Positively-charged water-soluble diclofenac prodrugs with high skin penetration velocity

A technology for transdermal administration of diclofenac, which is applied to the preparation of organic active ingredients, organic compounds, and medical preparations containing active ingredients, etc., and can solve problems such as difficult administration of diclofenac

Inactive Publication Date: 2015-10-14
于崇曦 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is difficult to administer therapeutically effective plasma concentrations of diclofenac in the host by formulation methods

Method used

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  • Positively-charged water-soluble diclofenac prodrugs with high skin penetration velocity
  • Positively-charged water-soluble diclofenac prodrugs with high skin penetration velocity
  • Positively-charged water-soluble diclofenac prodrugs with high skin penetration velocity

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Embodiment approach

[0055] Preparation of dimethylaminoethyl 2-[(2,6-dichlorophenyl)amino]phenylacetate acetate

[0056] 35.1 g (0.1 mol) of 2-[(2,6-dichlorophenyl)amino]phenylacetyl chloride hydrochloride was dissolved in 100 ml of acetone. The mixture was cooled to 0°C. 8.9 g (0.1 mol) of N,N-dimethylaminoethanol was added to the reaction mixture. Add 20g of sodium bicarbonate and 100ml of water to the mixture. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated to dryness. 100ml of acetone was added to the reaction mixture. The solid by-product was removed by filtration and washed 3 times with 30 ml of acetone. 6g of acetic acid was stirred into the mixture. The organic solvent was evaporated to dryness. After drying, 38 g of the hygroscopic target product was obtained with a yield of 88.9%. Solubility in water: 410mg / ml; Elemental analysis: C 20 h 24 Cl 2 N 2 o 4 ;Molecular weight: 427.32. Theoretical value (%) C: 56.21; H: 5.66; Cl: 16.59, N: 6.5...

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Abstract

The invention provides positively-charged water-soluble diclofenac prodrugs with high skin penetration velocity. In a ''structural formula 1'' of a general formula (1), novel positively-charged water-soluble diclofenac prodrugs are designed and synthesized. The compounds as shown in the above-mentioned ''structural formula 1'' of the general formula (1) can be synthesized by reaction of functionalized derivatives (like acid halides or mixed anhydrides) of diclofenac with proper alcohol, thioalcohol or amine. Positively-charged amino groups on prodrug molecules greatly improve the solubility of a drug, and promote the drug to enter cytoplasm by combination with negative charges on biological membrane phosphate terminal groups. Experimental results show that the prodrug, i.e., 2-[(2,6-dichlorophenyl)amino]phenylacetate diethylaminoethyl acetate, has a human skin penetration velocity which is nearly 250 times as fast as the human skin penetration velocity of the prodrugs, i.e., 2-[(2,6-dichlorophenyl)amino]phenylacetate (diclofenac) and 2-[(2,6-dichlorophenyl)amino]phenylacetate ethyl. In plasma, more than 90% of the prodrugs can return to a parent drug in a few minutes. The prodrugs can be applied in medicine to treat human or animal states that any diclofenac can treat; in treatment, oral administration and transdermal administration are available, so that most of side effects of diclofenac are avoided, wherein the most significant side effects comprise gastrointestinal discomforts like indigestion, bleeding in stomach and duodenal, gastric ulcer and gastritis. Through a controlled release transdermal administration system of the prodrugs, the plasma drug concentration is stabilized in an optimal therapeutic level, so the treatment effects are improved, and the side effects of diclofenac are decreased.

Description

technical field [0001] The present invention relates to positively charged water-soluble prodrugs of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid (diclofenac) and any diclofenac-therapeutic prodrugs thereof for medical use in the treatment of humans or animals. State medical use. Specifically, the present invention aims to overcome the side effects caused by the use of diclofenac. These prodrugs can be administered orally or transdermally. technical background [0002] Diclofenac is a nonsteroidal anti-inflammatory drug of the aryl and heterocyclic aryl acetate class. Diclofenac was synthesized for the first time in 1969 (A. Sallman and R. Pfister, Ger. Patent No. 1,815,802). Diclofenac is available in 120 different countries and is probably the most commonly used NSAID in the world. Diclofenac has the aryl alkanoic acid and anthranilic acid structures of anti-inflammatory drugs, and has anti-inflammatory, analgesic and antipyretic effects. In terms of analgesia, the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/42C07C227/18A61K31/196A61P29/00A61P19/02A61P35/00A61P25/06
Inventor 于崇曦徐丽娜
Owner 于崇曦
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