WO2020231146A1 - Novel salt of pelubiprofen, preparation method therefor and pharmaceutical composition comprising same - Google Patents

Novel salt of pelubiprofen, preparation method therefor and pharmaceutical composition comprising same Download PDF

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WO2020231146A1
WO2020231146A1 PCT/KR2020/006219 KR2020006219W WO2020231146A1 WO 2020231146 A1 WO2020231146 A1 WO 2020231146A1 KR 2020006219 W KR2020006219 W KR 2020006219W WO 2020231146 A1 WO2020231146 A1 WO 2020231146A1
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felubiprofen
tromethamine
tromethamine salt
present
pharmaceutical composition
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PCT/KR2020/006219
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French (fr)
Korean (ko)
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김철우
박상욱
신상윤
조민용
이원일
손세일
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대원제약주식회사
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Priority to CN202080030464.0A priority Critical patent/CN113891873B/en
Publication of WO2020231146A1 publication Critical patent/WO2020231146A1/en

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    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/80—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings
    • C07C59/82—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings the keto group being part of a ring
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Definitions

  • the present invention relates to a novel salt of felubiprofen, a method for preparing the same, and a pharmaceutical composition comprising the same. More specifically, the present invention relates to a pelubiprofen tromethamine salt having excellent solubility, improved stability, and significantly improved gastrointestinal side effects, a method for preparing the same, and a pharmaceutical composition comprising the same.
  • Pelubiprofen (molecular formula: C 16 H 18 O 3 , MW: 258.31) is usually referred to as 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid. As a compound, it has a structure represented by the following formula (1).
  • Felubiprofen represented by Chemical Formula 1 is disclosed in Korean Patent No. 0922519 (Patent Document 1).
  • Felubiprofen is a nonsteroidal anti-inflammatory analgesic (NSAIDs) having various pharmacological activities such as anti-inflammatory analgesic and antipyretic, and is an excellent drug for treating arthritis, low back pain, and upper respiratory tract.
  • NSAIDs nonsteroidal anti-inflammatory analgesic
  • felubiprofen is a poorly soluble drug, and since it is an acidic drug having a high solubility at a basic pH, there is a problem that its solubility is low at an acidic pH.
  • felubiprofen is a substance in which gastrointestinal side effects are significantly reduced compared to existing NSAIDs, but it still has gastrointestinal side effects, and the stability of the raw material is poor, so there is a problem that an effort to improve the formulation to solve this problem is required.
  • Patent Document 2 only describes a method for preparing a compound represented by the following general formula I, which is a novel compound, and for the salt of the general formula I or the salt of felubiprofen. The contents are not described.
  • the object of the present invention is that it exhibits superior physicochemical properties such as having superior solubility and improved stability than felubiprofen, minimizing the occurrence of related substances, etc. It is to provide a novel salt of felubiprofen with improved gastrointestinal side effects, a method for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases containing a novel salt of felubiprofen as an active ingredient.
  • Another object of the present invention is to provide a method for preventing or treating inflammatory diseases, comprising administering a novel salt of felubiprofen to a subject in need thereof in a therapeutically effective amount.
  • an object of the present invention is to provide a use of a pharmaceutical composition comprising a novel salt of felubiprofen for the prevention or treatment of inflammatory diseases.
  • the pellubiprofen tromethamine salt of the present invention has excellent solubility under various pH conditions compared to pelubiprofen, and shows high stability under severe conditions (80 ⁇ 1°C or RH 90 ⁇ 1%), and is equal to or greater than It can exhibit excellent bioavailability.
  • felubiprofen tromethamine salt of the present invention can improve gastrointestinal side effects by minimizing gastric mucosa damage when compared with the free base of felubiprofen.
  • the present invention provides felubiprofen tromethamine salt.
  • Felubiprofen tromethamine salt of the present invention is a compound represented by the following formula (2).
  • felubipropene tromethamine salt represented by Chemical Formula 2 is 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid ⁇ tromethamine [2-( It is named 4-[(E)-(2-oxocyclohexylidene)methyl]phenyl)propionic acid tromethamine].
  • the felubiprofen tromethamine salt of the present invention includes stereoisomers.
  • stereoisomer refers to a compound that has one or more chiral centers (*) and each center can exist in R or S form.
  • Stereoisomers include both diastereomer, enantiomer and epimer forms, as well as racemates and mixtures thereof.
  • salt form can improve the physical or pharmaceutical properties of a compound with pharmacological activity, before the salt form is actually prepared and characterized, predict which salt form may have strengths for a particular purpose. It is impossible to do. Since salt formation can change the physicochemical properties of a drug without altering the chemical structure of the drug, the selection of an appropriate salt is an important consideration for solubility and stability. In particular, solubility is an important property that can affect its suitability for use as a drug.
  • Felubiprofen tromethamine salt according to the present invention has superior physicochemical properties compared to felubiprofen.
  • the pelubiprofen tromethamine salt of the present invention exhibits excellent solubility values under various pH conditions.
  • the pelubiprofen tromethamine salt of the present invention has improved stability against light, heat, moisture, pH, etc., thereby minimizing the occurrence of related substances.
  • the related material does not exceed the standard under high temperature conditions (80 ⁇ 1 °C) or high humidity conditions (RH 90 ⁇ 1%), and the content is uniform, so it has very stable characteristics under high temperature or high humidity conditions.
  • RH 90 ⁇ 1% high humidity conditions
  • Felubiprofen tromethamine salt according to the present invention can significantly improve the side effects of gastrointestinal disorders, and thus can be usefully applied as pharmaceuticals for inflammatory diseases.
  • the felubiprofen tromethamine salt may be a combination of pelubiprofen and tromethamine in a molar ratio of 1:1.
  • the felubiprofen tromethamine salt of the present invention may have a differential scanning calorie (DSC) endothermic peak at 123.5 ⁇ 2° C. as shown in FIG. 2, but is not limited thereto.
  • DSC differential scanning calorie
  • Felubiprofen tromethamine salt according to the present invention can exhibit excellent pharmacological effects. Therefore, it can be usefully used as a new active ingredient of a pharmaceutical composition that can treat various indications such as low back pain, osteoarthritis, rheumatoid arthritis, acute upper respiratory tract, and antipyretic, and is equivalent to felubiprofen free base when administered orally or parenterally. It can represent the bioavailability of.
  • the present invention provides a method of preparing a felubiprofen tromethamine salt represented by the following formula (2).
  • the manufacturing method of the present invention comprises the steps of (a) reacting felubiprofen and tromethamine in an organic solvent; (b) adding an anti-solvent to form a felubipropene tromethamine salt represented by Chemical Formula 2; And (c) filtering and drying.
  • the step (a) is a step of reacting by mixing pelubiprofen with an organic solvent and then adding tromethamine, or mixing tromethamine with an organic solvent, and then pelubiprofen. It may be a step of reacting by adding, but is not limited thereto.
  • the tromethamine in step (a) may be added in a molar ratio of 0.8 to 1.5 equivalents based on 1.0 equivalent of felubiprofen, but is not limited thereto.
  • the organic solvent in step (a) may be selected from the group consisting of methanol, ethanol, 2-propanol, butanol, acetone, ethyl acetate, methylene chloride, and a mixed solvent thereof, It is not limited thereto, and specifically, the organic solvent in step (a) may be methanol, ethanol, acetone, or ethyl acetate.
  • the step (a) may be performed at a temperature of 10 to 65 °C, but is not limited thereto.
  • the anti-solvent in step (b) is selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, n-hexane, isopropyl ether, isopropyl alcohol, and a mixed solvent thereof. It may, but is not limited thereto, specifically, the anti-solvent in step (b) may be acetone, n-hexane, isopropyl ether.
  • the anti-solvent of step (b) may be a different type from the organic solvent of step (a).
  • step (b) may be performed at a temperature of 10 to 50°C, but is not limited thereto.
  • the drying in step (c) may be performed at 30 to 80° C., but is not limited thereto.
  • the manufacturing method of the present invention comprises the steps of (a) reacting felubipropene and tromethamine in an organic solvent to form pelubipropene tromethamine salt represented by Formula 2; And ( b ) filtering and drying.
  • the step (a) is a step of reacting by mixing pelubiprofen with an organic solvent and then adding tromethamine, or mixing tromethamine with an organic solvent, and then pelubiprofen. It may be a step of reacting by adding, but is not limited thereto.
  • the tromethamine in step (a) may be added in a molar ratio of 0.8 to 1.5 equivalents based on 1.0 equivalent of felubiprofen, but is not limited thereto.
  • the organic solvent in step (a) may be selected from the group consisting of methanol, ethanol, 2-propanol, butanol, acetone, ethyl acetate, methylene chloride, and a mixed solvent thereof, It is not limited thereto, and specifically, the organic solvent of step (a) may be methanol, ethanol, 2-propanol, or methylene chloride.
  • the step (a) may be performed at a temperature of 10 to 65 °C, but is not limited thereto.
  • the step (a) may be performed at a temperature of 10 to 65 °C and then cooled to a temperature of -5 to 30 °C to perform the reaction, but is not limited thereto.
  • the drying in step (b) may be performed at 30 to 80° C., but is not limited thereto.
  • felubiprofen tromethamine salt prepared according to the present invention is applied equally as long as it does not contradict each other with the pelubiprofen tromethamine salt above.
  • composition for preventing or treating inflammatory diseases containing felubiprofen tromethamine salt as an active ingredient
  • the present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing pelubiprofen tromethamine salt as an active ingredient.
  • the pharmaceutical composition of the present invention is formulated using a pharmaceutically acceptable carrier according to a method that can be easily carried out by a person skilled in the art to which the present invention belongs. It may be prepared in a dosage form or may be prepared by placing it in a multi-dose container.
  • carrier means a compound that facilitates addition of the compound into cells or tissues
  • pharmaceutically acceptable is physiologically acceptable and when administered to humans, usually It refers to a composition that does not cause allergic reactions such as gastrointestinal disorders or dizziness or similar reactions.
  • the pharmaceutically acceptable carrier is commonly used in formulation, and lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. It is not limited.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like in addition to the above components.
  • the content of the additive included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the content range used for conventional formulation.
  • the composition of the present invention is a solution, suspension, powder, granule, tablet, capsule, pill, extract, emulsion, syrup, aerosol, etc. according to a conventional method according to each purpose of use. It can be formulated and used in various forms, such as oral formulations of sterilized injectable solutions and injections of sterile injectable solutions. It can be administered parenterally through a variety of routes.
  • the term ⁇ treatment'' partially or completely reduces, ameliorates, alleviates, inhibits or delays the onset of a specific disease, disorder and/or disease, reduces the severity, or causes one or more symptoms or characteristics. Means to reduce.
  • prevention means a delay in onset of a disease, disorder or disease. Prevention can be considered complete if the onset of the disease, disorder or condition is delayed for a predetermined period of time.
  • the inflammatory disease is dermatitis, acute or chronic upper respiratory tract infection, fever, inflammatory bowel disease, asthma, osteoarthritis, rheumatoid arthritis, bronchitis, Th-2 type autoimmune disease, systemic erythematodes, severe Myasthenia gravis, chronic GVHD, clonal disease, spondylitis deformed, back pain, gout, inflammation after surgical trauma, relief of swelling, neuralgia, pharyngitis, cystitis, hepatitis, hepatitis B, hepatitis C, and arteriosclerosis It may be, specifically, acute upper respiratory tract, fever, osteoarthritis, rheumatoid arthritis, or low back pain.
  • the present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases by containing felubiprofen tromethamine salt at 30 mg as felubiprofen and administered three times a day.
  • the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease by containing felubiprofen tromethamine salt at 45 mg as felubiprofen and administered twice a day.
  • the pharmaceutical composition of the present invention may be a sustained-release pharmaceutical composition.
  • the present invention provides a method for preventing or treating an inflammatory disease comprising administering a therapeutically effective amount of felubiprofen tromethamine salt to an individual in need thereof.
  • the term "individual” means mammals such as monkeys, cows, horses, dogs, cats, rabbits, rats and mice, and particularly includes humans.
  • the term "therapeutically effective amount” refers to the amount of the felubiprofen tromethamine salt of the present invention that is effective in the prevention or treatment of inflammatory diseases, preferably pelubiprofen tromethamine salt. 30 mg as rubiprofen may be administered three times a day, or felubiprofen tromethamine salt as felubiprofen 45 mg may be administered twice a day, but the therapeutically effective amount is in the pharmaceutical composition. It can be interpreted as encompassing all doses that improve or cure the symptoms of inflammatory disease.
  • the prevention or treatment method of the present invention includes not only dealing with the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms thereof by administering the pharmaceutical composition.
  • the prophylactic or therapeutic method of the present invention may further include administration of a therapeutically effective amount of an additional active agent useful for disease treatment together with the pharmaceutical composition, and the additional active agent has a synergistic effect with the pharmaceutical composition. Alternatively, it may exhibit additive effects.
  • the present invention provides a use of a pharmaceutical composition comprising felubiprofen tromethamine salt for the manufacture of a medicament for the prevention or treatment of inflammatory diseases.
  • the pharmaceutical composition containing the felubiprofen tromethamine salt of the present invention for the manufacture of a drug may be mixed with a pharmaceutically acceptable adjuvant, a diluent, a carrier, etc. It can have a synergistic effect by being prepared as a combination formulation with the active agent.
  • felubiprofen tromethamine salt according to the present invention has superior stability compared to felubiprofen, it is possible to increase the stability of the formulation by lowering the amount of impurities produced during storage of the product.
  • the pellubiprofen tromethamine salt of the present invention has a significantly improved solubility compared to felubiprofen, so that it can be used as an active ingredient in a pharmaceutical composition useful for anti-inflammatory analgesic, antipyretic and various effects with a pharmaceutically acceptable carrier. I can.
  • the pelubiprofen tromethamine salt of the present invention since the pelubiprofen tromethamine salt of the present invention has excellent solubility, it can be prepared as a liquid formulation, so that it can be taken in an appropriate dose depending on age, and it is convenient to carry when packaged in a pouch. Can be promoted.
  • felubiprofen tromethamine salt of the present invention has improved gastrointestinal side effects and can exhibit excellent drug delivery to the intended target site.
  • Figure 2 shows a differential scanning calorimetry (DSC) curve of felubiprofen tromethamine salt according to the present invention.
  • Figure 3 shows the Fourier Transform Infrared (FTIR) spectrum of the felubiprofen tromethamine salt according to the present invention.
  • DSC differential scanning calorimetry
  • FTIR Fourier transform infrared
  • FIG. 7 shows the results of a gastrointestinal disorder efficacy test of felubiprofen tromethamine salt according to the present invention.
  • DSC is a method used to measure the temperature and heat flow associated with the heat transfer of a material.
  • Pelubiprofen tromethamine salt prepared according to Example 1 of the present invention and felubiprofen according to Comparative Example 1 were measured by heating at 10° C./min under nitrogen conditions using TA DSC Q20.
  • the DSC measurement graph of rubiprofen tromethamine salt is shown in FIG. 2, and the DSC measurement graph of felubiprofen is shown in FIG. 5.
  • Example 1 of the present invention was different from the felubiprofen according to Comparative Example 1, and it was found that the compound synthesized according to Example 1 was a pelubiprofen tromethamine salt. there was.
  • Example 1 of the present invention was different from the pellubiprofen according to Comparative Example 1, and the compound synthesized according to Example 1 was pellubiprofen tromethamine salt.
  • felubiprofen tromethamine salt prepared according to Example 1 of the present invention was compared.
  • the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention exhibited high stability under severe conditions.
  • felubiprofen has a standard of 0.1% or less for individual related substances under general stability evaluation conditions, and felubiprofen tromethamine salt is a very stable substance as it meets the standard on the 21st even under more severe conditions. I could confirm.
  • felubiprofen has a content standard of 98.0% or more under general stability evaluation conditions, and felubiprofen tromethamine salt satisfies the standard on the 21st even under more severe conditions, and thus it was confirmed that it is a very stable substance.
  • felubiprofen tromethamine salt prepared according to Example 1 of the present invention does not require a separate formulation study for securing stability.
  • the pelubiprofen tromethamine salt prepared according to Example 1 of the present invention has excellent stability and is easy to handle and store, and is very useful for mass production in pharmaceutical terms.
  • Pelubiprofen tromethamine salt (5 g) according to Example 1 and felubiprofen (5 g) according to Comparative Example 1 were respectively purified water (5 mL), pH 1.2 solution (5 mL) , After dissolving in pH 4.0 solution (5 mL), pH 6.8 solution (5 mL), stirred for 24 hours, filtered with PVDF, prepare a calibration curve by HPLC analysis, and the concentration of saturated solution from the linear function of the calibration curve was calculated.
  • the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention has an excellent solubility of 108 to 21,807 times in various pH conditions than the felubiprofen according to Comparative Example 1. .
  • felubiprofen according to Comparative Example 1 is an acidic drug with high solubility at a basic pH, so the solubility in acidic (pH 1.2) conditions is 0.03 mg. It was confirmed to be the lowest in /mL. However, it was confirmed that the solubility was increased by about 21,807 times in the acidic (pH 1.2) condition by the formation of salts of felubiprofen and tromethamine.
  • the excellent solubility of the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention under various pH conditions does not add to any particular difficulties in the manufacturing process of the finished drug product as a solid preparation for oral administration. There is an advantage.
  • pelubiprofen tromethamine salt prepared according to Example 1 of the present invention can be prepared as a liquid formulation because it has excellent solubility under various pH conditions.
  • the formulation packaged in a pouch has the advantage of being convenient to carry and improving ease of use.
  • Male Sprague Dawley rats (6 weeks old, 160-240 g) were purchased from Orient Bio (Sungnam, Gyeonggi-do, South Korea), and animal experiments were conducted at Notus (Guri, Gyeonggi-do, South Korea). Performed. For one week after animal acquisition, all male Sprague Dawley rats were free to consume water and food. The male Sprague Dawley rats were separated into 3 groups of 10 animals per group.
  • the rat's body weight was measured before administration and calculated as the average weight, and the test drug felubiprofen 300 mg/kg and pelubiprofen tromethamine salt 440.7 mg/kg (pelubiprofen As 300 mg/kg) was suspended.
  • G1 group is a group that was not administered pelubiprofen tromethamine salt prepared according to Example 1 of the present invention and felubiprofen according to Comparative Example 1, and group G2 was pelubiprofen according to Comparative Example 1. 300 mg/kg was administered, and G3 was a group administered with 440.7 mg/kg of felubiprofen tromethamine salt prepared according to Example 1 of the present invention.
  • Image data taken with a digital camera were analyzed.
  • the area of the damaged area of the gastric mucosa was analyzed using Image J software (NIH, Bethesda, MD). Analysis results are shown in Table 4 and FIG. 7.
  • the G3 group administered with the felubiprofen tromethamine salt according to Example 1 of the present invention had significantly greater gastric damage compared to the G2 group administered with the pellubiprofen according to Comparative Example 1. It was confirmed that it was reduced.

Abstract

The present invention relates to a novel salt of pelubiprofen, and a preparation method therefor and a pharmaceutical composition comprising same. Particularly, the present invention relates to a novel tromethamine salt of pelubiprofen, having stability and solubility remarkably superior to those of pelubiprofen and having reduced gastrointestinal disorder side effects.

Description

펠루비프로펜의 신규 염, 이의 제조방법 및 이를 포함하는 약학적 조성물New salt of felubiprofen, method for preparing the same, and pharmaceutical composition comprising the same
본 발명은 펠루비프로펜의 신규 염, 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것이다. 보다 구체적으로, 본 발명은 용해도가 우수하고, 안정성이 향상되며, 위장장애 부작용이 현저히 개선된 펠루비프로펜 트로메타민 염과 이의 제조방법 및 이를 포함하는 약학적 조성물에 관한 것이다.The present invention relates to a novel salt of felubiprofen, a method for preparing the same, and a pharmaceutical composition comprising the same. More specifically, the present invention relates to a pelubiprofen tromethamine salt having excellent solubility, improved stability, and significantly improved gastrointestinal side effects, a method for preparing the same, and a pharmaceutical composition comprising the same.
펠루비프로펜 (pelubiprofen; 분자식: C 16H 18O 3, MW: 258.31)은 통상적으로 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산으로 명명하는 화합물로서 하기 화학식 1로 표시되는 구조를 갖는다.Pelubiprofen (molecular formula: C 16 H 18 O 3 , MW: 258.31) is usually referred to as 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid. As a compound, it has a structure represented by the following formula (1).
[화학식 1][Formula 1]
Figure PCTKR2020006219-appb-img-000001
Figure PCTKR2020006219-appb-img-000001
상기 화학식 1로 표시되는 펠루비프로펜은 한국등록특허 제0922519호 (특허문헌 1)에 개시되어 있다.Felubiprofen represented by Chemical Formula 1 is disclosed in Korean Patent No. 0922519 (Patent Document 1).
펠루비프로펜은 소염진통 그리고 해열 같은 여러가지의 약리학적 활성을 갖는 비스테로이드성 소염 진통제 (NSAIDs)이며, 관절염, 요통, 상기도염 등의 치료약으로서 우수한 약제이다.Felubiprofen is a nonsteroidal anti-inflammatory analgesic (NSAIDs) having various pharmacological activities such as anti-inflammatory analgesic and antipyretic, and is an excellent drug for treating arthritis, low back pain, and upper respiratory tract.
그러나, 펠루비프로펜은 난용성 약물로서, 염기성 pH에서 용해도가 높은 산성 약물이기 때문에 산성 pH에서는 용해도가 낮다는 문제가 있다. 또한, 펠루비프로펜은 기존 NSAIDs에 비하여 위장관 부작용이 많이 경감된 물질이지만 여전히 위장관 부작용을 지니고 있으며, 원료의 안정성이 좋지 않아 이를 해결하기 위한 제제개선 노력이 별도로 필요하다는 문제가 있다.However, felubiprofen is a poorly soluble drug, and since it is an acidic drug having a high solubility at a basic pH, there is a problem that its solubility is low at an acidic pH. In addition, felubiprofen is a substance in which gastrointestinal side effects are significantly reduced compared to existing NSAIDs, but it still has gastrointestinal side effects, and the stability of the raw material is poor, so there is a problem that an effort to improve the formulation to solve this problem is required.
따라서, 산성 pH 조건에서 용해도를 크게 개선시킬 수 있고, 제제의 안정성을 높일 수 있으며, 위장장애 부작용이 현저히 개선된 펠루비프로펜의 신규 염에 대한 연구 개발이 필요하다.Accordingly, there is a need for research and development on a new salt of felubiprofen, which can significantly improve the solubility under acidic pH conditions, improve the stability of the formulation, and significantly improve gastrointestinal side effects.
일본등록특허 제1637767호 (특허문헌 2)는 신규한 화합물인 하기 일반식 I로 표시되는 화합물을 제조하는 방법만이 기재되어 있을 뿐, 상기 일반식 I의 염이나 펠루비프로펜의 염에 대한 내용은 기재되어 있지 않다.Japanese Patent No. 1637767 (Patent Document 2) only describes a method for preparing a compound represented by the following general formula I, which is a novel compound, and for the salt of the general formula I or the salt of felubiprofen. The contents are not described.
[일반식 I][General Formula I]
Figure PCTKR2020006219-appb-img-000002
Figure PCTKR2020006219-appb-img-000002
본 발명의 목적은 펠루비프로펜보다 용해도가 우수하고 안정성이 개선되어 유연물질의 발생을 극소화 시키는 등 물리 화학적으로 우수한 성질을 나타내며, 제조에 있어 대량생산의 적용이 가능하고 균질한 품질로 고순도로 얻을 수 있으며, 위장장애 부작용이 개선된 펠루비프로펜의 신규 염과 이의 제조방법 및 이를 유효성분으로서 포함하는 약학적 조성물을 제공하는 것이다.The object of the present invention is that it exhibits superior physicochemical properties such as having superior solubility and improved stability than felubiprofen, minimizing the occurrence of related substances, etc. It is to provide a novel salt of felubiprofen with improved gastrointestinal side effects, a method for preparing the same, and a pharmaceutical composition comprising the same as an active ingredient.
본 발명의 다른 목적은 펠루비프로펜의 신규 염을 유효성분으로 함유하는 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory diseases containing a novel salt of felubiprofen as an active ingredient.
본 발명의 다른 목적은 필요로 하는 개체에게 펠루비프로펜의 신규 염을 치료학적 유효량으로 투여하는 단계를 포함하는 염증성 질환의 예방 또는 치료방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating inflammatory diseases, comprising administering a novel salt of felubiprofen to a subject in need thereof in a therapeutically effective amount.
본 발명의 목적은 염증성 질환의 예방 또는 치료용 약제의 제조를 위한 펠루비프로펜의 신규 염을 포함하는 약학적 조성물의 용도를 제공하는 것이다.It is an object of the present invention to provide a use of a pharmaceutical composition comprising a novel salt of felubiprofen for the manufacture of a medicament for the prevention or treatment of inflammatory diseases.
마지막으로, 본 발명의 목적은 펠루비프로펜의 신규 염을 포함하는 약학적 조성물의 염증성 질환의 예방 또는 치료를 위한 용도를 제공하는 것이다.Finally, an object of the present invention is to provide a use of a pharmaceutical composition comprising a novel salt of felubiprofen for the prevention or treatment of inflammatory diseases.
상기 과제를 해결하기 위하여, 본 발명인 펠루비프로펜의 신규 염인 하기 화학식 2로 표시되는 펠루비프로펜 트로메타민 염을 개발하였다.In order to solve the above problems, a new salt of felubiprofen of the present invention, a felubiprofen tromethamine salt represented by the following formula (2), was developed.
[화학식 2][Formula 2]
Figure PCTKR2020006219-appb-img-000003
Figure PCTKR2020006219-appb-img-000003
본 발명인 펠루비프로펜 트로메타민 염은 펠루비프로펜과 비교하여 다양한 pH 조건에서 우수한 용해도를 가지며, 가혹 조건 (80±1 ℃ 또는 RH 90±1 %)에서의 높은 안정성을 보이며, 동등 이상의 우수한 생체이용률을 나타낼 수 있다. The pellubiprofen tromethamine salt of the present invention has excellent solubility under various pH conditions compared to pelubiprofen, and shows high stability under severe conditions (80±1°C or RH 90±1%), and is equal to or greater than It can exhibit excellent bioavailability.
또한, 본 발명인 펠루비프로펜 트로메타민 염은 펠루비프로펜의 유리 염기와 대비하였을 때 위점막 손상을 최소화함으로써 위장장애 부작용을 개선할 수 있음을 확인하였다.In addition, it was confirmed that the felubiprofen tromethamine salt of the present invention can improve gastrointestinal side effects by minimizing gastric mucosa damage when compared with the free base of felubiprofen.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
펠루비프로펜 트로메타민 염Felubiprofen tromethamine salt
본 발명은 펠루비프로펜 트로메타민 염을 제공한다. 본 발명의 펠루비프로펜 트로메타민 염은 하기 화학식 2로 표시되는 화합물이다.The present invention provides felubiprofen tromethamine salt. Felubiprofen tromethamine salt of the present invention is a compound represented by the following formula (2).
[화학식 2][Formula 2]
Figure PCTKR2020006219-appb-img-000004
Figure PCTKR2020006219-appb-img-000004
구체적으로, 상기 화학식 2로 표시되는 펠루비프로펜 트로메타민 염은 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산·트로메타민 [2-(4-[(E)-(2-oxocyclohexylidene)methyl]phenyl)propionic acid tromethamine]으로 명명된다.Specifically, the felubipropene tromethamine salt represented by Chemical Formula 2 is 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid·tromethamine [2-( It is named 4-[(E)-(2-oxocyclohexylidene)methyl]phenyl)propionic acid tromethamine].
본 발명의 펠루비프로펜 트로메타민 염은 입체 이성질체를 포함한다.The felubiprofen tromethamine salt of the present invention includes stereoisomers.
본 발명에 있어서, 용어 「입체이성질체」란, 하나 이상의 키랄 센터(*)를 가지고 각 센터는 R 또는 S 형으로 존재할 수 있는 화합물을 의미한다. 입체 이성질체는 부분입체 이성질체 (diastereomer), 거울상 이성질체 (enantiomer) 및 에피머 (epimer) 형태 뿐만 아니라 라세미체 및 그 혼합물을 모두 포함한다.In the present invention, the term "stereoisomer" refers to a compound that has one or more chiral centers (*) and each center can exist in R or S form. Stereoisomers include both diastereomer, enantiomer and epimer forms, as well as racemates and mixtures thereof.
염 형태의 제조가 약학적 활성을 갖는 화합물의 물리적 또는 약학적 성질들을 개선시킬 수 있다고 공지되어 있을지라도, 염 형태가 실제 제조되고 특성화되기 전에, 어떤 염 형태가 특정 목적에 강점을 가질 수 있을지 예측하는 것은 불가능하다. 염 형성은 약물의 화학구조를 변형시키지 않으면서 약물의 물리 화학적 특성을 변화시킬 수 있기 때문에 적절한 염의 선택은 용해도 및 안정성에 중요한 고려사항이다. 특히, 용해도는 약물로서 사용하기 위한 적합성에 영향을 줄 수 있는 중요한 특성이다.Although it is known that the preparation of a salt form can improve the physical or pharmaceutical properties of a compound with pharmacological activity, before the salt form is actually prepared and characterized, predict which salt form may have strengths for a particular purpose. It is impossible to do. Since salt formation can change the physicochemical properties of a drug without altering the chemical structure of the drug, the selection of an appropriate salt is an important consideration for solubility and stability. In particular, solubility is an important property that can affect its suitability for use as a drug.
본 발명에 따른 펠루비프로펜 트로메타민 염은 펠루비프로펜에 비해 우수한 물리 화학적 성질을 갖는다.Felubiprofen tromethamine salt according to the present invention has superior physicochemical properties compared to felubiprofen.
구체적으로, 본 발명의 펠루비프로펜 트로메타민 염은 다양한 pH 조건에서 우수한 용해도 값을 나타낸다.Specifically, the pelubiprofen tromethamine salt of the present invention exhibits excellent solubility values under various pH conditions.
구체적으로, 본 발명의 펠루비프로펜 트로메타민 염은 광, 열, 수분, pH 등에 대한 안정성이 향상되어 유연물질의 발생을 극소화 시킬 수 있다. 특히, 고온 조건 (80±1 ℃) 또는 고습도 조건 (RH 90±1 %) 하에서 유연물질이 기준을 초과하지 않으며, 함량이 균일하여 고온 또는 고습도 조건에서 매우 안정한 특성을 갖는다. 또한, 상대습도 범위에서 낮은 흡습성을 나타내므로 제제화, 의약품 가공 및 보관이 용이함은 물론, 제제의 제조 후 장기간 보관 시에도 동일한 상태를 유지하여 제제의 함량 균일성이 안정적으로 유지될 수 있어 대량생산에 용이하게 적용될 수 있다. Specifically, the pelubiprofen tromethamine salt of the present invention has improved stability against light, heat, moisture, pH, etc., thereby minimizing the occurrence of related substances. In particular, the related material does not exceed the standard under high temperature conditions (80±1 ℃) or high humidity conditions (RH 90±1%), and the content is uniform, so it has very stable characteristics under high temperature or high humidity conditions. In addition, since it exhibits low hygroscopicity in the relative humidity range, it is easy to formulate, process and store pharmaceuticals, and maintain the same state even during long-term storage after preparation of the preparation, so that the content uniformity of the preparation can be stably maintained. It can be easily applied.
본 발명에 따른 펠루비프로펜 트로메타민 염은 위장장애 부작용을 현저히 개선시킬 수 있어, 염증성 질환의 의약품 등으로 유용하게 적용될 수 있다.Felubiprofen tromethamine salt according to the present invention can significantly improve the side effects of gastrointestinal disorders, and thus can be usefully applied as pharmaceuticals for inflammatory diseases.
본 발명의 일 구현예에 있어서, 상기 펠루비프로펜 트로메타민 염은 펠루비프로펜과 트로메타민이 1:1의 몰비율로 결합된 것일 수 있다.In one embodiment of the present invention, the felubiprofen tromethamine salt may be a combination of pelubiprofen and tromethamine in a molar ratio of 1:1.
본 발명의 일 구현예에 있어서, 본 발명의 펠루비프로펜 트로메타민 염은 도 2와 같이 123.5±2 ℃에서 시차주사열량 (DSC) 흡열 피크를 가질 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the felubiprofen tromethamine salt of the present invention may have a differential scanning calorie (DSC) endothermic peak at 123.5±2° C. as shown in FIG. 2, but is not limited thereto.
본 발명에 따른 펠루비프로펜 트로메타민 염은 우수한 약리효과를 나타낼 수 있다. 따라서, 요통, 골관절염, 류마티스 관절염, 급성 상기도염, 해열 등의 다양한 적응증을 치료할 수 있는 약학 조성물의 새로운 유효성분으로써 유용하게 사용할 수 있으며, 경구 또는 비경구 투여 시 펠루비프로펜 유리 염기와 동등 수준의 생체이용률을 나타낼 수 있다. Felubiprofen tromethamine salt according to the present invention can exhibit excellent pharmacological effects. Therefore, it can be usefully used as a new active ingredient of a pharmaceutical composition that can treat various indications such as low back pain, osteoarthritis, rheumatoid arthritis, acute upper respiratory tract, and antipyretic, and is equivalent to felubiprofen free base when administered orally or parenterally. It can represent the bioavailability of.
펠루비프로펜 트로메타민 염의 제조방법Method for preparing felubiprofen tromethamine salt
본 발명은 하기 화학식 2로 표시되는 펠루비프로펜 트로메타민 염을 제조하는 방법을 제공한다.The present invention provides a method of preparing a felubiprofen tromethamine salt represented by the following formula (2).
[화학식 2][Formula 2]
Figure PCTKR2020006219-appb-img-000005
Figure PCTKR2020006219-appb-img-000005
본 발명의 제조방법은 (a) 펠루비프로펜과 트로메타민을 유기용매 중에서 반응시키는 단계; (b) 반용매를 첨가하여 상기 화학식 2로 표시되는 펠루비프로펜 트로메타민 염을 형성하는 단계; 및 (c) 여과하고 건조하는 단계를 포함한다.The manufacturing method of the present invention comprises the steps of (a) reacting felubiprofen and tromethamine in an organic solvent; (b) adding an anti-solvent to form a felubipropene tromethamine salt represented by Chemical Formula 2; And (c) filtering and drying.
본 발명의 일 구현예에 있어서, 상기 단계 (a)는 펠루비프로펜을 유기용매와 혼합한 후 트로메타민을 첨가하여 반응시키는 단계 또는 트로메타민을 유기용매와 혼합한 후 펠루비프로펜을 첨가하여 반응시키는 단계일 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the step (a) is a step of reacting by mixing pelubiprofen with an organic solvent and then adding tromethamine, or mixing tromethamine with an organic solvent, and then pelubiprofen. It may be a step of reacting by adding, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 단계 (a)의 트로메타민은 펠루비프로펜 1.0 당량에 대하여 0.8 내지 1.5 당량의 몰비로 첨가될 수 있으며, 이에 한정되는 것은 아니다. In one embodiment of the present invention, the tromethamine in step (a) may be added in a molar ratio of 0.8 to 1.5 equivalents based on 1.0 equivalent of felubiprofen, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 단계 (a)의 유기용매는 메탄올, 에탄올, 2-프로판올, 부탄올, 아세톤, 에틸아세테이트, 메틸렌 클로라이드 및 이들의 혼합 용매로 구성된 군에서 선택되는 것일 수 있으며, 이에 한정되는 것은 아니고, 구체적으로 단계 (a)의 유기용매는 메탄올, 에탄올, 아세톤, 에틸아세테이트 일 수 있다.In one embodiment of the present invention, the organic solvent in step (a) may be selected from the group consisting of methanol, ethanol, 2-propanol, butanol, acetone, ethyl acetate, methylene chloride, and a mixed solvent thereof, It is not limited thereto, and specifically, the organic solvent in step (a) may be methanol, ethanol, acetone, or ethyl acetate.
본 발명의 일 구현예에 있어서, 상기 단계 (a)는 10 내지 65 ℃의 온도에서 수행되는 것일 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the step (a) may be performed at a temperature of 10 to 65 °C, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 단계 (b)의 반용매는 아세톤, 메틸에틸케톤, 에틸아세테이트, n-헥산, 이소프로필 에테르, 이소프로필 알코올 및 이들의 혼합 용매로 구성된 군에서 선택되는 것일 수 있으며, 이에 한정되는 것은 아니고, 구체적으로 단계 (b)의 반용매는 아세톤, n-헥산, 이소프로필 에테르 일 수 있다. 상기 단계 (b)의 반용매는 상기 단계 (a)의 유기용매와 다른 종류를 이용할 수 있다.In one embodiment of the present invention, the anti-solvent in step (b) is selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, n-hexane, isopropyl ether, isopropyl alcohol, and a mixed solvent thereof. It may, but is not limited thereto, specifically, the anti-solvent in step (b) may be acetone, n-hexane, isopropyl ether. The anti-solvent of step (b) may be a different type from the organic solvent of step (a).
본 발명의 일 구현예에 있어서, 상기 단계 (b)는 10 내지 50 ℃의 온도에서 수행되는 것일 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, step (b) may be performed at a temperature of 10 to 50°C, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 단계 (c)의 건조는 30 내지 80 ℃에서 수행되는 것일 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the drying in step (c) may be performed at 30 to 80° C., but is not limited thereto.
본 발명의 제조방법은 (a) 펠루비프로펜과 트로메타민을 유기용매 중에서 반응시켜 상기 화학식 2로 표시되는 펠루비프로펜 트로메타민 염을 형성하는 단계; 및 ( b) 여과하고 건조하는 단계를 포함한다.The manufacturing method of the present invention comprises the steps of (a) reacting felubipropene and tromethamine in an organic solvent to form pelubipropene tromethamine salt represented by Formula 2; And ( b ) filtering and drying.
본 발명의 일 구현예에 있어서, 상기 단계 (a)는 펠루비프로펜을 유기용매와 혼합한 후 트로메타민을 첨가하여 반응시키는 단계 또는 트로메타민을 유기용매와 혼합한 후 펠루비프로펜을 첨가하여 반응시키는 단계일 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the step (a) is a step of reacting by mixing pelubiprofen with an organic solvent and then adding tromethamine, or mixing tromethamine with an organic solvent, and then pelubiprofen. It may be a step of reacting by adding, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 단계 (a)의 트로메타민은 펠루비프로펜 1.0 당량에 대하여 0.8 내지 1.5 당량의 몰비로 첨가될 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the tromethamine in step (a) may be added in a molar ratio of 0.8 to 1.5 equivalents based on 1.0 equivalent of felubiprofen, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 단계 (a)의 유기용매는 메탄올, 에탄올, 2-프로판올, 부탄올, 아세톤, 에틸아세테이트, 메틸렌 클로라이드 및 이들의 혼합 용매로 구성된 군에서 선택되는 것일 수 있으며, 이에 한정되는 것은 아니고, 구체적으로 단계 (a)의 유기용매는 메탄올, 에탄올, 2-프로판올, 메틸렌 클로라이드 일 수 있다.In one embodiment of the present invention, the organic solvent in step (a) may be selected from the group consisting of methanol, ethanol, 2-propanol, butanol, acetone, ethyl acetate, methylene chloride, and a mixed solvent thereof, It is not limited thereto, and specifically, the organic solvent of step (a) may be methanol, ethanol, 2-propanol, or methylene chloride.
본 발명의 일 구현예에 있어서, 상기 단계 (a)는 10 내지 65 ℃의 온도에서 수행되는 것일 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the step (a) may be performed at a temperature of 10 to 65 °C, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 단계 (a)는 10 내지 65 ℃의 온도에서 수행한 후 -5 내지 30 ℃의 온도로 냉각하여 반응을 수행되는 것일 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the step (a) may be performed at a temperature of 10 to 65 °C and then cooled to a temperature of -5 to 30 °C to perform the reaction, but is not limited thereto.
본 발명의 일 구현예에 있어서, 상기 단계 (b)의 건조는 30 내지 80 ℃에서 수행되는 것일 수 있으며, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the drying in step (b) may be performed at 30 to 80° C., but is not limited thereto.
본 발명에 따라 제조된 펠루비프로펜 트로메타민 염은 위의 펠루비프로펜 트로메타민 염과 서로 모순되지 않은 한 동일하게 적용된다.The felubiprofen tromethamine salt prepared according to the present invention is applied equally as long as it does not contradict each other with the pelubiprofen tromethamine salt above.
펠루비프로펜 트로메타민 염을 유효성분으로 포함하는 염증성 질환을 예방 또는 치료하기 위한 약학적 조성물Pharmaceutical composition for preventing or treating inflammatory diseases containing felubiprofen tromethamine salt as an active ingredient
본 발명은 펠루비프로펜 트로메타민 염을 유효성분으로 함유하는 염증성 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing pelubiprofen tromethamine salt as an active ingredient.
본 발명의 일 구현예에 있어서, 본 발명의 약학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라 약제학적으로 허용되는 담체를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다.In one embodiment of the present invention, the pharmaceutical composition of the present invention is formulated using a pharmaceutically acceptable carrier according to a method that can be easily carried out by a person skilled in the art to which the present invention belongs. It may be prepared in a dosage form or may be prepared by placing it in a multi-dose container.
본 발명에 있어서, 용어 「담체」란, 세포 또는 조직 내로 화합물의 부가를 용이하게 하는 화합물을 의미하고, 용어 「약학적으로 허용되는」 이란, 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다.In the present invention, the term "carrier" means a compound that facilitates addition of the compound into cells or tissues, and the term "pharmaceutically acceptable" is physiologically acceptable and when administered to humans, usually It refers to a composition that does not cause allergic reactions such as gastrointestinal disorders or dizziness or similar reactions.
본 발명의 일 구현예에 있어서, 상기 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 제한되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.In one embodiment of the present invention, the pharmaceutically acceptable carrier is commonly used in formulation, and lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. It is not limited. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like in addition to the above components.
본 발명의 일 구현예에 있어서, 상기 약학적 조성물에 포함되는 첨가제의 함량은 특별히 제한되는 것은 아니며 통상의 제제화에 사용되는 함량 범위 내에서 적절하게 조절될 수 있다.In one embodiment of the present invention, the content of the additive included in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the content range used for conventional formulation.
본 발명의 일 구현예에 있어서, 본 발명의 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 액제, 현탁제, 산제, 과립제, 정제, 캡슐제, 환제, 엑스제, 에멀젼, 시럽제, 에어로졸 등의 경구 제형, 멸균 주사용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥 내, 복강 내, 피하, 피내, 근육 내, 척추, 척추강 또는 직장 내 국소 투여 또는 주입 등을 포함한 다양한 경로를 통해 비경구 투여될 수 있다.In one embodiment of the present invention, the composition of the present invention is a solution, suspension, powder, granule, tablet, capsule, pill, extract, emulsion, syrup, aerosol, etc. according to a conventional method according to each purpose of use. It can be formulated and used in various forms, such as oral formulations of sterilized injectable solutions and injections of sterile injectable solutions. It can be administered parenterally through a variety of routes.
본 발명에 있어서, 용어 「치료」란, 특정 질병, 장애 및/또는 질환의 발병을 부분적으로 또는 완전히 경감, 개선, 완화, 저해 또는 지연시키며, 중증도를 감소시키거나, 하나 이상의 증상 또는 특징의 발생을 감소시키는 것을 의미한다.In the present invention, the term ``treatment'' partially or completely reduces, ameliorates, alleviates, inhibits or delays the onset of a specific disease, disorder and/or disease, reduces the severity, or causes one or more symptoms or characteristics. Means to reduce.
본 발명에 있어서, 용어 「예방」은, 질병, 장애 또는 질환의 발병의 지연을 의미한다. 질병, 장애 또는 질환의 발병이 예정된 기간 동안 지연된 경우 예방은 완전한 것으로 간주될 수 있다.In the present invention, the term "prevention" means a delay in onset of a disease, disorder or disease. Prevention can be considered complete if the onset of the disease, disorder or condition is delayed for a predetermined period of time.
본 발명의 일 구현예에 있어서, 염증성 질환은 피부염, 급성 또는 만성 상기도염, 해열, 염증성 장질환, 천식, 골관절염, 류마티스 관절염, 기관지염, Th-2형 자기면역질환, 전신성 에리테마토데스, 중증 근무력증, 만성 GVHD, 클론병, 변형성 척추염, 요통, 통풍, 수술 외상 후의 염증, 종창의 완해, 신경통, 인후두염, 방광염, 간염, B형 간염, C형 간염 및 동맥경화로 이루어진 군에서 선택된 어느 하나 이상일 수 있으며, 구체적으로는 급성 상기도염, 해열, 골관절염, 류마티스 관절염 또는 요통일 수 있다.In one embodiment of the present invention, the inflammatory disease is dermatitis, acute or chronic upper respiratory tract infection, fever, inflammatory bowel disease, asthma, osteoarthritis, rheumatoid arthritis, bronchitis, Th-2 type autoimmune disease, systemic erythematodes, severe Myasthenia gravis, chronic GVHD, clonal disease, spondylitis deformed, back pain, gout, inflammation after surgical trauma, relief of swelling, neuralgia, pharyngitis, cystitis, hepatitis, hepatitis B, hepatitis C, and arteriosclerosis It may be, specifically, acute upper respiratory tract, fever, osteoarthritis, rheumatoid arthritis, or low back pain.
본 발명은 펠루비프로펜 트로메타민 염을 펠루비프로펜으로서 30 mg으로 포함하며 1일 3회 투여하여 염증성 질환을 예방 또는 치료하기 위한 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating inflammatory diseases by containing felubiprofen tromethamine salt at 30 mg as felubiprofen and administered three times a day.
본 발명은 펠루비프로펜 트로메타민 염을 펠루비프로펜으로서 45 mg으로 포함하며 1일 2회 투여하여 염증성 질환을 예방 또는 치료하기 위한 약학적 조성물을 제공한다. 구체적으로 본 발명의 약학적 조성물은 서방성 약학조성물일 수 있다.The present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease by containing felubiprofen tromethamine salt at 45 mg as felubiprofen and administered twice a day. Specifically, the pharmaceutical composition of the present invention may be a sustained-release pharmaceutical composition.
염증성 질환의 예방 또는 치료방법Methods of preventing or treating inflammatory diseases
본 발명은 필요로 하는 개체에게 펠루비프로펜 트로메타민 염을 치료학적 유효량으로 투여하는 단계를 포함하는 염증성 질환의 예방 또는 치료방법을 제공하는 것이다.The present invention provides a method for preventing or treating an inflammatory disease comprising administering a therapeutically effective amount of felubiprofen tromethamine salt to an individual in need thereof.
본 발명에 있어서, 용어 「개체」란, 원숭이, 소, 말, 개, 고양이, 토끼, 레트, 마우스 등의 포유 동물을 의미하며, 특히, 인간을 포함한다.In the present invention, the term "individual" means mammals such as monkeys, cows, horses, dogs, cats, rabbits, rats and mice, and particularly includes humans.
본 발명에 있어서, 용어 「치료학적으로 유효한 양」이란, 염증성 질환의 예방 또는 치료에 유효한 본 발명의 펠루비프로펜 트로메타민 염의 양으로, 바람직하게는 펠루비프로펜 트로메타민 염을 펠루비프로펜으로서 30 mg을 1일 3회 투여하거나, 펠루비프로펜 트로메타민 염을 펠루비프로펜으로서 45 mg을 1일 2회 투여할 수 있으나, 상기 치료학적 유효한 양은 상기 약학적 조성물에 의해 염증성 질환의 증세가 호전되거나 완치되는 모든 용량을 포괄하는 것으로 해석될 수 있다.In the present invention, the term "therapeutically effective amount" refers to the amount of the felubiprofen tromethamine salt of the present invention that is effective in the prevention or treatment of inflammatory diseases, preferably pelubiprofen tromethamine salt. 30 mg as rubiprofen may be administered three times a day, or felubiprofen tromethamine salt as felubiprofen 45 mg may be administered twice a day, but the therapeutically effective amount is in the pharmaceutical composition. It can be interpreted as encompassing all doses that improve or cure the symptoms of inflammatory disease.
본 발명의 예방 또는 치료방법은 약학적 조성물을 투여함으로써, 징후의 발현 전에 질병 그 자체를 다룰 뿐만 아니라, 이의 징후를 저해하거나 피하는 것을 포함한다. The prevention or treatment method of the present invention includes not only dealing with the disease itself before the onset of symptoms, but also inhibiting or avoiding the symptoms thereof by administering the pharmaceutical composition.
또한, 본 발명의 예방 또는 치료방법은 약학적 조성물과 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며, 추가적인 활성제제는 약학적 조성물과 함께 시너지 효과 또는 상가적 효과를 나타낼 수 있다.In addition, the prophylactic or therapeutic method of the present invention may further include administration of a therapeutically effective amount of an additional active agent useful for disease treatment together with the pharmaceutical composition, and the additional active agent has a synergistic effect with the pharmaceutical composition. Alternatively, it may exhibit additive effects.
염증성 질환의 예방 또는 치료용 약제의 제조를 위한 펠루비프로펜 트로메타민 염을 포함하는 약학적 조성물의 용도Use of a pharmaceutical composition containing felubiprofen tromethamine salt for the manufacture of a medicament for the prevention or treatment of inflammatory diseases
본 발명은 염증성 질환의 예방 또는 치료용 약제의 제조를 위한 펠루비프로펜 트로메타민 염을 포함하는 약학적 조성물의 용도를 제공한다.The present invention provides a use of a pharmaceutical composition comprising felubiprofen tromethamine salt for the manufacture of a medicament for the prevention or treatment of inflammatory diseases.
본 발명의 일 구현예에 있어서, 약제의 제조를 위한 본 발명의 펠루비프로펜 트로메타민 염을 포함하는 약학적 조성물은 약학적으로 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성 제제와 함께 복합 제제로 제조되어 상승 작용을 가질 수 있다.In one embodiment of the present invention, the pharmaceutical composition containing the felubiprofen tromethamine salt of the present invention for the manufacture of a drug may be mixed with a pharmaceutically acceptable adjuvant, a diluent, a carrier, etc. It can have a synergistic effect by being prepared as a combination formulation with the active agent.
펠루비프로펜 트로메타민 염을 포함하는 약학적 조성물의 염증성의 질환 예방 또는 치료를 위한 용도Use of a pharmaceutical composition containing felubiprofen tromethamine salt for the prevention or treatment of inflammatory diseases
본 발명의 목적은 펠루비프로펜 트로메타민 염을 포함하는 약학적 조성물의 염증성의 질환 예방 또는 치료를 위한 용도를 제공한다.It is an object of the present invention to provide a use of a pharmaceutical composition containing felubiprofen tromethamine salt for the prevention or treatment of inflammatory diseases.
본 발명의 약학적 조성물, 치료 방법 및 용도에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the pharmaceutical composition, method of treatment and use of the present invention apply equally unless contradictory to each other.
본 발명에 따른 펠루비프로펜 트로메타민 염은 펠루비프로펜에 비하여 우수한 안정성을 가지고 있기 때문에, 제품의 보관 과정에서 불순물의 생성량을 낮추어 제제의 안정성을 높일 수 있다.Since the felubiprofen tromethamine salt according to the present invention has superior stability compared to felubiprofen, it is possible to increase the stability of the formulation by lowering the amount of impurities produced during storage of the product.
또한, 본 발명의 펠루비프로펜 트로메타민 염은 펠루비프로펜에 비하여 용해도가 매우 크게 개선되어 약학적으로 허용가능한 담체와 함께 소염진통, 해열 및 여러가지 효능에 유용한 약학 조성물의 유효성분으로 사용될 수 있다. In addition, the pellubiprofen tromethamine salt of the present invention has a significantly improved solubility compared to felubiprofen, so that it can be used as an active ingredient in a pharmaceutical composition useful for anti-inflammatory analgesic, antipyretic and various effects with a pharmaceutically acceptable carrier. I can.
또한, 본 발명의 펠루비프로펜 트로메타민 염은 용해도가 우수하기 때문에 액상 제제로 제조가 가능하여 연령에 따라 적정 용량으로 복용이 가능할 뿐만 아니라 파우치에 포장될 경우 휴대하기가 편리한 등 복용편의성을 증진시킬 수 있다. In addition, since the pelubiprofen tromethamine salt of the present invention has excellent solubility, it can be prepared as a liquid formulation, so that it can be taken in an appropriate dose depending on age, and it is convenient to carry when packaged in a pouch. Can be promoted.
또한, 본 발명의 펠루비프로펜 트로메타민 염은 위장장애 부작용이 개선되어 의도된 표적 부위에 대한 우수한 약물 전달성을 나타낼 수 있다.In addition, the felubiprofen tromethamine salt of the present invention has improved gastrointestinal side effects and can exhibit excellent drug delivery to the intended target site.
도 1은 본 발명에 따른 펠루비프로펜 트로메타민 염의 1H-핵자기공명 (NMR) 스펙트럼을 도시한다.1 shows a 1 H-nuclear magnetic resonance (NMR) spectrum of felubiprofen tromethamine salt according to the present invention.
도 2은 본 발명에 따른 펠루비프로펜 트로메타민 염의 시차주사열량도 (DSC) 곡선을 도시한다.Figure 2 shows a differential scanning calorimetry (DSC) curve of felubiprofen tromethamine salt according to the present invention.
도 3는 본 발명에 따른 펠루비프로펜 트로메타민 염의 푸리에 변환 적외선 (FTIR) 스펙트럼을 도시한다.Figure 3 shows the Fourier Transform Infrared (FTIR) spectrum of the felubiprofen tromethamine salt according to the present invention.
도 4는 비교예 1에 따른 펠루비프로펜의 1H-핵자기공명 (NMR) 스펙트럼을 도시한다.4 shows a 1 H-nuclear magnetic resonance (NMR) spectrum of felubiprofen according to Comparative Example 1.
도 5은 비교예 1에 따른 펠루비프로펜의 시차주사열량도 (DSC) 곡선을 도시한다.5 shows a differential scanning calorimetry (DSC) curve of felubiprofen according to Comparative Example 1.
도 6은 비교예 1에 따른 펠루비프로펜의 푸리에 변환 적외선 (FTIR) 스펙트럼을 도시한다.6 shows a Fourier transform infrared (FTIR) spectrum of felubiprofen according to Comparative Example 1.
도 7은 본 발명에 따른 펠루비프로펜 트로메타민 염의 위장장애 효력시험 결과를 도시한다.7 shows the results of a gastrointestinal disorder efficacy test of felubiprofen tromethamine salt according to the present invention.
이하, 실시예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들 실시예에 의해 한정되는 것은 아니다.Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.
또한, 이하에서 언급된 각종 시약 및 용매는 Sigma Aldrich, TCI, 대정 등으로부터 구입하였다.In addition, various reagents and solvents mentioned below were purchased from Sigma Aldrich, TCI, Daejeong, etc.
실시예 1. 펠루비프로펜 트로메타민 염 (화학식 2의 화합물)의 제조Example 1. Preparation of pelubiprofen tromethamine salt (compound of formula 2)
일본등록특허 제1637767호에 기술된 것과 동일한 방법으로 제조된 화합물 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산 (펠루비프로펜, 5 g, 19.36 mmol)을 메탄올 (25 mL)에 용해시켜 용액을 제조하고, 상기 용액에 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산 (펠루비프로펜) 1.0 당량에 대하여 약 1.002 당량의 몰비로 2-아미노-2-(히드록시메틸)프로판-1,3-디올 (트로메타민, 2.35 g, 19.40 mmol)을 적가한 후 40 ℃에서 1시간 동안 교반하였다.Compound 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (pelubipropene, 5 g, 19.36) prepared by the same method as described in Japanese Patent No. 1637767 mmol) in methanol (25 mL) to prepare a solution, and in the solution 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (pelubipropene) 1.0 2-amino-2-(hydroxymethyl)propane-1,3-diol (tromethamine, 2.35 g, 19.40 mmol) was added dropwise at a molar ratio of about 1.002 equivalent to the equivalent, followed by stirring at 40° C. for 1 hour. .
이후 상온 (20~25 ℃)으로 냉각하고 감압 (76 cmHg) 하에 농축하였다.After cooling to room temperature (20 ~ 25 ℃) and concentrated under reduced pressure (76 cmHg).
농축물에 아세톤 (70 mL)을 천천히 적가한 후 상온 (20~25 ℃)에서 2시간 동안 교반한 후 여과하였다. 여과물을 메탄올과 아세톤의 혼합용매 100 mL (메탄올:아세톤 = 1:3 v/v)로 세척한 후 얻어진 고체를 40 ℃에서 진공 건조하여 펠루비프로펜 트로메타민 염을 얻었다.Acetone (70 mL) was slowly added dropwise to the concentrate, followed by stirring at room temperature (20-25 °C) for 2 hours, and then filtered. The filtrate was washed with 100 mL of a mixed solvent of methanol and acetone (methanol:acetone = 1:3 v/v), and the obtained solid was dried in vacuo at 40° C. to obtain felubipropene tromethamine salt.
- 수득량: 7.8 g -Yield: 7.8 g
- 수득율: 94 % -Yield: 94%
- 순도: 98.5 %-Purity: 98.5%
실시예 2. 펠루비프로펜 트로메타민 염 (화학식 2의 화합물)의 제조Example 2. Preparation of pelubiprofen tromethamine salt (compound of formula 2)
일본등록특허 제1637767호에 기술된 것과 동일한 방법으로 제조된 화합물 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산 (펠루비프로펜, 5 g, 19.36 mmol)을 에탄올 (3 mL)에 용해시켜 용액을 제조하고, 상기 용액에 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산 (펠루비프로펜) 1.0 당량에 대하여 약 1.004 당량의 몰비로 2-아미노-2-(히드록시메틸)프로판-1,3-디올 (트로메타민, 2.35 g, 19.44 mmol)을 적가한 후 20 ℃에서 3시간 동안 교반하였다.Compound 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (pelubipropene, 5 g, 19.36) prepared by the same method as described in Japanese Patent No. 1637767 mmol) in ethanol (3 mL) to prepare a solution, and in the solution 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (pelubipropene) 1.0 2-amino-2-(hydroxymethyl)propane-1,3-diol (tromethamine, 2.35 g, 19.44 mmol) was added dropwise at a molar ratio of about 1.004 equivalent to the equivalent, followed by stirring at 20° C. for 3 hours. .
이후 저온 (0~5 ℃)으로 냉각하고 4시간 동안 교반한 후 여과하였다. 여과물을 아세톤 2 mL로 세척한 후 얻어진 고체를 60 ℃에서 진공 건조하여 펠루비프로펜 트로메타민 염을 얻었다.After cooling to low temperature (0 ~ 5 ℃), stirred for 4 hours and then filtered. The filtrate was washed with 2 mL of acetone, and the resulting solid was vacuum-dried at 60° C. to obtain pelubipropene tromethamine salt.
- 수득량: 6.8 g -Yield: 6.8 g
- 수득율: 92.6 % -Yield: 92.6%
- 순도: 98.8 %-Purity: 98.8%
실시예 3. 펠루비프로펜 트로메타민 염 (화학식 2의 화합물)의 제조Example 3. Preparation of pelubiprofen tromethamine salt (compound of formula 2)
일본등록특허 제1637767호에 기술된 것과 동일한 방법으로 제조된 화합물 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산 (펠루비프로펜, 5 g, 19.36 mmol)과 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산 (펠루비프로펜) 1.0 당량에 대하여 약 1.004 당량의 몰비로 2-아미노-2-(히드록시메틸)프로판-1,3-디올 (트로메타민, 2.35 g, 19.44 mmol)을 2-프로판올 (50 mL)에 넣고 60 ℃으로 가온하여 용해시켜 용액을 제조하고, 60 ℃에서 1시간 동안 교반하였다.Compound 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (pelubipropene, 5 g, 19.36) prepared by the same method as described in Japanese Patent No. 1637767 mmol) and 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (pelubipropene) in a molar ratio of about 1.004 equivalents to 1.0 equivalent of 2-amino-2-( Hydroxymethyl) propane-1,3-diol (tromethamine, 2.35 g, 19.44 mmol) was added to 2-propanol (50 mL) and heated to 60° C. to dissolve to prepare a solution, and then at 60° C. for 1 hour. Stirred.
이후 저온 (0~5 ℃)으로 냉각하고 4시간 동안 교반한 후 여과하였다. 여과물을 아세톤 10 mL로 세척한 후 얻어진 고체를 60 ℃에서 진공 건조하여 펠루비프로펜 트로메타민 염을 얻었다.After cooling to low temperature (0 ~ 5 ℃), stirred for 4 hours and then filtered. The filtrate was washed with 10 mL of acetone, and the resulting solid was vacuum-dried at 60° C. to obtain pelubipropene tromethamine salt.
- 수득량: 6.1 g -Yield: 6.1 g
- 수득율: 83.0 % -Yield: 83.0%
- 순도: 97.9 %-Purity: 97.9%
비교예 1. 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산 (펠루비프로펜)의 제조Comparative Example 1. Preparation of 2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid (pelubipropene)
일본등록특허 제1637767호에 기술된 것과 동일한 방법으로 하기 화학식 1로 표시되는 2-[4-[(E)-(2-옥소사이클로헥실리덴)메틸]페닐]프로피온산 유리 염기를 제조하였다.2-[4-[(E)-(2-oxocyclohexylidene)methyl]phenyl]propionic acid free base represented by the following Formula 1 was prepared in the same manner as described in Japanese Patent No. 1637767.
이하, 실험예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 이들 실험예는 오로지 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들 실험예에 의해 한정되는 것은 아니다.Hereinafter, the configuration and effects of the present invention will be described in more detail through experimental examples. These experimental examples are for illustrative purposes only, and the scope of the present invention is not limited by these experimental examples.
실험예 1. 1H-NMR (핵자기공명) 스펙트럼 분석Experimental Example 1. 1H-NMR (nuclear magnetic resonance) spectrum analysis
본 발명의 실시예 1 내지 3에 따라 제조된 펠루비프로펜 트로메타민 염과, 비교예 1의 펠루비프로펜에 대하여 Bruker Avance II 500 (500 MHz)을 사용하여 1H-핵자기공명 (NMR) 분석을 수행하였다. 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염의 1H-핵자기공명 (NMR) 스펙트럼은 도 1에 나타냈고, 비교예 1에 따른 펠루비프로펜의 1H-핵자기공명 (NMR) 스펙트럼은 도 4에 나타냈다.For the felubiprofen tromethamine salt prepared according to Examples 1 to 3 of the present invention and the felubiprofen of Comparative Example 1, using Bruker Avance II 500 (500 MHz) 1 H-nuclear magnetic resonance ( NMR) analysis was performed. The 1 H-nuclear magnetic resonance (NMR) spectrum of the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention is shown in FIG. 1, and the 1 H-nuclear magnetic of felubiprofen according to Comparative Example 1 The resonance (NMR) spectrum is shown in FIG. 4.
펠루비프로펜 트로메타민 염Felubiprofen tromethamine salt
실시예 1)Example 1)
1H-NMR (500 MHz, CH 3OD) δ 7.46-7.38 (m, 5H), 3.66-3.61 (m, 7H), 2.88-2.85 (m, 2H), 2.51 (t, 2H), 1.96-1.91 (m, 2H), 1.81-1.76 (m, 2H), 1.45 (d, 3H). 1 H-NMR (500 MHz, CH 3 OD) δ 7.46-7.38 (m, 5H), 3.66-3.61 (m, 7H), 2.88-2.85 (m, 2H), 2.51 (t, 2H), 1.96-1.91 (m, 2H), 1.81-1.76 (m, 2H), 1.45 (d, 3H).
실시예 2) Example 2)
1H-NMR (500 MHz, CH 3OD) δ 7.45-7.37 (m, 5H), 3.67-3.61 (m, 7H), 2.86-2.84 (m, 2H), 2.51 (t, 2H), 1.95-1.91 (m, 2H), 1.81-1.76 (m, 2H), 1.44 (d, 3H). 1 H-NMR (500 MHz, CH 3 OD) δ 7.45-7.37 (m, 5H), 3.67-3.61 (m, 7H), 2.86-2.84 (m, 2H), 2.51 (t, 2H), 1.95-1.91 (m, 2H), 1.81-1.76 (m, 2H), 1.44 (d, 3H).
실시예 3) Example 3)
1H-NMR (500 MHz, CH 3OD) δ 7.47-7.39 (m, 5H), 3.64-3.60 (m, 7H), 2.87-2.85 (m, 2H), 2.52 (t, 2H), 1.94-1.90 (m, 2H), 1.82-1.76 (m, 2H), 1.45 (d, 3H). 1 H-NMR (500 MHz, CH 3 OD) δ 7.47-7.39 (m, 5H), 3.64-3.60 (m, 7H), 2.87-2.85 (m, 2H), 2.52 (t, 2H), 1.94-1.90 (m, 2H), 1.82-1.76 (m, 2H), 1.45 (d, 3H).
펠루비프로펜Felubiprofen
1H-NMR (500 MHz, CH 3OD) δ 7.44-7.36 (m, 5H), 3.78-3.72 (m, 1H), 2.85-2.82 (m, 2H), 2.50 (t, 2H), 1.94-1.89 (m, 2H), 1.78-1.73 (m, 2H), 1.47 (d, 3H). 1 H-NMR (500 MHz, CH 3 OD) δ 7.44-7.36 (m, 5H), 3.78-3.72 (m, 1H), 2.85-2.82 (m, 2H), 2.50 (t, 2H), 1.94-1.89 (m, 2H), 1.78-1.73 (m, 2H), 1.47 (d, 3H).
이를 통해 본 발명의 실시예 1 내지 3에 따라 합성된 화합물은 비교예 1에 따른 펠루비프로펜과 상이함을 확인하였고, 실시예 1 내지 3에 따라 합성된 화합물은 펠루비프로펜 트로메타민 염 임을 알 수 있었다.Through this, it was confirmed that the compounds synthesized according to Examples 1 to 3 of the present invention are different from felubiprofen according to Comparative Example 1, and the compounds synthesized according to Examples 1 to 3 are pelubiprofen tromethamine. It was found that it was salt.
실험예 2. DSC (Differential scanning calorimetry, 시차주사열량계) 분석Experimental Example 2. DSC (Differential scanning calorimetry, differential scanning calorimetry) analysis
DSC는 물질의 열전이와 관련된 온도와 열흐름을 측정하기 위해 이용되는 방법이다. 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염과 비교예 1에 따른 펠루비프로펜에 대하여 TA DSC Q20을 이용하여 질소 조건 하에서 10 ℃/min으로 승온하여 측정하였고, 펠루비프로펜 트로메타민 염의 DSC 측정 그래프는 도 2에 나타내었고, 펠루비프로펜의 DSC 측정 그래프는 도 5에 나타내었다.DSC is a method used to measure the temperature and heat flow associated with the heat transfer of a material. Pelubiprofen tromethamine salt prepared according to Example 1 of the present invention and felubiprofen according to Comparative Example 1 were measured by heating at 10° C./min under nitrogen conditions using TA DSC Q20. The DSC measurement graph of rubiprofen tromethamine salt is shown in FIG. 2, and the DSC measurement graph of felubiprofen is shown in FIG. 5.
펠루비프로펜 트로메타민 염Felubiprofen tromethamine salt
흡열 피크: 123.5 ℃Endothermic Peak: 123.5 °C
펠루비프로펜Felubiprofen
흡열 피크: 111.46 ℃ Endothermic Peak: 111.46 °C
이를 통해 본 발명의 실시예 1에 따라 합성된 화합물은 비교예 1에 따른 펠루비프로펜과 상이함을 확인하였고, 실시예 1에 따라 합성된 화합물은 펠루비프로펜 트로메타민 염 임을 알 수 있었다.Through this, it was confirmed that the compound synthesized according to Example 1 of the present invention was different from the felubiprofen according to Comparative Example 1, and it was found that the compound synthesized according to Example 1 was a pelubiprofen tromethamine salt. there was.
실험예 3. FTIR (푸리에 변환 적외선 분광) 분석Experimental Example 3. FTIR (Fourier Transform Infrared Spectroscopy) Analysis
본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염과 비교예 1에 따른 펠루비프로펜에 대하여 ThermoFischer Scientific iS-10(상품명)을 사용하여 푸리에 변환 IR 스펙트럼을 수득하였고, 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염의 IR 스펙트럼을 도 3에 나타냈고, 비교예 1에 따른 펠루비프로펜의 IR 스펙트럼을 도 6에 나타냈다.Fourier transform IR spectra were obtained using ThermoFischer Scientific iS-10 (trade name) for the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention and the felubiprofen according to Comparative Example 1, and the present invention The IR spectrum of the felubiprofen tromethamine salt prepared according to Example 1 of the present invention is shown in FIG. 3, and the IR spectrum of the felubiprofen according to Comparative Example 1 is shown in FIG. 6.
도 6을 참조하면, 펠루비프로펜의 IR 스펙트럼에서 1,729 cm -1의 진동 피크는 펠루비프로펜의 카르복실기의 C=O 결합에서 기인한 것으로 예상된다.Referring to FIG. 6, the vibration peak of 1,729 cm -1 in the IR spectrum of felubiprofen is expected to be due to C=O bonding of the carboxyl group of felubiprofen.
그러나, 도 3를 참조하면, 펠루비프로펜 트로메타민 염의 스펙트럼에서는 1,670 cm -1로 진동 피크가 시프트 된 것을 확인하였다. 이는 펠루비프로펜의 C=O 결합이 트로메타민과의 염의 형성으로 인하여 COO -로 변한 것으로 인해 펠루비프로펜 트로메타민 염이 형성된 것으로 확인되었다.However, referring to FIG. 3, it was confirmed that the vibration peak shifted to 1,670 cm -1 in the spectrum of the felubiprofen tromethamine salt. It was confirmed that pelubiprofen tromethamine salt was formed because the C=O bond of felubiprofen was changed to COO − due to the formation of a salt with tromethamine.
또한, 도 3을 참조하면, 펠루비프로펜 트로메타민 염의 IR 스펙트럼에서 2,800~2,000 cm -1의 범위에 존재하는 다수의 강한 대역들은 양성자화된 아민기의 오버톤 (overtone) 및 혼합 연신 진동 (combination stretching vibration)으로부터 생성된 것으로 예상되어 펠루비프로펜 트로메타민 염이 형성된 것으로 확인되었다.In addition, referring to Figure 3, in the IR spectrum of the pelubiprofen tromethamine salt, a number of strong bands present in the range of 2,800 to 2,000 cm -1 are the overtone of the protonated amine group and the mixed stretching vibration ( combination stretching vibration), it was confirmed that pelubiprofen tromethamine salt was formed.
이를 통해 본 발명의 실시예 1에 따라 합성된 화합물은 비교예 1에 따른펠루비프로펜과 상이함을 확인하였고, 실시예 1에 따라 합성된 화합물은 펠루비프로펜 트로메타민 염 임을 유추할 수 있었다.Through this, it was confirmed that the compound synthesized according to Example 1 of the present invention was different from the pellubiprofen according to Comparative Example 1, and the compound synthesized according to Example 1 was pellubiprofen tromethamine salt. Could
실험예 4. 가혹 안정성 시험Experimental Example 4. Severe stability test
본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염과 펠루비프로펜의 가혹 안정성을 비교하였다.The severe stability of felubiprofen tromethamine salt prepared according to Example 1 of the present invention and felubiprofen was compared.
구체적으로, 가혹 조건 (80±1 ℃또는 RH 90±1 %)에서의 안정성 실험을 실시하고, 고속액체크로마토그래피 (HPLC) 분석법을 이용하여 분석하였다. 분석기기는 Agilent 1260 HPLC system을 사용하였다. 그 결과를 표 1 및 2에 나타내었다.Specifically, a stability test under severe conditions (80±1° C. or RH 90±1%) was conducted, and analyzed using high-speed liquid chromatography (HPLC) analysis. An Agilent 1260 HPLC system was used as the analyzer. The results are shown in Tables 1 and 2.
[표 1][Table 1]
Figure PCTKR2020006219-appb-img-000006
Figure PCTKR2020006219-appb-img-000006
[표 2][Table 2]
Figure PCTKR2020006219-appb-img-000007
Figure PCTKR2020006219-appb-img-000007
상기 표 1 및 2에서 볼 수 있듯이, 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염은 가혹 조건에서 높은 안정성을 나타내었다. As can be seen in Tables 1 and 2, the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention exhibited high stability under severe conditions.
구체적으로, 펠루비프로펜은 일반적인 안정성 평가 조건 하에서 개별유연물질의 기준이 0.1% 이하인데, 펠루비프로펜 트로메타민 염은 이보다 더 가혹한 조건 하에서도 21일에 기준에 적합하여 매우 안정한 물질임을 확인할 수 있었다.Specifically, felubiprofen has a standard of 0.1% or less for individual related substances under general stability evaluation conditions, and felubiprofen tromethamine salt is a very stable substance as it meets the standard on the 21st even under more severe conditions. I could confirm.
또한, 펠루비프로펜은 일반적인 안정성 평가 조건 하에서 함량 기준이 98.0% 이상인데, 펠루비프로펜 트로메타민 염은 이보다 더 가혹한 조건 하에서도 21일에 기준에 적합하여 매우 안정한 물질임을 확인할 수 있었다.In addition, felubiprofen has a content standard of 98.0% or more under general stability evaluation conditions, and felubiprofen tromethamine salt satisfies the standard on the 21st even under more severe conditions, and thus it was confirmed that it is a very stable substance.
따라서, 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염은 안정성 확보를 위한 제제연구가 별도로 필요하지 않음을 예상할 수 있다.Therefore, it can be expected that the felubiprofen tromethamine salt prepared according to Example 1 of the present invention does not require a separate formulation study for securing stability.
특히 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염은 안정성이 우수하여 취급, 보관에도 용이하며 약적학적으로도 대량생산에 매우 유용함을 확인하였다.In particular, it was confirmed that the pelubiprofen tromethamine salt prepared according to Example 1 of the present invention has excellent stability and is easy to handle and store, and is very useful for mass production in pharmaceutical terms.
실험예 5. 용해도 시험Experimental Example 5. Solubility test
본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염의 pH에 따른 물에 대한 용해도를 비교예 1에 따른 펠루비프로펜과 비교 평가하였다.The solubility of the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention in water according to the pH was compared with the pellubiprofen according to Comparative Example 1.
용해도 시험 평가 대상인 실시예 1에 따른 펠루비프로펜 트로메타민 염 (5 g) 및 비교예 1에 따른 펠루비프로펜 (5 g)을 각각 정제수 (5 mL), pH 1.2 용액 (5 mL), pH 4.0 용액 (5 mL), pH 6.8 용액 (5 mL)에 용해시킨 후, 24시간 동안 교반하고, PVDF 필터한 후, HPLC 분석법으로 검량선을 작성하고, 작성된 검량선의 일차함수로부터 포화용액의 농도를 산출하였다.Pelubiprofen tromethamine salt (5 g) according to Example 1 and felubiprofen (5 g) according to Comparative Example 1 were respectively purified water (5 mL), pH 1.2 solution (5 mL) , After dissolving in pH 4.0 solution (5 mL), pH 6.8 solution (5 mL), stirred for 24 hours, filtered with PVDF, prepare a calibration curve by HPLC analysis, and the concentration of saturated solution from the linear function of the calibration curve Was calculated.
그 결과를 하기 표 3에 나타내었다.The results are shown in Table 3 below.
[표 3][Table 3]
Figure PCTKR2020006219-appb-img-000008
Figure PCTKR2020006219-appb-img-000008
상기 표 3을 참조하면, 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염은 비교예 1에 따른 펠루비프로펜 보다 다양한 pH 조건에서 108 내지 21,807배 용해도가 우수한 것을 확인하였다.Referring to Table 3, it was confirmed that the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention has an excellent solubility of 108 to 21,807 times in various pH conditions than the felubiprofen according to Comparative Example 1. .
특히, 표 3에서 비교예 1에 따른 펠루비프로펜의 용해도를 살펴보면, 비교예 1에 따른 펠루비프로펜은 염기성 pH에서 용해도가 높은 산성 약물이기 때문에 산성 (pH 1.2) 조건에서 용해도가 0.03 mg/mL으로 가장 낮음을 확인하였다. 그러나, 펠루비프로펜과 트로메타민이 염을 형성함으로써 산성 (pH 1.2) 조건에서 용해도가 약 21,807배 증가함을 확인하였다.In particular, looking at the solubility of felubiprofen according to Comparative Example 1 in Table 3, felubiprofen according to Comparative Example 1 is an acidic drug with high solubility at a basic pH, so the solubility in acidic (pH 1.2) conditions is 0.03 mg. It was confirmed to be the lowest in /mL. However, it was confirmed that the solubility was increased by about 21,807 times in the acidic (pH 1.2) condition by the formation of salts of felubiprofen and tromethamine.
이처럼 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염이 다양한 pH 조건에서 용해도가 우수하다는 것은 경구 투여용 고형 제제로의 완제 의약품의 제조공정에 있어 특별한 곤란함을 가중하지 않는다는 이점이 있다.As described above, the excellent solubility of the pellubiprofen tromethamine salt prepared according to Example 1 of the present invention under various pH conditions does not add to any particular difficulties in the manufacturing process of the finished drug product as a solid preparation for oral administration. There is an advantage.
또한, 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염은 다양한 pH 조건에서 용해도가 우수하기 때문에 액상 제제로 제조가 가능하며, 액상 제제로 제조함에 따라 어른부터 어린아이들까지 적정 용량으로 복용이 가능함은 물론, 파우치에 포장된 제제의 경우 휴대하기 편리하여 복용편의성을 증진시킬 수 있다는 장점이 있다.In addition, pelubiprofen tromethamine salt prepared according to Example 1 of the present invention can be prepared as a liquid formulation because it has excellent solubility under various pH conditions. In addition to being able to be taken in a dose, the formulation packaged in a pouch has the advantage of being convenient to carry and improving ease of use.
실험예 6. 위장관 부작용 개선 효력 시험Experimental Example 6. Gastrointestinal side effect improvement effect test
1. 동물 실험1. Animal testing
수컷 Sprague Dawley 랫 (6주령, 160~240 g)을 오리엔트바이오 (Orient Bio, Sungnam, Gyeonggi-do, South Korea)에서 구입하고, ㈜노터스 (Guri, Gyeonggi-do, South Korea)에서 동물 실험을 수행하였다. 동물 입수 후 1주일 동안 모든 수컷 Sprague Dawley 랫들은 물과 음식을 자유롭게 섭취하였다. 상기 수컷 Sprague Dawley 랫을 한 그룹당 10마리씩 3군으로 분리하였다.Male Sprague Dawley rats (6 weeks old, 160-240 g) were purchased from Orient Bio (Sungnam, Gyeonggi-do, South Korea), and animal experiments were conducted at Notus (Guri, Gyeonggi-do, South Korea). Performed. For one week after animal acquisition, all male Sprague Dawley rats were free to consume water and food. The male Sprague Dawley rats were separated into 3 groups of 10 animals per group.
구체적으로, 투약 전 랫의 체중을 측정하여 평균체중으로 산출하고, 0.5 % CMC에 시험약물인 펠루비프로펜 300 mg/kg과 펠루비프로펜 트로메타민 염 440.7 mg/kg (펠루비프로펜으로서 300 mg/kg)을 현탁하였다.Specifically, the rat's body weight was measured before administration and calculated as the average weight, and the test drug felubiprofen 300 mg/kg and pelubiprofen tromethamine salt 440.7 mg/kg (pelubiprofen As 300 mg/kg) was suspended.
G1군은 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염과 비교예 1에 따른 펠루비프로펜을 투약하지 않은 군이며, G2군은 비교예 1에 따른 펠루비프로펜 300 mg/kg을 투여한 군이고, G3군은 본 발명의 실시예 1에 따라 제조된 펠루비프로펜 트로메타민 염 440.7 mg/kg을 투여한 군이다.G1 group is a group that was not administered pelubiprofen tromethamine salt prepared according to Example 1 of the present invention and felubiprofen according to Comparative Example 1, and group G2 was pelubiprofen according to Comparative Example 1. 300 mg/kg was administered, and G3 was a group administered with 440.7 mg/kg of felubiprofen tromethamine salt prepared according to Example 1 of the present invention.
약물 투여 48시간 전부터 절식을 시작하였다. 실험동물을 경배부 피부 고정법으로 고정하고, 경구 투여용 존데 (oral zonde)를 이용하여 G2 및 G3군의 랫의 위 내에 직접 투여 하였다. 약물 투여 6시간 후 디에틸에테르로 마취한 후, 위를 적출하여 위 점막면을 디지털카메라로 촬영하였다.Fasting was started 48 hours before drug administration. The experimental animals were fixed by the cervical skin fixation method, and administered directly into the stomach of the rats of the G2 and G3 groups using an oral zonde. After 6 hours of drug administration, anesthesia was performed with diethyl ether, the stomach was removed, and the gastric mucosa was photographed with a digital camera.
2. 결과분석2. Result analysis
디지털카메라로 촬영한 이미지 자료를 분석하였다. 위점막의 손상된 부위 면적은 Image J software (NIH, Bethesda, MD)를 이용하여 분석하였다. 분석결과는 표 4 및 도 7에 나타내었다.Image data taken with a digital camera were analyzed. The area of the damaged area of the gastric mucosa was analyzed using Image J software (NIH, Bethesda, MD). Analysis results are shown in Table 4 and FIG. 7.
[표 4][Table 4]
Figure PCTKR2020006219-appb-img-000009
Figure PCTKR2020006219-appb-img-000009
표 4 및 도 7을 참조하면, 본 발명의 실시예 1에 따른 펠루비프로펜 트로메타민 염을 투여한 G3 군은 비교예 1에 따른 펠루비프로펜을 투여한 G2군 대비 위 손상이 현저히 감소되었음을 확인하였다.Referring to Table 4 and FIG. 7, the G3 group administered with the felubiprofen tromethamine salt according to Example 1 of the present invention had significantly greater gastric damage compared to the G2 group administered with the pellubiprofen according to Comparative Example 1. It was confirmed that it was reduced.

Claims (13)

  1. 하기 화학식 2로 표시되는 펠루비프로펜 트로메타민 염:Felubiprofen tromethamine salt represented by the following formula (2):
    [화학식 2][Formula 2]
    Figure PCTKR2020006219-appb-img-000010
    .
    Figure PCTKR2020006219-appb-img-000010
    .
  2. 제1항에 있어서, 123.5±2 ℃에서 시차주사열량 (DSC) 흡열 피크를 갖는 것인 펠루비프로펜 트로메타민 염.The pellubiprofen tromethamine salt according to claim 1, which has a differential scanning calorie (DSC) endothermic peak at 123.5±2°C.
  3. (a) 펠루비프로펜과 트로메타민을 유기용매 중에서 반응시키는 단계;(a) reacting felubiprofen and tromethamine in an organic solvent;
    (b) 반용매를 첨가하여 하기 화학식 2로 표시되는 펠루비프로펜 트로메타민 염을 형성하는 단계; 및(b) adding an anti-solvent to form a felubiprofen tromethamine salt represented by the following formula (2); And
    (c) 여과하고 건조하는 단계를 포함하는, 하기 화학식 2로 표시되는 제1항의 펠루비프로펜 트로메타민 염의 제조방법:(c) a method for preparing the pelubiprofen tromethamine salt of claim 1 represented by the following formula (2), including filtering and drying:
    [화학식 2][Formula 2]
    Figure PCTKR2020006219-appb-img-000011
    .
    Figure PCTKR2020006219-appb-img-000011
    .
  4. 제3항에 있어서, 상기 단계 (a)는 펠루비프로펜을 유기용매와 혼합한 후 트로메타민을 첨가하여 반응시키는 단계 또는 트로메타민을 유기용매와 혼합한 후 펠루비프로펜을 첨가하여 반응시키는 것인 제조방법.The method of claim 3, wherein the step (a) is a step of reacting by mixing felubiprofen with an organic solvent and then adding tromethamine, or mixing tromethamine with an organic solvent and then adding pelubiprofen. The manufacturing method of reacting.
  5. 제3항에 있어서, 상기 단계 (a)의 트로메타민은 펠루비프로펜 1.0 당량에 대하여 0.8 내지 1.5 당량의 몰비로 첨가되는 제조방법.The method of claim 3, wherein the tromethamine of step (a) is added in a molar ratio of 0.8 to 1.5 equivalents based on 1.0 equivalent of felubiprofen.
  6. 제3항에 있어서, 상기 단계 (a)의 유기용매는 메탄올, 에탄올, 2-프로판올, 부탄올, 아세톤, 에틸아세테이트, 메틸렌 클로라이드 및 이들의 혼합 용매로 구성된 군에서 선택되는 것인 제조방법.The method of claim 3, wherein the organic solvent in step (a) is selected from the group consisting of methanol, ethanol, 2-propanol, butanol, acetone, ethyl acetate, methylene chloride, and a mixed solvent thereof.
  7. 제3항에 있어서, 상기 단계 (b)의 반용매는 아세톤, 메틸에틸케톤, 에틸아세테이트, n-헥산, 이소프로필 에테르, 이소프로필 알코올 및 이들의 혼합 용매로 구성된 군에서 선택되는 것인 제조방법.The method of claim 3, wherein the anti-solvent in step (b) is selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, n-hexane, isopropyl ether, isopropyl alcohol, and a mixed solvent thereof. .
  8. (a) 펠루비프로펜과 트로메타민을 유기용매 중에서 반응시켜 하기 화학식 2로 표시되는 펠루비프로펜 트로메타민 염을 형성하는 단계; 및(a) reacting felubiprofen and tromethamine in an organic solvent to form a felubiprofen tromethamine salt represented by the following formula (2); And
    (b) 여과하고 건조하는 단계를 포함하는, 하기 화학식 2로 표시되는 제 1항의 펠루비프로펜 트로메타민 염의 제조방법:(b) a method for preparing the pelubiprofen tromethamine salt of claim 1 represented by the following formula (2), including filtering and drying:
    [화학식 2][Formula 2]
    Figure PCTKR2020006219-appb-img-000012
    Figure PCTKR2020006219-appb-img-000012
  9. 제1항에 따른 펠루비프로펜 트로메타민 염을 유효성분으로 함유하는 염증성 질환의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for the prevention or treatment of inflammatory diseases containing felubiprofen tromethamine salt according to claim 1 as an active ingredient.
  10. 제9항에 있어서, 상기 염증성 질환은 피부염, 급성 또는 만성 상기도염, 해열, 염증성 장질환, 천식, 골관절염, 류마티스 관절염, 기관지염, Th-2형 자기면역질환, 전신성 에리테마토데스, 중증 근무력증, 만성 GVHD, 클론병, 변형성 척추염, 요통, 통풍, 수술 외상 후의 염증, 종창의 완해, 신경통, 인후두염, 방광염, 간염, B형 간염, C형 간염 및 동맥경화로 이루어진 군에서 선택된 어느 하나 이상인 것인 염증성 질환의 예방 또는 치료용 약학적 조성물.The method of claim 9, wherein the inflammatory disease is dermatitis, acute or chronic upper respiratory tract infection, fever, inflammatory bowel disease, asthma, osteoarthritis, rheumatoid arthritis, bronchitis, Th-2 type autoimmune disease, systemic erythematodes, myasthenia gravis, Chronic GVHD, clonal disease, degenerative spondylitis, low back pain, gout, post-operative inflammation, swelling relief, neuralgia, pharyngitis, cystitis, hepatitis, hepatitis B, hepatitis C, and arteriosclerosis. Pharmaceutical composition for the prevention or treatment of inflammatory diseases.
  11. 제1항에 따른 펠루비프로펜 트로메타민 염을 포함하는 약학적 조성물의 치료학적으로 유효한 양을 투여하는, 염증성 질환의 예방 또는 치료 방법.A method for preventing or treating inflammatory diseases, by administering a therapeutically effective amount of a pharmaceutical composition comprising the felubiprofen tromethamine salt according to claim 1.
  12. 염증성 질환의 예방 또는 치료용 약제의 제조를 위한 제1항에 따른 펠루비프로펜 트로메타민 염을 포함하는 약학적 조성물의 용도.Use of a pharmaceutical composition comprising a felubiprofen tromethamine salt according to claim 1 for the manufacture of a medicament for the prevention or treatment of inflammatory diseases.
  13. 염증성 질환의 예방 또는 치료를 위한 제1항에 따른 펠루비프로펜 트로메타민 염을 포함하는 약학적 조성물의 용도.Use of a pharmaceutical composition comprising a felubiprofen tromethamine salt according to claim 1 for the prevention or treatment of inflammatory diseases.
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