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Pharmaceutical formulations for the sustained release of interleukins and therapeutic applications thereof
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An interleukin, sustained-release technology, applied in the pharmaceutical preparation of sustained-release interleukin and its therapeutic application, can solve the problems of denaturation, loss of biological activity, protein contact, etc., and achieve the effect of prolonging the release time
Inactive Publication Date: 2013-01-16
FLAMEL TECHNOLOGIES
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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
[0050] Among the preparations disclosed in the prior art related to the colloidal suspension of nanoparticles of hydrophobically modified polyamino acids, none of them can do the following two points:
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Embodiment 1
[0262] Example 1: Amphiphilic Polymer P1
[0263] Synthesis of Linked Polyglutamic Acid and Synthetic α-Vitamins
[0264] 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 of D, L-α-vitamin (>98%, ), 0.09 g of 4-dimethylaminopyridine pre-dissolved in 6 ml DMF and 0.57 g of diisopropylcarbodiimide pre-dissolved in 6 ml 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 water...
Embodiment 2
[0265] Example 2: Amphiphilic polymers P1, P2, P3, P4, P5 and P6
[0266] 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.
[0267] Table 1
[0268]
[0269] 1 equivalent to polyoxyethylene
[0270] 2 Molecular attachment rates assessed by proton NMR
[0271] 3 synthetic source
Embodiment 3
[0272] Example 3: Preparation of long-acting interleukin 2 (IL2) formulations of the invention based on polymer P3
[0273] 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.
[0274] The required amount of lyophilized IL2 was concentrated to X / (X-1) times the desired final concentration.
[0275] The precise concentration of the concentrated IL2 solution was determined by a Perkin Elmer Lambda 35 UV spectrophotometer at 280 nm.
[0276] 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 for the formulation is referred to as Y.
[0277] The protein solution and polymer solution were then mixed at room temperature, ad...
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Abstract
A liquid pharmaceutical formulation (I) for prolonged release of interleukin(s) (IL) comprises a low viscosity aqueous colloidal suspension of submicron particles of water-soluble, biodegradable polymers (II) carrying hydrophobic groups, non-covalently associated with IL(s) and optionally other active agent(s), where on parenteral injection (I) forms a gelled depot for prolonging the duration of active agent release to more than 24 hours. A liquid pharmaceutical formulation (I) for prolonged release of interleukin(s) (IL) comprises a low viscosity aqueous colloidal suspension (with water as dispersion medium) based on submicron particles (SMP's) of water-soluble, biodegradable polymers (II) carrying hydrophobic groups (HG's), non-covalently associated with IL(s) and optionally other active agent(s). On parenteral injection, (I) forms a gelled depot in vivo (at least partially due to physiological proteins), controlling and prolonging the duration of active agent release to more than 24 hours. (I) is liquid under the injection conditions; at physiological temperature and / or pH; and / or in presence of physiological electrolytes at physiological concentrations and / or surfactant(s). Independent claims are included for: (1) a variant of (I) as described above, where the duration of release of active agents is not restricted but the concentration of (II) is sufficiently high to form a gelled depot in vivo in presence of protein(s) after parenteral injection; (2) novel derived products (preferably in powder or gel form), consisting of SMP's formed by non-covalent association of (II) and active agents as above and obtained from (I); and (3) methods of preparation of (I). ACTIVITY : Antiinflammatory; immunomodulator. MECHANISM OF ACTION : T-Lymphocyte activator; T-lymphocyte proliferation profieration inducer.
Description
technical field [0001] The present invention relates to novel pharmaceutical formulations based on sustained release of proteinaceous active ingredients, interleukins (IL), based on stable, fluid solution-colloid suspensions, and to the therapeutic use of these formulations. These active pharmaceutical preparations 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 their well-...
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