日本日油NOF 药用的修饰性PEG

NOF produces the world s best quality Activated PEGs from our high-quality methoxypoly(ethylene glycol) (mPEG). NOF also supplies our proprietary high-purity branched, multi-arm and hetero-functional Activated PEGs tailored to meet our customers PEG Drugs. NOF can supply Activated PEGs produced under GMP standards in our state-of-the-art GMP facility. NOF can help you to modify your drugs by using our PEGylation technology and our high-quality Activated PEGs.

Nof从我们的高质量甲氧基聚乙二醇(MPEG)中生产出世界上最优质的活化支架.NOF还提供我们的专利高纯度分支，多臂和异功能活化钉定制，以满足我们的客户的PEG药物。在我们最先进的gmp设施中，Nof可以提供按GMP标准生产的活化钉.Nof可以通过使用我们的PEG化技术和我们的高质量的激活钉来帮助您修改您的药物。

Activated PEGsOverviewPEGylationFunctional GroupQualityGMP SupplyCustom MfgOverviewNOF has been producing a high-quality activated PEGs, SUNBRIGHT series, which possess the most suitable quality for preparation of physiologically active drug and biologics. SUNBRIGHT series are characterized as extremely high-purity PEGs with a variety of functional groups, whereby the products of this series are recognized as optimal PEGylation drugs. As illustrated in this figure, application of the activated PEGs with various functional groups enable introduction of the 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 the PEGylated phospholipids are used as liposomes, the aqueous layer can be added to its surface, with homogeneous dispersal of the liposome preparations encapsulating drugs within them.

As stated above, PEGylation plays an important role in the stabilization of drugs, reduction of their antigenicity and decrease in the drug doses, besides augmenting the targeting ability via binding biologics onto their surfaces. We can do supply our activated PEGs from small scale reagent grade to huge amount GMP grade with high purity.

PEGylationPEGylation technology is applied for biologics modifications such as cytokines, antibody fragment, interleukins, hormones, oligonucleotides and some of proteins and peptides.

PEGylation can be effected to

Improving BioavailabilityProlonging Blood CirculationMaximizing PharmacokineticsLow-profiling ImmunogenicityNOF 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, which is a starting material of activated PEG for pharmaceutical area. Our activated PEGs have a narrow polydisperity and low diol content with wide range of molecular weight, from 2kDa to 80kDa.

PEG -conjugationAnalysis of PEG-ALD-Insulin by SDS-PAGE with Coomassie brilliant blue. Insulin was reacted with NOF PEG-ALD at 4°C. The PEGylated insulin was purified on Q Sepharose Fast Flowcolumn.

lane M molecular weight markerslane 1 Insulinlane 2 PEG(ME-050AL)-insulin eluatelane 3 PEG(ME-100AL)-insulin eluatelane 4 PEG(ME-200AL)-insulin eluatelane 5 PEG(ME-300AL)-insulin eluateCoupling of PEG derivatives to Proteins: examples of conditions

Coupling of PEG-NHS derivatives to protein amines (PEG-NHS + Protein-NH 2) Conditions 1: 50 mM phosphate buffer (pH 7.2), 4℃, 6 hrs *1)Conditions 2: Borate-phosphate buffer (pH 8.0), 25℃, 2 hrs *2)Coupling of PEG-Aldehyde derivatives to the NH 2 group of proteins (PEG-Ald + Protein-NH 2)Conditions : sodium cyanoborohydride (10 eq . .), 4 deg C, 20 hrs *3)Coupling of PEG-Maleimide derivatives to the SH group of proteins (PEG-Maleimide + Protein-SH)Conditions: 100 mM phosphate buffer (pH 6.5), 4 deg C, 4 hrsCoupling of PEG-NH 2 derivatives to the COOH group of proteins (PEG-NH 2 + Protein-COOH)Conditions: 50mM phosphate buffer (pH 7.2), WSC (2 eq.), 4 deg C, 10 hrsCoupling of PEG-p-Nitrophenyloxycarbonyl derivatives to the NH 2 group of proteins (PEG-NP + Protein-NH 2)Conditions: borate-phosphate buffer (pH 8.0-8.3), r.t, overnight *2)References:*1) Abuchowski, A., et al. (1984) Cancer Biochem. Biophys. 7, 175.*2) Sartore, L., et al. (1991) Appl. Biochem. Biotechnol. 27, 45*3) US 5,824,784Functional GroupWe supply different series of PEG derivatives with various versatile functional groups.

Quality

Purity of NOF’s activated productsWe use our advanced technologies to measure the quality of our activated PEGs. The following are the typical analysis data for each type of activated PEGs which are measured by NMR or HPLC methods. Please note that those numbers are not specification of the product.

NHS type

CS type mPEG-succinimidyl succinate (Mw 2k and 5k) : activity over 95% (NMR)

GS type mPEG-succinimidyl glutarate (Mw 5k, 10k, 20k, 30k and 40k) : activity around 95% (NMR)

AS type mPEG-succinimidyl methyl ester (Mw 2k and 5k) : activity around 95% (NMR)

HS type mPEG-succinimidyl pentyl ester(Mw 5k, 10k, 20k, 30k and 40k): activity around 95% (NMR)

TS type mPEG-succinimidyl carbonate(Mw 5k, 10k, 12k, 20k, 30k and 40k): activity over 95% (HPLC)

pNP type (NP series)

mPEG-p-nitrophenyl (Mw 2k, 5k, 10k, 20k, 30k and 40k): activity over 95% (HPLC)

Aldehyde type(AL series)

mPEG-propylaldehyde (Mw 5k, 10k, 20k, 30k and 40k): activity over 85% (HPLC). The activity for Mw20k, it is over 92% as actual data by HPLC.

Amine type

PA type mPEG-propylamine (Mw 2k, 5k, 10k, 12k, 20k, 30k and 40k): activity over 95% (HPLC)

EA type mPEG-ethylamine (Mw 5k, 10k, 20k, 30k and 40k): activity over 95% (HPLC)

thiol type(SH series)

mPEG-thiol (Mw 2k, 5k, 10k, 20k, 30k and 40k): activity around 95% (HPLC)

Maleimide type(MA series)

mPEG-maleimide (Mw 2k, 5k, 10k, 20k, 30k and 40k): activity around 95% (HPLC)

Oxyamine type(CA series)

mPEG-oxyamine (Mw 10k, 20k, 30k and 40k): activity around 95% (HPLC)

Iodoacetoamide type(IA series)

mPEG-irdoacetoamide (Mw 20k, 30k and 40k): activity around 90% (HPLC)

Analytical Technology

NOF has more than 20 years history for manufacturing of high-quality mPEGs and Activated PEGs. These experiences enable NOF to have thorough knowledge of PEGs and considerable achievement in analysis of Activated PEGs. We also have invented innovative analytical methods for assaying purity of activated PEGs and for determining impurity levels. (*Patent No.: JP4543917) Previously, the activity for activated PEGs is measured by NMR. However, this method is not very good detection due to polymer, especially for high molecular weight. We developed the analysis method by using HPLC. As the result of the analysis, the activity sometime seems lower than the result of NMR because main peak can completely separate from non-active peak and activated impurity peaks (like dimer).

HPLC analysis for M-PEG-COOH

GPC Analysis of M-PEG5K and M-PEG-30K

MALDI-TOF-MS Analysis of M-PEG5K and M-PEG-30K

GMP Supply

cGMP Manufacturing FacilitiesNOF Activated PEGs, SUNBRIGHT® series are produced in facilities with state-of-the-art technology, operated under cGMP. The cGMP facilities are capable of producing small to large batch sizes, using proprietary know-how on scale-up procedure, depending on customers needs. These cGMP facilities have been audited by pharmaceutical companies throughout the world. NOF receives high reputation from our customers.

Research DevelopmentOur R D facility was opened in December 2005. This allows us to continue our development of novel activated PEGs and technologies for PEGylation.Custom MfgResearch DevelopmentOur R D facility was opened in December 2005. This allows us to continue our development of novel activated PEGs and technologies for PEGylation.

Custom Manufacturing

NOF has over 20 years of experience in supplying high-quality methoxy polyethylene glycol (mPEG) for pharmaceutical market. The mPEG is starting material of PEG derivatives, which are patented through our proprietary technology. Based on extensive range of technological know-how and capabilities, NOF offers custom manufacturing of Activated PEGs from early stage development to commercial scale. Sizewise, we can offer gram size synthesis to kg size for non GMP product. We also offer cGMP custom synsthesis.

Please feel free to contact us : Contact form1. Mono-functional Linear PEGs2. Bi-Functional PEGs3. Multi-Arm PEGs4. Branched PEGs5. Forked PEGs6. Heterofunctional PEGs7. Single Molecule PEGs PUREBRIGHT® Series8. Poly-Hydroxyl Activated PEGS10. Biodegradable Polymers for gene / nucleic acid Delivery SUNBRIGHT® ME-DT DT series11. Biodegradable block polymer for drug delivery12.PEGylation Service

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PUREBRIGHT® 2TS-B12-AZ

Molecular weight: 1555.66

PUREBRIGHT® 2TS-B12-BO

Molecular weight: 1530.65

PUREBRIGHT® 2TS-B12-DB

Molecular weight: 1717.85

PUREBRIGHT® 2TS-B12-MA

Molecular weight: 1581.65

PUREBRIGHT® A-L08-PC

X = 8 Molecular weight: 441.51

PUREBRIGHT® A-L12-PC

X=12 Molecular weight: 617.72

PUREBRIGHT® BO-L08-PC

X=8 Molecular weight: 541.63

PUREBRIGHT® BO-L12-PC

X=8 Molecular weight: 717.84

PUREBRIGHT® MA-L08-PC

X=8 Molecular weight: 592.63

PUREBRIGHT® MA-L08-PS

X=8 Molecular weight: 689.71

PUREBRIGHT® MA-L12-PC

X=12 Molecular weight: 768.84

PUREBRIGHT® MA-L12-PS

X=12 Molecular weight: 865.92

日本日油NOF代理

自1910年成立以来，作为日本油化学领域的先驱，油化企业一直是该行业的领头羊。

油化业务是NOF集团的核心业务，该集团作为石油化学的先驱，在日本一直处于该领域的领先地位。

目前，除油酸及其衍生物、表面活性剂等油化产品外，还有多种以环氧乙烷衍生物、(甲基)丙烯酸酯等为基础的功能性产品。在石油化学领域，资源、环境和能源领域、电子和信息技术领域、医疗保健领域等技术创新已成为新兴领域的发展方向。

今后，油化企业不仅将在油脂、新材料等领域寻求更大的发展潜力，而且将在长期积累的原有技术基础上，在油化学、石化等多个领域开发高功能、高附加值的产品，以高技术拓展这些增长领域的业务。

Functional Chemicals Polymers Division has being expanding organic peroxides business since the start of production in 1957, and we are now developing various businesses based on organic peroxides, functional polymers and petrochemicals.

NOF CORPORATION has become a world leading manufacturer of organic peroxides by continuous R D for new products and applications in this field.

In the business of functional polymers, we develop high performance polymers such as unique graft and block copolymers applied to the improvement of plastics and other synthetic resins.

In the business of petrochemicals, we produce polybutene, isoparafin-baced odorless solvents and other products, which make a substantial contribution to the various industrial field.

We will continue to focus on the cutting edge materials for the next-generation technology and develop the frontier of chemistry by innovation.

自1957年开始生产以来，功能化学品和聚合物部门一直在扩大有机过氧化物业务，目前我们正在开发各种基于有机过氧化物、功能聚合物和石油化学品的业务。

Nof公司已成为世界领先的有机过氧化物制造商，通过不断研发新产品和在这一领域的应用。

在功能聚合物行业中，我们开发了高性能的聚合物，如独特的接枝共聚物和嵌段共聚物，用于改善塑料和其他合成树脂。

在石化行业，我们生产聚丁烯、异氰酸酯无味溶剂等产品，为各种工业领域做出了巨大贡献。

我们将继续专注于下一代技术的尖端材料，以创新开拓化学前沿。

The Functional Foods Division has always been a pioneer in the innovations in edible oils and fats re-fining and processing techniques since it was established in 1917. At present, it is expanding its business areas such as processing oils and fats for food and the health related business.

The processing of oils and fats for food contributes widely to the food industry by striving for the development of products in pursuit of deliciousness based on the technologies cultivated as a pioneer of processing oils and fats such as margarine, shortening, refined fat for confectionery use, depanning oil, filling and topping materials, powder oils and fats, and materials for cooking and frozen foods.

The health related business has developed one new product after another such as functional lipids, emulsifying and nano-emulsion products, oils and fats coating products, and external nutritional products while striving for steady researches to provide the society with health.

The Functional Foods Division will supply products which can contribute to the society by enriching people s food culture step by step, tasty and healthy.

自1917年成立以来，功能食品部一直是食用油和油脂精制和加工技术创新的先驱。目前，该公司正在扩大其业务领域，如食品加工油脂和与健康有关的业务。

食品油脂的加工为食品工业作出了广泛的贡献，致力于开发追求美味的产品，这些技术是作为加工油脂的先驱而培育的，如人造黄油、酥油、糖果用精制脂肪、脱皮油、填充和浇头材料、粉末油和脂肪以及烹饪和冷冻食品材料。

健康相关企业在不断开发功能油脂、乳化纳米乳液产品、油脂包衣产品、外营养产品等一系列新产品的同时，努力寻求稳定的研究，为社会提供健康。

功能食品部将提供能为社会做出贡献的产品，逐步丰富人们的\"食品文化”，美味可口，健康。

PEG or polyglycerin attached phospholipids (PEG phospholipid) are available for long circulating liposome formulations.Activated functional group attached phospholipids either PEG end or non PEG end are also available for immunoliposome or targeting use liposome.NOF also offers custom-made synthesis of phospholipid and provide unique liposome research kit (Empty liposome) for drug delivery systems (DDS). 3. Ultra-Purity Polysorbate 80Polysorbate 80(HX) of NOF is ultra-purity Polysorbate 80 for injectable grade which has outstanding features as follows;

Our Polysorbate 80(HX) has an outstanding safer characteristic and will be a world wide standard product in pharmaceutical especially for injectable purpose.