TW483757B - A pharmceutical formulation containing melatonin for use in treating preventing symptoms of dependence on, tolerance of, or addiction to benzodiazepine drugs - Google Patents
A pharmceutical formulation containing melatonin for use in treating preventing symptoms of dependence on, tolerance of, or addiction to benzodiazepine drugs Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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Abstract
Description
經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明(1 ) 一本發明關於褪黑激素用於製造用以治療,或預防對苯并 二氮革蔡劑依賴,具忍受性,或上瘾之徵狀,用以治療多 重藥物成瘾之醫藥品,及關於用於此類治療之醫禁組合物 〇 依賴苯并二氮萆通常發生於使用它們來謗發睡眠之失眠 症患者,及於***撤除過程中,變得對苯并二氮萆類上 瘾以缓和焦慮與痙攣之患者中。然而,習慣性投禁苯并二 氮革(而苯并二氮革通常具有長半衰期價値)可能因未知 之機制謗發忍<性,其表現於劑量之無效增加。而且,於 動物與人類中均觀察到,常在猝然停止此等藥劑後發生之 復原或"撤除,,現象會導致上瘾(Greenbiatt,D· J.,及Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (1) The present invention relates to melatonin used in the manufacture or treatment of or prevention of benzodiazepine leather agent dependence, or Symptoms of addiction, medicines used to treat multiple drug addictions, and incontinence compositions for such treatments. Dependence on benzodiazepines usually occurs in patients with insomnia who use them to slander sleep, and Patients who become addicted to benzodiazepines to relieve anxiety and spasm during the withdrawal of sleeping pills. However, the habitual prohibition of benzodiazepines (and benzodiazepines usually have long half-life values) may be due to an unknown mechanism, which is manifested by an ineffective increase in dose. Furthermore, it has been observed in animals and humans that recovery or " removal, which often occurs after abrupt stopping of these agents, can lead to addiction (Greenbiatt, D.J., and
Shader, R.I·, Drug Metab· Rev·, 1978, 8:13_28)。於 1990年美國使用精神治療醫藥之家族調查中,大約8%安眠 藥使用者自行增加其預先之劑量,其較先前於1979年之報 告增加25%。斟酌該調查發現,2.6%美國人民服用苯并二 氮萆安眠禁(比較於1979年爲2.4%),而估計美國中發生 忍受性與依賴性之人數僅爲560,000。此等數値不包括於 醫禁或社會正常規範外之物質使用及多重藥物濫用。尚未 報導於發生對苯幷二氮萆***依賴之病患中,在有效改 變治療後有快速撤除之方法,而且此問題在***物成癮 者之復健與復原上係一大障礙。 已知褪黑激素(爲一種於夜晚時由松果腺產生之ϋ引口朵-衍生之激素)在參與週期性睡眠-喚醒循環中及調節睡眠 本紙張尺度適用中國國家標準(CNS ) Α4規格(210 X 297公釐) (請先閲讀背面之注意事項再填寫本頁)Shader, R.I., Drug Metab. Rev., 1978, 8: 13_28). In the 1990 US Family Survey of the Use of Psychotherapy Medicine, approximately 8% of sleeping pill users increased their own pre-dose, which is a 25% increase from the previous report in 1979. Taking this survey into account, 2.6% of the American population was taking benzodiazepines for incontinence (compared with 2.4% in 1979), compared with an estimated 560,000 people in the United States who experienced tolerance and dependence. These figures do not include substance use and multiple drug abuse outside the limits of medical bans or social norms. It has not been reported that patients with dependence on benzodiazepine sleeping pills have rapid withdrawal after effective treatment changes, and this problem is a major obstacle to the rehabilitation and recovery of narcotic drug addicts. It is known that melatonin (a hormone derived from the pineal gland that is derived from the pineal gland at night) participates in the cyclic sleep-wake cycle and regulates sleep. This paper applies the Chinese National Standard (CNS) Α4 specification. (210 X 297 mm) (Please read the notes on the back before filling this page)
483757 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(2 ) 方面扮演主要的角色。亦有某些證據顯示褪黑激素可增加 苯并二氮萆之功效’參見’例如,Cardinali,D.P·等人 ,Adv. Biochem. Psychopharm.? 1986, 42:155-164; Acuna Castroviejo,D.等人,j· pineal Res·,1986, 3:101-102;及 Niles,L.P·等人,J· Neural Transm. 70 :117-124〕。又,褪黑激素於老鼠中可增加苯甲二氮萆之 解焦慮功效(Guardiola-Lemaitre,B·等人,Pharmacol · Biochem· Behav·,1992,41,405-4080〉。另一方面, 業經暗示苯并二氮萆(於某些種類,包括人類中)可增強 由GABA-謗發之對褪黑激素合成與分泌之抑制作用 (McIntyre, Ι·Μ·等人,Biol· Psychiat·,1988,24:105 -108),以及於人類中血漿褪黑激素之夜間增加會受苯并 二氮萆壓制,而因此擾亂白天之褪黑激素周期性(Kabuto, Μ·等人,Endocr. Japon·,1986,33,405-414)。然而, 業經觀察得,慢性以去甲鲽基安定(oxazepam)治療,會改 變兔子腦中夜晚褪黑激素受體密度之曰間變化,而此作用 未在切除松果腺之動物中觀察得(Anis,Y·等人,J· Neural Transm·, 1992, 89:155-166)。 本發明已令人驚異地發現褪黑激素同時與苯并二氮萆一 起投禁可潛在地⑴使病患擺脱對此等藥物之依賴,成瘾或 忍受性,及⑵於已經診斷爲需要苯并二氮萆藥劑之病患個 案中(而此等不希望之徵狀尚未發生),預防此等徵狀之 發生。 發明之魏座· 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇X 297公釐) (請先閱讀背面之注意事項再填寫本頁) ▼ 483757483757 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. The invention description (2) plays a major role. There is also some evidence that melatonin can increase the efficacy of benzodiazepines. 'See, for example, Cardinali, DP. Et al., Adv. Biochem. Psychopharm.? 1986, 42: 155-164; Acuna Castroviejo, D. Et al., J. Pineal Res., 1986, 3: 101-102; and Niles, LP, et al., J. Neural Transm. 70: 117-124]. In addition, melatonin can increase the anxiolytic effect of benzodiazepine in mice (Guardiola-Lemaitre, B. et al., Pharmacol. Biochem. Behav., 1992, 41, 405-4080>. On the other hand, It is suggested that benzodiazepine (in some species, including humans) can enhance the inhibitory effect of melatonin synthesis and secretion by GABA (McIntyre, Ι · Μ · et al., Biol · Psychiat ·, 1988 , 24: 105 -108), and the nocturnal increase in plasma melatonin in humans is suppressed by benzodiazepines, thus disrupting the melatonin cycle during the day (Kabuto, M. et al., Endocr. Japon · , 1986, 33, 405-414). However, it has been observed that chronic treatment with oxazepam can change the night-time changes in the density of melatonin receptors in rabbit brains. Observed in pineal gland-removed animals (Anis, Y. et al., J. Neural Transm., 1992, 89: 155-166). The present invention has surprisingly found that melatonin is simultaneously associated with benzodiazepine Prohibition together can potentially free patients from dependence on these drugs, addiction Tolerance and prevention in patients who have been diagnosed with the need for benzodiazepines (and these undesired symptoms have not yet occurred) to prevent these symptoms from occurring. Wei Zuo of Invention · Paper Size Applicable to China National Standard (CNS) A4 (21〇X 297 mm) (Please read the precautions on the back before filling this page) ▼ 483757
經濟部中央標準局員工消費合作社印製 因此本發㈣-方面提供,褪黑激素於製造用以治療多 重禁物成瘛’或具有變續料二氮轉劑依賴具忍受 性二或上瘛之徵狀之患者,或治療業經臨床珍斷爲具有容 易藉施藥苯弁二氮革_減缓痛若之病況的患者,同時預 防患者發生對該苯弁二氮萆藥劑依賴,具忍受性,或上癔 之徵狀的醫藥品之用途。 另一方面,本發明提供一種用於治療多重禁物成瘾,或 具有變成對苯并二氮萆藥劑依賴,具忍受性,或上瘾之徵 狀之患者,或治療業經臨床診斷爲具有容易藉施藥苯并二 氮萆藥劑減缓痛苦之病況的患者,同時預防患者發生對該 苯并二氮萆藥劑依賴,具忍受性,或上瘾之徵狀的醫藥調 配物,其包含至少一種稀釋劑,載體或佐劑及作爲活性成 扮之苯并二氮蕈藥劑與褪黑激素。 該醫藥品可爲適於口服,直腸,非經腸道或穿皮投藥之 醫禁調配物,且其包含至少一種稀釋劑,載體或佐劑,且 又可以下列性質爲特徵:(i)其爲單位劑量形式,各單位 劑量包含含量範園介於0.0025-100毫克之褪黑激素;(a ) 其爲受控釋放調配物之形式,其中褪黑激素較佳地係以預 定受控之速率釋出;(iii)其亦包含至少一種褪黑激素受體 調節劑及/或褪黑激素作用輪廓調節劑。該醫禁品亦可包 含,且根據本發明之醫藥調配物包含,至少一種苯并二氮 萆禁劑,如至少一種Alprazolam,利眠寧,Clorazepate ,安定,Flunitrazepam,Flurazepam,Helazepam,氣雞 去甲安定,去甲羥基安定,Prazepam,Temazepam,*** 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) (請先閲讀背面之注意事項再填寫本頁) 、?τ • J— n —J. · 經濟部中央標準局員工消費合作社印製 483757 A7 --— __B7 五、發明説明(Π 一 ----— 苯并二氮萆。包含至少一種苯并二氮革藥劑之調配物亦可 進-步以-或多項如上述之性質⑴,(ii)及(iii)作爲特 徵。 於將本發明應用於治療多重藥物成瘾或具有已對笨并二 氮萆藥劑依賴,具忍受性或上瘾之徵狀之患者方面,係持 續投藥苯并二氮萆藥劑予患者(至少於開始時),且同時將 有效減缓至少一項此類徵狀之褪黑激素投禁予患者。 在此項治療之特别具體實施例中,苯并二氮萆藥劑或褪 黑激素可以適於口服,直腸,非經腸道或穿皮施藥之醫禁 調配物形式存在,且包含至少一種稀釋劑,載體或佐劑。 另外,因此調配成之苯并二氮萆禁劑與褪黑激素可各别投 藥,或組合成包括二氮萆類藥劑及褪黑激素之單一醫藥調 配物。 ' 關於褪黑激素之投藥,不論各别投藥或與一或多種苯 并二氮萆禁劑共同投禁,施禁有效量可爲介於(例如)〇 〇1 〜100毫克範固之每日劑量率;其可以受控釋出調配物之 形式投藥。舉例説明,1-2毫克以受控釋出調配物形式之 褚黑激素可於晚間投藥。褪黑激素可與楗黑激素受體調節 劑或褪黑激素作用輪廓調節劑共同投蔡。 節劑之實例爲短程作用之苯并二氮革如去甲;=體; 黑激素作用輪廓調節劑之實例爲苯并二氮萆,貝他_阻斷 劑及血清素吸收抑制劑。除使用此等作用輪靡調節劑之外 | ,褪黑激素之作用輪廓可藉使患者於褪黑激素投藥之前, 之後或期間接受光照作用。 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) (請先閲讀背面之注意事項再填寫本頁}Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. This document provides-melatonin is used in the manufacture of multiple forbidden substances, or it has a resilience to dinitrogen transfer agents, which has a tolerant second or upper sign. Patients, or patients who have been clinically cherished as having a condition that can be easily treated with benzodiazepine _ to alleviate painful conditions, and prevent patients from becoming dependent on the benzodiazepine drug, have tolerance, or Use of medicines with the symptoms of sacrifice. In another aspect, the present invention provides a patient for the treatment of multiple contraceptive addictions, or a patient who has become dependent on benzodiazepine drugs, has tolerance, or has symptoms of addiction, or is clinically diagnosed as having an easy loan A benzodiazepine drug to alleviate painful conditions in a patient, and at the same time prevent the patient from developing a dependence on the benzodiazepine drug, which is tolerant, or addictive, which contains at least one diluent, Carrier or adjuvant and active benzodiazepine agent and melatonin. The medicine can be a medically contraindicated formulation suitable for oral, rectal, parenteral or transdermal administration, and it contains at least one diluent, carrier or adjuvant, and can be characterized by the following properties: (i) its Unit dosage forms, each unit dose containing melatonin in a range of 0.0025-100 mg; (a) in the form of a controlled release formulation, wherein melatonin is preferably at a predetermined controlled rate Release; (iii) it also contains at least one melatonin receptor modulator and / or melatonin action profile modulator. The medical contraindication may also include, and the pharmaceutical formulation according to the present invention comprises at least one benzodiazepine contraceptive, such as at least one Alprazolam, Limening, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Helazepam, Qi chicken go Methalazine, Normoxazol, Prazepam, Temazepam, Triazole This paper is sized for the Chinese National Standard (CNS) A4 (210x297 mm) (Please read the precautions on the back before filling this page),? Τ • J— n —J. · Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 483757 A7 --- __B7 V. Description of the invention (Π 一 ----— Benzodiazepine. Formulation containing at least one benzodiazepine leather agent The substance can further be characterized by-or a plurality of properties as described above, (ii) and (iii). In the application of the present invention to the treatment of multiple drug addiction or having dependence on a benzodiazepine drug, For patients with symptomatic or addictive symptoms, benzodiazepine medication is continuously administered to patients (at least at the beginning), and at the same time melatonin is effectively banned to relieve at least one of these symptoms . In a particular embodiment of this treatment, the benzodiazepine agent or melatonin may be in the form of a medically contraceptive formulation suitable for oral, rectal, parenteral or transdermal administration, and contains at least one diluent , Carrier or adjuvant. In addition, the benzodiazepine and melatonin formulated can be administered separately or combined into a single pharmaceutical formulation including diazepine drugs and melatonin. '' About fading For administration of melanin, whether administered separately or co-administered with one or more benzodiazepines, the effective amount of the ban can be a daily dose rate of, for example, 0.001 to 100 mg Fangu; It can be administered in the form of a controlled release formulation. For example, 1-2 mg of melatonin in the form of a controlled release formulation can be administered at night. Melatonin can be used with melatonin receptor modulators or fading. The melatonin action profile regulator is co-administered with Tsai. An example of a saver is a short-range action benzodiazepine, such as formazan; the body; the melatonin action profile modifier is benzodiazepine, beta-block Agents and serotonin absorption inhibitors. In addition to other effects, other regulators, the melatonin effect profile can allow patients to receive light before, after or during melatonin administration. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 Mm) (Please read the notes on the back before filling out this page}
IT—I 經濟部中央標準局員工消費合作社印製 483757 A7 ___—__B7 五、發明説明(5 ) 本文所指之苯幷二氮箪可能引發依賴性,忍受性及/或 上癌徵狀之危險。無對此概論具任何偏見,此類藥物可爲 如上所述之一或多種Alprazolam,利眠寧,Clorazepate ’安定 ’ Flunitrazepam,Flurazepam, Helazepam,氣經 去甲安定,去甲經基安定,Prazepam,Temazepam及三咬 苯二氮萆。 於另一應用本發明治療上述徵狀之具體實施例中,最初 將苯并二氮萆藥劑持績(與褪黑激素同時)以實質上與先 前建議以褪黑激素治療患者所接受相同之每曰劑量投藥予 患者。於另一應用本發明治療此等徵狀之具體實施例中, 將苯并二氮萆蔡劑(與褪黑激素同時)以相較於先前建議 以褪黑激素治療患者所接受之每日劑量逐漸減少之劑量投 禁予患者。於此具體實施例中,該逐漸減少之每曰施藥率 可持續(例如)至達到預定之穩定投藥率,或另外地(例 如)至苯并二氮萆之投藥量爲零爲土。 於應用本發明在預防目的之方面,即用以治療業經臨床 診斷爲具有容易藉施藥苯并二氮萆樂劑減缓痛苦之病況的 患者,同時預防患者發生對該苯并二氮萆藥劑依賴,具忍 受性,或上瘾之徵狀,係將苯并二氮箪藥劑以有效減緩該 病況之量投藥,同時將有效預防至少一項此類徵狀之量之 褪黑激素施予患者。上述各項可應用於治療具有所指徵狀 之患者的具體實施例,亦可對應地應用於預防目的,除非 習知該技藝人士有自明其不適用之理由,例如,於此以苯 并二氮萆藥劑治療爲迫切需要之例子中,明顯地所施用苯 本紙張尺度適用中國國家標準(CNS ) A4規格(2]l〇X297公釐) (請先閱讀背面之注意事項再填寫本頁) 訂 483757 A7 五、發明説明(6 ) 并二氪萆之量將不會減至零,而其於任何特定情況甲可能 由醫師決定減低。 然而,於本發明預防性應用之範菌中,不僅對施用者, 同時輿褪黑激素使用時,苯并二氪萆藥劑以習用之每曰劑 量率來達到特定目的,而且另對同樣地施用者,以少於習 用每曰劑量之此類藥劑投藥予患者,以減缓該病況仍在本 發明之範園内。 如上所指,本發明亦延伸至包括至少一種苯并二氮萆及 褪黑激素之醫藥調配物。因爲苯并二氮革禁劑通常每曰施 藥1-4次,褪黑激素每日率爲〇 〇1_1〇〇毫克(代表性地於 夜晚施用),故以苯并二氮萆之相同調配物,或各别施樂 係以如下施藥苯并二氮萆之例達成: 因此 曰數 苯并二氮萆之單位劑量範園 1 2 3 4 0· 100毫克 0.05 - 50 毫克 0.033 - 33.3毫克 0.025 - 25 毫克 經濟部中央標準局員工消費合作社印製 〇 當本發明之醫藥調配物爲單位劑量形式時,各劑量 單位較佳係於夜晚施藥且較佳地包含含量範園爲〇·〇〇25-100毫克之褪黑激素。 下表給予用以治療成人中上述病況之苯并二氮萆藥劑量 。對於進一步資料,例如限制條件,半衰期,適於孩童或 本、,.氏張尺度適用中)从規格(2公羞了 483757 A7 B7 五、發明説明(7 ) 嬰兒之施藥形式與劑量,參見Goodman & Gilman’s "治療 之藥理學基礎",第7版,1985 (MacMillan出版公司), 關於使用苯并二氮萆之章節(例如第352, 437頁),所有 此等章節皆併入本文作爲參考文獻。 苯并二氮萆 單位口服劑量値,一 毫克(X每天) 鎮靜量 安眠量 般每日口服劑量* ,解焦慮 Alprazolam 0.75-1.5 利眠寧 10-100(1-3) 50-100 15-40 Clorazepate 3.75-15(2-4) 15 - 30 30 安定 5-10(3-4) 5 -10 4-40 Flurazepam 15-30 Helazepam 60-160 氣m去甲安定 2-4 2-6 去甲m基安定 15-30(3-4) 15-30 30 - 60 Prazepam 20 - 40 Temazepam 15 - 30 ***苯二氮萆 0.25-0.5 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) *毫克,通常分成2-4單位劑量;對於進一步資料(包括 非經腸道劑量率)參見上所引述之Goodman & Gilman· 根據本發明之調配物之製備及釋放剖面圖或其應用舉例 説明如下。 (a)待將粉末狀物質,即2毫克/片劑褪黑激素(Biosynth 公司,瑞士)與丙烯酸樹脂載體(Rohn Pharma),其爲 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 483757 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(8 )Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs IT-I 483757 A7 ___—__ B7 V. Description of the Invention (5) The benzodiazepines referred to in this article may cause dependence, tolerance and / or the risk of cancer symptoms . Without any prejudice to this overview, such drugs may be one or more of the aforementioned Alprazolam, Limening, Clorazepate 'Diazepam' Flunitrazepam, Flurazepam, Helazepam, Qi-Nordiazepam, Normexyl-Diazepam, Prazepam, Temazepam and tribenzidine. In another embodiment in which the above symptoms are treated using the present invention, the benzodiazepine drug is initially maintained (at the same time as melatonin) at substantially the same level as that previously recommended for patients receiving melatonin treatment. The dose is administered to the patient. In another embodiment in which the present invention is used to treat these symptoms, the benzodiazepine (at the same time as melatonin) is compared to the daily dose received by patients who have previously been recommended to treat melatonin Reduced doses are banned from administration to patients. In this specific embodiment, the gradually decreasing daily application rate may continue (for example) to reach a predetermined stable dosage rate, or otherwise (for example) until the dosage of benzodiazepine is zero. In the application of the present invention for prevention purposes, it is used to treat patients who have been clinically diagnosed as having a condition to ease pain by administration of benzodiazepines, while preventing patients from developing the benzodiazepines Symptoms of dependence, tolerance, or addiction are those in which the benzodiazepine agent is administered in an amount effective to slow the condition, while melatonin is administered to the patient in an amount effective to prevent at least one of these symptoms. The above items can be applied to specific examples of treating patients with the indicated symptoms, and can be correspondingly applied to preventive purposes, unless those skilled in the art have a reason for their inapplicability, for example, benzodi In the case where the nitrogen treatment is urgently needed, it is obvious that the size of the benzene paper to be applied is in accordance with the Chinese National Standard (CNS) A4 (2) 10 × 297 mm. (Please read the precautions on the back before filling this page) Order 483757 A7 V. Description of the invention (6) The amount of the two will not be reduced to zero, and in any particular case A may be reduced by the physician's decision. However, in the prophylactic bacteria of the present invention, not only to the applicator, but also melatonin, the benzodiazepine agent achieves a specific purpose at the conventional dose rate, and it is also applied to the same Or, it is still within the scope of the present invention to administer the agent to a patient in a dosage of less than a conventional dose. As indicated above, the invention also extends to pharmaceutical formulations comprising at least one benzodiazepine and melatonin. Because benzodiazepines are usually administered 1-4 times per day, the daily rate of melatonin is 0.001 to 100 mg (typically at night), so the same formulation of benzodiazepine is used. Benzodiazepines were achieved with the following examples: Therefore, the unit dose of benzodiazepines was 1 2 3 4 0 · 100 mg 0.05-50 mg 0.033-33.3 mg 0.025 -25 mg Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. When the pharmaceutical formulation of the present invention is in the form of a unit dose, each dosage unit is preferably applied at night and preferably contains a content range of 0.000. 25-100 mg of melatonin. The following table gives the benzodiazepine doses used to treat the above conditions in adults. For further information, such as restrictions, half-life, suitable for children or this, in the application of Zhang's scale) from the specifications (2 males 483757 A7 B7 V. Description of the invention (7) infants' application forms and dosages, see Goodman & Gilman's " The Pharmacological Basis of Treatment ", 7th edition, 1985 (MacMillan Publishing Company), chapter on the use of benzodiazepines (eg pages 352, 437), all of which are incorporated This article serves as a reference. Benzodiazepine unit oral dose 値, one milligram (X per day) sedative amount sleep-like daily oral dose *, anxiety relief Alprazolam 0.75-1.5 rimienine 10-100 (1-3) 50 -100 15-40 Clorazepate 3.75-15 (2-4) 15-30 30 Diazepam 5-10 (3-4) 5 -10 4-40 Flurazepam 15-30 Helazepam 60-160 Dimethoate diazepam 2-4 2 -6 Normidine Diazepam 15-30 (3-4) 15-30 30-60 Prazepam 20-40 Temazepam 15-30 Triazole benzodiazepine 0.25-0.5 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please Read the notes on the back before filling out this page) * mg, usually divided into 2-4 unit doses For further information (including parenteral dose rates), please refer to the Goodman & Gilman quoted above. The preparation and release profile of the formulation according to the invention or its application is illustrated below. (A) Powdery substance to be 2 mg / tablet melatonin (Biosynth, Switzerland) and acrylic resin carrier (Rohn Pharma), which is the standard of this paper and applies the Chinese National Standard (CNS) A4 (210X 297 mm) 483757 Central Standard of the Ministry of Economic Affairs A7 B7 printed by the Bureau's Consumer Cooperatives V. Invention Description (8)
Eudrgit RS100 (配方SR-Ms )或Eudragit RSP0 (配方SR-Eudrgit RS100 (Recipe SR-Ms) or Eudragit RSP0 (Recipe SR-
Mf )’此外如下所示之其他組成:配方SR~Ms : Eudragit RS100 48·8%,乳糖50%,褪黑激素 1 ·2% ;配方 SR-Mf :Mf) ’In addition to the other components shown below: Formula SR ~ Ms: Eudragit RS100 48 · 8%, lactose 50%, melatonin 1.2%; formula SR-Mf:
Eudragit RSP0 35.3% ;乳糖 16.7%,磷酸氫鈣41.4%,滑 石1.3%,硬脂酸鎂4%,褪黑激素1.3%,乾燥混合後,於7 毫米圓柱形穿孔器於2.5噸下壓縮。SR-Ms與SR-Mf爲持續 釋出配方。 ' 習用之劑量形式(RM)係類似於配方SR-Mf製備得,但使 用乳糖取代Eudrgit作爲載體。 (b)如(a)段所述製備得之片劑的可能釋放剖面圖首先以 活體外於37¾下褪黑激素於蒸餾水中之溶解而研究得,表 A之結果列示於設定時間間隔時已溶解之褪黑激素含量% (爲6片劑之平均値>。 ""Eudragit RSP0 35.3%; lactose 16.7%, calcium hydrogen phosphate 41.4%, talc 1.3%, magnesium stearate 4%, melatonin 1.3%, after drying and mixing, compress in a 7 mm cylindrical perforator at 2.5 tons. SR-Ms and SR-Mf are sustained release formulations. '' The conventional dosage form (RM) was prepared similarly to the formulation SR-Mf, but used lactose instead of Eudrgit as a carrier. (b) The possible release profile of the tablets prepared as described in paragraph (a) was first studied with the dissolution of melatonin in distilled water at 37¾ in vitro. The results in Table A are shown at the set time interval. Dissolved melatonin content% (average of 6 tablets). &Quot; "
4__A 時間(小時) 1 2 4 6 8 10 褪黑激素(%) 由下列釋出: SR-Ms 12 29 62 84 90 100 SR-Mf 32 51 76 88 100 RM 93 96 100 ^ ^ ^ (C)如(a)段所述製備得之SR-Mf片劑之活體内剖面圖,係 藉於上午1〇時(即當循環之褪黑激素無法偵測時)對健康 男子(年紀36歲)口服施藥兩次而研究得。褪黑激素於、舌 10 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) —-------抽衣-------訂----- (請先閱讀背面之注意事項再填寫本頁〕 483757 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(9 ) 體内所釋出之量係藉其主要代謝物(6-硫酸根氧基褪黑激 素)於尿液中之放射免疫分析而測定得。尿液之6_硫酸根 氧基褪黑激素含量密切反應該激素之血液濃度。表B之結 果列示所測定得褪黑激素對總所施用褪黑激素之%(爲2 片劑之平均値)。 A__B_ 褪黑激素從SR-Mf之活體内釋出 時間(小時) 1 2 4 6 8 10 於間隔之%釋出 10.7 25.7 40.6 14.0 7.0 1.9 累積之釋出% 10.7 36.4 77.0 91.0 98.0 99.9 注意,由於活性化合物於釋出之早期階段會被組織吸收 之現象,褪黑激素於活體外之釋出(表A所説明)僅提供 活體内釋出剖面圖之大约指示。 褪黑激素於持續釋出調配物中之含量可改變爲(例如) 0.5,1或5毫克/片劑,而未影響於含有2毫克/片劑 褪黑激素所發現之釋出型式。 於本發明中,作爲實質上於人體中仿效褪黑激素作用之 技藝已知的褪黑激素類似物,將被認爲其係褪黑激素之明 顯化學相等物。 根據本發明,可將一或多種苯并二氮萆以如上所述之量 併入上述調配物中。 本發明將以下列實施例舉例説明。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁)4__A Time (hours) 1 2 4 6 8 10 Melatonin (%) is released by: SR-Ms 12 29 62 84 90 100 SR-Mf 32 51 76 88 100 RM 93 96 100 ^ ^ ^ (C) If The in vivo cross-sectional view of the SR-Mf tablets prepared in paragraph (a) was taken orally at 10 am (ie when circulating melatonin could not be detected) to a healthy man (age 36). The drug was studied twice. Melatonin Yu, Tongue 10 This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) ----------- Sliding ------- Order ----- (Please Read the precautions on the back before filling this page] 483757 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9) The amount released in the body is based on its main metabolite (6-sulfate oxygen Based on radioimmunoassay in urine. The 6-sulfate oxymelatonin content in urine closely reflects the blood concentration of the hormone. The results in Table B show the measured melatonin. % Of total administered melatonin (average of 2 tablets). A__B_ Release time of melatonin from SR-Mf in vivo (hours) 1 2 4 6 8 10 Released at% of interval 10.7 25.7 40.6 14.0 7.0 1.9 Cumulative release% 10.7 36.4 77.0 91.0 98.0 99.9 Note that due to the phenomenon that active compounds are absorbed by tissues in the early stages of release, the release of melatonin in vitro (as described in Table A) is only provided An approximate indication of the cross-section of the release in vivo. The content can be changed to, for example, 0.5, 1 or 5 mg / tablet without affecting the release pattern found in melatonin containing 2 mg / tablet. In the present invention, as substantially in the human body Melatonin analogues known to mimic the action of melatonin will be considered to be the obvious chemical equivalent of melatonin. According to the present invention, one or more benzodiazepines can be treated as described above. The amount is incorporated into the above-mentioned formulation. The present invention will be illustrated by the following examples. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)
483757 A7 ______B7 五、發明説明(10 ) 實施例1 研究習慣性苯并二氮蕈與褪黑激素施藥對腦中褪黑激素 及苯并·一氮革觉體之交互影響’以及梗黑激素逆轉此等影 響之能力。將雄性大鼠於24士 2ec下維持每日14小時光照 :10小時黑暗之時間表(光照:05.00h ;冷白色熒光照明 )。食物與飲水無限制供應。將動物(2個月大),分成 4組,各含5隻動物。其中一組動物(CON)每天於16:00時 以i.P·注射載體(200微升食鹽水)。第二組動物(VAL)每 天於16:00時以i.p·注射安定(1毫克存於2〇〇微升載體中 ;Roche)。第三組動物(MEL)每天於16:00時以載體注射; 此組之飲水含有褪黑激素(4毫克溶解於1〇〇微升乙醇中 並稀釋至1升)。第四組動物(VAL/MEL)每夭於16:00時注 射安定(1毫克存於200微升載體中);此組之飲水含有 褪黑激素(4毫克溶解於100微升乙醇中並稀釋至1升) 。待21天後終止處理並將動物稱重。於VAL (274士 20克) 與VAL/MEL組(239士 30克)之平均體重値發現較CON (292士 30克)或MEL組(285土 30克)之値稍低。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 將動物於次日之18-19.00時斷頭(於此時雜質橋中之2-125卜碘褪黑激素濃度應爲最大);迅速將其腦取出並如所 述製備粗突觸體丸粒,並如Laudon,M.及Zisapel, N., FEBS Lett·,1986,197: 9-12所述分析褪黑激素受體。 藉如Amiri, Z·等人,Brain Res·,1991,553:155-158 所述測量 3 H-f lunitrazepam ( 3 H-FNZ)與 3 h-RO 15-1788 之結合而分析苯并二氮萆受體。從平衡結合數據計算結合 -12 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 483757 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(η ) 參數。Bmax値代表2-丨25 I-碘褪黑激素,3 H-FNZ或3 H-RO 15-1788於飽和下之專一結合,而Kd値爲表觀解離常數。 藉由分析接著作多重比較之Student-Newman-Keul ’s測試 的分散,比較各組之結合參數。若Ρ<〇·〇5則認爲具顯著差 異。以安定(1毫克i ·Ρ於16·00時)注射至雄性大鼠3週 ,明顯減低髓質橋中2-挪卜碘褪黑激素結合部位之密度( 表1 ),而苯并二氮萆之結合未明顯受影響(表2 )。若 褪黑激素受體與睡眠-喚醒循環有關,該等結果暗示習慣 性投藥苯并二氮蕈導致褪黑激素反應之機制及後續之生 理活性減低。 褪黑激素,藉由飲水口服給予3週,顯著增強3 H-RO 15-1788於髓質橋中之結合(表2,3),而2-挪I-碘褪黑 激素之結合不受影響。由褪黑激素處理所謗發之髓質橋中 苯并二氮萆結合位置密度與表觀Kd增加,與先前於大鼠皮 質中所觀察之增加相符,且顯示由類阿片肽類居間參與( Gomar,M .D·等人,神經内分泌學1993,4:987-990 )。此 增加即使於受安定處理之動物中仍保留之事實,可能排除 褪黑激素與苯并二氮蕈於苯并二氮萆結合位置上之競爭作 每日投藥安定與褪黑激素,増強3 H-R0 15-1788於髓質 橋中之結合,並逆轉由安定謗發2-丨25 I-碘褪黑激素於此區 域結合之壓制作用(表1,2)。此等結果如先前所示係令 人意外的(Anis,Υ·等人,於倉鼠腦中之褪黑激素結合 位置:褪黑激素之衝擊。Molec· Cell. Endocrinol., -13 - 本紙張尺度適用中國國家標準(CNS〉A4規格(21057公釐丁" (請先閱讀背面之注意事項再填寫本頁) 擎裝· 訂 483757 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(12 ) 1989,67:121-128; Oaknin-Bendahan, S·等人,J·483757 A7 ______B7 V. Description of the Invention (10) Example 1 Study the interaction between benzodiazepine and melatonin administration on melatonin and benzo-nitrogen leather sensory body in the brain and melatonin The ability to reverse these effects. The male rats were maintained at 24 ± 2ec for 14 hours a day: 10 hours dark schedule (light: 05.00h; cold white fluorescent lighting). Unlimited food and water supply. The animals (2 months old) were divided into 4 groups, each containing 5 animals. One group of animals (CON) was injected with i.P. vehicle (200 microliters of saline) daily at 16:00. Animals of the second group (VAL) were stabilized i.p. injection at 16:00 every day (1 mg in 2000 microliters of vehicle; Roche). Animals in the third group (MEL) were injected with vehicle at 16:00 daily; drinking water in this group contained melatonin (4 mg dissolved in 100 microliters of ethanol and diluted to 1 liter). Animals in the fourth group (VAL / MEL) were injected with diazepam at 16:00 (1 mg in 200 microliters of vehicle); the water in this group contained melatonin (4 mg was dissolved in 100 microliters of ethanol and diluted) To 1 liter). The treatment was terminated after 21 days and the animals were weighed. The mean body weights in the VAL (274 ± 20g) and VAL / MEL groups (239 ± 30g) were found to be slightly lower than those in the CON (292 ± 30g) or MEL groups (285 ± 30g). Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The animals are decapitated at 18-19.00 the next day (at this time, 2-125 iodine in the impurity bridge fades The hormone concentration should be maximal); quickly remove the brain and prepare coarse synaptosome pellets as described, and analyze as described by Laudon, M. and Zisapel, N., FEBS Lett., 1986, 197: 9-12 Melatonin receptor. Analysis of benzodiazepines by measuring the combination of 3 Hf lunitrazepam (3 H-FNZ) and 3 h-RO 15-1788 as described by Amiri, Z · et al., Brain Res ·, 1991, 553: 155-158 body. Calculate the combination from the balanced combination data -12-This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 483757 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of invention (η) parameters. Bmax 値 represents 2- 丨 25 I-iodine melatonin, 3 H-FNZ or 3 H-RO 15-1788 is a specific combination under saturation, and Kd 値 is the apparent dissociation constant. By analyzing the scatter of Student-Newman-Keul's test for multiple comparisons, the binding parameters of each group were compared. If P < 0.05, it is considered to be significantly different. Diazepam (1 mg i · P at 16:00) was injected into male rats for 3 weeks, which significantly reduced the density of the 2-norbiodine melatonin binding site in the medullary bridge (Table 1), while benzodiazepines The combination of rhenium was not significantly affected (Table 2). If the melatonin receptor is related to the sleep-wake cycle, these results suggest that the habitual administration of benzodiazepines leads to the mechanism of melatonin response and subsequent decrease in physiological activity. Melatonin, given orally by drinking water for 3 weeks, significantly enhanced the binding of 3 H-RO 15-1788 to the medullary bridge (Tables 2, 3), while the binding of 2-N-I-iodine melatonin was not affected . The density of benzodiazepine-binding sites in the medullary bridges elicited by melatonin treatment increased with apparent Kd, consistent with the increase previously observed in rat cortex, and showed an intervening involvement of opioid peptides ( Gomar, M.D. et al. Neuroendocrinology 1993, 4: 987-990). The fact that this increase is retained even in animals treated with stabilization may preclude competition between melatonin and benzodiazepine at the benzodiazepine binding site for daily dosing of stability and melatonin, stubborn 3 H -R0 15-1788 binding in the medullary bridge and reversed the suppression of 2-I-25 I-melatonin binding in this region by diazepam (Table 1, 2). These results are surprising as shown previously (Anis, Υ · et al., Melatonin binding site in hamster brain: the impact of melatonin. Molec · Cell. Endocrinol., -13-paper size Applicable to Chinese National Standards (CNS> A4 specifications (21057 mm Ding " (Please read the notes on the back before filling this page)) Assembling and ordering 483757 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (12) 1989, 67: 121-128; Oaknin-Bendahan, S. et al., J.
Basic Clin. Physiol. Pharmacol., 1992, 3:253^268) ,且亦於本研究中確定,藉由早晨或傍晚注射,或經由飲 水口服投禁褪黑激素,不會影響褪黑激素於大部份腦區域 (包括髓質橋)中褪黑激素之密度或日間之變化。然而, 松果腺切除術並未廢止2-既卜碘褪黑激素結合位置於日間 之變化,雖然其影響它們的相位置(Oaknin-Bendahan等 人,1992,在同處)。因此,褪黑激素結合位置密度之改 變可能不是由於因褪黑激素引起之受體自我調節作用。 於大腦皮質中,褪黑激素稍微減低3 H-R0 15-1788與 3 H-FNZ之結合。以安定處理未顯著影響3 h-R〇 15-1788 與3 H-FNZ之結合,但防止由褪黑激素參與之減低(表2, 3)。此等數據首先暗示,褪黑激素對苯并二氮萆結合位 置之作用爲局限性的,而非發生對結合之普遍壓制或促進 ,而第二,褪黑激素取代治療法可抵制某些慢性苯并二氮 萆治療所產生之有害作用。 表1以Kd (單位nM),及Bmax (單位微莫耳/毫克蛋白 質)之平均與S · D ·値等術語,列示於由經安定及/或梗黑 激素處理與未經處理之大鼠的髓質橋區域獲得之突觸體製 備物中2-125 I-碘褪黑激素結合位置之平衡結合參數。表1 中以相同符號指示之値無顯著差異。(具有相同意義之符 號亦用於表2及表3中,如下。) 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇Χ297公釐) |裝-- (請先閱讀背面之注意事項再填寫本頁) 訂 .1· 483757 A7 B7 五、發明説明(13 ) 表 1 組别 Kd士 sd Bmax士 sd C0N 0·87士 0·2 a 7.9士1.0a MEL 1·16士 0·3 a 7.7土1.0a YAL 0 · 98士 0·21a 5·1土0.5b YAL/MEL 2·27士0.75b 12.5土2.0c 表2以Kd (單位nM)及Bmax (單位微莫耳/毫克蛋白質 )之平均與S.D.値等術語,列示由經安定及/或褪黑激素 處理與未經處理之大鼠的髓質橋區域獲得之突觸體製備物 中 3 H-R0 15-1788結合位置之平衡結合參數 ο 表 2 組别 Kd土 sd Bmax士 sd C0N 2·3土 0·4a 310土22a MEL 2.8士0.2a 476土26b VAL 2·5士0.4a 295土34a YAL/MEL 2 · 6士 0·5a 375土87b (請先閱讀背面之注意事項再填寫本頁) 擎裝-------訂----- 經濟部中央標準局員工消費合作社印製 表3以平均與S.D.値之術語(單位微莫耳/毫克蛋白質 )列示安定或褪黑激素對3 H-FNZ及3 H-RO 15-1788於大 鼠大腦皮質膜中之結合的影響。 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X297公釐) 、發明説明(14 ) 表 3 3 H-FNZ —一-〜 3 H-R0 15-1788 —· — — _ 935土31a 1354土48a 765土78b 1060土26b 870士22a 1264土99a 980土16a 1362土155aBasic Clin. Physiol. Pharmacol., 1992, 3: 253 ^ 268), and it was also determined in this study that banning melatonin by morning or evening injection or oral administration via drinking water will not affect melatonin Melatonin density or day-to-day changes in parts of the brain (including medullary bridges). However, pineal glandectomy does not abolish the diurnal changes in 2-iodine-melatonin binding sites, although it affects their phase positions (Oaknin-Bendahan et al., 1992, at the same place). Therefore, changes in the density of melatonin-binding sites may not be due to receptor self-regulation by melatonin. In the cerebral cortex, melatonin slightly reduces the combination of 3 H-R0 15-1788 and 3 H-FNZ. Treatment with diazepam did not significantly affect the combination of 3 h-R0 15-1788 and 3 H-FNZ, but prevented the reduction of melatonin involvement (Tables 2, 3). These data first suggest that the effect of melatonin on benzodiazepine binding sites is limited, rather than the general suppression or promotion of binding, and second, that melatonin replacement therapy can resist some chronic Harmful effects of benzodiazepine treatment. Table 1 shows the average values of Kd (unit nM) and Bmax (units of micromolar / mg protein) and S · D · 値. Equilibrium binding parameters of 2-125 I-iodine melatonin binding sites in synaptosome preparations obtained from rat medulla bridge regions. There are no significant differences in Table 1 indicated by the same symbols. (Symbols with the same meaning are also used in Tables 2 and 3, as follows.) This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇 × 297 mm) | Installation-(Please read the precautions on the back first Refill this page) Order. 1.483757 A7 B7 V. Description of the invention (13) Table 1 Group Kd ± sd Bmax ± sd C0N 0 · 87 ± 0 · 2 a 7.9 ± 1.0a MEL 1 · 16 ± 0 · 3 a 7.7 soil 1.0a YAL 0 · 98 ± 0 · 21a 5 · 1 soil 0.5b YAL / MEL 2 · 27 ± 0.75b 12.5 soil 2.0c Table 2 uses Kd (unit nM) and Bmax (unit: micromole / mg protein) The average and SD 値 terms list the 3 H-R0 15-1788 binding sites in synaptosome preparations obtained from the medullary bridge region of stabilized and / or melatonin treated and untreated rats Balance binding parameters ο Table 2 Group Kd soil sd Bmax ± sd C0N 2 · 3 soil 0 · 4a 310 soil 22a MEL 2.8 ± 0.2a 476 soil 26b VAL 2 · 5 ± 0.4a 295 soil 34a YAL / MEL 2 · 6 Taxi 0 · 5a 375 Soil 87b (Please read the precautions on the back before filling out this page) SD 値 terminology ( Units of micromoles per milligram of protein) show the effects of diazepam or melatonin on the binding of 3 H-FNZ and 3 H-RO 15-1788 to rat cerebral cortex. This paper size is applicable to China National Standard (CNS) A4 (210X297 mm), invention description (14). Table 3 3 H-FNZ — One-~ 3 H-R0 15-1788 — · — — _ 935 soil 31a 1354 Soil 48a 765 Soil 78b 1060 Soil 26b 870 People 22a 1264 Soil 99a 980 Soil 16a 1362 Soil 155a
組别 —、-一 _ CON MEL VAL VAL/MEL (請先閱讀背面之注意事項再填寫本頁) 實施例2 訂 經濟部中央標準局員工消費合作社印製 j實施例説明褪黑激素於促進自苯幷二氮萆細忍受性 常快速撤回方面之驚奇作用。有位年43歲已婚有兩小孩 並e惟患失眠症10年並具有時常且嚴重之偏頭痛。 2完全之神經學評估爲負値。精神或其他器官之問題亦被 』除。經過這些年她已接受苯并二氮萆,三環類抗憂#劑 2安定鎮痛劑,以及以生物回饋及舒解方法等治療,但無 月顯改善。最近這年她已每晚服用4〜8毫克氣轉去甲安定c 與:項於提爾艾維(Tel Aviv)大學睡眠實驗室之完全精神 予評估,未揭示任何明顯之病狀。睡眠性質係藉追蹤經由 接至手腕之小型裝置,自動偵測睡眠時熟睡-甦醒之型式的 作用圖譜而分析得。該追蹤連續記綠3天,並顯示擾亂之 睡眠型式••效率減低,長的睡眠潛伏及多次喚醒***。每 】時收集尿液(36小時)並分析主要之褪黑激素代謝物: 匕人酸根氧基褪黑激素,作爲血漿褪黑激素日間分泌作用 扣標物。結果顯示6_硫酸根氧基褪黑激素***量較同年齡 16 -Group — 、-一 _ CON MEL VAL VAL / MEL (Please read the precautions on the back before filling this page) Example 2 Order printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Benzamidine diazepam has a surprising effect on fine tolerance and often rapid withdrawal. A 43-year-old married with two children and only suffered from insomnia for 10 years and had frequent and severe migraines. 2 A complete neurological assessment is negative. Problems with mental or other organs are also eliminated. After these years, she has received benzodiazepine, tricyclic anti-anxiety agent # 2 diazepam analgesics, and biofeedback and relief methods, but no significant improvement. In recent years, she has taken 4 to 8 mg of qi to nortriprolidone per night and the complete spirit of the sleep laboratory at Tel Aviv University has been evaluated. No obvious symptoms have been revealed. The nature of sleep is analyzed by tracking the action map of the type of asleep-wake during sleep through a small device connected to the wrist. This track records green for 3 consecutive days and shows disturbed sleep patterns. • Reduced efficiency, long sleep latency, and multiple wake insertions. Urine was collected at every hour (36 hours) and the main melatonin metabolites were analyzed: human acid oxymelatonin, as a day-to-day secretion of plasma melatonin. The results showed that 6_ sulfate melatonin excretion was more than the same age 16-
483757 A7 B7 五、發明説明(15 ) 個人低,並缺乏典型之週期規律(表4)。 開始以口服投藥含有1毫克褪黑激素(Neurim製禁公司 ,以色列)片劑形式之受控釋出褪黑激素調配物,以校正 褪黑激素週期之缺陷與畸變。每日於上午8:30施予一片劑 。要求該患者逐漸減少於每晚服用之苯并二氮萆禁片數目 。意外地’於2天内,該患者完全停止使用苯并二氮箪安 眠藥,並宣稱其失眠症已明顯改善。此外,其頭痛症亦逐 漸平息。於3週治療後重覆作用圖譜之追蹤顯示其睡眠型 式有顯著改善。 停止治療,並於2週後再度每3小時收集尿液(36小時) 且分析6-硫酸根氧基褪黑激素。結果(表4 )指示尿液之 6-硫酸根氧基褪黑激素量增加且具有明顯之夜間高峰。5 個月之後續追縱確定該患者仍維持其睡眠性質並且很少再 患頭痛。於無治療6個月後,睡眠性質_惡化並再予褪黑 激素治療。 此個案報告可能指示一項解除許多其生活性質已受苯并 一氮萆安眠禁成瘾而破壞之患者痛苦的突破。投藥外源性 褪黑激素更可作爲快速且無徵狀從對苯弁二氮萆具忍受性 患者撤除之方法。 (請先閱讀背面之注意事項再填寫本頁)483757 A7 B7 V. Description of the invention (15) Individuals are low and lack typical cycle rules (Table 4). Began oral administration of a controlled release melatonin formulation in the form of a tablet containing 1 mg melatonin (Neurim Prohibition Company, Israel) to correct defects and distortions in the melatonin cycle. One tablet is administered daily at 8:30 AM. The patient was asked to gradually reduce the number of benzodiazepine tablets that were taken every night. Unexpectedly, within 2 days, the patient completely stopped using benzodiazepine sleeping pills and claimed that her insomnia had improved significantly. In addition, his headache gradually subsided. Tracking of the repetitive effect spectrum after 3 weeks of treatment showed significant improvement in sleep patterns. Treatment was discontinued, and urine was collected again every 3 hours (36 hours) after 2 weeks and 6-sulfate oxymelatonin was analyzed. The results (Table 4) indicate an increase in the amount of 6-sulfateoxymelatonin in the urine and a significant nighttime peak. A follow-up of 5 months confirmed that the patient still maintained his sleep and rarely had headaches. After 6 months of no treatment, the nature of sleep worsened and melatonin was given again. This case report may indicate a breakthrough to relieve the suffering of many patients whose nature of life has been disrupted by benzodiazepine addiction. Administration of exogenous melatonin can also be used as a rapid and symptom-free method to remove p-benzodiazepine-bearing patients. (Please read the notes on the back before filling this page)
經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) M規格(21〇χ297公羞) 五、發明説明(16^ -—— 苯并〜氮萆—依賴性患者中於褪黑激素治療法之前 、之後的尿液6'硫酸根氧基褪黑激素(微克/小時) -— 時間 治療前 ~ ------— 治療後 15.00 0.3 0.11 18.00 0.16 0.45 21.00 0.18 0.11 24.00 0.13 1.24 3.00 0.23 0.74 6.00 0.23 0.36 9.00 0.22 0.21 12.00 0.13 0.01 15.00 0.22 0.04 (請先閱讀背面之注意事項再填寫本頁} I裝· 訂 經濟部中央標準局員工消費合作社印製 實施例3 此實施例説輞長期投藥褪黑激素治療對苯并二氮萆藥劑 依賴之患者的失眠症之影響。 兩名自願者,Y.L· ( 80歲男性)與E· L· ( 73歲女性) 已罹患失眠症多年及/或於夜間常覺醒,並且之後很難再 入睡。此二者均發現具有低褪黑激素分泌(藉由測定尿液 中代謝物6-硫酸根氧基褪黑激素之量)。二名患者於每晚 就寢前皆口服卜2毫克f lunitrazepam。 每位患者以逐漸減少f 1uni trazePam劑量而將其安排去 本紙張尺度適用中國國家標準(CNS ) A4规格(21〇x297公釐) 483757 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明(17 ^且同時Π服投藥褪黑激素(每E12毫克以受控釋出形 式)超過2個月。自從該時期結束後,每位患者持續服用 相同形式及相同劑量率之褪黑激素長達约2年。 每位患者均主觀地報告有良好的睡眠謗導且於睡眠性質 方面有實質的改善。特别地,患者E.L.於安排期間開始時 即於睡眠性質方面記綠有改善,而Y.L·於進入安排期間約 二題時記綠有相似之作用。每位患者於開始安棑期間後數 天内皆報告於白夭疲勞減少,且亦指出褪黑激素已使於早 晨不殘留疲倦,或無任何宿醉感覺。兩位患者均未報告有 任何副作用。 實施例4 此實施例,設計爲隨機化,雙盲,交又研究,説明褪黑 激素取代治療法改善習慣性使用苯并二氮萆藥劑之年長患 者睡眠持績性的功能。 一組平均年紀爲78歲(SD=9 · 7)由八名男性與五名女性組 成,其皆患有長期失眠症且使用各種苯并二氮雜箪來謗發 睡眠。於大约每4小時收集尿液15小時,並以RiA重覆分 析夜間6-硫酸根氧基褪黑激素(主要之褪黑激素尿液代謝 物)的排出。此等患者之尿液分析顯示低量且延遲之6-硫 酸根氧基褪黑激素排出(〈14微克每晚,相較於年輕成人 爲25微克每分鐘)。研究計劃包含兩次各爲三週之治療時 期,及介於兩次治療時期之間的一週洗去間隔。於治療時 期内,患者於睡前口服投藥予2毫克受控釋出之褪黑激素 片劑,或安慰劑。五位患者於最初之實驗時間以外持續褪 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁) f裝· 訂 483757 A7 B7 五、發明説明(18 ) 黑激素治療達2個月。 於各治療時期結束時使用手腕配載之作用圖譜客觀分析 患者之睡眠連續三個夜晚。使用Neurini演算法分析運動記 綠以測定睡眠潛伏,睡眠效率,總睡眠時間,睡眠開始後 之甦醒與覺醒次數,作爲個人三個晚上之平均。六次配對 標記排列分析顯示於褪黑激素與安慰劑處理時期之排列之 間的睡眠參數具有統計上之顯著差異。結果列示於表5中 〇 表5:以褪黑激素取代苯并二氮萆藥劑對睡眠參數之作用 參數 3週之治療後 褪黑激素安慰劑 +2個月褪黑激素 治療後 睡眠 82% 75% 效率 (ζ=-2.82, ρ=0·005) 睡眠潛伏 17分鐘 39分鐘 7分鐘 (ζ=_2·12, ρ=0·03) 睡眠開始後 59分鐘 39分鐘 7分鐘 之甦醒 (ζ=-2·00, ρ=0·04) 覺醒次數 11 17 10 (ζ=-2.70, ρ=0·007) 總睡眠時間 386分鐘 375分鐘 348分鐘 (ζ二-0.57, ρ二0·58) 由上述結果,結論得褪黑激素取代治療法可改善具有低 經濟部中央標準局員工消費合作社印製 ^^^1' ^il·· ϋϋ mV —ϋ mi 士ιϋ_— ϋϋ In ϋϋ mu- —ϋ 一 ^ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) 483757 A7 B7 五、發明説明(19 ) 内生性褪黑激素之使用苯并二氮萆藥劑的年長患者之睡眠 引發及持績。褪黑激素治療之助益隨時間而增加,暗示已 發生週期系統之再組織。 本發明進一步包括製造用以治療多重禁物成瘾,或具有 成爲對苯并二氮萆藥劑依賴,具忍受性,或上瘾之徵狀之 患者,或治療業經臨床診斷爲具有容易藉施藥苯并二氮萆 藥劑減缓痛苦之病況的患者,同時預防患者發生對該苯并 二氮萆藥劑依賴,具忍受性,或上瘾之徵狀的醫藥品之方 法;該方法包含藉將褪黑激素與至少一種稀釋劑,載體或 佐劑混合而調配於適於口服,直腸,非經腸道或穿皮施藥 之單位劑量形式中,各單位劑量含有範園介於0.0025-2毫 克(較佳爲0.01-2毫克)量之褪黑激素,且較佳地適合使 褪黑激素以預定之受控速率釋出。另外可將至少一種褪黑 激素受體調節劑及/或褪黑激素作用輪廓調節劑,及/或 至少一種苯幷二氮萆禁劑如Alprazolam,利眠寧, Clorazepate,安定,Flunitrazepam, Flurazepam, Helazepam,氣雞去甲安定,去甲麟基安定,Prazepam, Temazepam及三。坐苯并二氮萆與褪黑激素混合。 (請先閲讀背面之注意事項再填寫本頁) ϊ m .1^1. V —ϋ —ϋ m ϋϋ ϋϋ ml I I. —ϋ—^二= ϋϋ 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) 483757Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. The paper size is applicable to the Chinese National Standard (CNS) M specification (21 × 297 mm). 5. Description of the invention (16 ^--benzo ~ azepine-dependent patients) Urine 6 'sulfate oxymelatonin (micrograms / hour) before and after melatonin treatment--time before treatment ~ -------after treatment 15.00 0.3 0.11 18.00 0.16 0.45 21.00 0.18 0.11 24.00 0.13 1.24 3.00 0.23 0.74 6.00 0.23 0.36 9.00 0.22 0.21 12.00 0.13 0.01 15.00 0.22 0.04 (Please read the notes on the back before filling out this page} I. Ordering and Printing by the Central Standards Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs Example 3 This Example The effects of long-term administration of melatonin treatment on insomnia in benzodiazepine-dependent patients are described. Two volunteers, YL · (80-year-old male) and E · L · (73-year-old female) have suffered from insomnia. Waking up at night and / or at night and having difficulty falling asleep afterwards. Both have been found to have low melatonin secretion (by measuring the amount of metabolite 6-sulfateoxymelatonin in the urine). All patients took 2 mg of flunitrazepam orally every night before going to bed. Each patient was scheduled to reduce the dose of f 1uni trazePam to this paper. This paper applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 483757 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (17 ^ and at the same time melatonin (12 mg per E12 in a controlled release) was administered for more than 2 months. Since the end of this period, every Patients continued to take melatonin in the same form and at the same dose rate for about 2 years. Each patient reportedly subjectively reported good sleep defamation and substantial improvement in the nature of sleep. In particular, patient EL was scheduled At the beginning of the period, there was an improvement in sleep quality in the nature of sleep, and YL · had a similar effect in recording green when entering the second period of about two questions. Each patient reported a reduction in fatigue in white peony within a few days after starting the rest period, It was also pointed out that melatonin had left no fatigue or no hangover sensation in the morning. Neither patient reported any side effects. Example 4 This example, Randomized, double-blind, and cross-study studies show that melatonin replacement therapy improves sleep performance in older patients who are habitually using benzodiazepines. A group with an average age of 78 years (SD = 9 · 7) Consists of eight men and five women, all of whom suffer from chronic insomnia and use various benzodiazepines to provoke sleep. Urine was collected for approximately 15 hours approximately every 4 hours, and weighted as RiA. Analysis of 6-sulfate oxymelatonin, the major melatonin urine metabolite, was performed at night. Urinalysis of these patients showed low and delayed 6-sulfateoxymelatonin excretion (<14 micrograms per night, compared to 25 micrograms per minute in young adults). The study plan included two treatment periods of three weeks each, and a weekly wash-out interval between the two treatment periods. During the treatment period, patients were orally administered 2 mg of controlled-release melatonin tablets or placebo before bedtime. Five patients continued to fade outside of the initial experiment time. The paper size applies the Chinese National Standard (CNS) A4 (210X297 mm) (please read the precautions on the back before filling this page) f. Binding 483757 A7 B7 V. Description of the invention (18) Melanin treatment for 2 months. At the end of each treatment period, a wrist-loaded effect map was used to objectively analyze the patient's sleep for three consecutive nights. Neurini algorithm was used to analyze exercise log green to determine sleep latency, sleep efficiency, total sleep time, and the number of wakes and awakenings after sleep onset as the average of three nights in the individual. Six-pair marker-array analysis showed statistically significant differences in sleep parameters between the array of melatonin and placebo-treated periods. The results are shown in Table 5. Table 5: Effect of melatonin-substituted benzodiazepine on sleep parameters Parameter of melatonin placebo after 3 weeks of treatment + 82% of sleep after 2 months of melatonin treatment 75% efficiency (ζ = -2.82, ρ = 0.005) Sleep latency 17 minutes 39 minutes 7 minutes (ζ = _2 · 12, ρ = 0 · 03) 59 minutes 39 minutes and 7 minutes wake up after sleep onset (ζ = -2 · 00, ρ = 0.04) Number of awakenings 11 17 10 (ζ = -2.70, ρ = 0.007) Total sleep time 386 minutes 375 minutes 348 minutes (ζII-0.57, ρII 0.58) by From the above results, it is concluded that melatonin replacement therapy can improve the printing of consumer cooperatives with employees of the Central Standards Bureau of the Ministry of Economic Affairs ^^^ 1 '^ il · · ϋϋ mV —ϋ mi 士 ιϋ_— ϋϋ In ϋϋ mu- —ϋ ϋ ^ (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 483757 A7 B7 V. Description of the invention (19) The use of endogenous melatonin Sleep Initiation and Persistence of Diazepam in Older Patients. The benefits of melatonin therapy increase over time, suggesting that reorganization of the cyclic system has occurred. The present invention further includes manufacturing patients for treating multiple addictions, or patients who have become dependent on benzodiazepines, have tolerance, or have symptoms of addiction, or have been clinically diagnosed by the treatment industry as having an easy-to-use drug. A method of diazepine medicine to alleviate painful patients and prevent patients from relying on the benzodiazepine medicine, having tolerance, or symptoms of addiction; the method comprises using melatonin and At least one diluent, carrier or adjuvant is mixed and formulated in a unit dosage form suitable for oral, rectal, parenteral or transdermal administration, each unit dose containing 0.0025-2 mg (preferably 0.01-2 mg) of melatonin, and is preferably adapted to release melatonin at a predetermined controlled rate. In addition, at least one melatonin receptor modulator and / or melatonin action profile modulator, and / or at least one benzodiazepine inhibitor such as Alprazolam, Limening, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Helazepam, qi chicken nor nail stability, norrinthidine stability, Prazepam, Temazepam and three. Sitting benzodiazepine is mixed with melatonin. (Please read the notes on the back before filling out this page) ϊ m .1 ^ 1. V —ϋ —ϋ m ϋϋ ϋϋ ml I I. —ϋ— ^ 二 = 印 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 483757
A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明() 專利申請案第85104319號 ROC Patent Appln. No. 85104319 補充t實例中文本-附件一 Supplemental Examples in Chinese - Enel. I (民國90年5月4日送呈) (Submitted on May 4 , 2001) 實施例5 : 研究褪黑激素對34位40-90歲成年病患的影響乃進扞 起初的六週期(第I期)及隨後之第二個六週期(第n期), 該等病患最初為了失眠症每晚服用1至2顆選自下列藥劑 之才示準旋劑:Alprazolam、Brotizolam、Flunitrazepam、 Lorazepam、Nitrazepam、Oxazepam 及 Triazolam,這些病 患被要求於最初六週的每週睡前兩小時服用2毫克CRM (控制之釋出型配劑)型式之褪黑激素(n=18)或相同型式之 placebo (n=16),且另服用標準劑量之苯并二氮箪(第一 週)、標準劑量之50% (第二週)、標準劑量之25% (第三 及四週),以及免服用苯并二氮箪(第五及六週),結果經 褪黑激素治療之病患其苯并二氮箪間斷服用率明顯地超過 經placebo治療之病患(14/18對4/16)。 於第Π期中,以相同的速率將CRM施用至第I期的 CRM病患(15/18)及placebo病患(15/16),於第I期中 未能成功停止服用苯并二氮箪之病患經鼓勵進一步於第 8、9-10及11-12週中分別減少50%、75%及100%苯并二 氮輩之服用量;結果當進入第Π期的第一週後,於最初 placebo組的病患中又有六位終止服^用苯并二氮輩。在成功 終止服用苯并二氮箪的個案中並未發現與施用的苯并二氮 輩特定類別有明顯之關聯性。 •22- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) -------1·-------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 483757 r A7 B7 五、發明說日沾完▲第Π期之30位個體(其中24位已停止服用 苯并二氮輩)被選來繼續服用褪黑激素,經六週後,24位 中的19位仍免服用苯并二氮箪,但有5位恢復服用(有些 係服用降低之劑量)。在12週測試期間,在與第I期服用 用褪黑激素之病患相較下,整個期間皆 服用盤屋激:、有整整11週之睡眠品質分數皆一致性 ί也車交南 期末了’兩組病患之睡眠品質分數則呈 一致0 結論:根據此實施例以褪黑激素治療,在明顯地多數 中,會導致去除對苯并二氮箪的依賴性、忍受性或上瘾, 且於些個案中支^持良好睡眠品質的情況下,可減低苯 并二氮箪之劑量。 補充說明:於此實施例中,很明顯地,病患係服用個 別劑f之苯并二氮箪及褪黑激素,選撰地,其可根據本發 明以單一醫藥組成物型式施用等量的苯并二氮苯及褪黑激 素0 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -23- H:\EVA\85155-claims.doc 本紙張尺度適用中關家標準(CNS)A4規格⑵q χ撕公髮〉A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description () ROC Patent Appln. No. 85104319 Patent Application No. 85104319 Supplemental Examples in Chinese-Enel. I (Republic of China 90 (Submitted on May 4, 2001) Example 5: To study the effects of melatonin on 34 adult patients aged 40-90 years is to defend the first six cycles (Phase I) and subsequent In the second six cycles (phase n), these patients initially took 1 or 2 quasi-rotors selected from the following agents for insomnia each night: Alprazolam, Brotizolam, Flunitrazepam, Lorazepam, Nitrazepam, Oxazepam, and Triazolam, These patients were required to take 2 mg of CRM (controlled release formulation) melatonin (n = 18) or the same type of placebo (n = 16) two hours before bedtime each week for the first six weeks, In addition, take the standard dose of benzodiazepine (first week), 50% of the standard dose (second week), 25% of the standard dose (third and fourth weeks), and avoid taking benzodiazepine (No. Five and six weeks) The treatment of patients which dan stopped taking benzodiazepines rate significantly exceeds that of patients after placebo treatment (4/16 to 14/18). In Phase Π, CRM was administered to CRM patients in Phase I (15/18) and patients in Placebo (15/16) at the same rate, and failed to stop taking benzodiazepines in Phase I. Patients are encouraged to further reduce the amount of benzodiazepines by 50%, 75%, and 100% in weeks 8, 9-10, and 11-12, respectively; as a result, after entering the first week of period Π, Six of the patients in the initial placebo group discontinued benzodiazepines. No significant association with the specific class of benzodiazepines administered was found in cases of successful discontinuation of benzodiazepines. • 22- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------- 1 · ----------------------- ------- (Please read the notes on the back before filling in this page) 483757 r A7 B7 V. The day of invention is finished ▲ 30 individuals of Phase Π (24 of them have stopped taking benzodiazepine Generation) was selected to continue taking melatonin. After six weeks, 19 of the 24 people were still exempt from benzodiazepine, but 5 of them resumed taking it (some reduced doses). During the 12-week test period, compared with the patients taking melatonin in Phase I, they were all taking Panyaji for the entire period: they had consistent sleep quality scores for a full 11 weeks. 'The sleep quality scores of the two groups of patients were consistent. 0 Conclusion: Treatment with melatonin according to this embodiment will result in the removal of dependence, tolerance or addiction to benzodiazepine in a significant majority, and In some cases where good sleep quality is supported, the dose of benzodiazepine can be reduced. Supplementary note: In this example, it is clear that the patient is taking the individual doses of benzodiazepine and melatonin. Selectively, it can be administered in the form of a single medicinal composition in the same amount according to the present invention. Benzodiazepine and Melatonin 0 (Please read the notes on the back before filling out this page) Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-23- H: \ EVA \ 85155-claims.doc This paper standard applies Zhongguanjia Standard (CNS) A4 size ⑵q χ tear public hair>
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US08/381,535 US6469044B1 (en) | 1995-02-01 | 1995-02-01 | Method for treating patients suffering from drug dependencies which lead to plasma melationin deficiencies |
EP95303853A EP0724878B1 (en) | 1995-02-01 | 1995-06-06 | Use of melatonin for treating patients suffering from drug dependencies |
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SK287508B6 (en) | 2000-01-05 | 2010-12-07 | Neurim Pharmaceuticals (1991) Ltd. | Use and formulation for treating resistance to antihypertensives and related conditions |
IL149377A (en) * | 2002-04-28 | 2012-10-31 | Neurim Pharma 1991 | Pharmaceutical formulation comprising melatonin for the potentiation of the effect of hypnotic compounds |
IL155666A (en) | 2003-04-29 | 2013-12-31 | Neurim Pharma 1991 | Composition for treating insomnia |
US9119846B2 (en) | 2003-04-29 | 2015-09-01 | Neurim Pharmaceuticals (1991) Ltd. | Method and composition for enhancing cognition in alzheimer's patients |
KR20180100450A (en) | 2012-01-26 | 2018-09-10 | 반다 파마슈티칼즈, 인코퍼레이티드. | Treatment of circadian rhythm disorders |
US11918557B2 (en) | 2012-01-26 | 2024-03-05 | Vanda Pharmaceuticals Inc. | Treatment of circadian rhythm disorders |
KR102148990B1 (en) | 2012-12-18 | 2020-08-27 | 반다 파마슈티칼즈, 인코퍼레이티드. | Treatment of circadian rhythm disorders |
US11090285B2 (en) | 2013-11-12 | 2021-08-17 | Vanda Pharmaceuticals Inc | Treatment of circadian rhythm disorders |
US10376487B2 (en) | 2013-11-12 | 2019-08-13 | Vanda Pharmaceuticals Inc. | Method of treatment |
SI3337462T1 (en) * | 2016-10-31 | 2021-01-29 | Neurim Pharmaceuticals Ltd. | Melatonin mini-tablets and method of manufacturing the same |
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