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WO2023043207A1 - Pharmaceutical composition with improved stability comprising propionic acid-based drug and stabilizer - Google Patents

Pharmaceutical composition with improved stability comprising propionic acid-based drug and stabilizer Download PDF

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Publication number
WO2023043207A1
WO2023043207A1 PCT/KR2022/013751 KR2022013751W WO2023043207A1 WO 2023043207 A1 WO2023043207 A1 WO 2023043207A1 KR 2022013751 W KR2022013751 W KR 2022013751W WO 2023043207 A1 WO2023043207 A1 WO 2023043207A1
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Prior art keywords
stabilizer
pharmaceutical composition
propionic acid
based drug
cyclodextrin
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PCT/KR2022/013751
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French (fr)
Korean (ko)
Inventor
전선덕
윤복영
안선욱
최인실
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GUJU PHARM CO Ltd
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GUJU PHARM CO Ltd
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Priority claimed from KR1020210122837A external-priority patent/KR20230039908A/en
Priority claimed from KR1020210122835A external-priority patent/KR102675664B1/en
Application filed by GUJU PHARM CO Ltd filed Critical GUJU PHARM CO Ltd
Publication of WO2023043207A1 publication Critical patent/WO2023043207A1/en
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a pharmaceutical composition containing a propionic acid-based drug with improved stability and a method for preparing the same.
  • Non-steroidal anti-inflammatory drugs are widely used drugs for the treatment of pain, inflammation and fever, and are used for various diseases such as osteoarthritis, rheumatoid arthritis, gout, headache, toothache, and menstrual pain.
  • NSAIDs are classified into salicylic acid, acetic acid, propionic acid, mefenamic acid, and oxicam based on structure.
  • Propionic acid class drugs include ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flubiprofen, oxaprozin, loxoprofen, and felubiprofen. do.
  • Propionic acid-based drugs are currently marketed as oral preparations for the treatment of pain, inflammation and fever under various trade names.
  • propionic acid-based drugs can be decarboxylated by ambient conditions such as light or heat, and can produce related substances, which affects the stability of the drug.
  • the decarboxylation reaction of propionic acid-based drugs proceeds slowly, but the reaction proceeds more rapidly in the liquid state. Accordingly, it is important to develop a composition capable of inhibiting the decomposition of propionic acid-based drugs and the generation of related substances and improving stability.
  • An object of the present invention is to provide a pharmaceutical composition containing a propionic acid-based drug with improved stability.
  • An object of the present invention is to provide a method for preparing a pharmaceutical composition containing a propionic acid-based drug having improved stability.
  • the stabilizer is ⁇ -cyclodextrin ( ⁇ CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), tocopherol polyethylene glycol 1000-succinate (tocopherol polyethylene glycol 1000- succinate (TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and at least one pharmaceutical composition selected from the group consisting of cysteine.
  • ⁇ CD ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • tocopherol polyethylene glycol 1000-succinate tocopherol polyethylene glycol 1000- succinate
  • BHA butylated hydroxyanisol
  • ASA ascorbic acid
  • MET methionine
  • at least one pharmaceutical composition selected from the group consisting of cysteine selected from the group consisting of cysteine.
  • the stabilizer is hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), tocopherol polyethylene glycol 1000-succinate (TPGS), A pharmaceutical composition comprising at least one selected from the group consisting of butylated hydroxyanisol (BHA), methionine (MET), and cysteine.
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • TPGS tocopherol polyethylene glycol 1000-succinate
  • BHA butylated hydroxyanisol
  • MET methionine
  • cysteine cysteine
  • composition according to 1 above, wherein the composition is for injection.
  • the stabilizer is ⁇ -cyclodextrin ( ⁇ CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), tocopherol polyethylene glycol 1000-succinate (tocopherol polyethylene glycol 1000- Preparation of at least one pharmaceutical composition selected from the group consisting of succinate, TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and cysteine method.
  • ⁇ CD ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • tocopherol polyethylene glycol 1000-succinate tocopherol polyethylene glycol 1000- Preparation of at least one pharmaceutical composition selected from the group consisting of succinate, TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and cysteine method.
  • the pharmaceutical composition of the present invention can minimize the loss of the active ingredient, propionic acid-based drug, and the generation of impurities during the manufacturing or storage step.
  • the pharmaceutical composition of the present invention does not change in properties under harsh or accelerated conditions, hardly generates related substances, and exhibits an effect of stably maintaining propionic acid-based drugs, so that it can be usefully used as a pharmaceutical composition that can be stored for a long period of time.
  • Figure 2 is a graph showing the accelerated stability test results of Examples 4 to 6.
  • Example 4 is a graph showing the results of the severe stability test of Example 6 and Comparative Example 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a propionic acid-based drug and a stabilizer.
  • the pharmaceutical composition of the present invention is a composition with improved stability by inhibiting the decomposition and impurity production of propionic acid-based drugs, which are active ingredients.
  • Propionic acid-based drugs are drugs containing the propionic acid group and are a type of non-steroidal anti-inflammatory drug, and can be used to treat pain, inflammation, and fever.
  • Propionic acid-based drugs include a propionic acid group having the structure of Chemical Formula 1, which is also referred to as a propionic acid group.
  • Propionic acid-based drugs have low chemical stability and can be easily decomposed by external environments such as light, heat, or humidity, and there is a problem in that related substances are generated due to decomposition.
  • the pharmaceutical composition of the present invention can provide a pharmaceutical composition with improved stability by including a specific stabilizer to minimize the loss of the active ingredient propionic acid-based drug and inhibit the increase of impurities. That is, certain stabilizers can act as stabilizers in pharmaceutical compositions.
  • the propionic acid-based drug is ibuprofen or a pharmaceutically acceptable salt thereof; or naproxen or a pharmaceutically acceptable salt thereof.
  • the stabilizer is ⁇ -cyclodextrin ( ⁇ CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), tocopherol polyethylene glycol 1000-succinate , TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and may be at least one selected from the group consisting of cysteine.
  • ⁇ CD ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇
  • the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and methionine.
  • the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and hydroxypropyl- ⁇ -cyclodextrin.
  • the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and tocopherol polyethylene glycol 1000-succinate.
  • the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and butylated hydroxyanisole.
  • the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and cysteine.
  • the pharmaceutical composition of the present invention may include naproxen or a pharmaceutically acceptable salt thereof, and methionine.
  • the pharmaceutical composition of the present invention may include naproxen or a pharmaceutically acceptable salt thereof, and tocopherol polyethylene glycol 1000-succinate.
  • the pharmaceutical composition of the present invention may include naproxen or a pharmaceutically acceptable salt thereof, and hydroxypropyl- ⁇ -cyclodextrin.
  • the stabilizer may be appropriately included to the extent of inhibiting the production of related substances from propionic acid-based drugs, and the content of the stabilizer included in the pharmaceutical composition of the present invention is not limited. Through the present examples, it was confirmed that the production of related substances from propionic acid-based drugs was inhibited and the stability was excellent even when the stabilizer was included in a small amount.
  • the stabilizer may be included in an amount of 0.001 parts by weight or more, 0.001 to 400 parts by weight based on 100 parts by weight of the propionic acid-based drug.
  • the stabilizer is 0.001 to 5.6 parts by weight, 0.005 to 5 parts by weight, 0.002 to 5 parts by weight, 0.002 to 4 parts by weight, 0.002 to 3 parts by weight, 0.002 to 2.1 parts by weight, 0.01 to 3 parts by weight, based on 100 parts by weight of the propionic acid-based drug. 1.8 parts by weight.
  • the stabilizer may be included in an amount of 0.05 parts by weight or more, 0.05 to 10 parts by weight, 0.04 to 5.6 parts by weight, 0.02 to 2.1 parts by weight, or 0.01 to 1.8 parts by weight, based on 100 parts by weight of the propionic acid-based drug.
  • methionine is 0.001 parts by weight or more, 0.05 parts by weight or more, 0.05 to 10 parts by weight, 0.04 to 5.6 parts by weight, 0.02 to 2.1 parts by weight, or 0.01 to 1.8 parts by weight based on 100 parts by weight of ibuprofen or a pharmaceutically acceptable salt thereof. It may be included in parts by weight.
  • the stabilizer may be included in an amount of 0.001 part by weight or more, 0.01 part by weight or more, 0.01 to 200 parts by weight, or 0.1 to 200 parts by weight based on 100 parts by weight of naproxen or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition containing the propionic acid-based drug of the present invention may not include other additives in addition to the above-described stabilizers, but additionally, additional stabilizers commonly used in the art, solubilizers, tonicity agents, pH adjusting agents, etc. are limited You can optionally include more so that it does not happen.
  • the additional stabilizer means a different type of stabilizer from the above-mentioned stabilizers.
  • additional stabilizer any material capable of further improving the stability of the pharmaceutical composition is sufficient, and the type thereof is not limited.
  • additional stabilizers include phenolic acid, sorbic acid, sodium sulfite, sodium bisulfite, sodium metabisulfite, acetylcysteine, sodium thiosulfate (sodium thiosulfate),
  • the additional stabilizer may be sodium ethylenediaminetetraacetate (EDTA Na).
  • Additional stabilizers may affect the immediate stabilization of the drug, but may affect stabilization in the long term, if not immediately.
  • the solubilizing agent may be at least one selected from the group consisting of arginine, meglumine, lysine, histidine, magnesium oxide, sodium acetate and sodium citrate.
  • Arginine may be L-arginine or D-arginine.
  • the solubilizing agent may be L-arginine.
  • the solubilizing agent may serve to dissolve propionic acid or a pharmaceutically acceptable salt thereof having low solubility in water.
  • the isotonic agent is sufficient to use those commonly used in the art, and may be, for example, sodium chloride or glucose.
  • a pH adjusting agent may be used to adjust the pH of the pharmaceutical composition of the present invention, and the type is not limited.
  • the pharmaceutical composition of the present invention has a pH of 7.0 to 8.5, such as 7.0 to 8.5, 7.1 to 8.4, 7.2 to 8.3, 7.3 to 8.2, 7.4 to 8.1, 7.5 to 8.0, 7.6 to 7.9, 7.7 to 7.9, or 7.8 to 7.9. can be regulated.
  • the pharmaceutical composition of the present invention may be in liquid form (ie liquid formulation) or solid form, but is not limited thereto.
  • the pharmaceutical composition of the present invention may be a liquid pharmaceutical composition. Since the stability of propionic acid-based drugs is lower in liquid form, from the result of confirming that the pharmaceutical composition of the present invention exhibits excellent stability in a liquid phase, it can be seen that the pharmaceutical composition of the present invention can exhibit better stability in a solid phase. can
  • the pharmaceutical composition of the present invention may be a pharmaceutical composition for injection.
  • the pharmaceutical composition for injection may be in the form of a liquid or solid, and may specifically be in the form of a liquid or dry powder, but is not limited thereto.
  • the dry powder for injection When the dry powder for injection is administered to a patient, it may be reconstituted with water for injection, physiological saline, glucose solution, amino acid solution, etc. and then administered to the patient.
  • the drying may be performed by a conventional drying method, for example, lyophilization, rotary evaporation, spray drying, or fluidized bed drying, and may be specifically performed by lyophilization.
  • the pharmaceutical composition of the present invention can be formulated according to conventional methods.
  • the form of the pharmaceutical formulation is not limited, and may be in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or injection solutions.
  • the present invention can provide a pharmaceutical preparation containing a propionic acid-based drug and a specific stabilizer.
  • the pharmaceutical formulation of the present invention includes a propionic acid-based drug and a stabilizer
  • the stabilizer is ⁇ -cyclodextrin ( ⁇ CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), tocopherol polyethylene glycol 1000-succinate (tocopherol polyethylene glycol 1000- It may be at least one selected from the group consisting of succinate (TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and cysteine. Since the propionic acid-based drugs and stabilizers have been described above, detailed descriptions thereof will be omitted.
  • the pharmaceutical formulation of the present invention may not include other additives in addition to the above-described stabilizers, but may optionally further include, but are not limited to, additional stabilizers, solubilizers, isotonic agents, pH adjusters, etc. commonly used in the art. there is. Additional stabilizers, solubilizers, tonicity agents, and pH adjusters have been described above, and therefore, detailed descriptions thereof will be omitted.
  • the pharmaceutical formulation of the present invention may be a liquid form or a solid pharmaceutical formulation.
  • the pharmaceutical formulation of the present invention may be a pharmaceutical formulation for injection.
  • the pharmaceutical formulation of the present invention may inhibit the decomposition of propionic acid-based drugs or the generation of impurities (eg, related substances).
  • the present invention provides a method for preparing a pharmaceutical composition
  • a solvent is not limited as long as it is a solvent used in the art, and may specifically be an aqueous solvent, such as sterile water.
  • a solubilizer or an additional stabilizer may be further added.
  • the order of dissolution by adding a stabilizer, a solubilizer, an additional stabilizer, and a propionic acid-based drug may be adjusted.
  • the manufacturing method of the present invention may further include adjusting the pH to 7.0 to 8.5 after dissolving the propionic acid-based drug.
  • the manufacturing method of the present invention includes a stabilizer dissolution step of dissolving the stabilizer in a solvent;
  • It may include; a drug dissolution step of dissolving a propionic acid-based drug in a solution in which the stabilizer is dissolved.
  • the stabilizer is ⁇ -cyclodextrin ( ⁇ CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), tocopherol polyethylene glycol 1000-succinate (tocopherol polyethylene glycol 1000- succinate (TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and at least one selected from the group consisting of cysteine.
  • ⁇ CD ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • tocopherol polyethylene glycol 1000-succinate tocopherol polyethylene glycol 1000- succinate
  • BHA butylated hydroxyanisol
  • ASA ascorbic acid
  • MET methionine
  • the stabilizer is hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), tocopherol polyethylene glycol 1000-succinate (TPGS), butylated hydroxyanisole (butylated hydroxyanisol, BHA), ascorbic acid (ASA), methionine (MET), and may be at least one selected from the group consisting of cysteine.
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • TPGS tocopherol polyethylene glycol 1000-succinate
  • BHA butylated hydroxyanisole
  • ASA ascorbic acid
  • MET methionine
  • the manufacturing method of the present invention may further include adding a solubilizer or isotonic agent to the sterilized water before dissolving the stabilizer.
  • the manufacturing method of the present invention may further include adjusting the pH of the solution in which the propionic acid-based drug is dissolved to 7.0 to 8.5 by adding a pH adjusting agent to the solution obtained after performing the drug dissolution step.
  • the step of adjusting the pH is to adjust the pH to 7.0 to 8.5, 7.1 to 8.4, 7.2 to 8.3, 7.3 to 8.2, 7.4 to 8.1, 7.5 to 8.0, 7.6 to 7.9, 7.7 to 7.9, or 7.8 to 7.9.
  • Samples containing ibuprofen were prepared in various compositions as shown in Table 1 below (unit: mg).
  • an injection solution was prepared by completely dissolving it while sequentially adding a predetermined amount of a solubilizer, an isotonic agent, and a stabilizer, respectively.
  • An appropriate amount of ibuprofen was added to the injection solution, completely dissolved, and then the marked line was adjusted. Thereafter, the pH of the injection solution was measured, and an appropriate amount of a pH adjusting agent was added to adjust the pH to 7.8 to 7.9.
  • the pH-adjusted injection was filtered through a 0.2 ⁇ m filter, filled into an injection container, and a rubber stopper was inserted, followed by capping with an aluminum cap. Dissolved oxygen was minimized by replacing air with nitrogen during the preparation/filling/capping process of the injection.
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 6 Propionic acid class drugs ibuprofen 100 100 100 100 100 100 100 100 100 100 solubilizing agent L-Arginine 78 78 78 78 78 78 stabilizer EDTA Na hydrate 0.1 0.1 0.1 0.1 0.1 0.1 ⁇ -cyclodextrin 0 0.16 0 0 0 0 0 0 0 Hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) 0 0 400 0 0 0 0 0 0 0 0 Tocopherol polyethylene glycol 1000-succinate (TPGS) 0 0 0 0.2 0 0 0 0 Butylated hydroxyanisole (BHA) 0 0 0 0 0.2 0 0 ascorbic acid 0 0 0 0 0 0 0 10 0 methionine 0 0 0 0 0 0 0 0.63
  • Samples containing ibuprofen were prepared with the composition shown in Table 2 below (Unit: mg/mL).
  • a liquid solution was prepared by completely dissolving while sequentially adding a solubilizer and a stabilizer of a predetermined content, respectively.
  • An appropriate amount of ibuprofen was added to the liquid solution, completely dissolved, and then the marked line was adjusted.
  • the vial was filled and a rubber stopper was inserted, followed by capping with an aluminum cap.
  • Samples containing naproxen were prepared with various compositions as shown in Table 3 below (unit: mg/mL).
  • a liquid solution was prepared by completely dissolving while sequentially adding a solubilizer and a stabilizer of a predetermined content, respectively.
  • An appropriate amount of naproxen was added to the liquid solution, completely dissolved, and then the mark was adjusted.
  • the vial was filled and a rubber stopper was inserted, followed by capping with an aluminum cap.
  • Example 12 Example 13
  • Example 14 Example 15 Propionic acid class drugs naproxen 100 100 100 100 100 solubilizing agent L-Arginine 85 85 85 stabilizer methionine 0 0.625 0 0 0 ascorbic acid 0 0 10 0 0 TPGS 0 0 0 0.2 0 HP- ⁇ -CD 0 0 0 0 200
  • UV absorbance photometer detection wavelength: 254 nm
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Example 6 the first 0.005 0.005 0.003 0.002 0.00002 0.039 0.0004 1 month 0.039 0.037 0.019 0.011 0.005 0.053 0.003 2 months 0.056 0.056 0.030 0.014 0.012 0.054 0.004 3 months 0.090 0.072 0.043 0.016 0.016 0.058 0.005
  • Examples produced less related substances. Specifically, in Examples 2 and 3, compared to Comparative Example 1, the degree of production of related substances was lowered by about 50% or more after 3 months under accelerated storage conditions. After six months, the degree of production of related substances was lowered by about 70% or more. In particular, it was confirmed that in Examples 4 and 6, compared to Comparative Example 1, related substances at the initial time were significantly reduced (see Table 4 and FIGS. 1 and 2).
  • hydroxypropyl- ⁇ -cyclodextrin HP- ⁇ - It was confirmed that CD), tocopherol or its derivatives, butylated hydroxyanisole (BHA), and methionine effectively inhibited the production of related compounds derived from ibuprofen, a propionic acid-based drug, and increased stability.
  • Test point Until 1 or 2 weeks have elapsed from the date of manufacture
  • test samples were extracted at 1 week and 2 weeks, and liquid chromatography was performed using a solution adjusted to a constant concentration of ibuprofen as a sample solution according to the test method for ibuprofen related substances in the USP raw material section. The degree (%) of related substances in the solution was analyzed and the results are shown in Table 5.
  • UV absorbance photometer detection wavelength: 254 nm
  • Example 16 the first 0.005 0.000 1 week 0.042 0.003 2 weeks 0.096 0.005
  • Example 16 Unlike Comparative Example 4, no related substances were detected in Example 16 under harsh storage conditions, and the production of related substances was effectively suppressed even after 2 weeks.
  • Test samples were extracted 1 week and 2 weeks after starting storage, and liquid chromatography was performed under the following conditions by referring to the Naproxen Related Substance Test Method in the EP raw material section using a solution adjusted to a constant concentration of naproxen as a sample solution. The degree (%) of related substances in the solution was analyzed and the results are shown in Table 6.
  • UV absorbance photometer detection wavelength: 230 nm
  • Mobile phase Dissolve 1.36 g of potassium dihydrogen phosphate in 900 mL of water, add phosphoric acid to adjust the pH to 2.0, and then add water to make exactly 1 L to prepare the first solution. A mixture of 580 mL of the first solution and 420 mL of acetonitrile is used as a mobile phase
  • Example 12 Example 13
  • Example 14 Example 15 the first 0.37 0.11 0.38 ND 1) 0.04 1 week 0.39 0.13 0.41 N.D. 0.05 2 weeks 0.39 0.13 0.41 N.D. 0.04
  • Example 12 Not Detected
  • Example 14 under harsh storage conditions significantly reduced related substances at the first time compared to Comparative Example 3.
  • Example 14 showed related substances was not detected (see Table 6).
  • methionine, hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD), and especially tocopherol polyethylene glycol 1000-succinate (TPGS) were found to be related to naproxen, a propionic acid-based drug, from the manufacturing stage. It was confirmed that the production was effectively inhibited and the stability was increased.
  • the method for preparing the remedy is the same as the method described in '1.(1) Preparation of Liquid Composition Containing Ibuprofen-1' above, but the type and content of the stabilizer is changed to produce ibuprofen in various compositions as shown in Table 7 below. A sample containing was prepared (unit: mg).
  • Example 6 Example 7
  • Example 8 Example 9
  • Example 10 Example 11 ibuprofen 100 100 100 100 100 100 100 100 L-Arginine 78 78 78 78 78 EDTA Na hydrate 0.1 0 0.1 0.1 0.1 0.1 methionine 0.63 0.63 0.42 0.01 0.9 1.8
  • test samples are extracted at 1 week and 2 weeks, and the solution adjusted to a constant concentration of ibuprofen is used as the test solution.
  • Liquid chromatography was performed under the same conditions as described in 'Stability test under storage conditions'. The degree (%) of related substances in the injection was analyzed and the results are shown in Table 8 and FIG. 3.
  • Test time Until 1 or 2 weeks have elapsed from the date of manufacture
  • Example 6 Example 7
  • Example 8 Example 9
  • Example 10 Example 11 the first 0.0004 0.002 0.0004 0.0037 0.001 0.0008 1 week 0.005 0.005 0.008 0.011 0.002 0.001 2 weeks 0.01 0.008 0.014 0.017 0.003 0.002
  • Example 7 containing only methionine without EDTA Na hydrate, production of related substances was effectively suppressed at the initial stage and even after 2 weeks (see Table 8 and FIG. 3).
  • Test time Until 1, 2, 4 weeks have elapsed from the date of manufacture
  • Example 6 the first 0.053 0.0004 1 week 0.106 0.006 2 weeks 0.137 0.013 4 weeks 0.168 0.038
  • Comparative Example 2 which is a commercially available product, it was confirmed that the production of related substances was effectively inhibited in Example under harsh conditions (see Table 9 and FIG. 4).

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Abstract

The present invention relates to a pharmaceutical composition with improved stability, comprising a propionic acid-based drug. More specifically, the pharmaceutical composition comprises at least one stabilizer selected from the group consisting of β-cyclodextrin (βCD), hydroxypropyl β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000-succinate (TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and cysteine, and thus, loss of the propionic acid-based drug and the generation of impurities can be minimized in a preparation step or a storage step.

Description

안정성이 향상된 프로피오닉산 계열 약물 및 안정화제를 포함하는 약학 조성물Pharmaceutical composition containing a propionic acid-based drug with improved stability and a stabilizer

본 발명은 안정성이 향상된 프로피오닉산 계열 약물을 포함하는 약학 조성물 및 이의 제조 방법에 관한 것이다.The present invention relates to a pharmaceutical composition containing a propionic acid-based drug with improved stability and a method for preparing the same.

비스테로이드 항염증제(non-steroidal anti-inflammatory drugs, NSAIDs)는 통증과 염증 및 해열에 대한 치료로 널리 사용되는 약물로, 골관절염, 류마티스 관절염, 통풍, 두통, 치통, 생리통 등 다양한 질환에 사용되고 있다. NSAID는 구조에 따라 살리실산, 아세트산, 프로피오닉산, 메페남산, 옥시캄 계열 등으로 구분된다.Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs for the treatment of pain, inflammation and fever, and are used for various diseases such as osteoarthritis, rheumatoid arthritis, gout, headache, toothache, and menstrual pain. NSAIDs are classified into salicylic acid, acetic acid, propionic acid, mefenamic acid, and oxicam based on structure.

프로피오닉산 계열 약물에는 이부프로펜, 덱시부프로펜, 나프록센, 페노프로펜, 케토프로펜, 덱스케토프로펜, 플루비오프로펜, 옥사프로진, 록소프로펜, 펠루비프로펜 등이 포함된다. 프로피오닉산 계열 약물은 현재 다양한 상품명으로 진통, 염증 및 발열 등의 치료를 위한 경구 투여용 제제로 시판되고 있다.Propionic acid class drugs include ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flubiprofen, oxaprozin, loxoprofen, and felubiprofen. do. Propionic acid-based drugs are currently marketed as oral preparations for the treatment of pain, inflammation and fever under various trade names.

한편 프로피오닉산 계열 약물은 빛 또는 열 등 주변 조건에 의해 디카복실화될 수 있고 유연물질을 생성할 수 있으며, 이는 약물의 안정성에 영향을 미치게 된다. 통상적으로 프로피오닉산 계열 약물의 디카복실화 반응은 서서히 진행되나, 액상 상태에서는 반응이 보다 빠르게 진행된다. 이에, 프로피오닉산 계열 약물의 분해 및 유연물질의 발생을 억제하고, 안정성을 높일 수 있는 조성물을 개발하는 것이 중요하다.On the other hand, propionic acid-based drugs can be decarboxylated by ambient conditions such as light or heat, and can produce related substances, which affects the stability of the drug. In general, the decarboxylation reaction of propionic acid-based drugs proceeds slowly, but the reaction proceeds more rapidly in the liquid state. Accordingly, it is important to develop a composition capable of inhibiting the decomposition of propionic acid-based drugs and the generation of related substances and improving stability.

본 발명은 안정성이 향상된 프로피오닉산 계열 약물을 포함하는 약학 조성물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a pharmaceutical composition containing a propionic acid-based drug with improved stability.

본 발명은 안정성이 향상된 프로피오닉산 계열 약물을 포함하는 약학 조성물의 제조방법을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a method for preparing a pharmaceutical composition containing a propionic acid-based drug having improved stability.

1. 프로피오닉산 계열 약물 및 안정화제를 포함하고,1. Contains propionic acid-based drugs and stabilizers;

상기 안정화제는 β-사이클로덱스트린(β-cyclodextrin, βCD), 하이드록시프로필-β-사이클로덱스트린(hydroxypropyl β-cyclodextrin, HP-β-CD), 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(tocopherol polyethylene glycol 1000-succinate, TPGS), 부틸레이티드하이드록시아니솔(butylated hydroxyanisol, BHA), 아스코르브산(ascorbic acid, ASA), 메티오닌(methionin, MET), 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나인 약학 조성물.The stabilizer is β-cyclodextrin (βCD), hydroxypropyl β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000-succinate (tocopherol polyethylene glycol 1000- succinate (TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and at least one pharmaceutical composition selected from the group consisting of cysteine.

2. 위 1에 있어서, 상기 프로피오닉산 계열 약물은 이부프로펜 또는 이의 약학적으로 허용가능한 염; 또는 나프록센 또는 이의 약학적으로 허용가능한 염인 약학 조성물.2. The method of 1 above, wherein the propionic acid-based drug is ibuprofen or a pharmaceutically acceptable salt thereof; or naproxen or a pharmaceutically acceptable salt thereof.

3. 위 1에 있어서, 상기 안정화제는 하이드록시프로필-β-사이클로덱스트린(hydroxypropyl β-cyclodextrin, HP-β-CD), 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(tocopherol polyethylene glycol 1000-succinate, TPGS), 부틸레이티드하이드록시아니솔(butylated hydroxyanisol, BHA), 메티오닌(methionin, MET) 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나인 약학 조성물.3. In the above 1, the stabilizer is hydroxypropyl β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000-succinate (TPGS), A pharmaceutical composition comprising at least one selected from the group consisting of butylated hydroxyanisol (BHA), methionine (MET), and cysteine.

4. 위 1에 있어서, 상기 프로피오닉산 계열 약물은 이부프로펜 또는 이의 약학적으로 허용가능한 염이고, 상기 안정화제는 부틸레이티드하이드록시아니솔, 메티오닌 또는 시스테인인 약학 조성물.4. The pharmaceutical composition according to 1 above, wherein the propionic acid-based drug is ibuprofen or a pharmaceutically acceptable salt thereof, and the stabilizer is butylated hydroxyanisole, methionine or cysteine.

5. 위 1에 있어서, 상기 프로피오닉산 계열 약물은 나프록센 또는 이의 약학적으로 허용가능한 염이고, 상기 안정화제는 토코페롤 폴리에틸렌 글리콜 1000-석시네이트인 약학 조성물.5. The pharmaceutical composition according to 1 above, wherein the propionic acid-based drug is naproxen or a pharmaceutically acceptable salt thereof, and the stabilizer is tocopherol polyethylene glycol 1000-succinate.

6. 위 1에 있어서, 상기 안정화제는 상기 프로피오닉산 계열 약물 100 중량부 대비 0.001 내지 400 중량부로 포함되는 약학 조성물.6. The pharmaceutical composition according to 1 above, wherein the stabilizer is included in an amount of 0.001 to 400 parts by weight based on 100 parts by weight of the propionic acid-based drug.

7. 위 1에 있어서, 상기 안정화제는 상기 프로피오닉산 계열 약물 100 중량부 대비 0.01 내지 1.8 중량부로 포함되는 약학 조성물.7. The pharmaceutical composition according to 1 above, wherein the stabilizer is included in an amount of 0.01 to 1.8 parts by weight based on 100 parts by weight of the propionic acid-based drug.

8. 위 1에 있어서, 상기 조성물은 액상 형태인 약학 조성물.8. The pharmaceutical composition according to 1 above, wherein the composition is in liquid form.

9. 위 1에 있어서, 상기 조성물은 주사용인 약학 조성물.9. The pharmaceutical composition according to 1 above, wherein the composition is for injection.

10. 안정화제를 용매에 용해시키는 안정화제 용해 단계; 및10. A stabilizer dissolution step of dissolving the stabilizer in a solvent; and

상기 안정화제가 용해된 용액에 프로피오닉산 계열 약물을 첨가하여 용해시키는 약물 용해 단계;를 포함하고,A drug dissolution step of dissolving by adding a propionic acid-based drug to a solution in which the stabilizer is dissolved;

상기 안정화제는 β-사이클로덱스트린(β-cyclodextrin, βCD), 하이드록시프로필-β-사이클로덱스트린(hydroxypropyl β-cyclodextrin, HP-β-CD), 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(tocopherol polyethylene glycol 1000-succinate, TPGS), 부틸레이티드하이드록시아니솔(butylated hydroxyanisol, BHA), 아스코르브산(ascorbic acid, ASA), 메티오닌(methionin, MET), 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나 이상인 약학 조성물의 제조방법.The stabilizer is β-cyclodextrin (βCD), hydroxypropyl β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000-succinate (tocopherol polyethylene glycol 1000- Preparation of at least one pharmaceutical composition selected from the group consisting of succinate, TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and cysteine method.

11. 위 10에 있어서, 상기 약물 용해 단계를 수행한 후 수득한 용액에 pH 조절제를 첨가하여 상기 프로피오닉산 계열 약물이 용해된 용액의 pH를 7.0 내지 8.5로 조절하는 pH 조절 단계;를 더 포함하는, 약학 조성물의 제조방법.11. The method of 10 above, further comprising a pH adjusting step of adjusting the pH of the solution in which the propionic acid-based drug is dissolved to 7.0 to 8.5 by adding a pH adjusting agent to the solution obtained after performing the drug dissolution step. To, a method for producing a pharmaceutical composition.

본 발명의 약학 조성물은 특정 안정화제를 포함함으로써 제조 단계나 보관 단계에서 활성성분인 프로피오닉산 계열 약물의 손실 및 불순물의 생성을 최소화할 수 있다.By including a specific stabilizer, the pharmaceutical composition of the present invention can minimize the loss of the active ingredient, propionic acid-based drug, and the generation of impurities during the manufacturing or storage step.

본 발명의 약학 조성물은 가혹 또는 가속 조건에서 성상의 변화가 없고 유연물질이 거의 발생하지 않으며, 프로피오닉산 계열 약물이 안정하게 유지되는 효과를 나타내어, 장기간 저장 가능한 약학 조성물로 유용하게 사용될 수 있다.The pharmaceutical composition of the present invention does not change in properties under harsh or accelerated conditions, hardly generates related substances, and exhibits an effect of stably maintaining propionic acid-based drugs, so that it can be usefully used as a pharmaceutical composition that can be stored for a long period of time.

도 1은 실시예 1 내지 3 및 비교예 1의 가속안정성 시험결과를 나타낸 그래프이다.1 is a graph showing the accelerated stability test results of Examples 1 to 3 and Comparative Example 1.

도 2는 실시예 4 내지 6의 가속안정성 시험결과를 나타낸 그래프이다.Figure 2 is a graph showing the accelerated stability test results of Examples 4 to 6.

도 3은 실시예 6 내지 11의 가혹안정성 시험결과를 나타낸 그래프이다.3 is a graph showing the results of the severe stability test of Examples 6 to 11.

도 4는 실시예 6과 비교예 2의 가혹안정성 시험결과를 나타낸 그래프이다.4 is a graph showing the results of the severe stability test of Example 6 and Comparative Example 2.

이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.

본 발명은 프로피오닉산 계열 약물 및 안정화제를 포함하는 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition comprising a propionic acid-based drug and a stabilizer.

본 발명의 약학 조성물은 활성성분인 프로피오닉산 계열 약물의 분해 및 불순물 생성을 저해시켜 안정성이 개선된 조성물이다.The pharmaceutical composition of the present invention is a composition with improved stability by inhibiting the decomposition and impurity production of propionic acid-based drugs, which are active ingredients.

프로피오닉산 계열 약물은 프로피오닉산 그룹을 포함하는 약물로 비스테로이드 소염제의 한 종류이며, 진통, 염증 및 발열 등의 치료에 사용될 수 있다. 프로피오닉산 계열 약물은 화학식 1의 구조의 프로피오닉산 그룹을 포함하며 이는 프로피온산 그룹으로도 명명된다.Propionic acid-based drugs are drugs containing the propionic acid group and are a type of non-steroidal anti-inflammatory drug, and can be used to treat pain, inflammation, and fever. Propionic acid-based drugs include a propionic acid group having the structure of Chemical Formula 1, which is also referred to as a propionic acid group.

[화학식 1][Formula 1]

Figure PCTKR2022013751-appb-img-000001
Figure PCTKR2022013751-appb-img-000001

프로피오닉산 계열 약물은 화학적 안정성이 낮아 빛, 열 또는 습도 등의 외부 환경에 의해 쉽게 분해될 수 있고, 분해로 인해 유연물질 등이 발생되는 문제가 있다.Propionic acid-based drugs have low chemical stability and can be easily decomposed by external environments such as light, heat, or humidity, and there is a problem in that related substances are generated due to decomposition.

본 발명의 약학 조성물은 특정 안정화제를 포함함으로써 활성성분인 프로피오닉산 계열 약물의 손실을 최소화하고 불순물이 증가하는 것을 저해해 안정성이 개선된 약학 조성물을 제공할 수 있다. 즉, 특정 안정화제는 약학 조성물 내에서 안정화제의 역할을 할 수 있다.The pharmaceutical composition of the present invention can provide a pharmaceutical composition with improved stability by including a specific stabilizer to minimize the loss of the active ingredient propionic acid-based drug and inhibit the increase of impurities. That is, certain stabilizers can act as stabilizers in pharmaceutical compositions.

프로피오닉산 계열 약물은 이부프로펜, 덱시부프로펜, 나프록센, 페노프로펜, 케토프로펜, 덱스케토프로펜, 플루비오프로펜, 옥사프로진, 록소프로펜, 펠루비프로펜, 펜부펜(Fenbufen), 베녹사프로펜(Benoxaprofen), 서프로펜(Suprofen), 피르프로펜(pirprofen), 인도프로펜(indoprofen), 티아프로펜산 (Tiaprofenic acid), 이부프록삼(ibuproxam), 플루녹사프로펜 (Flunoxaprofen), 알미노프로펜(Alminoprofen), 덱스케토프로펜(Dexketoprofen), 베다프로펜(Vedaprofen), 카프로펜(Carprofen), 테폭살린(Tepoxalin) 및 이의 약학적으로 허용가능한 염으로 이루어진 군에서 선택된 적어도 하나일 수 있다. 일 구현예에 따르면, 프로피오닉산 계열 약물은 이부프로펜 또는 이의 약학적으로 허용가능한 염; 또는 나프록센 또는 이의 약학적으로 허용가능한 염일 수 있다.Ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flubiprofen, oxaprozin, loxoprofen, felubiprofen, and fenbufen (Fenbufen), Benoxaprofen, Suprofen, Pirprofen, Indoprofen, Tiaprofenic acid, Ibuproxam, Flunoxa Composed of Flunoxaprofen, Alminoprofen, Dexketoprofen, Vedaprofen, Carprofen, Tepoxalin and pharmaceutically acceptable salts thereof It may be at least one selected from the group. According to one embodiment, the propionic acid-based drug is ibuprofen or a pharmaceutically acceptable salt thereof; or naproxen or a pharmaceutically acceptable salt thereof.

안정화제는 β-사이클로덱스트린(β-cyclodextrin, βCD), 하이드록시프로필-β-사이클로덱스트린(hydroxypropyl β-cyclodextrin, HP-β-CD), 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(tocopherol polyethylene glycol 1000-succinate, TPGS), 부틸레이티드하이드록시아니솔(butylated hydroxyanisol, BHA), 아스코르브산(ascorbic acid, ASA), 메티오닌(methionin, MET), 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나일 수 있다. 상기 안정화제는 조합되어 본 발명의 약학 조성물에 포함될 수 있다. 구체적으로 안정화제는 하이드록시프로필-β-사이클로덱스트린, 토코페롤 폴리에틸렌 글리콜 1000-석시네이트, 부틸레이티드하이드록시아니솔, 메티오닌 또는 시스테인일 수 있다. 이들 안정화제는 프로피오닉산 계열 약물로부터 유연물질 생성을 억제하고 안정성을 높이는데 기여할 수 있다.The stabilizer is β-cyclodextrin (βCD), hydroxypropyl β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000-succinate , TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and may be at least one selected from the group consisting of cysteine. The above stabilizers may be combined and included in the pharmaceutical composition of the present invention. Specifically, the stabilizer may be hydroxypropyl-β-cyclodextrin, tocopherol polyethylene glycol 1000-succinate, butylated hydroxyanisole, methionine or cysteine. These stabilizers can contribute to suppressing the production of related substances from propionic acid-based drugs and increasing stability.

일 구현예에 따르면, 본 발명의 약학 조성물은 이부프로펜 또는 이의 약학적으로 허용가능한 염, 및 메티오닌을 포함할 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and methionine.

일 구현예에 따르면, 본 발명의 약학 조성물은 이부프로펜 또는 이의 약학적으로 허용가능한 염, 및 하이드록시프로필-β-사이클로덱스트린을 포함할 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and hydroxypropyl-β-cyclodextrin.

일 구현예에 따르면, 본 발명의 약학 조성물은 이부프로펜 또는 이의 약학적으로 허용가능한 염, 및 토코페롤 폴리에틸렌 글리콜 1000-석시네이트를 포함할 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and tocopherol polyethylene glycol 1000-succinate.

일 구현예에 따르면, 본 발명의 약학 조성물은 이부프로펜 또는 이의 약학적으로 허용가능한 염, 및 부틸레이티드하이드록시아니솔을 포함할 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and butylated hydroxyanisole.

일 구현예에 따르면, 본 발명의 약학 조성물은 이부프로펜 또는 이의 약학적으로 허용가능한 염, 및 시스테인을 포함할 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may include ibuprofen or a pharmaceutically acceptable salt thereof, and cysteine.

일 구현예에 따르면, 본 발명의 약학 조성물은 나프록센 또는 이의 약학적으로 허용가능한 염, 및 메티오닌을 포함할 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may include naproxen or a pharmaceutically acceptable salt thereof, and methionine.

일 구현예에 따르면, 본 발명의 약학 조성물은 나프록센 또는 이의 약학적으로 허용가능한 염, 및 토코페롤 폴리에틸렌 글리콜 1000-석시네이트를 포함할 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may include naproxen or a pharmaceutically acceptable salt thereof, and tocopherol polyethylene glycol 1000-succinate.

일 구현예에 따르면, 본 발명의 약학 조성물은 나프록센 또는 이의 약학적으로 허용가능한 염, 및 하이드록시프로필-β-사이클로덱스트린을 포함할 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may include naproxen or a pharmaceutically acceptable salt thereof, and hydroxypropyl-β-cyclodextrin.

안정화제는 프로피오닉산 계열 약물로부터 유연물질 생성을 저해할 수 있을 정도로 적절히 포함될 수 있으며 본 발명의 약학 조성물 내에 포함되는 안정화제의 함량은 제한되지 않는다. 본원 실시예를 통해 안정화제가 미량으로 포함되는 경우에도 프로피오닉산 계열 약물로부터 유연물질 생성이 저해되고, 안정성이 우수한 것을 확인하였다.The stabilizer may be appropriately included to the extent of inhibiting the production of related substances from propionic acid-based drugs, and the content of the stabilizer included in the pharmaceutical composition of the present invention is not limited. Through the present examples, it was confirmed that the production of related substances from propionic acid-based drugs was inhibited and the stability was excellent even when the stabilizer was included in a small amount.

아래는 본 발명의 약학 조성물에 포함된 안정화제의 함량 예시를 나타낼 뿐이며, 이에 제한되지 않는다. 안정화제는 프로피오닉산 계열 약물 100 중량부 대비 0.001 중량부 이상, 0.001 내지 400 중량부로 포함될 수 있다. 안정화제는 프로피오닉산 계열 약물 100 중량부 대비 0.001 내지 5.6 중량부, 0.005 내지 5 중량부, 0.002 내지 5 중량부, 0.002 내지 4 중량부, 0.002 내지 3 중량부, 0.002 내지 2.1 중량부, 0.01 내지 1.8 중량부로 포함될 수 있다. 안정화제는 프로피오닉산 계열 약물 100 중량부 대비, 0.05 중량부 이상, 0.05 내지 10 중량부, 0.04 내지 5.6 중량부, 0.02 내지 2.1 중량부 또는 0.01 내지 1.8 중량부로 포함될 수 있다.The following only shows examples of the content of the stabilizer included in the pharmaceutical composition of the present invention, but is not limited thereto. The stabilizer may be included in an amount of 0.001 parts by weight or more, 0.001 to 400 parts by weight based on 100 parts by weight of the propionic acid-based drug. The stabilizer is 0.001 to 5.6 parts by weight, 0.005 to 5 parts by weight, 0.002 to 5 parts by weight, 0.002 to 4 parts by weight, 0.002 to 3 parts by weight, 0.002 to 2.1 parts by weight, 0.01 to 3 parts by weight, based on 100 parts by weight of the propionic acid-based drug. 1.8 parts by weight. The stabilizer may be included in an amount of 0.05 parts by weight or more, 0.05 to 10 parts by weight, 0.04 to 5.6 parts by weight, 0.02 to 2.1 parts by weight, or 0.01 to 1.8 parts by weight, based on 100 parts by weight of the propionic acid-based drug.

예를 들어, 메티오닌은 이부프로펜 또는 이의 약학적으로 허용 가능한 염의 100 중량부 대비 0.001 중량부 이상, 0.05 중량부 이상, 0.05 내지 10 중량부, 0.04 내지 5.6 중량부, 0.02 내지 2.1 중량부 또는 0.01 내지 1.8 중량부로 포함될 수 있다. 예를 들어, 안정화제는 나프록센 또는 이의 약학적으로 허용 가능한 염의 100 중량부 대비 0.001 중량부 이상, 0.01 중량부 이상, 0.01 내지 200 중량부, 0.1 내지 200로 포함될 수 있다.For example, methionine is 0.001 parts by weight or more, 0.05 parts by weight or more, 0.05 to 10 parts by weight, 0.04 to 5.6 parts by weight, 0.02 to 2.1 parts by weight, or 0.01 to 1.8 parts by weight based on 100 parts by weight of ibuprofen or a pharmaceutically acceptable salt thereof. It may be included in parts by weight. For example, the stabilizer may be included in an amount of 0.001 part by weight or more, 0.01 part by weight or more, 0.01 to 200 parts by weight, or 0.1 to 200 parts by weight based on 100 parts by weight of naproxen or a pharmaceutically acceptable salt thereof.

본 발명의 프로피오닉산 계열 약물을 포함하는 약학 조성물은 전술한 안정화제 이외에 다른 첨가제를 포함하지 않아도 좋으나, 추가적으로 당업계에서 통상적으로 사용되는 추가 안정화제, 가용화제, 등장화제, pH 조절제 등을 제한되지 않게 선택적으로 더 포함할 수 있다.The pharmaceutical composition containing the propionic acid-based drug of the present invention may not include other additives in addition to the above-described stabilizers, but additionally, additional stabilizers commonly used in the art, solubilizers, tonicity agents, pH adjusting agents, etc. are limited You can optionally include more so that it does not happen.

상기 추가 안정화제는 전술한 안정화제와 다른 종류의 안정화제를 의미한다.The additional stabilizer means a different type of stabilizer from the above-mentioned stabilizers.

추가 안정화제는 약학 조성물의 안정성을 보다 향상시킬 수 있는 물질이면 충분하며 그 종류는 제한되지 않는다. 예를 들어, 추가 안정화제는 페놀산, 소르브산(sorbic acid), 소듐설파이트(sodium sulfite), 소듐비설파이트(sodium bisulfite), 소듐 메타비설파이트(sodium metabisulfite), 아세틸시스테인(Acetylcysteine), 소듐티오설페이트(sodium thiosulfate), As the additional stabilizer, any material capable of further improving the stability of the pharmaceutical composition is sufficient, and the type thereof is not limited. For example, additional stabilizers include phenolic acid, sorbic acid, sodium sulfite, sodium bisulfite, sodium metabisulfite, acetylcysteine, sodium thiosulfate (sodium thiosulfate),

이산화황(sulphur dioxide), 에틸렌디아민테트라아세트산(EDTA), 소듐니트라이트, 아스코르빌 스테아레이트, 아스코르비팔미테이트, 알파-티오글리세롤, 에리소르브산, 시스테인 하이드로클로라이드, 토코페롤, 비타민 E 및 그 유도체, 토코페롤아세테이트, 부틸하이드록시톨루엔(butylated hydroxytoluene), 대두 레시틴, 소듐 티오글리콜레이트, 프로필갈레이트(propyl gallate), 요산, 멜라토닌, 티오우레아, 트립토판(tryptophan), 글루타치온(Glutathione), 머캅토프로피오닐글라이신(Mercaptopropionylglycine), 리포익산(Lipoic acid), 및 이의 염으로 이루어진 군에서 선택된 적어도 하나일 수 있다. 일 구현예에 따르면, 추가 안정화제는 에틸렌디아민테트라아세트산 나트륨(EDTA Na) 일 수 있다.Sulfur dioxide, ethylenediaminetetraacetic acid (EDTA), sodium nitrite, ascorbyl stearate, ascorbipalmitate, alpha-thioglycerol, erythorbic acid, cysteine hydrochloride, tocopherol, vitamin E and its derivatives , tocopherol acetate, butylated hydroxytoluene, soy lecithin, sodium thioglycolate, propyl gallate, uric acid, melatonin, thiourea, tryptophan, glutathione, mercaptopropionyl It may be at least one selected from the group consisting of glycine (Mercaptopropionylglycine), lipoic acid (Lipoic acid), and salts thereof. According to one embodiment, the additional stabilizer may be sodium ethylenediaminetetraacetate (EDTA Na).

이러한 추가 안정화제는 약물의 즉각적인 안정화에 영향을 줄 수 있으나 즉각적이지 않더라도 장기적으로 안정화에 영향을 줄 수 있다.These additional stabilizers may affect the immediate stabilization of the drug, but may affect stabilization in the long term, if not immediately.

가용화제는 아르기닌, 메글루민, 라이신, 히스티딘, 산화마그네슘, 초산나트륨 및 구연산나트륨으로 이루어진 군에서 선택되는 적어도 하나일 수 있다. 아르기닌은 L-아르기닌 또는 D-아르기닌일 수 있다. 일 구현예에 따르면, 가용화제는 L-아르기닌일 수 있다. 가용화제는 물에 대한 용해도가 낮은 프로피오닉산 또는 이의 약학적으로 허용가능한 염을 용해시키는 역할을 할 수 있다.The solubilizing agent may be at least one selected from the group consisting of arginine, meglumine, lysine, histidine, magnesium oxide, sodium acetate and sodium citrate. Arginine may be L-arginine or D-arginine. According to one embodiment, the solubilizing agent may be L-arginine. The solubilizing agent may serve to dissolve propionic acid or a pharmaceutically acceptable salt thereof having low solubility in water.

등장화제는 당 업계에서 통상적으로 사용되는 것을 사용하면 충분하며, 예컨대 염화나트륨 또는 포도당일 수 있다.The isotonic agent is sufficient to use those commonly used in the art, and may be, for example, sodium chloride or glucose.

pH 조절제는 본 발명의 약학 조성물의 pH를 조절하기 위해 사용될 수 있으며, 그 종류는 제한되지 않는다. 본 발명의 약학 조성물의 pH는 7.0 내지 8.5, 예컨대 7.0 내지 8.5, 7.1 내지 8.4, 7.2 내지 8.3, 7.3 내지 8.2, 7.4 내지 8.1, 7.5 내지 8.0, 7.6 내지 7.9, 7.7 내지 7.9, 또는 7.8 내지 7.9로 조절될 수 있다.A pH adjusting agent may be used to adjust the pH of the pharmaceutical composition of the present invention, and the type is not limited. The pharmaceutical composition of the present invention has a pH of 7.0 to 8.5, such as 7.0 to 8.5, 7.1 to 8.4, 7.2 to 8.3, 7.3 to 8.2, 7.4 to 8.1, 7.5 to 8.0, 7.6 to 7.9, 7.7 to 7.9, or 7.8 to 7.9. can be regulated.

본 발명의 약학 조성물은 액상 형태(즉 액상 제제) 또는 고체 형태일 수 있으나, 이에 제한되지 않는다. 일 구현예에 따르면 본 발명의 약학 조성물은 액상 형태의 약학 조성물일 수 있다. 프로피오닉산 계열 약물은 액상 형태일 때 안정성이 더 낮기 때문에, 본 발명의 약학 조성물이 액상에서 뛰어난 안정성을 나타내는 것을 확인한 결과로부터, 본 발명의 약학 조성물이 고상에서 더욱 우수한 안정성을 나타낼 수 있는 것을 알 수 있다.The pharmaceutical composition of the present invention may be in liquid form (ie liquid formulation) or solid form, but is not limited thereto. According to one embodiment, the pharmaceutical composition of the present invention may be a liquid pharmaceutical composition. Since the stability of propionic acid-based drugs is lower in liquid form, from the result of confirming that the pharmaceutical composition of the present invention exhibits excellent stability in a liquid phase, it can be seen that the pharmaceutical composition of the present invention can exhibit better stability in a solid phase. can

일 구현예에 따르면 본 발명의 약학 조성물은 주사용 약학 조성물일 수 있다. 주사용 약학 조성물은 액체 또는 고체의 형태일 수 있고, 구체적으로 액제 또는 건조 분말의 형태일 수 있으나, 이에 제한되지 않는다. 상기 주사용 건조 분말은 환자에 게 투여시 주사용수, 생리식염수, 포도당액, 아미노산액 등으로 재구성하여 환자에게 투여될 수 있다. 상기 건조는 통상의 건조방법, 예를 들어 동결건조, 회전증발건조, 분무건조, 또는 유동층 건조에 의해 수행될 수 있으며, 구체적으로 동결건조에 의해 수행될 수 있다.According to one embodiment, the pharmaceutical composition of the present invention may be a pharmaceutical composition for injection. The pharmaceutical composition for injection may be in the form of a liquid or solid, and may specifically be in the form of a liquid or dry powder, but is not limited thereto. When the dry powder for injection is administered to a patient, it may be reconstituted with water for injection, physiological saline, glucose solution, amino acid solution, etc. and then administered to the patient. The drying may be performed by a conventional drying method, for example, lyophilization, rotary evaporation, spray drying, or fluidized bed drying, and may be specifically performed by lyophilization.

본 발명의 약학 조성물은 통상의 방법에 따라 제제화될 수 있다. 약학적 제제의 형태는 제한되지 않고, 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 주사용액의 형태일 수 있다.The pharmaceutical composition of the present invention can be formulated according to conventional methods. The form of the pharmaceutical formulation is not limited, and may be in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or injection solutions.

본 발명은 프로피오닉산 계열 약물 및 특정 안정화제를 포함하는 약학 제제를 제공할 수 있다. The present invention can provide a pharmaceutical preparation containing a propionic acid-based drug and a specific stabilizer.

구체적으로 본 발명의 약학 제제는 프로피오닉산 계열 약물 및 안정화제를 포함하고,Specifically, the pharmaceutical formulation of the present invention includes a propionic acid-based drug and a stabilizer,

상기 안정화제는 β-사이클로덱스트린(β-cyclodextrin, βCD), 하이드록시프로필-β-사이클로덱스트린(hydroxypropyl β-cyclodextrin, HP-β-CD), 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(tocopherol polyethylene glycol 1000-succinate, TPGS), 부틸레이티드하이드록시아니솔(butylated hydroxyanisol, BHA), 아스코르브산(ascorbic acid, ASA), 메티오닌(methionin, MET) 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나일 수 있다. 상기 프로피오닉산 계열 약물 및 안정화제에 대해서는 전술한 바 있어 구체적인 설명은 생략한다.The stabilizer is β-cyclodextrin (βCD), hydroxypropyl β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000-succinate (tocopherol polyethylene glycol 1000- It may be at least one selected from the group consisting of succinate (TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and cysteine. Since the propionic acid-based drugs and stabilizers have been described above, detailed descriptions thereof will be omitted.

본 발명의 약학 제제는 전술한 안정화제 이외에 다른 첨가제를 포함하지 않아도 좋으나, 추가적으로 당업계에서 통상적으로 사용되는 추가 안정화제, 가용화제, 등장화제, pH 조절제 등을 제한되지 않게 선택적으로 더 포함할 수 있다. 추가 안정화제, 가용화제, 등장화제, pH 조절제에 대해서는 전술한 바 있어 구체적인 설명은 생략한다.The pharmaceutical formulation of the present invention may not include other additives in addition to the above-described stabilizers, but may optionally further include, but are not limited to, additional stabilizers, solubilizers, isotonic agents, pH adjusters, etc. commonly used in the art. there is. Additional stabilizers, solubilizers, tonicity agents, and pH adjusters have been described above, and therefore, detailed descriptions thereof will be omitted.

본 발명의 약학 제제는 액상 형태 또는 고형의 약학 제제일 수 있다.The pharmaceutical formulation of the present invention may be a liquid form or a solid pharmaceutical formulation.

본 발명의 약학 제제는 주사용 약학 제제일 수 있다.The pharmaceutical formulation of the present invention may be a pharmaceutical formulation for injection.

본 발명의 약학 제제는 특정 안정화제를 포함함으로써 프로피오닉산 계열 약물이 분해되거나 불순물(예컨대 유연물질)의 생성이 저해될 수 있다.By including a specific stabilizer, the pharmaceutical formulation of the present invention may inhibit the decomposition of propionic acid-based drugs or the generation of impurities (eg, related substances).

또한, 본 발명은 안정화제 및 프로피오닉산 계열 약물을 용매에 용해시키는 단계를 포함하는 약학 조성물의 제조방법을 제공한다. 용매는 당업계에서 사용되는 용매라면 제한되지 않고, 구체적으로 수성 용매일 수 있고, 예컨대 멸균수일 수 있다.In addition, the present invention provides a method for preparing a pharmaceutical composition comprising dissolving a stabilizer and a propionic acid-based drug in a solvent. The solvent is not limited as long as it is a solvent used in the art, and may specifically be an aqueous solvent, such as sterile water.

용매에 용해시키는 단계에서 가용화제 또는 추가 안정화제를 더 첨가할 수 있다. 이 때, 안정화제, 가용화제, 추가 안정화제, 프로피오닉산 계열 약물을 첨가하여 용해시키는 순서는 조절될 수 있다.In the step of dissolving in a solvent, a solubilizer or an additional stabilizer may be further added. At this time, the order of dissolution by adding a stabilizer, a solubilizer, an additional stabilizer, and a propionic acid-based drug may be adjusted.

본 발명의 제조방법은 프로피오닉산 계열 약물을 용해시킨 후 pH를 7.0 내지 8.5로 조절하는 단계를 더 포함할 수 있다.The manufacturing method of the present invention may further include adjusting the pH to 7.0 to 8.5 after dissolving the propionic acid-based drug.

구체적으로, 본 발명의 제조방법은 안정화제를 용매에 용해시키는 안정화제 용해 단계; 및Specifically, the manufacturing method of the present invention includes a stabilizer dissolution step of dissolving the stabilizer in a solvent; and

상기 안정화제가 용해된 용액에 프로피오닉산 계열 약물을 용해시키는 약물 용해 단계;를 포함할 수 있다.It may include; a drug dissolution step of dissolving a propionic acid-based drug in a solution in which the stabilizer is dissolved.

상기 안정화제는 β-사이클로덱스트린(β-cyclodextrin, βCD), 하이드록시프로필-β-사이클로덱스트린(hydroxypropyl β-cyclodextrin, HP-β-CD), 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(tocopherol polyethylene glycol 1000-succinate, TPGS), 부틸레이티드하이드록시아니솔(butylated hydroxyanisol, BHA), 아스코르브산(ascorbic acid, ASA), 메티오닌(methionin, MET), 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나일 수 있다.The stabilizer is β-cyclodextrin (βCD), hydroxypropyl β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000-succinate (tocopherol polyethylene glycol 1000- succinate (TPGS), butylated hydroxyanisol (BHA), ascorbic acid (ASA), methionine (MET), and at least one selected from the group consisting of cysteine.

상기 안정화제는 하이드록시프로필-β-사이클로덱스트린(hydroxypropyl β-cyclodextrin, HP-β-CD), 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(tocopherol polyethylene glycol 1000-succinate, TPGS), 부틸레이티드하이드록시아니솔(butylated hydroxyanisol, BHA), 아스코르브산(ascorbic acid, ASA), 메티오닌(methionin, MET) 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나일 수 있다.The stabilizer is hydroxypropyl β-cyclodextrin (HP-β-CD), tocopherol polyethylene glycol 1000-succinate (TPGS), butylated hydroxyanisole (butylated hydroxyanisol, BHA), ascorbic acid (ASA), methionine (MET), and may be at least one selected from the group consisting of cysteine.

본 발명의 제조방법은 안정화제를 용해시키기 전에 상기 멸균수에 가용화제 또는 등장화제를 첨가하는 것을 더 포함할 수 있다.The manufacturing method of the present invention may further include adding a solubilizer or isotonic agent to the sterilized water before dissolving the stabilizer.

본 발명의 제조방법은 상기 약물 용해 단계를 수행한 후 수득한 용액에 pH 조절제를 첨가하여 상기 프로피오닉산 계열 약물이 용해된 용액의 pH를 7.0 내지 8.5로 조절하는 단계를 더 포함할 수 있다. 예컨대, pH를 조절하는 단계는 pH를 7.0 내지 8.5, 7.1 내지 8.4, 7.2 내지 8.3, 7.3 내지 8.2, 7.4 내지 8.1, 7.5 내지 8.0, 7.6 내지 7.9, 7.7 내지 7.9, 또는 7.8 내지 7.9로 조절하는 것일 수 있다.The manufacturing method of the present invention may further include adjusting the pH of the solution in which the propionic acid-based drug is dissolved to 7.0 to 8.5 by adding a pH adjusting agent to the solution obtained after performing the drug dissolution step. For example, the step of adjusting the pH is to adjust the pH to 7.0 to 8.5, 7.1 to 8.4, 7.2 to 8.3, 7.3 to 8.2, 7.4 to 8.1, 7.5 to 8.0, 7.6 to 7.9, 7.7 to 7.9, or 7.8 to 7.9. can

이하, 본 발명을 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다.Hereinafter, examples will be described in detail to explain the present invention in detail.

1. 프로피오닉산 계열 약물을 포함하는 액상 조성물 제조1. Preparation of a liquid composition containing a propionic acid-based drug

(1) 이부프로펜을 포함하는 액상 조성물 제조-1(1) Preparation of liquid composition containing ibuprofen-1

아래의 표 1과 같은 다양한 조성으로 이부프로펜을 포함하는 샘플을 제조하였다(단위: mg). 먼저, 주사용 멸균 정제수를 제조 용기에 넣은 후, 각각 소정 함량의 가용화제, 등장화제 및 안정화제를 순차적으로 첨가하면서 완전히 용해시켜 주사제 용액을 제조하였다. 주사제 용액에 적정량의 이부프로펜을 추가하여 완전히 녹인 후 표선을 맞추었다. 그 후 주사제 용액의 pH를 측정하고, pH 조절제를 적당량 추가하여 pH가 7.8~7.9가 되도록 조절하였다. pH가 조절된 주사제를 0.2μm filter로 여과한 후, 주사제 용기에 충전하고 고무마개를 끼운 후 알루미늄 캡으로 캡핑(capping)하였다. 주사제 조제/충전/캡핑 과정에서 공기를 질소로 치환하여 용존 산소를 최소화하였다.Samples containing ibuprofen were prepared in various compositions as shown in Table 1 below (unit: mg). First, after putting sterilized purified water for injection into a preparation container, an injection solution was prepared by completely dissolving it while sequentially adding a predetermined amount of a solubilizer, an isotonic agent, and a stabilizer, respectively. An appropriate amount of ibuprofen was added to the injection solution, completely dissolved, and then the marked line was adjusted. Thereafter, the pH of the injection solution was measured, and an appropriate amount of a pH adjusting agent was added to adjust the pH to 7.8 to 7.9. The pH-adjusted injection was filtered through a 0.2 μm filter, filled into an injection container, and a rubber stopper was inserted, followed by capping with an aluminum cap. Dissolved oxygen was minimized by replacing air with nitrogen during the preparation/filling/capping process of the injection.

구분(mg/ml)Classification (mg/ml) 비교예1Comparative Example 1 실시예1Example 1 실시예2Example 2 실시예3Example 3 실시예4Example 4 실시예5Example 5 실시예6Example 6 프로피오닉산 계열 약물Propionic acid class drugs 이부프로펜ibuprofen 100100 100100 100100 100100 100100 100100 100100 가용화제solubilizing agent L-아르기닌L-Arginine 7878 7878 7878 7878 7878 7878 7878 안정화제stabilizer EDTA Na 수화물EDTA Na hydrate 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 0.10.1 β-사이클로덱스트린β-cyclodextrin 00 0.160.16 00 00 00 00 00 하이드록시프로필-β-사이클로덱스트린 (HP-β-CD)Hydroxypropyl-β-cyclodextrin (HP-β-CD) 00 00 400400 00 00 00 00 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(TPGS)Tocopherol polyethylene glycol 1000-succinate (TPGS) 00 00 00 0.20.2 00 00 00 부틸레이티드하이드록시아니솔(BHA)Butylated hydroxyanisole (BHA) 00 00 00 00 0.20.2 00 00 아스코르브산ascorbic acid 00 00 00 00 00 1010 00 메티오닌methionine 00 00 00 00 00 00 0.630.63

(2) 이부프로펜을 포함하는 액상 조성물 제조-2(2) Preparation of liquid composition containing ibuprofen-2

아래의 표 2와 같은 조성으로 이부프로펜을 포함하는 샘플을 제조하였다 (단위: mg/mL). 먼저, 멸균된 정제수를 제조 용기에 넣은 후, 각각 소정 함량의 가용화제와 안정화제를 순차적으로 첨가하면서 완전히 용해시켜 액상 용액을 제조하였다. 액상 용액에 적정량의 이부프로펜을 추가하여 완전히 녹인 후 표선을 맞추었다. 제조된 용액을 0.2 μm filter로 여과한 후, 바이알에 충전하고 고무마개를 끼운 후 알루미늄 캡으로 캡핑(capping) 하였다.Samples containing ibuprofen were prepared with the composition shown in Table 2 below (Unit: mg/mL). First, after putting sterilized purified water into a manufacturing container, a liquid solution was prepared by completely dissolving while sequentially adding a solubilizer and a stabilizer of a predetermined content, respectively. An appropriate amount of ibuprofen was added to the liquid solution, completely dissolved, and then the marked line was adjusted. After filtering the prepared solution with a 0.2 μm filter, the vial was filled and a rubber stopper was inserted, followed by capping with an aluminum cap.

구분(mg/mL)Classification (mg/mL) 비교예4Comparative Example 4 실시예16Example 16 프로피오닉산 계열 약물Propionic acid class drugs 이부프로펜ibuprofen 100100 100100 가용화제solubilizing agent L-아르기닌L-Arginine 8585 8585 안정화제stabilizer L-시스테인L-cysteine 00 1One

(3) 나프록센을 포함하는 액상 조성물 제조(3) Preparation of a liquid composition containing naproxen

아래의 표 3과 같은 다양한 조성으로 나프록센을 포함하는 샘플을 제조하였다 (단위: mg/mL). 먼저, 멸균된 정제수를 제조 용기에 넣은 후, 각각 소정 함량의 가용화제와 안정화제를 순차적으로 첨가하면서 완전히 용해시켜 액상 용액을 제조하였다. 액상 용액에 적정량의 나프록센을 추가하여 완전히 녹인 후 표선을 맞추었다. 제조된 용액을 0.2 μm filter로 여과한 후, 바이알에 충전하고 고무마개를 끼운 후 알루미늄 캡으로 캡핑(capping) 하였다.Samples containing naproxen were prepared with various compositions as shown in Table 3 below (unit: mg/mL). First, after putting sterilized purified water into a manufacturing container, a liquid solution was prepared by completely dissolving while sequentially adding a solubilizer and a stabilizer of a predetermined content, respectively. An appropriate amount of naproxen was added to the liquid solution, completely dissolved, and then the mark was adjusted. After filtering the prepared solution with a 0.2 μm filter, the vial was filled and a rubber stopper was inserted, followed by capping with an aluminum cap.

구분(mg/mL)Classification (mg/mL) 비교예3Comparative Example 3 실시예12Example 12 실시예13Example 13 실시예14Example 14 실시예15Example 15 프로피오닉산 계열 약물Propionic acid class drugs 나프록센naproxen 100100 100100 100100 100100 100100 가용화제solubilizing agent L-아르기닌L-Arginine 8585 8585 8585 8585 8585 안정화제stabilizer 메티오닌methionine 00 0.6250.625 00 00 00 아스코르브산ascorbic acid 00 00 1010 00 00 TPGSTPGS 00 00 00 0.20.2 00 HP-β-CDHP-β-CD 00 00 00 00 200200

2. 프로피오닉산 계열 약물을 포함하는 액상 조성물의 안정성 시험 12. Stability test of liquid composition containing propionic acid-based drug 1

(1) 가속보관 조건에서의 안정성 시험(1) Stability test under accelerated storage conditions

위 '1. (1) 이부프로펜을 포함하는 액상 조성물 제조-1'에서 제조한 주사제 샘플을 아래의 가속보관 조건 하에서 3개월간 보관하였고, 가속안정성 시험을 수행하였다.Above '1. (1) Preparation of liquid composition containing ibuprofen-1 The injection sample prepared in '1' was stored for 3 months under the following accelerated storage conditions, and an accelerated stability test was performed.

- 가속보관 안정성 시험조건 -- Accelerated storage stability test conditions -

1) 온도 및 습도: 가속보관조건(40℃±2℃, 75% 상대습도)1) Temperature and humidity: Accelerated storage conditions (40℃±2℃, 75% relative humidity)

2) 샘플포장형태: 무색 투명 바이얼2) Sample packaging type: colorless and transparent vials

3) 보관기간: 제조일로부터 3개월 경과된 시점까지3) Storage period: Until 3 months have elapsed from the date of manufacture

보관을 시작한 후 1, 2, 3개월의 시점에서 주사제 샘플을 추출하여 이부프로펜이 일정한 농도가 되도록 조절한 용액을 검액으로 하여 USP 원료항의 이부프로펜 유연물질 시험법으로 액체크로마토그래피를 수행하였다. 주사제 내의 유연물질의 생성 정도(%)를 분석하여 그 결과를 표 4, 도 1 및 2에 나타내었다.At 1, 2, and 3 months after the start of storage, injection samples were extracted and liquid chromatography was performed using a solution adjusted to a constant concentration of ibuprofen as a sample solution according to the test method for ibuprofen related substances in the USP raw material section. The degree (%) of related substances in the injection was analyzed and the results are shown in Table 4 and FIGS. 1 and 2.

<액체크로마토그래피 분석 조건><Liquid chromatography analysis conditions>

검출기 : 자외선 흡광광도계(검출파장 : 254 nm)Detector: UV absorbance photometer (detection wavelength: 254 nm)

컬 럼 : 4.6 × 250 ㎜, C18, 5um Column: 4.6 × 250 mm, C18, 5um

컬럼온도 : 실온 Column temperature: room temperature

유 속 : 2.0 mL/minFlow rate: 2.0 mL/min

주입량 : 5 uL Injection volume: 5 uL

이동상 : 클로로아세트산 4.0g을 물 400mL에 녹인 다음 수산화암모늄으로 pH3.0으로 조정한 액과 아세토니트릴 600mL를 혼합한 액Mobile phase: A mixture of 4.0 g of chloroacetic acid dissolved in 400 mL of water, adjusted to pH 3.0 with ammonium hydroxide, and 600 mL of acetonitrile

구분(%)division(%) 비교예1Comparative Example 1 실시예1Example 1 실시예2Example 2 실시예3Example 3 실시예4Example 4 실시예5Example 5 실시예6Example 6 최초the first 0.0050.005 0.0050.005 0.0030.003 0.0020.002 0.000020.00002 0.0390.039 0.00040.0004 1개월1 month 0.0390.039 0.0370.037 0.0190.019 0.0110.011 0.0050.005 0.0530.053 0.0030.003 2개월2 months 0.0560.056 0.0560.056 0.0300.030 0.0140.014 0.0120.012 0.0540.054 0.0040.004 3개월3 months 0.0900.090 0.0720.072 0.0430.043 0.0160.016 0.0160.016 0.0580.058 0.0050.005

분석결과 가속보관 조건에서 비교예 1에 비해 실시예들은 유연물질을 적게 생성하였다. 구체적으로, 실시예 2 및 3은 비교예 1에 비해 가속보관 조건에서 3개월 경과 시 유연물질의 생성 정도가 약 50% 이상 낮았고, 실시예 4 및 6은 비교예 1에 비해 가속보관 조건에서 3개월 경과 시 유연물질의 생성 정도가 약 70% 이상 낮았다. 특히 실시예 4 및 6은 비교예 1에 비해 최초 시점의 유연물질이 크게 감소되었음을 확인하였다(표 4, 도 1 및 도 2 참조).이를 통해 하이드록시프로필-β-사이클로덱스트린(HP-β-CD)와 토코페롤 또는 그 유도체, 부틸레이티드하이드록시아니솔(BHA) 및 메티오닌이 프로피오닉산 계열 약물인 이부프로펜에서 기인하는 유연물의 생성을 효과적으로 억제하고 안정성을 높이는 것을 확인하였다.As a result of the analysis, compared to Comparative Example 1 under accelerated storage conditions, Examples produced less related substances. Specifically, in Examples 2 and 3, compared to Comparative Example 1, the degree of production of related substances was lowered by about 50% or more after 3 months under accelerated storage conditions. After six months, the degree of production of related substances was lowered by about 70% or more. In particular, it was confirmed that in Examples 4 and 6, compared to Comparative Example 1, related substances at the initial time were significantly reduced (see Table 4 and FIGS. 1 and 2). Through this, hydroxypropyl-β-cyclodextrin (HP-β- It was confirmed that CD), tocopherol or its derivatives, butylated hydroxyanisole (BHA), and methionine effectively inhibited the production of related compounds derived from ibuprofen, a propionic acid-based drug, and increased stability.

(2) 가혹보관 조건에서의 액상 조성물의 안정성 시험(2) Stability test of liquid composition under harsh storage conditions

1) 이부프로펜을 포함하는 액상 조성물의 안정성 시험1) Stability test of liquid composition containing ibuprofen

위 '1.(2) 이부프로펜을 포함하는 액상 조성물 제조-2'에서 제조한 샘플을 아래의 가혹보관 조건 하에서 2주간 보관하였고, 가혹안정성 시험을 수행하였다.The sample prepared in '1. (2) Preparation of liquid composition containing ibuprofen-2' above was stored for 2 weeks under the following harsh storage conditions, and a harsh stability test was performed.

- 가혹보관 안정성 시험조건 -- Severe Storage Stability Test Conditions -

i) 온도 및 습도 : 50°C±2°C, 75% 상대습도i) Temperature and humidity: 50°C±2°C, 75% relative humidity

ii) 샘플포장형태 : 무색 투명한 바이알ii) Sample packaging type: colorless and transparent vial

iii) 시험지점 : 제조일로부터 1, 2 주간 경과된 시점까지iii) Test point: Until 1 or 2 weeks have elapsed from the date of manufacture

보관을 시작한 후 1주, 2주에 시험 샘플들을 추출하여 이부프로펜이 일정한 농도가 되도록 조절한 용액을 검액으로 하여 USP 원료항의 이부프로펜 유연물질 시험법으로 액체크로마토그래피를 수행하였다. 용액 내의 유연물질의 생성 정도(%)를 분석하여 그 결과를 표 5에 나타내었다.After the start of storage, test samples were extracted at 1 week and 2 weeks, and liquid chromatography was performed using a solution adjusted to a constant concentration of ibuprofen as a sample solution according to the test method for ibuprofen related substances in the USP raw material section. The degree (%) of related substances in the solution was analyzed and the results are shown in Table 5.

<액체크로마토그래피 분석 조건><Liquid chromatography analysis conditions>

검출기 : 자외선 흡광광도계 (검출파장: 254 nm)Detector: UV absorbance photometer (detection wavelength: 254 nm)

컬 럼 : 4.6 X 250 mm, 5 μm, C18Column: 4.6 X 250 mm, 5 μm, C18

컬럼온도 : 실온Column temperature: room temperature

유 속 : 2.0 mL/minFlow rate: 2.0 mL/min

주입량 : 5 μLInjection volume: 5 μL

이동상 : 클로로아세트산 4.0g을 물 400mL에 녹인 다음 수산화암모늄으로 pH3.0으로 조정한 액과 아세토니트릴 600mL를 혼합한 액Mobile phase: A mixture of 4.0 g of chloroacetic acid dissolved in 400 mL of water, adjusted to pH 3.0 with ammonium hydroxide, and 600 mL of acetonitrile

구분(%)division(%) 비교예4Comparative Example 4 실시예16Example 16 최초the first 0.0050.005 0.0000.000 1주1 week 0.0420.042 0.0030.003 2주2 weeks 0.0960.096 0.0050.005

가혹보관 조건에서 실시예 16은 비교예 4와 다르게 유연물질이 검출되지 않았으며, 2주 경과 후에도 유연물질 생성이 효과적으로 억제되었다.Unlike Comparative Example 4, no related substances were detected in Example 16 under harsh storage conditions, and the production of related substances was effectively suppressed even after 2 weeks.

2) 나프록센을 포함하는 액상 조성물의 안정성 시험2) Stability test of liquid composition containing naproxen

위 '1. (3) 나프록센을 포함하는 액상 조성물 제조'에서 제조한 샘플을 아래의 가혹보관 조건 하에서 2주간 보관하였고, 가혹안정성 시험을 수행하였다.Above '1. (3) Preparation of a liquid composition containing naproxen' was stored for 2 weeks under the following severe storage conditions, and a severe stability test was performed.

- 가혹보관 안정성 시험조건 -- Severe Storage Stability Test Conditions -

i) 온도 및 습도: 50°C±2°C, 75% 상대습도i) Temperature and humidity: 50°C±2°C, 75% relative humidity

ii) 샘플포장형태: 무색 투명한 바이알ii) Sample packaging type: colorless and transparent vials

iii) 보관기간: 제조일로부터 1, 2 주간 경과된 시점까지iii) Storage period: Until 1 or 2 weeks have elapsed from the date of manufacture

보관을 시작한 후 1주, 2주에 시험 샘플들을 추출하여 나프록센이 일정한 농도가 되도록 조절한 용액을 검액으로 하여 EP 원료항의 나프록센 유연물질 시험법을 참고하여 아래 조건으로 액체크로마토그래피를 수행하였다. 용액 내의 유연물질의 생성 정도(%)를 분석하여 그 결과를 표 6에 나타내었다.Test samples were extracted 1 week and 2 weeks after starting storage, and liquid chromatography was performed under the following conditions by referring to the Naproxen Related Substance Test Method in the EP raw material section using a solution adjusted to a constant concentration of naproxen as a sample solution. The degree (%) of related substances in the solution was analyzed and the results are shown in Table 6.

<액체크로마토그래피 분석 조건><Liquid chromatography analysis conditions>

검출기 : 자외선 흡광광도계 (검출파장: 230 nm)Detector: UV absorbance photometer (detection wavelength: 230 nm)

컬 럼 : 4.6 X 75 mm, 3 μm, C18Column: 4.6 X 75 mm, 3 μm, C18

컬럼온도 : 40°CColumn temperature: 40°C

유 속 : 1.0 mL/minFlow rate: 1.0 mL/min

주입량 : 20 μLInjection volume: 20 μL

이동상 : 인산이수소칼륨 1.36 g을 물 900 mL에 녹이고 인산을 넣어 pH 2.0으로 맞춘 다음 물을 넣어 정확하게 1 L로 하여 제1액을 제조함. 상기 제1액 580 mL와 아세토니트릴 420 mL의 혼합액을 이동상으로 사용함Mobile phase: Dissolve 1.36 g of potassium dihydrogen phosphate in 900 mL of water, add phosphoric acid to adjust the pH to 2.0, and then add water to make exactly 1 L to prepare the first solution. A mixture of 580 mL of the first solution and 420 mL of acetonitrile is used as a mobile phase

구분(%)division(%) 비교예3Comparative Example 3 실시예12Example 12 실시예13Example 13 실시예14Example 14 실시예15Example 15 최초the first 0.370.37 0.110.11 0.380.38 N.D.1) ND 1) 0.040.04 1주1 week 0.390.39 0.130.13 0.410.41 N.D.N.D. 0.050.05 2주2 weeks 0.390.39 0.130.13 0.410.41 N.D.N.D. 0.040.04

(표 6에서 1): Not Detected)분석결과 가혹보관 조건에서 실시예 12, 실시예 14, 실시예 15는 비교예 3에 비해 최초 시점의 유연물질이 크게 감소되었으며, 특히 실시예 14는 유연물질이 검출되지 않았다 (표 6 참조).( 1 in Table 6) : Not Detected As a result of the analysis, Example 12, Example 14, and Example 15 under harsh storage conditions significantly reduced related substances at the first time compared to Comparative Example 3. In particular, Example 14 showed related substances was not detected (see Table 6).

위 안정성 실험 결과를 통해 메티오닌, 하이드록시프로필-β-사이클로덱스트린(HP-β-CD), 및 특히 토코페롤 폴리에틸렌 글리콜 1000-석시네이트(TPGS)가 제조 단계에서부터 프로피오닉산 계열 약물인 나프록센의 유연물질 생성을 효과적으로 억제하고 안정성을 높이는 것을 확인하였다.Through gastric stability test results, methionine, hydroxypropyl-β-cyclodextrin (HP-β-CD), and especially tocopherol polyethylene glycol 1000-succinate (TPGS) were found to be related to naproxen, a propionic acid-based drug, from the manufacturing stage. It was confirmed that the production was effectively inhibited and the stability was increased.

3. 프로피오닉산 계열 약물을 포함하는 액상 조성물의 안정성 시험 2 - 안정화제의 농도 변화에 따른 안정성 시험3. Stability test of liquid composition containing propionic acid-based drug 2 - Stability test according to concentration change of stabilizer

위 '2.(1) 가속보관 조건에서의 안정성 시험 결과'에서 안정화제로 가장 우수한 효과를 나타낸 메티오닌의 농도를 변화시켜 이부프로펜의 안정성을 확인하였다.The stability of ibuprofen was confirmed by changing the concentration of methionine, which showed the most excellent effect as a stabilizer in '2.(1) Stability test results under accelerated storage conditions' above.

구제척인 제조방법은 위 '1.(1) 이부프로펜을 포함하는 액상 조성물의 제조-1'에 기재된 방법과 동일하되, 안정화제의 종류와 함량을 변화시켜 아래의 표 7과 같은 다양한 조성으로 이부프로펜을 포함하는 샘플을 제조하였다(단위: mg).The method for preparing the remedy is the same as the method described in '1.(1) Preparation of Liquid Composition Containing Ibuprofen-1' above, but the type and content of the stabilizer is changed to produce ibuprofen in various compositions as shown in Table 7 below. A sample containing was prepared (unit: mg).

구분(mg/mL)Classification (mg/mL) 실시예6Example 6 실시예7Example 7 실시예8Example 8 실시예9Example 9 실시예10Example 10 실시예11Example 11 이부프로펜ibuprofen 100100 100100 100100 100100 100100 100100 L-아르기닌L-Arginine 7878 7878 7878 7878 7878 7878 EDTA Na 수화물EDTA Na hydrate 0.10.1 00 0.10.1 0.10.1 0.10.1 0.10.1 메티오닌methionine 0.630.63 0.630.63 0.420.42 0.010.01 0.90.9 1.81.8

아래의 가혹조건에서 보관을 시작하고 1주, 2주에 시험 샘플들을 추출하여 이부프로펜이 일정한 농도가 되도록 조절한 용액을 검액으로 하여 USP 원료항의 이부프로펜 유연물질 시험법으로 위 '2.(1) 가속보관 조건에서의 안정성 시험'에 기재된 것과 동일한 조건으로 액체크로마토그래피를 수행하였다. 주사제 내의 유연물질의 생성 정도(%)를 분석하여 그 결과를 표 8, 도 3에 나타내었다.After starting storage under the harsh conditions below, test samples are extracted at 1 week and 2 weeks, and the solution adjusted to a constant concentration of ibuprofen is used as the test solution. Liquid chromatography was performed under the same conditions as described in 'Stability test under storage conditions'. The degree (%) of related substances in the injection was analyzed and the results are shown in Table 8 and FIG. 3.

- 가혹보관 안정성 시험조건 -- Severe Storage Stability Test Conditions -

(1) 온도 및 습도 : 가혹보관조건 (50℃± 2℃, 75% 상대습도)(1) Temperature and humidity: harsh storage conditions (50℃±2℃, 75% relative humidity)

(2) 샘플포장형태 : 무색 투명한 바이얼(2) Sample packaging type: colorless and transparent vials

(3) 시험시점 : 제조일로부터 1, 2 주간 경과된 시점까지(3) Test time: Until 1 or 2 weeks have elapsed from the date of manufacture

구분(%)division(%) 실시예6Example 6 실시예7Example 7 실시예8Example 8 실시예9Example 9 실시예10Example 10 실시예11Example 11 최초the first 0.00040.0004 0.0020.002 0.00040.0004 0.00370.0037 0.0010.001 0.00080.0008 1주1 week 0.0050.005 0.0050.005 0.0080.008 0.0110.011 0.0020.002 0.0010.001 2주2 weeks 0.010.01 0.0080.008 0.0140.014 0.0170.017 0.0030.003 0.0020.002

분석결과 메티오닌이 미량으로 포함되는 경우에도 가혹보관 조건에서 유연물질 생성을 효과적으로 억제하고 안정성을 높이는 것을 확인하였다. 또한, EDTA Na 수화물이 포함되지 않고 메티오닌만 포함된 실시예 7도 초기 및 2주 경과 후에도 유연물질 생성이 효과적으로 억제되었다(표 8 및 도 3 참조).As a result of the analysis, it was confirmed that even when a trace amount of methionine was included, the production of related substances was effectively suppressed and stability was increased under harsh storage conditions. Also, in Example 7 containing only methionine without EDTA Na hydrate, production of related substances was effectively suppressed at the initial stage and even after 2 weeks (see Table 8 and FIG. 3).

4. 시판 제품과 안정성 비교 시험4. Stability comparison test with commercially available products

이부프로펜 주사제로 시판되고 있는 제품(비교예 2, 칼도롤)과 실시예 6의 안정성을 비교하는 시험을 수행하였다.A test was performed to compare the stability of a commercially available ibuprofen injection (Comparative Example 2, Caldolol) and Example 6.

아래의 가혹조건에서 보관을 시작하고 1주, 2주, 4주째에 샘플들을 추출하여 이부프로펜이 일정한 농도가 되도록 조절한 용액을 검액으로 하여 USP 원료항의 이부프로펜 유연물질 시험법으로 위 '2. 가속보관 조건에서의 안정성 시험'에 기재된 것과 동일한 조건으로 액체크로마토그래피를 수행하였다. 주사제 내의 유연물질의 생성 정도(%)를 분석하여 그 결과를 표 9 및 도 4에 나타내었다.After starting storage under the harsh conditions below, samples were extracted at the 1st, 2nd, and 4th weeks, and the solution adjusted to a constant concentration of ibuprofen was used as the test solution, and the above '2. Liquid chromatography was performed under the same conditions as described in 'Stability test under accelerated storage conditions'. The degree (%) of related substances in the injection was analyzed and the results are shown in Table 9 and FIG. 4.

- 가혹보관 안정성 시험조건 -- Severe Storage Stability Test Conditions -

(1) 온도 및 습도: 가혹보관조건 (50℃± 2℃, 75% 상대습도)(1) Temperature and humidity: harsh storage conditions (50℃±2℃, 75% relative humidity)

(2) 샘플포장형태: 무색 투명한 바이얼(2) Sample packaging form: colorless and transparent vials

(3) 시험시점: 제조일로부터 1, 2, 4 주간 경과된 시점까지(3) Test time: Until 1, 2, 4 weeks have elapsed from the date of manufacture

구분(%)division(%) 비교예2Comparative Example 2 실시예6Example 6 최초the first 0.0530.053 0.00040.0004 1주1 week 0.1060.106 0.0060.006 2주2 weeks 0.1370.137 0.0130.013 4주4 weeks 0.1680.168 0.0380.038

시판 제품인 비교예 2에 비해 실시예가 가혹 조건에서 유연물질의 생성이 효과적으로 억제되는 것을 확인하였다(표 9 및 도 4 참조).Compared to Comparative Example 2, which is a commercially available product, it was confirmed that the production of related substances was effectively inhibited in Example under harsh conditions (see Table 9 and FIG. 4).

위 실험결과들을 통해 HP-β-CD, TPGS, BHA, 메티오닌 등의 특정 종류의 안정화제가 프로피오닉산 계열 약물로부터 유연물질의 생성을 효과적으로 억제하고 안정성을 높이는 것을 확인하였다.Through the above experimental results, it was confirmed that specific types of stabilizers such as HP-β-CD, TPGS, BHA, and methionine effectively inhibited the production of related substances from propionic acid-based drugs and increased stability.

Claims (11)

프로피오닉산 계열 약물 및 안정화제를 포함하고,Including propionic acid-based drugs and stabilizers, 상기 안정화제는 β-사이클로덱스트린, 하이드록시프로필-β-사이클로덱스트린, 토코페롤 폴리에틸렌 글리콜 1000-석시네이트, 부틸레이티드하이드록시아니솔, 아스코르브산, 메티오닌, 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나인 약학 조성물.The stabilizer is at least one selected from the group consisting of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, tocopherol polyethylene glycol 1000-succinate, butylated hydroxyanisole, ascorbic acid, methionine, and cysteine. pharmaceutical composition. 청구항 1에 있어서, 상기 프로피오닉산 계열 약물은 이부프로펜 또는 이의 약학적으로 허용가능한 염; 또는 나프록센 또는 이의 약학적으로 허용가능한 염인 약학 조성물.The method according to claim 1, wherein the propionic acid-based drug is ibuprofen or a pharmaceutically acceptable salt thereof; or naproxen or a pharmaceutically acceptable salt thereof. 청구항 1에 있어서, 상기 안정화제는 하이드록시프로필-β-사이클로덱스트린, 토코페롤 폴리에틸렌 글리콜 1000-석시네이트, 부틸레이티드하이드록시아니솔, 메티오닌 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the stabilizer is at least one selected from the group consisting of hydroxypropyl-β-cyclodextrin, tocopherol polyethylene glycol 1000-succinate, butylated hydroxyanisole, methionine, and cysteine. 청구항 1에 있어서, 상기 프로피오닉산 계열 약물은 이부프로펜 또는 이의 약학적으로 허용가능한 염이고, 상기 안정화제는 부틸레이티드하이드록시아니솔, 메티오닌 또는 시스테인인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the propionic acid-based drug is ibuprofen or a pharmaceutically acceptable salt thereof, and the stabilizer is butylated hydroxyanisole, methionine, or cysteine. 청구항 1에 있어서, 상기 프로피오닉산 계열 약물은 나프록센 또는 이의 약학적으로 허용가능한 염이고, 상기 안정화제는 토코페롤 폴리에틸렌 글리콜 1000-석시네이트인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the propionic acid-based drug is naproxen or a pharmaceutically acceptable salt thereof, and the stabilizer is tocopherol polyethylene glycol 1000-succinate. 청구항 1에 있어서, 상기 안정화제는 상기 프로피오닉산 계열 약물 100 중량부 대비 0.001 내지 400 중량부로 포함되는 약학 조성물.The pharmaceutical composition according to claim 1, wherein the stabilizer is included in an amount of 0.001 to 400 parts by weight based on 100 parts by weight of the propionic acid-based drug. 청구항 1에 있어서, 상기 안정화제는 상기 프로피오닉산 계열 약물 100 중량부 대비 0.01 내지 1.8 중량부로 포함되는 약학 조성물.The pharmaceutical composition according to claim 1, wherein the stabilizer is included in an amount of 0.01 to 1.8 parts by weight based on 100 parts by weight of the propionic acid-based drug. 청구항 1에 있어서, 상기 조성물은 액상 형태인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the composition is in liquid form. 청구항 1에 있어서, 상기 조성물은 주사용인 약학 조성물.The pharmaceutical composition according to claim 1, wherein the composition is for injection. 안정화제를 용매에 용해시키는 안정화제 용해 단계; 및A stabilizer dissolution step of dissolving the stabilizer in a solvent; and 상기 안정화제가 용해된 용액에 프로피오닉산 계열 약물을 첨가하여 용해시키는 약물 용해 단계;를 포함하고,A drug dissolution step of dissolving by adding a propionic acid-based drug to a solution in which the stabilizer is dissolved; 상기 안정화제는 β-사이클로덱스트린, 하이드록시프로필-β-사이클로덱스트린, 토코페롤 폴리에틸렌 글리콜 1000-석시네이트, 부틸레이티드하이드록시아니솔, 아스코르브산, 메티오닌, 및 시스테인으로 이루어진 군에서 선택되는 적어도 하나 이상인 약학 조성물의 제조방법.The stabilizer is at least one selected from the group consisting of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, tocopherol polyethylene glycol 1000-succinate, butylated hydroxyanisole, ascorbic acid, methionine, and cysteine. A method for preparing a pharmaceutical composition. 청구항 10에 있어서, 상기 약물 용해 단계를 수행한 후 수득한 용액에 pH 조절제를 첨가하여 상기 프로피오닉산 계열 약물이 용해된 용액의 pH를 7.0 내지 8.5로 조절하는 pH 조절 단계;를 더 포함하는, 약학 조성물의 제조방법.The method according to claim 10, further comprising a pH adjusting step of adjusting the pH of the solution in which the propionic acid-based drug is dissolved to 7.0 to 8.5 by adding a pH adjusting agent to the solution obtained after performing the drug dissolving step. A method for preparing a pharmaceutical composition.
PCT/KR2022/013751 2021-09-15 2022-09-15 Pharmaceutical composition with improved stability comprising propionic acid-based drug and stabilizer Ceased WO2023043207A1 (en)

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