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1 奈 Stabilization and Controlled Release of Active Agents via a Degrading Nano-Carrier 料 : 年六 1

2 奈 奈 兩 奈 料 來 奈 理 行 料 數 聯 度 粒 例 數 量 度 度 量 數 數 度 料 良 量 降 數 不 不易 力奈 來 參 ABSTRACT The object of this study was to manipulate the drug permeability and stability of nano Ca-deficient hydroxyapatite/chitosan (CDHA/CS) nanocomposite membrane incorporated with vitamins for drug storage and controlled release. The physical properties and drug permeation behaviors of Ca-deficient hydroxyapatite/chitosan (CDHA/CS) nanocomposite membrane were systematically investigated in terms of different synthetic sequence and inorganic filler amount. It was found that the lowest permeation coefficient was obtained via in-situ process (P-CS-Ca), which was probably due to the higher crosslinking extent, better interface between filler and matrix, and smaller particle size, as well as dispersion. With an increase of CDHA content, both crosslinking and diffusion path would be increased so that the permeation coefficient of CDHA/CS composite membrane was reduced compared to that of pure chitosan membrane. A minimum permeation coefficient occurs at the CDHA content of 90%. In this condition, the drug can be safely stored for a long time. 2

3 料 了 例 : 療 料 不 連 料 不 奈 料 不 力 烈 C 見 C 療 了便 C 來 療 了 療 奈 量 度 料 類 料 料 料 料 不 良 料 不 率 來 ε 奈 度 了 不 異 奈 領 都 奈 領 奈 料 率 in-situ process 念 來 奈 (carrier)) 3

4 (Denature) 奈 料 率 歷 都 降 量 β β 來 料 來 來 量 離 不 領 聯 利 離 不 降 料 不 數 理 度 異 度 兩 料 例 量 來 理 度 不 料 度 了 度 不 料來 度 量 狀 類 類 量 類 理 4

5 兩 力 利 不 聯 蠟 利 利 粒 狀 度 利 來 不 载 率 利 利 不 度 利 來 不 度 料 度 粒 兩 量 料 料 量 量 利 度 來 度 度 度 理 離 料 5

6 CS 數 不 不 量 A PCSCa IP B CaCSP IC C CDHACS NI 6

7 立葉 奈 料 度 濾 度 奈 料 兩 都 奈 不 量 不 例 奈 例 理 聯 7

8 離 量 量测 不 度 度 度 量 聯 兩 連 量 度 錄數 利 量 度 利 數 C 1 V 1 C 2 V 2 [ DH ] C10 2 At ln = C C 1 2 δ V 數 數 兩 兩 度 數 料 來 Å 流 率 立葉 8

9 料 度 數 利 降 度 率 利 度 度 率 率 狀 流 粒 9

10 論 料 量 不 數 理 度 異 不 料 2θ 20 o (102) (022)(200)(040)(220)(140)CDHA 26 o 28 o 32 o 40 o 47 o 50 o 度 (002) (210) (211)(112)(300)(310)(222)(213) 不 都 CDHA 粒度 都 異不 量 例 度 料 度都 不 料 FTIR FTIR 數 1652 cm -1 (amide I, C-O)1580 cm -1 (-NH 2 bending)2990 cm -1 (methylene, -CH 2 ) 1100 cm cm cm cm -1 CDHA PO 4 3- OH CDHA CDHA 料 1580 cm cm -1 都 度 降 1580 cm -1 -NH 2 bending 1100 cm -1 CDHA (-PO 4 3- )(-NH 2 ) (-NH 3 + ) CDHA (-PO 4 3- ) 理 度 A 兩 度 異 A (-NH 2 ) 離 (-PO 4 3- ) 理 兩 來 度 異 5-3 TGA 量 CDHA 料 料 TGA 量 5% 量 兩 連 降 量 ( 見 ) TPP 離 量 10% 留量 TPP 離 10

11 降 降 都 連 降 度 了 離 連 降 度 TGA 類 TPP 兩 A B C CDHA TPP 度 A 離 A CDHA B C 來 A TGA 不 異 DMTA 異 數 (DH)( 見 ) 度 B C A A DH 1CDHA 良 DH 降 2 度 不易 DH 降 3CDHA 率 TEM 兩 DH TGA 度 不 CDHA 不 DH CDHA 料 TEMSEM TEM 料 CDHA 狀 80nm 20nm TEM A 料 B C 5-8 料 狀 CS A BC 不 量 度 數 兩 料 例 量 理 度 5-9 XRD 量 CDHA 度 來 不 量 90% 11

12 peak CDHA 5-10 FTIR 量 2990 cm -1 (methylene,-ch 2 )1580 cm -1 (-NH 2 bending) peak 來 1580 cm -1 (-NH 2 bending) CDHA 量 更 度 來 TGA 兩 量 CDHA 量 了 連 降 2.5 cm CDHA 量 數 CS 量 30% 10% 兩 數 數 CS50%CS100% CS70%CS90% CDHA DH 降 CDHA 量 度 CDHA 量 數 CDHA 量 度 數 5-15 不 量 量 率 數 12

13 6 論 聯 度 粒 來 2. 例 不 數 50%100%70%90% CDHA 量 度 DH 降 CDHA 量 度 數 兩 量 90% 數 數 降 度 奈 粒 量 數 都不行 力 13

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18 Intensity (a.u.) CS P-CS-Ca Ca-Cs-P CDHA-CS CDHA θ (degree) 量 18

19 CS 90% Absorbance (a.u.) CS 100% P-CS-Ca Ca-CS-P CDHA-CS CDHA Wave number (cm -1 ) 量 不 聯 19

20 Weight % CS 90% P-CS-Ca Ca-CS-P CDHA-CS CS Temperature ( o C) 量 不 聯 20

21 Weight % TPP ion-crosslinking CS 90% P-CS-Ca Ca-CS-P CDHA-CS CS Temperature ( o C) 量 不 聯 21

22 Conc. (mg/ml) CS P-CS-Ca CDHA-CS Ca-CS-P Time (hr) 量 不 聯 22

23 DH (cm 2 /hr) CS P-CS-Ca CDHA-CS Ca-CS-P PROCESS 量 不 聯 數 23

24 100 nm P-CS-Ca 100 nm Ca-CS-P 100 nm CDHA-CS 量 不 24

25 20m 4m CS 20m 4m P-CS-Ca 20m 4m Ca-CS-P 20m 4m CDHA-CS 量 不 25

26 P-CS-Ca, CS content intensity (a. u.) 100% 90% 70% 50% 30% 10% CDHA θ (degree) 不 量 26

27 P-CS-Ca, CS content Absorbance (a.u.) 100% 90% 70% 50% 30% 10% Wave number (cm -1 ) 不 量 聯 27

28 100 P-CS-Ca, CS content Weight % % 30% 50% 70% 90% 100% Temperature ( o C) 不 量 聯 28

29 Weight % P-CS-Ca,TPP ion-crosslinking CS content 10% 30% 50% 70% 90% 100% Temperature ( o C) 不 量 聯 29

30 Conc. (mg/ml) % 70% 90% 100% P-CS-Ca, CS content TIME (hr) 不 量 聯 30

31 P-CS-Ca DH (cm 2 /hr) CS content % 不 量 聯 數 31

32 20m 4m CS50% 20m 4m CS70% 20m 4m CS90% 20m 4m CS 不 量 32