Hydrocortisone pharmaceutical solution for injection device

Abstract

Hydrocortisone Pharmaceutical Solution for Injection Device. The invention relates to a hydrocortisone pharmaceutical solution comprising, in mg per 1 mL of solution: - between 150 mg and 170 mg of hydrocortisone or a pharmaceutically acceptable salt thereof in equivalent quantity, - between 2 mg and 7.5 mg of monothioglycerol, - q.s. 1 mL of solvent. The invention also relates to its use in the treatment of acute adrenal insufficiency and asthma. The invention further relates to an injection kit comprising an injection device and this pharmaceutical solution. Figure for the abstract: Fig. 1.

Description

Title of the invention: Pharmaceutical hydrocortisone solution for injection device

[0001] The invention relates to a pharmaceutical solution of hydrocortisone or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as "pharmaceutical solution of hydrocortisone") intended to be injected parenterally, in particular intramuscularly.

[0002] Hydrocortisone and hydrocortisone salts are known to be used as anti-inflammatory agents. It is common to use these active substances in the treatment of asthma, endocrine disorders, dermatological disorders and allergic conditions, as well as acute adrenal insufficiency.

[0003] Hydrocortisone and its salts belong to the corticosteroid family.

[0004] Hydrocortisone, as well as its salts, are sensitive to oxidation. Therefore, pharmaceutical solutions of these active substances always include at least one antioxidant.

[0005] For example, the pharmaceutical product marketed by the company AMDIPHARM under the trade name Efcortesol® is known, which is a pharmaceutical solution of hydrocortisone sodium phosphate at a concentration of 13.39% w / v (in other words, there are 13.39 g of this salt in 100 mL of solution). This product is packaged either in 1 mL ampoules containing 100 mg of hydrocortisone, or in 5 mL ampoules containing 500 mg of hydrocortisone. Efcortesol® further comprises: - two antioxidants: disodium ethylenediaminetetraacetate (hereinafter abbreviated as “disodium EDTA”) which also functions as a chelating agent, and sodium formaldehyde bisulfite which is also an antimicrobial, - sodium hydrogen phosphate and sodium dihydrogen phosphate, - water for injection.

[0006] However, sodium formaldehyde bisulfite is not listed on the FDA's GRAS list ("GRAS" being the acronym for "Generally Recognized As Safe"). Furthermore, this antioxidant is not described in the international reference source of information on pharmaceutical excipients, the "Handbook of pharmaceutical excipients".

[0007] Furthermore, in order to respect the dose necessary for the therapeutic indication (for example acute adrenal insufficiency, asthma or any disease requiring rapid and significant administration of a corticosteroid) during an intramuscular injection which involves a smaller injected volume, a higher concentration of the pharmaceutical solution than that proposed by the pharmaceutical product Efcortesol® may be required.

[0008] Therefore, it would be desirable to have a new pharmaceutical solution of hydrocortisone or a pharmaceutically acceptable salt thereof which can be more concentrated than the known Efcortesol® solution and which is stable over time. It would also be advantageous if said solution had, as far as possible, a minimum of unknown impurities for which a laborious characterization and toxicity study would be necessary.

[0009] The inventors of the present invention have sought to develop a new pharmaceutical solution of hydrocortisone or a pharmaceutically acceptable salt thereof intended to be injected parenterally, in particular intramuscularly, by substituting the antioxidants of Efcortesol ®, namely sodium formaldehyde bisulfite and disodium EDTA, with another antioxidant appearing in the lists of pharmaceutical excipients of reference works such as the one mentioned above, said solution having to be free of unknown impurities in significant quantities which would require characterization and being stable over time.

[0010] The inventors of the present invention have discovered that the use of the antioxidant monothioglycerol at a determined concentration in a pharmaceutical solution of hydrocortisone or a pharmaceutically acceptable salt thereof makes it possible to perfectly achieve all these objectives.

[0011] The present invention has as its first subject a pharmaceutical solution of hydrocortisone which comprises in mg per 1 mL of said solution at least: - between 150 mg and 170 mg of hydrocortisone or a pharmaceutically acceptable salt thereof in equivalent quantity, - between 2 mg and 7.5 mg of monothioglycerol, - Qsp 1 mL of solvent.

[0012] “Qsp” is the abbreviation for “quantity sufficient for” meaning that the quantity of solvent is such that the volume of the solution is made up to 1 mL.

[0013] The use of monothioglycerol at a concentration between 2 mg / mL and 7.5 mg / mL gives the hydrocortisone solution a perfectly remarkable stability over time.

[0014] Furthermore, monothioglycerol is an excipient authorized by pharmaceutical administrations.

[0015] Finally, it has been found that a pharmaceutical solution according to the invention has a very low level of impurities, and this under storage conditions (namely temperature- temperature and relative humidity) varied and forced.

[0016] The present invention therefore lies in the selection of monothioglycerol as an antioxidant at a concentration of between 2 mg / mL and 7.5 mg / mL to stabilize a pharmaceutical solution of hydrocortisone.

[0017] The pharmaceutically acceptable salt of hydrocortisone may be selected from hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone hydrogen succinate, hydrocortisone butyrate and hydrocortisone acetate.

[0018] Preferably, the pharmaceutically acceptable salt of hydrocortisone is hydrocortisone sodium phosphate.

[0019] In one embodiment of the invention, the concentration of hydrocortisone in said pharmaceutical solution is 160 mg / mL.

[0020] In one embodiment of the invention, the concentration of monothioglycerol is between 2.5 mg / mL and 5 mg / mL.

[0021] In one embodiment of the invention, the concentration of monothioglycerol is between 5 mg / mL and 7.5 mg / mL.

[0022] The solvent may be any pharmaceutically acceptable solvent that is compatible with hydrocortisone and its salts and all other compounds that comprise said pharmaceutical solution according to the invention. It may be water, in particular water used in injection devices (in other words water for injection), as well as water containing isotonic additives or sodium chloride solutions. The water for injection is ultra-pure and free from bacterial contaminants.

[0023] The pharmaceutical solution may further comprise at least one buffer. For example, it may be a buffer selected from sodium acetate, sodium citrate, sodium dihydrogen phosphate and sodium hydrogen phosphate.

[0024] Preferably, the buffer is a mixture of sodium dihydrogen phosphate and sodium hydrogen phosphate. Most advantageously, the ratio of the mass of sodium dihydrogen phosphate to the mass of sodium hydrogen phosphate is between 0.03 and 0.06.

[0025] In one embodiment of the invention, the buffer concentration in said solution is between 0.1 mg / mL and 3.5 mg / mL.

[0026] The pH of the pharmaceutical solution is advantageously between 7 and 9, preferably between 7.5 and 8.5.

[0027] Said pharmaceutical solution may further comprise at least one acceptable pharmaceutical excipient other than monothioglycerol.

[0028] In one embodiment of the invention, the pharmaceutical solution comprises in mg per 1 mL of said solution: - between 210 mg and 220 mg of hydrocortisone sodium phosphate, - between 2 mg and 7.5 mg, preferably between 2 mg and 5 mg, of monothioglycerol, - between 0.1 mg and 3.5 mg, of at least one buffer, - Qsp 1 mL of solvent, preferably water for injection.

[0029] Preferably, in this embodiment of the invention, the pharmaceutical solution comprises as buffer a mixture of sodium dihydrogen phosphate and sodium hydrogen phosphate, the ratio of the mass of sodium dihydrogen phosphate to the mass of sodium hydrogen phosphate of which is between 0.03 and 0.06.

[0030] The present invention also relates to a process for preparing the pharmaceutical solution according to the invention as described above which comprises at least the following steps: a) a mixture comprising at least the solvent and the monothioglycerol is prepared with stirring; b) hydrocortisone or a pharmaceutically acceptable salt thereof is added thereto with stirring so as to obtain said pharmaceutical solution; c) optionally, at least one filtration step is carried out on the pharmaceutical solution obtained at the end of step b).

[0031] If the pharmaceutical solution comprises buffers, these buffers are, preferably prior to step a), mixed together before being added to the mixture of step a).

[0032] When the pharmaceutical solution comprises at least one pharmaceutically acceptable excipient other than monothioglycerol, this excipient may be added to the mixture of step a).

[0033] The filtration step may comprise at least one filtration chosen from clarifying filtration and sterilizing filtration.

[0034] Preferably, the filtration step consists of a clarifying filtration followed by a sterilizing filtration.

[0035] The invention also relates to the pharmaceutical solution as described above for its use in the treatment of diseases chosen from acute adrenal insufficiency, asthma or any disease requiring the rapid and significant intake of a corticosteroid. Preferably, this is the treatment of acute adrenal insufficiency and asthma.

[0036] Said solution is advantageously in a form suitable for parenteral administration, preferably intramuscularly.

[0037] The present invention also relates to an injection kit, preferably an intramuscular injection kit, comprising: - an injection device; - the pharmaceutical solution according to the invention as described above.

[0038] Advantageously, the injection volume of the injection device is between 0.60 mL and 0.65 mL.

[0039] Said injection device may be single-use. For example, it is a ready-to-use pre-filled tube.

[0040] In a preferred embodiment of the invention, said device is a pre-filled, single-use, needle-free and automatic injection device thanks to a gas generator with which it is equipped. It may be a needle-free injection device with a pyrotechnic cartridge. In this regard, patent applications FR 2 815 544 A1 and FR 2 807 946 A1 describe an example of this injection device.

[0041] In a completely advantageous manner, the injection device is a device marketed by the company Crossject under the trade name ZENEO®.

[0042] Thus, in one embodiment of the injection kit according to the invention, the injection device is a needle-free injection device with a pyrotechnic cartridge.

[0043] The invention will be better understood with the aid of the detailed description which is set out below with reference to the appended drawing representing, by way of non-limiting example, experimental results of solutions according to the invention and comparative results.

[0044] [Fig. 1] [Fig. 1] is a graph of the content of a first impurity as a function of time for different pharmaceutical solutions according to the invention and comparative ones.

[0045] [Fig.2] [Fig.2] is a graph of the content of a 2nd impurity as a function of time for different pharmaceutical solutions according to the invention and comparative ones.

[0046] EXPERIMENTAL PART:

[0047] Experiments were carried out in order to compare the physicochemical properties and in particular their impurity content of: - 4 solutions according to the invention whose concentration of hydrocortisone sodium phosphate was 214.7 mg / mL and the concentration of monothioglycerol was between 2 mg / mL and 7.5 mg / mL; - 4 comparative solutions with a hydrocortisone sodium phosphate concentration of 214.7 mg / mL and a monothioglycerol concentration of 0 to 1 mg / mL, and finally - a solution similar to the reference product Efcortesol ® except that its hydrocortisone sodium phosphate concentration had been increased and had been set at 214.7 mg / mL, to correspond to the hydrocortisone sodium phosphate concentration of the solutions according to the invention and of the comparative solutions to be in the same test conditions.

[0048] Table 1 below details the composition of the solution similar to the reference product Efcortesol ® (hereinafter: “Ref”) in mg per 1 mL of said solution.

[0049] [Tables 1] Ingredients Quantity in mg Hydrocortisone sodium phosphate 214.7 Sodium hydrogen phosphate 2.9 Sodium hydrogen phosphate 0.1 Disodium EDTA 0.9 Sodium formaldehyde bisulfite 1.7 Water Qsp 1ml

[0050] Table 2 below details the composition of the 4 comparative solutions (Cl to C4) and the 4 solutions according to the invention (IQ1 to IQ4) in mg per 1 mL of solution.

[0051] [Tables2] ingredients Cl C2 C3 C4 IQ1 IQ2 IQ3 IQ4 hydrocortisone sodium phosphate 214.7 sodium hydrogen phosphate 2.9 sodium dihydrogen phosphate 0.1 mono-thioglycerol 0 0.1 0.5 1.0 2.0 2.5 5.0 7.5 water Qsp 1ml

[0052] In all the solutions prepared and as detailed in Tables 1 and 2 below, above, the hydrocortisone sodium phosphate concentration of 214.7 mg / mL is equivalent to a concentration of 160 mg / mL of hydrocortisone.

[0053] All solutions were obtained in the following manner: (a) a mixture containing sodium dihydrogen phosphate and sodium hydrogen phosphate in water was prepared under stirring, in order to obtain a buffer solution at pH 8.0; b) bubbling of the solution obtained in step a) was carried out; (c) except for solution Cl which was devoid of antioxidant, the antioxidant (i.e. disodium EDTA and sodium formaldehyde bisulfite for solution Ref; and monothioglycerol for all other solutions) was added with stirring, and stirring was maintained until the compounds were completely dissolved; (d) the hydrocortisone sodium phosphate was then added to the mixture while still stirring, said stirring being continued until this salt was completely dissolved so as to obtain a solution.

[0054] Steps c) and d) were carried out under an isolator swept by a nitrogen flow.

[0055] Nitrogen bubbling is a partial inerting which makes it possible to reduce the contact of the pharmaceutical solution with oxygen and therefore to limit the oxidation of said solution.

[0056] The solutions thus obtained were packaged in glass tubes equipped with two stoppers at their ends.

[0057] Specifically, the tubes were filled with 0.65 mL of solution. A nitrogen sweep was applied to the surface of the solutions to remove the oxygen present in the headspace of these tubes. Finally, the tubes were closed.

[0058] For all solutions, the pH and the amount of monothioglycerol were determined at different storage times under a relative humidity of 75% and at a temperature of 40°C.

[0059] Furthermore, from analyses by high-performance liquid chromatography (hereinafter abbreviated as "HPLC"), the following were determined at time intervals for all the solutions: - the area percentages of all impurities present in said solutions; which made it possible to deduce the percentage of purity of said solutions; - the area percentages of two impurities (namely “impurity 1” whose relative elution time was 1.26 minutes and “impurity 2” whose relative elution time was 1.29 minutes); which made it possible to deduce the evolution of the content of these 2 impurities in said solutions over time and which is detailed in tables 7 and 8 and represented in figures 1 and 2.

[0060] These area percentages are expressed relative to the area of ​​the main peak of the solution considered.

[0061] The HPLC analyses were carried out under the following conditions: - a column marketed by the company Phenomenex under the trade name Luna®C18(2) having a particle size of 5 pm and dimensions (250 x 4.6) mm; - flow rate of 1.5 mL / minute; - injection volume of 5 pL; - ultraviolet detector with variable wavelength between 190 and 400 nm or photodiode detector; - wavelength of 254 nm; - column temperature 25°C (+ / -) 2°C; - sample at room temperature; - mobile phase A: 0.1% (v / v) trifluoroacetic acid in purified water; - mobile phase B: 0.1% (v / v) trifluoroacetic acid in acetonitrile.

[0062] Table 3 below details the composition of the mobile phase as a function of time. [Tables 3] Time (minutes) Phase A (%) Phase 8 0 85 15 10 85 15 22 55 45 38 30 70 38.1 85 15 43 85 15

[0063] Table 4 below details the pH values ​​obtained at t equal to 0, then after 1, 3 and 5 months of storage of the solutions at 40°C and under a relative humidity of 75%. The initial monothioglycerol contents of said solutions are recalled in this Table 4. These are the figures in parentheses. “ND” is the abbreviation for “not determined”.

[0064] [Tables4] Time Ref Cl C2 €3 (0.5) C4 U) im R) IQ2 (2.5} IQ3 (5) IQ4 (7.5} 0 8.07 8.22 8.21 8.20 8.14 8.12 8.12 8.16 8.12 1 7.98 8.08 8.07 8.09 8.11 8.09 8.08 8.05 8.04 3 8.00 8.05 8.06 3.09 8.06 8.06 8.01 8.03 8.02 5 ND 8.04 8.05 8.06 8.07 8.03 8.04 8.04 8.01

[0065] In view of the results detailed in Table 4, it is noted that the pH of all the solutions remains stable over time, despite storage under severe conditions, namely at 40°C and with a relative humidity of 75%.

[0066] Table 5 below details the monothioglycerol content in solutions C2 to C4 and IQ1 to IQ4 at 1, 3 and 5 months of storage of the solutions at 40°C and at a relative humidity of 75%. The initial monothioglycerol contents of said solutions are recalled in this Table 5. These are the figures in parentheses.

[0067] [Tables5] Time C2 (0.1) C3 (0.5) C4 U) IQ1 (2) IQ2 (2.5) IQ3 (5) IQ4 (7.5) 1 0 0.05 0.34 1.11 1.50 3.41 5.55 3 0 0 0.04 0.60 0.97 2.79 4.81 5 0 0 0 0.31 0.62 2.33 4.11

[0068] In view of the results detailed in Table 5, it is noted that for solutions C2 to C4, the monothioglycerol content decreases during storage until it disappears completely after 5 months (and after 3 months for solutions C2 and C3). The reduction, or even the absence of monothioglycerol in the tested solution results in the generation of impurities and therefore the instability of the tested solution.

[0069] Unlike solutions C2 to C4, solutions according to the invention IQ1 to IQ4 still have a high monothioglycerol content after 5 months under severe storage conditions.

[0070] Thus, monitoring the evolution of the monothioglycerol content in the solutions tested over time shows that the solutions according to the invention IQ1 to IQ4 are particularly stable in comparison with the comparative solutions C2 to C4.

[0071] Table 6 below details the purity percentages of the solutions at t equal to 0, then after 1, 3 and 5 months of storage at 40°C and under a relative humidity of 75%. The initial monothioglycerol contents of said solutions are recalled in this table 6. These are the figures in parentheses.

[0072] [Tableauxô] Time Ref Cl C2 (0.1) CB (%5) C4 (1) IQ1 (2) IQ2 (2.5} IQ3 (5) 1Q4 (7.5} O 100 iœ 100 WD 100 100 100 100 100 1 99.65 99.87 99.77 99.87 99.87 99.87 99.87 99.87 99.86 3 99.17 99.. 33 99.40 99.42 99.71 99.62 99.61 99.61 99.59 5 ND 98.96 98.97 99.13 99.26 99.28 99.20 99.30 99.30

[0073] In view of the results detailed in Table 6, it is noted that the solutions according to the invention IQ1 to IQ4 exhibit, after 5 months of storage under severe conditions, an excellent purity of the order of 99.3%.

[0074] Table 7 below details the area percentages of the aforementioned impurity 1 at time t equal to 0, then after 1, 3 and 5 months of storage of the solutions at 40°C and under a relative humidity of 75%. The initial monothioglycerol contents of said solutions are recalled in this table 7. These are the figures in parentheses.

[0075] [Tables?] Time Cl (ô) C2 W C3 (0.5) C4 ui IQ1 (2) !Q2 (2.5) IQ3 (5) IQ4 (7.5) O 0 o 0 0 0 0 Ô 0 1 0.06 0.06 0 O 0. 0 0 0 3 0.13 0.13 0.12 0 0.06 0.05 0 0 5 0.21 0.21 0.20 0.17 0.09 0.07 0 0

[0076] [Fig.l] is a graph representing the area percentages of impurity 1 as a function of time for each of the solutions.

[0077] In view of the results detailed in Table 7 and in view of the evolution of the curves in [Fig.l], it can be seen that the solutions according to the invention IQ1 to IQ4 have a percentage of area of ​​impurity 1 much lower than that of the comparative solutions C1 to C4.

[0078] Table 8 below details the area percentages of the aforementioned impurity 2 at time t equal to 0, then after 1, 3 and 5 months of storage of the solutions at 40°C and under a relative humidity of 75%. The initial monothioglycerol contents of said solutions are recalled in this table 8. These are the figures in parentheses.

[0079] [Tables8] Time Cl (O) C2 (0.1) C3 (S, C4 (1) IQ1 (2) IQ2 (2.5) IQ3 (5) !Q4 (7.5) 0 0 0 O 0 0 O 0 0 1 0.07 0.05 0 0 0 0 0 0 3 0.16 0.14 0.08 □ 0 0 0 0 5 0.24 0.21 0.14 0.06 0 0 Y 0

[0080] [Fig.2] is a graph representing the area percentages of impurity 2 as a function of time for each of the solutions.

[0081] In view of the results detailed in Table 8 and in view of the evolution of the curves in [Fig.2], it can be seen that the solutions according to the invention IQ1 to IQ4 do not include of impurity 2 unlike the comparative solutions Cl to C4 whose content tends to increase over time.

Claims

Claims

1. Pharmaceutical solution of hydrocortisone which comprises in mg per 1 mL of said solution at least: - between 150 mg and 170 mg of hydrocortisone or a pharmaceutically acceptable salt thereof in equivalent quantity, - between 2 mg and 7.5 mg of monothioglycerol, - Qsp 1 mL of solvent, "Qsp" being the abbreviation for "quantity sufficient for" meaning that the quantity of solvent is such that the volume of the solution is made up to 1 mL.

2. Pharmaceutical solution according to claim 1, characterized in that the pharmaceutically acceptable salt of hydrocortisone is chosen from hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone hydrogen succinate, hydrocortisone butyrate and hydrocortisone acetate.

3. Pharmaceutical solution according to claim 2, characterized in that the pharmaceutically acceptable salt of hydrocortisone is hydrocortisone sodium phosphate.

4. Pharmaceutical solution according to any one of claims 1 to 3, characterized in that it further comprises at least one buffer.

5. Pharmaceutical solution according to claim 4, characterized in that the buffer is chosen from sodium acetate, sodium citrate, sodium dihydrogen phosphate and sodium hydrogen phosphate.

6. Pharmaceutical solution according to any one of claims 1 to 5, characterized in that the pH of the pharmaceutical solution is between 7 and 9, preferably between 7.5 and 8.

5.

7. Pharmaceutical solution according to any one of claims 1 to 6, characterized in that the concentration of hydrocortisone in said pharmaceutical solution is 160 mg / mL.

8. Pharmaceutical solution according to any one of claims 4 to 7, characterized in that it comprises in mg per 1 mL of said solution: - between 210 mg and 220 mg of hydrocortisone sodium phosphate, - between 2 mg and 7.5 mg of monothioglycerol, - between 0.1 mg and 3.5 mg of at least one buffer, - Qsp 1 mL of solvent, preferably water for injection.

9. A pharmaceutical solution according to any one of claims 1 to 5. 8 for its use in the treatment of acute adrenal insufficiency and asthma.

10. Pharmaceutical solution according to claim 9, characterized in that said solution is in a form suitable for parenteral administration, preferably intramuscularly.

11. Injection kit comprising: - an injection device; - the pharmaceutical solution according to any one of claims 1 to R

12. 1 a O. Injection kit according to claim 11, characterized in that the injection device is a needle-free injection device with a pyrotechnic cartridge.

Images