WO2020231146A1 - Nouveau sel de pélubiprofène, son procédé de préparation et composition pharmaceutique le comprenant - Google Patents

Nouveau sel de pélubiprofène, son procédé de préparation et composition pharmaceutique le comprenant 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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English (en)
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/zh
Publication of WO2020231146A1 publication Critical patent/WO2020231146A1/fr

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    • C—CHEMISTRY; METALLURGY
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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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

La présente invention concerne un nouveau sel de pélubiprofène, un procédé de préparation associé et une composition cosmétique le comprenant. En particulier, la présente invention concerne un nouveau sel de trométhamine de pélubiprofène, ayant une stabilité et une solubilité remarquablement supérieures à celles du pélubiprofène et ayant des effets secondaires réduits de troubles gastro-intestinaux.
PCT/KR2020/006219 2019-05-13 2020-05-12 Nouveau sel de pélubiprofène, son procédé de préparation et composition pharmaceutique le comprenant WO2020231146A1 (fr)

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WO2023080299A1 (fr) * 2021-11-08 2023-05-11 일동제약(주) Nouveau sel d'un dérivé de l'acide phénylpropionique, son procédé de production et composition pharmaceutique le contenant
TW202345815A (zh) * 2022-03-25 2023-12-01 南韓商日東製藥股份有限公司 Glp-1受體激動劑化合物之新穎鹽類、其製備方法以及包含其之醫藥組合物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6038323A (ja) * 1983-08-10 1985-02-27 Sankyo Co Ltd 眼科用消炎剤
KR20040002890A (ko) * 2001-05-31 2004-01-07 히사미쓰 세이야꾸 가부시키가이샤 경피흡수형 첩부제
KR100922519B1 (ko) * 2008-11-12 2009-10-20 대원제약주식회사 펠루비프로펜을 함유하는 용출률 및 안정성이 개선된 경구투여용 약제학적 제제
US20110105443A1 (en) * 2008-03-07 2011-05-05 Laboratories Del Dr. Esteve, S.A. Salts of memantine and cox-inhibitors and their crystal form in the treatment of pain
KR20180101353A (ko) * 2015-12-01 2018-09-12 키노인 기요기스제르 에스 베기에스제티 테르메크에크 기야라 제트알티. 카르보프로스트 및 이의 트로메타민 염의 제조 방법

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037838A1 (fr) * 1999-11-24 2001-05-31 Wakamoto Pharmaceutical Co., Ltd. Preparation aqueuse ophtalmique
CN102079717B (zh) * 2009-11-26 2014-01-22 福州乾正药业有限公司 一种二元酯酸的精氨酸盐化合物及其制备方法和药物应用
CN102743341B (zh) * 2012-07-28 2014-02-26 西安德天药业股份有限公司 右旋酮洛芬氨丁三醇缓释微粒及其制备方法和缓释制剂
JP1637767S (fr) 2018-12-03 2019-07-29

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6038323A (ja) * 1983-08-10 1985-02-27 Sankyo Co Ltd 眼科用消炎剤
KR20040002890A (ko) * 2001-05-31 2004-01-07 히사미쓰 세이야꾸 가부시키가이샤 경피흡수형 첩부제
US20110105443A1 (en) * 2008-03-07 2011-05-05 Laboratories Del Dr. Esteve, S.A. Salts of memantine and cox-inhibitors and their crystal form in the treatment of pain
KR100922519B1 (ko) * 2008-11-12 2009-10-20 대원제약주식회사 펠루비프로펜을 함유하는 용출률 및 안정성이 개선된 경구투여용 약제학적 제제
KR20180101353A (ko) * 2015-12-01 2018-09-12 키노인 기요기스제르 에스 베기에스제티 테르메크에크 기야라 제트알티. 카르보프로스트 및 이의 트로메타민 염의 제조 방법

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