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High penetration compositions and uses thereof

Inactive Publication Date: 2009-09-24
TECHFIELDS BIOCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0005]Modifications of the known NSAIAs have been reported to improve their efficacy and decrease their side effects. However, to treat inflammation or pain at distal areas, a much higher plasma concentra

Problems solved by technology

Active agents or drugs that are effective in vitro may not be as effective in vivo due to the delivery difficulties in vivo, in particular, their limited penetration ability across one or more biological barriers before reaching the site of action where diseases occur in vivo.
Since higher dosage of drugs is required to reach a distal location in the systematic administration, drugs delivered by such a route may cause adverse reactions.
For instance, aspirin is known to cause gastric mucosal cell damage.
The side effects of NSAIAs appear to be dose-dependent, and in many cases severe enough to pose the risk of dyspepsia, gastroduodenal bleeding, gastric ulcerations, gastritis, ulcer perforation, and even death.
It is very difficult, however, to deliver therapeutically effective plasma levels of these drugs by the formulation.

Method used

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  • High penetration compositions and uses thereof
  • High penetration compositions and uses thereof
  • High penetration compositions and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of a HPP from a Parent Drug

[0433]i) Preparation of a HPP from a Parent Drug which Contains at Least One Carboxylic Group.

[0434]In certain embodiments, the parent compound having the following Structure C:

[0435]is converted to a HPP having Structure A:

[0436]including stereoisomers and pharmaceutically acceptable salts thereof, wherein:

[0437]X is selected from the group consisting of nothing, O, P(O)OR1, NH, NR1 and S; and

[0438]each R1, R2, R3 and R4 are independently selected from the group consisting of nothing, H, CH2COOR6, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxyl, substituted and unsubstituted perfluoroalkyl, substituted and unsubstituted alkyl halide, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl groups, wherein any CH2 in R1, R2, R3 and R4 may be further independently replaced with O, S, P, NR1, or any other pharmaceutical...

example 2

The HPPs have Higher Aqueous Solubility Comparing to their Parent Drugs

[0515]HPPs have higher aqueous solubility comparing to their parent drugs (Table 1).

TABLE 1Solubility of NSAIAs and NSAIA-HPPsHPP(g / L)Parent Drug(g / L)diethylaminoethyl acetylsalicylate•AcOH in pH 7>300Aspirin0.01phosphate bufferdiethylaminoethyl 5-(2,4-difluorophenyl)salicylate•AcOH>400Diflunisal0.05in waterdiethylaminoethyl salicylsalicylate•AcOH>350Salsalate0.07diethylaminoethyl salicylate•AcOH>400salicylic acid0.1diethylaminoethyl 2-(ρ-isobutylphenyl) propionate•AcOH>300Ibuprofen0.05in waterdiethylaminoethyl 2-(3-benzoylphenyl)propionate•AcOH>450Ketoprofen0.1in waterdiethylaminoethyl 2-(3-phenoxyphenyl)propionate•AcOH>450Fenoprofen0.1diethylaminoethyl 2-(6-methoxy-2->450Naproxen0.1,naphthyl)propionate•AcOHdiethylaminoethyl α-methyl-4-(2->400Suprofen0.1thienylcarbonyl)benzeneacetate•AcOH,diethylaminoethyl α-methyl-(p-chlorobenzoyl)-5->450α-methyl-(p-0.2methoxy-2-methylindole 3-acetate•AcOH,chlorobenzoyl)-5-meth...

example 3

HPPs have Higher In Vitro Penetration Rates Across Human Skin Comparing to their Parent Drugs

[0516]The penetration rates of HPPs and their parent drugs through human skin are measured in vitro by modified Franz cells. The Franz cells have two chambers, the top sample chamber and the bottom receptor chamber. The human skin tissue (360-400 μm thick) that separates the top and the receptor chambers is isolated from the anterior or posterior thigh areas.

[0517]The compound tested (2 mL, 20% in 0.2 M phosphate buffer, pH. 7.4) are added to the sample chamber of a Franz cell. The receptor chamber contains 10 ml of 2% bovine serum albumin in saline which is stirred at 600 rpm. The amount of the tested compound penetrating the skin is determined by high-performance liquid chromatography (HPLC) method. The results are shown in FIG. 1. The apparent flux values of the tested compounds are calculated from the slopes in FIG. 1 and summarized in Table 2.

[0518]Because the lowest detectable apparent...

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Abstract

The present invention relates to compositions and uses of novel high penetration compositions or high penetration prodrugs (HPP), in particular HPPs for non-steroidal anti-inflammatory agents (NSAIAs), which are capable of crossing biological barriers with high penetration efficiency. The HPPs herein are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, due to the ability of penetrating biological barriers, the HPPs herein are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs herein can be administered to a subject through various administration routes. For example, the HPPs can be locally delivered to an action site of a condition with a high concentration due to their ability of penetrating biological barriers and thus obviate the need for a systematic administration. For another example, the HPPs herein can be systematically administer to a biological subject and enter the general circulation with a faster rate.

Description

PRIORITY CLAIM[0001]The present application is a continuation-in-part application of International Application PCT / WO2008 / 007171, with an international filing date of Jul. 9, 2006; a continuation-in-part application of International Application PCT / WO2008 / 010025, with an international filing date of Jul. 18, 2006; a continuation-in-part application of International Application PCT / WO2008 / 012602, with an international filing date of Jul. 25, 2006; a continuation-in-part application of International Application PCT / WO2008 / 012603, with an international filing date of Jul. 26, 2006; a continuation-in-part application of International Application PCT / WO2008 / 012605, with an international filing date of Jul. 27, 2006; a continuation-in-part application of International Application PCT / WO2008 / 017903, with an international filing date of Aug. 8, 2006; a continuation-in-part application of International Application PCT / WO2008 / 020270, with an international filing date of Aug. 15, 2006; a conti...

Claims

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Application Information

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IPC IPC(8): A61K31/625A61K31/60A61B10/00A61P9/10A61P9/04A61P9/12A61P25/28A61P25/16A61P37/02A61P19/02A61P29/00A61P17/06A61P17/10A61P17/00A61P35/00A61P35/02A61P19/10A61P19/08
CPCA61K47/48023A61K31/216A61K31/24A61K47/54A61P9/04A61P9/10A61P9/12A61P17/00A61P17/06A61P17/10A61P19/02A61P19/08A61P19/10A61P25/16A61P25/28A61P29/00A61P35/00A61P35/02A61P37/02A61K9/0014A61K9/0043A61K9/0073A61K9/703A61L15/44A61L2300/21
Inventor YU, CHONGXIXU, LINA
Owner TECHFIELDS BIOCHEM CO LTD
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