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Pharmaceutical formulations for the sustained release of active ingredient(s), as well as their applications, especially therapeutic application

A preparation and amphoteric molecule technology, applied in the field of new pharmaceutical preparations, can solve the problem of limited release time in a few days, and achieve the effect of good local tolerance

Active Publication Date: 2009-06-24
FLAMEL IRELAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when relatively high concentrations of therapeutic protein are administered, as in the case of human growth hormone, the release time is limited to a few days

Method used

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  • Pharmaceutical formulations for the sustained release of active ingredient(s), as well as their applications, especially therapeutic application
  • Pharmaceutical formulations for the sustained release of active ingredient(s), as well as their applications, especially therapeutic application
  • Pharmaceutical formulations for the sustained release of active ingredient(s), as well as their applications, especially therapeutic application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0344] Embodiment 1: Amphiphilic polymer PO

[0345] Synthesis of Grafted Polyglutamic Acid Using α-Tocopherol as Synthetic Source

[0346] 15 g of α-L-polyglutamic acid (molecular weight of about 16,900 Da relative to polyoxyethylene standard obtained by polymerizing NCAGluOMe followed by hydrolysis as described in patent application FR-A-2801226) was heated at 80°C until it was dissolved in 288 ml in dimethylformamide (DMF). The solution was cooled to 15°C, and 2.5 g of D, L-α-tocopherol (>98%, purchased from Fluka ), 280 mg 4-dimethylaminopyridine pre-dissolved in 1 ml DMF and 1.6 g diisopropylcarbodiimide pre-dissolved in 6 ml DMF. After stirring for 3 hours, the reaction medium is poured into 1200 ml of water containing 15% sodium chloride and hydrochloric acid (pH=2). The precipitated polymer was then recovered by filtration and washed with 0.1N hydrochloric acid, water and diisopropyl ether. The polymer was then dried in a vacuum oven at 40°C, giving a yield of ab...

Embodiment 2

[0347] Example 2: Preparation of 100 g colloidal suspension of polymeric PO nanoparticles loaded with hGH

[0348] 2.1 Preparation of colloidal solution of amphiphilic polymer PO

[0349] The polymer was left in solution overnight to reach a constant temperature of 30°C.

[0350] 35.3 g of the polymer PO of Example 1 were weighed out.

[0351] Dilute with 26.65 g sterile water for injection (for a polymer PO concentration of 28.4 mg / g).

[0352] The polymer solution was stirred magnetically.

[0353] The osmolarity of the solution was adjusted to 300±20 mOsm by adding 1.89 g of 5.13M aqueous NaCl (30% w / w).

[0354] The pH was adjusted to 7.4 ± 0.2 by adding 0.38 g of 1 N NaOH solution.

[0355] 64.22 g of a polymer solution having a concentration of 15.61 mg / g was obtained.

[0356] 2.2 Binding of protein and polymer

[0357] Recombinant human growth hormone (referred to as hGH) solution was thawed at 25°C for 90 minutes.

[0358] Then 35.92 g of hGH solution (conc...

Embodiment 3

[0362] Embodiment 3: with MgCl 2 Preparation of Microparticle Suspensions

[0363] The suspension was prepared from the solution prepared in Example 2, which had adjusted pH and osmolarity and contained 10.0 mg / g PO.

[0364] a) Using a controlled motion syringe with a delivery rate of about 20ml / h, add 1M MgCl under stirring (Apparatus No. 9) 2 The solution flocculates the solution. In this case the proportion of cations added:

[0365] r = 2 × [ Mg 2 + ] [ Glu ]

[0366] Equal to 3.36. A solution containing 8.51 mg / g PO was obtained.

[0367] b) Centrifuge at 2500 rpm for 25 minutes. The osmolarity of the clear supernatant was 646 mOsm.

[0368] c) Wash the residue with sterile water (1 / 8 of the initial solution volume) and...

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Abstract

The present invention concerns new pharmaceutical formulations based on aqueous colloidal suspensions for sustained release of active ingredient(s) - AI - in particular, protein(s) and peptide(s), as well as the applications, especially therapeutic, of these formulations. This formulation comprises an aqueous colloidal suspension with low viscosity based on micrometric particles of amphiphilic polymer PO that is biodegradable, hydrosoluble and carrying hydrophobic groups (HG) - alpha-tocopherol- and ionizable hydrophilic groups (IG) - Glu -, ionized at least in part, said particles being suitable for spontaneously combining non-covalently with an AI at pH = 7.0 under isotonic conditions; and with a size between 0.5 and 100 [mu]m. This suspension contains multivalent ions (Mg<++>) with a polarity opposite that of IH groups of the PO, the ratio r fulfilling the formula (A) where - n is the valence of said multivalent ions - [MI] is the molar of multivalent ions, [IG] is the molar concentration of ionizable groups IG, is between 0.3 and 10.

Description

technical field [0001] The present invention relates to novel pharmaceutical formulations based on hydrocolloid suspensions for the prolonged release of one or more active substances AP, especially protein and peptide active ingredients, and to the use of these formulations, especially in therapeutics Applications. [0002] These pharmaceutical preparations are used both in humans and in animals. Background technique [0003] In the field of prolonged release of active pharmaceutical ingredients, especially therapeutic proteins, it is in many cases ensured that the plasma protein or peptide concentrations of patients are as close as possible to the values ​​of healthy subjects. [0004] This goal cannot be achieved due to the short duration of the protein in plasma, thus requiring repeated injections of the therapeutic protein. Plasma concentrations of therapeutic proteins thus have a "sawtooth" shape, characterized by peaks of high concentration and troughs of very low co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K9/16A61K9/10A61K9/19A61K38/27A61K38/21A61K38/28
CPCA61K38/27A61K38/28A61K9/19A61K9/1676A61K38/212A61K9/0019A61P25/32A61P43/00A61K9/08A61K9/16
Inventor 塞西尔·博内-戈内大卫·绍尼奥特奥利维耶·苏拉阿兰·孔斯坦西斯
Owner FLAMEL IRELAND