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Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate

A compound and composition technology, applied in skin diseases, organic chemistry, antipyretics, etc., can solve problems such as slow skin penetration

Active Publication Date: 2009-08-12
TECHFIELDS BIOCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the slow skin penetration of these drugs, it is difficult to achieve therapeutically effective plasma concentrations by means of formulations

Method used

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  • Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate
  • Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate
  • Positively charged water-soluble prodrugs of acetaminophen and related compounds with very fast skin penetration rate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0049] Preparation of N-acetyl-4-aminophenyl diethylaminobutyrate hydrochloride

[0050] 15.1 g (0.1 mol) of acetaminophen and 16 g (0.1 mol) of diethylaminobutyric acid were dissolved in 300 ml of dichloromethane. The reaction was cooled to 0°C with an ice bath. 20.6 g (0.1 mol) of N,N'-dicyclohexylcarbodiimide are added. The mixture was stirred at 0°C for 1 hour and at room temperature for 2 hours. The solids were removed by filtration. The dichloromethane solution was washed twice with 100ml of 5% sodium bicarbonate solution, and then washed three times with 100ml of water. The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added to the reaction mixture with stirring. The solid product was collected by filtration. After drying, 27 g of the hygroscopic target product was obtained with a yield of 82.1%. Solubility in water: 400mg / ml; Elemental analysis: C 16 h 25 ClN 2 o 3 ;Molecular weigh...

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PUM

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Abstract

The novel positively charged pro-drugs of acetaminophen, acetaminosalol, and related compounds in the general formula (1) 'Structure 1' were designed and synthesized. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin ~150 times faster than does acetaminophen, acetaminosalol, and related compounds. It takes 1-2 hours for acetaminophen and acetaminosalol, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about ~50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can be changed back to the parent drugs in a few minutes. The prodrugs can be used medicinally for treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and avoid most of the side effects of NSAIAs. Controlled transdermal administration systems of the prodrugs enables acetaminophen, acetaminosalol, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of acetaminophen, acetaminosalol, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

Description

technical field [0001] The present invention relates to positively charged, water-soluble prodrugs of acetaminophen, acetaminophen, and related compounds and their use in the treatment of any acetaminophen and acetaminophen-treated state in humans or animals Applications. Specifically, the present invention is directed to overcoming the side effects associated with the use of acetaminophen and its related compounds. These prodrugs can be administered orally or transdermally. Background technique [0002] N-acetyl-p-aminophenol (acetaminophen), 4-acetylaminophenyl salicylic acid (acetamoxalol) and their related compounds belong to the 4-aminophenol nonsteroidal anti-inflammatory drugs. N-acetyl-p-aminophenol (acetaminophen) is a major antipyretic and analgesic drug. Acetaminophen is well tolerated, does not have many of the side effects of aspirin, and is available without a prescription. They are used to relieve the signs and symptoms of rheumatoid arthritis and osteoart...

Claims

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Application Information

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IPC IPC(8): C07C211/64C07C215/42C07C233/07
CPCC07C233/25A61P11/06A61P17/00A61P27/06A61P27/16A61P29/00A61P35/00
Inventor 于崇曦徐丽娜
Owner TECHFIELDS BIOCHEM CO LTD
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