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Drug delivery conjugate capable of controlled release, and use thereof

A technology of conjugates and drugs, applied in the direction of drug combination, drug delivery, nano-medicine, etc., can solve problems such as hyperlipidemia, abnormal lipoprotein pattern, red blood cell aggregation, irreversible peripheral neuropathy, etc., and achieve the effect of enhancing the effect

Inactive Publication Date: 2014-12-24
POSTECH ACAD IND FOUND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cremophor EL is polyoxyethylene castor oil, which helps Paclitaxel dissolve in water, but has side effects, causing severe allergic reactions, hypersensitivity reactions, hyperlipidemia, abnormal lipoprotein patterns, erythrocyte aggregation, irreversible peripheral neuropathy, etc. (Gelderblom, H., Verweij, J., Nooter, K., and Sparreboom, A. (2001) Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur. J. Cancer 37, 1590-1598., Weiss, R.B., Donehower, R.C., Wiernik, P.H., Ohnuma, T.Gralla, R.J., Trump, D.L.; Baker Jr, J.R., Van Echo, D.A., Von Hoff, D.D., and Leyland-Jones, B. (1990) Hypersensitivity Reactions from taxol.J.Clin.Oncol.,8,1263-1268.; Lorenz,W.,Riemann,H.J., and Schmal,A.(1997)Histamine release in dogs by Cremophor EL and its derivatives:oxyethylate oleic acid is the most effective constituent. Agents Actions 7,63-67)

Method used

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  • Drug delivery conjugate capable of controlled release, and use thereof
  • Drug delivery conjugate capable of controlled release, and use thereof
  • Drug delivery conjugate capable of controlled release, and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: Preparation of drug delivery conjugates

[0053] To prepare polymers incorporating cyclodextrin and poly(maleic anhydride), the hydroxyl groups of β-cyclodextrin (1 g), consisting of seven monosaccharides, were activated with lithium hydride (LiH; 7.0 mg) for 12 h (in the absence of Under water and nitrogen, and in the presence of dimethylformamide (DMF; 20 mL), the resulting reaction solution was then added to a poly(maleic anhydride) (poly(IB-alt-MAnh)) solution (90 mg / 10mL of DMF), reacted for 12 hours, purified by dialysis (MWCO 3,500), and lyophilized to obtain poly-x-CD polymer (poly(IB-alt -Manh)-g-CD b ). The conjugation ratio of cyclodextrin and poly(maleic anhydride) can be widely adjusted by adjusting the amount of cyclodextrin (1 g or 0.5 g).

[0054] To prepare polymers incorporating paclitaxel and poly(maleic anhydride), the hydroxyl groups of paclitaxel (33.3 mg) were activated with LiH (1 mg) for 12 hours (under anhydrous nitrogen and in...

Embodiment 2

[0068] Example 2: Characterization of Drug Delivery Conjugates

[0069] 2-1. Measurement of drug delivery conjugate size

[0070] In order to measure the size and surface charge of the drug delivery conjugate prepared by the method of Example 1, a surface charge measurement system (nanolaser particle sizer Z) and a size measurement system (nanolaser particle sizer S) were used to measure the drug in aqueous solution Size and surface charge of the delivery conjugate. Where poly-x-CD and poly-x-PTX conjugates, poly-x-CD 20 and poly-x-PTX 7 The combination of was used for further study due to its enhanced water solubility. The measurement results are shown in Table 2 below.

[0071] 【Table 2】

[0072] serial number

sample

Size (r,nm)

Zetapotential (mV)

1

PTX

806.4±235.9

–39.2±1.50

2

pCD::PTX

420.3±50.6

–58.6±2.62

[0073] 3

PPTX

183.2±12.6

–41.7±2.03

4

pCD::pPTX

54.6±11...

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Abstract

The present invention relates to a hydrophobic drug delivery conjugate, to which cyclodextrin, poly(maleic anhydride), and a hydrophobic drug is bonded, and to a pharmaceutical composition comprising the hydrophobic drug delivery conjugate as an active ingredient. The hydrophobic drug delivery conjugate according to the present invention can effectively control the release rate and the delivery rate of a hydrophobic drug by regulating the physicochemical bonding and / or composition of the cyclodextrin, poly(maleic anhydride), and hydrophobic drug, and can also increase the effect of the drug by significantly increasing the solubility of the hydrophobic drug. Further, the present invention can enable the type of hydrophobic drug to be varied, as well as a peptide having target directivity to the surface of the conjugate to be introduced, such that the present invention can be applied to the treatment of various diseases in addition to cancer treatment.

Description

technical field [0001] The present invention relates to controlled-release drug delivery conjugates, and pharmaceutical compositions comprising the conjugates. Background technique [0002] Tumors are the product of abnormal, uncontrolled and disordered cell growth resulting from an excess of abnormal cells. Tumors are classified as malignant when they show destructive proliferation, infiltration and metastasis. Specifically, in terms of molecular biology, tumors can be referred to as genetic diseases caused by gene mutations. Each tumor is known to have an average of 50 to 80 mutated genes that are absent in normal cells. Therefore, in an aging society, the incidence of cancer may increase. The accumulation of mutated genes increases the likelihood that aging cells will mutate into cancerous cells. Furthermore, in Korea, 100,000 cancer patients were newly added in 1999, and will increase to over 180,000 in 2008 (reported by the Ministry of Health and Welfare in 2010). ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/40A61K47/48A61K47/30A61K31/337
CPCA61K9/0019A61K9/5161B82Y5/00A61K47/58A61K47/62A61K47/6951A61K31/337A61P35/00A61K47/50A61K47/30A61K47/40
Inventor 金园钟南宫烂李炳宪金仁山霍夫曼·阿伦
Owner POSTECH ACAD IND FOUND