NEW HYDROCORTISONE HEMISUCCINATE LYOPHILIZATE

Abstract

A lyophilized powder for the preparation of a solution for intravenous or parenteral injection comprising: from 1% to 30% of hydrocortisone hemisuccinate; from 40% to 98% of a bulking agent chosen from mannitol, trehalose, lactose, sucrose, raffinose or sorbitol; from 1% to 30% of a buffering agent; and use thereof for the preparation of a solution for intravenous or parenteral injection useful for the prevention or the treatment of the bronchopulmonary dysplasia in premature infants.

Claims

1. A lyophilized powder for the preparation of a solution for intravenous or parenteral injection comprising: from 1% to 30% of hydrocortisone hemisuccinate; from 40% to 98% of a bulking agent chosen from mannitol, trehalose, lactose, sucrose, raffinose or sorbitol; from 1% to 30% of a buffering agent.

2. The lyophilized powder according to claim 1, wherein it contains from 5% to 15% of hydrocortisone hemisuccinate.

3. The lyophilized powder according to claim 1, wherein the bulking agent is chosen as being mannitol or trehalose.

4. The lyophilized powder according to claim 1, wherein it contains from 60% to 90% of bulking agent.

5. The lyophilized powder according to claim 1, wherein the buffering agent is chosen as being citrate, phosphate, TRIS, histidine or HEPES as well as the associated salts.

6. The lyophilized powder according to claim 1, wherein it contains from 5% to 15% of buffering agent.

7. A method of preparing a lyophilized powder according to claim 1 comprising the following steps: addition at room temperature of the buffering agent at 70% (v/v) to 90% (v/v) of the total water necessary for the preparation of the solution before lyophilization; addition of the hydrocortisone hemisuccinate; adjustment of the pH of the solution to a value varying from 7 to 8; addition of the bulking agent; addition of the rest of the necessary water; filtration of the solution; lyophilization of the obtained solution.

8. A use of a lyophilized powder according to claim 1 for the preparation of a solution for intravenous or parenteral injection in premature or very premature infants.

9. A kit for the preparation of a solution for intravenous or parenteral injection in premature or very premature infants comprising: the lyophilized powder according to claim 1; and a reconstitution solution.

10. A solution for intravenous or parenteral injection obtained from the kit according to claim 9 for use in the prevention or the treatment of the bronchopulmonary dysplasia in premature or very premature infants.

Description

EXAMPLE 1

Preparation of a Lyophilized Powder according to the Invention

[0049] 1.1 Lyophilizate L1

[0050] A lyophilized powder L1, the composition of which is reported in the following Table 1, was prepared according to the method described below.

TABLE-US-00001 TABLE 1 Lyophilizate L1 Ingredient % (w/w) Hydrocortisone hemisuccinate 10.5% Trehalose (bulking agent) .sup. 79% Sodium phosphate (buffering agent)   1% Disodium phosphate (buffering agent)  9.5% Sodium hydroxide (pH adjustment) qs target pH Orthophosphoric acid (pH adjustment) qs target pH

[0051] 0.23 g of sodium phosphate and 2.41 g of disodium phosphate are solubilized in 800 ml of water for a preparation injectable at room temperature. After stirring and complete dissolution, 2.66 g of hydrocortisone hemisuccinate are added, still with stirring. The pH is adjusted to 7.4 until the active ingredient is completely dissolved. 20 g of trehalose are then added to the solution. All the powders being solubilized, the pH is adjusted to the target, i.e., 7.0 +/−0.1, and the water level is topped up to 1 liter.

[0052] The lyophilization is then carried out according to the cycle reported in the following Table 2.

TABLE-US-00002 TABLE 2 Lyophilization cycle No. Step Temperature Pressure Duration 1 Freezing −45° C. Atmospheric 1 hour 2 Annealing −25° C. Atmospheric 5 hours 3 Primary dessiccation −30° C. 70 μbar 44 hours 4 Secondary dessiccation +30° C. 25 μbar 10 hours 5 Capping under nitrogen +5° C. 50 mbar N/A

[0053] 1.2 Lyophilizate

[0054] A lyophilized powder L2, the composition of which is reported in Table 3, is prepared according to the method described in Example 1.1 above.

TABLE-US-00003 TABLE 3 Lyophilizate L2 Ingredient % (w/w) Hydrocortisone hemisuccinate 17.4% Mannitol (bulking agent) 65.4% Sodium phosphate (buffering agent) 1.6% Disodium phosphate (buffering agent) 15.7% Sodium hydroxide (pH adjustment) qs target pH Orthophosphoric acid (pH adjustment) qs target pH

[0055] 1.3 Reference

[0056] A so-called reference lyophilized powder “L.sub.ref”, the composition of which is reported in Table 4, is prepared according to the method described in Example 1.1 above,

TABLE-US-00004 TABLE 4 Reference lyophilizate L.sub.ref. Ingredient % (w/w) Hydrocortisone hemisuccinate 2% Glucose (bulking agent) 97%  Disodium phosphate (buffering agent) 1% Hydrochloric acid qs target pH Sodium hydroxide qs target pH

[0057] 2. Reconstitution of the Injection Solution

[0058] The reconstitution of the injection solution is carried out by adding 1 ml of a water/glucose reconstitution solution (4.5/95,5) to a lyophilizate containing 1 mg of hydrocortisone (L1, L2 or L.sub.ref). 1 ml of hydrocortisone solution at 1 mg/ml is thus obtained.

[0059] With the lyophilizates L1 and L2, reconstitution is done immediately after a slight stirring of the the vial to homogenize the solution. The reconstitution therefore does not have any difficulty and is carried out as easily as with the lyophilized powders currently on the market which do not contain bulking agent.

[0060] The solution can then be withdrawn for injection using a syringe and a needle or a syringe and a transfer device with no further dilution required. Thus, the risk of calculation or handling error that could lead to a dosage error as well as the risk of microbial contamination are greatly reduced compared to the products currently on the market.

[0061] On the contrary, with the lyophilizate L.sub.ref., there is a marked tendency to collapse regardless of the storage temperature, which makes the reconstitution more difficult, The reconstitution time is thus about 30 seconds when the lyophilizate is stored at 5° C. and can go up to 150 seconds when the lyophilizate is stored at 25° C. or 40° C. In addition, this marked tendency to collapse reveals an instability over time of the lyophilizate, regardless of the storage temperature.

[0062] 3. Stability of the Lyophilizates

[0063] The lyophilizates L1 and L2 were stored at the temperatures of 5° C., 25° C. and under accelerated stability conditions at 40° C. Analyzes aimed at determining the level of impurities (i.e., free hydrocortisone), and therefore the physico-chemical stability of the formulations, were carried out at T.sub.0, T.sub.0+1 month, T.sub.0+2 months and T.sub.0+3 months.

[0064] The results are reported in the following Table 5.

TABLE-US-00005 TABLE 5 Evolution of the free hydrocortisone impurity for the formulations L1 and L2 at T.sub.0, T.sub.0 + 1 month, T.sub.0 + 2 months and T.sub.0 + 3 months at 5° C., 25° C. and 40° C. Free hydrocortisone ratio (% (w/w)) Formulation/ T.sub.0 + 1 T.sub.0 + 2 T.sub.0 + 3 Storage conditions T.sub.0 month months months L1/5° C. 0.6 0.8 0.8 0.8 L1/25° C. 0.6 0.9 1.0 1.1 L1/40° C. 0.6 1.4 1.9 2.4 L2/5° C. 0.7 0.8 0.9 1.0 L2/25° C. 0.7 1.8 3.0 4.0 L2/40° C. 0.7 7.0 12.4 15.6

[0065] The tolerated impurity limit ratio is 6.7% (w/w).

[0066] It is noted that the lyophilizates L1 and L2 are stable when stored at 5° C. and at 25° C. at T.sub.0+3 months. The lyophilizate L1 remains stable even when stored under accelerated storage conditions at 40° C.