臺灣博碩士論文加值系統

由於近年來國人食用維生素與礦物質等保健食品有顯著上升的趨勢，因此，本實驗乃針對市面上所販售之維生素B群為主的營養補充劑進行檢測。
首先為建立HPLC分析維生素B混合物之檢測法，乃使用ODS C18層析管 ( 25 X 4.6 mm ) 分析。其中，藉由增加移動相中甲醇的比例，可獲得較適當之條件，並得知移動相之組成為水 / 甲醇 / 冰醋酸為 62 / 38 / 1。其次pH會影響其溶出時間，經檢測以pH 3.0最為適當。此HPLC方法之專一性、精密度、準確度、線性及回收率等，均經實驗證實具有良好之效應。
另外，製備維生素B混合物膠囊，並添加5% 不同的賦型劑Chitosan、Collagen和Ascorbic acid等，與一般的賦型劑進行崩散試驗，經比較其溶解情形，結果得知並無顯著差異。另外，進行溶離試驗以確認主成分之溶出情形，藉以推測營養補充劑經人體服用後之溶解情況。結果發現添加5% Chitosan作為賦型劑者其主成分溶出效果較添加5% Ascorbic acid及傳統賦型劑 Potato starch者差，其中以Thiamine HCl 影響較大，顯示添加5% Chitosan會影響維生素B混合物的主成分釋出率。由結果推測，Chitosan不適合添加於維生素B混合物中作為賦型劑。另外，添加5% Ascorbic acid於初期部分主成分釋出情形有微幅上升趨勢，但經儲存9個月後則無顯著差異。
不同劑型在不同儲藏條件下之維生素B群的安定性，經檢測後得知以室溫儲藏8個月維生素B群之產品，其維生素含量顯著下降，其中尤其以Thiamine HCl下降最為明顯，其安定性情形為：糖衣錠＞錠劑＞膠囊。控制儲藏溫度於20-25℃時，其安定性情形亦優於室溫儲存者。另外，置於55℃存放者，其安定情形則以錠劑＞糖衣錠＞膠囊。
添加5% Ascorbic acid作為賦型劑之維生素B複合劑膠囊，經儲存8個月後Thiamine HCl較對照組有顯著下降的情形，而添加5% Chitosan及5% Collagen者，Thiamine HCl含量急速下降，而Riboflavin、
Nicotinamide及Pyridoxine HCl之安定性程度則以添加5% 之Ascorbic acid＞Chitosan＞Collagen。
其次，採購和檢測市售維生素B群之產品，經比較標示值和實際檢測值後，發現部分市售之標示值不符合實際測定值。其中尤以食品級之兩件檢體，各項維生素B成分均偏低或甚至缺乏，而市售藥品級維生素B群產品之標示尚可信，顯示食品級者須加以管制。

According to survey, nutrition supplement (such as vitamin and mineral) consumption in Taiwan is rising. Our experiments targeted vitamin B complex. First, we tried to build a method using HPLC with ODS C18 (25 X 4.6 mm) to analyze vitamin B. The best conposition of mobile phase was as follows : water / methanol / glacial acetic acid = 40 / 60 / 1. Second, the pH value affected the retention time of vitamin B. We have found pH 3.0 was the best. The determination method was proved to be specificity, accuracy, linearacy, and good recovery.
The vitamin B complex capsule was added 5% excipient such as chitosan, collagen, and ascorbic acid. It was found to be no significant difference for dissolution test. On the other hand, the dissolved main component in the capsule was also determined. We found the dissolution of nutrient from the vitamin B capsule with adding 5% chitosan excipient was worse than that of the vitamin B capsule with adding 5% ascorbic acid excipient or potato starch excipient, especially for thiamine HCl. It indicated that chitosan who not suitable for excipient in vitamin B complex capsule.
Different vitamin B product requires different storage condition to keep its stability. From experiment we found the component of vitamin B product was reduced significantly, especially for thiamine HCl. Among different packags, sugar coated tablet showed the best stability, followed by tablet and capsule, when stored at 20-25℃ range.
The vitamin B capsule with adding 5% ascorbic acid as excipient was stored for eight months, thiamine HCl level was reduced significantly. In addition, the vitamin B component in the capsules with adding 5% chitosan and 5% collagen were reduced rapidly. Components such as riboflavin, nicotinamide and pyridoxine HCl increased the stability by adding 5% with ascorbic acid, followed by collagen and chitosan.
Finally, the commercial vitamin B products collected from the markets were determined. It was found that 2 samples of food grade vitamin were particularly low for all vitamin B components or even lack. The medical grade vitamin B products were more credible on its label.

目 錄
頁次
中文摘要………………………………………………………… 1
英文摘要……………………………………………………………… 3
第一章 文獻整理………………………………………………………5
一、維生素營養補充劑的背景、銷售及相關法規…………………6
二、維生素B群的特性、功能及劑量………………………………11
三、藥品的安定性試驗……………………………………………20
四、影響藥品安定性的因素………………………………………26
五、高分子天然聚合物或抗氧化劑作為藥品載體………………29
1. 幾丁質與幾丁聚醣…………………………………………30
2. 膠原蛋白……………………………………………………38
3. 維生素C ……………………………………………………42
六、維生素B群的檢驗分析…………………………………………42
七、崩散及溶離試驗………………………………………..46
八、圖表…………………………………………………………50
第二章、分析方法驗證及市售樣品檢測…………………………..59
一、前言………………………………………………………………60
二、材料與方法……………………………………………………….62
三、結果……………………………………………………………69
四、討論……………………………………………………………..72
五、圖表………………………………………………………………74
第三章 、安定性試驗…………………………………………………89
一、前言………………………………………………………………90
二、材料與方法……………………………………………………….93
三、結果……………………………………………………………96
四、討論……………………………………………………………..99
五、圖表………………………………………………………………104
第四章、溶離及崩散試驗………………………………………….…….111
一、前言………………………………………………………………112
二、材料與方法……………………………………………………….113
三、結果……………………………………………………………115
四、討論……………………………………………………………..118
五、圖表………………………………………………………………120
總結………………………………………………………………………………..125
參考文獻………………………………………………………………..128
誌謝…………………………………………………………………………139

王大鵬、張立乾、黃志賢，1994a。固體口服劑型溶離安定性之探討(一)。醫院藥學 11 : 16-26。
王大鵬、張立乾、黃志賢，1994b。固體口服劑型溶離安定性之探討(二)。醫院藥學 11 : 156-164。
江晃榮，1997，日本生體高分子化合物(甲殼質、膠原蛋白)的市場與發展。生技/醫藥產業透析 10：24-26。
行政院衛生署，2000。中華藥典，第五版。行政院衛生署。台北。
李世代，1999。維他命與礦物質。當代醫學27 (3)：20-30。
李文婷，2000，生物科技的新材料-基因重組膠原蛋白。化工資訊 10：21-29。
李美葉，2000。幾丁質類物質在膳食與醫療之助益及潛在問題。生物技術 2(2)：29-33。
李族祺、李功固、許興智，1977。維生素製劑之安定性，開南書局。台南。
林文一，2002。補充維他命之需要與重要：預防相血管疾病與減少癌症。高雄醫師會誌7 : 31-32。
林金梅、劉敏主、林士銓，1995。應用高效液相層析儀對輔助飼料中維生素B1、B2、B6、菸鹼酸之同時檢測方法的開發。台灣省畜衛所研報31：93-99。
林倫輝，1995。前列腺素膠原蛋白凝膠釋放系統。台北醫學院，台北醫學院藥學研究所碩士論文。台北。
林瑩禎，1998。我國食用維生素與礦物質保健產品市場概況。食品市場資訊87(11)：1-3。
林瑩禎，1999。美國營養補充劑市場慨況。食品市場資訊12：4-6。
林慧、周賢忠，1996。藥品安定性研究綜論。藥物食品分析4(2)：99-116。
林澤青，1998。幾丁聚醣-果膠顆粒pH值敏感性及蛋白質控制釋出特性。國立台灣海洋大學食品科學研究所碩士論文。基隆。
吳勇毅，2002。不同方法製備幾丁聚醣膠粒之膨潤及其控制釋放特性。國立台灣海洋大學食品科學研究所碩士論文。基隆。
徐世昌，2001。生物性高分子-幾丁質與幾丁聚醣之解邵與應用。化工資訊2：36-45。
徐進興、糜福龍，1999。海洋資源與化工技術-幾丁質與幾丁聚醣在化工領域之應用。化工技術46 (3)：51-66。
袁國方，2000。幾丁質/幾丁聚聚醣在膳食與醫療之助益及潛在問題。食品工業32 (4)：1-8。
許富銀、鄭明鎮、王盈錦，1998。膠原蛋白在醫學上的應用。生物產業 9 (1)：21-26。
陳岳鴻，2000。藥物化學精要。東華書局。台北。
陳淑娥，2000。實踐大學生的維生素/礦物質營養補充劑使用狀況之調查分析研究。實踐學報31：21-52。
陳惠美，1998。維他命的臨床應用。醫院藥學15：231-239。
陳慶源，2000。幾丁聚醣在藥物運送系統上之應用。食品工業32 (4)：18-28。
黃玲惠，1996。膠原蛋白生物技術。化工資訊 40：136-141。
張為憲、李敏雄、呂政義、張永和、陳昭雄、孫璐西、陳怡宏、張基郁、顏國欽、林志城、林慶文，1999。食品化學，初版。華香園書局。台北。
楊炯琳、陳瑞祥，1999。膠原蛋白生物材料應用。生化技術 7(40) 136-141。
楊建俊、廖捷玲、陳美惠，1991。幾丁質系列產品作為藥品釋放控制擔體之應用研究。中國農業化學會誌 29(3)：281-289。
鄭慧文、朱懷祖，1997。保健類食品：美國食品及藥品管理史上的重大變革。食品工業月刊29 (4)：1-7。
劉錦至，1996。維生素與健康。氰胺牧苑4：12-13。
劉興華、陳思萍、陳文穎、康雅斐，2001。簡明藥物學，第五版。華杏書局。台北。
顏文俊，1992。食品營養的維生素及礦物質強化。生物產業3：61-77。
蕭鳳岐，1998。罐裝飲料中水溶性維生素的變動-生產、儲存時的穩定性。食品營養7(151)：68-71。
糜福隆，1997。幾丁聚醣應用於藥物及疫苗傳輸系統之設計與研究。國立中央大學化學工程研究所碩士論文。台北。
Akbuga, J. and Gurosy, A. 1987. Effect of moisture sorption and desorption on furosemide tablets properties. Drug Dev. Ind. Pharm. 13: 1827-1845.
Akbuga, J. and Durmaz, G. 1994. Preparation and evaluation of crosslinked chitosan microspheres containing furosemide. Int. J. Pharm. 100: 257-261.
Andreas, B. S. 2000. Chitosan and its derivations: Potential excipient for preoral peptide delivery systems. International Journal of Pharm. 194: 1-13.
Browne, C. R., Shiu, G. K. and Croitoru, A. 1998. Stability of ergotamine tartrate sublingual tablets. Journal of Food and Drug Analysis 6(1): 405-412.
Cartwright, A. C. 1989. Stability tests on active substances and finished products: New European guideline. Drug Devel. Ind. Pharm. 15: 1743-1757.
Chang, C. H. and Chiang T. L. 2002. Vitamin / calcium supplement use in Taiwan : Findings from the 1994 national health interview survey. J. Med. Sci. 18: 171-181.
Chan, M. C., Joung, H. K. and Won, J. C. 2000. Simultaneous determination of water soluble vitamins excreted in human urine after eating an overdose of vitamin pills by HPLC method coupled with a solid phase extraction. Talanta 51: 799-806.
Chow, S. C. and Pone, A. 1995. Current issues in regulatory requirements of drug stability. Journal of Food and Drug Analysis 3(2): 75-85.
Gil-alegre, M. E., Bernabeu, J. A., Camacho, M. A. and Torrer-suarez, A. I. 2001. Statistical evaluation for stability studies under stress storage conditions. Pharmacol. 56: 877-883.
Friess, W. 1998. Collagen — biometerial for drug delivery. Eurpoean J. Pharm. Biopharm. 45: 113-136.
Hirano, S. and Noishiki, Y. 1985. The blood compatibility of chitosan and N-acetylchitosans. J. Biomed. Mater. Res. 19: 413-417.
Hsu, H. C., Ju, H. L. and Chen, C. Y. 1997. The mean kinetic temperature and relative humidity for drugs and products stability testing in Taiwan. Journal of Food and Drug Analysis 5(3): 179-184.
Koide, S. S. 1998. Chitin-chitosan: Properties, benefits and risks. Nutrition Research 18(6): 1091-1101.
Lee, K. Y., Ha, W. S. and Park, W. H. 1995. Blood compatibility and biodegradability of partitlly N-acetyl chitosan derivatives. Biomaterials 16: 1211-1216.
Ling, T. K. and Liou, W. S. 2002. The concept of B vitamins in prevention of cardiovascular diseases. J. Med. Sci. 22(6): 273-276.
Merck Co., Inc. 1989. The Merck Index. 11 th. New Jersey。
Moreno, P. and Salvado, V. 2000. Determination of eight water and fat soluble vitamins in multi-vitamin pharmaceutical formulations by high-performance liquid chromatography. Journal of Chromatography A. 870: 207-215.
Nicolaidou, E. and Katasmbas, A. D. 2000. Vitamins A, B, C, D, E, F, trace elements and heavy metals : Unapproved uses or indications. Clinics in Dermatology 18: 87-94.
Nigalaye, A. G., Adusumilli, P. and Bolton. S. 1990. Investigation of prolonged drug release from matrix formulation of chitosan. Drug Devel. Ind. Pharm. 16: 449-467.
Nishioka, A. G., Kyotani, S., Okamura. M., Miyazaki, M., Okazaki. K., Ohnishi. S., Yamamoto, Y. and Ito, K. 1990. Release characteristics of cisplatin chitosan microspheres and effect of containing chitin. Chem. Pharm. Bull. 38: 2871-2873.
Okuyama, K., Noguchi, K., Kanenari, M., Egawa, T., Osawa, K. and Ogawa, K. 2000. Strucrural diversity of chitosan and its complexes. Carbonhydrate Polymers 41: 237-247.
Ortega-barrales, P., Fernandez-de cordova, M. L. and Molina-diaz, A. 1998. Micordetermination of vitamin B1 in the presence of vitamins B2, B6, and B12 by solid-phase UV spectrophotometry. Analytical Chemistry 70(2): 271-275.
Puri, S. C. and Mullen, K. 1980. Mutiple compirision. In: Applied Stacics for Food and Agricultural Scientists (ed. By Hall G. K.), Medcal Publishers, Boster, MA, pp. 146-162.
Remero, A. J., Grady, L. T. and Rhodes, C. T. 1988. GMP aspects of stability programs. Drug Devel. Ind. Pharm. 14: 1549-1586.
Sabnis, S. and Block, L.H. 2000. Chitosan as an enabling excipient for drug delivery system I. Molecular modifications. International Journal of Biological Macromolecules 27: 181-186.
Sanchze, J. M. and Salvado, V. 2002. Comparison of micellar and microemulsion electrokinetic chromatography for the analysis of water and fat soluble vitamins. Journal of Chromatography A 950: 241-247.
Sakkinen, M., Seppala, U., Heinanen, P. and Marvola, M. 2002. In vitro evaluation of microcrystalline chitosan (MCCh) as gel-forming excipient in matrix granules. Eurp. J. Pharm. Bio. 54: 33-40.
Sanchez-mata, M. C., Camara, C. and Diez-marques, C. 2003. Extending shelf-life and nutritive value of green beans (Phaseolus vulgaris L.), by controlled atmosphere storage : Micronutrients. Food Chemistry 80: 317-322.
Sawayanagi, Y., Nambu. N. and Nagai. T. 1982. Directly compressed tablets containing chitin or chitosan in addition to lactose or potato starch. Chem. Pharm. Bull. 30: 2935-2940.
Sharpless, K. E., Margolis, S. and Thomas, J. B. 2000. Determination of vitamin in food-matrix standard reference materials. Journal of Chromatography A 881: 171-181.
Su, S. C., Chou, S. S., Hwang, D. F., Chang, P. C. and Liu, C. H. 2001. Capillary zone electrophoresis and micellar electrokinetic capillary chromatography for determining water-soluble vitamins in commercial capsules and tablets. Journal of Food and Drug Analysis 8 (3): 180-186.
Su, S. C., Lee, S. C., Wong, Y. H. and Chou, S. S. 1995. Analysis of vitamin B1, B2 and C in baby foods by high performance liquid chromatography. Journal of the Chinese Nutrition Society 20(2): 157-172.
Takayma, K., Hirata, M., Machida. Y., Masada. T., Sannan. T. and Nagai. T. 1990. Effect of interpolymer complex formation on bioadhesive property and drug release phenomenon of compressed tablets consisting of Chitosan and sodium hyaluronate. Chem. Pharm. Bull. 38: 1993-1997.
Thanou, M., Verhoef, J. C. and Junginger, H. E. 2001. Oral drug absorption enhancement by chitosan and its derivatives. Advances Drug Delivery Review 52: 117-126.
The Stationery Office, UK. 1999. British pharmacopoeia (BP). London.
The United States Pharmacopeia Convention, Inc. 1998. Drug Information for the Health Care Professional Volume I. 18th. Rockville, MD.
The United States Pharmacopeia Convention, Inc. 2002. The United States Pharmacopeia and National Formulary, Asian edition. USP25 /NF 20. Rockville, MD.
Udelea, O. K. and Okore, V. C. 1990. Effect of storage conditions on the physical properties and in vitro dissolution of directly compressed tablets. Drug Devel. Ind. Pharm. 16: 2339-2344.
Wasilewska, A. and Szydlowska, W. L. 2000. The level of vitamins affecting homocysteine metabolism in different groups of patients. Internal Symposium on Athersclerosis 6: 25-29.
Whitney, E. N. and Rolfes S. R. 1999. Understanding Nutrition。Wadsworth Puslishing Company. USA.