Patent Application
20240408110
The invention concerns a pharmaceutical solution of hydrocortisone or a salt pharmaceutically acceptable thereof (hereinafter abbreviated «pharmaceutical hydrocortisone solution») intended to be injected parenterally, in particular intramuscularly.
The hydrocortisone and the hydrocortisone salts are known to be used as anti-inflammatory agents. It is common to use these active substances in the treatment in particular of asthma, endocrine disorders, dermatological disorders and allergic conditions, as well as acute adrenal insufficiency.
The hydrocortisone and its salts belong to the family of corticosteroids.
The hydrocortisone, as well as its salts, are sensitive to oxidation. This is why pharmaceutical solutions of these active substances always comprise at least one antioxidant.
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% m/v (in other words there is a 13.39 g of this salt in 100 mL of solution). This product is packaged either in 1 mL ampoules which contain 100 mg of hydrocortisone, or in 5 mL ampoules which contain 500 mg of hydrocortisone. The Efcortesol® further comprises:
However, the sodium formaldehyde bisulfite does not appear on the GRAS list («GRAS» being the acronym for «Generally Recognized As Safe» of the FDA («FDA» being the acronym for «Food and Drug Administration». Furthermore, this antioxidant is not described in the international reference work as a source of information on the pharmaceutical excipients, which is the «Handbook of pharmaceutical excipients».
Moreover, in order to respect the dose necessary for the therapeutic indication (for example acute adrenal insufficiency, asthma or any disease requiring the rapid and significant intake of a corticosteroid) during an intramuscular injection which implies a lower injected volume, a concentration of the pharmaceutical solution higher than that offered by the pharmaceutical product Efcortesol® may be required.
The dose of hydrocortisone to be injected necessary for the therapeutic indication is generally in the range of 100 mg and taking into account the volumes of pharmaceutical solution that the injection devices can contain (in particular needle-free injection devices with pyrotechnic cartridge) which are approximately 0.6 to 0.7 mL, a pharmaceutical solution containing hydrocortisone at a concentration comprised between 150 and 170 mg/ml or a pharmaceutically acceptable salt thereof in equivalent amount would be perfectly appropriate.
This is why 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 solution of Efcortesol® and which is stable over time. It would also be advantageous if said solution presents, as far as possible, a minimum of unknown impurities for which a characterization and a laborious toxicity study would be necessary.
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® which are sodium formaldehyde bisulfite and disodium EDTA with another antioxidant appearing in the lists of pharmaceutical excipients in reference works such as the one mentioned above, said solution must:
The inventors of the present invention have discovered that the use of the monothioglycerol antioxidant at a determined concentration in a pharmaceutical solution of hydrocortisone at a concentration comprised between 150 and 170 mg/ml or of a pharmaceutically acceptable salt thereof in equivalent amount made it possible to perfectly achieve all these objectives.
The present invention has as its first object a pharmaceutical solution of hydrocortisone which comprises in mg per 1 mL of said solution at least:
«Qsp» is the abbreviation for «sufficient amount for» meaning that the amount of solvent is such that the volume of the solution is completed to 1 mL.
The use of monothioglycerol at a concentration comprised between 2 mg/mL and 7.5 mg/mL gives the hydrocortisone solution perfectly remarkable stability over time.
Furthermore, the monothioglycerol is an excipient authorized by the pharmaceutical administrations.
Finally, it was found that a pharmaceutical solution according to the invention has a very low level of impurities, and this under varied and forced storage conditions (namely temperature and relative humidity).
The present invention therefore lies in the selection of monothioglycerol as an antioxidant at a concentration comprised between 2 mg/mL and 7.5 mg/mL to stabilize a pharmaceutical solution of hydrocortisone.
The pharmaceutically acceptable salt of hydrocortisone may be selected from hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone hydrogen succinate, hydrocortisone butyrate and hydrocortisone acetate.
Preferably, the pharmaceutically acceptable salt of hydrocortisone is the hydrocortisone sodium phosphate.
In an embodiment of the invention, the concentration of hydrocortisone in said pharmaceutical solution is 160 mg/mL.
In an embodiment of the invention, the monothioglycerol concentration is comprised between 2.5 mg/mL and 5 mg/mL.
In an embodiment of the invention, the monothioglycerol concentration is comprised between 5 mg/mL and 7.5 mg/mL.
The solvent can be any pharmaceutically acceptable solvent which is compatible with hydrocortisone and its salts and all the other compounds which comprise said pharmaceutical solution according to the invention. This may be water, particularly water used in the injection devices (in other words water for injection), as well as water containing isotonicity additives or sodium chloride solutions. Water for injection is ultra-pure and free of bacterial contaminants.
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.
Preferably, the buffer is a mixture of sodium dihydrogen phosphate and sodium hydrogen phosphate. Quite advantageously, the ratio of the mass of sodium dihydrogen phosphate to the mass of sodium hydrogen phosphate is comprised between 0.03 and 0.06.
In an embodiment of the invention, the concentration of buffer in said solution is comprised between 0.1 mg/ml and 3.5 mg/mL.
The pH of the pharmaceutical solution is advantageously comprised between 7 and 9, preferably between 7.5 and 8.5.
Said pharmaceutical solution may further comprise at least one acceptable pharmaceutical excipient other than monothioglycerol.
In an embodiment of the invention, the pharmaceutical solution comprises in mg per 1 ml of said solution:
Preferably, in this embodiment of the invention, the pharmaceutical solution comprises as buffer a mixture of sodium dihydrogen phosphate and sodium hydrogen phosphate whose mass ratio of sodium dihydrogen phosphate on the mass of sodium hydrogen phosphate is comprised between 0.03 and 0.06.
The subject of the present invention is also a method for preparing the pharmaceutical solution according to the invention as described above which comprises at least the following steps:
If the pharmaceutical solution comprises buffers, these buffers are, preferably before step a), mixed together before being added to the mixture of step a).
When the pharmaceutical solution comprises at least one pharmaceutically acceptable excipient other than monothioglycerol, this excipient can be added to the mixture of step a).
The filtration step may comprise at least one filtration selected from the clarifying filtration and the sterilizing filtration.
Preferably, the filtration step consists of a clarifying filtration followed by a sterilizing filtration.
The invention also relates to the pharmaceutical solution as described above for its use in the treatment of diseases selected 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.
Said solution is advantageously in a form suitable for parenteral, preferably intramuscular administration.
The present invention also relates to an injection kit, preferably an intramuscular injection kit, including:
Advantageously, the volume delivered by the injection device is comprised between 0.60 mL and 0.65 mL.
Said injection device can be single-use. For example, it comes in a pre-filled tube ready to use.
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.
Quite advantageously, the injection device is a device marketed by the company Crossject under the trade name ZENEO®.
Thus, in an embodiment of the injection kit according to the invention, the injection device is a needle-free injection device with a pyrotechnic cartridge.
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 and comparative results of solutions according to the invention.
Experiments were carried out in order to compare the physicochemical properties and in particular the impurity content of:
Table 1 below details the composition of the solution similar to the product of reference Efcortesol® (hereinafter: «Ref») in mg for 1 ml of said solution.
Table 2 below details the composition of the 5 comparative solutions (C1 to C5) and the 4 solutions according to the invention (IQ1 to IQ4) in mg per 1 mL of solution.
In all the prepared solutions and as detailed in Tables 1 and 2 above, the hydrocortisone sodium phosphate concentration of 214.7 mg/mL is equivalent to a concentration of 160 mg/mL of hydrocortisone.
All the solutions were obtained in the following manner:
Steps c) and d) were carried out under an insulator swept by a flow of nitrogen.
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.
The solutions thus obtained were packaged in glass tubes equipped with two caps at their ends.
More precisely, the tubes were filled with 0.65 mL of solution. Nitrogen sweep was applied to the surface of the solutions to remove oxygen present in the headspace of these tubes. Finally, the tubes were closed.
For all the solutions, the pH, the osmolarity and the amount of monothioglycerol were determined at different storage times under a relative humidity of 75% and at a temperature of 40° C.
Moreover, from analyzes by high-performance liquid chromatography (hereinafter abbreviated «HPLC»), the time limits for all the solutions were determined:
These area percentages are expressed relative to the area of the main peak of the considered solution.
The HPLC analyzes were carried out under the following conditions:
Table 3 below details the composition of the mobile phase as a function of time.
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 Table 4.
These are the numbers in parentheses. «ND» is the abbreviation for «not determined».
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 in severe conditions, namely at 40° C. and with a relative humidity of 75%.
Table 5 below details the monothioglycerol content remaining in the solutions C2 to C5 and IQ1 to IQ4 at 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 shown in Table 5. These are the numbers in parentheses.
In view of the results detailed in Table 5, it is noted that for the solutions C2 to C4, the monothioglycerol content decreases during the storage until it completely disappears after 5 months (and from 3 months for the solutions C2 and C3). The reduction or even absence of monothioglycerol in the tested solution results in the generation of impurities and therefore the instability of the tested solution.
Unlike solutions C2 to C4, the solutions according to the invention IQ1 to IQ4 always have a high monothioglycerol content after 5 months under severe storage conditions.
Thus, the monitoring of the evolution of the monothioglycerol content in the solutions tested over time demonstrates that the solutions according to the invention IQ1 to IQ4 are particularly stable in comparison with the comparative solutions C2 to C4.
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 Table 6.
These are the numbers in parentheses.
In view of the results detailed in Table 6, it is noted that the solutions according to the invention IQ1 to IQ4 present, after 5 months of storage under severe conditions, an excellent purity of about 99.3%.
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 relative humidity of 75%. The initial monothioglycerol contents of said solutions are recalled in Table 7. These are the numbers in parentheses.
In view of the results detailed in Table 7 and in view of the evolution of the curves in
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 relative humidity of 75%. The initial monothioglycerol contents of said solutions are shown in Table 8. These are the numbers in parentheses.
In view of the results detailed in Table 8 and in view of the evolution of the curves in
Table 9 below details the osmolarity (expressed in mOsm) of the solutions tested 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 Table 9. These are the numbers in parentheses.
The main objectives to be achieved in the context of the development of a pharmaceutical solution intended to be injected parenterally are:
In view of the results detailed in Table 9 above, it is noted that the comparative solution C5 (namely the solution whose monothioglycerol content is 10 mg/mL) has a higher osmolarity than that of the solutions according to the invention IQ1 to IQ4. The osmolarity parameter of the comparative solution C5 is therefore less efficient in comparison with the solutions according to the invention IQ1 to IQ4.
Furthermore, in the context of these experiments, a Derringer desirability function was used in order to identify among the tested solutions the pharmaceutical solutions which best satisfied the objectives 1) and 2) detailed above.
In this regard, the publication entitled «Simultaneous optimization of several response Variables» by George Derringer et al., Journal of quality technology, vol 12, nº4, October 1980, pages 214-219, describes the calculation methodology of this desirability function.
In summary, the Derringer desirability function is a mathematical tool allowing the simultaneous optimization of several variable responses (hereinafter referred to as «criteria»). The use of this mathematical tool is very classic in the field of pharmacy to demonstrate the performance of a pharmaceutical solution which has been developed in order to best satisfy different objectives based on several criteria.
As part of these experiments, there were the following 3 criteria to evaluate:
The 1st step consisted of defining the Derringer functions for each of the 3 aforementioned criteria, after 5 months of storage at 40° C. and under a relative humidity of 75%.
The duration of 5 months is an interesting duration, because it represents a time at the end of which impurities, if there must be any in the tested pharmaceutical solution, have had time to be developed under storage conditions at 40° C. and under a relative humidity of 75%.
The values of the criteria d1 to d3 were calculated for each tested solution. To do this, a change of variable was made in order to have, for each evaluated criterion, a desirability value comprised between 0 and 1.
More precisely, for each criterion, the value of 1 was assigned to the value of the considered criterion which was the most satisfactory among all the tested solutions (namely the lowest area percentage of the impurity 1 for criterion d1, the lowest area percentage of the impurity 2 for criterion d2 and the lowest osmolarity for criterion d3). The value of 0 was assigned to the value of the considered criterion which was the least satisfactory among all the tested solutions (namely the highest area percentage of the impurity 1 for the criterion d1, the highest area percentage of the impurity 2 for criterion d2 and the highest osmolarity for the criterion d3).
Tables 10 to 12 below summarize these assigned values from 1 and 0 for the criteria d1 to d3 respectively.
From these 3 tables, 3 linear desirability functions f1, f2 and f3 were determined for respectively the evaluated criteria d1 to d3.
From the desirability function f1 of the criterion d1, it is calculated for each tested solution its desirability value for said criterion d1.
Table 13 below details for each tested solution the area percentage of the impurity 1 and its desirability value for the criterion d1 which was calculated from the function f1.
From the desirability function f2 of the criterion d2, for each tested solution its desirability value for said criterion d2 was calculated.
Table 14 below details for each tested solution the area percentage of the impurity 2 and its desirability value for the criterion d2 which was calculated from the function f2.
From the desirability function f3 of the criterion d3, for each tested solution its desirability value for said criterion d3 was calculated.
Table 15 below details for each tested solution its osmolarity and its desirability value for the criterion d3 which was calculated from the function f3.
Then, the total desirability «D» which corresponds to the geometric mean of all the desirability values for a tested pharmaceutical solution was calculated. This total desirability D makes it possible to compare the different tested pharmaceutical solutions with each other and to classify them in relation to each other: a tested solution which obtains a high total desirability value D corresponds to a pharmaceutical solution which best satisfies all of the set objectives detailed above.
Table 16 below details the total desirability D for each of the tested pharmaceutical solutions.
Furthermore,
In view of the results detailed in Table 16 and in view of
Thus, the mathematical tool implementing the Derringer desirability function clearly demonstrates that the selection of a monothioglycerol concentration comprised between 2 and 7.5 mg/ml makes it possible to obtain pharmaceutical solutions of hydrocortisone at a concentration comprised between 150 and 170 mg/mL (or a pharmaceutically acceptable salt thereof in equivalent amount) which are optimized because they perfectly meet the objectives defined above for the development of pharmaceutical solutions which are the stability over time and the lowest possible osmolarity.
It should be noted that this optimization is not observed outside of this interval 2 to 7.5 mg/ml of the monothioglycerol concentration. Indeed, the total desirability D is lower on either side of this interval (namely for the solutions C1 to C4 on the one hand and for the solution C5 on the other hand). The solutions C1 to C4 are not optimized with regard to their impurity contents. The solution C5 is not optimized regarding its osmolarity.
| Number | Date | Country | Kind |
|---|---|---|---|
| 21/11880 | Nov 2021 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/081164 | 11/8/2022 | WO |
