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3. eSUNBRIGHT COATSOME and PUREBRIGHT are registered trademarks of NOF CORPORATION in the U S and registered trademarks or trademarks in other countries NOFABLE is a trademark of NOF CORPORATION in the U S and a registered trademark or trademark in other countries e SAINT is a trademark of Synvolux Therapeutics B V in the U S and other countries LIPONIZER is a trademark of Nomura Micro Science Co Ltd in the U S and a registered trademark or
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9. 006 4 3 IV Novel Excipients for Pharmaceutical Development PUREBRIGHT MB series MPC Polymers for Hydrophobic Drug Formulations Through introduction of a hydrophilic phosphorylcholine moiety into a hydrophobic methacrylic acid polymer we offer innovative formulation excipients for any hydrophobic drugs Using our PUREBRIGHT MB series any drug can be dissolved in aqueous solutions MPC Self emulsifying Solubilizer SL 11 Novel Nano Formulation for Hydrophobic Drugs Solubilizer SL 11 is clear liquid with superior solvent properties for many kinds of hydrophobic drugs to prepare nano emulsions with particle s
10. Stability of modified L Asparaginase Stability at 65 AM 2090P L asparaginase AM 1510K L asparaginase Native L asparaginase Activity relative Incubation Time min Activated PEG for PEGylation 28 21 elie Ej Jelp ormciations Using the latest synthetic and purification technologies NOF manufactures and supplies highly purified phospholipid derivatives COATSOME Series suitable for lipid emulsion formulations and liposome formulations which are extensively used for pharmaceuticals and cosmetics Various kinds and grades of such phospholipids are readily available In addition we can respond to requests from our customers with tailor made synthesis of any phospholipid with the desired structures To benefit easy liposomal capture of drugs at customer facilities NOF provides empty liposome kits liposomal formulations and liposomal drug delivery systems When PEGylated phospholipids are used as liposomes the aqueous corona at the liposome surface facilitates stable dispersion in aqueous solutions
11. 6 4 Application Data for the COATSOME EL Series Cationic Liposomes COATSOME EL 01 C Particle Size nm Encapsulation Efficiency Drug Bucladesine sodium 0 5mg ml 173 Sodium salicylate 0 16mg ml 162 DNA Salmon Testes 100uo ml 942 20 25 40 45 100 Nonionic Liposomes COATSOME EL 01 N For enhancement of the encapsulation efficiency the concentration of the cationic drug needs to be controlled at below 1mM Thus to achieve higher encapsulation efficiency the molar ratio of DPPG 3mM against the drug should be not less than 3 Anionic Liposomes COATSOME EL 01 A Particle Size nm 1mM DPPG 3mM 3 Encapsulation Efficiency Drug Doxorubicin hydrochloride 1 mg ml 150 Amikacin sulfate 1 mg ml 140 Streptomycin sulfate 1 mg ml 145 Procainamide hydrochloride 1 mg ml 192 Epirubicin hydrochloride 1mg ml 146 Pirarubicin
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13. PUREBRIGHT SL 110 PORES S18 220 PUREBRIGHT SL 310 PUREBRIGHT SL 350 PUREBRIGHT SL 411 PUREBRIGHT SL 000 S N nm m PUREBRIGHT PUREBRIGHT SL 110 72 POI 5220 PUREBRIGHT SL 310 9 10 PUREBRIGHT 850 219 PUREBRIGHT 51 411 References 1 K Ishihara et al Polym J 31 1231 1236 1999 2 T Konno et al J Biomed Mater Res 65A 2 209 214 2003 3 H Ishiwata et al Chem Pharm Bull 46 1907 1913 1998 4 Ucheobu F et al Int J Pharm 155 7 17 1997 5 Tasset C et al Int J Pharm 58 41 48 1990 6 Ucheobu IF et al Pharm Res 12 1019 1024 1995 7 Uchegbu IF et al 9 Pharma Sci 6 33 43 1996 8 Dimitrijevic D et al J Pharm Pharmacol 49 611 616 1997 9 Ucheobu F et al J Pharm Pharmacol 49 606 610 1997 10 Auth R et al Akt Dermatol 10 6 215 220 1984 MPC polymer based PUREBRIGHT MB 37 100T PEG phospholipid based SUNBRIGHT DSPE 020CN PEG cholesterol based1 SUNBRIGHT CS 010 PEG cholesterol based2 SGUNBRIGHT CS 050 Phospholipid complex based COATSOME MC 4040 COATSOME MG 4040LS SUNBRIGHT COATSOME PUREBRIGHT gt ju Q FE 2 ju 0
14. USP EP JP JPE 200 400 Biocompatible PEG Anchors for Cell Membrane Insertion We provide a cell modifying agent that acts without exerting any injurious effects on the cells Employment of the BAM concept contributes to both modification of the cells or tissue surfaces with physiologicaly active substances such as proteins or drugs and live cell immobilization of cells or tissues on the surfaces of various kinds of materials without any damage to the target cells and tissues BAM Using these high quality products CORPORATION provides custom formulation expertise and assistance on request Polyethyleneglycol chain dioi iby ie ITE ee L Various Drug Protein Peptide Phospholipid Enzyme Cytokine etc Bi
15. WA NBA HRA 15
16. FDA DMF 7 27 Coles Ron ARE C GC es 3 i R1 i R2 O II Nr N COATSOME MC 1010 1 2 Didecanoyl sn glycero 3 phosphocholine 99 up 565 7 10 0 10 0 6 DLPC MC 2020 1 2 Dilauroyl sn glycero 3 phosphocholine 99 up 120 0 DMPC COAISOME MC 4040 1 2 Dimyristoyl sn glycero 3 phosphocholine 99 up 677 9 C14 0 C14 0 23 DPPC COATSOME MC 6060 1 2 Dipalmitoyl sn glycero 3 phosphocholine Goo 7340r CICO DSPC COATSOME MC 8080 1 2 Distearoyl sn glycero 3 phosphocholine 99 up 790 2 C18 0 C1 amp 0 55 DOPC COATSOME MC 8181 1 2 Dioleoyl sn glycero 3 phosphocholine 786 22 DLoPC COATSOME MC 8282 1 2 Dilinoleoyl sn glycero 3 phosphocholine 99 782 2 C18 2 C182 53 DEPC COATSOME MC 2121AL 1 2 Dierucoyl sn glycero 3 phosphocholine go up 5085 622 C22 EPA PC COATSOME MC 1515AL 1 2 Dieicosapentaenoyl sn
17. 100 000 2 3 Alk 40C Quantitative determination of the encapsulated drug After removal of the non encapsulated drug according to the methods described above perform quantitative determination of the drug encapsulated in the liposomes after destroying the liposomes Two methods are available for the destruction of liposomes addition of surfactants and separation of the aqueous layer from the solvent layer by the addition of an appropriate solvent chloroform After decapsulating the liposomes you can analyze the quantitative assay of the released drug by its own method
18. Liposome ready agitate 3 4 1 COATSOME EL 2 16C 40 CORMAN C 3 3 5 4 o DPPG C Q 2 E O 2 E 0 2 S C U 2 0 es 0 41 na and Lipids for Liposomal Formulations lt COATSOMIE Series C jo T E cS O LL
19. Phospholipids and Lipids for Liposomal Formulations In early 1990 s we commenced supply of GMP grade phospholipids to every corner of the world Our products have been used in commercialized liposomal drugs for anti fungal and oncology use which led to our outstanding reputation in this field For the benefit of our customers we have also developed a ready to use liposomal formulation called EMPTY LIPOSOMES into which customers can encapsulate their own drugs Ultra purity Polysorbate 80 Our Polysorbate 80 HX2 is the ultra purity polysorbate 80 surfactant and we are proud of its rating of the highest quality around the world with less impurities compared to conventional grade Favorable features such as less impurities and lower susceptibility to oxidation are responsible for negligible production of peroxides and aldehydes which are well known to induce degradation of drug formulations In addition owing to its high quality Polysorbate 80 HX2 shows superior safety features including a lower incidence of allergic hemolytic cytotoxic and acute toxicity reactions compared to conventional grade Polysorbate 80 HX2 can be applied to various drugs as a multi purpose surfactant e g as a solubilizing agent for poorly hydrophilic drugs as a stabilizing agent for injectable preparati
20. cGMP 2005 PEG PEGylation 20 FROM mPEG PEG PEG Application Chart for PEG Derivatives We supply different series of PEG derivatives with various PEG versatile functional groups CO CH2CH2 COO NHS NH2 SH GS CO CH2CH2CH2 COO NHS Hi s ho GS2 CH2CH2CH2 NHCO CH2CH2CH2 COO NHS NH2 SH GS3 CH2CH2 NHCO CH2CH2CH2 COO NHS Da Sa AS CH2 COO NHS NH2 OH SH HS CH2CH2CH2CH2CH2 COO NHS NH2 SH COO phenyl NO2 2 AL AL2 CH2CH2 CHO CONH CH2CH2 CHO 2 NH2 CH2CH2CH2
21. PEG PEG PEG 2 000 18 0 18 0 N 3 phosphoethanolamine sodium salt SUNBRIGHT DSPE 050CN 5 000 C18 0 C18 0 SUNBRIGHT PP 020CN 220 C16 0 C16 0 SUNBRIGHT PP 050CN MO C16 0 C16 0 SUNBRIGHT PM 020CN N Carbonyl methoxypolyethyleneglycol 2000 1 2 dimyristoyl sn glycero 2 000 C14 0 C14 0 3 phosphoethanolamine sodium salt NOF CORPORATION is the sole patent holder of these high quality PEG phospholipids Patent No US6679822 i O II Ro O00 COH CH OCH5CH5 n7 OCHs i T CH OPO CH CH2NHCO CH ONa SUNBRIGHT make to order SUNBRIGHT DSPE 020GL2U Bfrononpoheryeneghea Z000 2 2000 SUNBRIGHT DSPE 050GL2U N Carbonyl 2 3 Bis methoxypolyethyleneglycol 5000 1 2 5 000 C18 0 C18 0 distearoyl sn glycero 3 phosphoethanolamine sodium salt SUNBRIGHT make to order a and Lipids for Liposomal Formulations lt COATSOMIE Series New New 3 2 New hydrophilic phospholipid derivatives As listed below NOF provides new types of phospholipid
22. 80 C CXHRC S S Ri C13 Egg SPM COATSOME NM 10 Egg Sphingomyelin 98 u Ca 703 gg PN Re C15 0 17 0 Ri C13 C24 Milk SPM COATSOME NM 70 Milk Sphingomyelin 98 UD C 79 5 15 0 C210 C220 023 0 2 Highly purified Synthetic Phospholipids We use fatty acids that are highly purified by our own technologies for the manufacture of a variety of phospholipid derivatives that is NOF can synthesize derivatives containing a variety of fatty acids Our phospholipids are manufactured in FDA inspected facilities meeting GMP standards Our quality assured products can be safely used for the production of pharmaceuticals NOF as a contracted manufacturer also synthesizes novel phospholipid derivatives and has completed DMF registrations for numerous novel derivatives we are ina position to supply relevant lipids from test reagent grade to commercial production scales that are approved for manufacture of pharmaceuticals after clinical studies 2 1 Phosphatidylcholine
23. 80 HX2 UP NF und Excipients Tor Bdceutical Phar Development PUREBRIGHT MIB Series NMIPC Polymers for Hydrophobic Drug Formulations NOF provides unique hydrophilic polymers PUREBRIGHT MB that allow ready solubilization of hydrophobic drugs in aqueous solutions These polymers consist of copolymers of 2 methacryloyloxyethyl phosphorylcholine MPC and n butyl methacrylate BMA Introduction of hydrophobic BMA units leads to solubilization of drugs via hydrophobic interactions PUREBRIGHT MB Series MPC n B MA BMA MN CH2 OPOCH2CH3N CH3 s O MPC unit BMA unit Hydrophilic Unit Hydrophobic Unit Advantage of PUREBRIGHT MB Series e High Solubility Performance for any Hydrophobic Drug e Phosphorylcholine Base Biocompatible Polymer e No Irritation e No Toxicity e Nano Particl
24. COATSOME PEG PEG Liposomes were by Ltd using Cryo TEM TECNAI F20TWIN Cryo purified Smthes k l T nandi PU Ss 4 Purified Phospholipids from natural sources 1 1 Soybean Phospholipids NOF manufactures high purity lecithin containing higher contents of phosphatidylcholine by using strictly selected natural soybeans uncontaminated with ge
25. BE 8 b
26. 5 D 5
27. TF 01 PL wo lt N E E m 6 5 gt i 2 gt TF modified Control Liposome i v test using test period 18 days OHP oxaliplatin Cancer cell TF transferrin colon26 5mgOHP kg twice daily Transferrin bound liposomes are directed toward the transferrin receptors on the surface of cancer cells e Reagent for preparing transferrin modified liposomes Preparation of the drug containing liposomes involves three steps e Addition of the drug solution e Mixing and hydration of the drug with the reagent e Preparation of the liposomes by size adjustment and sterilization Increased effectiveness of the drug e Prolonged halrl life of the drug in blood e Avoidance of RES uptake Facilitation of R amp D of DDS preparations e Composed of highly purified starting materials including high purity phospholipids e Ready for bulk supply This product is intended to be used for research purposes only They are not to be used
28. 0 2 um G00nm EEO 0 1 u m 150nm 8 Liposomal Formulations Optimization amp manufacturing of customer s liposome encapsulated hydrophilic hydrophobic cationic drugs Based on our ample experience accumulated in the phospholipid liposome fields we are ready to comply with custom manufacture and custom development of the druge ncapsulated liposomes We can offer proposals for the development of various functional liposomes such as those with improved half life of the drug in the blood and those with immunoregulatory functions Long circulation Immuno regulation vaccine allergy therapy jaracteristics of immuno regulating has developed immuno regulating Liposomes Inducing substantial IgG antibody Inducing CTL Cytotoxic Lymphocyte Suppressing IgE antibody NOF has developed immunoregulatory liposomes and technology This technology essentially requires production of an appropriate amount of IgG antibody while concomitantly inhibiting the production of IgE antibody Due to the well Known advantages of strong cellular immunity CTL activity this technology can be applied to the prepar
29. Bioactive Substance CH30 CH45CH50 CH 20 000 New 40 000 New SUNBRIGHT PTE2 200EA SUNBRIGHT PTE2 400EA SUNBRIGHT PTE2 200MA2 SUNBRIGHT PTE2 400MA2 CH2CH2 NHCO CH2 2 maleimide Ethylamine 20 000 New CH2CH2NH2 40 000 New Maleimide 20 000 New 40 000 New make to order 7 Releasable PEGs New e SUNBRIGHT BE Linker series Pegylated therapeutic protein or small molecule pharmacology would be substantially expanded if the original therapeutic proteins or small molecules could be regenerated in vivo Diminution of activity of both enzymes and protein ligands is commonly encountered following permanent conjugation with polyethylene glycol PEG However Enzon s releasable PEG linkers have the ability to improve the pharmaceutical properties of therapeutic proteins or small molecules through releasable PEGylation and maintain the therapeutic effect of these molecules by regenerating the bioactive proteins or small molecules in vivo To make available Enzon s releasable linker technology NOF introduces the Benzyl Elimination BE linkers i e PEG BE NHS SUNBRIGHT BE Series as listed in the following
30. PEG Concerning this product NOF has officially registered its product L patent in Japan kasi CO CH il Hoc CO CH CH2O CH2CH20 nCH3 SUNBRIGHT GM 020 1 2 Dimyristoyl sn glycerol methoxypolyethylene Glycol 2 000 C14 0 C14 0 C 0 10 E O LL 5 O 2 z Q U ie st fe A SUNBRIGHT GM 050 1 2 Dimyristoyl sn glycerol methoxypolyethylene Glycol 5 000 C14 0 SUNBRIGHT GP 020 1 2 Dipalmitoyl sn glycerol methoxypolyethylene Glycol 2 000 C16 0 C16 0 SUNBRIGHT GP 050 1 2 Dipalmitoyl sn glycerol methoxypolyethylene Glycol 5 000 C 60 C 16 0 SUNBRIGHT GS 020 1 2 Distearoyl sn glycerol methoxypolyethylene Glycol 2 000 C18 0 C18 0 SUNBRIGHT GS 050 1 2 Distearoyl sn glycerol methoxypolyethylene Glycol 5 000 19 0 C18 0 SUNBRIGHT GO 020 1 2 Dioleoyl sn olycerol methoxypolyethylene Glycol 2 000 C18 1 C18 1 SUNBRIGHT GO 050 1 2 Dioleoyl sn gly
31. 80 HX2 80 80 In vivo H OCH CHg O O CH2CH20 pH O CHsCHbOH O CHCH O CH CH O 4C CH3 CH CH CH 3 7CHs Product name Description Polysorbate 80 HX2 Polyoxyethylene Sorbitan monooleate CAS NO Regulatory Status 9005 65 6 JP EP NF 1 JP Japanese Pharmacopoeia EP European Pharmacopoeia NF National Formulary NOF Conventional Polysorbate 80 Polysorbate 80 Appearance comparison of Ultra purity Polysorbate 80 bl O 00 0 0 O 02 gt a 3 A 0 m Ultra Purity Polysorbate 80 Degranulation Test An allergic study model 80 without Polysorbate 80 eo Polysorbate 8
32. PEG Enzon PEG PEG PEG Enzon SUNBRIGHT BE Releasing drug from PEG drug conjugates SUNBRIGHT BE Linker series pre i Spacer Y 1 linker X mmm m Y carbonate ester Spacer CH CH etc X functional group conjugation Custom ii NE Bioactive substance Spacer Y linker HNH Q trigger 6 release Stepl hydrolysis enzymatic or non enzymatic Step2 release H regenerate original drug SUNBRIGHT ME BE200CH TS SUNBRIGHT ME BE200CM TS SUNBRIGHT ME BE200EH5 TS SUNBRIGHT ME BE200EM5 TS The Releasable Activated PEG belong to ENZON Pharmaceuticals Inc is sold by NOF for research and development purpose only CH30 CH2CH20 n p c 0 20 000 O CH3 CH 0 C
33. SUNBRIGHT PEG PEG DDS BAITS PEG PEG PEG PEG High purity mPEG OH Starting Material for Activated PEGs NOF manufactures high purity methoxy PEG OH characterized by absence of contaminating by impurities and narrow molecular weights distribution These highly pure methoxy PEG OH have so far been used for various commercial PEGylation drugs such as PEG Interferon and PEG GCSF CHsO C H20 NOF CORPORATION js the sole worldwid
34. e CHzOPO CHsCHzNHC OCHzCH2 OCHzCHzCH DSPE PEG ALD SUNBRIGHT DSPE 034AL N 3 oxopropoxy polyethyleneglycol carbamyl distearoyl ethanolamine 3 400 New 4 3 Fluorescent phospholipids SUNBRIGHT make to order NBD DPPE Dansyl DPPE n N an 4 R C O CH 0 Y O NO 8 CC 3 CaHa eae O C2H5 CoHs Nt CoHs CoHs N CoHs NBD DPPE COATSOME FE 6060NB 12 dipalmtoyl sn gycero 3 phosphoethanolamine N 956 3 C16 0 C16 0 Dansyl DPPE COATSOME FE 6060DA bir h s 10265 16 0 C16 0 NBD DPPE Dansyl DPPE jou ace 464nm 529nm Emission Fluorescence Intensity a u 350 400 450 500 550 Wavelength nm 600 650 Fluorescence Intensity a u 250 300 350 400 450 500 550 600 650 Wavelength nm C jo 2 E O LL 2 a 0 g E C Q g 0 fu i E D 0 LL O O 5 2 0 5 o 0 O 0 ena and Lipids for Liposomal Formulations lt COATSOMIE Series 5 Novel Lipids and Cationic Lipids 5 1 Ether phospholipid 9 II o P o YW _ C10 0 Diether COATSOME EC 1010 1 2 Di O Deoyl sn glycero 3 phosphocholine 537 8 COATSOME 5 2 DOTAP O Z Z N Y QY
35. AS lt CS lt GS lt TS lt HS PEGylation CS GS 2 conjugate AS TS HS 5 SUNBRIGHT ME 020CS SUNBRIGHT ME 050CS SUNBRIGHT ME 100CS SUNBRIGHT ME 200CS SUNBRIGHT ME 300CS SUNBRIGHT ME 400CS 2 000 5 000 10 000 20 000 30 000 40 000 make to order GS Type O oS II II CH30 C 2 CCH CH CH CO SUNBRIGHT ME 050GS 5 000 SUNBRIGHT ME 100GS 10 000 SUNBRIGHT ME 200GS 20 000 SUNBRIGHT ME 300GS 30 000 SUNBRIGHT ME 400GS 40 000 O AS Type CH30 CH5CH50 CH5CO N SUNBRIGHT ME 020AS SUNBRIGHT ME 050AS 2 000 5 000 New HS Type CHsO G H CH2O 5CO E N O SUNBRIGHT ME 050HS 5 000 SUNBRIGHT ME 100HS 10 000 SUNBRIGHT ME 200HS 20 000 SUNBRIGHT ME 300HS 30 000 SUNBRIGHT ME 400HS 40 000 TS Type CH30 H5CH5O 4 CO N O SUNBRIGHT ME 0501S 5 000 SUNBRIGHT ME 1001S 10 000 SUNBRIGHT ME 1201S 12 000 SUNBRIGHT ME 2001S 20 000 SUNBRIGHT ME 3001S 30 000 SUNBRIGHT ME 4001S 40 000 eSUNBRIGHT NP Series O p Nitrophenyl Carbonate PEG
36. Most suitable for SEDDS agent SEDDS Improvement of intestinal absorption following oral administration Custom development for formulations Comply with bulk supply requests Specification Content mixture of pharmaceutical excipients Volume 509 100g 1kg Container glass bottle Storage Storage under room temperature Keep container closed Solubilizer SL 11 8 Probucolin SL 11 Nano Emulsion 0 8 Probucol miim 5 _1 1 em 10 os os 625 SL 11 17 particle size nm POE 35 1 tt ttt I Insoluble 12 16 20 Time hr Pep Peptide type drug IND Indomethacin NFD Nifedipine PRB Probucol PIX Paclitaxel sn mm e 0 gt 0 45 0 0 0 0 LE O 0 2 2 0 x gt 2 PUREBRIGHT SL Series Hydrophobic Drug Solubilization Kit NOF produces Solubilization Kits for hydrophobic drugs using our various DDS technologies The procedures for the use of these kits are very simple facilitating your screening of new chemical entities at early test stages DDS
37. 2 No SUNBRIGHT MENP 20H 2 000 SUNBRIGHT 50 5 000 SUNBRIGHT 10 10 000 SUNBRIGHT 20 20 000 SUNBRIGHT MENP 30T 30 000 SUNBRIGHT 40 40 000 O eSUNBRIGHT AL Series Aldehyde PEG T CHaO CH CH O CH CH CH Exploting our latest technologies we supply mPEG 2 PEG aldehydes without any reactive problematic impurities e g MPEG bifunctional aldehydes SUNBRIGHT ME 050AL 5 000 SUNBRIGHT ME 100AL 10 000 SUNBRIGHT ME 200AL 20 000 SUNBRIGHT ME 300AL 30 000 SUNBRIGHT ME 400AL2 40 000 Activated PEG for PEGylation Activated PEG for PEGylation esSUNBRIGHTY PA Series PEG SUNBRIGHT MEPA 20H SUNBRIGHT MEPA 50H SUNBRIGHT 10 SUNBRIGHT MEPA 12T SUNBRIGHT MEPA 20T SUNBRIGHT MEPA 30T SUNBRIGHT 40 sSUNBRIGHT EA Series Aminoethyl PEG SUNBRIGHT ME 020EA SUNBRIGHT ME 050EA SUNBRIGHT ME 100EA SUNBRIGHT ME 200EA SUNBRIGHT ME 300EA SUNBRIGHT ME 400EA eSUNBRIGHT SH Series Thiol PEG CH30 C H CH O n CH5CH5CH5NH5 2 000 5 000 10 000 12 000 20 000 30 000 40 000 CH340 H5CH5O0 4 CHCH NH 2 000 5 000 10 000 20 000 30 000 40 000 CH O CH CH O CH CH SH SUNBRIGHT ME 020SH SUN
38. derivatives bound to polyglycerin and multi arm PEGs PEG hydrophilic polymers O X Linker AA ME VN NI AN O O O II II II I CH Hi 9 3C X ONa DSPE SUNBRIGHT CHOH Polyglycerin DSPE PG8G CH2CHO H 8 n DSPE SUNBRIGHT eee i 2 000 io O Multi arm PEG DSPE PTEO20 ocio n CHCH gt 1 7 DSPE SUNBRIGHT bt to Comb shaped DSPE 5 2 PEG 5 20 000 O CH CHzO nCH k SUNBRIGHT make to order 1000 0 DSPE PG8G 2 08mM DSPE PTE020 1 04mM DSPE AM0530K 0 52mM E DSPE 020CN 1 04mM 100 0 oc gt 10 0 o 1 0 0 24 48 72 96 120 Time h In vivo Plasma Clearance Profile for PEG based Liposomes and Polyglycerine based Liposome Q 45 L O LL 2 E 0 2 S C Q 29 2 O s 0 n D asia and Lipids for Liposomal Formulations lt COATSOMIE Series gt 3 3 Diacylglycerol PEG Because of direct attachment of PEG chains to diacylglycerol this product series is devoid of phosphorylethanolamine groups and other coupling chemistry Accordingly they are resistant to hydrolysis and are suitable for application to drugs that are vulnerable to ionic charges
39. 4 5 1 2 3
40. SL 11 SEDDS DDS NOFABLE NOFABLE SUNBRIGHT DKH 02HB DKH 03HB and DKH 04HB MACROGOL PEG 200 300 and 400 We have been providing ultra pure polyethylene glycol PEG 200 300 and 400 as an excipient specifically useful for pharmaceutical formulations without any impurities such as EG ethylene glycol and DEG diethylene glycol We supply PEG200 300 and 400 that meet the requirements stipulated in the USP EP and JP JPE SUNBRIGHT OE Series EG DEG
41. P 0 gt 0 gt c 0 2 0 9 z id T nm III J CORPORATION CORPORATION OVERVIEW oeeie esisi esirin reri reri re 3 DDS PRODUCT OVERVIEW 4 Activated PEG for PEGylation 6 NOF s Product Advantages e High purity mPEG OH Starting Material for Activated PEGs e About PEGylation e Capabilities High purity Activated PEGs e Application Chart for PEG Derivatives e Custom Manufacturing 1 Monofunctional Linear PEGs 2 Bi Functional PEGs 3 Multi Arm PEGs 3 1 4 arm Functional PEG Series 3 2 8 arm Functional PEG Series 4 Branched PEGs 4 1 2 arm Branched PEG 4 2 3 arm Branched PEG 4 3 4 arm Branched PEG 4 4 Lysine Branched PEG Heterofunctional PEGs Forked PEGs Releasable PEGs Comb shaped co polymers CON Phospholipids and Lipids for Liposomal Formulations 28 Purified Phospholipids from natural sources Highly purified Synthetic Phospholipids PEGylated Lipids Functionalized Phospholipids Novel Lipids and Cationic Lipids Empty Liposomes lt COATSOME EL Series gt Transferrin Pre liposome Liposomal Formulations LIPONIZER for Liposome Production NOF s Capabilities and Customer Advantages O O Q P gt N Ultra purity Polysorbate 80 51 IV Novel Excipients f
42. 5 O z Q U A eCOATSOME EL Series COATSOME EL 01 C DPPC Cholesterol Stearyl amine 52 40 8 57 Cationic COATSOME EL 01 N Nonionic DPPC Cholesterol DPPG 54 40 6 61 COATSOME EL 01 A Anionic DPPC Cholesterol DPPG 30 40 30 61 COATSOME EL 11 C Cationic POPC Cholesterol Stearyl amine 52 40 8 EL 11 N Nonionic Slightly anionic POPC CholesteroliPOPG 54 40 6 61 COATSOME EL 11 A Anionic POPC Cholesterol POPG 30 40 30 61 COATSOME EL P Series O Z SZ NZ Q ll O O O T 2 3 CH CHO H ONa 8 DSPE PG8G SUNBRIGHT DSPE PG8G COATSOME EL 01 PN Slightly anionic COATSOME EL 01 PA Anionic e COATSOME EL 01 D We also provide new cationic liposomes COATSOME EL 01 D applicable to gene delivery systems This novel cationic liposome contains not only O O ditetradecanoyl N trimethylammonioacetyl diethanolamine chloride DC 6 1 4 as a cationic lipid but also DOPE and cholesterol and confers the characteristics of efficient transfection activity and expression ability both in vitro serum containing media and in vivo assay systems O O H A ININININIV Z i N CCHN cr NN UN NY 9 b DSPE PG8G DPPC Cholesterol DPPGz24 2 20 5 15 2 2 3 29 DSPE PG8G DPPC Cholesterol DPPG 4 2 11 4 15 2
43. C O Z ZN N YN N N XN C O O N Cl DOTAP COATSOME CL 8181TA 1 2 Dioleoyloxy 3 trimethylammonium propane chloride 698 5 COATSOME 5 3 SAINT Solid 1 SN 010 New er C N HsC N SAINT Solid 1 SN 010 4 9Z 28Z heptatriaconta 9 28 dien 19 yl 1 methylpyridin 1 ium chloride 644 5 New Patent No EP755924 US5853694 US6726894 Licensing information is available from Synvolux Therapeutics B V DNA Delivery SIRNA Delivery Protein Delivery Comparison of GFP Expression in SAINT RED Comparison Delivery of DNA Modifying Enzymes Murine Embryonic Stem Cells Silencing of EGP 2 in SKOV 3 Cells Delivery of DNA methyltransferase M Sss ee into high E cadherin expressing 16HBE cells 100 90 35 Bo Blank M Sssl SAINT M Sssl 30 70 25 60 so 5 r 40 30 20 10 2 Silencing Expression SAINT MIX Others 1 Others 2 Others 3 SAINT RED Others Others B Others C Others D Others E References Note Bernardia T F van der Gun et al J Control Release 123 228 238 2007 This product is covered by one or more paent Bernardia T F van der Gun et al Int J Cancer 123 484 489 2008 applications and or foreign conter part patent Sigridur A Asgeisdottir et al J Control Release 141 241 251 2010 applications owned by Synvolux Therapeutics Joanna E Adrian et
44. PEG ZR PEG 2 000 80 000 PEG 100 80 60 40 20 Comparisons of GPC analysis of NOF mPEG OH MW5 000 left and conventional product right About PEGvlation PEGylation technology is applied for biologics modifications including cytokines therapeutic antibody fragments interleukins hormones oligonucleotides and other proteins and peptides PEGylation can be effective for e mproving Bioavailability Prolonging Blood Circulation Maximizing Pharmacokinetics Low profile Immunogenicity NOF provides high performance activated PEGs for PEGylated drugs from early development stage to commercial use with our 20 years of experience of manufacturing high quality methoxy polyethylene glycol Our starting material for activated PEGs for pharmaceutical area Our activated PEGs have a narrow polydispersity and low diol content with wide range of molecular weights from 2kDa to 80kDa PEGylation Service Please feel free to contact us if you need PEGylated drugs using NOF Activated PEGs SUNBRIGHT series Contact ddsinfo nof co jp Reference 1 PEG conjugation Following figure shows several examples of NOF PEG aldehyde conjugation with human insulin for various PEG molecular weights M 1 2345
45. 0 0 O 1 2 2 0 X 0 gt 1 Excipients for Pharmaceutical Development Hydrophobic Solbilization Methods P gt K gt 1 2 3 lt Preparation gt The following instructions are for preparation of 5 vials of the test solution simultaneously 1 Weigh drugs into test tube or cuvette according to the desired concentration in the final solution If you wish to make 1mg mL of the final solution weigh 12 mg of the drug add 3mL of ethanol select other solvent when drug is not soluble in ethanol into the test tube and then dissolve completely by gentle shaking 2 Pipette out 500uL of the drug solution and transfer the solution into each vial of PUREBRIGHT SL Kit respectively 3 Dissolve completely by shaking Warm the vial to 50 C to obtain a clear solution 4 Evaporate the solvent from the vial according to one of the following methods a Place the vial into vacuum chamber previously warmed to 50 C then evaporate the solvent under vacuum b Evaporate the solvent by a gas stream at 50 C over vials placed in a warm bath Exercise caution in handling to avoid fires or accidents caused by volatile solvent 5 Add 2mL of deionized water into the vial and the dissolve completely with shaking Add 1 8mL of deionized water in case of using PUREBRIGHT SL 411 Drug in aqueous solution e g 1mg ml is now ready Remarks Temperature
46. make to order The Lysine Branched PEG belong to ENZON Pharmaceuticals Inc is sold by NOF for research and development purpose only Activated PEG for PEGylation Ai Activated PEG for PEGylation 5 Heterofunctional PEGs 2 By using hetero type activated PEGs different molecules PEG be conjugated onto the each end of the PEGs They are also useful for surface modification e Hydroxy PEG Amine HO CHsCHzO CHsCHsCHzNHz SUNBRIGHT HO 020PA 2 000 SUNBRIGHT HO 034PA 3 400 SUNBRIGHT HO 050PA 5 000 SUNBRIGHT HO 100PA 10 000 SUNBRIGHT 200 20 000 SUNBRIGHT 400 40 000 make to order eAmino PEG Carboxylic acid II 3 0 5 5 SUNBRIGHT PA 020HC 2 000 SUNBRIGHT PA 034HC 3 400 SUNBRIGHT PA 050HC 5 000 make to order eBoc protected Amino PEG Carbonate NHS 5 O 3 ll II HaC C7 OCNHCH CH CH O CH2CH2 0 CO N CH3 O SUNBRIGHT BO 020TS 2 000 SUNBRIGHT BO 034TS 3 400 SUNBRIGHT 050 5 000 SUNBRIGHT 100 5 10 000 SUNBRIGHT BO 200TS 20 000 make to order Maleimide PEG Carbonate NHS O 5 O II I N CH gt SCNHCH gt CH CH OCH CH2 O CO N O O SUNBRIGHT MA 020TS 2 000 SUNBRIGHT MA 034
47. NOF AMERICA NOF METAL COATINGS KOREA Co Ltd NOF METAL COATINGS SHANGHAI Co Ltd NOF Shanghai Co Ltd Changshu Chemical Ltd Taiwan Nichiyu Ltd Singapore Office NOF METAL COATINGS i SOUTH AMERICA IND P T NOF MAS Chemical Industries E COM LTDA DDS PRODUCT OVERVIEW I Activated PEG for PEGylation We manufacture high purity methoxy polyethylene glycols mPEGs with molecular weights from 2kDa to 80kDa producing high purity activated PEG derivatives of methoxy PEG amines maleimides and carboxylic acids Various alterations of the terminal PEG chemistry permit drug modification as per customers expectations and needs Furthermore use of PEGylated phospholipids composed of our high purity phospholipids and PEGs prolong the plasma circulating half life of liposome drugs 7 2 000 80 000 PEG PEG PEG PEG
48. 20k X 2 CH30 CH jCH O O H5C O CH5CH5CH5NHC CH5 5CO N SUNBRIGHT GL2 200GS2 SUNBRIGHT GL2 400GS2 SUNBRIGHT GL2 600GS2 SUNBRIGHT GL2 800GS2 TS Type NHS Carbonate PEG O 20 000 40 000 60 000 80 000 make to order CH30 CH5CH5O 4 CH5 CH30 CH53CH50 CH H2C OCO N SUNBRIGHT GL2 200TS SUNBRIGHT GL2 400TS SUNBRIGHT GL2 600TS SUNBRIGHT GL2 800TS NP Type P Nitrophenyl Carbonate PEG 20 000 40 000 60 000 80 000 make to order CH3O CH2CH50O 47 CH30O C H5CH5O 4 CH O SUNBRIGHT GL2 100NP SUNBRIGHT GL2 200NP SUNBRIGHT GL2 400NP SUNBRIGHT GL2 600NP SUNBRIGHT GL2 800NP 10 000 20 000 40 000 60 000 80 000 make to order Activated PEG for PEGylation AL3 Type Aldehyde PEG CH O CH CHzO CH O CH CH O CH H C OCNHCH CH CH Activated PEG for PEGylation SUNBRIGHT GL2 200AL3 20 000 SUNBRIGHT GL2 400AL3 40 000 SUNBRIGHT GL2 600AL3 60 000 SUNBRIGHT GL2 800AL3 80 000 make to order PA Type Aminopropyl PEG CH30 CH2CH20 7 CH CH40 CH2CH50 CH H C CH5CH5CH5NH5 SUNBRIGHT GL2 200PA 20 000 SUNBRIGHT GL2 400PA 40 000 SUNBRIGHT GL2 600PA 60 000 SUNBRIGHT GL2 800PA 80 000 H O CHzCHzO CH C2 MA Type Maleimide PEG sO GHC nC CHs0O CH2CH20O CH II H2C OCH2CH2CH2NHC CH2 2 N O
49. lt Preparation of liposomes lt Syringe filtration gt lt High Pressure filtration gt Dilution purification D TF OT PL 9 TF 01 PL D 6 0 22 m D 300nm zr Add 9
50. 0 5 O 2 z Q U 0 st 1 3 Sphingomyelin Phospholipids are known to be the primary constituents of biological membranes Recently however it has been clarified that phospholipids are not only constituents of the cell membrane but also play important direct roles in the cell membrane functions Among the phospholipids sphingomyelin has been revealed to be significantly important in both the formation and maintenance of lipid rafts Considering that the lipid rafts have been shown to be involved in various signaling pathways including immunological responses and transportation of specific materials sphingomyelin has drawn much attention as a substance with important roles in the expression of specific cellular functions such as intracellular information transmission and maintenance of membrane structure Despite containing long fatty acid chains sphingomyelin exhibits some advantageous characteristics such as a low phase transition temperatures Tc that render it uniquely suitable for liposomal formations NOF supplies high purity sphingomyelin derived from milk and egg yolk Concerning yolk derived sphingomyelin palmitic acid accounts for about 80 of the fatty acid chains bound by amide bonds in sharp contrast however milk derived sphingomyelin contains a broader range of long chain fatty acids including palmitic acid or longer chain fatty acids Bec
51. 11 4 29 lt COATSOME EL 01 D gt COATSOME EL 01 D O O ditetradecanoyI N a trimethylammonioacetyl diethanolamine chloride DC 6 14 DOPE in vitro in vivo O O ditetradecanoyl N a trimethylammonioacetyl diethanolamine chloride DC 6 14 COATSOME EL 01 D DOPE Cholesterol DC 6 14 0 75 0 75 1 00 1 51 6 2 Suggestions for use COATSOME EL How to use When 2 mL of distilled water is added the osmotic pressure ratio of the product becomes 0 8 to 1 1 The osmotic pressure should be adjusted according to the need in the intended experiment b For enhancement of the encapsulation efficiency of the drug by electrostatic interaction the molar ratio of the charged lipids either stearylamine or DPPG against the drug solution plays an important role the molar ratio should be at least more than 2 and preferably not less than 3 c Adjust the temperature range for storage of the aqueous drug solution between 16 C and 40 C d Use the liposomal drugs immediately after the
52. 20 897 904 2004 2 K Kato et al BioTechniques 35 1014 1021 2003 Application II Anchoring of cell on a BAM modified surface 4 or 0 ju gt 0 6 3 ju 0 0 Be A 8 42 2 O x LLI gt O Z l Ordering Information In the Americas In the region except in Americas Europe NOF AMERICA CORPORATION NOF CORPORATION One North Broadway Suite 1012 DDS Development Division White Plains NY 10601 USA 20 3 Ebisu 4 chome Shibuya ku Tel 914 681 9790 Tokyo 150 6019 Japan Fax 914 681 9791 Tel 81 3 5424 6741 E mail info nofamerica com Fax 81 3 5468 0901 Home Page http www nofamerica com E mail ddsinfo nof co jp Home Page http www dds drug com In Europe In Japan NOF EUROPE BELGIUM N V Bouwelven 1 DDS BE 2280 Grobbendonk Belgium ri Tel 32 14 25 98 26 4 20 3 Fax 32 14 22 45 63 Tel 03 5424 6741 E mail infoGnofeurope com Fax 03 5468 0901 Home Page http www nofeurope com E mail ddsinfo nof co jp Home Page http www dds drug com A faxed confirmation is required for every order Delivery Standard deliveries in Japan in stock product are by domestic courier International shipment is delivered via air transport The buyer is responsible for all international duties
53. 2002 Phospholipids and Lipids for Liposome Formulations 45 Phospholipids and Lipids for Liposome Formulations Phospholipids and Lipids for Liposomal Formulations lt COATSOIVIES Series gt How to prepare transferrin modified drug containing liposomes Add drug solution Mix and hydrate Remove TF 01 PL from the refrigerator and bring to room temperature 2 Inject drug solution into the vial 3 Gently shake the and mix the drug solution with the TF 01 PL powder to hydrate the powder 4 Shake it gently every 5 minutes for 15 minutes rolling shakers can also be used so to ensure the formation of a homogeneous mixture Note 1 The amount of drug solution This product contains 20 mg lipid in a vial Addition of the drug solution to obtain a lipid of 1 2 is recommended the amount of drug solution to be added is 1 2 mL Be careful not to lose the amount of solution during the filtering process described below since the amount of solution is very small Adding 1ml of purified water will make an approximately 30mM phosphate buffer Adjust the drug solution buffer or salt concentration accordingly lt Syringe filtration gt 5 Suction the mixed solution prepared 6 Attach a disposable cellulose acetate filter pore diameter 0 22um to the syringe and filter the solution Transferrin modified drug containing liposomes particle diameter approximate
54. High purity Oleic Acid GLC Conditions Instrument Shimadzu GC 9A Column Capillary SP 2560 100m x 0 25mm Program 160 C x 60min 210 C x 40min Conventional Oleic Acid Low Linoleic type EE u u u k i Gas chromatogram for NOF Oleic acid COSAS to conventional product Crystal of EXTRA OLEIN 99 Oxidation Stability of Oleic Acid Dermal Absorption Enhancement with Oleic Acid 9 a 8 e without Oleic acid a EXTRA OLEIN 99 D Conventional S NC Oleic Acid Conventional Oleic acid 9 gt 1 0 2 EXTRA OLEIN 99 E 0 5 10 15 2 4 Time h Time h Formation of peroxides in oleic acid during incubation at 50 Dermal Absorption Enhancement of Indomethacin with Highly Purified Oleic Acid EXTRA Series 2 Ultra Purity Oleic Acid Derivatives eSorbitan Oleate HO OH pH O CHCH20C CH 2 CHzCH CH 5 CHa O eGlycerol Oleate HO CH2 CH OH CH2 OCO CH2 7CH CH CH2 7CHs NOFABLE GO 991 Glycerol monooleate gt 99 25496 72 4 Ethyl Oleate CHs CH2 CH CH CH gt 2 COOCH gt CHs NOFABLE EO 99 Ethyl oleate gt 99 111 62 6 JPE 1 JPE Japanese Pharmaceutical Excipients 4 or is ju gt 70 5 3 ju O 0 Be 0 0 2 O x LLI gt O 2 q Excipients for Pharmaceutical Development SUNBRIGHT DKH O2HB
55. SH groups in proteins MAL Phospholipid R i Ro CO CH O II II CHzOPOCHzCHNH CCH CH N O Na DMPE MAL COATSOME 4040 N 3 Maleimide 1 oxopropyl L a phosphatidylethanolamine Dimyristoyl SAR ORs Sle Br xp Ba BB 9L RI U target PEG PEG Targeting moiety antibody peptide moiety PEG corona Liposome SH 00 NH BP SH O Maleimide MAL derivative for SH group reaction O C14 0 C14 0 8090 _ DPPE MAL COATSOME FE 6060MA3 N 8 Maleimide 1 oxopropyl L phosphatidylethanolamine Dipalmitoyl 160 C16 0 865 1 DSPE MAL COATSOME FE 8080MA3 N 3 Maleimide 1 oxopropyl L a phosphatidylethanolamine Distearoyl C18 0 C18 0 921 2 POPE MAL COATSOME FE 6081MA3 N 8 Maleimide 1 oxopropyl L a phosphatidylethanolamine 1 Palmitoyl 2 o
56. derivative for O SH group reaction O i i CH2CHNHC OCH2CH2 nO CH2 NHCCH2CH2 N OH O DSPE PEG MAL SUNBRIGHT DSPE 020MA N 8 Maleimide 1 oxopropyljaminopropyl polyethyleneglycol carbamyl 2 000 distearoylohosphatidyl ethanolamine N 3 Maleimide 1 oxopropyl aminopropyl polyethyleneglycol carbamyl 3 400 distearoylphosphatidyl ethanolamine N 3 Maleimide 1 oxopropyl aminopropyl polyethyleneglycol carbamyl DSPE PEG MAL SUNBRIGHT DSPE 050MA distearoylphosphatidyl ethanolamine 5 000 SUNBRIGHT make to order DSPE PEG MAL SUNBRIGHT DSPE 034MA Phospholipid PEG NHS O PET a Activated carboxylic acid NHS O for NH2 group coupling reaction N S O O O II gt 2CHz nO CH 5 3 5 3 O DSPE PEG NHS SUNBRIGHT DSPE 020GS DSPE PEG NHS SUNBRIGHT DSPE 034GS DSPE PEG NHS SUNBRIGHT DSPE 050GSY Phospholipid PEG ALD New i Ee t 3 N succinimidyloxyglutaryl aminopropyl polyethyleneglycol carbamyl 2 000 distearoylohosphatidyl ethanolamine 3 N succinimidyloxyglutaryl aminopropyl polyethyleneglycol carbamyl distearoylphosphatidyl ethanolamine 3 400 3 N succinimidyloxyglutaryl aminopropyl polyethyleneglycol carbamyl 5 000 distearoylphosphatidyl ethanolamine SUNBRIGHT gt make to order Aldehyde ALD derivative for NH group coupling reaction O
57. illegal or unenforceable the validity legality and enforceability of the remaining provisions shall not be affected or impaired thereby The paragraph headings herein are for convenience only they form no part of these Terms and Conditions and shall not affect their interpretation These Terms and Conditions shall be binding upon inure to the benefit of and enforceable by the parties hereto and their respective heirs personal representatives Successors and assigns Governing Law and Jurisdiction All disputes as to the legality interpretation application or performance of the Sales or any of these Terms and Conditions shall be governed by the law of Japan and subject to the exclusive jurisdiction of the Tokyo District Court for first instance 85261 19 551 DDS
58. was already in the possession of the Buyer e is independently developed without use of Confidential Information and f is required to be disclosed to comply with any applicable law regulation or court order provided that the Buyer shall provide prior written notice of such disclosure to the Seller and take reasonable and lawful actions to avoid or minimize the degree of such disclosure Technical Assistance At Buyer s request Seller may at Seller s discretion furnish technical assistance and information with respect to Products SELLER MAKES NO WARRANTIES OF ANY KIND OR NATURE EXPRESS OR IMPLIED INCLUDING ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR ANY PARTICULAR PURPOSE WITH RESPECT TO TECHNICAL ASSISTANCE OR INFORMATION PROVIDED BY SELLER OR SELLER S PERSONNEL ANY SUGGESTIONS BY SELLER REGARDING USE SELECTION APPLICATION OR SUITABILITY OF THE PRODUCTS SHALL NOT BE CONSTRUED AS AN EXPRESS OR IMPLIED WARRANTY UNLESS SPECIFICALLY DESIGNATED AS SUCH IN A WRITING SIGNED BY AN OFFICER OR OTHER AUTHORIZED REPRESENTATIVE OF SELLER Buyer s Use of Products Buyer agrees and acknowledges that Seller s products are intended primarily for laboratory research purpose and unless otherwise states on product labels Sellers s catalogue or in other literature furnished to Buyer are not to be used for any other purposes including without limitation in vitro diagnostic purposes in foods drugs medical devices or cosmetics for huma
59. 2 lyso sn glycero 3 phosphocholine 99 up SA exe 0 Q 5 E I E O 2 ER O 0 2 I g O 0 Phospholipids and Lipids for Liposomal Formulations lt COATSOIVIES Series gt 2 3 Phosphatidylglycerol T II gt OH CH OPO tae X Na or NH4 COATSOME NG 21LS Hydrogenated Soybean phosphatidylglycerol sodium salt 9596 up HSPG Na EPG Na COATSOME NG 50LS Non hydrogenated Egg phosphatidylglycerol sodium salt 9596 up DLPG Na COATSOME MG 2020LS 1 2 Dilauroyl sn glycero 3 phosphoglycerol sodium salt 99 up 632 8 42120 DMPG Na COATSOME MG 4040LS 1 2 Dimyristoyl sn glycero 3 phosphoglycerol sodium salt 99 up 688 9 DMPG NH4 COATSOME MG 4040LA 0 1 2 Dimyristoyl sn glycero 3 phosphoglycerol ammonium salt 99 up 683 9 14 0 C14 0 DPPG Na COATSOME MG 6060LS 1 2 Dipalmitoyl sn glycero 3 phosphoglycerol sodium salt 99 up 745 0 C 16 00 G16 0 DPPG NH4 MG 6060LA 12 Dipalmitoyl sn glycero 3 phosphoglycerol ammonium salt 98 up 740 0 C16 0 C16 0 DSPG Na COATSOME MG 8080LS 1 2 3 sodium salt 99 801 1 180 2 DSPG NH4 COATSOME MG 8080LA 1 2 Distearoyl sn glycero 3 phosphoglycerol ammonium sat 99 up 796 1 C18 0 C18 0 o DOPG Na COATSOME MG 8181LS 0 1
60. DKH O3HB and o 0 gt 0 0 0 0 O 0 2 2 0 x gt 2 Formaldehyde NOF produces top quality Polyethylene Glycols containing only with extremely low levels of EG ethylene glycols and DEG diethylene glycols whereby our Polyethylene Glycols can be specifically used as pharmaceutical excipients From the toxicological perspective EP has stipulated that the upper limits of EG and DEG should not exceed 4000 ppm while the USP stipulates that the upper limits of EG and DEG should not exceed 2500 ppm NOF can guarantee much lower levels of EG and DEG than those stipulated by both EP and USP In addition we pride ourselves in the fact that our Polyethylene Glycols contain extremely low levels of impurities including ethylene oxides dioxane peroxides and aldehyde derivatives NOF can supply high quality PEG 200 300 and 400 all of which would meet the specifications of EP USP JP and JPE Concerning this product NOF has officially registered its product patent in the United States of America Patent No US6620976 EG DEG ID EG DEG EP 4000ppm USP 2500pp
61. PEG ALD at 4 C The PEGylated insulin was purified Q Sepharose Fast Flowcolumn lane M molecular weight markers lane 1 insulin lane 2 PEG ME 050AL insulin eluate lane 3 PEG ME 100AL insulin eluate lane 4 PEG lane 5 PEG ME 300AL insulin eluate ME 200AL insulin eluate Activated PEG for PEGylation 1 5 0 gt 0 O 9 a U 0 2 0 lt I naoa PEG for PEGvlation lt SUNBRIGHT Series gt 2 Coupling of PEG derivatives to Proteins examples of simple conjugation conditions PEG 1 Coupling of PEG NHS derivatives to protein amines PEG NHS Protein NHz2 Conditions 1 50 mM phosphate buffer pH 7 2 6 hrs Conditions 2 Borate phosphate buffer pH 8 0 25 C 2 hrs 2 Coupling of PEG Aldehyde derivatives to protein amines PEG Ald Protein NHz2 Conditions sodium cyanoborohydride 10 equiv 4 C 20 hrs 9 3 Coupling of PEG Maleimide derivatives to protein sulfhydryls PEG Maleimide Protein SH Conditions 100 mM phosphate buffer pH 6 5 4 C 4 hrs 4 Coupling of PEG NHz derivatives to protein carboxylates PEG NH2 Protein COOH Conditions 50mM phosphate buffer pH 7 2 WSC 2 equiv 4 C 10 hrs 5 Coupling of PEG p Nitrophenyloxycarbonyl derivatives to protein amines PEG NP Protein NH2 Conditions
62. SEDDS Self Emulsifying Drug Delivery System SL 11 SEDDS Content Solubilizer SL 1 1 reparation Method I Method Remarks Temperature may be changed depending upon drug stability Mixture of pharmaceutical excipients Method I D Dissolve drug in a suitable solvent such as ethanol etc 2 Add the drug solution prepared D to Solubilizer 51 11 thoroughly mix to completely dissolve the contents Solubilizer SL 11 3 The drug SL 11 solution with solvent is prepared SL 11 4 Evaporate the solvent at 50 for about 1 hour to remove the solvent or remove the solvent under a nitrogen stream SOC 1 The concentrated solution o
63. adjustment Note Not for use in humans OAKS AMT clc KO BBD 0 8 1 1 0 DPPG 2 3 c 16C 40C d 6 3 Determination of liposome encapsulation efficiency Method for removal of the unencapsulated drugs a Dialysis Place the prepared drug liposome solution in a dialyzing tube and dialyze it against an isotonic solution the unencapsulated drug leaks into the isotonic solution outside the tube b Gel filtration Pass the prepared liposome solution through a column filled with a packing material for gel filtration The liposomes and the unencapsulated drug are eluted from the column in that order Select the packing materials according to the molecular weight of the drug to be removed e g Sephadex G 50 for low molecular weight Sepharose 4B for high molecular
64. al J Control Release 144 341 349 2007 B V 6 Empty Liposomes lt COATSOME EL Series gt In general preparation of liposomal drugs requires tedious adjustments of the liposomal composition and also control of the particle size and encapsulation efficiency which make researchers usually reluctant to formulate liposomal drugs NOF has successfully overcome these problems by developing unique experimental kits for the investigation of liposomal drug delivery systems DDS Freeze dried ready to use liposome powder called Empty Liposomes filled in vials is composed of several kinds of phospholipids and electrolytes When a drug solution is injected into a vial and gently shaken the drug is easily encapsulated in the liposomes Empty Liposomes have a special advantage in that even drugs such as the anthracyclines and aminoglycosides can be efficiently encapsulated without the need for special technologies such as extrusion How to use Coatsome 1 1 COATSOME EL removed from cool storage and allowed to come to room temperature 2 Add aqueous solution of a drug in the temperature range of 16 C to 40 C 3 Shake the vial gently three to five times by hand 4 The liposomal drug is now ready for use 6 1 EL Series Product Characteristics Product compositions and characteristics are shown below Cationic charged liposomes are prepared by incorporating stearylamine as a charged lipid into the formulation Nonio
65. alpha 3 beta cholest 5 en 3 yl omega hydroxy 1 000 14 SUNBRIGHT CS 020 Poly oxy 1 2 ethanediyl alpha 3 beta cholest 5 en 3 yl omega hydroxy 2 000 27 SUNBRIGHT CS 050 Poly oxy 1 2 ethanediyl alpha 3 beta cholest 5 en 3 yl omega hydroxy 5 000 105 SUNBRIGHT Serum clearance efficiency of new PEG Lipid derivatives in Liposomes serum clearance References K Maruyama et al Bio Pharm Bull 19 10 1347 1996 without PEG derivative with PEG derivative RES Blood with PEG derivative with PEG derivative CS 050 0 25 50 75 100 Liposome composition DSPC Chol 1 1 mol mol containing 6mol PEG derivatives After 6 hours of circulation 4 Functionalized Phospholipids Use of functionalized phospholipids enables researchers to do protein lipidation attaching various peptides or other biologics to the surfaces of lipid emulsions or liposomes that allows some desired target features to be obtained and increase of the plasma half life of the modified drugs with the introduction of PEG chains into the target drugs NOF can supply various kinds of high purity derivatives because we have the advantage of manufacturing our own pure highly reactive PEG PEG grafted lipid 4 1 Activated phospholipids Activated phospholipids include both maleimide groups reactive with SH groups in biologics and activated carboxylic esters which react with NH2 and
66. borate phosphate buffer pH 8 0 8 3 rt overnight 2 References 1 AbuchowskiA et al Cancer Biochem Biophys 7 175 1984 2 Sartore L et al Appl Biochem Biotechnol 27 45 1991 3 U S Patent 5 824 784 Capabilities CGMP Manufacturing Facilities NOF Activated PEGs SUNBRIGHT series are produced in facilities using state of the art technology operated under CGMP The cGMP facilities are capable of producing small to large batch sizes using proprietary know how with scale up procedures depending on customers needs These cGMP facilities have been audited by pharmaceutical companies throughout the world NOF receives a consistent high reputation from our customers Research amp Development Our new R amp D facility was opened in December 2005 This allows us to continue our development of novel activated PEGs and new technologies for PEGylation Analytical Technologies NOF has more than 20 years history for manufacturing of high quality mPEGs and Activated PEGs These experiences endow NOF with a thorough knowledge of PEGs and considerable achievement in analysis of Activated PEGs We also invented innovative analytical methods for assaying purity of activated PEGs and for determining impurity levels CGMP PEG SUNBRIGHT
67. enzymes and other pharmaceutical substance Recently these PEGs are applied for hydrogel components for base matrix of iPS cells or EPS cells in tissue engineering X OCH2CH2 n O 2 PEG Id SHB SORBAICUTKEAANT IPS 8 Succinimidylsuccinate SUNBRIGHT DE 034CS 3 400 CO CH2CH2 COO NHS SUNBRIGHT DE 034GS 3 400 Succinimidylglutarate SUNBRIGHT DE 100GS 10 000 CO CH2CH2CH2COO NHS SUNBRIGHT DE 200GS 20 000 Succinimidylcarboxymethyl SUNBRIGHT DE 030AS 3 000 CH2 COO NHS SUNBRIGHT DE 034HS mM 3 400 Succinimidylcarboxypentyl SUNBRIGHT DE 100HS 10 000 CH2CH2CH2CH2CH2 COO NHS SUNBRIGHT DE 200HS 20 000 SUNBRIGHT DE 010PA SUNBRIGHT DE 020PA SUNBRIGHT DE 034PA SUNBRIGHT DE 100PA SUNBRIGHT DE 200PA SUNBRIGHT DE 300PA SUNBRIGHT DE 034SH SUNBRIGHT DE 100SHY SUNBRIGHT DE 200SH SUNBRIGHT DE 100MA SUNBRIGHT DE 200MA 1 000 2 000 Propylamine 3 400 CH2CH2CH2NH2 10 000 20 000 30 000 3 400 Ethanethiol 10 000 CH2CH2SH 20 000 Maleimide 10 000 CH2 3 NHCO CH2CH2 Maleimide 20 000 make to order 3 Multi Arm PEGs We supply various derivatives in which functional
68. for drug or diagnostic purpose nor are intended for human use They shall not be used as food cosmetics or utensils etc Specifications Reference Dried powder consists of PC and other suitable lipids containing transferrin attached phospholipid e 3 e e e e RES DDS e e Content Phosholipid cholesterol and transferrin 1 O Ishida et al Pharm Res 18 7 1042 1048 2001 Human Holo transferrin Volume Lipid 20mg Transferrin 1mg per vial Container 10ml glass vial Storage Keep refrigerated 2 H Inuma et al Int J Cancer 99 130 137
69. groups are attached 4 8 PEG to the terminals of multi arm 4 arm and 8 arm PEGs Multi arm PEGs can be used not only as the starting materials for hydrogels but PEG also as modifiers to improve the solubility of hydrophobic drugs 3 1 4 arm Functional PEG Series PTE Series Pentaerythritol tetra polyethylene glycol ether m 9 O O X X O Succinimidylsuccinate SUNBRIGHT PTE 100CS 10 000 CO CH2CH2 COO NHS SUNBRIGHT PTE 050GS 5 000 SUNBRIGHT PTE 100GS 10 000 Succinimidylglutarate SUNBRIGHT PTE 150GS 15 000 CO CH2CH2CH2 COO NHS SUNBRIGHT PTE 200GS 20 000 SUNBRIGHT PTE 400GS 40 000 SUNBRIGHT PTE 100HS _ 10 000 Succinimidylcarboxypentyl SUNBRIGHT PTE 200HS 20 000 CH2CH2CH2CH2CH2 COO NHS SUNBRIGHT PTE 400HS 40 000 SUNBRIGHT PTE 100NP 10 000 p Nitrophenylcarbonate SUNBRIGHT PTE 200NP 20 000 COO phenyl NO2 SUNBRIGHT PTE 400NP 40 000 SUNBRIGHT PTE 100PA 10 000 SUNBRIGHT PTE 150PA Propylamine 15 009 SUNBRIGHT PTE 200PA CH2CH2CH2NH2 20 000 SUNBRIGHT PTE 400PA 40 000 SUNBRIGHT P
70. hydrochloride 1mg ml 129 Improvement of the encapsulation efficiency requires maintenance of the cationic drug concentration below 5mM If higher encapsulation efficiency is desired the molar ratio of DPPG 15mM against the drug should be kept at not less than 3 97 100 98 100 95 100 80 85 97 100 97 100 SMM DPPG 15mM 3 C Q T E O 2 E 2 0 S C n E 0 43 Phospholipids and Lipids for Liposomal Formulations lt Series gt Comparison of pharmacokinetics in Mannitol EL Series 237 448 0 174 Mannitol Bangham Method 2204 398 0 179 Inulin EL Series 2137 408 0 175 Inulin Bangham Method 2515 373 O174 K Yachi et al Biopharm amp Drug Dispos 17 589 605 1996 Composition DPPC DPPG Chol 27 53 20 Anionic Liposomes Cationic Liposomes for gene delivery COATSOME EL 01 D Transfection Activities in vitro by Luciferase Assay Light units mg protein sec Serum 6 048 6 291 1 325 Serum Wises 2913 689 Transfection Activities vivo in intraperitoneal disseminated
71. may be changed depending upon the drug stability 4 S 6 4 1mg mL 4mg mL PUREBRIGHT SL 1 500 L TAI STU 50CC 1 50C 2 50C 2mL PUREBRIGHT SL 411 1 8mL TAB ZT 1mg mL MPS Medroxyprogesterone acetate CLF Clofibrate PTX Paclitaxel Drug Solubilization with PUREBRIGHT 8 Drug Pep IND MPS CLF NFD PRB CLM PTX E Concentration mg mL 6 0 2 5 075 155 2 5 5 0 015 170 E PUREBRIGHT SL 110 S S PUREBRIGHT
72. reactions sidereaction an obstacle to PEGylation can be completely prevented SUNBRIGHT PEG 2 PEG PE 6 eSUNBRIGHT CS GS AS HS and TS Series NHS active esters carbonate We supply five types of monomethoxy NHS activated ester carbonate PEGs that differ in terms of the NHS carboxylate attachment chemistry The reactivity order of these linkers in aqueous solution from lowest to highest is HS lt TS lt GS lt CS lt AS After PEGylation CS and GS types possessing ester groups are relatively susceptible to hydrolysis whereas AS TS and HS types are resistant to hydrolysis because of their different chemical structures Therefore our customers can select the appropriate type according to the purposes among the five types available CS Type D 5 II CH30 C H5CH5O 4 C CH5CH 5 CO N 5 NHS PEG HS lt TS lt GS lt CS lt AS
73. tariffs taxies and other importing fee Except in a few case we have a stock of the products in this catalogue without made to order product indicated with asterisk In case we don t have any stock of the product the lead time of its shipment will be 6 to 8 weeks after buyer s purchase order Warranty Unless otherwise any consent between NOF and buyer all of the products in this catalogue are offered for research purpose only and they are not intended for human use The buyer assumes all risk and liability for the use and or results obtained by the use of products described in this catalogue Custom Orders Order of derivatives of other molecular weight and or chemical structure like PEG PLA and so on require custom synthesis Custom orders are not returnable or refundable Please contact our sale office above shown for a quote on your request product Pricing Offer Pricing is available for orders of 1 gram or more for non GMP GMP pricing is available for orders of 1000 grams or more Please call our sale office above shown for each quote GMP manufacturing Many of the products listed in this catalogue are currently available as non GMP materials However some products are already manufactured to cGMP at dedicated cGMP plant Please ask our sale office for the detail information Terms and Conditions of Sales Definitions Seller means NOF CORPORATION Buyer means the purchaser of Products hereunder and Products m
74. trademark in other countries e CIMZIA is a registered trademark of USB Group of Companies in the U S and a registered trademark or trademark in other countries e PEGASYS is a registered trademark of Hoffman La Roche Ltd in the U S and a registered trademark or trademark in other countries MACUGEN is a registered trademark of Eyetech Inc in the U S and a registered trademark or trademark in other countries e ALL other registered trademarks and trademarks are the property of their respective owners 55 CORPORATION DDS Development Div Head Office Yebisu Garden Place Tower 20 3 Ebisu 4 chome Shibuya ku Tokyo 150 6019 Tel 81 3 5424 6741 Fax 81 3 5424 6769 Web http www dds drug com E mail ddsinfo nof co jp NOF AMERICA CORPORATION Tel 1 866 663 0001 toll free Web http www nofamerica com E mail info nofamerica com New York Office One North Broadway Suite 1012 White Plains NY 10601 USA Tel 1 914 681 9790 Fax 1 914 681 9791 California Office 2102 Business Center Drive Suite 215E Irvine CA 92612 USA Tel 1 949 253 5764 Fax 1 949 253 5765 NOF EUROPE BELGIUM N V Bouwelven 1 Industriezone Klein Gent B 2280 Grobbendonk Belgium Tel 32 14 25 98 28 Fax 32 14 22 45 63 Web http www nofeurope com E mail info nofeurope com DDS 150 6019 4 20 3 03 5424 6741 Fax
75. yolk phospholipids are also employed as carriers for lipophilic drugs as one of the major ingredients of lipid microspheres jl Ri CO CH Ro CO CH CH OPO O EPC COATSOME 50 HEPC COATSOME NC 11 Hydrogenated Soybean phosphatidylcholine Non hydrogenated Egg phosphatidylcholine Hydrogenated Soybean phosphatidylcholine 98 up Ca 85 90 up 785 RiCOO C12 C22 saturated fatty acids 2 C12 C20 unsaturated fatty acids 95 up Ca 773 Hydrogenated Egg phosphatidylcholine 95 UD Ca 777 Q 45 2 E LI O 2 ES I O 9 2 C 9 2 29 ena and Lipids for Liposomal Formulations lt COATSOMIE Series C Q T E E O LL
76. 0 Conventional Grade A 40 20 Degree of Degranulation 96 0 00 0 10 0 50 1 00 Concentration of Polysorbate 80 96 Effect of Polysorbate 80 on degranulation of RBL 2H3 mast cells Cells were treated with different concentrations of Polysorbate 80 for 60 mins The degree of degranulation was determined by measurement of the released B hexosaminidase into the supernatant Influence on Basophillic leukocyte Non Treated Control Cell Toxicity Test NOF Polysorbate 80 8 Conventional Grade Suvival Rate 96 0 2 0 4 0 6 0 8 1 0 Concentration wt v 96 Effect of Polysorbate 80 concentration on the cytotoxicity using SIRC Cells Cells were treated with each Polysorbate 80 for 24 hrs The number of viable cells was determined by the Neutral Red Uptake method Conventional Polysorbate 80 Damaged NOF Polysorbate 80 Not Damaged Basophilic leukocytes were immersed in 196 Polysorbate 80 solution for 30 min The cells were immobilized in glutaraldehyde and observed by SEM Hemolysis Test Conventional Grade 100 Conventional Grade A NOF Polysorbate 80 lt 80 9 60 cc E zu 5 5 20 k 1 5 10 0 5 Concentration of Polysorbate 80 mg mL Effect of Polysorbate 80 concentration on the Hemolytic Ratio Red blood Survival Rate FI Conventional Grade Conventional Grade A NOF Polysorbate 80 Effect of Polysorbate 80 conce
77. 03 5424 6 769 http www dds drug com E mail ddsinfo nof co jp Prepared Oct 2011 1 2000
78. 1 H Takeuchi et al Digestion 82 187 191 2010 2 T Kamei et al Cancer Sci 102 1 200 205 2010 3 D Soma et al Cancer Sci 100 10 1979 1985 2009 2 DNA Delivery M Ukawa et al Biomaterials 31 24 6355 6362 2010 0 gt 0 a 0 0 4 0 0 2 2 0 x gt Reference 1 T Konno et al J Biomed Mater Res 65A 2 209 214 2003 2 T Konno et al Proceed Int l Symp Control Rel Bioact Mater 29 464 2002 Self emulsifying Solubilizer SL 171 Solubilizer SL 11 occurring as a transparent liquid can be used to prepare nano emulsions of various hydrophobic drugs particle sizes are below 50 nm Since this possesses excellent self emulsifying properties this is the most appropriate agent for SEDDS Self Emulsifying Drug Delivery Systems Following oral administration this solubilizer SL 11 augments intestinal absorption of drugs Once the hydrophobic drug is dissolved in SL 11 as directed in the attached protocol SEDDS reagents containing the drug can be easily prepared NOF has also capability for custom development by using this technology Product Name Solubilizer SL 11 50nm
79. 2 Dioleoyl sn glycero 3 phosphoglycerol sodium salt 9896 up 797 0 C18 1 Clea DEPG Na MG 2121LS 1 2 Dierucoyl sn glycero 3 phosphoglycerol sodium salt 98 up 909 2 22 1 0221 5 POPG Na COATSOME MG 6081LS _ 1 Palmitoyl 2 oleoyl sn glycero 3 phosphoglycerol sodium salt 98 up 771 0 16 0 CE 2 4 Phosphatidic acid 008 O II Oo Ro COATSOME MA 2020LS C12 0 120 1 2 Dilauroyl sn glycero 3 phosphatidic acid sodium salt 98 up 558 7 DLPA Na DMPA Na COATSOME MA 4040LS 1 2 Dimyristoyl sn glycero 3 phosphatidic acid sodium salt 98 up 6148 C14 0 C14 0 DPPA Na COATSOME MA 6060LS 1 2 Dipalmitoyl sn glycero 3 phosphatidic acid sodium 99 up 670 9 C16 0 C16 0 DSPA Na COATSOME MA 8080LS 1 2 Distearoyl sn glycero 3 phosphatidic acid sodium salt 99 up 7270 C18 0 18 0 2 5 Phosphatidylethanolamine T 4 II Ro CO CH O II CH23CH5NHs make to order O _ Productname Description MW R2COO HSPE COATSOME NE 21 Hydrogenated Soybean phosphatidylethanolamine 95 up EPE COATSOME NE 50 Non hydrogenated Egg phosphatidylethanolamine 95 up DLPE COATSOME ME 2020 1 2 Dilauroyl sn glycero 3 phosphoethanolamine 99 up 579 8 C12 0 C12 0 DMPE COATSOME ME 4040 1 2 Dimyristoyl sn glycero 3 phosphoethanolamine 99 up 635 9 01480 DPPE COATSOME ME 6060 1 2 Dipalmitoyl sn glyc
80. 3HB DKH 04HB Completeness and color solution PasS Viscosity 3 9 4 8 5 4 6 4 6 8 8 0 Average molecular weight 190 210 285 315 380 420 pH 4 5 7 5 Residue on ignition 90 USP NMT 0 1 Heavy metals ppm NMT 5 NMT 10 Free ethylene oxide and 1 4 dioxane ppm Ethylene oxide NMT 1 1 4 Dioxane NMT 10 Limit of ethylene glycol and diethylene glycol NMT 0 05 Organic volatile impurities Pass Peroxide value meq Kg NOE NMT 3 Formaldehyde ppm NMT 5 NOF can also supply products without anti oxidant agent BHT SUNBRIGHT OE Series NOF supplies a unique Biocompatible Anchor for cell Membranes BAM without eliciting ovservable cell damage BAM contains both oleyl groups as a hydrophobic cell membrane anchor and polyethylene glycol PEG which imparts hydrophilicity chemical structure is designed to have various reactive groups at the PEG terminals allowing them to attach to physiologically active substances or surfaces of materials Employment of BAM enables researchers to modify the surfaces of cells and tissues with physiologically active substances such as proteins or drugs without injuring cells and tissues and also to immobilize live cells and tissues on the surfaces of various kinds of materials Since BAM exerts excellent cell interfacing functions beyond conventional concepts it can be extensively used in pharmaceuticals and cosmetics BAM Biocompatib
81. 4 branched derivatives Although aqueous solutions of higher molecular PEG derivatives tend to show increased viscosity use of higher branched Activated PEGs such as 3 branched and 4 branched derivatives reduces the viscosity of the relevant aqueous solutions even without altering the molecular weights 4 1 2 arm Branched PEG SUNBRIGHT GL2 series GS2 Type NHS ester PEG CH30 CH CH O CH PEG PEG 3 4 PEG 3 4 PEG HO O CH2CH20 n 60kDa 30k X 2 80kDa 40k X 2 O CH CH O X Reactive group Total Mw 40
82. 51 220 S S N PUREBRIGHT SL 310 S S S S S 5 5 PUREBRIGHT SL 350 5 5 PUREBRIGHT SL 411 5 N N N N 5 N N E Polyoxyl 35 Castor oil A PUREBRIGHT amp Polyoxyl 35 Castor 3 w w 5 Soluble Almost soluble 1 Insoluble N data Pep Peptide type Drug NFD Nifedipine Z IND Indomethacin PRB Probucol CLM Chlormadinone acetate NOFABLE Series has established the manufacturing processes for 99 99 oleic acid Durity in commercial production scale Removal of unsaturated fatty acids susceptible to oxidation is eventually associated with improvement of product stability against oxidation with the result that derivatives with less impurities peroxides and aldehydes can be obtained Ultra pure oleic acid derivatives are the most suitable for efficacious drug formulations 1 Ultra Purity Oleic Acid lt EXTRA OLEIN 99 gt CH3 CH2 7 CH CH CH2 7 COOH Product name Description Oleic acid Content CAS NO Regulatory Status EXTRA OLEIN 99 Oleic Acid gt 99 112 80 1 JPE NF EXTRA OLEIN 99
83. 71 9 DPPE Glu COATSOME FE 6060GL N Glutary L o phosphatidylethanolamine Dipalmitoyl 9267 DSPE Glu FE 8080GL N Glutary L o phosphatidylethanolamine Distearoyl 18 0 180 884 2 POPE Glu COATSOME FE 6081GL N Glutary L o phosphatidylethanolamine 1 Palmitoyl 2 oleoyl C16 0 181 854 1 DOPE Glu COATSOME FE 8181GL N Glutaryl L o phosphatidylethanolamine Dioleoyl C18 1 C18 880 1 PDP Phospholipid New 1 R4 CO CH5 R gt CO CH N Dithiopyridiny PDP derivative for SH group reaction DPPE PDP COATSOME FE 6060DT _ N I 2 Pyridinyldithio 1 oxopropyl L g phosphatidylethanolamine Dipalmitoyl 16 0 16 0 911 2 New Phospholipids and Lipids for Liposome Formulations 4 2 Activated PEG phospholipids Phospholipid PEG NH Amine derivative for amidation reactions O O II 11 SHOP gt gt nO CH 5 39NH 2 ONa DSPE PEG NH2 SUNBRIGHT DSPE 020PA N aminopropyl polyethyleneglycol carbamyl distearoylphosphatidyl ethanolamine 2 000 DSPE PEG NH2 SUNBRIGHT DSPE 034PA gt N aminopropyl polyethyleneglycol carbamyl distearoylphosphatidyl ethanolamine 3 400 DSPE PEG NH2 SUNBRIGHT DSPE 050PA polyethyleneglycol carbamyl distearoylphosphatidyl ethanolamine 5 000 SUNBRIGHT make to order Phospholipid PEG MAL MM Maleimide MAL
84. BRIGHT ME 050SH SUNBRIGHT ME 100SH SUNBRIGHT ME 200SH SUNBRIGHT ME 300SH SUNBRIGHT ME 400SH eSUNBRIGHT MA Series Maleimide PEG C2 Type 2 000 5 000 10 000 20 000 30 000 40 000 O O CH O CH CH O CH aNHC CH N O SUNBRIGHT ME 020MA SUNBRIGHT ME 050MA SUNBRIGHT ME 100MA SUNBRIGHT ME 200MAOB SUNBRIGHT ME 300MA SUNBRIGHT ME 400MA X Patent No 056875841 C5Type New 2 000 5 000 10 000 20 000 30 000 40 000 O O CHsO CHsCHsOa CH sNHC CHs N O SUNBRIGHT ME 050MAS3 SUNBRIGHT ME 100MA3 SUNBRIGHT 200 SUNBRIGHT ME 400MA3 5 000 10 000 20 000 40 000 make to order New New New New New New New eSUNBRIGHT IA series lodoacetamide CH3O CH5CH5O CH5CH5CH N C CHol SUNBRIGHT 200 20 000 SUNBRIGHT 30 000 SUNBRIGHT 400 40 000 sSUNBRIGHT CA series Aminoxy PEG O CH O C H5CH5O CNHCHsCHsONH gt SUNBRIGHT ME 100CA 10 000 SUNBRIGHT ME 200CA 20 000 SUNBRIGHT ME 300CA 30 000 SUNBRIGHT ME 400CA 40 000 eSUNBRIGHT HZ series Hydrazide PEG 7 CH30 CH2CH50 47 C H5 s C CN NH SUNBRIGHT ME 200HZ 20 000 SUNBRIGHT ME 300HZ 30 000 SUNBRIGHT ME 400HZ 40 000 make to order Activated PEG for PEGylation Activated PEG for PEGylation 2 Bi Functional PEGs Bi functional PEGs are the most popular derivatives for crosslinking proteins
85. HT GL4 series X O O CHsCH20 O CH2CH20 CH3 Total Mw 40kDa 5k X2 7 5kx 4 60kDa 5kX2 12 5kx 4 80kDa 5k X2 17 5kx 4 O CH2CH20 SUNBRIGHT GL4 400GS2 40 000 Succinimidylglutarate aminopropyloxy SUNBRIGHT GL4 600GS2 60 000 CH2CH2CH2 NHCO CH2 3 COO NHS SUNBRIGHT GL4 800GS2 80 000 SUNBRIGHT GL4 400TS 22 40 000 Succinimidylcarboxy SUNBRIGHT GL4 600TS 60 000 COO NHS SUNBRIGHT GL4 800TS 80 000 SUNBRIGHT GL4 400NP 40 000 p Nitrophenylcarbonate SUNBRIGHT GL4 600NP 60 000 COO phenyl NO2 SUNBRIGHT GL4 800NP 80 000 SUNBRIGHT GL4 400AL3 40 000 Aldehyde SUNBRIGHT GL4 600AL3 60 000 CONH CH2CH2 CHO SUNBRIGHT GL4 800AL3 80 000 SUNBRIGHT GL4 400PA 40 000 Propylamine SUNBRIGHT GL4 600PA 60 000 CH2CH2CH2NH2 SUNBRIGHT GL4 800PA 80 000 SUNBRIGHT GL4 400MA 40 000 Maleimide SUNBRIGHT GL4 600MAY 60 000 CH2 3 NHCO CH2CH2 maleimide SUNBRIGHT GL4 800MA 80 000 SUNBRIGHT GL4 400CA 40 000 SUNBRIGHT GL4 600CA 60 000 CONH CH2CH2 ONH2 SUNBRIGHT GL4 800CA 80 000 make to order 2 SUNBRIGHT XY4 series New HC O CH CH O CH3 O CH CH O O CH CH20 CH3 n HzC OCH CH O CH SUNBRIGHT XY4 200GS2 Succinimidylglutarate aminopropyloxy 20 000 SUNBRIGHT XY4 400GS2 CH2CH2CH2 NHCO CH2 3 COO NHS 40 000 New SUNBRIGHT XY4 200TS Succinimidylcarboxy 20 000 New SUNBRIGHT XY4 400T
86. HaCH20 n C O 7 CH0 b g 20 000 I 5 CHs0 CHaCH20 n CH2 s C 0 CH20 C O N 20 000 O CH3 GHsO dsHsOn CHs s 0 dz0 o N 20 000 O make to order Orders for other molecular weights and linkers may require custom synthesis Please e mail at ddsinfo nof co jp for a quote on custom reagents Activated PEG for PEGylation New 6 PEG for PEGvlation lt SUNBRIGHT Series gt Characteristics of SUNBRIGHT BE Linker eEffects of PEG BE Linker on Lysozyme Regeneration 100 90 80 70 60 50 40 SC PEG conjugated 30 20 10 Mono BE PEG conjugated O 2 gt 0 O 9 0 0 2 0 lt Di BE PEG conjugated Activity PEG Succinimidyl Carbonate 0 20 40 60 80 Time h Regeneration of lysozyme from PEG BE lysozyme conjugates in rat plasma S Lee et al Bioconjugate Chem 12 2 163 169 2001 e Antitumor effects of PEG BE immunotoxin BE PEG SS1P 600 Control 500 Dose SS1P 2 400 0 6mg kg 5 BE PEG SS1P 1 0mg kg X2 dose S 200 5 8 BE PEG SS1P albis 2 0mg kg 0 Days Antitumor effects of PEG BE SS1P and SS1P on A431 K5 solid tumors Cells 3x106 were injected s c into nude mice on day On day 7 tumor volume 140 mm animals were treated with i v injections of the compounds at the indicated do
87. M 2100kD 125 0kD 101 0kD 56 2KD 35 8kD 29 0kD 21 1kD 6 9kD 4 insulin PEGylation PEGylation e PEG PEG PEG PEG PEG 2 000 5 80 000 PEG PEG Analysis of PEG ALD Insulin by SDS PAGE with Coomassie brilliant blue Insulin was reacted with NOF
88. NH2 CH2CH2 NH2 COOH COOH CH2CH2 SH SH Maleimide COOH CH2CH2CH2 NHCO CH2CH2 Maleimide MA2 CH2CH2 NHCO CH2CH2 Maleimide SH CH2CH2CH2 NHCO CH2CH2CH2CH2CH2 Maleimide CH2CH2CH2 NHCO CHal CONH CH2CH2 ONH2 CHO CH2 5 CONH NH2 Custom Manufacturing NOF has over 20 years of experience in supplying high quality methoxy polyethylene glycol mPEG to pharmaceutical markets The highest quality mPEG is our starting material of PEG derivatives patented through our proprietary technology Based on our extensive range of technological know how and capabilities NOF offers custom manufacturing from early stage development to commercial scale CHO PEG Reactive group X O CH2CH20 n X or O X 20 MPEG PEG Activated PEG for PEGylation co Activated PEG for PEGylation 4 IMonofunctional Linear PEGs The mono functional SUNBRIGHT series comprising highly purified methoxy PEG as the starting material contains negligible bifunctional PEG derived from diol impurities Accordingly bridging
89. S COO NHS 40 000 New SUNBRIGHT XY4 200NP p Nitrophenylcarbonate 20 000 New SUNBRIGHT XY4 400NP COO phenyl NO2 40 000 New SUNBRIGHT XY4 200AL3 Aldehyde 20 000 New SUNBRIGHT XY4 400AL3 CONH CH2CH2 CHO 40 000 New SUNBRIGHT 4 200 Maleimide 20 000 New SUNBRIGHT XY4 400MA CH2 3 NHCO CH2CH2 maleimide 40 000 New make to order Comparison Data of PEG Solution Viscosity MeO PEG 40kDa Linear GL2 40kDa GL4 40kDa XY4 40kDa as aqueous solution at 10 wt96 at 40 C 4 4 Lysine Branched PEG New SUNBRIGHT LY series Collaborating with Enzon Pharmaceuticals Inc NOF has a n right to manufacture and sell their unique Lysine Branched PEG NHCO CH 2CH20 NOF s Trade Name is SUNBRIGHT LY series for customer research purpose only Lysine Branched PEG has been already O i used in several marketed PEGylated drugs such as PEGASIS CH MACUGEN and CIMZIA for 10 years NHCO CHgCHsOjnCHs PEG PEG PEG c3 ENZON ENZON PEG Succinimidyl ester SUNBRIGHT LY 400NS 40 000 Aldehyde SUNBRIGHT LY 400AL3 40 000 New NH CH2CH2 CHO Maleimide SUNBRIGHT LY 400MA 40 000 New NH CH2 2 NHCO CH2 2 maleimide
90. SUNBRIGHT GL2 200MA 20 000 SUNBRIGHT GL2 400MA 40 000 SUNBRIGHT GL2 600MA 60 000 SUNBRIGHT GL2 800MA 80 000 C5 Type Maleimide PEG New CHsO CHzCH2O CHz CH30 C H CH O CH O 11 H2C OCH CH gt CHoNHC CH2 s N SUNBRIGHT GL2 400MA3 40 000 ew make to order CA Type Aminoxy PEG CH30 CH2CH20 CH2 CH40 CH CH O CH P H C OCNHCH CH ONH SUNBRIGHT GL2 100CA 10 000 SUNBRIGHT GL2 200CA 20 000 SUNBRIGHT GL2 400CA 40 000 SUNBRIGHT GL2 600CA 60 000 SUNBRIGHT GL2 800CA 80 000 make to order SUNBRIGHT GL3 series O CH CH O 4 2 3 arm Branched PEG Po 2 20 X O CH CH O CH Total Mw 50kDa Mw of 2 part about 10kDa Activated PEG for PEGylation Succinimidylglutarate SUNBRIGHT GL3 400GS100U 50 000 CO CH2CH2CH2 COO NHS Succinimidylcarboxypentyl SUNBRIGHT GL3 400HS100U 50 000 CH2CH2CH2CH2CH2 COO NHS Succinimidylcarboxy SUNBRIGHT GL3 400TS100U 50 000 COO NHS p Nitrophenylcarbonate SUNBRIGHT GL3 400NP 100U 50 000 COO phenyl NO2 Aldehyde SUNBRIGHT GL3 400AL 1 00U 50 000 CH2 CH2 CHO Propylamine SUNBRIGHT GL3 400PA100U 50 000 CH2CH2CH2NH2 Maleimide SUNBRIGHT GL3 400MA100U 50 000 CH2 3 NHCO CH2CH2 maleimide Aminoxy SUNBRIGHT GL3 400CA100U 50 000 CONH CH2CH2 ONH2 10 Activated PEG for PEGylation 4 3 4 arm Branched PEG O CH CH O CH 1 SUNBRIG
91. TE 050SH 5 000 Ethanethiol SUNBRIGHT PTE 100SH 10 000 CH2CH2SH SUNBRIGHT PTE 200SH 20 000 SUNBRIGHT PTE 100MA 10 000 Maleimide SUNBRIGHT 200 m 20 000 CH2 s NHCO CH2CHe Maleimide SUNBRIGHT PTE 400MA 40 000 make to order Activated PEG for PEGylation Iz Activated PEG for PEGylation 3 2 8 arm Functional PEG Series X OCH2CH2 n O CH2 HGEO Series Hexa glycerine octa polyethylene glycol ether HC O CH2CH2On X CH2 HC O CH2CH20 n X CH 9 CH2 HC O CH2CH20 n X H2C O CH2CH2O s X Succinimidylsuccinate SUNBRIGHT HGEO 150CS 15 000 CO CH2CH2 COO NHS SUNBRIGHT HGEO 150GS 15 000 Succinimidylolutarate SUNBRIGHT HGEO 200GS 20 000 CO CH2CH2CH2 COO NHS SUNBRIGHT HGEO 400GS 40 000 SUNBRIGHT HGEO 200NP p Nitrophenylcarbonate 20 000 SUNBRIGHT HGEO 400NP COO phenyl NO2 40 000 Propylamine SUNBRIGHT HGEO 150PA 15 000 CH2CH2CH2NH2 Ethanethiol SUNBRIGHT HGEO 200SH 20 000 CH2CH2SH make to order 4 Branched PEGs NOF provides 2 branched Activated PEGs as illustrated below Both the molecular weights of the respective PEG chains and the linker moieties leading to the functional groups are adjustable These are available with amino aldehyde maleimide carbonate and carboxylate activated esters as the terminal functional groups Furthermore NOF has also developed newer types of Branched Activated PEGs such as 3 branched and
92. TS 3 400 SUNBRIGHT MA 050TS 5 000 SUNBRIGHT MA 100TS 10 000 SUNBRIGHT MA 200TS 20 000 SUNBRIGHT MA 400TS 40 000 make to order eHydroxy PEG Aldehyde HO CH5CH20 CH2CH5CH SUNBRIGHT HO 050AL 5 000 SUNBRIGHT HO 100AL 10 000 SUNBRIGHT HO 200AL 20 000 SUNBRIGHT HO 300AL 30 000 eBiotin PEG Carbonate NHS O O O H 4CNHCH CH CH OCH CH O CO N O SUNBRIGHT BI O50TS 5 000 make to order Activated PEG for PEGylation Activated PEG for PEGylation 6 Forked PEGs New eSUNBRIGHTS PTE2 Series Forked structures have the advantage of placing two reactive groups at precise distances apart These Forked PEGs have become very popular for mimicking the heavy chain domain in an antibody or fragment antibody and other applications where two proteins held in proximity are advantageous CH O CH5CH5O C Hs SUNBRIGHT PTE2 200GS3 SUNBRIGHT PTE2 400GS3 CH O CH CH O Succinimidyl ester CH2CH2 NHCO CH2 3 COO NHS 1 PEG 2 2 PEG PEG
93. UREBRIGHT from UV area from HPLC Camptothecin CTP 0 03 mg mL MB Series AmB CTP TXL Paclitaxel TXL Less than 0 01 mg mL 10 wt 100 2 5 8 735 1 wt 84 9 2 8 618 0 1 wt 1 8 2 8 580 1 T Konno et al J Biomed Mater Res 65A 2 209 214 2003 2 T Konno et Proceed Int l Symp Control Rel Bioact 014 1414 5 Mater 29 464 2002 10 wt DMSO 3 M Wada et al Anticancer Res 27 1431 1436 2007 aqueous solution 1 0 1 0 1 0 Control 5 Toxicological Data Safety data of PUREBRIGHT MB 37 series shows similar activity in comparison with other solubilizers such as Acute O i OOT Cura Dol 09 poloxamer and polyoxyethylene castor oil LDs of more than Acute toxicity 507 Intravenous injection LDs Rats 25 000mg kg mice orally and more than 1 000mg kg rats gt 1 000 mg Kg iv have been obtained Antigenicity 50T Negative Mutagenecity 5OT Negative LDso 25 000 mg kg 1 000 mg kg Skin sensitization 1007 Non skin sensitization Guinea pig Skin toxicity 100T Non primary irritation Rabbit Eye irritation 1001 to 6 Unique Feature Water soluble film of drug 7 Pharmaceutical applications published and PUREBRIGHT MB 37 series 1 Oncology Drug Formulation
94. ation of vaccines for infections and cancer as well as for the treatment of allergies including pollen allergy First immunization Second immunization 10000 IgG Response _ x 1000 lt lt lt 100 lt lt 10 0 7 2 3 4 5 6 rf 8 9 week after first immunization Aluminium Adjuvant Liposome Adjuvant IgG IgE CTL First immunization Second immunization 14 IgE Response 12 10 O O 0 1 2 3 4 5 6 7 8 9 week after first immunization Anti OVA antibody production in mice with immunized Aluminum and Liposomal adjuvants 8 weeks old femate BALBC mi
95. ause of these differences in the physical properties customers can select between the two sources depending on their needs 22 Q 2 II CH20PO N l O b Tc
96. ce were immunized intraperitoneally After immunization blood sample were taken from the tail vein Anti OVA antibodies in the sera were determined C Q 2 E O 2 ES U 5 C U 2 fs 0 47 9 LIPONIZER for Liposome Production LIPONIZER is available only in Japan API AP CIP SIP LIPONIZER Lineup Phospholipids and Lipids for Liposome Formulations LIPONIZER LP 90 500 w
97. cerol methoxypolyethylene Glycol 5 000 ox o 3 4 Cholesterol PEG derivatives In addition to methoxypolyethyleneglycol NOF provides various kinds of high purity monoalkyl substituted polyethyleneglycols When hydrocarbon moieties comprising more than 8 carbons in the alkyl groups are used several unique surface active effects can be obtained These derivatives can be employed not only for surface modification of liposomes but also for PEGylation of proteins by the introduction of various functional groups to the PEG chain terminals Usefulness of these products as solubilizers is also demonstrated 2 SUNBRIGHT CS 010 SUNBRIGHT make to order 8 PEG Poly oxy 1 2 ethanediyl
98. cts and b shall notify Seller in writing of any claims for shortages defects or damage identified in such inspection Thereafter Buyer shall hold Products for Seller pursuant to written instructions concerning disposition If Buyer fails to notify Seller within such five 5 day period Products shall conclusively be deemed to conform to the terms and conditions of the sales and transactions covered herein hereinafter Sales with respect to any such shortages defects or damage and to have been irrevocably accepted by the Buyer in their short defective or damaged condition Force Majeure Seller shall not be liable for any delay or other failure to perform hereunder due to any cause beyond Seller s reasonable control including without limitation acts of Buyer governmental actions or regulation fire explosion accident theft vandalism riot acts of war strikes or other labor difficulties lighting flood tornado typhoon windstorm or other acts of God transportation delays or inability to obtain necessary labor fuel materials supplies or power at current prices Allocation of Products If Seller is unable for any reason to supply the total demands for Products specified in Buyer s order Seller may allocate its available supply among any or all buyers on such basis as Seller may deem fair and practical without liability for any failure of performance which may result therefrom Payment Terms of payment are net 30 days of date of i
99. e Drug Delivery possible High Solubility Performance for any Hydrophobic Drug 1 High Solubility Performance Lyophilized powder of paclitaxel with PUREBRIGHT MB 37 left can be easily dissolved in water e Paclitaxel 2mg e PUREBRIGHT MB 37 30mg e Distilled water 1mL Reference Konno J Watanabe K Ishihara J Biomed Mater Res 65A 209 214 2003 Product name Description MW PUREBRIGHT MB 37 50T MPC Polymer ca 30 000 PUREBRIGHT MB 37 100T MPC Polymer 100 000 Patent JP3571878 JP4233251 JP4402350 US6214957 G is 0 EX 70 5 0 Hu D c 2 D 2 90mm q Excipients for Pharmaceutical Development 2 Solubilization of Paclitaxel T 3 Typical solubilization method a 1ml of 50mg mL Paclitaxel solution solvent EtOH 9ml of 100mg mL PUREBRIGHT MB Series aqueous no solution PUREBRIGHT Series Paclitaxel mixture Turbid Heating 70 C Increase in the mobility of PUREBRIGHT MB Series aggregate 1 0 Concentration of Paclitaxel mo mL 9 0 9 0 09 0 009 0 0009 0 Concentration of PUREBRIGHT MB Series wt Clear solution at 25 Paclitaxel 5 0mg mL 4 Relative solubilization activity of PUREBRIGHT MB series vs DMSO solution control Abbreviation Water solubility Concentration of ratio of abs ratio of peak AmphotericinB AmB 0 0005 mg mL P
100. e patent holder of these high purity mPEG OH and all their derivatives PEG PEG PEG PEG GCSF PEG Patent No JP3050228 U S Patent 6455639 KR 0358276 Our methoxy PEG OH have the advantage of extremely low diol contents relative to those of competitors products As shown in the following graphs our methoxy PEG 5000 contains remarkably low levels of diol as impurities besides providing a narrower distribution of molecular weights in comparison with our competitors products Employment of our methoxy PEG OH as the starting materials yields higher purity and higher activity of Activated PEGs We manufacture highly pure methoxy PEGs with molecular weights from 2kDa to 80kDa 100 60 40 20 PEG PEG 5000 PEG s
101. eans the items or goods sold by Seller to Buyer hereunder Acceptance All sales are subject and limited to and conditioned upon these Term and Conditions No variations bind Seller unless contained in a writing signed by an offer of Seller Changes Orders may be changed or amended only pursuant to a writing signed by both Buyer and Seller setting forth the changes to be made Buyer may not cancel an order unless Seller agrees to such cancellation in writing In such event Buyer shall pay all storage and shipment costs costs of producing non standard material costs of purchasing non returnable materials cancellation costs imposed on Seller by its suppliers and any other costs resulting from such cancellation all as specified to Buyer by Seller Delivery All sales are Delivered Duty Unpaid DDU International Rules for the Interpretation of the Trade Terms 2000 at the port of destination Seller shall deliver the Products to Buyer at Seller s cost and Seller bears all risk of loss or damage in transit thereafter Seller reserves the right to make delivery in installments all such installments shall be separately invoiced and paid for when due per invoice without regard to subsequent deliveries Delay in Delivery of any installment shall not relieve Buyer of its obligation to accept remaining deliveries Inspection Within five 5 days after receipt a Buyer shall inspect whether Products contains for chipped glass broken seals and other patent defe
102. ection was performed in the presence of 10 FBS Data shown represent mean SD n 3 4 ND Not done 5 Reference A Kikuchi et al HUMAN GENE THERAPY 10 947 955 1999 7 Transferrin Pre liposome Numerous transporters and select markers are expressed on the surfaces of cells accordingly with the use of liposomes chemically bound to for example transferrin targeting of cancer cells over expressing transferin receptors might become feasible By using the lipid mixtures available from NOF it would be possible to prepare liposomes possessing custom cell targeting ability at your own laboratories TF 01 PL is a specific lipid mixture containing phospholipids conjugated with phosphatidylcholine and transferrin If the directions in the instructions provided with your purchase are adopted drug containing liposomes with cancer cell targeting ability can be prepared Drug Delivery System Transferrin Dru Liposome Endocytosis Cellular uptake TF 01 PL Transferrin Pre liposome
103. ero 3 phosphoethanolamine 99 up 692 0 C16 0 C16 0 DSPE COATSOME ME 8080 1 2 Distearoyl sn glycero 3 phosphoethanolamine 99 up 748 1 27508 DOPE COATSOME ME 8181 1 2 Dioleoyl sn glycero 3 phosphoethanolamine 99 up 744 0 C18 1 C18 1 DLoPE COATSOME ME 8282 1 2 Dilinoleoyl sn glycero 3 phosphoethanolamine 9996 up 740 0 C18 2 2182 DEPE COATSOME ME 2121AL 1 2 Dierucoyl sn glycero 3 phosphoethanolamine 99 up 856 3 C22 1 C22 1 POPE COATSOME ME 6081 1 Palmitoyl 2 oleoyl sn glycero 3 phosphoethanolamine 99 up 718 0 C160 2 6 Phosphatidylserine DMPS Na DPPS Na DSPS Na DOPS Na POPS Na MS 4040LS COATSOME MS 6060LS COATSOME MS 8080L S COATSOME MS 8181LS COATSOME MS 6081LS Ri CO CH gt O II CO CH 1 2 Dimyristoyl sn glycero 3 phospho L serine sodium salt 1 2 Dipalmitoyl sn glycero 3 phospho L serine sodium salt 1 2 Distearoyl sn glycero 3 phospho L serine sodium salt 1 2 Dioleoyl sn glycero 3 phospho L sodium salt 1 Palmitoyl 2 oleoyl sn 3 phospho L serine sodium salt 85 up 8596 up 85 up 9796 up 85 up C14 0 C16 0 C18 0 C18 1 C16 0 C14 0 C16 0 C18 0 18 1 Phospholipids and Lipids for Liposome Formulations domm C 19 HD 0 E cS O LL 0 5 O g z Q o 0 fe st A 3 PEGylated Lipids PEGylated lipids can be applied to liposomal drug formulation
104. f SL 11 and the drug is prepared SL 11 6 Soft capsules can be prepared by using the concentrated solution in Method II 2 Depending on the drug it can be dissolved directly in SL 11 If required warm the solution to about 50 C to dissolve completely SL 11 d 50 The concentrated solution of SL 11 and the drug is made SL 11 6 Soft capsules can be prepared by using the concentrated solution in 4 or is gt n 0 5 3 ju 0 0 Be A 4 C 2 O x LLI gt O Z 1 Excipients for Pharmaceutical Development Cutting Edge Technology for Self emulsifying Agents Particle size lt 50nm lt 50nm Easy preparation Applicable to various kinds of hydrophobic drugs Applicable to soft capsules for oral use
105. glycero 3 phosphocholine 98 up 826 2 C205 G20 DHA PC COATSOME MC 2626AL 1 2 Didocosahexaenoyl sn glycero 3 phosphocholine 98 up 2 1 C2260 MONEO MPPC COATSOME MC 4060 1 Myristoyl 2 palmitoyl sn glycero 3 phosphocholine 99 706 0 C14 C16 0 35 COATSOME MC 4080 1 Myristoyl 2 stearoyl sn glycero 3 phosphocholine 99 7340 C140 C18 0 40 PMPC COATSOME MC 6040 1 Palmitoyl 2 myristoyl sn glycero 3 phosphocholine 99 up 7060 C16 0 C14 0 28 PSPC COATSOME MC 6080 1 Palmitoyl 2 stearoyl sn glycero 3 phosphocholine UE CS SMPC MC 8040 1 Stearoyl 2 myristoyl sn glycero 3 phosphocholine 99 up 734 0 180 140 30 SPPC COATSOME MC 8060 1 Stearoyl 2 palmitoy sn glycero 3 phosphocholine CCO COAISOME MC 4081 1 Myristoyl 2 oleoyl sn glycero 3 phosphocholine 99 7320 C14 0 18 1 6081 1 Palmitoyl 2 oleoyl sn glycero 3 phosphocholine 327000 B SOPC COATSOME MC 8081 1 Stearoyl 2 oleoyl sn glycero 3 phosphocholine 99 7881 180 C18 6 2 2 Lyso Phosphatidylcholine R4 CO CH HO CH T S 2 N i N COATSOME MC 40H 1 Myristoyl 2 lyso sn glycero 3 phosphocholine C14 0 9996 up M LysoPC 467 6 P LysoPC COATSOME MC 60H 1 Palmitoyl 2 lyso sn glycero 3 phosphocholine 9996 up 495 6 C16 0 S LysoPC COATSOME MC 80H 1 Stearoyl 2 lyso sn glycero 3 phosphocholine 9996 up 523 7 C18 0 O LysoPC COATSOME MC 81H 1 Oleoyl
106. gs NOF has already submitted more than 32 DMFs regarding various kinds of NOF phospholipids manufactured to the US FDA so that customers can rely on our quality We submit DMFs according to customers requests and development needs Custom Synthesis Custom synthetic phospholipids and lipids can be produced at customer s request Price List for Reagents Price list for phospholipids is downloaded from the NOF CORPORATION website http www phospholipid jp The reagents grades are high quality products as well as GMP products E D LL O O 5 2 0 5 o O ic 0 i P P 7 1 ee j F a Mart Mi se ge 4 E n 4 4 Polyoxyethylene Sorbitan Oleate Polysorbate 80 HX2 produced by NOF CORPORATION is a high purity product of the highest quality in the world with extremely low aldehyde and peroxide levels These characteristics contribute to its safety in a rat study Polysorbate 80 HX2 as compared to conventional Polysorbate 80 formulations triggered less histamine release from rat mast cells The latest in vivo dog study has also indicated less histamine release with our Polysorbate 80 HX2 as a natural consequence because of the lower incidence of allergy noted our Polysorbate 80 HX2 has drawn worldwide attention
107. ith 0 5 liter tank 90mm 0 5 liter LIPONIZER LP 90 90mm 3 5 liter LIPONIZER LP 90 5 liter tank system 90mm 5 liter LIPONIZER LP 142 142mm 5 10 liter LIPONIZER LP 142 10 liter tank system 142mm 10 liter LIPONIZER LP 293 293mm 25 50 liter LIPONIZER LP 293 25 liter tank system 293mm 25 liter Material SUS316L Design pressure Feed tank Lineup for LIPONIZER LP 90 500 Cut model LP 142 Example of LP 90 500 use N2 Gas Pressure Reduction Valve N Gas Safety Valve Flexible Hose etc m ui Li B L ae Gas Valve Wa N2 Gas Cylinder Liponizer LP 90 500 Example of LP 142 use N2 Gas Valve Gas Safety Valve Gas Pressure Reduction Valve L1 m Fiexible Hose etc _Diaphragm Valve Flexible Hose etc Diaphragm Valve g Gas Cylinder Feed raed OL LiporizeriLP 142 49 ena and Lipids for Liposomal Formulations lt COATSOMIE Series 10 NOF s Capabilities and Customer Advantages GMP manufacturing facility Bulk phospholipids produced at our own validated facility under cGMP operation have been supplied worldwide commercial drugs for many years with a good reputation for quality and reliability Drug Master Filein
108. itute any assumption of any liability for such accident or incident by Seller Confidentiality The Buyer shall keep confidential and shall not publish or otherwise disclose and shall not use for any purpose other than the purpose of the purchase of Products all confidential or proprietary information data documents or other materials supplied by the Seller in connection with the Sales and marked or otherwise identified in written form as Confidential including information derived from a site visit to Sellers s facility by Buyer hereinafter Confidential Information The Buyer shall use at least the same standard of care as it uses to protect its own confidential information to ensure that the Buyer i only makes use of Confidential Information for purposes of the purchase of Products and ii does not disclose or make any unauthorized use of such Confidential Information Notwithstanding the foregoing the provisions of these Terms and Conditions shall not apply to Confidential Information that the Buyer can show by written records a is in the public domain other than by acts of the Buyer in contravention of these Terms and Conditions b was permitted to be disclosed by prior consent of the Seller c has become known to the Buyer by a third party provided such Confidential Information was not obtained by such third party directly or indirectly from the Seller under these Terms and Conditions on a confidential basis d prior to disclosure
109. izes below 50 nm Solubilizer SL 11 is highly suitable as a SEDDS Self Emulsifying Drug Delivery System agent Solubilizer SL 11 can also help increase intestinal absorption Nano emulsions and SEDDS agents containing hydrophobic drugs can be easily prepared following simple protocols PUREBRIGHT SL Series Hydrophobic Drug Solubilization Kit We supply new solubilization kits for hydrophobic drugs by using our proprietary DDS technologies Because of the simple procedures for kit use screening of new chemical entities and safety studies can be easily performed NOFABLE Series Ultra Purity Oleic Acid Derivatives Using high purity oleic acid we produce the non ionic surfactant NOFABLE series and its derivatives Since impurities derived from oxidation are eliminated in our process for the product any degradation and degeneration of drug formulations using it can be prevented In addition oil adjuvant formulation for vaccines also exploits the NOFABLE series Solubilizer SL 11 335 RIA ER T8 BEAK ATER AMET ME 50nm SEDDS Self Emulsifying Drug Delivery System
110. le Anchor for cell Membrane BAM PEG PEG BAM Oleyl O PEG X Biocompatible Anchor for cell Membrane BAM Physiologically active g y O is fe X substance BAM Protein y u n PEG chain X Reactive group Protein enzyme Drug etc Product name Reactive Group X Mw SUNBRIGHT OE 020CS 2 000 SUNBRIGHT OE 040CS CO CH2CH2 COO NHS 4 000 SUNBRIGHT OE 080CS 8 000 SUNBRIGHT Application Anchoring of BAM Protein conjugate to the cell membrane Protein Cell membrane References 1 K Kato et al Biotechnol Prog
111. leoy C16 0 181 891 1 DOPE MAL COATSOME FE 8181MAS3 N 3 Maleimide 1 oxopropyl L ar phosphatidylethanolamine Dioleoy C18 1 C18 1 917 1 NHS Phospholipid R CO CH gt O R CO CH O CH OPOCH CH NH C CHaCO N Activated carboxylic acid NHS ONat for NH2 group reaction O _ Productname Description RCOORCOOMW DMPE NHS COATSOME FE 4040SU5 N Succinimidyloxy glutaryl L av phosphatidylethanolamine Dimyristoyl C14 0 C14 0 869 0 DPPE NHS COATSOME FE 6060SU5 N Succinimidyloxy glutaryl L a phosphatidylethanolamine Dipalmitoyl 16 99 925 1 DSPE NHS COATSOME FE 8080SU5 N Succinimidyloxy glutaryl L a phosphatidylethanolamine Distearoyl C18 0 C1 amp 0 981 2 POPE NHS COATSOME FE 6081SU5 N Succinimidyloxy glutaryl L o phosphatidylethanolamine 1 Palmitoyl 2 oleoyl esp ex ex 951 2 DOPE NHS COATSOME FE 8181SU5 N Succinimidyloxy glutaryl L o phosphatidylethanolamine Dioleoyl C18 1 C184 977 2 C Q 2 E O 2 E 0 2 C U 2 0 fe Phospholipids and Lipids for Liposomal Formulations lt COATSOME Series gt Glu Phospholipid CO n II gt CO CH i 04 2 C CH5 3COH Carboxylic acid Glu derivative for group reaction O Na DMPE Glu COATSOME FE 4040GL N Glutaryl L a phosphatidylethanolamine Dimyristoyl C14 0 C14 0 7
112. ly 300nm are obtained Note2 Syringe filtration This simple method can be employed to prepare liposomes when there are no specific requirements in terms of the liposome diameter or the amount of drug to be encapsulated in the liposomes Aseptic injection directly into the vial after filtration will provide aseptic filtration at the same time This product yields approximately 800ul of liposomes when 1ml of the drug solution is used and the solution is filtered with a 13 mm diameter filter lt High Pressure filtration gt Put solution into a pressure filtration system equipped with a polycarbonate filter Operate the pressure filtration system to filter the solution Transferrin modified drug containing liposomes are obtained The particle diameter will be approximately 200 nm when a 0 2um pore diameter filter is used The drug containing liposomes can be used after dilution or purification as needed Note 3 Refining the outer water phase When the drug containing liposomes are biologically evaluated the drug in the outer water phase should be used after purification according to the purpose of your research Purification in the outer water phase can be performed by conventional methods such as ultrafiltration dialysis gel filtration and centrifugation Note 4 Concentration Lipid concentration of 10mg mL 1 or less is recommended Note 5 High Pressure filtration system Contact us for further information and purchase
113. m EP USP DEG EP USP JP JPE PEG200 300 400 Product Name Description MW PEG200 SUNBRIGHT DKH 02HB Polyethyleneglycol 200 PEG300 SUNBRIGHT DKH 03HB Polyethyleneglycol 300 PEG400 SUNBRIGHT DKH 04HB Polyethyleneglycol 400 SUNBRIGHT Stability Test EG DEG Content 20 10 X DKH 03HB PEG300 Conventional Grade 5 5 DKH 04HB PEG300 Conventional Grade PEG400 Conventional Grade DKH 04HB PEG400 Conventional Grade 0 4 DKH 03HB on gt E Conventional A Conventional E Conventional PEG Time month Time month PEG200 PEG300 PEG400 This formaldehyde test was performed This pH test was performed under N gt under 2 sealed condition at 40C sealed condition at 40 C Specifications ITEM Method Specification DKH 02HB DKH 0
114. nd information and environment and energy Corporate Overview Head Office Tokyo Japan Founded July 1 1937 zz 24 7 1 Capital 204 million US as of Mar 31 2011 17742 BAB 2010438318 Employees 3 817 as of 31 2011 3 817 2011438318 Sales 1 8 billion US Fiscal year 2010 Ls US Y86 81 154 121 eo10 F Corporate Organization Corporate R amp D Div NOF CORPORATION Oleo amp Speciality Chemicals Div 3 n Electronic Materials Dept Amagasaki Plant Anti Corrosion Coatings Group DDS Development Division is organized within NOF s DDS family of complementary business units offering cGMP innovation and cGMP capabilities to pharmaceutical biomedical products Overseas Subsidiaries and Joint Ventures NOF METAL COATINGS EUROPE S A Michigan Metal Coatings Co NOF METAL COATINGS NORTHAMERICA INC NOF EUROPE NOF CORPORATION BELGIUM N V Head Office J NOF AMERICA CORPORATION California omes M e a Georgia Metal Coatings Co
115. nding site Amide ester Maleimide etc Polymeric Micelle Carrier NOF has a long reputation for producing a high quality Activated PEGs the SUNBRIGHT Series that possess the most suitable quality for preparation of physiologically active drugs biologics Our SUNBRIGHT series is characterized as extremely high purity PEGs with a variety of functional groups The products of this series are internationally recognized as optimal PEGylation drugs As illustrated in this figure application of Activated PEGs with various functional groups enables introduction of PEG chains into drugs enzymes phospholipids and other biologics Covalent conjugation of hydrophobic macromolecules with Activated PEGs leads to the formation of macromolecular micelles Polymer Micelles which allow homogeneous dispersion of hydrophobic drugs in aqueous media Furthermore when PEGylated phospholipids are used as liposomes the aqueous corona added stabilities homogeneous dispersal of the liposome preparations encapsulating drugs within them PEGylation plays an important role in the stabilization of drugs increased circulation time reduction of their antigenicity and decrease in drug dosing besides augmenting the targeting ability via binding biologics onto their surfaces PEG SUNBRIGHT Series
116. netically modified soybeans The high purity product is useful to obtain favorable color and odor of the final product What is more the less unsaturated double bonds in the acyl chains from higher hydrogenation result in excellent stability together with easier handling of this lecithin in its powder form RiCOO 2 C12 C20 fatty acids Q R4 CO CH Q Ro CO CH I Z O HSPC COATSOME NC 21E HSPC COATSOME NC 21 1 2 Egg yolk Phospholipids Egg yolk phospholipids are manufactured using virusfree yolk as the starting material followed by removal of impurities through strict purification procedures Unique NOF advantages include major phospholipids containing two different acyl groups saturated and unsaturated fatty acids in the same molecule These unique chemical structures provide excellent dispersing ability in aqueous solution and favorable surfactant effects Egg
117. nic and anionic charged liposomes are prepared by altering the ratio of DPPG as the charged lipid While preparing an aqueous solution of the drug in water Distilled Water for Injection it is necessary to decide the concentrations according to the molarity of the DPPG as the charged lipid For further details please refer to Suggestions for use in the next section DDS
118. ns or animals or for commercial purposes Seller has not tested the products for safety and efficacy in food drug medical device cosmetic commercial or any other use unless otherwise stated in Seller s literature furnished to Buyer Infringement The Buyer shall indemnify and hold the Seller harmless from and against any and all infringement with regard to including but not limited to patent utility model design trademark copyright trade secret or any other intellectual property right in connection with the Products in any country hereinafter referred to as the Infringement The Buyer shall at its own cost defend settle or otherwise dispose of claims suits or legal proceeding in connection with Infringement Returns Products may not be returned for credit except with Seller s permission and then only in strict compliance with Seller s return shipment instructions Miscellaneous Seller s waiver of any default by Buyer or any failure by Seller to strictly enforce any provisions of these Term and Condition or to exercise any right arising hereunder shall not constitute a waiver of a any subsequent default or b Seller s right to strictly enforce such Terms and Conditions or to exercise such right thereafter All rights and remedies under the Sales are cumulative and are in addition to any other rights and remedies Seller may have at law or in equity If any provision of these Terms and Conditions shall be held to be invalid
119. ntration on the Survival Rate of BALB c mice Stability Test Formaldehyde Conventional Grade B Polysorbate 80 Formaldehyde ppm 0 75 1 Dose ml mice Time month This formaldehyde test was performed under N2 sealed conditions at 40 C cells from the guinea pig were treated with Polysorbate 80 for 60 mins The hemolytic ratio was determined by the Polysorbate 80 was diluted with PBS and administered to mice by intravenous injection absorbance of the solution at 576 nm Status of European Pharmacopoeia EP European Pharmacopoeia EP 5th edition stipulates a highest limit for oleic acid 58 85 in Polysorbate 80 It is paradoxical that the highest quality Polysorbate 80 HX2 in the world does not satisfy the specification of EP As a result of our negotiations with the EP Agency the upper limit for the content of oleic acid has been eliminated from EP ed 5 4 Now our Polysorbate 80 HX2 meets the requirements stipulated in the Tripartite Compendia JP EP NF European Pharmacopoeia EP 5th EDITION 80 58 85 80 HX2 EP EP 5 4
120. nvoice If insecure as to the collection of amounts due Seller may delay or postpone delivery of Products and change the payment terms to payment in full or in part in advance of shipment of the undelivered Products If Buyer defaults in the payment of the purchase price or other terms of this or any other order Seller may defer delivery cancel the Sales or sell products on hand for the Buyer s account and apply the proceeds against the purchase price Buyer shall pay any balance to Seller on demand Buyer shall pay all costs including without limitation reasonable attorney and accounting fees and other expenses of collection resulting from any default by Buyer in any of the terms hereof A late payment charge of 1 5 per month shall accrue on delinquent amounts until paid Taxes Buyer shall pay any tax duty custom fee or charge imposed by any governmental authority on or measured by the Sales and Buyer shall reimburse Seller for any payment by Seller thereof Pricing Buyer shall remit payment by wire transfer to the bank account mentioned in invoice Buyer shall contact Seller for current prices if Buyer requires this information prior to placing an order Seller guarantees pricing contained in its written quotations for 30 days When placing an order Buyer should reference Seller s quoted prices or the quote number Seller will contact Buyer by phone fax or e mail in the event of any discrepancy between order and Seller s pricing or
121. ons containing proteins as a stabilizer for vaccines Polysorbate 80 HX2 is vegetable derived material and meets the ICH Harmonized Tripartite Guideline on New Drug Substances and Products published April 2006 This has validated its extensive use around the world as a standard product in the pharmaceutical field 1990 GMP 80 HX2 HLB
122. or Pharmaceutical Development PUREBRIGHT MB Series 53 Self emulsifying Solubilizer SL 11 55 PUREBRIGHT SL Series 57 NOFABLETM Series 59 SUNBRIGHT DKH 02HB DKH 03HB and DKH 04HB 60 SUNBRIGHT OE Series 61 From the Biosphere to Outer Space The Group pursues multi faceted business development 9 in nine divisions of activities based on its own technologies endeavors to realize its management philosophy of Creating new values in a broad spectrum from biosphere to outer space by focusing particularly on the fields of life 37 science electronics a
123. other terms Warranties Seller will make available to Buyer a Certificate of Analysis for Products purchased Provided Buyer notifies Seller in writing of any shortages or patent defects or damage within the five 5 day period described in the Inspection section above or for any other products defect within thirty 80 days after the date of the invoice for such Products Seller will reprocess or replace at Seller s sole option any Products which are defective in material or workmanship THE FOREGOING CONSTITUTES BUYER S SOLE RECOURSE SELLER EXPRESSLY DISCLAIMS ALL OTHER WARRANTIES AND LIABILITY WHATSOEVER WHETHER EXPRESS OR IMPLIED INCLUDING WITHOUT LIMITATION WARRANTIES OF MERCHANTABILITY AND OR FITNESS FOR A PARTICULAR PURPOSE BUYER BEARS ALL RISK RESULTING FROM THE PARTICULAR USE IT CHOOSES FOR THE PRODUCTS No employee agent or representative of Buyer has the authority to bind Seller to any oral representation or warranty concerning any Products Seller s warranties shall not be effective if Seller determines that Buyer has misused Products in any manner failed to use Products in accordance with industry standards and practices or failed to use Products in accordance with instructions if any furnished by Seller Seller s sole and exclusive liability and Buyer s exclusive remedy with respect to Products proved to Seller s satisfaction to be defective or nonconforming shall be the replacement or reprocessing of such Products without cha
124. p General Characteristics of PEG SUNBRIGHT AM series SUNBRIGHT AM 0530K ca 500 SUNBRIGHT AM 1510K ca 1 500 SUNBRIGHT AM 2090P ca 2 000 polymers PEGylation using generic single chain PEG derivatives Moreover with the use of this compound the hydrophilic lipophilic balance can be adjusted by changing the composition ratios of the ethylene oxide and propylene oxide in the polyalkylene glycol present in this compound Efficacy of Comb type PEG Enzyme Conjugation Stability of Modified Protease in water at 40 C PEG Modifier Enzyme ratio wt wt 100 Residual activity 96 O O O O N native week References for modified enzymes using SUNBRIGHT AM series 4 Y Kodera et al Bioconjugate Chem 5 283 1994 5 K Matsuo et al Adv Bioseparation Eng 1993 3 56 1994 1 J Kajiuchi et al J Chem Eng Japan 25 202 1992 2 T Masunaga et al J SCCJ 27 3 276 1993 3 H Sasaki et al Biochem Biophys Res Commun 197 287 1993 Comb shaped type PEG chain Enzyme Drug Protein or Surface ca 30 40 ca 15 000 20 000 10 19 ca 15000 20 000 ca 10 20 20 000 40 000 1 Degree of Polymerization PEGylation using Comb shaped co polymers
125. purchased herein in accordance with Buyer s Use of Product as described below and that any such use of Products will not violate any law or regulation Buyer shall indemnify and hold harmless Seller its employees agents successors officers and assigns from and against any suites losses claims demands liabilities costs and expenses including attorney and accounting fees that Seller may sustain or incur as a result of any claim against Seller based upon negligence breach of warranty strict liability in tort contract or any other theory of law brought by Buyer its officers agents employees successors or assigns by Buyer s customers by end users by auxiliary personnel such as freight handlers etc or by other third parties arising out of directly or indirectly the use of Products or by reason of Buyer s failure to perform its obligations contained herein Buyer shall notify Seller in writing within fifteen 15 days of Buyer s receipt of knowledge of any accident or incident involving Products which results in claimed personal injury or damage to property and Buyer shall fully cooperate with Seller in the investigation and determination of the cause of such accident and shall make available to Seller all statements reports and tests made by Buyer or made available to Buyer by others The furnishing of such information to Seller and any investigation by Seller of such information or incident report shall not in any way const
126. rge or refund of the purchase price in Seller s sole discretion upon the return of such Products in accordance with Seller s instructions SELLER SHALL NOT IN ANY EVENT BE LIABLE FOR INDIRECT INCIDENTAL CONSEQUENTIAL PUNITIVE OR SPECIAL DAMAGES OF ANY KIND RESULTING FROM THE SALE DELIVERY USE OR FAILURE OF THE PRODUCTS EVEN IF SELLER HAS BEEN ADVISED OF THE POSSIBILITY OF SUCH DAMAGE INCLUDING WITHOUT LIMITATION LIABILITY FOR LOSS OF USE LOSS OF WORK IN PROGRESS DOWN TIME LOSS OF REVENUE OR PROFITS FAILURE TO REALIZE SAVINGS LOSS OF PRODUCTS OF BUYER OR OTHER USE OR ANY LIABILITY OF BUYER TO A THIRD PARTY ON ACCOUNT OF SUCH LOSS OR FOR ANY LABOR OR ANY OTHER EXPENSE DAMAGE OR LOSS OCCASIONED BY SUCH PRODUCTS INCLUDING PERSONAL INJURY OR PROPERTY DAMAGE UNLESS SUCH PERSONAL INJURY OR PROPERTY DAMAGE IS CAUSED BY SELLER S GROSS NEGLIGENCE SELLER S AGGREGATE LIABILITY FOR DAMAGES HEREUNDER WHETHER IN CONTRACT TORT OR OTHERWISE SHALL NOT EXCEED THE PURCHASE PRICE PAID BY BUYER FOR THE PARTICULAR PRODUCTS INVOLVED All claims must be brought within one 1 year of delivery regardless of their nature Compliance with Laws Seller certifies that to the best of its knowledge Products are produced in compliance with applicable requirements of the Labor Standard Law in Japan as amended and regulations rules and orders issued pursuant thereto Buyers Representations and Indemnity Buyer represents and warrants that it shall use all Products
127. s to prolong the circulating plasma half life of drugs Coating of the liposomal surface with polyethylene glycol suppresses drug clearance in vivo by the reticuloendothelial system thereby prolonging the half life of the drug PEG modified lipids can also be used as emulsifiers and stabilizers of microspheres in aqueous solutions Lipid emulsion 3 1 PEG phospholipids PEG phospholipids of the carbamate linked type are resistant to hydrolysis and therefore used for commercial production of PEGylated liposomes As NOF employs its own high quality Activated PEGs and phospholipids high quality PEG phospholipids can be supplied i i R CO CH i i OF E CH CH NHC OCH 2 OCH 3 ONa SUNBRIGHT DSPE 020CN Carbonyl methoxypolyethyleneglycol 2000 1 2 distearoyl sn glycero PEG Liposomes PEG
128. ses Control mice received vehicle only D Filpula et al Bioconjugate Chem 18 9 773 784 2007 eHydrolysis Cytotoxicity Antitumor activity of PEG BE Daunorubicin t 4 2 hr t 1 z hr Compound buffer Esters Bp oz Tbe ica m R2 Carbonates CH O ll ll PEG 0 cHz0 C NH DNR CHa 51 Half maximal 50 inhibitory concentration Inhibition of P388 leukemia 2 3 mg kg dose of DNR to BALB c mice bearing subcutaneous Madison lung carcinoma M 109 on days 1 and 4 ip 3 and 6 iv 3 Percent treatment over control T C RB Greenwald et al J Med Chem 42 3657 3667 1999 26 8 Comb shaped co polymers carboxylic anhydride type When these reactive polymers are used for modification of enzymes less reactivity is required to introduce more PEG chains onto the enzyme surfaces than that of a single polymeric PEG modifier Consequently the activities of the modified enzymes can be improved PEG PEG R1 C CHe CH CH T O R1 H or R2 CHs or other alkyl group AO n R2 m AO alkylene oxide grou
129. tumors COATSOME EL 01 D 1 00 0 11 5 Commercially available A r 020 Commercially available B 0 62 0 21 Commercially available n 26 Relationship Between Transfection Efficiencies and Cell Mitotic Activities Phospholipids and Lipids for Liposome Formulations HRA 42 9 3 8 68 2 1 6 mEIIL jJ sci 00 0 A Ola 1 2 ES 2 23 7 1 9 3 3 0 9 41 9 4 5 OVHS 1 04 05 1 05 CLENA MCAS lt 01 51 5 641 SKOV3 S 02 02 Ooze 12 32 11 04 04 34 4 9 7 04 282 cm ALS KOC 3S 5 9 2 1 2 6 1 6 ND 4 Nakajima 9 22 ND 4 KF 155 22 3 O12 04 ND 4 SW626 260 ALG 02 ND 4 Colo320DM sb 4 ND 4 HRA 429 120 ND 4 mEIIL 4 5 1 0 0 6 0 1 ND 4 Normal cell lines 00 Fibroblast TIG 9 6 2 2 0 9 0 2 42 4 E 107 Fibroblast IMR 250A 1 6 0 5 14 2 3 2 HUVEC0103 lt 0 1 lt 0 1 22 2 1 6 HUVEC1204 lt O 1 0 ae IO LS O HUVEC0923 lt 0 1 lt 0 1 1822 44 1 Transfection performed the absence or presence of 10 fetal bovine serum 5 Data shown represent mean of three experiments 2 mEllL_cells growing in peritoneal cavities of nude mice were transfected with liposome CAG lacZ 2014 and the percentage of lacZ positive cells was determined Data shown represent mean SD 3 Percentages of LacZ positive cells and labeling indexes were determined Transf
130. weight c Centrifugation When centrifugation is performed at high speeds after the addition of physiological saline 150mM NaCl the liposomal drug is precipitated After removal of the supernatant add saline once again This procedure usually needs to be repeated two or three times at 100 000rpm Regardless of the procedure employed it is absolutely essential to maintain both the inside and outside layers of the liposomes isotonic and the temperature below the liposome phase transition temperature throughout the procedure During centrifugation the temperature should be below 40 C b Sephadex G 50 Sepharoce C 150mM NaCl

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