肺部藥物傳輸系統已被廣泛應用在治療局部性及全身性之疾病，由於其給藥方式屬低侵入性，因此病人順應性相對較高，更重要的是肺部傳輸可避免首渡效應發生，除能有效減少所需劑量外，也可減少副作用的產生。因此肺部傳輸系統極適合作為抗發炎藥物治療肺部及全身性發炎相關疾病。厚朴酚(Magnolol)為雙酚類物質，於抗發炎及降低氧化壓力上有良好之功效，然而厚朴酚具疏水性高及顆粒分布不均等問題，進而降低其臨床可用性，因此需要找出增加厚朴酚生物可利用率之方法。本研究主要利用生物可降解性高分子聚縮酮(Polyketal)及及聚乳酸-甘醇酸（PLGA），結合醣類與噴霧乾燥方式，製備適用於肺部傳輸之微奈米顆粒，藉由顆粒特性分析，並比較不同尺寸顆粒體外釋放測試、體外抗發炎能力測試，及觀察細胞顆粒吞噬情形，評估微奈米開發肺部遞藥劑型之潛能，以提升厚朴酚於肺部傳輸之應用性。
研究結果顯示，包覆厚朴酚之微奈米顆粒之粒徑為 3. 45 ± 0.83μm，藥物包覆率為10.93 -20.42 %，體外釋放測試顯示微奈米顆粒所包覆之奈米顆粒可穩定釋放厚朴酚，細胞實驗結果顯示，此微奈米顆粒相較其他對照組之顆粒，能更有效降低NO、TNF–α等發炎指標，於抗氧化壓力上亦有良好表現。

The pulmonary drug delivery system becomes an attractive strategy for the delivery of anti-inflammatory drugs for treating both systemic and local diseases, due to its less invasive property and lower first pass effect. Magnolol was found to have anti-inflammatory and anti-oxidative abilities in the preclinical experiments. However, the poor solubility and the poor suspension property of magnolol have hindered its success. In this study, the spray - dried microparticles containing biodegradable nanoaprticles were developed for improving the pulmonary delivery efficiency of magnolol.
The results showed that the particle size of microparticles containing nanoaprticles is 3. 45 ± 0.83μm, which is suitable for pulmonary delivery. The encapsulation efficiency of microparticles containing magnolol loaded biodegradable nanoaprticles is about 10.93 -20.42 %. In vitro release results indicate that the magnolol loaded nanoaprticles can continuously release magnolol within 48 hours. Microparticles containing magnolol loaded biodegradable exhibited a great aqueous dispensability and low cytotoxicity. It also showed better inhibitory effects on NO and TNF-α production from LPS -activated RAW 264.7 cells when compared to other vehicles at the same condition. Also, microparticles containing magnolol loaded biodegradable nanoparticles showed better inhibitory effects on superoxide production from LPS -activated RAW 264.7 cells.

[1] 汪嘉林. 我國生技製藥產業創新演化的回顧與前瞻. 科學發展, 2011年1月: 146-150.
[2] 湯谷清. 我國明星產業競爭優勢及市場利基研究-生技及國際醫療. 臺北: 湯谷清, 101.
[3] 汪嘉林. 2012生技產業白皮書. 台北市: 經濟部工業局, 101.
[4] Costanzo, Linda S. Physiology. Saunders, 2009.
[5] JE Cotes, DJ Chinn, MR Miller. Lung function: physiology, measurement and application in medicine. Wiley, 2009.
[6] Vasant V. Ranade B. Cannon J. Drug Delivery Systems. CRC Press Taylor & Francis group, 2011.
[7] Patton JS. The promise of pulmonary drug delivery. Drug Delivery Rep. 2004; 35-38.
[8] Lo YC, Teng CM, Chen CF, Chen CC, Hong CY. Magnolol and honokiol isolated from Magnolia officinalis protect rat heart mitochondria against lipid peroxidation. Biochemical pharmacology. 1994;47:549-53.
[9] Taira J, Ikemoto T, Mimura K, Hagi A, Murakami A, Makino K. Effective inhibition of hydroxyl radicals by hydroxylated biphenyl compounds. Free radical research communications. 1993;19 Suppl 1:S71-7.
[10] Son HJ, Lee HJ, Yun-Choi HS, Ryu JH. Inhibitors of nitric oxide synthesis and TNF-alpha expression from Magnolia obovata in activated macrophages. Planta Med .2000;66:469–71.
[11] Seo JU, Kim MH, Kim HM, Jeong HJ. Anticancer potential of magnolol for lung cancer treatment. Archives of pharmacal research. 2011;34:625-33.
[12] Hsieh MT, Chueh FY, Lin MT. Magnolol decreases body temperature by reducing 5-hydroxytryptamine release in the rat hypothalamus. Clinical Experiment Pharmacology Physiology. 1998;25:813–7.
[13]Teng CM, Ko FN, Wang JP, Lin CN, Wu TS, Chen CC, et al. Antihaemostatic and antithrombotic effect of some antiplatelet agents isolated from Chinese herbs. J Pharm Pharmacology. 1991;43:667–9.
[14] Ai J,Wang X, Nielsen M. Honokiol and magnolol selectively interact with GABAA receptor subtypes in vitro.Pharmacology. 2001;63:34–41.
[15] Fiore VF, Lofton MC, Roser-Page S, Yang SC, Roman J, Murthy N, et al. Polyketal microparticles for therapeutic delivery to the lung. Biomaterials. 2010;31:810-7.
[16] Schurch S, Gehr P, Im Hof V, Geiser M, Green F. Surfactant displaces particles toward the epithelium in airways and alveoli. Respir Physiol. 1990;80:17–32.
[17] Patton JS, Byron PR. Inhaling medicines: Delivering drugs to the body through the lungs. Nat Rev Drug Discovery .2007;6(1):67–74.
[18] Brain JD. Inhalation, deposition, and fate of insulin and other therapeutic proteins. Diabetes Technology Therapy .2007;9 (Supply 1):S4–S15.
[19] Rogueda PG, Traini D. The nanoscale in pulmonary delivery. Part 2: formulation platforms. Expert opinion on drug delivery. 2007;4:607-20.
[20] Edwards DA, Dunbar C. Bioengineering of therapeutic aerosols. Annu Rev Biomed Eng .2002;4:93–107.
[21] Sung JC, Pulliam BL, Edwards DA. Nanoparticles for drug delivery to the lungs. Trends Biotechnol .2007;25(12):563–570.
[22] Musante CJ, Schroeter JD, Rosati JA, Crowder TM, Hickey AJ, Martonen TB. Factors affecting the deposition of inhaled porous drug particles. J Pharm Sci. 2002;91(7):1590–1600.
[23] Sham JO, Zhang Y, Finlay WH, Roa RL. Formulation and characterization of spray-dried powders containing nanoparticles for aerosol delivery to the lung. Int J Pharm. 2004;269:457–67.
[24] Ohashi K, Kabasawa T, Ozeki T, Okada H. One-step preparation of rifampicin/poly(lactic-co-glycolic acid) nanoparticle – containing mannitol microspheres using a four-fluid nozzle spray drier for inhalation therapy of tuberculosis. Journal of controlled release : official journal of the Controlled Release Society. 2009;135:19-24.
[25] 衛生福利部(20130604)：民國101年死因結果摘要表，全國主要死亡原因。取自：http://www.mohw.gov.tw/cht/DOS/Statistic.aspx?f_list_no=312&fod_list _no=2747民國102年7月12日檢索）。
[26] World Health Organization, Tuberculosis Facts, 2013 WHO, Geneva, 2013.
[27] World Health Organization, Pneumonia Facts, 2013. WHO, Geneva, 2013.
[28] Jang JL, Chao H L. Pneumocystis Pneumonia. Formosan Medical Association. 2008;107:830-42.
[29] Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, et al. Global strategy for asthma management and prevention: GINA executive summary. The European respiratory journal. 2008;31:143-78.
[30] Wheeler AP, Bernard GR. Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet. 2007;369:1553-64.
[31] Proudfoot AG, McAuley DF, Griffiths MJ, Hind M. Human models of acute lung injury. Dis Model Mech. 2011;4:145-53.
[32] Martin C, Frija J, Burgel PR. Dysfunctional lung anatomy and small airways degeneration in COPD. International journal of chronic obstructive pulmonary disease. 2013;8:7-13.
[33] Biesalsk H K, Mesquita B B, Grimble R. European Consensus Statement on Lung Cancer: Risk Factors and Prevention. European consensus statement on lung cancer. 1998;48:167-76.
[34] Nykamp V. Surgical treatment of non-small cell lung cancer. South Dakota medicine: the journal of the South Dakota State Medical Association. 2010;Spec No:57-9.
[35] Taratula O, Kuzmov A, Shah M, Garbuzenko OB, Minko T. Nanostructured lipid carriers as multifunctional nanomedicine platform for pulmonary co-delivery of anticancer drugs and siRNA. Journal of controlled release: official journal of the Controlled Release Society, 2013.
[36] Tiano SL, Dalby RN. Comparison of a respiratory suspension aerosolized by an air-jet and an ultrasonic nebulizer. Pharm Dev Technology. 1996;1(3):261–268.
[37] Siddiqui MA, Plosker GL. The Novolizer: A multidose dry powder inhaler. Treat Respir Med. 2005;4(1):63–69.
[38] Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, Douglas G, Muers M, Smith D, White J.Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: A systematic review of the literature. Health Technology Assess. 2001;5(26):1–149.
[39] Kohler D. Novolizer: The new technology for the management of asthma therapy. Curr Opin Pulm Med .2003;9 (Supply 1):S11–S16.
[40] Kshirsagar N. Drug delivery systems. Medknow Publications, 2000.
[41] Rajera R, Nagpal K, Singh SK, Mishra DN. Niosomes: a controlled and novel drug delivery system. Biological & pharmaceutical bulletin. 2011;34:945-53.
[42] Lu Y, Chen SC. Micro and nano-fabrication of biodegradable polymers for drug delivery. Advanced drug delivery reviews. 2004;56:1621-33.
[43] Freiberg S, Zhu XX. Polymer microspheres for controlled drug release. International Journal of Pharmaceutics. 2004;282:1-18.
[44] Chow CKW, Matear DW, Lawrence HP. Efficacy of antifungal agents in tissue conditioners in treating candidiasis. Gerodontology. 1999;16:110-8.
[45] Mishra A, Ramteke S. Formulation and Evaluation of Mucoadhesive Buccal Film of Flurbiprofen. IntJ PharmTech Res. 2011;3:1825-30.
[46] Amiji M. M.Nanomedicine for Cancer Therapy. Pharmaceutical Research .(2011);28(2): 181-186.
[47] Byrne J. D,T. Betancourt. Active targeting schemes for nanoparticle systems in cancer therapeutics. Advanced Drug Delivery Reviews .(2008);60(15): 1615-1626.
[48] Maeda H, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Critical reviews in therapeutic drug carrier systems. 1989;6:193-210.
[49] Allen TM, Cullis PR. Drug Delivery Systems: Entering the Mainstream. Science. 2004;303:1818-22.
[50] Ganta S, Devalapally H, Shahiwala A, Amiji M. A review of stimuli-responsive nanocarriers for drug and gene delivery. Journal of controlled release : official journal of the Controlled Release Society. 2008;126:187-204.
[51] Mahapatro A, Singh DK. Biodegradable nanoparticles are excellent vehicle for site directed in-vivo delivery of drugs and vaccines. Journal of nanobiotechnology. 2011;9:55.
[52] Vanderhoff JW, El Aasser MS, Ugelstad J. Polymer emulsification process. US Patent 4,177,177 (1979).
[53] Rao JP, Geckeler KE. Polymer nanoparticles: Preparation techniques and size-control parameters. Progress in Polymer Science. 2011;36:887-913.
[54] Lemoine D, Preat V. Polymeric nanoparticles as delivery system for influenza virus glycoproteins. J Control Release. 1998;54:15–27.
[55] Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm. 1989;55:R1–4.
[56] Mishra B, Patel BB, Tiwari S. Colloidal nanocarriers: a review on formulation technology, types and applications toward targeted drug delivery. Nanomedicine: NBM .2010;6:9–24.
[57] Loscertales IG, Barrero A, Guerrero I, Cortijo R, Marquez M, Ganan-Calvo AM. Micro/nano encapsulation via electrified coaxial liquid jets. Science.2002;295:1695-8.
[58] Almeria B, Deng W, Fahmy TM, Gomez A. Controlling the morphology of electrospray-generated PLGA microparticles for drug delivery. Journal of colloid and interface science. 2010;343:125-33.
[59] Mosen K, Backstrom K, Thalberg K. Particle formation and capture during spray drying of inhalable particles. Pharm Dev Technol.2004;9:409–418.
[60] Duddu SP, Sisk SA, Walter YH, et al. Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder.Pharm Res. 2002;19:689–695.
[61] Takashima Y, Saito R, Nakajima A, Oda M, Kimura A, Kanazawa T, et al. Spray-drying preparation of microparticles containing cationic PLGA nanospheres as gene carriers for avoiding aggregation of nanospheres. International journal of pharmaceutics. 2007;343:262-9.
[62] Yang YT, Chen CT, Yang JC, Tsai T. Spray-dried microparticles containing polymeric micelles encapsulating hematoporphyrin. The AAPS journal. 2010;12:138-46.
[63] Makadia HK, Siegel SJ. Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier. Polymers. 2011;3:1377-97.
[64] Suzan Commandeur, Heleen M.M. VAN Beusekom. Polymers, Drug Release, and Drug-Eluting Stents. Journal of Interventional Cardiology. 2006;19:500-6.
[65] Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Preat V. PLGA-based nanoparticles: an overview of biomedical applications. Journal of controlled release : official journal of the Controlled Release Society. 2012;161:505-22.
[66] Yang SC, Bhide M, Crispe IN, Pierce RH, Murthy N. Polyketal copolymers: a new acid-sensitive delivery vehicle for treating acute inflammatory diseases. Bioconjug Chem. 2008;19:1164-9.
[67] DiVincenzo GD, Ziegler DA. Metabolic fate of 1,4-cyclo[14C]hexanedimethanol in rats. Toxicology and applied pharmacology. 1980;52:10-5.
[68] Sungmun Lee, Stephen C. Yang, Michael J. Heffernan, Robert Taylor, Murthy N. Polyketal Microparticles: A New Delivery Vehicle for Superoxide Dismutase. Bioconjugate Chem. 2007;18:4-7.
[69] Sy JC, Seshadri G, Yang SC, Brown M, Oh T, Dikalov S, et al. Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction. Nat Mater. 2008;7:863-9.
[70] Lee S, Yang SC, Kao CY, Pierce RH, Murthy N. Solid polymeric microparticles enhance the delivery of siRNA to macrophages in vivo. Nucleic Acids Res. 2009;37:e145.
[71] US Food and Drug Administration. Guidance for industry: metered dose inhaler (MDI) and dry powder inhaler (DPI) drug products –chemistry, manufacturing, and controls documentation. Rockville, IN: US Department of Health and Human Services,1998.
[72] Kawashima Y, Serigano T, Hino T, Yamamoto H, Takeuchi H. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate. Int J Pharm. 1998;172:179–188.
[73] Steckel H, Bolzen N. Alternative sugars as potential carriers for dry powder inhalations. Int J Pharm. 2004;270:297–306.
[74] Harjunen P, Lankinen T, Salonen H, Lehto VP, Jarvinen K. Effects of carriers and storage of formulation on the lung deposition of a hydrophobic and hydrophilic drug from a DPI. Int J Pharm.2003;263:151–163.
[75] Gjoerup J, Hilberg O, Bendstrup E. Inhaled mannitol in the treatment of non-cystic fibrosis bronchiectasis in adults. Respirology. 2012;17:927-32.
[76] Fujita S, Taira J. Biphenyl compounds are hydroxyl radical scavengers: their effective inhibition for UV-induced mutation in Salmonella typhimurium TA102. Free radical biology & medicine. 1994;17:273-7.
[77] Wang JP, Hsu MF, Raung SL, Chen CC, Kuo JS, Teng CM. Antiinflammatory and analgesic effects of magnolol. Naunyn Schmiedebergs Arch Pharmacol .1992;346:707–12.
[78] HsuMF, LuMC,TsaoLT,Kuan YH, Chen CC,Wang JP. Mechanisms of the influence of magnolol on eicosanoid metabolism in neutrophils. Biochem Pharmacol. 2004;67:831–40.
[79] Homma M, Minami M, Taniguchi C, Oka K, Morita S, Niitsuma T, et al. Inhibitory effects of lignans and flavonoids in saiboku-to, a herbal medicine for bronchial asthma, on the release of leukotrienes from human polymorphonuclear leukocytes. Planta Med. 2000;66:88–91.
[80] Hamasaki Y, Kobayashi I, Zaitu M, Tsuji K, Kita M, Hayasaki R, et al. Magnolol inhibits leukotriene synthesis in rat basophilic leukemia-2H3 cells. Planta Med. 1999;65:222–6.
[81] Han SJ, Bae EA, Trinh HT,Yang JH,Youn UJ, Bae KH, et al. Magnolol and honokiol: inhibitors against mouse passive cutaneous anaphylaxis reaction and scratching behaviors. Biol Pharm Bull. 2007;30:2201–3.
[82] Tanaka K, Hasegawa J, Asamitsu K, Okamoto T. Magnolia ovovata extract and its active component magnolol prevent skin photoaging via inhibition of nuclear factor kappaB. Eur J Pharmacol. 2007;565:212–9.
[83] Lin SY, Chang YT, Liu JD, Yu CH, Ho YS, Lee YH, et al. Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells. Mol Carcinog. 2001;32:73–83.
[84] Yang SE, Hsieh MT, Tsai TH, Hsu SL. Effector mechanism of magnololinduced
apoptosis in human lung squamous carcinoma CH27 cells. Br J Pharmacol.2003;138:193–201.
[85] Huang SH, Chen Y, Tung PY,Wu JC, Chen KH,Wu JM, et al. Mechanisms for the magnolol-induced cell death of CGTHW-2 thyroid carcinoma cells. J Cell Biochem.2007;101:1011–22.
[86] You Q, Li M, Jiao G. Magnolol induces apoptosis via activation of both mitochondrial and death receptor pathways in A375-S2 cells. Arch PharmRes. 2009;32:1789–94.
[87] Ikai T, Akao Y, Nakagawa Y, Ohguchi K, Sakai Y, Nozawa Y. Magnolol-induced apoptosis is mediated via the intrinsic pathway with release of AIF from mitochondria in U937 cells. Biol Pharm Bull. 2006;29:2498–501.
[88] Lee MM, Huang HM, Hsieh MT, Chen CS, Yeh FT, Kuo JS. Anti-inflammatory and neuroprotective effects of magnolol in chemical hypoxia in rat cultured cortical cells in hypoglycemic media. Chin J Physiol. 2000;43:61–7.
[89] Jawan B, Goto S, Pan TL, Lai CY, Luk HN, Eng HL, et al. The protective mechanism of magnolol, a Chinese herb drug, against warm ischemiareperfusion injury of rat liver. J Surg Res. 2003;110:378–82.
[90] Lin YR, Chen HH, Ko CH, Chan MH. Effects of honokiol and magnolol on acute and inflammatory pain models in mice. Life Sci. 2007;81:1071–8.
[91] Bang KH, Kim YK, Min BS, Na MK, Rhee YH, Lee JP, et al. Antifungal activity of magnolol and honokiol. Arch Pharm Res. 2000;23:46–9.
[92] Clark AM, El-Feraly FS, Li WS. Antimicrobial activity of phenolic constituents of Magnolia grandiflora L. J Pharm Sci. 1981;70:951–2.
[93] Bae EA, Han MJ, Kim NJ, Kim DH. Anti-Helicobacter pylori activity of herbal medicines. Biol Pharm Bull. 1998;21:990–2.
[94] Wang YJ, Chien YC, Wu CH, Liu DM. Magnolol-loaded core-shell hydrogel nanoparticles: drug release, intracellular uptake, and controlled cytotoxicity for the inhibition of migration of vascular smooth muscle cells. Molecular pharmaceutics. 2011;8:2339-49.
[95] Calvin Yu-Chian C. Magnolol encapsulated by different acyl chain length of liposomes on inhibiting proliferation of smooth muscle cells. Journal of the Taiwan Institute of Chemical Engineers. 2009;40:380-6.
[96] Yoon Yeo, Kinam Park. Control of Encapsulation Efficiency and Initial Burst in Polymeric Microparticle Systems. Archives of pharmacal research. 2004;27:1-12.
[97] Lai C-S, Lai Y-S, Kuo D-H, Wu C-H, Ho C-T, Pan M-H. Magnolol potently suppressed lipopolysaccharide-induced iNOS and COX-2 expression via downregulating MAPK and NF-κB signaling pathways. Journal of Functional Foods. 2011;3:198-206.