臺灣博碩士論文加值系統

本研究目的為發展脂質奈米微粒作為 buprenorphine 及其前驅藥之載體，以經皮吸收及注射劑型作為藥物傳輸系統。前驅藥相較於其原母藥較具親脂性，且前驅藥於血漿及皮膚均質液存在下，能夠水解釋出原母藥 buprenorphine 而產生作用。脂乳劑 (LE)、固態脂質奈米微粒 (SLN)、奈米結構脂質載體 (NLC) 作為藥物載體；隨著前驅藥的烷基長度增長，藥物穿透皮膚的量則隨之減少，促進藥物穿透量依序為 SLN > LE > NLC。採用不同比例的液體油/固態脂質製備脂質奈米微粒作為 buprenorphine 與其前驅藥的注射製劑載體，探討延長止痛時間的能力。體外釋放實驗顯示 SLN 皆具有最高的促進能力，而隨著前驅藥的碳鏈增長則釋放能力降低。冰酒精閃尾試驗是用來檢視止痛劑的止痛活性，以 SLN 包覆 buprenorphine 及 NLC 包覆 Bu-C3，相較於 buprenorphine 水溶液控制組，具有延長止痛的作用，其中以 NLC 包覆 Bu-C3 投與後，最大延遲時間持續達 10 小時。依本研究實驗結果證實將 buprenorphine 設計為前驅藥模式，並以脂質奈米微粒為載體，經皮傳輸系統與注射劑投與，具有控制及延長藥物止痛的療效。

The purpose of this study was to develop and characterize lipid nanoparticles as transdermal and parenteral drug delivery systems for buprenorphine and its prodrugs. Buprenorphine prodrugs with various alkyl chain lengths were synthesized. The prodrugs were more lipophilic than their parent drug as evaluated by capacity factor, partitioning between lipid and water and solubility. The prodrugs were susceptibility to be hydrolysed to the parent drug when exposed to plasma and skin homogenate. Colloidal systems such as lipid emulsions (LE), solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) were prepared. The in vitro permeation was found that prodrug with higher chain length showed the lower permeation across skin. SLN rendered the highest drug/prodrug permeation followed by LE and NLC. Evaluate the feasibility of lipid nanoparticles with different oil/fatty ester ratios for buprenorphine injection. The in vitro release study was found that SLN showed the highest release for each drug/prodrug tested, followed by NLC and LE. In vivo cold ethanol tail-flick test was examined for antinociceptive actions of opioid analgesics. The Bu-C3 in NLC could last the latency to 10 h. This study indicates the feasibility of using lipid nanoparticles, especially SLN and NLC, as the parenteral delivery system and transdermal system for buprenorphine and its prodrugs.

指導教授推薦書
口試委員會審定書
授權書 iv
誌謝 iv
中文摘要 v
Abstract vi
縮寫表 vii
總目錄 viii
表目錄 xiii
圖目錄 xiv
第一章、緒論 1
第一節、麻醉止痛劑 1
第二節、前驅藥 2
第三節、皮膚 3
第四節、經皮輸藥系統 4
1. 藥物穿透皮膚的途徑 6
2. 前驅藥之經皮吸收能力 7
第五節、脂質奈米微粒 9
1. 脂乳劑 9
2. 固態脂質奈米微粒 9
3. SLN 組成成分 11
4. SLN 製備方法 12
5. 奈米結構脂質載體 13
6. NLC 的形態 14
第六節、模式藥物 15
1. 鴉片止痛劑來源 15
2. 丁基原啡因 16
3. Buprenorphine 的臨床應用 18
4. Buprenorphine 的前驅藥 19
第七節、研究目的與動機 21
第二章、材料與方法 23
第一節、實驗試劑與醫材、儀器設備 23
1. 試劑與醫材 23
2. 儀器 25
第二節、實驗方法 27
Buprenorphine 及前驅藥以脂質奈米微粒作為載體之經皮吸收傳輸研究 27
1. Buprenorphine 及其前驅藥之溶解度測試 27
2. Buprenorphine 及其前驅藥之親脂性測試 28
2.1 HPLC 之容積因子 28
2.2 藥物對不同脂質溶媒的油水分配係數 28
3. Buprenorphine 前驅藥之體外水解試驗 29
4. Buprenorphine 及其前驅藥之 HPLC 分析條件的建立 30
5. 脂質奈米微粒的製備 31
5.1 脂質奈米微粒之顆粒粒徑及表面電位測定 32
5.2 脂質奈米微粒之界面張力測定 33
6. 疏水性試驗 33
7. 示差熱掃描分析儀 34
8. 脂質微粒包覆 buprenorphine 及其前驅藥物之體外經皮穿透試驗 34
8.1 實驗動物皮膚製備 34
8.3 體外試驗藥物皮內含量 36
9. 雷射共軛焦掃描式顯微鏡 37
10. 統計方法 37
Buprenorphine 及前驅藥利用脂質奈米微粒為藥物載體系統 38
1. 藥物對不同脂質溶媒的油水分配係數 38
2. 脂質奈米微粒的製備 38
3. 脂質奈米微粒之顆粒粒徑及表面電位測定 39
4. 劑型的疏水性試驗 39
5. 示差熱掃描分析儀 (DSC) 39
6. 穿透式電子顯微鏡 39
7. 紅血球溶血 (erythrocyte hemolysis) 試驗 40
7.1 紅血球混合懸浮溶液製備 40
7.2 紅血球溶血測試 40
8. 白血球中乳酸脫氫酶的釋放實驗 41
9. 脂質奈米微粒中 buprenorphine 及其前驅藥之體外釋放試驗 41
10. 活體藥效學試驗-冰酒精閃尾試) 42
10.1 實驗動物 42
10.2 理想動物模式之建立 42
10.3 Buprenorphine 及其前驅藥止痛效用之偵測 42
11. 統計方法 43
第三章、結果與討論 44
Buprenorphine 及前驅藥以脂質奈米微粒作為載體之經皮吸收傳輸研究 44
1. Buprenorphine 及其前驅藥之物理化學性質 44
1.1 Buprenorphine 及其前驅藥的溶解度測試結果 44
1.2 Buprenorphine 及其前驅藥之油水分配係數及容積因子評估親脂性程度 46
2. 前驅藥體外水解作用結果 47
3. 脂質奈米微粒的物理化學性質評估 47
3.1 探討不同脂質對劑型粒徑大小、界面電位與粒徑離散程度的影響 48
3.2 探討添加不同乳化劑對 SLN 系統的物化性質影響 49
4. 脂質奈米微粒包覆藥物之體外經皮穿透與皮內含量試驗 52
4.1 探討藥物經皮穿透速率 52
4.2 脂質微粒包覆藥物之體外經皮穿透試驗 53
5. 體外試驗之皮內藥物含量 59
6. 脂質奈米微粒的疏水性試驗 61
7. 示差熱掃描分析儀 62
8. 雷射共軛焦掃描式顯微鏡 66
第四章 綜合討論 71
第五章 結論 79
參考文獻 80


表目錄
表一、Buprenorphine 及其前驅藥之化學結構 20
表二、Buprenorphine 及其前驅藥之 HPLC 移動相比例 31
表三、Buprenorphine 及其前驅藥的基本特性 45
表四、比較 buprenorphine 及其前驅藥之物理化學性質 46
表五、添加不同種類之脂質對脂質奈米微粒之影響 49
表六、親油性乳化劑 Myverol 對脂質奈米微粒物化性質的影響 50
表七、Soybean phosphatidylcholine 對脂質奈米微粒物化影響 51
表八、L-α-phosphatidylcholine 對脂質奈米微粒物化影響 51
表九、3-sn-phosphatidylethanolamine 對脂質奈米微粒物化影響 52
表十、Buprenorphine 及其前驅藥之體外穿透速率 53
表十一、各系統處方組成與比例 55


圖目錄
圖一、皮膚結構圖 4
圖二、藥物經皮傳輸之路徑圖 7
圖三、藥物分布在 SLN 內的形態 10
圖四、藥物存在 SLN 與 NLC 粒子結構中的情形 14
圖五、NLC 的三種形態 15
圖六、Buprenorphine 基本結構 17
圖七、Franz diffusion cell 裝置圖 36
圖九、固態脂質 Precirol ATO-5 的結構分解圖 49
圖十、液體油脂 squalene 結構圖 49
圖十一、探討不同系統之經皮穿透速率比較圖 54
圖十二、Buprenorphine 與前驅藥在不同處方下探討以裸鼠皮為穿透障壁之藥物穿透速率 56
圖十三、比較在不同劑型 SLN、NLC 及 LE系統下以裸鼠皮為穿透障壁之體外藥物累積釋放曲線圖 59
圖十四、Buprenorphine 與前驅藥在不同劑型系統情況下探討體外試驗皮內藥物含量 60
圖十五、以尼羅紅螢光強度判斷脂質奈米微粒之疏水性差異 62
圖十六、NLC 之 DSC 圖譜 63
圖十七、SLN-Myverol 之 DSC 圖譜 63
圖十八、SLN-SPC 之 DSC 圖譜 64
圖十九、CLSM 觀察投與 FITC 劑型裸鼠皮內表現情形 68
圖二十、CLSM 觀察Rh B 劑型裸鼠皮內表現的情形 70

Barry, B.W., 2002. Drug delivery routes in skin: a novel approach. Adv. Drug Deliv. Rev. 54, Suppl. 1, S31-S40.
Bjerregaard, S., Wulf-Andersen, L., Stephens, R.W., Lund, L.R., Vermehren, C., Söderberg, I., Frokjaer, S., 2001. Sustained elevated plasma aprotinin concentration in mice following intraperitoneal injections of w/o emulsions incorporating aprotinin. J. Control. Release 71, 87-98.
Boonme, P., 2007. Applications of microemulsions in cosmetics. J. Cosmet. Dermatol. 6, 223-228.

Boothby, L.A., Doering, P.L., 2007. Buprenorphine for the treatment of opioid dependence. Am. J. Health-Syst. Pharm. 64, 266-272.
Bose, S., Ravis, W.R., Lin, Y.J., Zhang, L., Hofmann, G.A., Banga, A.K., 2001. Electrically-assisted transdermal delivery of buprenorphine. J. Control. Release 73, 197-203.
Boyum, A., Lovhaug, D., Tresland, L., Nordlie, E.M., 1991. Separation of leucocytes: improved cell purity by fine adjustments of gradient medium density and osmolality. Scand. J. Immunol. 34, 697-712.
Brown, M.B., Traynor, M.J., Martin, G.P., Akomeah, F.K., 2008. Transdermal drug delivery systems: skin perturbation devices. Methods Mol. Biol. 437, 119-139.
Bunjes, H., Koch, M.H., Westesen, K., 2003. Influence of emulsifiers on the crystallization of solid lipid nanoparticles. J. Pharm. Sci. 92, 1059-1520.
Bunjes, H., Westesen, K., Koch, M.H.J., 1996. Crystallization tendency and polymorphic transitions in triglyceride nanoparticles. Int. J. Pharm. 129, 159-173.
Buszello, K., Harnish, S., Müller, R.H., Müller, B.W., 2000. The influence of alkali fatty acids on the properties and the stability of parenteral O/W emulsions modified with solutol HS 15. Eur. J. Pharm. Biopharm. 49, 143-149.
Cady, J., 2001. Understanding opioids tolerance in cancer pain. Oncol. Nurs. Forum. 28, 1561-1568.
Chan, S.Y., Li, W.P.A., 1989. Prodrugs for dermal delivery. Int. J. Pharm. 55, 1-16.
Charcosset, C., El-Harati, A., Fessi, H., 2005. Preparation of solid lipid nanoparticles using a membrane contactor. J. Control. Release 108, 112-120.
Chen, H., Chang, X., Du, D., Liu, W., Liu, J., Weng, T., Yang, Y., Xu, H., Yang, X., 2006. Podophyllotoxin-loaded solid lipid nanoparticles for epidermal targeting. J. Control. Release 110, 296-306.
Chen, Y., Dalwadi, G., Benson, H.A.E., 2004. Drug delivery across the blood-brain barrier. Curr. Drug Deliv. 1, 361-376.
Chin, L.S., Huang, K.L., Liu, K.S., Chu, C.C., Tzeng, J.I., Ho, S.T., Wang, J.J., 2005. An esterification method for synthesizing prodrugs of buprenorphine. Acta Anaesthe. Taiwan. 43, 223-229.
Clogston, J., Rathman, J., Tomasko, D., Walker, H., Caffrey, M., 2000. Phase behavior of a monoacylglycerol (Myverol 18-99K)/water system. Chem. Phys. Lipids 107, 191-220.
Cury-Boaventura, M.F., Gorjão, R., de Lima, T.M., Piva, T.M., Peres, C.M., Soriano, F.G., Curi, R., 2006. Toxicity of a soybean oil emulsion on human lymphocytes and neutrophils. J. Parenter. Enteral. Nutr. 30, 115-123.
Dahan, A., Yassen, A., Bijl, H., Romberg, R., Sarton, E., Teppema, L., Olofsen, E., Danhof, M., 2005. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br. J. Anaesth. 94, 825-34.
Doh, H.J., Cho, W.J., Yong, C.S., Choi, H.G., Kim, J.S., Lee, C.H., Kim, D.D., 2003. Synthesis and evaluation of ketorolac ester prodrugs for transdermal delivery. J. Pharm. Sci. 92, 1008-1017.
Driscoll, D.F., 2006. Lipid injectable emulsions: pharmacopeial and safety issues. Pharm. Res. 23, 1959-1969.
DuPen, A., Shen, D., Ersek, M., 2007. Mechanisms of opioid-induced tolerance and hyperalgesia. Pain Manage. Nurs. 8, 113-121.
Esposito, E., Fantin, M., Marti, M., Drechsler, M., Paccamiccio, L., Mariani, P., Sivieri, E., Lain, F., Menegatti, E., Morari, M., Cortesi, R., 2008. Solid lipid nanoparticles as delivery systems for bromocriptine. Pharm. Res. 25, 1521-1530.
Ettmayer, P., Amidon, G.L., Clement, B., Testa, B., 2004. Lessons learned from marketed and investigational prodrugs. J. Med. Chem. 47, 2393-2404.
Fang, J.Y., Leu, Y.L., 2006. Prodrug strategy for enhancing drug delivery via skin. Curr. Drug Discov. Technol. 3, 211-224.
Gokce, E.H., Sandri, G., Bonferoni, M.C., Rossi, S., Ferrari, F., Güneri, T., Caramella, C., 2008. Cyclosporine A loaded SLNs: evaluation of cellular uptake and corneal cytotoxicity. Int. J. Pharm. 364, 76-86.
Gopal, S., Tzeng, T.B., Cowan, A., 2002. Characterization of the pharmacokinetics of buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine. Eur. J. Pharm. Sci. 15, 287-293.
Gutiérrez, J.M., Gonzalez, C., Maestro, A., Pey, C.M., Nolla, J., 2008. Nano-emulsions: new applications and optimization of their preparation. Curr. Opin. Colloid Interface Sci. 13, 245-251.
Hammell, D.C., Stolarczyk, E.I., Klausner, M., Hamad, M.O., Crooks, P.A., Stinchcomb, A.L., 2005. Bioconversion of naltrexone and its 3-O-alkyl-ester prodrugs in a human skin equivalent. J. Pharm. Sci. 94, 828-836.
Han, J., Davis, S.S., Washington, C., 2001. Physical properties and stability of two emulsion formulations of propofol. Inter. J. Pharm. 215, 207-220.
Hu, F.Q., Jiang, S.P., Du, Y.Z., Yuan, H., Ye, Y.Q., Zeng, Q.S., 2006. Preparation and characteristics of monostearin nanostructured lipid carriers. Int. J. Pharm. 314, 83-89.
Hwang, T.L., Li, G.L., Lan, Y.H., Chia, Y.C., Hsieh, P.W., Wu, Y.H., Wu, Y.C., 2009. Potent inhibition of superoxide anion production in activated human neutrophils by isopedicin, a bioactive component of the Chinese medicinal herb Fissistigma oldhamii. Free Rad. Bio. Med. 46, 520-528.
Imoto, H., Zhou, Z., Stinchcomb, A.L., Flynn, G., 1996. Transdermal prodrug concepts: permeation of buprenorphine and its alkyl esters through hairless mouse skin and influence of vehicles. Biol. Pharm. Bull. 19, 263-267.
Jenning, V., Thünemann, A.F., Gohla, S.H., 2000. Characterization of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids. Int. J. Pharm. 199, 167-177.
Johson, R.E., Fudala, P.J., Payne, R., 2005. Buprenorphine: considerations for pain management. J. Pain Symptom Manage. 29, 297-326.
Jores, K., Haberland, A., Wartewig, S., Mäder, K., Mehnert, W., 2005. Solid lipid nanoparticles (SLN) and oil-loaded SLN studied by spectrofluorometry and Raman spectroscopy. Pharm. Res. 22, 1887-1897.
Jores, K., Mehnert, W., Drechsler, M., Bunjes, H., Johann, C., Mäder, K., 2004. Investigation on the structure of solid lipid nanoparticles (SLN) and oil-loaded solid lipid nanoparticles by photon correlation spectroscopy, field-flow fractionation and transmission electron microscopy. J. Control. Release 95, 217-227.
Jores, K., Mehnert, W., Mäder, K., 2003. Physicochemical investigations on solid lipid nanoparticles and on oil-loaded solid lipid nanoparticles: a nuclear magnetic resonance and electron spin resonance study. Pharm. Res. 20, 1274-1283.
Juntunen, J., Majumdar, S., Sloan, K.B., 2008. The effect of water solubility of solutes on their flux through human skin in vitro: a prodrug database integrated into the extended Flynn database. Int. J. Pharm. 351, 92-103.
Kalia, Y.N., Guy, R.H., 2001. Modeling transdermal drug release. Adv. Drug Deliv. Rev. 48, 159-172.
Katzung, B.G., 2004. Basic & chinical pharmacology 9th edition, the McGraw-Hill Companies 497-516.
Kaur, I.P., Bhandari, R., Bhandari, S., Kakkar, V., 2008. Potential of solid lipid nanoparticles in brain targeting. J. Control. Release 127, 97-109.
Kim, B.D., Choi, H.K., 2005. Preparation and characterization of solid lipid nanoparticles (SLN) made of cacao butter and curdlan. Eur. J. Pharm. Sci. 24, 199-205.
Kogan, A., Garti, N., 2006. Microemulsions as transdermal drug delivery vehicles. Adv. Colloid Interface Sci. 123-126, 369-385.
Kuo, Y.C., Chen, H.H., 2009. Entrapment and release of saquinavir using novel cationic solid lipid nanoparticles. Int. J. Pharm. 365, 206-213.
Kuo, Y.C., Chen, H.H., 2009. Entrapment and release of saquinavir using novel cationic solid lipid nanoparticles. Int. J. Pharm. 365, 206-213.
Lipp, R., Laurent, H., Günther, C., Riedl, J., Esperling, P., Täuber, U., 1998. Prodrugs of gestodene for matrix-type transdermal drug delivery systems. Pharm. Res. 15, 1419-1424.
Liu, A.C., Lin, T.Y., Su, L.W., Fuh, M.R., 2008. Online solid-phase extraction liquid chromatography-electrospray-tandem mass spectrometry analysis of buprenorphine and three metabolites in human urine. Talanta 75, 198-204.
Liu, K.S., Lin, C.N., Shieh, J.P., Chu, C.C., Kuei, C.H., Wang, J.J., 2006. The novel depot of buprenorphine propionate has a long-acting effect on physical dependence on morphine. Drug Develop. Res. 67, 462-469.
Liu, S.Y., Liu, K.S., Kuei, C.H., Tzeng, J.I., Ho, S.T., Wang, J.J., 2005. Simultaneous determination of buprenorphine and its prodrug, buprenorphine propionate, by high-preformance liquid chromatography with fluorescence detection: application to pharmacokinetic studies in rabbits. J. Chromatogr. B 818, 233-239.
Lombardi Borgia, S., Regehly, M., Sivaramakrishnan, R., Mehnert, W., Korting, H.C., Danker, K., Röder, B., Kramer, K.D., Schäfer-Korting, M., 2005. Lipid nanoparticles for skin penetration enhancement-correlation to drug localization within the particle matrix as determined by fluorescence and parelectric spectroscopy. J. Control. Release 110, 151-163.
Mehnert, W., Mäder, K., 2001. Solid lipid nanoparticles: production, characterization and applications. Adv. Drug Deliv. Rev. 47, 165-196.
Meidan, V.M., Bonner, M.C., Michniak, B.B., 2005. Transfollicular drug delivery-is it a reality? Int. J. Pharm. 306, 1-14.
Moghimi, H.R., Williams, A.C., Barry, B.W., 1996. A lamellar matrix model for stratum corneum intercellular lipids. Ⅱ. Effect of geometry of the stratum corneum on permeation of model drugs 5-fluorouracil and oestradiol. Inter. J. Pharm. 131, 117-129.
Montenegro, L., Carbone, C., Maniscalco, C., Lambusta, D., Nicolosi, G., Ventura, C.A., Puglisi, G., 2007. In vitro evaluation of quercetin-3-O-acyl esters as topical prodrugs. Int. J. Pharm. 336, 257-262.
Müller, R.H., Mäder, K., Gohla, S., 2000. Solid lipid nanoparticles (SLN) for controlled drug delivery-a review of the state of the art. Eur. J. Pharm. Biopharm. 50, 161-177.
Müller, R.H., Petersen, R.D., Hommoss, A., Pardeike, J., 2007. Nanostructured lipid carriers (NLC) in cosmetic dermal products. Adv. Drug Deliv. Rev. 59, 522-530.
Müller, R.H., Radtke, M., Wissing, S.A., 2002a. Nanostructured lipid matrices for improved microencapsulation of drugs. Int. J. Pharm. 242, 121-128.
Müller, R.H., Radtke, M., Wissing, S.A., 2002b. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv. Drug Deliv. Rev. 54, Suppl. 1, S131-S155.
Muguet, V., Seiller, M., Barratt, G., Ozer, O., Marty, J.P., Grossiord, J.L., 2001. Formulation of shear rate sensitive multiple emulsions. J. Control. Release 70, 37-49.
Nathan, C., 2006. Neutrophils and immunity: challenges and opportunities. Nat. Rev. Immunol. 6, 173-182.
Ohtani, M., 2007. Basic pharmacology of buprenorphine. Eur. J. Pain Supp. 1, 69-73.
Ostacolo, C., Marra, F., Laneri, S., Sacchi, A., Nicoli, S., Padula, C., Santi, P., 2004. Α-tocopherol pro-vitamins: synthesis, hydrolysis and accumulation in rabbit ear skin. J. Control. Release 99, 403-413.
Park, I., Kim, D., Song, J., In, C.H., Jeong, S.W., Lee, S.H., Min, B., Lee, D., Kim, S.O., 2008. Buprederm™, a new transdermal delivery system of buprenorphine: pharmacokinetic, efficacy and skin irritancy studies. Pharm. Res. 25, 1052-1062.
Pavan, B., Dalpiaz, A., Ciliberti, N., Biondi, C., Manfredini, S., Vertuani, S., 2008. Progress in drug delivery to the central nervous system by the prodrug approach. Molecules 13, 1035-1065.
Pople, P.V., Singh, K.K., 2006. Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin A. AAPS Pharm. Sci. Tech. 7, Article 91.
Puglia, C., Blasi, P., Rizza, L., Schoubben, A., Bonina, F., Rossi, C., Ricci, M., 2008. Lipid nanoparticles for prolonged topical delivery: an in vitro and in vivo investigation. Int. J. Pharm. 357, 295-304.
Que, J., Lin, L.C., Chu, C.C., Liu, K.S., Ho, S.T., Wang, J.J., 2005. A novel long-acting analgesic: buprenorphine palmitate in rats. Acta Anaesthe. Taiwan. 43, 11-16.
Radtke, M., Souto, E.B., Müller, R.H., 2005. Nanostructured lipid carriers: a novel generation of solid lipid drug carriers. Pharm. Tech. Europe 17, 45-50.
Raffa, R.B., Ding, Z., 2007. Examination of the preclinical antinociceptive efficacy of buprenorphine and its designation as full- or partial-agonist. Acute Pain 9, 145-152.
Ranade, V.V., 1991. Drug delivery systems. 6. Transdermal drug delivery. J. Clin. Pharmacol. 31, 401-418.
Rautio, J., Kumpulainen, H., Heimbach, T., Oliyai, R., Oh, D., Järvinen, T., Savolainen, J., 2008. Prodrugs: design and clinical applications. Nat. Rev. Drug Discov. 7, 255-270.
Rautio, J., Taipale, H., Gynther, J., Nevalainen, T., Jarvinen, T., 1998. In vitro evaluation of acyloxyalkyl esters as dermal prodrugs of ketoprofen and naproxen. J. Pharm. Sci. 87, 1622-1628.
Roy, S.D., Roos, E., Sharma, K., 1994. Transdermal delivery of buprenorphine through cadaver skin. J. Pharm. Sci. 83, 126-130.
Russo, M.A., Wasiak, J., 2007. A clinical snapshot of transdermal buprenorphine in pain management. Eur. J. Pain Suppl. 1, 74-77.
Sarker, D.K., 2005. Engineering of nanoemulsions for drug delivery. Curr. Drug Deliv. 2, 297-310.
Schäfer-Korting, M., Mehnert, W., Korting, H.C., 2007. Lipid nanoparticles for improved topical application of drugs for skin diseases. Adv. Drug Deliv. Rev. 59, 427-443.
Schubert, M.A., Harms, M., Müller-Goymann, C.C., 2006. Structural investigations on lipid nanoparticles containing high amounts of lecithin. Eur. J. Pharm. Sci. 27, 226-236.
Shah, K.A., Date, A.A., Joshi, M.D., Patravale, V.B., 2007. Solid lipid nanoparticles (SLN) of tretinoin: potential in topical delivery. Inter. J. Pharm. 345, 163-171.
Singh, S., Singh, J., 1993. Trandermal drug delivery by passive diffusion and iontophoresis: a review. Med. Res. Rev. 13, 569-621.
Singla, A.K., Garg, A., Aggarwal, D., 2002. Paclitaxel and its formulations. Int. J. Pharm. 235, 179-192.
Sittl, R., Griessinger, N., Likar, R., 2003. Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: a multicentre, randomized, double-blind, placebo-controlled trial. Clin. Ther. 25, 150-168.
Sloan, K.B., Wasdo, S., 2003. Designing for topical delivery: prodrugs can make the difference. Med. Res. Rev. 23, 763-793.
Sorge, J., Sittl, R., 2004. Transdermal buprenorphine in the treatment of chronic pain: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. Clin. Ther. 26, 1808-1820.
Souto, E.B., Almeida, A.J., Müller, R.H., 2007. Lipid nanoparticles (SLN®, NLC®) for cutaneous drug delivery: structure, protection and skin effects. J. Biomed. Nanotechnol. 3, 317-331.
Souto, E.B., Wissing, S.A., Barbosa, C.M., Müller, R.H., 2004. Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery. Int. J. Pharm. 278, 71-77.
Stinchcomb, A.L., Dua, R., Paliwal, A., Woodard, R.W., Flynn, G.L., 1995. A solubility and related physicochemical property comparison of buprenorphine and its 3-alkyl esters. Pharm. Res. 12, 1526-1529.
Stinchcomb, A.L., Paliwal, A., Dua, R., Imoto, H., Woodard, R.W., Flynn, G.L., 1996. Permeation of buprenorphine and its 3-alkyl-ester prodrugs through human skin. Pharm. Res. 13, 1519-1523.
Swenson, J., Olgun, S., Radjavi, A., Kaur, T., Reilly, C.M., 2007. Clinical efficacy of buprenorphine to minimize distress in MRL/lpr mice. Eur. J. Pharmacol. 567, 67-76.
Teeranachaideekul, V., Boonme, P., Souto, E.B., Müller, R.H., Junyaprasert, B.V., 2008. Influence of oil content on physicochemical properties and skin distribution of nile red-loaded NLC. J. Control. Release 128, 134-141.
Teeranachaideekul, V., Souto, E.B., Junyaprasert, V.B., Müller, R.H., 2007. Cetyl palmitate-based NLC for topical delivery of coenzyme Q10-development, physicochemical characterization and in vitro release studies. Eur. J. Pharm. Biopharm. 67, 141-148.
Thomas, J.D., Sloan, K.B., 2008. In vitro evaluation of alkylcarbonyloxymethyl (ACOM) ethers as novel prodrug of phenols for topical delivery: ACOM prodrugs of acetaminophen. Int. J. Pharm. 346, 80-88.
Trotta, M., Peira, E., Carlotti, M.E., Gallarate, M., 2004. Deformable liposomes for dermal sdministration of methotrexate. Int. J. Pharm. 270, 119-125.
Vaddi, H.K., Hamad, M.O., Chen, J., Banks, S.L., Crooks, P.A., Stinchcomb, A.L., 2005. Human skin permeation of branched-chain 3-O-alkyl ester and carbonate prodrugs of naltrexone. Pharm. Res. 22, 758-765.
Valjakka-Koskela, R., Kirjavainen, M., Monkkonen, J., Urtti, A., Kiesvaara, J., 1998. Enhancement of percutaneous absorption of naproxen by phospholipids. Int. J. Pharm. 175, 225-230.
Vance, D.E., Vance, J. (eds) 2002. Biochemistry of lipids, lipoproteins and membranes. (4th edition). Elsevier Publisher, Amsterdam.
Venkateswarlu, V., Manjunath, K., 2004. Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles. J. Control. Release 95, 627-638.
Vighi, E., Ruozi, B., Montanari, M., Battini, R., Leo, E., 2007. Re-dispersible cationic solid lipid nanoparticles (SLNs) freeze-dried without cryoprotectors: characterization and ability to bind the pEGFP-plasmid. Eur. J. Pharm. Biopharm. 67, 320-328.
Vivek, K., Reddy, H., Murthy, R.S.R., 2007. Investigations of the effect of the lipid matrix on drug entrapment, in vitro release, and physical stability of danzapine-loaded solid lipid nanoparticles. AAPS Pharm. Sci. Tech. 8, Article 83.
Wang, J.J., Ho, S.T., Hu, O.Y.P., Chu, K.M., 1995. An innovative cold tail-flick test: the cold ethanol tail-flick test. Anesth. Analg. 80, 102-107.
Wilding, I.R., Davis, S.S., Rimoy, G.H., Rubin, P., Kurihara-Bergstrom, T., Tipnis, V., Berner, B., Nightingale, J., 1996. Pharmacokinetic evaluation of transdermal buprenorphine in man. Inter. J. Pharm. 132, 81-87.
Wissing, S., Craig, D.Q.M., Barker, S.A., Moore, W.D., 2000. An investigation into the use of stepwise isothermal high sensitivity DSC as a means of detecting drug-excipient incompatibility. Inter. J. Pharm. 199, 141-150.
Wissing, S.A., Kayser, O., Müller, R.H., 2004. Solid lipid nanoparticles for parenteral drug delivery. Adv. Drug Deliv. Rev. 56, 1257-1272.
Yang, C., Lan, K.M., Liu, K.S., Chen, Y.W., Tzeng, J.I., Ho, S.T., Wang, J.J., 2004. The antinociceptive effect of buprenorphine and long-acting ester buprenorphine benzoate in rat. Acta Anaesthe. Taiwan. 42, 135-139.
Zhang, X., Pan, W., Gan, L., Zhu, C., Gan, Y., Nie, S., 2008. Preparation of a dispersible PEGylate nanostructured lipid carriers (NLC) loaded with 10-hydroxycamptothecin by spray-drying. Chem. Pharm. Bull. 56, 1645-1650.
zur Mühlen, A., Schwarz, C., Mehnert, W., 1998. Solid lipid nanoparticles (SLN) for controlled drug delivery-drug release and release mechanism. Eur. J. Pharm. Biopharm. 45, 149-155.