WO2024043661A1 - Composé de liaison ionique de pelubiprofen et de tramadol, composition le comprenant, et procédé de préparation associé - Google Patents

Composé de liaison ionique de pelubiprofen et de tramadol, composition le comprenant, et procédé de préparation associé Download PDF

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WO2024043661A1
WO2024043661A1 PCT/KR2023/012400 KR2023012400W WO2024043661A1 WO 2024043661 A1 WO2024043661 A1 WO 2024043661A1 KR 2023012400 W KR2023012400 W KR 2023012400W WO 2024043661 A1 WO2024043661 A1 WO 2024043661A1
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tramadol
felubiprofen
compound
ionic
free base
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Korean (ko)
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박은정
오준현
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대원제약 주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • It relates to a novel compound in which felubiprofen and tramadol are ionically bonded, a composition containing the same, and a method for producing the same.
  • Felubiprofen is a type of non-steroidal anti-inflammatory drug (NSAID) and has pharmacological anti-inflammatory, analgesic, and antipyretic effects.
  • NSAID drugs such as felubiprofen inhibit the function of cyclooxygenase (COX), which is required to synthesize prostaglandin (PG), thereby dulling the sensation caused by pain by regulating inflammatory responses and inflammatory mediators.
  • COX side effects are mainly caused by inhibition of COX-1, which is responsible for maintaining homeostasis such as protecting the gastrointestinal mucosa, maintaining renal blood flow, and regulating platelet activity.
  • COX-2 is inhibited, cardiovascular side effects also occur, so COX-1 and COX- It is necessary to adjust 2 to an appropriate ratio.
  • Felubiprofen is known to regulate COX-1 and COX-2 in an appropriate ratio of about 3:7.
  • Tramadol is an opioid analgesic that acts on the central nervous system and has been mainly used for severe and severe acute and chronic pain. It is a non-narcotic analgesic. Tramadol exerts analgesic effects through two mechanisms: one is a non-narcotic action that stimulates the secretion of serotonin and suppresses pain by inhibiting the reuptake of norepinephrine and serotonin, and the other is mu ( ⁇ ), one of the opioid receptors. ) It acts on receptors to suppress pain. Side effects that may occur when tramadol is taken long-term or in high doses include serotonin syndrome, which is caused by increased serotonin concentration.
  • the main symptoms of serotonin syndrome are tremors, seizures, muscle stiffness, and neuromuscular problems that make it difficult to maintain a proper posture.
  • Symptoms of dysautonomia include blood pressure fluctuations, tachycardia, sweating, diarrhea, and nausea.
  • Other side effects that may occur when tramadol is taken long-term or in high doses include symptoms related to opioid receptors, such as drowsiness, dizziness, lethargy, confusion, and insomnia.
  • WO2011-015360 relates to a salt of desmethyl-tramadol and a COX inhibitor, but does not disclose specific preparation examples for a compound combined with felubiprofen.
  • Desmethyl-tramadol is an active metabolite of tramadol and is structurally different from tramadol in that the methoxy group of tramadol is changed to a hydroxy group. This structural difference affects ionic bonding, making it difficult to produce ionic compounds.
  • Korean Patent Publication No. 10-2013-0129070 relates to salts of diclofenac and tramadol, but does not disclose ionic compounds of felubiprofen and tramadol.
  • felubiprofen is not only structurally different in that it has a 2-phenylpropanoic acid group, but is also a different compound with different charges, so it is difficult to predict whether an ionic bond will be formed.
  • Pelubiprofen forms ionic bonds more difficult than diclofenac because the methyl group is close to the carboxylic acid group that forms ionic bonds, forming steric hindrance.
  • tramadol is used in the form of tramadol hydrochloride due to the instability of the free base form.
  • Tramadol hydrochloride shows high water solubility, but felubiprofen is a poorly soluble drug with low water solubility, so it is a drug that can exhibit the effects of both pharmacologically active ingredients.
  • the present inventors completed the present invention by manufacturing felubiprofen with tramadol and an ionic compound, thereby developing a pharmaceutical that exhibits the effects of both pharmacologically active ingredients while improving physicochemical stability.
  • One aspect is to provide a novel ionic compound with improved physicochemical properties by combining felubiprofen and tramadol by a non-covalent bond.
  • Another aspect is to provide a pharmaceutical composition for treating pain containing an ionic compound of felubiprofen and tramadol as an active ingredient.
  • Another aspect is to provide a method for producing the ionic compound of felubiprofen and tramadol.
  • One aspect provides an ionic compound of felubiprofen and tramadol.
  • felubiprofen and tramadol are combined in a molar ratio of 1:1.
  • Another aspect provides a pharmaceutical composition for treating pain containing an ionic compound of felubiprofen and tramadol as an active ingredient.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives selected from the group consisting of disintegrants, diluents, binders, lubricants, and any combinations thereof.
  • Another aspect provides a method for producing the ion-binding compound of felubiprofen and tramadol.
  • the manufacturing method is
  • trimadol free base is obtained by extracting a solution of tramadol hydrochloride with an organic solvent to obtain an organic layer, which is washed, dried, and filtered.
  • the novel ionic compound of felubiprofen and tramadol of the present invention is a compound in which two pharmacologically active ingredients are combined at a constant stoichiometric ratio, and has improved physical properties in terms of dissolution rate, hygroscopicity, and stability compared to a physical mixture of the two ingredients. It has chemical properties.
  • the compound of the present invention has various advantages in terms of formulation and production compared to a physical mixture of two components, and has an economic advantage in that the process of formulating a single compound is overall simpler and easier than formulating two types of compounds. to provide.
  • Figure 1 shows the results of measuring Fourier transform IR spectra for felubiprofen and tramadol ionic compounds (felubiprofen and tramadol salts), tramadol free base, tramadol hydrochloride, and felubiprofen.
  • Figure 2 shows the results of measuring the property stability of Example 1 and Comparative Example 1 over time under high temperature (80 ⁇ 1°C) conditions.
  • Figure 3 shows the results of measuring the property stability of Example 1 and Comparative Example 1 over time under high humidity (90 ⁇ 1%) conditions.
  • ionic bond used in this specification is a cohesive bond that occurs when cations and anions are combined by electrostatic attraction. More specifically, an ionic bond refers to a type of chemical bond in which one or more electrons are completely transferred from one atom to another, changing a neutral atom into a charged ion, and positive and negative ions are bonded through electrostatic attraction.
  • ionic bonding compound used in this specification refers to a compound formed by ionic bonding and is composed of ions with opposite charges due to electrostatic force in a sequential arrangement through ionic bonding. Also referred to as “ionic compound”.
  • the ionic bonding compound according to the present invention refers to a single compound in which the ions of two or more active drug molecules are bonded through an ionic bond.
  • the ionic compound according to the present invention is distinguished from a co-crystal in that it is a bond of ions with opposite charges, which is a weak bond, for example, a nonionic bond or noncovalent bond between molecules. , It is also distinguished from co-crystals, which contain inactive molecules, that is, coformers, among the molecules constituting the crystal.
  • “Pelubiprofen” means ( ⁇ )-(E)-2-[4-(2-(oxo-cyclohexylidenemethyl)-phenyl]propionic acid (( ⁇ )-(E)-2- [4-(2-(Oxo-cyclohexylidenemethyl)-phenyl] propionic acid) refers to the common name of the compound.
  • Felubiprofen is a poorly soluble drug and has a water solubility of approximately 0.092 mg/mL.
  • tramadol is the compound 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol. Refers to the common name.
  • the water solubility of tramadol is about 0.75 mg/mL, and the water solubility of tramadol hydrochloride is about 100-1000 mg/mL (freely soluble).
  • the compound of felubiprofen and tramadol according to one embodiment of the present invention is a solid state material in which felubiprofen and tramadol are bonded, preferably by a non-covalent bond, and more preferably by an ion formed by an ionic bond. It is a binding compound.
  • Solid-state substances composed of two or more molecules can be manufactured in the form of co-crystals, solvates, hydrates, salts, etc., depending on the properties of the molecular compound.
  • ionic bonds are formed when there is a large difference in electronegativity between two elements, for example between a metal and a non-metal or between non-metallic substances.
  • the compound according to the present invention is an ionic compound prepared in the form of a salt.
  • the compound prepared in the form of a salt has each component arranged based on ion-pairing and is formed through an acid-base reaction by proton transfer from an acid to a base.
  • the compound according to one embodiment of the present invention is an ionic compound prepared in salt form through an acid-base reaction in which a proton is transferred from felubiprofen to tramadol.
  • the compound of felubiprofen and tramadol according to one embodiment of the present invention is different from general salt compounds or ionic compounds in that the two pharmacologically active ingredients are bonded by an ionic bond.
  • multi-drug ionic bond compounds such as the compound according to one embodiment of the present invention, are more difficult to manufacture than general salt compounds due to the chemical structure, charge difference, and steric hindrance of the molecular compound forming the ionic bond, and are actually manufactured. Without this, it is difficult to predict the formation of ionic bonds and the molecular structure of the compound.
  • two different pharmacologically active ingredients are combined by an ionic bond to form one compound, and therefore, two or more pharmacologically active ingredients exist simply as a physically mixed mixture. It is clearly distinguished from the combination drug.
  • a combination drug two different drug molecules are mixed without forming a specific bond, whereas in the compound according to one embodiment of the present invention, two different pharmacologically active ingredients are mixed with a specific bond, preferably a non-covalent bond. , more preferably, to form an ionic bond to form one compound.
  • the ionic binding compound of felubiprofen and tramadol is that the two active pharmaceutical ingredients (API), felubiprofen and tramadol, are in ionic form with opposite charges, that is, , felubiprofen anion and tramadol cation combine to form a salt.
  • API active pharmaceutical ingredients
  • the ionic compound is a compound in which two different drug molecules are combined at a constant stoichiometric ratio.
  • felubiprofen and tramadol are combined in a molar ratio of 1:1.
  • the two pharmacologically active ingredients act as one compound during the manufacturing process of the drug or before taking the drug, but reach the pharmacologically active site after taking the drug. Before doing so, each pharmacologically active ingredient can be substantially separated in the body to exhibit its respective medicinal effects.
  • two or more pharmacologically active ingredients behave as one compound during the manufacturing process, so problems that may arise when simply mixing them and manufacturing them in a solid form such as tablets, for example, each ingredient Distribution unevenness can be resolved.
  • the ionic compound of felubiprofen and tramadol shows improvements in physicochemical properties such as stability, hygroscopicity, solubility, and dissolution rate compared to a mixture in which each pharmacologically active substance is simply mixed. Because of these improved physicochemical properties, the compounds of the present invention offer a variety of unexpected advantages in pharmaceutical formulation over physical mixtures. In addition, it provides an economic advantage in that the process of formulating a single compound is overall simpler and easier compared to formulating two types of drugs.
  • Another aspect provides a pharmaceutical composition for treating pain containing an ionic compound of felubiprofen and tramadol as an active ingredient.
  • the pharmaceutical composition may include a therapeutically effective amount of the ionic compound of felubiprofen and tramadol.
  • the pharmaceutical composition may be formulated for oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration.
  • the pharmaceutical composition may further include one or more pharmaceutically acceptable additives selected from the group consisting of disintegrants, diluents, binders, lubricants, and any combinations thereof.
  • the excipient is any substance known to those skilled in the art to be useful in preparing the formulation, and its components and content can be adjusted as needed, for example, depending on the form to be formulated or the mode of administration of the drug.
  • Another aspect provides the use of felubiprofen and tramadol ionic compounds in the treatment of pain.
  • Another aspect provides a method of treating pain comprising administering to a subject an ionic compound of felubiprofen and tramadol.
  • the dosage of the ionic-binding compound or a pharmaceutical composition containing the same is an amount effective for the purpose of treating pain in the subject, including the subject's weight, age, gender, health condition, diet, administration time, administration method, and disease.
  • the dose can be adjusted appropriately by an expert, taking into account various related factors such as the severity of the disease.
  • treating pain includes reducing, suppressing, eliminating, ameliorating or preventing pain.
  • treatment refers to inhibiting a disease, condition or disorder in a subject experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, i.e. preventing further development of the pathology and/or symptoms, or Ameliorating a disease, e.g. ameliorating a disease, condition or disorder in a subject experiencing or exhibiting pathology or signs of the disease, condition or disorder, i.e. reversing the pathology and/or signs, e.g. disease severity This means reducing.
  • prophylaxis refers to preventing a disease, e.g., preventing a disease, condition or disorder in a subject who may be predisposed to the disease, condition or disorder but has not yet experienced or exhibited symptoms or pathology of the disease. It says what to do.
  • the term "subject”, “individual”, or “patient” refers to a living mammalian organism, such as a primate, human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or a transgenic thereof. Includes species.
  • the term “effective” means suitable to achieve a desired, expected, or intended result, as the term is used in the specification and/or claims. “Effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” when used in the context of treating a patient or subject with a compound, when the compound is administered to a subject, individual, or patient to treat or prevent a disease. means the amount of a compound that is sufficient to bring about such treatment or prevention of.
  • the term "pharmaceutically acceptable” refers to human and animal tissues, organs, and tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction, or other problems or complications proportional to a reasonable benefit/risk ratio. /Or refers to a form suitable for use in contact with body fluids.
  • the trimadol free base in step (1) may be obtained by extracting a solution of tramadol hydrochloride with an organic solvent to obtain an organic layer, which is washed, dried, and filtered.
  • the organic layer of the trimadol free base may be washed with an aqueous sodium chloride solution and dried by removing water using sodium sulfate.
  • the free base of trimadol in step (1) may be trans, cis, or a racemic mixture thereof.
  • the trimadol free base in step (1), can be obtained in the form of an oily solution.
  • the solid reactant in step (2) may be added, mixed, filtered, and dried with felubiprofen divided into fractions in an organic solvent solution of trimadol free base.
  • the organic solvent may be methyl t-butyl ether, di-ethyl ether, toluene, dichloromethane, or ethyl acetate, and preferably may be methyl t-butyl ether.
  • the production method may further include the step of extracting the tramadol hydrochloride solution with an organic solvent to obtain an organic layer and washing, drying, and filtering the tramadol hydrochloride solution to obtain trimadol free base prior to step (1).
  • the tramadol hydrochloride solution may be obtained by adding and mixing an organic solvent and sodium hydroxide to an aqueous solution of tramadol hydrochloride.
  • the organic solvent may be methyl t-butyl ether, di-ethyl ether, toluene, dichloromethane, or ethyl acetate, and preferably may be methyl t-butyl ether.
  • the ionic compound of felubiprofen and tramadol prepared as a result not only exhibits a pain suppressing effect as a substance combining two pharmacologically active ingredients, but is also more effective than a physical mixture of the two ingredients, such as a simple mixture of felubiprofen and tramadol hydrochloride. It is more useful as a pharmaceutical raw material because it can exhibit improved physicochemical properties in terms of property stability, generation of related substances, and solubility. In addition, compared to manufacturing two types of drug substances with different physicochemical characteristics into one tablet, it also provides an economic advantage in that the process of formulating a single compound is overall simple and easy.
  • terms such as “have,” “may have,” “includes,” or “may include” indicate the presence of the corresponding feature (e.g., numerical value, or component such as an ingredient). indicates, does not rule out the presence of additional features.
  • FT-IR analysis of the ion-binding compounds of felubiprofen and tramadol obtained in Example 1 was performed by measuring Fourier transform IR spectra using a Thermo Fischer Scientific IS-10. Fourier transform IR spectra were measured for tramadol free base, tramadol hydrochloride, and felubiprofen using the same method.
  • Figure 1 shows the results of measuring Fourier transform IR spectra for felubiprofen and the ionic compound of tramadol, tramadol free base, tramadol hydrochloride, and felubiprofen.
  • the vibration peak was shifted to 1690 ⁇ .
  • the absorption bands of the FT-IR spectrum of the ionic compound of felubiprofen and tramadol (1:1) are 3199, 2933, 2858, 1675, 1590, 1501, 1481, 1454, 1436, 1418, 1390, 1331. , 1270, 1254, 1202, 1144, 1115, 1041, 1016, 989, 973, 933, 875, 854, 842, 817, 755, 723 and 702 ⁇ .
  • felubiprofen 1.3 g of felubiprofen and 1.5 g of tramadol hydrochloride were mixed to form a 1:1 mixture of felubiprofen and tramadol hydrochloride.
  • Example 1 and Comparative Example 1 The property stability of Example 1 and Comparative Example 1 was confirmed. Specifically, the properties of Example 1 and Comparative Example 1 were confirmed under high temperature (80 ⁇ 1°C) and high humidity (90 ⁇ 1%) conditions, respectively, and the results are shown in Figures 2 and 3, respectively.
  • Figure 2 shows the results of measuring the property stability of Example 1 and Comparative Example 1 over time under high temperature (80 ⁇ 1°C) conditions.
  • Example 1 when measured under high temperature conditions (80 ⁇ 1°C), Example 1 showed almost no discoloration until 6 months, but Comparative Example 1 was confirmed to have severe discoloration to dark yellow.
  • Figure 3 shows the results of measuring the property stability of Example 1 and Comparative Example 1 over time under high humidity (90 ⁇ 1%) conditions.
  • Example 1 when measured under high humidity conditions (90 ⁇ 1%), Example 1 showed little change in properties until 6 months, but Comparative Example 1 changed from a solid to a yellowish-white sticky liquid (or a yellowish-white sticky oil ( It was confirmed that the appearance had changed to the form of off-white sticky oil.
  • felubiprofen and tramadol ion-binding compounds of the present invention showed improved property stability under both high temperature and high humidity conditions.
  • the ion-binding compounds of felubiprofen and tramadol of the present invention have excellent characteristics as pharmaceutical raw materials in that they facilitate formulation research for development into pharmaceuticals as their property stability is improved.
  • Example 1 A severe stability test was conducted on Example 1 and Comparative Example 1. Specifically, stability tests were conducted under harsh conditions (80 ⁇ 1°C, 90 ⁇ 1%) and analyzed using high-performance liquid chromatography (HPLC) analysis.
  • HPLC high-performance liquid chromatography
  • Mobile phase A Take 1 mL of phosphoric acid and add water to make 2 L. (1->2000 water)
  • Mobile phase B Take 1 mL of phosphoric acid and add acetonitrile (CAN) to make 2 L. (1->2000 acetonitrile)
  • Example 1 Solubility according to pH was measured for Example 1, Comparative Example 1, and felubiprofen. 200 mg of each material was weighed and dissolved in pH 1.2 (5 mL), pH 6.8 (5 mL), and purified water (5 mL), stirred, PVDF filtered, and confirmed by HPLC analysis. The HPLC analysis method is the same as in Experimental Example 4.
  • Example 1 As shown in Table 3, the solubility of Example 1 in purified water was significantly higher than that of Comparative Example 1, and at pH 1.2, it was confirmed to be slightly higher than that of Comparative Example 1.

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Abstract

L'invention concerne un composé de liaison ionique de pelubiprofen et de tramadol, une composition le comprenant, et un procédé de préparation associé.
PCT/KR2023/012400 2022-08-23 2023-08-22 Composé de liaison ionique de pelubiprofen et de tramadol, composition le comprenant, et procédé de préparation associé WO2024043661A1 (fr)

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