 0 Omg褪黑激素以及一種或多種選自載劑、稀釋劑及 佐劑之物質，而該組成物適合於控制釋出褪黑激素，而其 量足以有效改善或預防患者之病症的發展。 2 .如申請專利範圍第1項之藥學組成物，其另外具 有一種或多種之下列特徵： (i )其適合經口、直腸、胃腸外或皮膚的形式投服 -2 (請先聞讀背面之注意事項再填寫本頁) π )其係爲單位劑型，而每個單位劑型含有2 m g褪黑激素； (iii )該組成物經調製成褪黑激素係根據預先設定的 速率釋放出的形式； 經濟部智慧財產局員工消費合作社印製 (iv )其亦包含一種或多種選自褪黑激素受體改良劑 及褪黑激素作用改良劑之物質。 3 · —種用於治療病患遲發性運動障礙或預防遲發性 運動障礙病症之發展的藥學組套，其包括第一容器，其中 含有如申請專利範圍第1項之藥學組成物；及第二容器， 其中含有一種或多種精神安定性化合物，其量足以對需要 此類治療之病患有效產生精神安定之作用。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 1236906 A8 B8 C8 D8 、申請專利範圍 (請先聞讀背面之注意事項再填寫本頁) 4 ·如申請專利範圍第3項之藥學組套，其中該精神 安定性化合物係選自含有一種或多種下列環系統之化合物 :即哌啶、哌嗪、嗎啉、5 ，6，7，8 —四氫吲哚、吩 噻嗪和噻噸。 5 .如申請專利範圍第3項之藥學組套，其中該精神 安定性化合物係選自氯丙嗪（chlorpromazine )、三氟丙嗪 (triflupromazine)、米索噠嗪（mesoridazine)、哌乙醢嗪 (pipe racetazi η έ)、甲硫噠嗪（thioridazine)、乙醯芬乃靜 (acetophenazine )、氟芬乃靜（fluphenazine )、皮芬乃靜 (perphenazine)、三氟拉嗪（trifluoperazine )、泰爾登（ chlorprothixene )、氨硕噻 _ ( thiothixene )、哈泊度（ haloperidol)、羅塞平（loxapine)、莫林冬（molindone) 、氯塞平（clothiapine)、克塞平（clozapine)、歐拉塞平 (olanzapine )、利斯普冬（risperidone )和反克羅米芬醋 酸鹽（zuclopenthixolacetate)，及其藥學上可接受之鹽。 6 .如申請專利範圍第3至5項中任一項之藥學組套 ，其另外具有一種或多種之下列特徵〆 (i )其適合經口、直腸、非經腸或皮膚的形式投服 經濟部智慧財產局員工消費合作社印製 (Π )其係爲單位劑型，而每個單位劑型含有2 · 5 —2 0 m g褪黑激素； (iii )該組成物經調製成褪黑激素係根據預先設定的 速率釋放出的形式； (iv )其亦包含一種或多種選自褪黑激素受體改良劑 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 1236906 A8 B8 C8 D8 、申請專利範圍 及褪黑激素作用改良劑之物質。 (請先閲讀背面之注意事項再填寫本頁) 1^^. 訂 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）
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| IL13017199A IL130171A (en) | 1999-05-27 | 1999-05-27 | Melatonin for use in preventing and treating tardive dyskinesia, pharmaceutical preparations containing it and its use in the manufacture of medicines |
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| EP (1) | EP1183024A4 (zh) |
| JP (1) | JP2003500446A (zh) |
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| EA (1) | EA004057B1 (zh) |
| EE (1) | EE200100623A (zh) |
| HK (2) | HK1046089A1 (zh) |
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Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ527142A (en) * | 2003-07-23 | 2006-03-31 | Douglas Pharmaceuticals Ltd | A stable suspension formulation |
| CA2556753C (en) * | 2004-02-20 | 2014-11-25 | Lifescape Biosciences Incorporated | Compositions and methods for sleep regulation |
| CN1299680C (zh) * | 2005-08-29 | 2007-02-14 | 陈彦方 | 一种治疗失眠的黑白制剂 |
| US7494674B2 (en) | 2006-09-22 | 2009-02-24 | Lapointe Andrew T | Nutraceutical with tart cherries and method of treatment therewith |
| WO2008116004A2 (en) | 2007-03-19 | 2008-09-25 | Vita Sciences, Llc | Transdermal patch and method for delivery of vitamin b12 |
| WO2008128166A1 (en) * | 2007-04-13 | 2008-10-23 | Concert Pharmaceuticals Inc. | Deuterated derivatives of 4-(6-fluoro-1, 2-benzisoxazol-3-yl) piperidine compounds |
| US20100256197A1 (en) * | 2009-04-02 | 2010-10-07 | Silver Eagle Labs Nv, Llc | Nicotine Dissolving Film With Or Without Menthol |
| US20100256215A1 (en) * | 2009-04-02 | 2010-10-07 | Silver Eagle Labs Nv, Llc | Menthol-Melatonin Dissolving Film |
| US9532952B2 (en) | 2011-01-28 | 2017-01-03 | Physician's Seal, LLC | Controlled-release compositions of melatonin combined with sedative and/or analgesic ingredients |
| WO2012103411A2 (en) | 2011-01-28 | 2012-08-02 | Zx Pharma, Llc | Controlled-release melatonin composition and related methods |
| FR3000896B1 (fr) | 2013-01-14 | 2016-08-26 | Philippe Perovitch | Forme galenique pour l'administration de principe(s) actif(s) permettant l'induction acceleree du sommeil et/ou le traitement des troubles du sommeil |
| US11071739B1 (en) | 2020-09-29 | 2021-07-27 | Genus Lifesciences Inc. | Oral liquid compositions including chlorpromazine |
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|---|---|---|---|---|
| US5691324A (en) * | 1994-01-14 | 1997-11-25 | Sandyk; Reuven | Methods useful for the treatment of neurological and mental disorders related to deficient serotonin neurotransmission and impaired pineal melatonin functions |
| US6469044B1 (en) * | 1995-02-01 | 2002-10-22 | Neurim Pharmaceuticals (1991) Ltd. | Method for treating patients suffering from drug dependencies which lead to plasma melationin deficiencies |
| AUPO274596A0 (en) * | 1996-10-04 | 1996-10-31 | Armstrong, Stuart Maxwell | Method for the treatment of neurological or neuropsychiatric disorders |
| AUPO588297A0 (en) * | 1997-03-26 | 1997-04-24 | Luminis Pty Limited | Mediation in melatonin production |
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