LIQUID DOSAGE FORM OF EDARAVONE OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF WHICH IS STABLE IN STORAGE, TRANSPORTATION AND USE

Abstract

The invention relates to a method fr producing a liquid dosage form of the drug Edaravone for parenteral use which is stable in storage and transportation and convenient for use, which involves: preparing a solution comprising Edaravone or pharmaceutically acceptable salts thereof as the active ingredient, and excipients (an acidic component, an alkaline component, an antioxidant, an osmolar agent and/or a stabilizer); packaging said dosage form in a pre-sterilized glass bottle having a cap at least partially coated with an anti-adhesive coating; sealing the bottle with said cap at least partially coated with an anti-adhesive coating, and sterilizing the bottle containing a solution comprising Edaravone or pharmaceutically acceptable salts thereof as the active ingredient, and excipients. The invention further relates to a method for packaging a liquid dosage form of the drug Edaravone for parenteral use which is stable in storage and transportation and convenient for use, which involves: sterilizing a glass bottle having a cap; pouring a solution comprising Edaravone or pharmaceutically acceptable salts thereof as the active ingredient, and excipients (an acidic component, an alkaline component, an antioxidant, an osmolar agent and/or a stabilizer) into said sterilized glass bottle; closing (sealing) the bottle containing the solution using said cap, which is at least partially coated with an anti-adhesive coating; and sterilizing the sealed bottle containing the liquid dosage form. The invention further relates to a bottle filled with a liquid dosage form of a drug for parenteral use comprising Edaravone or pharmaceutically acceptable salts thereof as the active ingredient, and excipients (an acidic component, an alkaline component, an antioxidant, an osmolar agent and/or a stabilizer), said bottle being made of glass and being closed with a cap which is made of a material based on flexible polymers and which is at least partially coated with an anti-adhesive coating.

Claims

1. A method of obtaining a liquid dosage form of an edaravone drug, stable during storage, transportation and convenient for use, for parenteral administration, said method provides: i) preparing a solution containing as active ingredient edaravone or its pharmaceutically acceptable salts and excipients (acid component, alkaline component, antioxidant, osmolarizing agent and/or stabilizer); ii) packing said dosage form into a pre-sterilized glass vial with a lid covered at least partially by an adhesive coating; iii) closure of the vial with a lid at least partially covered with an anti-adhesive coating and sterilization the vial containing a solution of edaravone or its pharmaceutically acceptable salts as the active ingredient and excipients.

2. The method according to claim 1, wherein the glass vial is made of borosilicate glass.

3. The method according to claim 1, wherein the cover is made of a material of the class of elastic polymers.

4. The method according to claim 1, wherein the lid is coated inside or fully anti-adhesive coating of polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy alkane (PFA), ethylene tetrafluoroethylene (ETFE), fluoroethylenepropylene (FEP), perfluoropolyether (PFPE) or polyvinyldene fluoride (PVDF).

5. A method of packing liquid dosage form of edaravone drug, that is stable during storage, transportation and convenient to use, for parenteral administration, said method involves: i) sterilization of a glass vial and a lid, ii) spill a solution containing edaravone or its pharmaceutically acceptable salts as the active ingredient and excipients (acid component, alkaline component, antioxidant, osmolarizing agent and/or stabilizer), into a sterilized glass vial; iii) closure of the vial containing solution with a lid covered at least partially by an anti-adhesive coating; iv) sterilization of the sealed vial containing liquid dosage form.

6. The method according to claim 5, wherein the glass vial is made of borosilicate glass.

7. The method according to claim 5, wherein the cover is made of rubber derivative or thermoplastic.

8. The method according to claim 5, wherein the cover inside or fully covered with an anti-adhesive coating of polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy alkane (PFA), ethylene tetrafluoroethylene (ETFE), fluoroethylenepropylene (FEP), perfluoropolyether (PFPE) or polyvinyldene fluoride (PVDF).

9. A vial filled with a liquid dosage form of a medicinal product for parenteral administration containing as active ingredient edaravone or its pharmaceutically acceptable salts, and excipients (acid component, alkaline component, antioxidant, osmolarizing agent and/or stabilizer), and the vial is made of glass, covered by a lid made of a material based on elastic polymers, the lid is at least partially covered with an anti-adhesive coating.

10. The vial according to claim 9, made of borosilicate glass.

11. The vial according to claim 9, wherein the lid is made of rubber derivative or thermoplastic.

12. The vial according to claim 9, wherein the lid is covered inside or fully with an anti-adhesive coating of polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy alkane (PFA), ethylene tetrafluoroethylene (ETFE), fluoroethylenepropylene (FEP), perfluoropolyether (PFPE) or polyvinyldene fluoride (PVDF).

13. The vial according to claim 9, wherein an aluminum cap that squeezes the lid of the vial to seal the container with the solution is used during packaging.

Description

EXAMPLE 1

[0030] Studies have shown that when a drug based on edaravone is stored in the above-described package there is no interaction of the solution with the packaging materials. That makes increasing impurities impossible.

[0031] A comparative analysis of the drug edaravone properties under storing in different standard packaging for such drugs was carried out (Table 1). Ready-to-use solution containing edaravone as the active substance and excipients such as acid, alkaline components, antioxidant, osmolarizing agent and stabilizer was placed in a polymeric package, borosilicate glass vial, sealed with a rubber lid, a plastic container, manufactured by blow technology-fill-seal and into a borosilicate glass vial with a lid made of isopropylene isoprene rubber coated with a fluorine-containing polymer according to the technical solution. The packaged preparation was kept under the same conditions for 24 months, checking the solutions in different packages was carried out after 3, 6, 12 and at the end of the holding period, after 24 months.

[0032] The results showed that packaging of a solution of edaravone using glass is more efficient, and the use of a fluorine-containing polymer to cover the lid in combination with borosilicate glass of the vial extended the shelf life from 6 to 24 months.

EXAMPLE 2

[0033] Various variants of the composition (solution) of edaravone were prepared using different types of fluorine-containing substances to cover the lid of the vial containing the drug solution. The options are given in Examples 2.1-2.8.

EXAMPLE 2.1

[0034]

TABLE-US-00001 Component Content in 1 ml of the drug Edaravon 0.3 mg Chloride acid 1.5 mg Sodium hydroxide 1.5 mg Cysteine 0.1 mg Sodium chloride 8.0 mg Sodium Bisulfite 0.2 mg

[0035] A package is a borosilicate glass vial, sealed with lid made of a rubber derivative-based material, the lid is coated with ETFE polymer.

EXAMPLE 2.2

[0036]

TABLE-US-00002 Component Content in 1 ml of the drug Edaravon 0.3 mg Sulfate acid 1.5 mg Sodium hydroxide 1.5 mg Sodium chloride 8.5 mg Sodium metabisulfite 0.2 mg

[0037] The package is a borosilicate glass vial, sealed with the lid made of a thermoplastic, the lid is coated with PCTFE polymer.

EXAMPLE 2.3

[0038]

TABLE-US-00003 Component Content in 1 ml of the drug Edaravon 0.3 mg Phosphoric acid 1.0 mg Sodium hydroxide 1.5 mg Sodium chloride 8.6 mg Sodium metabisulfite 0.2 mg

[0039] A package is a borosilicate glass vial, sealed with lid made of a rubber derivative-based material, the lid is coated with FEP polymer.

EXAMPLE 2.4

[0040]

TABLE-US-00004 Component Content in 1 ml of the drug Edaravon 0.3 mg Phosphoric acid 1.0 mg Sodium hydroxide 1.5 mg Sodium chloride 8.6 mg Sodium Bisulfite 0.2 mg

[0041] The package is a borosilicate glass vial, sealed with the lid made of a thermoplastic, the lid is coated with PVDF polymer.

EXAMPLE 2.5

[0042]

TABLE-US-00005 Component Content in 1 ml of the drug Edaravon 0.3 mg Phosphoric acid 1.0 mg Potassium hydroxide 1.5 mg Sodium chloride 8.6 mg Ascorbic acid 0.1 mg

[0043] A package is a borosilicate glass vial, sealed with lid made of a rubber derivative-based material, the lid is coated with PFA polymer.

EXAMPLE 2.6

[0044]

TABLE-US-00006 Component Content in 1 ml of the drug Edaravon 0.3 mg Citric acid 1.0 mg Sodium hydroxide 1.5 mg Sodium chloride 8.6 mg Sodium metabisulfite 0.2 mg

[0045] A package is a borosilicate glass vial, sealed with lid made of a rubber derivative-based material, the lid is coated with PTFE polymer.

EXAMPLE 2.7

[0046]

TABLE-US-00007 Component Content in 1 ml of the drug Edaravon  0.3 mg Phosphoric acid  1.0 mg Sodium hydroxide  1.5 mg EDTA 0.15 mg Sodium chloride  8.6 mg Sodium metabisulfite  0.2 mg

[0047] The package is a borosilicate glass vial, sealed with the lid made of a thermoplastic, the lid is coated with PFPE polymer.

EXAMPLE 2.8

[0048]

TABLE-US-00008 Component Content in 1 ml of the drug Edaravon 0.3 mg Phosphoric acid 1.0 mg Sodium hydroxide 1.5 mg Cysteine 0.1 mg Sodium chloride 8.6 mg Sodium metabisulfite 0.2 mg

[0049] A package is a borosilicate glass vial, sealed with lid made of a rubber derivative-based material, the lid is coated with PVDF polymer.

[0050] The solutions prepared according to Examples 2.1-2.8 were packed in pre-sterilized glass vials, the vials were closed with a lid covered with an anti-adhesive coating, the vials with solution were sterilized and kept for a certain period.

[0051] Series of test were conducted on the quality and stability of the finished pharma product when stored at 25° C., 60% humidity (Table 2), 40° C., 75% humidity (Table 3). The finished pharma product were kept for 6 months to check the stability of the drug.

[0052] The average quality and stability of the finished products after the shelf life are shown in Table 2 and Table 3.

[0053] The above data demonstrate that the claimed combination of the drug in the described package can be stored for a specified shelf life of the drug −2 years at a temperature of 25° C., without degradation of quality. Therefore, the claimed composition is stable during the study period.

[0054] The results obtained show that the claimed technical solution has a new, unknown from the prior art set of essential features. Accordingly, the claimed invention meets the requirements of patentability novelty and industrial applicability.

[0055] The claimed technical solution makes it possible to obtain a stable storage, transportation and convenient to use composition (solution) of edaravone, significantly extend the shelf life of the drug. Obtained according to the claimed invention, the drug retains its therapeutic properties, does not form impurities, is safe when opening the container with solution and use.

TABLE-US-00009 TABLE 1 The results of the actual packaging of the compositions in different sets Quality characteristics of stability Time Accompanying Quantitative (storage) pH impurities determination Meets all to study From any impurity- Edaravone 0.285- requirements Type of packaging stability 3.0 to 4.5 not more 0.2% 0.315 (mg/ml) (yes/no) On release  0 month 4.2 Less than 0.05% 0.302 yes Polymeric package  3 month 4.1 Less than 0.05% 0.287 yes  6 month 3.9 0.06% 0.277 no 12 month 3.8 0.13% 0.271 no 24 month 3.6 0.24% 0.263 no Bottle of  3 month 4.2 Less than 0.05% 0.293 yes borosilicate glass,  6 month 4.0 Less than 0.05% 0.287 yes sealed with a 12 month 4.0 Less than 0.05% 0.281 no rubber cover 24 month 3.9 0.08% 0.278 no Plastic container  3 month 4.1 Less than 0.05% 0.271 no manufactured by  6 month 3.9 0.07% 0.253 no blow-fill-seal 12 month 3.7 0.15% 0.241 no technology 24 month 3.4 0.28% 0.234 no Packaging  3 month 4.2 Less than 0.05% 0.300 yes according to the  6 month 4.2 Less than 0.05% 0.299 yes claimed technical 12 month 4.1 Less than 0.05% 0.298 yes solution 24 month 4.0 Less than 0.05% 0.298 yes

TABLE-US-00010 TABLE 2 Results of the study the stability of the composition during storage at 25° C. Accompanying impurities Appearance Transp- The degree Any impurity Quantitative Transparent arency of color Osmol. — determination Characteristics colorless or Must Not more Mechanical pH From 275 Not more than 0,2%. Edaravone of quality light be intense inclusions From to 325 The amount of 0,285 - Sterility (stability) yellowish transpa for the Must stand 3,0 to mOsmol/ impurities — 0,315 (mg/ Must be QCT liquid. rent standard Y5 the test 4,5 kg not more than 0,5% ml) sterile On release Accord Accord Accord Accord 4,2 304 Less than 0,05% 0,302 Accord FEP Accord Accord Accord Accord 4,1 301 Less than 0,05% 0,301 Accord PTFE Accord Accord Accord Accord 4,2 297 Less than 0,05% 0,297 Accord PCTFE Accord Accord Accord Accord 4,1 302 Less than 0,05% 0,299 Accord PFA Accord Accord Accord Accord 4,0 306 Less than 0,05% 0,307 Accord ETFE Accord Accord Accord Accord 4,3 301 Less than 0,05% 0,303 Accord PVDF Accord Accord Accord Accord 4,0 298 Less than 0,05% 0,298 Accord PFPE Accord Accord Accord Accord 4,1 302 Less than 0,05% 0,304 Accord

TABLE-US-00011 TABLE 3 Results of the stability studies of the composition during storage at 40° C. Accompanying Appearance The degree impurities Quantitative Transparent Transp- of color Osmol. Any impurity determination Characteristics of colorless or arency Not more Mechanical pH From 275 — Edaravone quality (stability) light Must intense inclusions From to 325 The amount of 0,285 - Sterility QCT yellowish be for the Must stand 3,0 to mOsmol/ impurities — 0,315 (mg/ Must be plugs type liquid. rent standard Y.sub.5 the test 4,5 kg not more than 0,5% ml) sterile ΠpH BHIIycKy Accord Accord Accord Accord 4,2 304 Less than 0,05% 0,302 Accord FEP Accord Accord Accord Accord 3,9 301 Less than 0,05% 0,298 Accord PTFE Accord Accord Accord Accord 3,8 303 Less than 0,05% 0,295 Accord PCTFE Accord Accord Accord Accord 3,9 305 Less than 0,05% 0,299 Accord PFA Accord Accord Accord Accord 3,7 301 Less than 0,05% 0,301 Accord ETFE Accord Accord Accord Accord 3,8 297 Less than 0,05% 0,296 Accord PVDF Accord Accord Accord Accord 3,9 295 Less than 0,05% 0,298 Accord PFPE Accord Accord Accord Accord 4,0 304 Less than 0,05% 0,303 Accord