Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present disclosure relates to parenteral pharmaceutical solutions containing eribulin or a pharmaceutically acceptable salt thereof. More specifically, it relates to a parenteral pharmaceutical solution for injection containing eribulin without ethanol or a pharmaceutically acceptable salt thereof (particularly eribulin mesylate).
• Eribulin mesylate (chemical names: (2R, 3R, 3aS, 7R, 8aS, 9S, 10aR, 11S, 12R, 13aR, 13bS, 15S, 18S, 21S, 24S, 26R, 28R, 29aS) -2-[( 2S) -3-Amino-2-Hydroxypropyl] -3-Methoxy-2-26-Methyl-20,27-Dimethylindenehexacosahydro-11,15: 18, 21:24,28-Triepoxy-7,9-Etano -12, 15-Menyl 9H, 15H-Flo [3,2-i] Flo [2', 3': 5,6] Pyrano [4,3-b] [1,4] Dioxacyclopentacosin-5 (4H) -on monomesylate) is expressed by the following formula: Represented by, it inhibits the polymerization of tubulin and suppresses the elongation
• injections containing eribulin mesylate as an active ingredient are sold under names such as "Haraven (registered trademark) intravenous injection 1 mg” as a therapeutic agent for inoperable or recurrent breast cancer and malignant soft tissue sarcoma (non-surgery).
• This therapeutic agent contains 0.1 mL of absolute ethanol, that is, 5% of absolute ethanol in 2.0 mL of one vial, and has a problem that it is difficult to apply to patients with alcohol hypersensitivity.
• the present inventors have made ethanol-free eribulin or its own while maintaining the osmotic pressure ratio with respect to physiological saline at 0.5 or more by containing an isotonic agent without containing ethanol. It has been found that a parenteral pharmaceutical solution containing a pharmaceutically acceptable salt can be provided.
• the tonicity agent is at least one selected from the group consisting of sugar alcohols and polyhydric alcohols.
• the tonicity agent is D-mannitol or propylene glycol.
• the concentrations of the tonicity agent are 0.14 to 2.30 mol / L, 0.14 to 2.0 mol / L, 0.14 to 1.4 mol / L, 0.14 to 0.86. Molar / L, 0.14 to 0.57 mol / L, 0.14 to 0.43 mol / L, 0.14 to 0.34 mol / L, 0.17 to 2.3 mol / L, 0.
• the osmotic pressure ratio to physiological saline is 8 or less, 0.5 to 8, 0.6 to 8, 0.7 to 8, 0.8 to 8, 0.5 to 7, 0.6 to 7, 0. .7-7, 0.8-7, 0.5-5, 0.6-5, 0.7-5, 0.8-5, 0.5-3, 0.6-3, 0.7 ⁇ 3, 0.8 ⁇ 3, 0.5 ⁇ 2, 0.6 ⁇ 2, 0.7 ⁇ 2, 0.8 ⁇ 2, 0.5 ⁇ 1.5, 0.6 ⁇ 1.5, 0 .7 to 1.5, 0.8 to 1.5, 0.5 to 1.2, 0.6 to 1.2, 0.7 to 1.2 or 0.8 to 1.2 above [ 1]
• a parenteral pharmaceutical solution containing elibrin or a pharmaceutically acceptable salt thereof the inclusion of an isotonic agent does not cause hemolysis and is intended for patients with alcohol hypersensitivity.
• a parenteral pharmaceutical solution containing usable ethanol-free elibrin or a pharmaceutically acceptable salt thereof can be provided.
• more stable eribulin or pharmaceutically acceptable thereof may be used as the tonicity agent by using at least one selected from the group consisting of sugar alcohols and polyhydric alcohols.
• a parenteral pharmaceutical solution containing a salt can be provided.
• the parenteral pharmaceutical solution of the present disclosure contains eribulin as an active ingredient or a pharmaceutically acceptable salt thereof, and an isotonic agent, and has an osmotic pressure ratio of 0.5 or more with respect to physiological saline. , Ethanol is not contained.
• the parenteral pharmaceutical solution of the present disclosure is an ethanol-free parenteral pharmaceutical solution that is ethanol-free and does not cause hemolysis by coexisting an isotonic agent so that it can be used even for patients with alcohol hypersensitivity. It became possible.
• the osmotic pressure ratio to the physiological saline means the osmotic pressure of the solution in question when the osmotic pressure of the physiological saline is 1, and the same applies when it is simply described as the osmotic pressure ratio. ..
• the osmotic pressure was measured according to the osmotic pressure measurement method (osmolal concentration measurement method) of the Japanese Pharmacopoeia general test method, and for the measurement, for example, an osmometer OSMO STATION OM-6060 (manufactured by Arcley Co., Ltd.) should be used. Can be done.
• the expressions "ethanol-free” and “ethanol-free” usually mean that they do not contain ethanol substantially, and even if a small amount of ethanol is intentionally added, these are used. Although it is not included in the expression, it is not intended to exclude even the case where a trace amount of ethanol is contained, for example, when it remains in some raw material or the like. As the trace amount, for example, if it is 5000 ppm or less specified in the Residual Solvent Guideline for Pharmaceuticals (ICH Q3C), it is acceptable. Of course, it is preferable that ethanol is not detected even if the amount is trace.
• the expression "pharmaceutically acceptable salt” as used herein with respect to eribulin means a salt formed from the acidic and basic heteroatom-containing groups of eribulin.
• Such salts include acid and base salts, such as inorganic or organic salts (eg, hydrochlorides, sulfates, citrates, hydrobromide, hydroiodide, nitrates, heavy salts.
• the content of the active ingredient in the parenteral pharmaceutical solution is preferably 0.01 mg / mL or more, more preferably 0.05 mg / mL or more, still more preferably 0.1 mg / mL or more, based on the entire parenteral pharmaceutical solution. Most preferably 0.5 mg / mL or more.
• the stability of the active ingredient tends to be ensured.
• the content of the active ingredient in the parenteral pharmaceutical solution is preferably 1000 mg / mL or less, more preferably 100 mg / mL or less, further preferably 10 mg / mL or less, and 1 mg / mL or less with respect to the entire parenteral pharmaceutical solution. Is the most preferable.
• the solubility of the active ingredient tends to be ensured.
• the isotonic agent to be contained in the parenteral pharmaceutical solution is not particularly limited, but is limited to sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium hydrogen sulfite, citric acid, sodium citrate, and calcium bromide.
• Electrolyte substances such as sodium hydrogen hydrogen; sugar alcohols such as xylitol, D-sorbitol, D-mannitol; polyhydric alcohols such as glycerin (concentrated glycerin), propylene glycol, macrogol 400; other purified sucrose, trehalose, lactose, glucose, etc.
• propylene glycol is preferable. Further, D-mannitol and propylene glycol are more preferable from the viewpoint of an accelerated test in an environment of a temperature of 40 ° C. and a humidity of 75%, but propylene glycol is further preferable.
• the content of the tonicity agent in the parenteral pharmaceutical solution may be appropriately set so as to have a desired osmotic pressure ratio (0.5 to 8), and is not particularly limited, but for example, a non-electrolyte substance. If there is, 0.14 mol / L or more is preferable, 0.17 mol / L or more is more preferable, 0.20 mol / L or more is further preferable, and 0.23 mol / L or more is most preferable.
• the content in the parenteral pharmaceutical solution is preferably 0.14 osmol / L or more, more preferably 0.17 osmol / L or more, still more preferably 0.20 osmol / L or more.
• the content of the tonicity agent in the parenteral pharmaceutical solution is preferably 2.3 mol / L or less, more preferably 2.0 mol / L or less. 1.4 mol / L or less is further preferable, 0.86 mol / L or less is further preferable, 0.57 mol / L or less is further preferable, 0.43 mol / L or less is further preferable, and 0.34 mol / L or less. The following are the most preferable.
• the content in the parenteral pharmaceutical solution is preferably 2.3 osmoles / L or less, more preferably 2.0 osmoles / L or less, still more preferably 1.4 osmoles / L. L or less, more preferably 0.86 osmol / L or less, still more preferably 0.57 osmol / L or less, still more preferably 0.43 osmol / L or less, most preferably 0.34 osmol / L or less. You can set it. If the content of the tonicity agent is in the above range, the injection pain tends to be relieved.
• the tonicity agent when it is D-mannitol, it is preferably contained in the parenteral pharmaceutical solution at about 25 to 200 mg / mL, and when the tonicity agent is propylene glycol, it is preferably contained in the parenteral pharmaceutical solution at about 10 to 200 mg / mL. It is preferably contained at 170 mg / mL.
• parenteral pharmaceutical solutions of the present disclosure include additions commonly used in the art such as pH adjusters.
• Can include agents.
• the pH adjusting agent is not particularly limited, but includes bases such as sodium hydroxide, aqueous ammonia, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydrogencarbonate, and sodium carbonate, as well as hydrochloric acid, citric acid, and the like. Acids such as succinic acid, acetic acid, tartrate acid, carbon dioxide, lactic acid, sulfuric acid and phosphoric acid can be used.
• the parenteral pharmaceutical solution of the present disclosure usually contains water as a solvent.
• the water may be normal water (tap water / well water), purified water, sterilized purified water, water for injection, etc. according to the Japanese Pharmacopoeia, but it is preferable to use water for injection.
• the osmotic pressure ratio of the parenteral pharmaceutical solution of the present disclosure to physiological saline is preferably 8 or less, more preferably 7 or less, further preferably 5 or less, and even more preferably 3 or less. It is preferably 2 or less, more preferably 1.5 or less, and most preferably 1.2 or less.
• the osmotic pressure ratio of the parenteral pharmaceutical solution of the present disclosure to physiological saline is more preferably 0.5 or more, particularly preferably 0.6 or more, further preferably 0.7 or more, and 0.8. The above is the most preferable.
• the osmotic pressure ratio of the parenteral pharmaceutical solution of the present disclosure to physiological saline exceeds 8, it may cause significant injection pain to the patient when the parenteral pharmaceutical solution of the present disclosure is injected without dilution. If it is less than 5, hemolysis may occur in the patient who received the parenteral pharmaceutical solution of the present disclosure.
• the osmotic pressure ratio can be measured by, for example, the method described in Examples.
• the pH of the parenteral pharmaceutical solution of the present disclosure is not particularly limited, but is preferably 6.0 to 9.0, more preferably 7.0 to 8.8, still more preferably 7.5 to 8.6, and 8. Most preferably 0 to 8.5.
• the pH is within the above range, it becomes easy to suppress the production of eribulin-related substances during storage.
• the parenteral pharmaceutical solution is stable and the production of eribulin-related substances during storage is suppressed. Elibrin-related substances can be confirmed, for example, by analyzing a parenteral pharmaceutical solution as a sample solution using HPLC, and among the peaks detected in the HPLC analysis, only the active ingredient is removed from the sample solution. All peaks except the peak observed when the reference solution is injected and the peak of elibrin are defined as the peaks of related substances of elibrin.
• the total related substances contained in the parenteral pharmaceutical solution when subjected to a harsh test of storage in an environment of, for example, a temperature of 60 ° C. and a humidity of 75% for 20 days are used in the parenteral pharmaceutical solution.
• the active ingredient contained for example, eribulin mesylate
• 8.00% or less is preferable, 7.50% or less is more preferable, and 7.00% or less is further preferable.
• the amount (%) of such total related substances is, for example, as described later in Examples, the total area value of the peaks of related substances obtained by HPLC analysis of the sample solution, and the elibrin of the standard solution obtained by diluting the sample solution 100 times. It can be calculated from the following formula as a value divided by the peak area of.
• Total amount of related substances (%) total area value of peaks of related substances in sample solution / peak area value of eribulin in standard solution
• the parenteral pharmaceutical solution when subjected to a rigorous test of storage in an environment of, for example, a temperature of 60 ° C. and a humidity of 75% for 20 days is described as "Haraven (Registration)" which has already been sold. It is preferable that there is no related substance other than the related substance recognized when the solution having the same formulation as "Intravenous injection 1 mg" is subjected to the same harsh test.
• the parenteral pharmaceutical solution according to the present disclosure is useful for the treatment of inoperable or recurrent breast cancer, as well as malignant soft tissue tumors.
• the dose of the parenteral pharmaceutical solution according to the present disclosure can be the same as that of the existing eribulin mesylate preparation, and is not particularly limited.
• the route of administration of the parenteral pharmaceutical solution according to the present disclosure is not particularly limited as long as it is parenteral, and examples thereof include intravenous, intramuscular, and subcutaneous, and intravenous is preferable.
• the parenteral pharmaceutical solution according to the present disclosure may be directly administered as an injection, for example, intravenously, or diluted with physiological saline and then administered as an injection.
• the parenteral pharmaceutical solution according to the present disclosure can be contained in a container such as a vial, a syringe (including a so-called prefilled syringe), an ampoule, or a bag.
• a container such as a vial, a syringe (including a so-called prefilled syringe), an ampoule, or a bag.
• These containers may be made of glass or plastic, and may be made of a material having a semi-permeable gas.
• it is a treatment for suppressing alkali elution from the inner surface in order to suppress fluctuations in the pH of the liquid during storage (for example, FireBlast (registered trademark) treatment (fire blast treatment), etc.).
• a container made of glass for example, "VIALEX®” manufactured by Nipro Co., Ltd.
• an olefin polymer for example, cycloolefin polymer, polyethylene, polypropylene, etc.
• olefin polymer
• the method for producing the parenteral pharmaceutical solution of the present disclosure is not particularly limited, and for example, an active ingredient, an tonicity agent, other additives and the like are dissolved in a solvent (usually water) and then a pH adjuster. It may be adjusted to a desired pH by using.
• the pH is preferably adjusted in an environment in which acidic substances in the atmosphere such as carbon dioxide are reduced (for example, in an atmosphere of an inert gas such as nitrogen or argon).
• Example 1 250 mg of erybrin mesylate and 4.50 g of sodium chloride are placed in a glass beaker, and an appropriate amount of purified water is added to dissolve the mixture. Water was added to make the total volume 500 mL, and a pharmaceutical solution having the formulation shown in Table 1 was obtained. The obtained pharmaceutical solution was filled in a glass vial (VIALEX®; the same applies to the following examples and comparative examples) in an amount of 2 mL each, and a rubber stopper (Teflon laminated butyl rubber stopper; also in the following examples and comparative examples). (Same as above).
• VIALEX® glass vial
• a rubber stopper Teflon laminated butyl rubber stopper
• the pH of the solution was measured using a pH meter (F52 (manufactured by HORIBA, Ltd.)) in accordance with the pH measurement method of the Japanese Pharmacopoeia General Test Method (the same applies to the following examples and comparative examples). ..
• the osmotic pressure ratio of the obtained pharmaceutical solution is osmotic pressure (mOsm) using an osmometer OSMO STATION OM-6060 (manufactured by Arcley Co., Ltd.) according to the osmotic pressure measurement method (osmolal concentration measurement method) of the General Test Method of the Japanese Pharmacy.
• mOsm osmotic pressure
• osmolal concentration measurement method osmolal concentration measurement method
• Comparative Example 1 Put 250 mg of erybrin mesylate in a beaker, add an appropriate amount of purified water to dissolve it, add a pH adjuster to adjust the pH value as shown in Table 1, and add purified water to make the total volume 500 mL. A pharmaceutical solution having the formulation shown in Table 1 was obtained. The obtained pharmaceutical solution was filled in 2 mL each in a glass vial and sealed with a rubber stopper.
• Comparative Example 2 Put 200 mg of erybrin mesylate and 20 mL of absolute ethanol in a beaker, add an appropriate amount of purified water to dissolve it, add a pH adjuster to adjust the pH value to the pH value shown in Table 1, and then add purified water.
• the total volume was 400 mL, and a pharmaceutical solution having the formulation shown in Table 1 was obtained.
• the obtained pharmaceutical solution was filled in 2 mL each in a glass vial and sealed with a rubber stopper.
• Test Example 1 Stability test (harsh test) The solutions (medicinal solutions) immediately after being produced in Example 1 and Comparative Example 2 were each filled in a glass vial and sealed with a rubber stopper, and stored for 20 days in an environment of a temperature of 60 ° C. and a humidity of 75%.
• the presence of related substances was measured by HPLC using the following methods and conditions for each of the solutions on the 10th and 20th days from the start of storage, with the start of storage and the start of storage as the 0th day.
• Table 2 shows the total amount (%) of related substances calculated by the following formula.
• ⁇ Analysis method> The solution to be measured (medicinal solution) was designated as a "sample solution”, while 0.5 mL of the sample solution was accurately weighed and a mobile phase was added to make exactly 50 mL, which was designated as a "standard solution”. Accurately 100 ⁇ L each of the sample solution and the standard solution were taken and analyzed by high performance liquid chromatography under the following conditions. Each peak area was calculated by the automatic integration method.
• HPLC device High performance liquid chromatograph device LC-20A system, Shimadzu Corporation detector: Ultraviolet absorptiometer (measurement wavelength: 210 nm)
• Flow rate The eribulin retention time was adjusted to about 30 minutes.
• Example 1 in which sodium chloride was used as the tonicity agent, an osmotic pressure ratio that was acceptable even if it was ethanol-free could be obtained.
• Examples 2 to 6 Elibrine mesylate and each tonicity agent shown in Table 3 are placed in a beaker in an amount 10 times the amount shown in Table 3, and an appropriate amount of purified water is added to dissolve the acid, and then a pH adjuster is added. The pH value was adjusted to the pH value shown in Table 3, and purified water was further added to bring the total volume to 20 mL to obtain a pharmaceutical solution having the formulation shown in Table 3. The obtained pharmaceutical solution was filled in 2 mL each in a glass vial and sealed with a rubber stopper.
• Test Example 2 Stability test (harsh test) The solutions (medicinal solutions) immediately after being produced in Examples 2 to 6 and Comparative Example 3 were filled in a glass vial and stored in an environment of a temperature of 60 ° C. and a humidity of 75% for 20 days in a state of being sealed with a rubber stopper. bottom.
• the presence of related substances was measured by HPLC using the same method and conditions as in Test Example 1 for each of the solutions on the 10th and 20th days from the start of storage, with the start of storage and the start of storage as 0 days.
• the main related substances are, from the one having the shortest retention time, the related substance A, the related substance B, the related substance C, and the related substance D.
• Related substance E Table 4 shows the amounts (%) of the main related substances A to E and the total amount (%) of the related substances calculated by the following and the above formulas.
• ⁇ Calculation formula> -Amount of related substances (%) peak area value of any of related substances A to E in the sample solution / peak area value of eribulin in the standard solution
• Examples 7 and 8 Elibrine mesylate and each tonicity agent shown in Table 5 are placed in a stainless steel container in an amount 100 times the amount shown in Table 5, and an appropriate amount of purified water is added to dissolve them, and then a pH adjuster is added. The pH value was adjusted to the pH value shown in Table 5, and purified water was further added to bring the total volume to 200 mL to obtain a pharmaceutical solution having the formulation shown in Table 5. The obtained pharmaceutical solution was filled in 2 mL each in a glass vial and sealed with a rubber stopper.
• the following reagents from different manufacturers from the above reagents were used for D-mannitol, propylene glycol, and sodium hydroxide.
• Comparative Example 4 Put 50 mg of erybrin mesylate and 5 mL of absolute ethanol in a stainless steel container, add an appropriate amount of purified water to dissolve it, add a pH adjuster to adjust the pH value to the pH value shown in Table 5, and add purified water. In addition, the total volume was 100 mL, and a pharmaceutical solution having the formulation shown in Table 5 was obtained. The obtained pharmaceutical solution was filled in 2 mL each in a glass vial and sealed with a rubber stopper.
• Test Example 3 Stability test (accelerated test) The solution (medicinal solution) immediately after being produced in Examples 7 and 8 and Comparative Example 4 was filled in a glass vial and sealed with a rubber stopper for 6 months in an environment of a temperature of 40 ° C. and a humidity of 75%. saved.

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• 2021
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