1226239 A7 五、發明說明（/ ) 【本發明之領域】 本發明係關於一種止痛用醫藥組成物，尤指一種適用 於長效止痛之含那布扶林酯前驅藥（nalbuphine ester prodrug) 口服醫藥組成物。 【本發明之背景】 那布扶林（nalbuphine)為同時具有鴉片感受體親和性 及拮抗性雙重作用之親和劑。此類藥物改良了原來成瘾性鎮 痛劑之嚴重缺點，如大幅降低其成瘾性及加成性，並減弱其 呼吸抑制作用。 經濟部智慧財產局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 目削傳統之那布扶林（nalbuphine-HC1)之口服生體可 用率低於5%，因此，目前那布扶林（1^丨13111311丨116-]^(：：1)未有 口服劑型上市。而針對這個缺點，Harrels〇n j· dW〇ng Y. J·在 1 988 年提出之論文中，以 acetylsaHcylate ester prodrug之方式來增加那布扶林（naibuphine-HCl)之口服 吸收率並改善那布扶林（nalbuphine-HCl)之苦味。 acetylsalicylate ester prodrug可以增加約5倍之口服生體 利用率（由5 %增加至1 6 %)，不過依然不夠實際口服使用。 另外，Hussain Μ·Α·等人於1 988年所發表之論文中，以頰 内給藥之方式（buccal delivery)可以將鴉片類藥物之 prodrug之生體可用率提高到35%至5〇%，不過，頰内給藥 方式終究不如口服方便，病人之接受度也不如口服之方式。 因此，亟需一種具有高生體利用率之那布扶林基 (nalbuphine base) 口月艮劑型，以供醫療使用0 本紙張尺度適用中國國豕標準（CNS)A4規格（210 X 297 ) 12262391226239 A7 V. Description of the Invention (/) [Field of the Invention] The present invention relates to a pharmaceutical composition for analgesics, especially a nalbuphine ester prodrug containing oral medicine suitable for long-acting analgesia.组合 物。 Composition. [Background of the present invention] nalbuphine is an affinity agent having both the opioid receptor affinity and antagonistic effects. These drugs improve the serious shortcomings of the original addictive analgesics, such as greatly reducing their addictive and additive properties, and reducing their respiratory depression. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The oral bioavailability of traditional nalbuphine-HC1 is less than 5%. Therefore, at present, Nabufurin (1 ^ 丨 13111311 丨 116-] ^ (:: 1) has not been marketed as an oral dosage form. In response to this shortcoming, Harrelsnj · dWng y Y. J. in his 1988 paper, Use acetylsaHcylate ester prodrug to increase the oral absorption of naibuphine-HCl and improve the bitterness of nalbuphine-HCl. Acetylsalicylate ester prodrug can increase the oral bioavailability by about 5 times ( (From 5% to 16%), but it is still not practical for oral use. In addition, in a paper published by Hussain Μ · Α · et al. In 1988, opiates could be delivered by buccal delivery (buccal delivery). The bioavailability of prodrugs is increased to 35% to 50%. However, intrabuccal administration is not as convenient as oral administration, and patient acceptance is not as good as oral administration. Therefore, a high bioavailability is urgently needed. Nabufu Base (nalbuphine base) population on Burgundy dosage form for medical use 0 Paper-scale hog applicable Chinese national standard (CNS) A4 size (210 X 297) 1226239
經濟部智慧財產局員工消費合作社印製 五、發明說明（>) 發明人爰因於此’本於積極發明之精神，亟思一種可 以解決上述問題之「那布扶林酯前驅藥（nalbuphine ester prodrug) 口服醫藥組成物」，幾經研究實驗終至完成此項 發明。 【本發明之概述】 本發明之主要目的係在提供一種高生體利用率之那布 扶林酯前驅藥（nalbuphine ester prodrug) 口服醫藥組成 物，俾能提咼病人服用之方便性，並提高病人服用之接受 度。 本發明之主要目的係在提供一種那布扶林酯前驅藥 (nalbuphine ester prodrug) 口服醫藥組成物，俾能延長那 布扶林（nalbuphine)在體内之滯留時間。 本發明之醫藥組成物係為一種包含治療上有效量之那 布扶林酉旨削驅藥（nalbuphine ester prodrug) 口服醫藥組成 物、助溶劑以及油性劑之醫藥組成物。 由於本發明組成新穎，能提供產業上利用，且確有增 進功效，故依法申請發明專利。 【圖式簡單説明】 第1圖係口服餵食beagle狗本發明醫藥組成物及其他比較例 醫藥組成物後，血漿内那布扶林濃度變化。 【較佳具體實施例之詳細説明】 ^紙張尺度適财關家標準TcNS)A4規格（21G X 297 i髮) ----- (請先閱讀背面之注意事項再填寫本頁) ---------訂---------線▲ 1226239 A7 ---------2Z__：_ — 五、發明說明（^) (請先閱讀背面之注意事項再填寫本頁) 本發明口服醫藥組成物，為包括油性劑、助溶劑以及 治療上有效量之那布扶林（nalbuphine)、那布扶林衍生物 或其藥學上可接文之鹽類。那布扶林（nalbuphine)藥學上 可接受之衍生物較佳為那布扶林癸二酸酯（sebacoyl dinalbuphine ester，SDN)。而本發明口服醫藥組成物之 油性劑，包括芝麻油（sesame 〇u)及苯甲基苯基酸 (benzyl benzoate)。兩者之用量約為5〇%至6〇%重量百分 比之芝麻油（sesame 〇il)及4〇%至5〇%重量百分比之苯 甲基苯基酸（benzyl benzoate)。較佳之那布扶林多量酯油 除月1]包έ55/^重f百分比之芝麻油（sesarne〇ii)以及45 /重百分比之苯甲基苯基酸（benZyi benzoate)。那布扶 林癸二酸酯（sebacoyl dinalbuphine ester，SDN)於本發 明酱藥組成物之濃度較佳為1 〇 〇 m g / m 1。 為也讓貴審查委員能更瞭解本發明之技術内容，特舉 含那布扶林（nalbuphine) 口服醫藥組成物較佳具體實施例 説明如下。 製備例 經濟部智慧財產局員工消費合作社印製 先將5.5ml芝麻油與4.5ml苯甲基苯基酸（benzyl benzoate)混合調成油性劑，而後取i〇mi混合調成之油性劑 與 1 克那布扶林癸二酸酯（sebacoyl dinalbuphine ester， SDN)均勻混合調製成含i〇〇mg/ml那布扶林癸二酸酯 (sebacoyl dinalbuphine ester，SDN)之醫藥組成物。 實施例一 本紙張尺度適用中國國家標準（CNS)A4規格⑵。x 297心) ' """ 1226239 A7 五、發明說明（斗） 將含l〇〇mg/mi那布扶林癸二酸酯（sebac〇yl dinalbuphine ester，SDN)多量醋油性劑以口服方式给藥 與“叫卜狗，劑量為3〇mg/kg，並於給藥後〇 167、〇 ^、Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of Invention (>) Because of this, the inventor was based on the spirit of positive invention, and was thinking about a "nalbuphine prodrug (nalbuphine) that can solve the above problems. ester prodrug). After several research experiments, the invention was completed. [Summary of the present invention] The main object of the present invention is to provide a nalbuphine ester prodrug oral pharmaceutical composition with high bioavailability, which can improve the convenience of the patient and improve the patient's convenience. Acceptability. The main object of the present invention is to provide an oral pharmaceutical composition of nalbuphine ester prodrug, which can prolong the retention time of nalbuphine in the body. The medicinal composition of the present invention is a medicinal composition comprising a therapeutically effective amount of nalbuphine ester prodrug, an oral medicinal composition, a solubilizing agent, and an oily agent. Since the present invention has a novel composition, can provide industrial use, and does have an increasing effect, it has applied for an invention patent in accordance with the law. [Brief description of the figure] Figure 1 shows the change in the concentration of narbufurin in plasma after oral administration of a beagle dog's pharmaceutical composition and other comparative examples of the pharmaceutical composition. [Detailed description of the preferred embodiment] ^ Paper size TcNS) A4 specification (21G X 297 i) ----- (Please read the precautions on the back before filling this page) --- ------ Order --------- line ▲ 1226239 A7 --------- 2Z __ ： _ — V. Description of the invention (^) (Please read the notes on the back before filling (This page) The oral pharmaceutical composition of the present invention includes an oily agent, a solubilizer, and a therapeutically effective amount of nalbuphine, a nalbuphine derivative, or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable derivative of nalbuphine is preferably sebacoyl dinalbuphine ester (SDN). The oily agents of the oral pharmaceutical composition of the present invention include sesame oil and benzyl benzoate. The amount of the two is about 50% to 60% by weight of sesame oil and 40% to 50% by weight of benzyl benzoate. The best is Nabufulin, a large amount of ester oil. In addition, 1/55% of sesame oil (sesarneii) and 45 /% of benzyl benzoate are included. The concentration of sebacoyl dinalbuphine ester (SDN) in the sauce composition of the present invention is preferably 1,000 mg / m1. In order to make your reviewing committee better understand the technical content of the present invention, the preferred specific embodiments of nalbuphine oral pharmaceutical composition are described below. Preparation Example Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, first mix 5.5ml sesame oil with 4.5ml benzyl benzoate to make an oily agent, and then take iomi mixed oily agent and 1 g Sebacoyl dinalbuphine ester (SDN) is uniformly mixed to prepare a pharmaceutical composition containing 100 mg / ml of sebacoyl dinalbuphine ester (SDN). Example 1 This paper size is in accordance with China National Standard (CNS) A4 specification⑵. x 297 heart) '" " " 1226239 A7 V. Description of the invention (bucket) It will contain 100 mg / mi narbuferin sebacate (sebac〇yl dinalbuphine ester, SDN) a large amount of vinegar oil based Oral administration and "called Bu dog, the dose is 30mg / kg, and after the administration of 0167, 0 ^,
以及48小時抽取狗之前肢（forearm)靜脈血液，並以HpLC 为析血液樣品，其結果如圖丨實心圓之曲線所示，所產生之 那布扶林在狗體内之半衰期及生體可用率等藥物動力學參數 如表一所示。 比較例一 訂 將含純那布扶林癸二酸酯（sebac〇yl ester，SDN)之粉末（不含任何其他賦形劑或助劑）以口服 方式給藥與beagle狗，劑量為3〇mg/kg，並於給藥後 0.167、0·33、〇_5、〇·75、i、K5、2、3、4、6、8、 12、15、24、30以及48小時抽取狗之前肢（f〇rearm)靜脈 線 血液，並以HPLC分析血液樣品，其結果如圖丨實心方塊之 曲線所示，所產生之那布扶林在狗體内之半衰期及生物可用 率等藥物動力學參數如表一所示。 比較例二 將含3 0mg/kg那布扶林癸二酸酯（sebac〇yl dinalbuphine ester，SDN)之粉末（不含任何其他賦形劑 或助劑）以口服方式給藥與beagle狗，劑量43〇mg/kg， 並立刻再以口服給藥方式給與1〇111§/0之習知p_ glycoprotein inhibitor，verapamil 粉末，並於給藥後 1226239 A7 〜 B7 五、發明說明（女） 0·167、0·33、0·5、0.75、1、1·5、2、3、4、6、8、 1 2、1 5、24、3 0以及48小時抽取beagle狗之前肢 (forearm)靜脈血液，並以HPLC分析血液樣品，其結果如 圖1實心三角形之曲線所示，所產生之那布扶林在狗體内之 半衰期及生體可用率等藥物動力學參數如表一所示。 表一 那布扶林在狗體内之 藥物動力學參數 實施例一 比較例一 比較例二 排除半衰期（h) (elimination half-life ) 23·9±3·0 8.1 ± 1.6 9.5±2.3 AUC/Dose (h*ng*kg/ml/mg) 171 ± 18 39± 1 1 83±22 ' 生體可用率（％) (bioavailability ) 6 7 · 1 土 4 · 3 14.6土4.0 3 0 · 0 土 8 · 0 个JJata = mean 土 S.E· 由第1圖之比較可知，本發明醫藥組成物那布扶林癸二 酸酯（sebacoyl dinalbuphine ester，SDN)油性劑在口服 給與beagle狗後，血液中所產生那布扶林之濃度均較其他 那布扶林癸二酸醋（sebacoyl dinalbuphine ester，SDN) 醫藥組成物製劑高，且本發明醫藥組成物所產生之那布扶林 於beagle狗體内之排除半衰期或滯留時間也較長；而由表 一中比較可得之本發明醫藥組成物可將那布扶林之生體可用 率大幅提高至67%，遠較其他含那布扶林醫藥組成物高。 — I.------------ rtt先閱讀背面之注音？事項再填寫本頁} 訂---------線」 經濟部智慧財產局員工消費合作社印製And for 48 hours, the forearm venous blood was drawn from the dog, and HpLC was used to analyze the blood sample. The results are shown in the solid circle curve. The produced half-life of nabufurin in the dog and its usability in the body Rate and other pharmacokinetic parameters are shown in Table 1. Comparative Example No. 1 A powder containing pure nabufurin sebacyl ester (SDN) (without any other excipients or auxiliaries) was administered orally to a beagle dog at a dose of 30. mg / kg, and 0.167, 0.33, 〇-5, 0.75, i, K5, 2, 3, 4, 6, 8, 12, 15, 24, 30, and 48 hours after the administration Forearm (forearm) venous blood, and blood samples were analyzed by HPLC. The results are shown in the graph of the solid square. The pharmacokinetics of the produced nabufurin in the dog's body, such as its half-life and bioavailability The parameters are shown in Table 1. Comparative Example 2 A powder containing 30 mg / kg of sebacoyl dinalbuphine ester (SDN) (without any other excipients or auxiliaries) was administered orally to a beagle dog. 43.0mg / kg, and immediately given the conventional p_glycoprotein inhibitor, verapamil powder of 10111§ / 0 by oral administration, and after administration 1226239 A7 ~ B7 V. Description of the invention (female) 0 · 167, 0 · 33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 15, 24, 30, and 48 hours for the forearm veins of beagle dogs Blood, and the blood samples were analyzed by HPLC. The results are shown in the solid triangle curve in Figure 1. The pharmacokinetic parameters such as the half-life and bioavailability of nabufurin in dogs are shown in Table 1. Table 1 Pharmacokinetic parameters of Nabufurin in dogs Example 1 Comparative Example 1 Comparative Example 2 Elimination half-life 23 · 9 ± 3 · 0 8.1 ± 1.6 9.5 ± 2.3 AUC / Dose (h * ng * kg / ml / mg) 171 ± 18 39 ± 1 1 83 ± 22 'Bioavailability 6 7 · 1 soil 4 · 3 14.6 soil 4.0 3 0 · 0 soil 8 · 0 JJata = mean soil SE · From the comparison in Fig. 1, it can be seen that the blood composition of the pharmaceutical composition of the present invention, sebacoyl dinalbuphine ester (SDN), is orally administered to beagle dogs. The concentration of nabufurin produced is higher than other sebacoyl dinalbuphine ester (SDN) pharmaceutical composition preparations, and the nabufurin produced by the pharmaceutical composition of the present invention is in a beagle dog. Excluding half-life or residence time is also longer; and the pharmaceutical composition of the present invention, which is relatively available in Table 1, can greatly increase the bioavailability of nabufurin to 67%, which is much higher than other nabufurin-containing pharmaceutical compositions . — I .------------ rtt first read the phonetic on the back? Please fill out this page again for the order} Order --------- Line "Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs
I226239 B7 五、發明說明（) 一綠上所陳，本發明無論就目的、手段及功效，在在均 顯不其迥異於習知技術之特徵，$「那布扶林基 (nalbuphine base) 口服醫藥組成物」之一大突破，龈嘈 ，審查委員明察，早曰賜准專利，實感德便。惟應^意的 疋、，上述諸多實施例僅係為了便於説明而舉例而$私 所主張之權利範圍自應以巾請專利範圍所述二 於上述實施例。 、、、丰，而非僅限 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（210 X 297必釐）I226239 B7 V. Description of the invention (1) As described on the green, the present invention, regardless of the purpose, means and efficacy, shows characteristics that are quite different from the conventional technology. "Nabuphine base" is orally One of the major breakthroughs in "pharmaceutical composition" was that the gingival was noisy. The reviewing committee clearly observed that it had granted a quasi-patent early on, and it really felt good. However, it should be noted that the above-mentioned embodiments are merely examples for the convenience of description, and the scope of the claimed rights should be as described in the patent scope. 、、、 丰, but not limited to printing Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs This paper size applies to China National Standard (CNS) A4 (210 X 297 must)