臺灣博碩士論文加值系統

本實驗室一直以來均致力於發展藥物賦型劑之開發，經過去的實驗發現並證實一植物之萃取物為天然賦型劑，可利用於藥物的控制釋放。且由於對人體係屬無毒性、生物可降解性、高生物相容性之材質，因此大幅地提升了其可利用的價值。由先前實驗室已開發並建立了萃取方法，且實驗證明了此植物萃取之天然賦型劑對於藥物具有延遲釋放的能力，而本研究則著於開發其他可應用的空間。
本研究目的係為植物萃取物經熬煮萃取後，再由噴霧乾燥製造出來的粉末顆粒，此植物粉末為基質的錠劑，先以豬胃模擬體內的黏膜給藥系統，探討其基質型錠劑經水合後，與體內腸胃道的黏膜產生的黏性交互作用進行觀察，並且紀錄其黏著力。另外，也與市面上常見的合成聚合物【Methocel K100M；Methocel K15CR；Sod CMC …】等進行試驗比較，並觀察其黏性以等物化特性，以確立發展此植物天然萃取物之緩釋機制可應用的層面。此外，藉由模擬口腔黏膜的藥物釋放系統的舌下頰部給藥系統，利用豬的口腔黏膜，使此天然材質的黏著力與他種合成賦型劑進行比較實驗包括時間(10、30秒，1、3分鐘)、力量(0.05、0.1、0.5、1 N)以及探針的回程速度等物理性質之影響，證明此植物萃取物具有相當穩定的黏著力，對於設計成口腔黏給藥系統的口腔貼片而言，有很好的發展空間。

The purpose of this study is to evaluate a novel natural material as the mucoadhesive and sustained release excipient used in buccal adhesion tablet. The extract from a plant is obtained and dried by spray drying and other technologies.
The mucoadhesion between tablets made from dried plant extract and buccal mucosa of pig was thoroughly evaluated. Effect of contact time, pretest speed, post test speed, and contact force on the mucoadhesion were studied and compared with K15M CR. The mucoadhesion strength is close to K15M CR, but is lower than Sod CMC. The difference of contact time (such as 10 sec, 30 sec, 60 sec, and 180 sec) and applied force (such as 0.05 N, 0.1 N, 0.5 N, and 1.0 N) have effect on the mucoadhesion strength.
The mucoadhesion between tablets made from dried plant extract and gastric mucosa of pig was also evaluated and compared with various polymers.
The release rate of the buccal tablet was also studied. It was found that the material has a sustained release effect.
In conclusion, this material could be applied as a buccal tablet excipient with sustained release effect.

目錄
中文摘要．．．．．．．．．．．．．．．．．．．．．．．．．I
Abstract ．．．．．．．．．．．．．．．．．．．．．．．．．III
目錄．．．．．．．．．．．．．．．．．．．．．．．．．．．IV
表目錄．．．．．．．．．．．．．．．．．．．．．．．．． VIII
圖目錄．．．．．．．．．．．．．．．．．．．．．．．．． IX
附圖與附表目錄．．．．．．．．．．．．．．．．．．．．． XI
縮寫表．．．．．．．．．．．．．．．．．．．．．．．．． XII
第一章 ．．．．．．．．．．．．．．．．．．．．．．．．． 1
1.1 研究動機．．．．．．．．．．．．．．．．．．．．．．． 1
1.2 藥物的投遞途徑．．．．．．．．．．．．．．．．．．．． 1
1.3 首渡效應．．．．．．．．．．．．．．．．．．．．．．． 3
1.4 錠劑的劑型．．．．．．．．．．．．．．．．．．．．．． 4
1.5 物性測試儀(TA-XT2 Texture Analyser)．．．．．．．．．．． 5
1.6 賦形劑種類．．．．．．．．．．．．．．．．．．．．．． 7
1.6.1 植物萃取物．．．．．．．．．．．．．．．．．．．． 7
1.6.2 Hydroxypropylmethyl Cellulose (HPMC)．．．．．．．．．8
1.6.3 Sodium Carboxymethylcellulose (Sod CMC)．．．．．．． 9
1.6.4 其他聚合物．．．．．．．．．．．．．．．．．．．． 10
1.7 Mucoadhesion．．．．．．．．．．．．．．．．．．．．． 11
1.8 Buccal Adhesive．．．．．．．．．．．．．．．．．．．． 12
1.9 Benzydamine HCl ．．．．．．．．．．．．．．．．．．． 15
第二章 實驗儀器、材料、方法及步驟．．．．．．．．．．．16
2.1 實驗儀器．．．．．．．．．．．．．．．．．．．．．．． 16
2.2 材料．．．．．．．．．．．．．．．．．．．．．．．．． 18
2.3 植物的萃取．．．．．．．．．．．．．．．．．．．．．． 19
2.4 植物萃取液之黏性測定．．．．．．．．．．．．．．．．． 19
2.5 噴霧乾燥．．．．．．．．．．．．．．．．．．．．．．． 20
2.6 錠劑製程．．．．．．．．．．．．．．．．．．．．．．． 21
2.7 黏膜黏性試驗．．．．．．．．．．．．．．．．．．．．． 22
2.7.1 胃黏膜之黏著力．．．．．．．．．．．．．．．．．．．22
2.7.2 口腔黏膜之黏著力．．．．．．．．．．．．．．．．． 23
2.7.3黏著時間與黏著力的改變在口腔黏膜對於黏著力的影響．． 24
2.7.4 探針回程速度對於黏著力的影響．．．．．．．．．．．．25
2.8 黏著時間試驗．．．．．．．．．．．．．．．．．．．．．．26
2.9 溶離試驗．．．．．．．．．．．．．．．．．．．．．．．．27
第三章 結果．．．．．．．．．．．．．．．．．．．．．．． 28
3.1 胃黏膜的黏著力試驗．．．．．．．．．．．．．．．．．． 28
3.1.1植物萃取物之錠劑與胃黏膜黏之著時間影響．．．．．．． 28
3.1.2 各聚合物與植物萃取物在胃膜黏膜的黏著力比較試驗之比較．．．．．．．．．．．．．．．．．．．．．．．． 28
3.2 口腔黏膜之黏著力試驗．．．．．．．．．．．．．．．．．． 30
3.3黏著時間與推擠力量的改變在口腔黏膜對於黏著力的影響．．． 30
3.4探針回程速度對於黏著力的影響．．．．．．．．．．．．．． 31
3.5黏著時間試驗．．．．．．．．．．．．．．．．．．．．．． 32
3.6 溶離試驗．．．．．．．．．．．．．．．．．．．．．．．． 33
第四章 討論．．．．．．．．．．．．．．．．．．．．．．． 34
4.1胃黏膜的黏著力試驗之比較．．．．．．．．．．．．．．． 34
4.1.1植物萃取物黏著時間之影響．．．．．．．．．．．．． 34
4.1.2各種聚合物與胃膜黏的黏著力比較．．．．．．．．．． 35
4.2口腔黏膜黏著力之比較．．．．．．．．．．．．．．．．． 36
4.3黏著時間與推擠力量的改變在口腔黏膜對於黏著力的影響．．． 37
4.4 黏著分離時間試驗．．．．．．．．．．．．．．．．．．． 39
4.5 溶離試驗結果．．．．．．．．．．．．．．．．．．．．． 40
第五章 結論．．．．．．．．．．．．．．．．．．．．．．． 41
5.1錠劑在胃黏膜的黏著力試驗之比較．．．．．．．．．．．． 41
5.2 錠劑在口腔黏膜黏著力之比較．．．．．．．．．．．．．． 41
5.3黏著時間與推擠力量的改變在口腔黏膜對於黏著力的影響．．． 42
5.4 黏著時間試驗結果．．．．．．．．．．．．．．．．．．．． 42
5.5 溶離試驗結果．．．．．．．．．．．．．．．．．．．．． 43
5.6 總結．．．．．．．．．．．．．．．．．．．．．．．．． 43
參考文獻．．．．．．．．．．．．．．．．．．．．．．．．． 44
附表與附圖或附錄．．．．．．．．．．．．．．．．．．．．． 71













表目錄

(表一) 在胃黏膜接觸三分鐘的黏著力．．．．．．．．．．．．． 29
(表二) 黏著分離時間試驗．．．．．．．．．．．．．．．．．． 53















圖目錄

(圖一) 植物萃取物所製成的錠劑，在胃黏膜模擬系統黏著時間長短之
比較．．．．．．．．．．．．．．．．．．．．．．．．．． 54
(圖二) 多種聚合物與植物萃取物製成錠劑後，在胃黏膜的黏著力比較．55
(圖三) 多種聚合物與植物萃取物製成錠劑後，在胃黏膜接觸三分鐘的
黏著力．．．．．．．．．．．．．．．．．．．．．．．． 56
(圖四) 多種聚合物與植物萃取物製成錠劑後，在口腔黏著時間為十秒
鐘之黏著力比較．．．．．．．．．．．．．．．．．．．．． 57
(圖五) 各聚合物與植物萃取物製成錠劑後，在口腔黏著時間為三分鐘
之黏著力比較．．．．．．．．．．．．．．．．．．．．．． 58
(圖六) 植物萃取物製成錠劑後，在各時間與力量的作用表現．．．．．． 59
(圖七) K15M CR 製成錠劑之後在各時間與力量的作用表現．．．．．． 60
(圖八) 植物萃取物製成錠劑後，在各時間與力量的作左漯穛{．．． 61
(圖九) K15M CR 製成錠劑之後在各時間與力量的所作用左漯穛{．．． 62
(圖十) 探針回程速度對於黏著力之影響．．．．．．．．．．．．．． 63
(圖十一) 探針回程速度對於植物萃取物黏著做奶尬v響．．．．．．． 64
(圖十二) 探針回程速度對於K15M CR黏著做奶尬v響．．．．．．．． 65
(圖十三) 植物萃取物分離時間試驗．．．．．．．．．．．．．．．．． 66
(圖十四) K15M CR 黏著分離時間試驗．．．．．．．．．．．．．．． 67
(圖十五) Benzydamine HCl在pH6.8 phosphate buffer中植物萃取物所製
成錠劑與乳糖製成的錠劑之溶離比較．．．．．．．．．．．． 69
















附表與附圖目錄

(附圖一) Hydroxypropylmethyl Cellulose (HPMC)結構圖．．．．．．．． 70
(附圖二)Sodium Carboxymethylcellulose (Sod CMC)結構圖．．．．．． 71
(附圖三) Hydroxypropyl cellulose (HPC)結構圖．．．．．．．．．．．． 72
(附圖四) Hydroxylethylcellulose (HEC)結構圖．．．．．．．．．．．． 73
(附圖五) Carbopol 940結構圖．．．．．．．．．．．．．．．．．． 74
(附圖六) (a)從豬胃接近幽門取下之部位，(b) 豬胃黏膜自胃部的結締組
織上取下．．．．．．．．．．．．．．．．．．．．．．．． 75
(附圖七) TA.XT2以及黏著力試驗探頭套組．．．．．．．．．．．． 76
(附圖八) 黏著力試驗探頭套組下的動物組織．．．．．．．．．．．． 77
(附圖九) 植物萃取物內容物含量分析．．．．．．．．．．．．．．． 78
(附圖十)各種聚合物以0.5 N 與接觸3分鐘之黏著力．．．．．．．．． 79
(附圖十一) 口頰錠於各種配方下的黏著力．．．．．．．．．．．．． 80
(附圖十二) Thirawong N.(23)等人以相同的聚合物在不同的豬組織進行的
比較．．．．．．．．．．．．．．．．．．．．．．．． 81

參考文獻

1. Patel V, Prajapati B, Patel M. Effect of hydrophilic polymers on buccoadhesive eudragit patches of propranolol hydrochloride using factorial design. AAPS PharmSciTech. 2007; 8(2):E45
2. Alvarenga P, Palma P, Goncalves AP, et al. Evaluation of chemical and ecotoxicological characteristics of biodegradable organic residues for application to agricultural land. Environ Int. 2007; 33(4):505-13.
3. Scheller J, Henggeler D, Viviani A, et al. Purification of spider silk-elastin from transgenic plants and application for human chondrocyte proliferation. Transgenic Res. 2004; 13(1):51-7.
4. Konig Junior B, Forger SE, Mascaro MB, et al. Biocompatibility of the polyurethane resin of the castor bean inserted into the alveolar bone of the dog. Ann Anat. 1999; 181(6):581-4.
6. Abu-Huwaij R, Assaf S, Salem M, et al. Potential mucoadhesive dosage form of lidocaine hydrochloride: II. In vitro and in vivo evaluation. Drug Dev Ind Pharm. 2007; 33(4):437-48.
7. Giannola LI, De Caro V, Giandalia G, et al. Release of naltrexone on buccal mucosa: Permeation studies, histological aspects and matrix system design. Eur J Pharm Biopharm. 2007; [Epub ahead of print]
8. 徐人英 譯。藥效藥劑學與臨床藥品動態學。合記出版社。1984;10 75-93頁
9. 蔡秋帆 湯念湖 王耀宏。藥理學。新文京開發出版有限公司。2002; 1 2-18頁
10. 劉興華 趙國芳 楊筱蕙。醫護藥物學。華杏出版股份有限公司。2000; 3 23-24頁
11. Koffi AA, Agnely F, Ponchel G, et al. Modulation of the rheological and mucoadhesive properties of thermosensitive poloxamer-based hydrogels intended for the rectal administration of quinine. Eur J Pharm Sci. 2006;27(4):328-35. Epub 2005 Dec 13.
12. Tan YT, Peh KK, Al-Hanbali O. Effect of Carbopol and polyvinylpyrrolidone on the mechanical, rheological, and release properties of bioadhesive polyethylene glycol gels. AAPS PharmSciTech. 2000; 1(3):E24.
13. Martin L, Wilson CG, Koosha F, et al. Sustained buccal delivery of the hydrophobic drug denbufylline using physically cross-linked palmitoyl glycol chitosan hydrogels. Eur J Pharm Biopharm. 2003; 55(1):35-45.
14. http://www.texturetechnologies.com/pharmaceutical_papers.html
15. Hsien-Yi Huang. Physical Properties of Alkali-Treated Konjac Gel and Influences of Konjac/Gum Combination on the Quality of Reduced-Fat Frankfurter. 靜宜大學碩士論文。2003
16. Jones DS, Irwin CR, Woolfson AD, et al. Physicochemical characterization and preliminary in vivo efficacy of bioadhesive, semisolid formulations containing flurbiprofen for the treatment of gingivitis. J Pharm Sci. 1999; 88(6):592-8.
17. Owens TS, Dansereau RJ, Sakr A. Development and evaluation of extended release bioadhesive sodium fluoride tablets. Int J Pharm. 2005; 288(1): 109-22.
18. 馮水源。一種新基質型長效賦型劑之探討。嘉南藥理科技大學碩士論文。2006
19. Alur HH, Pather SI, Mitra AK, et al. Transmucosal sustained-delivery of chlorpheniramine maleate in rabbits using a novel, natural mucoadhesive gum as an excipient in buccal tablets. Int J Pharm. 1999; 188(1):1-10.
20. Zhenqing H, Zhenxi Z, Chuanxin Z, et al. Use of natural plant exudates (Sanguis Draxonis) for sustained oral insulin delivery with dramatic reduction of glycemic effects in diabetic rats. J Control Release. 2004; 97(3): 467-75.
21. Latha M, Pari L, Sitasawad S, et al. Insulin-secretagogue activity and cytoprotective role of the traditional antidiabetic plant Scoparia dulcis (Sweet Broomweed). Life Sci. 2004; 75(16): 2003-14.
22. Karthikeyan K, Ravichandran P, Govindasamy S. Chemopreventive effect of Ocimum sanctum on DMBA-induced hamster buccal pouch carcinogenesis. Oral Oncol. 1999; 35(1): 112-9.
23. Chary RB, Rao YM. Formulation and Evaluation of Methocel K15M Bioadhesive Matrix Tablets. Drug Dev Ind Pharm. 2000; 26(8): 901-6.
24. Perioli L, Ambrogi V, Angelici F, et al. Development of mucoadhesive patches for buccal administration of ibuprofen. J Control Release. 2004; 99(1): 73-82.
25. Perioli L, Ambrogi V, Rubini D, et al. Novel mucoadhesive buccal formulation containing metronidazole for the treatment of periodontal disease. J Control Release. 2004; 95(3): 521-33.
26. Ugwoke MI, Agu RU, Verbeke N, et al. Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives. Adv Drug Deliv Rev. 2005; 57(11): 1640-65.
27. Bertram U, Bodmeier R. In situ gelling, bioadhesive nasal inserts for extended drug delivery: in vitro characterization of a new nasal dosage form. Eur J Pharm Sci. 2006; 27(1): 62-71.
28. Sudhakar Y, Kuotsu K, Bandyopadhyay AK. Buccal bioadhesive drug delivery — A promising option for orally less efficient drugs. J Controlled Release. 2006; (114):15–40.
29. Wurster SH, Bonet V, Mayberry A, et al. Intraperitoneal Sodium Carboxymethylcellulose Administration Prevents Reformation of Peritoneal Adhesions Following Surgical Lysis. J Surg Res. 1995; 59(1): 97-102.
30. Ryan CK, Sax HC. Evaluation of a Carboxymethylcellulose Sponge for Prevention of Postoperative Adhesions. Am J Surg. 1995; 169(1): 154-9.
31. Grabovac V, Guggi D, Bernkop-Schnürch A. Comparison of the mucoadhesive properties of various polymers. Adv Drug Deliv Rev. 2005; 57(11): 1713-23.
32. Thirawong N, Nunthanid J, Puttipipatkhachorn S. Mucoadhesive properties of various pectins on gastrointestinal mucosa: An in vitro evaluation using texture analyzer. Eur J Pharm Biopharm. 2007; 67(1): 132-40
33. Mulhbacher J, Ispas-Szabo P, Ouellet M. Mucoadhesive properties of cross-linked high amylose starch derivatives. Int J Biol Macromol. 2006; 40(1): 9-14.
34. Giannola LI, De Caro V, Giandalia G, et al. Release of naltrexone on buccal mucosa: Permeation studies, histological aspects and matrix system design. Eur J Pharm Biopharm. 2007; 67(2): 425-33.
35. Langoth N, Kalbe J, Bernkop-Schnürch A. Development of a mucoadhesive and permeation enhancing buccal delivery system for PACAP (pituitary adenylate cyclase-activating polypeptide). Int J Pharm. 2005; 296(1-2): 103-11.
36. Ikinci G, Senel S, Wilson CG. Development of a buccal bioadhesive nicotine tablet formulation for smoking cessation. Int J Pharm. 2004; 277(1-2): 173-8.
37. Desai KG, Kumar TM. Preparation and evaluation of a novel buccal adhesive system. AAPS PharmSciTech. 2004; 5:e35.
38. Lopez CR, Portero A, Vila-Jato JL, et al. Design and evaluation
of chitosan/ethylcellulose mucoadhesive bilayered devices for buccal
drug delivery. J Control Release. 1998; 55: 143-152.
39. Pramodkumar TM, Desai KGH, Shivakumar HG. Buccal permeation enhancers. Ind J Pharm Edu. 2002; 36: 147-151.
42. Akbari J, Nokhodchi A, Farid D, et al. Development and evaluation of buccoadhesive propranolol hydrochloride tablet formulations: effect of fillers. Farmaco. 2004; 59(2): 155-61.
43. Agarwal V, Mishra B. Design, development, and biopharmaceutical properties of buccoadhesive compacts of pentazocine. Drug Dev Ind Pharm. 1999; 25(6): 701-9.
44. Yamsani VV, Gannu R, Kolli C, et al. Development and in vitro evaluation of buccoadhesive carvedilol tablets. Acta Pharm. 2007; 57(2): 185-197.
40. Sandri G, Poggi P, Bonferoni MC, et al. Histological evaluation of buccal penetration enhancement properties of chitosan and trimethyl chitosan. J Pharm Pharmacol. 2006; 58 (10): 1327-36.
41. Colonna C, Genta I, Perugini P, et al. 5-methyl-pyrrolidinone chitosan films as carriers for buccal administration of proteins. AAPS PharmSciTech. 2006; 7(3): 70.
45. Eouani C, Piccerelle P, Prinderre P, et al. In-vitro comparative study of buccal mucoadhesive performance of different polymeric films. Eur J Pharm Biopharm. 2001; 52(1): 45-55.
46. Kim JH, Chu FC, Lakshmi V, et al. Benzydamine HCl, a new agent for the treatment of radiation mucositis of the oropharynx. Am J Clin Oncol. 1986; 9(2): 132-4.
47. 蔡靖彥，蔡百榮。常用藥品手冊。杏欣出版社。2006; p56。
48. Wong CF, Yuen KH, Peh KK. An in-vitro method for buccal adhesion studies: importance of instrument variables. Int J Pharm. 1999; 180(1): 47-57.
49. Collier TO, Anderson JM, Kikuchi A, et al. Adhesion behavior of monocytes, macrophages, and foreign body giant cells on poly (N-isopropylacrylamide) temperature-responsive surfaces. J Biomed Mater Res. 2002; 59(1): 136-43.
50. Van Meerbeek B, Yoshida Y, Lambrechts P, et al. A TEM study of two water-based adhesive systems bonded to dry and wet dentin. J Dent Res. 1998; 77(1): 50-9.
51. Dal Zotto M, Realdon N, Ragazzi E, et al. Effects of two different kinds of silicium dioxide on release of drugs from suppositories: benzydamine hydrochloride. Farmaco. 1991; 46(5): 699-711.
52. Parodi B, Russo E, Gatti P, Cafaggi S. Development and in vitro evaluation of buccoadhesive tablets using a new model substrate for bioadhesion measures: the eggshell membrane. Drug Dev Ind Pharm. 1999; 25(3): 289-95.
53. Hill RJ, Bluck LJ, Davies PS. The hydration ability of three commercially available sports drinks and water. J Sci Med Sport. 2007.
54. Desai J, Alexander K, Riga A. Characterization of polymeric dispersions of dimenhydrinate in ethyl cellulose for controlled release. Int J Pharm. 2006; 308(1-2): 115-23.
55. Mulhbacher J, Ispas-Szabo P, Ouellet M. In vitro evaluation of calcium binding capacity of chitosan and thiolated chitosan poly (isobutyl cyanoacrylate) core–shell nanoparticles. Int J Biol Macromol. 2006; 40(1): 9-14
56. Lewis Shaila, Subramanian G, Pandey S, et al. Design, evaluation and pharmacokinetic study of mucoadhesive buccal tablets of nicotine for smoking cessation. Indian J Pharm Sci. 2006; 6: 829-831.
57. Ameye D, Mus D, Foreman P, et al. Spray-dried Amioca starch Carbopol 974P mixtures as buccal bioadhesive carriers. Int J Pharm. 2005 Sep; 301(1-2): 170-80.
58. Aboudzadeh MA, Mirabedini SM, Atai M. Effect of silane-based treatment on the adhesion strength of acrylic lacquers on the PP surfaces. Int J Adhesion & Adhesives. 2007; (27): 519–526
59. Harding SA, Jiang H, Jeong ML, et al. Functional genomics analysis of foliar condensed tannin and phenolic glycoside regulation in natural cottonwood hybrids. Tree Physiol. 2005; 25(12): 1475-86.
60. Narendra C, Srinath MS, Prakash Rao B. Development of three layered buccal compact containing metoprolol tartrate by statistical optimization technique. Int J Pharm. 2005; 304(1-2): 102-14.