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Acrylic and/or methacrylic polymer including alpha-tocopherol grafts

A technology of methacrylic acid and grafting side chains, which is applied in the directions of medical preparations containing active ingredients, preparations for skin care, and medical preparations without active ingredients, etc., can solve the problems of high manufacturing cost, high cost, and difficulty in dissolving.

Inactive Publication Date: 2012-08-22
FLAMEL TECHNOLOGIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] However, this approach has two major limitations in particular: on the one hand, moderately soluble AIs (e.g., peptides of average solubility) are difficult to dissolve in hydrophobic cores, and, on the other hand, the preparation of nanoparticles involves Dissolving PLGA phase, which should be avoided for some fragile AIs
[0013] However, this alternative has the disadvantage that it is particularly expensive, especially for polymers of the glutamic acid type.

Method used

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  • Acrylic and/or methacrylic polymer including alpha-tocopherol grafts
  • Acrylic and/or methacrylic polymer including alpha-tocopherol grafts
  • Acrylic and/or methacrylic polymer including alpha-tocopherol grafts

Examples

Experimental program
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Effect test

Embodiment 1

[0265]Synthesis of polymer 1: polyacrylic acid substituted with approximately 5 mole % of α-tocopherol grafted side chains linked through alanine

[0266] Stage 1: Purification of commercial polyacrylic acid (Degacryl 4779L)

[0267] 75 g of DEGACRYL 4779L solution (commercially available from Evonik) was diluted with 1425 g of milli-Q water, followed by diafiltration with 8 volumes of water. The solution obtained was then freeze-dried. The average molar mass Mn measured by size exclusion chromatography was 33.6 kDa in PMMA (polymethyl methacrylate) equivalent and the polydispersity index was 2.4.

[0268] Phase 2: Synthesis of alanine and alpha-tocopheryl ester (AlaVE)

[0269] Add 22.08 mL of N,N'-diisopropylcarbodiimide (DIPC) dropwise to 21.1 g of N-tert-butoxyalanine, 40 g of α-tocopherol and 0.567 g of dimethylamino A solution of pyridine (DMAP) in 400 mL of dichloromethane. After stirring at 20°C for 22 hours, the reaction mixture was washed successively with 0.1N h...

Embodiment 2

[0274] Synthesis of polymer 2: polyacrylic acid substituted with approximately 8 mole % of α-tocopherol grafted side chains linked through alanine

[0275] 1.20 g of AlaVE (stage 2 of Example 1) was dissolved in 10 mL of DMF and 0.31 mL of triethylamine. Meanwhile, 2 g of purified Degacryl (Stage 1 of Example 1) was dissolved in 50 mL of DMF and 0.14 g of DMAP. The solution was cooled to 15°C and a suspension of AlaVE / triethylamine and 0.49 g of DIPC were added successively. The reaction mixture was stirred overnight at 15°C. After adding 35% HCl solution (0.23 mL) diluted with 2 mL of DMF, the reaction mixture was neutralized with 1 N soda in 110 mL of water, and the resulting suspension was dialyzed against saline (0.9% NaCl), followed by water Dialyzed and finally concentrated to 250 mL. 110 mL of ethanol was added, and the resulting mixture was heated at 45° C. for 2 hours and then stirred overnight at room temperature. The solution obtained was diafiltered with 8 volu...

Embodiment 3

[0278] Synthesis of polymer 3: polyacrylic acid substituted with approximately 10 mole % of α-tocopherol grafted side chains linked through alanine

[0279] Stage 1: Purification of commercial polyacrylic acid (Acumer 1100)

[0280] 100 g of Acumer 1100 (commercially available from Rohm and Haas) was diluted with 1000 g of milli-Q water. The solution was adjusted to pH = 1.9 with 1N HCl solution and subsequently diafiltered with 8 volumes of water. The solution obtained was then freeze-dried. The average molar mass Mn measured by size exclusion chromatography was 14.5 kDa in PMMA (polymethylmethacrylate) equivalent and the polydispersity index was 1.27. Stage 2: Grafting of AlaVE onto purified polyacrylic acid

[0281] 7.48 g of AlaVE was dissolved in 190 mL of DMF and 1.95 mL of triethylamine. Meanwhile, 10 g of purified Acumer (stage 1) was dissolved in 250 mL of N,N-dimethylformamide (DMF) and 0.85 g of 4-dimethylaminopyridine (DMAP). The solution was cooled to 15°C an...

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Abstract

The present invention relates to a novel family of acrylic and / or methacrylic polymers, including alpha-tocopherol grafts, suitable for forming nanoparticles in an aqueous medium with neutral pH. The invention also relates to the use of such nanoparticles, associated in a non-covalent manner with an active agent, in particular an active agent with low or medium solubility in water, in order to convey, make soluble and / or increase the solubility in water of said active agent.

Description

technical field [0001] The present invention relates to a polymer having a linear backbone of the acrylic and / or methacrylic type, said polymer comprising alpha-tocopherol grafted side chains attached to said backbone. These polymers form nanoparticles in water which are able to bind various active ingredients, which has been shown to be particularly advantageous for the purpose of increasing the water solubility of the active ingredients. Background technique [0002] As described below, a large number of active ingredients, whether medical, prophylactic or cosmetic, may have formulation problems related to perceived insufficient water solubility. [0003] In particular, it has proven very difficult to formulate poorly water-soluble active ingredients in a form compatible with administration by the oral route, for which active ingredients are particularly useful, especially in terms of patient comfort and compatibility with bulk formulations . [0004] Thus, the oral bioa...

Claims

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Application Information

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IPC IPC(8): C08F220/30C08F220/58A61K8/81A61K31/337A61K31/403A61K31/496A61K47/32
CPCA61K8/8152A61K9/5138A61K31/00A61K47/32A61Q19/00C08F220/30C08F220/302C08F220/58A61K31/337
Inventor 陈友平奥利维尔·布雷内阿兰·康斯坦西斯
Owner FLAMEL TECHNOLOGIES
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