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Pharmaceutical formulations for the sustained release of interleukins and therapeutic applications thereof

A sustained-release technology for interleukin, applied in the pharmaceutical formulation of sustained-release interleukin and its therapeutic applications, can solve problems such as loss of biological activity, denaturation, and protein contact, and achieve good local tolerance, Extended release time, good and stable effect

Inactive Publication Date: 2007-03-07
FLAMEL TECHNOLOGIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

First, the irreversible modification of these proteins (now no longer human proteins) can lead to toxic and immunogenic problems in the long run
The second disadvantage stems from the partial loss of biological activity of interleukin IL2 after such modification
This method has some disadvantages: First, during the preparation of the microspheres, the protein is exposed to organic solvents that may denature it
However, the release of the drug is so fast that it does not provide an ideal sustained release

Method used

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  • Pharmaceutical formulations for the sustained release of interleukins and therapeutic applications thereof
  • Pharmaceutical formulations for the sustained release of interleukins and therapeutic applications thereof
  • Pharmaceutical formulations for the sustained release of interleukins and therapeutic applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0261] Example 1: Amphiphilic Polymer P1

[0262] Synthesis of Linked Polyglutamic Acid and Synthetic α-Vitamins

[0263] 5.5 g of α-L-polyglutamic acid (molecular weight of about 10,000 daltons, obtained by hydrolysis and polymerization of NCAGIuOMe relative to standardized polyoxyethylene, refer to patent application FR-a-2801226). Heat at 40°C for two hours and dissolve in 92 ml of dimethylformamide (DMF). After the polymer was dissolved, the temperature was lowered to 25° C., and 1.49 g D, L-alpha-vitamin (>98%, Fluka®) pre-dissolved in 6 ml DMF, 0.09 g 4-dimethylamino Pyridine and 0.57 g of diisopropylcarbodiimide predissolved in 6 ml of DMF. After stirring at 25° C. for 8 hours, the reaction system was poured into 800 ml of water containing 15% sodium chloride and hydrochloric acid (pH 2). The polymer precipitate was then filtered, washed with 0.1N hydrochloric acid and then water and recovered. The polymer was then redissolved in 75 ml DMF and reprecipitated in pH 2...

Embodiment 2

[0264] Example 2: Amphiphilic polymers P1, P2, P3, P4, P5 and P6

[0265] These polymers were prepared in the same manner as polymer P1. Table 1 below summarizes the properties of these polymers. The properties of polymer P1 are also given for comparison.

[0266] polymer

Molecular weight of polyglutamic acid

1 g / mol

Hydrophobic

% Connectivity (NMR) 2

polymer molecule

Amount 1g / mol

P1

10000

alpha-vitamins 3

7

13900

P2

10000

alpha-vitamins 3

4

14400

P3

16900

alpha-vitamins 3

4

15200

P4

10000

cholesterol

5

l1500

P5

16900

cholesterol

5

12900

P6

10000

n-dodecanol

15

11500

[0267] 1 equivalent to polyoxyethylene

[0268] 2 Molecular attachment rates assessed by proton NMR

[0269] 3 synthetic source

Embodiment 3

[0270] Example 3: Preparation of a long-acting interleukin 2 (IL2) formulation of the invention based on polymer P3

[0271] Sufficient amphiphilic polymer lyophilized powder and sterile water were placed in a flask to obtain a polymer concentration X that was 1.3 times the desired final concentration. The polymer was dissolved with magnetic stirring for 16 hours.

[0272] The required amount of lyophilized IL2 was concentrated to X / (X-1) times the desired final concentration.

[0273] The precise concentration of the concentrated IL2 solution was determined by a Perkin Elmer Lambda 35 UV spectrophotometer at 280 nm.

[0274] The IL2 solution was filtered through a 0.8-0.2 micron filter and stored at 4°C. The pH of the solution was adjusted to 11 with 1M NaOH. The ratio of the protein concentration of this solution to the concentration required by the recipe is called Y.

[0275] The protein solution and polymer solution were then mixed at room temperature, adding X-1 lite...

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Abstract

The invention relates to novel pharmaceutical formulations based on fluids and stable aqueous colloidal suspensions for the sustained release of an interleukin IL- (and one or more other optional active principles), and to the applications, particularly the therapeutic applications, of said formulations. The invention aims to provide a fluid pharmaceutical formulation for the sustained release ofinterleukin(s) (and one or more other optional active principles), such that, following parenteral injection, the in vivo IL release time is increased significantly, while the plasma concentration peak thereof is lowered. Moreover, said formulation must be storage stable and, in addition, biocompatible, non-toxic biodegradable, non-immunogenic and well tolerated locally. According to the invention, the formulation is a low-viscosity aqueous colloidal suspension of submicronic particles of water-soluble, biodegradable polymer PO bearing hydrophobic groups (GH). The aforementioned particles arenoncovalently associated with at least one interleukin (and one or more other optional active principles) and form a gelled deposit on the injection site, said gelling being caused by a protein present in the physiological medium.

Description

technical field [0001] The present invention relates to novel pharmaceutical formulations based on the sustained release of proteinaceous active ingredients, interleukins (IL), based on stable colloidal suspensions in fluid solutions, and to the therapeutic use of these formulations. These active pharmaceutical formulations are effective in both humans and animals. Background technique [0002] Interleukins are a group of proteins belonging to the cytokine family. They have numerous activities that modulate inflammatory and immune responses. However, their main role is to activate and induce T lymphocyte proliferation. IL-1, IL-2, IL-11 and IL-12 are one of the important members of this family. For example, IL-2 is produced by antigen activation of T lymphocytes. The purpose of IL-2 is to activate other T lymphocytes to initiate their activation and differentiation, thereby regulating cell-mediated immune responses. [0003] Interleukins are used in therapeutics, but th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/21A61K9/10A61K9/00A61K38/20A61K47/34A61K47/48
CPCA61K47/48907A61K38/20A61K9/0024A61K47/34A61K47/48853A61K38/2013A61K47/6921A61K47/6935A61P29/00A61P37/00A61P43/00A61K9/08
Inventor 索菲·比尼翁雷米·梅吕埃克斯奥利维耶·苏拉
Owner FLAMEL TECHNOLOGIES
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