Long-acting colloidal insulin formulation and its preparation
View Patent ↗The invention relates to injectable long-acting insulin formulations for the treatment of types I and II diabetes in humans and animals. The essential object of the invention is to provide an injectable long-acting insulin formulation in the form of a colloidal suspension which is stable, which has a good local tolerance and toxicity compatible with the chronic treatment of diabetics, and which maintains a substantial hypoglycemic effect extending over at least 24 hours after a single administration, e.g. by the subcutaneous route. To achieve this object, the invention relates to a stable aqueous colloidal formulation of insulin-laden nanoparticles of at least one poly(Leu-block-Glu) in which the pH is between 5.8 and 7.0, the osmolarity O (in mOsmol) . . . : 270≦O≦800, and the viscosity v (in mPa·s) is low, namely v≦40. The nanoparticles of poly(Leu-block-Glu) have a mean hydrodynamic diameter Dh such that: 15≦Dh≦40. The invention relates to an antidiabetic drug based on this long-acting insulin formulation and injectable using needles of gauge 29 G, 30 G or 31 G.
1. Injectable long-acting insulin formulation comprising a stable aqueous colloidal suspension of insulin-laden nanoparticles of at least one poly(L-leucine-b-sodium L-glutamate)—hereafter called poly(Leu-block-Glu)—characterized in that:
I—the pH of the formulation is: 5.8≦pH≦7.0
II—the osmolarity O (in mOsmol) of the formulation is: 270≦O≦800
III—the viscosity v (in mPa·s) of the formulation, measured by a procedure Mv, is: v≦40.
2. The formulation according to claim 1 , comprising at least one monovalent or polyvalent salt.
3. The formulation according to claim 1 , wherein the concentration of poly(Leu-block-Glu) is less than 60 mg/ml.
4. The formulation according to claim 1 , wherein the insulin/poly(Leu-block-Glu) weight ratio, expressed in %, is such that: 3≦insulin/poly(Leu-block-Glu).
5. The formulation according to claim 1 , wherein the maximum loading rate of the nanoparticles with insulin, Ta, expressed in % by weight of associated insulin relative to the weight of poly(Leu-block-Glu) and measured by a procedure Ma, is such that: 10≦Ta.
6. The formulation according to claim 1 , wherein the insulin is an unmodified human insulin.
7. The formulation according to claim 1 , wherein said formulation further comprises at least one preservative selected from the group consisting of phenols, cresols, methyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate and mixtures thereof.
8. A method for the preparation of the formulation of claim 1 said method comprising
mixing at least one poly(Leu-block-Glu) and insulin in an aqueous liquid medium,
stirring,
adjusting the pH to a value of between 5.8 and 7.0, and
filtering the resulting suspension.
9. A method for the preparation of the formulation of claim 1 said method comprising
mixing the poly(Leu-block-Glu) in a pulverulent state with an aqueous phase containing insulin.
10. A drug that comprises an injectable long-acting insulin formulation according to claim 1 .
11. Drug according to claim 10 , characterized in that it is intended for the treatment of diabetes.
12. Drug according to claim 10 wherein said drug is capable of providing a diabetic patient with a basal insulin level for at least 24 hours after a subcutaneous injection.