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RU-2861616-C2 - PHARMACEUTICAL SOLUTION OF HYDROCORTISONE FOR INJECTION DEVICE

RU2861616C2RU 2861616 C2RU2861616 C2RU 2861616C2RU-2861616-C2

Abstract

FIELD: pharmaceuticals. SUBSTANCE: group of inventions relates to a pharmaceutical solution of hydrocortisone for intramuscular administration, which contains, in mg per 1 ml of said solution, at least: from 210 to 220 mg of hydrocortisone sodium phosphate, from 2 to 7.5 mg of monothioglycerol, from 0.1 to 3.5 mg of at least one buffer selected from sodium dihydrogen phosphate and disodium hydrogen phosphate, and water for injection in an amount to bring the volume of the solution to 1 ml, wherein the pH of the pharmaceutical solution is from 7 to 9, and to an injection kit comprising an injection device and the pharmaceutical solution. EFFECT: providing a pharmaceutical solution of hydrocortisone sodium phosphate for intramuscular administration which is stable over time and contains a minimal amount of unknown impurities. 5 cl, 7 dwg, 16 tbl, 1 ex

Inventors

  • VINCENT LAURETTE
  • LACOMBE OLIVIER
  • IGUINIZ MARION

Dates

Publication Date
20260506
Application Date
20221108
Priority Date
20211109

Claims (12)

  1. 1. A pharmaceutical solution of hydrocortisone for intramuscular administration, which contains, in mg per 1 ml of said solution, at least:
  2. - from 210 to 220 mg of hydrocortisone sodium phosphate;
  3. - from 2 to 7.5 mg of monothioglycerol;
  4. - from 0.1 to 3.5 mg of at least one buffer selected from sodium dihydrogen phosphate and sodium hydrogen phosphate;
  5. - Qsp 1 ml of water for injection, where "Qsp" is an abbreviation of "quantity sufficient for", which means that the amount of water for injection is such that the volume of the solution is 1 ml;
  6. wherein the pH of the pharmaceutical solution is from 7 to 9.
  7. 2. The pharmaceutical solution according to claim 1, wherein the pH of the pharmaceutical solution is from 7.5 to 8.5.
  8. 3. A pharmaceutical solution according to item 1 or 2 for its use in the treatment of acute adrenal insufficiency and asthma.
  9. 4. Injection kit containing:
  10. - injection device;
  11. - a pharmaceutical solution according to paragraph 1 or 2.
  12. 5. An injection kit according to claim 4, wherein the injection device is a needle-free injection device with a pyrotechnic cartridge.

Description

[0001] The invention relates to a pharmaceutical solution of hydrocortisone or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as “pharmaceutical solution of hydrocortisone”), intended for parenteral administration, in particular intramuscular. [0002] Hydrocortisone and hydrocortisone salts are known to be used as anti-inflammatory agents. These active ingredients are commonly used 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 and its salts are sensitive to oxidation. Therefore, pharmaceutical solutions of these active substances always contain at least one antioxidant. [0005] For example, a pharmaceutical product sold by 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, 100 ml of the solution contains 13.39 g of this salt). 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® additionally includes: 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 GRAS (GRAS is an acronym for Generally Recognized as Safe) list of the FDA (FDA is an acronym for Food and Drug Administration). Furthermore, this antioxidant is not described in the international reference work as a source of information on pharmaceutical excipients, which is the Handbook of Pharmaceutical Excipients. [0007] Furthermore, to achieve the dose required for the therapeutic indication (e.g., acute adrenal insufficiency, asthma, or any condition requiring rapid and significant corticosteroid delivery) during intramuscular injection, which involves a smaller injected volume, a pharmaceutical solution concentration higher than that provided by the Efcortesol® pharmaceutical product may be required. [0008] The dose of hydrocortisone for injection required for therapeutic indications is typically in the range of 100 mg, and given the volumes of pharmaceutical solution that can be contained in injection devices (in particular, needle-free injection devices with a pyrotechnic cartridge), which are approximately 0.6 to 0.7 ml, a pharmaceutical solution containing hydrocortisone at a concentration of 150 to 170 mg/ml, or a pharmaceutically acceptable salt thereof in an equivalent amount, would be entirely suitable. [0009] Therefore, it would be desirable to have a new pharmaceutical solution of hydrocortisone or its pharmaceutically acceptable salt, which could be more concentrated than the known Efcortesol® solution and which is stable over time. It would also be useful if said solution contained, as far as possible, a minimum of unknown impurities, which would require characterization and labor-intensive toxicity studies. [0010] The inventors of the present invention sought to develop a new pharmaceutical solution of hydrocortisone or a pharmaceutically acceptable salt thereof, intended for parenteral administration, in particular intramuscular, by replacing the antioxidants Efcortesol®, which are sodium formaldehyde bisulfite and disodium EDTA, with another antioxidant specified in the lists of pharmaceutical excipients in reference works such as the one mentioned above, said solution should: not contain significant amounts of unknown impurities that would require characterization, be stable over time and present the lowest possible osmolarity. [0011] The present inventors have found that the use of the antioxidant monothioglycerol at a certain concentration in a pharmaceutical solution of hydrocortisone at a concentration of 150 to 170 mg/ml, or a pharmaceutically acceptable salt thereof in an equivalent amount, made it possible to ideally achieve all of these objectives. [0012] A first object of the present invention is a pharmaceutical solution of hydrocortisone which contains in mg per 1 ml of said solution at least: from 150 to 170 mg of hydrocortisone or its pharmaceutically acceptable salt in an equivalent amount, from 2 to 7.5 mg monothioglycerol, Qsp 1 ml solvent. [0013] "Qsp" is an abbreviation for "amount sufficient to", meaning that the amount of solvent is such that the volume of the solution is 1 ml. [0014] The use of monothioglycerol at a concentration of 2 to 7.5 mg/mL provides excellent stability of the hydrocortisone solution over time. [0015] In addition, monothioglycerol is an excipient approved for pharmaceutical administration. [0016] Finally, it was found that the pharmaceutical solution according to the in