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A drug betaine conjugate, its pharmaceutical composition and application

A technology of conjugates and betaine, which is applied in the field of medicine, can solve the problems of complex synthesis routes of drug phospholipid compounds, drug leakage, and difficulty in drug efficacy, and achieve low toxicity drug efficacy or anti-tumor activity, low toxicity Effects of side effects, superior efficacy, or antitumor activity

Active Publication Date: 2017-05-10
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the fluidity of the liposome membrane, the drug is easy to leak out, making it difficult for the encapsulated drug to exert a good drug effect
In addition, the synthetic route of pharmaceutical phospholipid compounds using phosphatidylcholine as the hydrophilic head is complicated

Method used

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  • A drug betaine conjugate, its pharmaceutical composition and application
  • A drug betaine conjugate, its pharmaceutical composition and application
  • A drug betaine conjugate, its pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Synthesis of chlorambucil betaine conjugates (synthetic route see figure 1 )

[0096] Chlorambucil (1.818g, 6mmol) and CDI (1.236g, 6mmol) were dissolved in 20mL of dichloromethane, stirred at 25°C for 2h, and filtered. 3-Dimethylamino-1,2-propanediol (0.119g, 1mmol) and DBU (0.244g, 0.2mmol) were added to the filtrate, and heated under reflux for 24h. The reaction solution was diluted to 50mL with dichloromethane, washed 3 times with 1M hydrochloric acid, Na 2 SO 4 After drying, the solvent was evaporated to dryness to obtain product 1. The reaction process was detected by TLC (the developing solvent was methanol:dichloromethane / 1:1, and ultraviolet detection (λ=254nm)); the structure of the product was determined by mass spectrometry. MS:[M+H] + m / z 690.4.

[0097] Dissolve product 1 (0.692g, 1mmol) in 20mL of dichloromethane, add N,N-diisopropylethylamine DIEA (0.516g, 4mmol), stir at 25°C for 20min, and slowly add tertiary bromoacetic acid to the reaction syst...

Embodiment 2

[0101] Preparation and Physicochemical Properties of Chlorambucil Betaine Conjugated Liposome Microspheres

[0102] Dissolve 0.1 g of the chlorambucil betaine conjugate of Example 1 in 20 mL of chloroform, evaporate the solvent at 60° C., add 10 mL of PBS (pH 7.4) solution, form a film at 60° C., and shake for 10 minutes to obtain phenbutylene Aqueous solution of mustardine betaine conjugated liposome microspheres. Particle Size Distribution and Zeta Potential of Chlorambucil Betaine Conjugated Lipid Granules See Figure 6 , see the morphology Figure 7 Transmission electron micrograph of chlorambucil betaine-conjugated liposomes.

Embodiment 3

[0104] Synthesis of camptothecin betaine conjugates (synthetic route see Figure 8 )

[0105] Camptothecin 0.5g, adipic anhydride 2.5g, DMAP 0.1g, triethylamine (Et 3 N) 1.5 g, dissolved in DMSO, heated to reflux for 12 hours; washed with 0.1M dilute hydrochloric acid for 3 times, filtered the dilute hydrochloric acid layer, and took the filter cake. Add 1.0 g of CDI, dissolve in 20 mL of dichloromethane, stir at 25°C for 2 h, and filter. Add 3-dimethylamino-1,2-propanediol (0.12g) and DBU (0.25g) to the filtrate, and heat to reflux for 24h. The reaction solution was diluted to 50mL with dichloromethane, washed 3 times with 1M hydrochloric acid, Na 2 SO 4 After drying, the solvent was evaporated to dryness to obtain intermediate product 1. The reaction process was detected by TLC (the developer was methanol:dichloromethane / 1:1, and the ultraviolet detection was λ254nm); the structure of the product was determined by mass spectrometry. MS:[M+H] + m / z, 1037.4.

[0106] 0...

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Abstract

The invention discloses a pharmaceutical betaine conjugate and a pharmaceutical composition and an application thereof. The pharmaceutical composition contains the pharmaceutical betaine conjugate or a pharmaceutic composition composed of the pharmaceutical betaine conjugate and a pharmacologically acceptable carrier and is made into liquid preparations, solid preparations, semi-solid preparations, capsules, granules, gels and injections. The pharmaceutical composition is of liposomal nano-particles made of the pharmaceutical betaine conjugate or the composition of the pharmaceutical betaine conjugate and auxiliaries, to be specific, 10-100nm in particle size. The pharmaceutical betaine conjugate and the liposomal nano-particles thereof can serve as the liquid preparations, the solid preparations, the semi-solid preparations, sterilization preparations and sterile preparations and are low in toxicity and applicable to various tumor efficient treatments.

Description

technical field [0001] The invention relates to a drug betaine conjugate with drug efficacy or antitumor effect, its pharmaceutical composition and application, and belongs to the technical field of medicine. Background technique [0002] Controlled release of hydrophobic drugs is an important topic in the field of pharmacy. Oral administration of hydrophobic drugs often has low absorption efficiency, which affects drug efficacy. In particular, many antitumor drugs are strongly hydrophobic, such as camptothecin, paclitaxel, aromatic nitrogen mustard, etc., and effective drug administration has always been a problem. The solubility of hydrophobic drugs can be appropriately increased by organic solvents, but the potential toxicity of organic solvents may cause harm to patients. [0003] Modifying the chemical structure of hydrophobic drugs to improve the hydrophilicity of hydrophobic drugs is the most common way to improve drug efficacy. Many hydrophobic drugs have achieved...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/54A61K9/127A61P35/00
Inventor 李新松方硕张伟凌龙兵张叶敏
Owner SOUTHEAST UNIV
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