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2 DDS DDS Solid-in-Oil DDS DDS Solid-in-Oil S/O S/O S/O S/O S/O S/O ELISA HRP S/O FITC YMP FITC FITC EGFP HRP

3 3 Solid-in-Oil Gregory M. Glenn Layer-by-layer-assembled films Solid-in-Oil S/O S/O OVA S/O HEL S/O Anti-OVA IgG from guinea pig, polyclonal ELISA Anti-HEL IgG from rabbit, polyclonal ELISA OVA S/O OVA S/O Anti-OVA IgG from guinea pig, polyclonal ELISA HEL S/O HEL S/O

4 lipoplex polyplex MEND PLGA ph ph STR-R pdna S/O S/O LIVE/DEAD assay WST assay ER-290 : PC S/W pdna Carreir # Carreir #

5 1 1. Drug Delivery System, DDS 4 DDS 1 DDS DDS DDS DDS 1 1 DDS Quality Of Life, QOL / 1000 % DDS 21 DDS 2 DDS DDS DDS DDS 1

6 1 2. DDS DDS DDS DDS DDS DDS DDS DDS [a] QOL 2.1. DDS 1 DDS 2 DDS 3 DDS 1 DDS DDS DDS [a] intradermal i.d. /intracutaneous/ percutaneous injection subcutaneous s.c. /hypodermic injection intravenous i.v. injection intramuscular i.m. injection 5 1 ~ 2 2

7 1 3 DDS DDS PEG 3 [b] DDS PEG PLGA DDS 2.3. DDS DDS DDS 2.4. DDS DDS [b] Polyethylene glycol PEG PEG PEG PEG DDS 3

8 1 PLGA DDS DDS ph 2 DDS DDS 4 ph enhanced permeation and retention EPR 5,6 [c] DDS 1986 EPR DDS EPR [c] EPR 200 nm 100 nm EPR 200 nm DDS EPR 4

9 1 3. DDS DDS DDS 1960 Alec Douglas Bangham DDS DDS 1 9 Fig.1.1 DDS DDS 7 [d] Fig.1.1 DDS 9 DDS 1990 Vadimir P. Torchilin Leaf Haung DDS 1 PEG immunoliposome PEG DDS PEG PEG DDS [d] 1964 Bangham TEM 5

10 1 PET MRI 4 in vitro DDS DDS 1 Table 1.1 DDS 1 1 DDS DDS multifunctional envelope type nano device, MEND DDS Table 1.1 DDS Core technologies Lipid-based carriers Liposomes, Lipid bilayers 9,10 DDS 2005, MEND 2011 Oil-in-warer colloids, Solid-lipid particles; Water-in-oil colloids, Reverse micelles 13 Oil-in-water DDS ,15 Solid-lipid particles DDS 2002, Micellar fibers, Supramolecular gels Samuel I. Stupp 2010 Inorganic carriers Carbon tubes ,21 PEG 2011 Quantum dots 22,23, , Gold particles, Gold rods 26,27 DDS 2008, Magnetic particles 29 DDS ,31 MRI 2008, 2009 Silica particles

11 1 Table 1.1 DDS Core technologies Polymeric carriers Linear chain, Macromolecular gels 34, , Polymeric micelles 38 Alexander V. Kabanov Pluronic Kazunari Kataoka 2009 Layer-by-layer (LbL) particles 40 LbL LbL MRI 2011 Spheres 42 PLGA PLGA 2011 Nanogels ,46 Kazunari Akiyoshi Kwangmeyung Kim 2010, 2009 Dendrimers 47,48,49 DDS 2004, 2005, Naturally-derived carriers Viral vectors 51 Targeted viral vectors 2007 Virus like particles 52 Virus capsid DDS DDS 1990 Masahiro Goto Noriho Kamiya Eiichi Toorisaka Hongyu Piao Solid-in-Oil S/O 53,54,55,56 DDS DDS Fig.1.2 7

12 1 2 S/O DDS S/O DDS 3 2 QOL DDS 3 2 S/O DDS 4 DDS S/O 2 5 8

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15 2 Solid-in-Oil 1. mab Table mab 6, Products Campany Table Enbrel Amgen, Takeda Pharmaceuticals, (etanercept) Wyeth Centocor (Johnson & Johnson), Remicade Rheumatism Mitsubishi Tanabe Pharma, (infliximab) (mab) Schering-Plough Avastin Lung/bowel cancer Chugai, Genentech, Roche (bevacizumab) (mab) Rituxan/MabThera Lymphatic malignancy Biogen-IDEC, Genentech, Roche (rituximab) (mab) Humira Rheumatism Abbott, Eisai (adalimumab) (mab) Epogen/Procrit Amgen, Janssen-Cilag, (Renal) anemia /Eprex/ESPO Kyowa Hakko Kirin, Ortho (Glycoprotein hormone) (epoetin alfa) Herceptin Breast cancer Genentech, Chugai, Roche (trastuzumab) (mab) Lantus Diabetes Sanofi-aventis (insulin glargine) (Insulin derivative) Neulasta Cancer immunotherapy Amgen (pegfilgrastim) (PEG-cytokine) Aranesp/Nespo (Renal) anemia Amgen, Kyowa Hakko Kirin (darbepoetin alfa) (Glycoprotein hormone) s.c.: subcutaneous ; i.v.: intravenous. Indication Administration (Biopharmaceuticals) Methods Cycle and Periods Rheumatism Twice a week s.c. (TNF receptor-fc) for 3-6 months i.v. (3-4 hours) i.v. (90 min) i.v. (2 hours) s.c. s.c./i.v. i.v. (60 min) s.c. s.c. i.v. (60 min) Once a week for 6 months Once per 2 weeks for 2-6 months Once a week for 3-6 months Once per 2 weeks for 3-6 months Once a week for 6 months Once a week for 6 months Once a day Once a day for one month Once per 2 weeks for 6 months Table 2.1 Quality Of Life, QOL 11

16 DDS Fig [a] 2 30 Alza Alejandro Zaffaroni Table 2.2 Zaffaroni 2 Advantages of the transdermal route for drug administation 1. Eliminates the vagaries of gastrointestinal absorption 2. Bypasses the portal circulation 3. Permits easy termination of therapy 4. Allows drug entry into the circulation when the gastrointestinal tract is not available or not suitable 5. Offers a means of painless systemic therapy for young children [a] Transdermal Transcutaneous Dermis Transdermal Epidermis Transepidermal Cutaneous Transcutaneous Dermatology Dermis Transdermal 12

17 2 Zaffaroni 1981 Table ph 1 Table 2.3 FDA 3 Year Drug/Product name Indication Company 1979 Scopolamine/Transderm-Scop Motion sickness Novartis Consumer Health 1981 Nitroglycerin/Transderm-Nitro Angina pectoris Novartis 1984 Clonidine/Catapres-TTS Hypertension Boehringer Ingelheim 1986 Estradiol/Estraderm Menopausal symptoms Novartis 1990 Fentanyl/Duragesic Chronic pain Janssen Pharmaceutica 1991 Nicotine/ ProStep, Nicoderm, Habitrol Smoking cessation Elan, GlaxoSmithKline, Novartis Consumer Health 1993 Testosterone/Testoderm Testosterone deficiency Alza 1995 Lidocaine with epinephrine / Local dermal analgesia Iomed Iontocaine (iontophoresis) 1998 Estradiol with norethidrone/combipatch Menopausal symptoms Novartis 1999 Lidocaine/Lidoderm Post-herpetic neuralgia pain Endo Pharmaceuticals 2001 Ethinyl estradiol with norelgestromin/ortho Evra Contraception Ortho-McNeil Pharmaceutical 2003 Estradiol with levonorgestrel/ Climara Pro Menopausal symptoms Bayer Healthcare Pharmaceuticals 2003 Oxybutynin/Oxytrol Overactive bladder watson Pharma 2004 Lidocaine (ultrasound)/sonoprep Local dermal anesthesia Echo Therapeutics 2005 Lidocaine with tetracaine/synera Local dermal analgesia Endo Pharmaceuticals 2006 Fentanyl HCl/Ionsys (iontophoresis) Acute postoperative pain Alza 2006 Methylphenidate/Daytrana Attention deficit hyperactivity disorder Shire 2006 Selegiline/Emsam Major depressive disorder Bristol-Myers Squibb 2007 Rotigotine/Neupro Parkinson s disease Schwarz Pharma 2007 Rivastigmine/Exelon Dementia Novartis FDA Table 2.3 QOL 3 Zaffaroni 13

18 Fig.2.2 5,9! Fig µm 2 mm 3 15 µm keratinocyte [b] melanocyte [c] [c] corneocyte, horny cell [b] 10 ~ 20 2 ~ 4 10 ~ 25 % 70 % ph 4.2 ~ cm ,5,6,7,8 2 [d] [b] [c] 4 [d] 1 1 M mg S cm 2 # L cm J = dm " 1 & % ( mg/ $ dt S ' cm 2 dc h x dx mg/cm3 /cm D! cm 2 /h J = D dc dx = D C 1 " C " 2 L! K = C 1 = C % 2 $ # C i C ' f & J = DK L C " ( i " C f ) C f = 0 P = DK % $ ' cm/h J = PC i # L & J! DDS C i DDS! P P 14!

19 2 1, , Fig.2.3 a b c 5,9 Fig.2.3a Fig.2.3a Fig.2.3bc Fig.2.3b Fig.2.3c Fig

20 Fig Jan D. Bos 2000 The 500 Dalton rule for the skin penetration of chemical compounds and drugs The 500 Dalton rule 2003 Samir Mitragotri 11 Fig.2.4a Mitragotri P cm/h Fig.2.4b Kenji Sugibayashi DFNa LSE-High, TOYOBO 16

21 DDS Zaffaroni 30 DDS sirna Table DDS DDS 1 DDS DDS 2 3 Fig.2.5 DDS 13 Fig.2.5 occlusive dressing therapy, ODT Fig.2.5a transdermal 3 Fig.2.5b Fig.2.5c Fig.2.5d Fig.2.5e DDS Fig.2.5f 17

22 k ~ 16 MHz 100 khz 16 Samir Mitragotri [e] Mitragotri Fig Table 2.1 Mitragotri ~ 100 msec MIT James C. Weaver [e] Yie W. Chien Fig.2.7 Fig [e] Mark R. Prausnitz MIT James C. Weaver James C. Weaver Robert Langer Samir Mitragotri 1995 Robert Langer

23 2 Calcitonin LH-RH Somatorelin Vasopressin somatostatin Fig Mark R. Prausnitz [e] 1998 Fig ,29 28 Prausnitz 2003 PLA PGA PLGA µm 200 ~ 800 µm ~ 2000 QOL 30 Zaffaroni Table

24 Table 2.4 Table 2.4 Peptides Sequences References Oligo-arginine TAT YARA WLR Antennapedia homeodomain Haptide LMWP TD-1 R n (n = 7-9) (YG)RKKRRQRRR YARAAARQARA (WLRRIKA) n (n = 1-3) RQIKIWFQNRRMKWKK TRWYSMKKTTMKIIPFNRL VSRRRRRRGGRRRR ACSSSPSKHCG 31,32,33,40,41 32,33,34,35,36,40,41 37, Paul A. Khavari Paul A. Wender R 7 A CsA 31 CsA Wender R 7 4 Khavari R 7 CsA ph 7.4 CsA S.Y. Choi R 9 TAT 32,33,34,35,36 L.B. Lopes YARA WLR heat shock protein 20 37,38,39 Lee R 9 TAT GFP 40,41 SIINFEKL CpG 42 haptide 43 LMWP 44 20

25 2 Chen in vivo TD-1 45, Khavari Khavari Lopes 38 Fig ,48,49 Fig.2.10a 47, Kazuo Ohtake Poly-L-Arg Fig.2.10b Gregor Cevc 1998 Cevc edge activator Fig.2.11a Transfersome Cevc IDEA AG 52 Transfersome IDEA AG 53 21

26 2 1 54, ,57 1 Joke A. Bouwstra 2000 Fig.2.11e 58,59 Bouwstra Transdersome Fig.2.11e 60 Fig.2.11b 61 Fig.2.11c Fig.2.11d Fig

27 DDS Solid-in-Oil Solid-in-Oil Solid-in-Oil S/O Fig.2.12 S/O Masahiro Goto Noriho Kamiya % - Goto Kamiya - 64,65,66,67,68,69, Solid-in-Oil S/O water-in-oil W/O 71,72,73,74,75,76,77,78 Fig.2.13a Fig.2.13b ,81,82,83,84,85,86 87,88 89 PEG 90,91,92,93,94,95 96,97,98 23

28 2 99,100,101, Eiichi Toorisaka 2003 W/O - DDS Toorisaka 2C 18 9 GE Toorisaka 103 S/O Toorisaka S/O oil-in-water Solid-in-Oil-inWater S/O/W 103 Hongyu Piao S/O S/O 105,106,107,108,109,110,111,112,113, S/O 115 Piao 2008 S/O , ,123,124,125,126,127,128, 129,130 Fig.2.13 S/O 81,71,103, S/O S/O W/O W/O W/O 24

29 2 - W/O Oil Water W/O Oil Solid Solid-in-Oil S/O Fig.2.14 S/O S/O Masahiro Goto S/O Solid-in-Oil S/O 131,132,133 PLGA S/O Fig.2.15a W/O/W Fig.2.15b 4 S/O PLGA S/O 20 % 1990 Goto PLGA Table 2.5 S/O 25

30 2 1.6 wt.% W/O 1 PEG PLGA S/O 2010 S/O PLGA 134 Fig.2.15 PLGA 133, 135 Table Solvent Solubility in water Solubility of water Dielectric constant Density g/ml Melting point C Boiling point C Vapor pressure Torr 20 C Non-polar n-hexane Cyclohexane Toluene 1,4-Dioxane Isopropyl Myristate Chloroform Diethyl ether % 20 C % 25 C % 25 C! < 0.1 % 20 C % 20 C 6.89 % 20 C 0.01 % 20 C 0.01 % 20 C 0.03 % 25 C! < 0.1 % 20 C 0.06 % 20 C 1.26 % 20 C < Polar aprotic Ethyl acetate Dichloromethane Tetrahydrofuran (THF) Acetone Dimethylformamide (DMF) Acetonitrile Dimethyl sulfoxide (DMSO) 8.7 % 20 C 1.60 % 20 C!!!!! 3.3 % 20 C 0.24 % 20 C!!!!! Polar protic Acetic acid Trifluoroacetic Acid (TFA) Isopropanol (Isopropyl alcohol) Ethanol (Ethyl alcohol) Methanol (Methyl alcohol) Water!!!!!!!!!!!!

31 2 1 S/O Fig.2.16 Masato Kukizaki 55 C 60 C W/O S/O 136 shirasu porous glass SPG C S/O/W solid lipid particle S/O 60 C 60 C Fig.2.16 S/O/W SPG 137,136 W/O Solid-in-Oil 1 nm ~ 1 µm emulsion µm nm Solid-in-Oil Solid-in-Oil Solid W/O Solid-in-Oil Solid Solid-in-Oil Solid 27

32 S/O S/O 138 W/O S/O 1 W/O S/O 5.0 mg/ml 3 W/O W/O 5 wt% 20 wt% 4 S/O 0.2 % w/v S/O Fig.2.16 Fig.2.17 S/O 116,117, Hongyu Piao S/O 116 Fig.2.17a S/O Fig.2.17a ER-290 S/O 2012 S/O 2005 Masahiro Goto S/O ASPION 2009 SO S/O VIVCO Fig.2.17c 28

33 S/O Table 2.6 S/O pdna DFNa NaCl L1695 W/O Milli-Q ER-290 L-195 W/O dinitrochlorobenzene IPM W/O Table 2.6 S/O S/O W/O Milli-Q W/O S/O ph W/O Milli-Q S/O Table 2.4 Fig.2.18 S/O W/O S/O ER-290 [f] L-195 [f] Fig.2.18 ER-290 L-195 S/O W/O Table 2.5 [f] ER-290 HLB 2 HLB 0 ~ 20 HLB ER-290 ER-290 ER HLB 2 90 L-195 ER-290 L-195 ER-290 L-195 Fig

34 2 S/O S/O W/O W/O W/O Table C S/O W/O - Fig.2.19 IPM Isopropyl myristate, IPM Fig.2.19 IPM 167 C 3 C IPM 141 S/O Fig.2.18 S/O S/O S/O ER-290 drug ER-290 [g] 1 50 S/O W/O ER mg/ml = 0.2 % w/v W/O 4 S/O W/O POLYTRON PT2500E POLYTRON!196 C FD5N; EYELA, Tokyo, Japan 20 C S/O W/O S/O [g] S/O S/O S/O 1 30

35 fluorescein isothiocyanate FITC Sigma-Aldrich Tokyo, Japan horseradish peroxidase HRP Wako Pure Chemical Industries Osaka, Japan ER-290 L-195 Mitsubishi-Kagaku Foods Co. Tokyo, Japan isopropyl myristate IPM Tokyo Kasei Co. Tokyo, Japan Yucatan micropig YMP, 5-month-old female 139 [h] Charles River Japan, Inc. Tokyo, Japan metal enhanced diaminobendizine DAB substrate kit Pierce Rockford, IL, USA 4 % Rhodamine-labeled 1,2-dioleoyl-sn-glycero- 3-phosphoethanolamine DOPE Avanti Polar Lipids Inc. Alabaster, AL HistoPrep TM Fisher Scientific NJ, USA Bovine insulin Enzyme-Linked ImmunoSorbent Assay ELISA kit Mercodia Wild-type enhanced green fluorescent protein EGFP His-tag 2.2. S/O S/O [i] mg/ml 5.0 ml [j] 25 mg/ml ER ml W/O ER IPM 5.0 ml S/O 1.0 mg/ml ER mg/ml Fig.2.20 [h] in vitro 1997 Makiko Fujii in vitro Yucatan micropig YMP 139 YMP 25 kg µm Yucatan micropig skin 40 ~ 200 µm 1.5 ~ 2 mm Wang 40 EGFP R9 YMP YMP 1000 YMP in vitro [i] OVA : ER : 50 w:w 2006 ~ ER-290 S/O 4 [j] FITC Milli-Q Milli-Q 2 HCl ph NaOH ph HCl ph PBS HCl NaOH PBS S/O 5.0 mg 0.01 M HCl 1.0 ml 0.01 M NaOH 0.50 ml Milli-Q 3.5 ml ph mg/ml 5.0 ml Milli-Q 1.0 ml 1.0 M HCl 40 µl 50 mg 0.01 M NaOH 0.7 ml Milli-Q 3.26 ml ph mg/ml 5.0 ml 31

36 Microviscometer AWVn; Anton Parr GmbH, Graz, Austria Zetasizer Nano-ZS Malvern, Worcestershire, UK [p] 2.4. in vitro 1 80 C YMP 2 mm 2! 2 cm YMP cm ml PBS ph C 500 rpm 1 YMP 3 S/O 0.50 ml YMP [k] 4 % 5 5 HistoPrep TM YMP 80 C CM1510; Leica, Wetzlar, Germany 20 µm 20 C 6 20 C PBS HistoPrep TM Fig.2.21 [k] 32

37 ELISA 7 3 YMP 1 mm [l] 140 [m] 1.5 ml 3 FITC 8 2 % BSA in PBS [l] 100 ~ 200 Mercodia Bovine insulin ELISA kit [n] calibrator 25 µl/well 9 ELISA kit HRP-labeled anti-insulin IgG from mouse, monoclonal conjugation buffer µl/well 10 2 ELISA kit wash buffer 5 times/well 11 Mercodia ELISA kit TMB 200 µl/well C M H 2 SO 4 50 µl/well nm O.D. Fig HRP HRP 14 6 DAB H 2 O 2 [o] HRP [l] 2 % BSA PBS ELISA 3 titer BSA [m] 0.04 M H 3PO M NaH 2PO 4 ph 2.3 A A 95 % B 3 : 7 A:B, v:v 140 [n] Mercodia bovine insulin ELISA kit ELISA conjugation buffer 1 1 HRP 1 2 ELISA ELISA kit calibrator FITC [o] HRP DAB HRP DAB HRP 2 33

38 S/O Table 2.7 FITC EGFP HRP S/O 1.0 mg/ml Fig.2.23 FITC S/O IPM Fig.2.23a S/O Fig.2.23b IPM Fig.2.23a ER-290 EGFP HRP FITC EGFP HRP S/O dynamic light scattering, DLS Fig.2.24 Fig.2.26 Table 2.7 mean Fig.2.23 FITC a IPM b S/O particle size poly dispersion index PDI distribution width S/O PDI distribution width IPM ER ~ 400 nm 1 1 S/O W/O S/O FITC Fig nm FITC 1 S/O ER-290-FITC 257 nm 1 40 FITC ER-290 FITC S/O 1 DLS Fig.2.28 Proteins FITC-labeld insulin EGFP HRP m.w. Table 2.7 S/O n = 6 [p] ca. 6 kda ca. 27 kda ca. 40 kda S/O nanodispersion Proteins ER-290 Weight ratio 5.0 mg 250 mg 1:50 Mean particle size [nm] 257 ± ± ± 22 PDI 0.16 ~ ~ ~ 0.48 Distribution width [nm] 115 ± ± ± 19 [p] DLS DLS DLS Fig.2.24a DLS 3 3 S/O PDI PDI > 0.2 Z average mean particle size distribution width DLS 68 % mean particle size ± distribution width 34

39 2 Fig.2.24 FITC S/O n = 6 [p] Fig.2.25 EGFP S/O n = 6 [p] Fig.2.26 HRP S/O n = 6 [p] 35

40 2 Fig.2.27 FITC n = 1 Fig FITC S/O n = Hongyu Piao S/O IPM 116 FITC EGFP HRP IPM 3.2. FITC FITC S/O S/O YMP YMP YMP Fig.2.29 Fig.2.29a Fig.2.29b 15 µm Fig.2.29b 200 µm Fig.2.29a 2 mm Fig.2.29c IPM Fig.2.29 YMP a 10 b 40 c 72 36

41 FITC Fig.2.30 FITC FITC S/O FITC PBS YMP 48 Control PBS Control Fig.2.30 YMP FITC S/O IPM Fig.2.30A Fig.2.30D Fig.2.30 FITC 48 [q] YMP Fig Fig.2.31A Fig.2.31A Fig.2.31E FITC Fig.2.31F FITC S/O IPM FITC Fig.2.31E 48 Fig.2.31A 0 24 FITC Fig.2.31 [q] [q] µm 37

42 2 Fig [q] Fig [q] 38

43 2 Proteins Table 2.8 FITC S/O FITC-labeld insulin S/O nanodispersion Proteins ER-290 L-195 Weight ratio 125 mg 1: mg 250 mg 1: mg 1:50 Fig [q] Fig.2.32 Fig S/O 24 FITC Fig FITC 4 ~ Table 2.8 Fig.2.34 W/O FITC S/O L FITC FITC 6,000 Sintov 140 Sintov HPLC 210 nm ELISA Table 2.9 [r] FITC Fig.2.35 YMP FITC ELISA Fig.2.35 S/O nanodispersion *p<0.05 FITC S/O 39

44 2 S/O 7 Lopes 2,000 P ~ 7 Table 2.8 Fig S/O 6,000 FITC S/O IPM IPM Table ml [r] Samples FITC-labeled insulin ER-290 IPM Milli-Q water PBS Aqueous solution (PBS) IPM solution W/O emulsion Physical mixture S/O nanodispersion 1.0 mg 1.0 mg 1.0 mg 1.0 mg 1.0 mg 50 mg 50 mg 50 mg 1.0 ml 0.9 ml 1.0 ml 1.0 ml 0.1 ml 1.0 ml Fig.2.35 FITC 48 [s] [r] IPM FITC IPM W/O 10 mg/ml FITC A ER-290 IPM B 1:9 A:B, v:v FITC ER-290 IPM 3 1 [s] Bartlett one-way ANOVA Dunnett post-hoc test 5 % *p<0.05 vs 40

45 2 Fig n = EGFP HRP S/O 6,000 ELISA Enhanced green fluorescent prtotein, EGFP 27,000 Horseradish peroxidase, HRP 40,000 Table 2.7 Fig.2.25 Fig.2.26 S/O FITC Fig.2.37 EGFP HRP 24 [t] FITC EGFP HRP EGFP HRP HRP HRP Fig.2.37A-D Fig.2.37E-H EGFP HRP 6 kda EGFP [t] A,C,E,G µm B,D,F,H µm 41

46 2 27 kda HRP 40 kda S/O Fig.2.37D Fig.2.37H EGFP HRP 15 µm FITC 3.4. S/O EGFP HRP Piao DFNa YMP PBS 116 ER-290-DFNa PBS ER-290-DFNa ER-290 DFNa ER-290-DFNa EGFP HRP S/O - Table 2.10 S/O 1.0 ml FITC-labeld insulin Rhodamine-labeld DOPE ER mg 1.0 mg 50 µg 50 µg 50 mg 50 mg 50 mg Fig.2.38 S/O ER-290 FITC S/O DOPE [u] DOPE ER-290 W/O 25 mg/ml ER-290 DOPE 25 µg/ml [u] DOPE 1302 IPM ER-290 L-195 IPM ER-290 DOPE ER

47 2 FITC DOPE Table 2.10 S/O Fig.2.38 S/O FITC DOPE DOPE S/O Fig.2.39 FITC DOPE 48 [v] Fig.2.39 Table FITC DOPE 1,302 S/O 1,055 ER-290 ER-290 S/O Fig.2.40 Fig.2.40 [v] FITC DOPE µm 43

48 2 S/O IPM Sato IPM 141 Bouwstra 58 Fig.2.3a IPM S/O Fig.2.3a YMP FITC EGFP PBS 6 kda FITC 27 kda EGFP FITC transdermal 6 kda FITC Fig.2.41 EGFP FITC 48 [w] S/O IPM ER-290 FITC Fig.2.30 Fig.2.34 EGFP HRP Fig.2.37 [w] µm 44

49 2 4. Yoshiro Tahara, Shota Honda, Noriho Kamiya, Hongyu Piao, Akihiko Hirata, Eiji Hayakawa, Takeru Fujii, Masahiro Goto, A solid-in-oil nanodispersion for transcutaneous protein delivery, Journal of Controlled Release 131 (2008) FITC 6,000 EGFP 27,000 HRP 40,000 Solid-in-Oil S/O IPM ER-290 L-195 FITC EGFP HRP S/O 200 nm IPM 1 Yucatan micropig YMP S/O in vitro S/O FITC YMP FITC ELISA ELISA IPM W/O S/O EGFP YMP EGFP HRP YMP HRP HRP 4 S/O FITC S/O DOPE YMP S/O IPM ER-290 S/O IPM DDS 45

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