New hydrocortisone hemisuccinate lyophilizate

Abstract

To provide a lyophilized powder for the preparation of a solution for intravenous or parenteral injection useful for the prevention or the treatment of bronchopulmonary dysplasia in premature infants.SOLUTION: The present invention provides a lyophilized powder, comprising: from 2% to 20% of hydrocortisone hemisuccinate; from 60% to 90% of a bulking agent selected from mannitol or trehalose; from 2% to 20% of a buffering agent selected from citrate, phosphate, TRIS, histidine, HEPES, or related salts.SELECTED DRAWING: None

Description

[Technical field]

[0001] The object of the present invention is a novel hydrocortisone hemisuccinate lyophilisate and its use for the preparation of an intravenous or parenteral injection solution useful for the prevention or treatment of bronchopulmonary dysplasia in premature infants. [Background technology]

[0002] Bronchopulmonary dysplasia (BPD) is a chronic lung disease common in preterm or very preterm infants (i.e., less than 32 weeks amenorrhea) who are low birth weight and require mechanical ventilation due to acute respiratory distress syndrome. BPD is one of the major complications and a leading cause of mortality and morbidity in preterm or very preterm infants.

[0003] In very preterm infants, alveolar development is not complete and even the smallest aggressions can alter alveolar maturation, especially when the amniotic fluid is infected.

[0004] In preterm infants, BPD is a risk factor for neonatal death or neurological sequelae, and increases the risk of respiratory problems in childhood. Even in adulthood, ventilatory function can be impaired.

[0005] Intravenous administration of corticosteroids reduces the risk of developing bronchopulmonary dysplasia in preterm or extremely preterm infants. However, to administer them at low doses, commercially available solutions generally need to be highly diluted. This step of preparing the solution before injection carries significant risks of drug formulation errors or microbial contamination of the injection solution.

[0006] To limit these risks, the Directive EMA / CHMP / QWP / 805880 / 2012 Rev. 2 relating to the pharmaceutical development of drugs for pediatric use issued by the European Medicines Agency (EMA) recommends avoiding such dilutions by developing preparations containing an appropriate concentration of the active ingredient.

[0007] Hydrocortisone hemisuccinate, also known as hydrocortisone succinate hydrogen, hydrogen succinate hydrocortisone, or simply hydrocortisone succinate, is a synthetic corticosteroid available commercially in many countries worldwide for the treatment of acute adrenal insufficiency in newborns, transient adrenal insufficiency, and congenital adrenal hyperplasia with salt-wasting syndrome (Debre-Fibiger syndrome).

[0008] This active ingredient is currently available commercially in the form of a lyophilized powder (or lyophilisate) containing 100 mg or 500 mg of hydrocortisone accompanied by a reconstitution solution, since the active ingredient is subject to rapid hydrolysis in aqueous media due to the instability of the ester bond between hydrocortisone and succinate.

[0009] However, the prescribed podosology for the prevention or treatment of bronchopulmonary dysplasia in preterm or extremely preterm infants is 0.5 mg hydrocortisone / kg / 12 hours for the first 7 days and 0.5 mg hydrocortisone / kg / 24 hours for the next 3 days, with the use of lyophilized and reconstituted products containing 100 mg hydrocortisone for administration. After reconstitution from the starting solution (2 ml), the solution obtained must be diluted 50-fold (using a 5% glucose solution).

[0010] At the time of the present invention, there are no preparations available that allow for intravenous (or parenteral) administration of hydrocortisone to preterm or very preterm infants in the doses and volumes described above that can be reconstituted by simply adding a reconstitution solution without subsequent dilution. Summary of the Invention [Problem to be solved by the invention]

[0011] Thus, the need for such compositions is recognized. However, the development of such compositions is very complicated. In fact, it is known that lyophilization is a complicated method and that several parameters must be considered to ensure a consistent product. This method significantly improves the stability of products that are unstable in aqueous media, but particular attention must be paid to the selection of the preparation. In particular, parameters such as pH, nature and amount of excipients in the preparation have a particularly significant effect on the stability of the final lyophilizate prepared. In addition, conflicting information may be obtained about the effect of different excipients on the stabilization of the pharmaceutical active ingredient, which makes it impossible to accurately determine the relationship between the structure of the lyophilizate and its stability, and furthermore, the combination of excipients has an unexpected effect on the stability of the lyophilizate, depending on their nature and proportion. Finally, the above difficulties are even greater when the lyophilizate contains a small (even very small) amount of active ingredient. In fact, a low (even very low) amount of active ingredient in the lyophilizate presupposes the presence of a large amount of bulking agent, which presents additional difficulties in the development of a stable and easily reconstituted preparation.

[0012] Furthermore, it has been discovered, quite unexpectedly, that the use of certain bulking agents in combination with the addition of an amount of buffering agent makes it possible to prepare lyophilisates containing small (even very small) amounts of hydrocortisone hemisuccinate that are stable over time and that can be easily dissolved in a small amount of reconstitution solution to prepare a solution ready for intravenous or parenteral injection into preterm or very preterm infants. [Means for solving the problem]

[0013] The object of the present invention is therefore a lyophilized powder for preparing a solution for intravenous or parenteral injection, comprising: 1 to 30% hydrocortisone hemisuccinate, 40-98% of a bulking agent selected from mannitol, trehalose, lactose, sucrose, raffinose or sorbitol; 1-30% buffer and It is a lyophilized powder comprising:

[0014] The lyophilized powder of the present invention is stable over time when stored at 5° C. and even at room temperature. Additionally, the lyophilized powder of the present invention allows the preparation of solutions for intravenous or parenteral injection into preterm (and even very preterm) infants by simple reconstitution without subsequent dilution for the prevention and treatment of bronchopulmonary dysplasia.

[0015] With respect to the present invention, "Lyophilized powder" or "lyophilisate" means any powder or dry powder containing less than 8% water, preferably less than 5% water, and prepared by any method making it possible to reach such a level of moisture, in particular lyophilization; "Hydrocortisone hemisuccinate" is 11β,17α,21-trihydroxypregn-4-ene-3,20-dione 21-hemisuccinate, CAS number 2203-97-6 (monohydrate form) or 83784-20-7 (anhydrous form) and the chemical structure: [ka] and its pharma- ceutically acceptable salts (especially its sodium salts), A "pharmaceutical acceptable salt" of an active ingredient means any addition salt of said active ingredient with a mineral or organic acid, by the action of such an acid in an organic or aqueous solvent, such as an alcohol, a ketone, an ether or a chlorinated solvent, and which is pharmaceutical acceptable; and "Buffer" means any compound or combination of compounds capable of maintaining the pH of a solution at a stable value (±1, preferably ±0.5). Examples of buffers include, inter alia, citrate, phosphate, TRIS, histidine and HEPES and their related salts.

[0016] In addition, in the context of the present invention, and unless otherwise stated, the percentages expressed in % correspond to mass percentages relative to the total weight of the object.

[0017] Thus, the object of the present invention is a lyophilized powder containing low (even very low) amounts of hydrocortisone hemisuccinate, bulking agents and buffering agents as defined above. Preferably, the object of the present invention is a lyophilized powder as defined above, having the following characteristics, taken alone or in combination: the lyophilized powder contains 2-20% hydrocortisone hemisuccinate, more preferably 5-15% hydrocortisone hemisuccinate, and most preferably 8-12% hydrocortisone hemisuccinate; the bulking agent is selected as being mannitol or trehalose, more preferably the bulking agent is selected as being trehalose; the lyophilized powder contains 50-95% bulking agent, preferably 60-90% bulking agent, and most preferably 75-85% bulking agent; the buffering agent is selected as being a phosphate or one of its salts, preferably the buffering agent is selected as being a phosphate in the form of a sodium salt, and most preferably the buffering agent is selected as being a mixture of monosodium phosphate and disodium phosphate; the lyophilized powder contains 2-20% buffer, preferably 5-15% buffer, and most preferably 8-12% buffer; The lyophilized powder also contains one or more compounds that allow for the adjustment of pH, such as sodium hydroxide or orthophosphoric acid.

[0018] The lyophilized powder according to the invention can be prepared according to any method conventionally used by those skilled in the art. As an example of a method for preparing the lyophilized powder defined above, mention may be made in particular of a method comprising the following steps: Before freeze-drying, prepare the solution by mixing 70-90% (v / v) of the buffer in water at room temperature. adding adding hydrocortisone hemisuccinate; adjusting the pH of the solution to a value in the range of 7.0 to 8.0, preferably 7.0 to 7.4; adding a bulking agent; adding the remainder of the required water; filtering the solution; freeze-drying the resulting solution.

[0019] Thus, the lyophilized powder of the present invention can be used to prepare a solution for intravenous or parenteral injection into preterm or extremely preterm infants by simply adding a reconstitution solution.

[0020] The invention therefore also relates to the use of a lyophilized powder as defined above for preparing a solution for intravenous or parenteral injection into preterm or very preterm infants.

[0021] The present invention also relates to a kit for preparing a solution for intravenous or parenteral injection into a preterm or very preterm infant, said kit comprising: A lyophilized powder as defined above; Reconstituted solution and It is a kit comprising:

[0022] Preferably, the kit according to the invention has the following features, taken either alone or in combination: the kit contains 1 to 50 mg of lyophilized powder, preferably 5 to 30 mg of lyophilized powder, more preferably 10 to 20 mg of lyophilized powder, and most preferably 13 mg of lyophilized powder; the kit contains 0.1 to 10 ml of reconstituted solution, preferably 0.2 to 5 ml of reconstituted solution, more preferably 0.5 to 2 ml of reconstituted solution, most preferably 1 ml of reconstituted solution, and / or The reconstitution solution is selected as being water or a mixture of water and an osmotic agent, preferably a mixture of water and glucose.

[0023] The intravenous or parenteral injection solution obtained from the kit according to the invention can therefore be immediately injected into a preterm (or extremely preterm) infant for the prevention or treatment of bronchopulmonary dysplasia.The invention therefore also relates to an injection solution obtained from the above kit for use in the prevention or treatment of bronchopulmonary dysplasia in preterm or extremely preterm infants.

[0024] Finally, the present invention also relates to a method for preventing or treating bronchopulmonary dysplasia in a preterm or extremely preterm infant, comprising administering to said infant a solution prepared from the kit described above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] The present invention will be described by the following examples without, however, being limited thereto.

[0026] Example 1 Preparation of freeze-dried powder according to the present invention

[0027] 1.1 Freeze-dried product L1 A lyophilized powder L1 having the composition shown in Table 1 below was prepared according to the method described below. [Table 1] Table 1 Freeze-dried product L1

[0028] To obtain a preparation that can be injected at room temperature, 0.23 g of sodium phosphate and 2.41 g of disodium phosphate are solubilized in 800 ml of water. After stirring and complete dissolution, 2.66 g of hydrocortisone hemisuccinate are added and further stirred. The pH is adjusted to 7.4 until the active ingredient is completely dissolved. Then, 20 g of trehalose is added to the solution. When all the powder is solubilized, the pH is adjusted to the target, i.e., 7.0±0.1, and the water level is increased to 1 liter.

[0029] Freeze-drying is then carried out according to the cycle shown in Table 2 below.

[0030] [Table 2] Table 2. Freeze-drying cycle

[0031] 1.2 Freeze-dried product L2 The sintered dry powder L2 having the composition shown in Table 3 is prepared according to the method described in Example 1.1 above.

[0032] [Table 3] Table 3 Freeze-dried product L2

[0033] 1.3 Standards The so-called reference freeze-dried powder "L ref " is prepared according to the method described in Example 1.1 above.

[0034] [Table 4] Table 4 Standard lyophilizate L ref

[0035] 2. Reconstitution of Injection Solution 1 mg of hydrocortisone (L1, L2 or L refThe injection solution is reconstituted by adding 1 ml of water / glucose reconstitution solution (4.5 / 95.5) to the lyophilisate containing 0.1% DMSO. In this way, 1 ml of a 1 mg / ml hydrocortisone solution is obtained.

[0036] With lyophilisates L1 and L2, reconstitution is completed immediately after gentle agitation of the vial to homogenise the solution, and therefore reconstitution is carried out without any difficulties and as easily as with currently available lyophilised powders that do not contain bulking agents.

[0037] The solution can then be drawn up for injection using a syringe and needle or a syringe and transfer device, without the need for further dilution. Hence, the risk of calculation or handling errors that could lead to dosage errors and the risk of microbial contamination are greatly reduced compared to currently available products.

[0038] On the other hand, lyophilized L ref It is significantly more prone to collapse and more difficult to reconstitute, regardless of storage temperature. Therefore, the reconstitution time is 100% when the lyophilisate is stored at 5°C. The time to disintegration is approximately 30 seconds when the lyophilisate is stored at 25° C. or 40° C., increasing to 150 seconds when the lyophilisate is stored at 25° C. or 40° C. In addition, this significant tendency to collapse indicates that the lyophilisate is unstable over time, regardless of storage temperature.

[0039] 3. Stability of the lyophilized product Lyophilisates L1 and L2 were stored at temperatures of 5° C., 25° C. and under accelerated stability conditions at 40° C. Analyses were carried out at the following time points: T0, T0+1, T0+2 and T0+3 months with the aim of determining the level of impurities (i.e. free hydrocortisone) and thus the physicochemical stability of the preparations.

[0040] The results are shown in Table 5 below. [Table 5] Table 5. Progression of free hydrocortisone impurity for preparations L1 and L2 at 5°C, 25°C and 40°C at months T0, T0+1, T0+2 and T0+3

[0041] The permitted impurity percentage limit is 6.7% (w / w).

[0042] The freeze-dried products L1 and L2 had the same T when stored at 5°C and 25°C. 0+3 Lyophilisate L1 remains stable even when stored under accelerated storage conditions at 40°C.

Claims

1. A lyophilized powder for preparing a solution for intravenous or parenteral injection, comprising: 1 to 30% hydrocortisone hemisuccinate; 40-98% of a bulking agent selected from mannitol, trehalose, lactose, sucrose, raffinose or sorbitol; 1-30% buffer; 13. A lyophilized powder comprising:

2. 2. The lyophilized powder of claim 1, wherein the lyophilized powder contains 5-15% hydrocortisone hemisuccinate.

3. 3. The lyophilized powder according to claim 1 or 2, characterized in that the bulking agent is selected as being mannitol or trehalose.

4. The lyophilized powder according to any one of claims 1 to 3, characterized in that the lyophilized powder contains 60 to 90% of a bulking agent.

5. The lyophilized powder according to any one of claims 1 to 4, characterized in that the buffering agent is selected as being citrate, phosphate, TRIS, histidine or HEPES and their related salts.

6. The lyophilized powder according to any one of claims 1 to 5, characterized in that the lyophilized powder contains 5 to 15% of a buffering agent.

7. A method for preparing the lyophilized powder according to any one of claims 1 to 6, comprising the steps of: adding, prior to lyophilization, 70-90% (v / v) of said buffer at room temperature to the total water required for preparation of said solution; adding said hydrocortisone hemisuccinate; adjusting the pH of the solution to a value in the range of 7.0 to 8.0; adding the bulking agent; adding the remainder of the required water; filtering the solution; freeze-drying the resulting solution; The method includes:

8. Use of the lyophilized powder according to any one of claims 1 to 6 for preparing a solution for intravenous or parenteral injection in a preterm or very preterm infant.

9. 1. A kit for preparing a solution for intravenous or parenteral injection into a preterm or very preterm infant, comprising: The freeze-dried powder according to any one of claims 1 to 6, Reconstituted solution and A kit comprising:

10. An intravenous or parenteral injection solution obtained from the kit of claim 9 for use in the prevention or treatment of bronchopulmonary dysplasia in preterm or very preterm infants.

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