Ionic bond compound of pelubiprofen and tramadol, composition containing same and preparation method of ionic bond compound

Abstract

Ionic bond compounds of pelubiprofen and tramadol, compositions comprising the same, and methods of making the same are provided.

Description

Technical Field

[0001] The present invention relates to a novel compound in which pebbiprofen and tramadol are ionically bonded, a composition containing the novel compound and a preparation method thereof. Background Art

[0002] Pelubiprofen is a non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic pharmacological effects. NSAIDs such as plubiprofen inhibit the function of cyclooxygenase (COX), which is necessary for the synthesis of prostaglandins (PG), thereby regulating inflammatory responses and inflammatory mediators, thereby reducing pain sensation. The side effects of NSAIDs are mainly caused by the inhibition of COX-1, which is responsible for maintaining homeostasis, such as protecting the gastrointestinal mucosa, maintaining renal blood flow, and regulating platelet activity; however, if COX-2 is inhibited, cardiovascular side effects will also occur, so it is necessary to control COX-1 and COX-2 in an appropriate ratio. It is known that plubiprofen controls COX-1 and COX-2 in an appropriate ratio of about 3:7.

[0003] Tramadol is an opioid analgesic used primarily for moderate to severe acute and chronic pain that affects the central nervous system, which is equivalent to a non-narcotic analgesic. Tramadol has analgesic effects through two mechanisms, one of which is a non-narcotic effect that stimulates serotonin secretion and inhibits the reuptake of norepinephrine and serotonin to inhibit pain, and the other is to act on μ receptors, one of the opioid receptors, to inhibit pain. Possible side effects of long-term or high-dose use of tramadol include serotonin syndrome, which is caused by increased serotonin concentrations. The main symptoms of serotonin syndrome include: neuromuscular symptoms such as tremor, cramps, muscle stiffness, and inability to maintain correct posture; high fever and mental symptoms such as anxiety and agitation; and symptoms of autonomic nervous system dysfunction, such as blood pressure fluctuations, tachycardia, sweating, diarrhea, and nausea. Other side effects that may occur with long-term or high-dose use of tramadol include drowsiness, dizziness, drowsiness, confusion, and insomnia related to opioid receptors.

[0004] In 2001, a tablet containing acetaminophen and tramadol hydrochloride as active ingredients was developed (Ultracet, Janssen) to compensate for the short duration of acetaminophen's efficacy and the side effects caused by high-dose tramadol; however, the problem of acetaminophen's hepatotoxicity and other side effects of tramadol still exists, and only a simple combination of acetaminophen and tramadol hydrochloride exists, that is, a single compound in which the two active ingredients are ionically bonded, such as an ionic compound of pelubiprofen and tramadol, is not disclosed.

[0005] International Publication No. WO2011-015360 relates to salts of desmethyl-tramadol and COX inhibitors, but does not disclose a specific preparation example of a compound combined with pelubiprofen. Desmethyl-tramadol is an active metabolite of tramadol, and is structurally different from tramadol in that the methoxy group of tramadol is replaced by a hydroxyl group. This structural difference affects ionic bonds, making it difficult to form ionic compounds.

[0006] Korean Patent Publication No. 10-2013-0129070 relates to salts of diclofenac and tramadol, but does not disclose an ionic compound of peglubiprofen and tramadol. Unlike diclofenac having a phenylacetic acid group, peglubiprofen has a 2-phenylpropionic acid group with a different structure, and since they are different compounds with different charges, it is difficult to predict whether an ionic bond will be formed. In addition, as the size of each molecule increases, it is difficult to form an ionic bond due to steric hindrance, and peglubiprofen forms a steric hindrance because it has a methyl group near the carboxylic acid group that forms an ionic bond, making it more difficult to form an ionic bond than diclofenac.

[0007] Meanwhile, tramadol is used in the form of tramadol hydrochloride due to the instability of the free base form, and tramadol hydrochloride shows high water solubility; however, peglucibirofen is a poorly soluble drug with low water solubility, so there are many difficulties in developing a pharmaceutical product that can have the effects of two pharmacologically active ingredients. Unexpectedly, the present inventors have completed the present invention by developing a pharmaceutical product that can have the effects of two pharmacologically active ingredients while improving the physicochemical stability by preparing peglucibirofen as an ionic compound with tramadol. Summary of the invention

[0008] Technical issues

[0009] One aspect is to provide a novel ionic compound having improved physicochemical properties by combining peblubiprofen and tramadol via a non-covalent bond.

[0010] Another aspect is to provide a pharmaceutical composition for treating pain, comprising an ionic compound of peblubiprofen and tramadol as active ingredients.

[0011] Another aspect is to provide a method for preparing an ionic compound of peblubiprofen and tramadol.

[0012] Technical solutions to the problem

[0013] The invention provides an ionic compound of peblubiprofen and tramadol.

[0014] In a specific embodiment, pebbiprofen and tramadol are combined in a 1:1 molar ratio.

[0015] The present invention also provides a pharmaceutical composition for treating pain, comprising an ionic compound of peblubiprofen and tramadol as active ingredients.

[0016] In a specific embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives selected from disintegrants, diluents, binders, glidants and any combination thereof.

[0017] The present invention also provides a method for preparing the ionic compound of peblubiprofen and tramadol.

[0018] In a specific embodiment, the method comprises:

[0019] (1) dissolving tramadol free base to obtain a solution; and

[0020] (2) Adding pebbleprofen to the solution to obtain a solid reactant.

[0021] In a specific embodiment, in step (1), tramadol free base is obtained by extracting a solution of tramadol hydrochloride with an organic solvent to obtain an organic layer, and then washing, drying and filtering the organic layer.

[0022] Other purposes and advantages of the present application will be more clearly understood through the claims and the specification of the present invention. Since the contents not described in this specification are completely recognizable and inferable to those skilled in the art of the present application or similar technical fields, the description thereof is omitted.

[0023] Beneficial Effects of the Invention

[0024] The novel ionic compound of peblubiprofen and tramadol of the present invention is a compound in which two pharmacologically active ingredients are combined in a certain stoichiometric ratio, which has improved physicochemical properties such as dissolution rate, hygroscopicity and stability compared with a physical mixture of the two ingredients. In addition, the compound of the present invention has various advantages in formulation and preparation compared with a physical mixture of the two ingredients, and also provides an economic advantage because the process of formulating a single compound is generally simpler and easier than formulating two types of compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Shown are the results of measuring Fourier transform infrared spectra of pelupiprofen and tramadol ion compounds (peelupiprofen and tramadol salt), tramadol free base, tramadol hydrochloride, and pelupiprofen.

[0026] Figure 2The results of measuring the stability of properties of Example 1 and Comparative Example 1 over time under high temperature (80±1° C.) conditions are shown.

[0027] Figure 3 The results of measuring the stability of properties of Example 1 and Comparative Example 1 over time under high humidity (90±1%) conditions are shown. DETAILED DESCRIPTION

[0028] Hereinafter, the present invention will be described in more detail.

[0029] Unless otherwise defined, all technical terms used in the present invention are used with the same meaning as those commonly understood by those skilled in the art related to the present invention. In addition, although preferred methods or samples are described in this specification, similar or equivalent methods or samples are also included in the scope of the present invention. The contents of all publications cited as references in this specification are all incorporated herein by reference.

[0030] The term "ionic bond" as used in this specification is a chemical bond obtained by electrostatic attraction between cations and anions. More specifically, an ionic bond refers to a chemical bond in which one or more electrons are completely transferred from one atom to another, turning a neutral atom into a charged ion, and then the cation and anion are combined by electrostatic attraction.

[0031] As used herein, the term "ionic bonding compound" refers to a compound formed by ionic bonding, in which ions with opposite charges are sequentially arranged by ionic bonds due to electrostatic forces, and the compound is also referred to as an "ionic compound". Preferably, the ionic compound according to the present invention refers to a single compound in which ions of two or more active drug molecules are bonded by ionic bonds.

[0032] The ionic compound according to the present invention is a combination of ions with opposite charges, and is therefore different from a co-crystal state in which the ions are combined by weak bonding forces (e.g., nonionic bonds or non-covalent bonds between molecules), and is also different from a co-crystal in which an inactive molecule (i.e., a coformer) is included in the molecules forming the crystal.

[0033] "Pelubiprofen" is the common name of the compound (±)-(E)-2-[4-(2-(OXo-cyclohexylidenemethyl)-phenyl]propionic acid. Pelubiprofen is a poorly soluble drug with a water solubility of about 0.092 mg / mL.

[0034] "Tramadol" is the common name for the compound 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol. The water solubility of tramadol is about 0.75 mg / mL, and the water solubility of tramadol hydrochloride is about 100 to 1000 mg / mL (freely soluble).

[0035] The compound of peglucibirofen and tramadol according to a specific embodiment of the present invention is a solid substance in which peglucibirofen and tramadol are preferably bound by a non-covalent bond, more preferably an ionic compound formed by an ionic bond.

[0036] Solid substances composed of two or more molecules can be prepared in the form of cocrystals, solvates, hydrates, salts, etc., depending on the nature of the molecular compounds. Generally, ionic bonds are formed when there is a large difference in electronegativity between two elements (e.g., between metals and nonmetals or between nonmetallic substances).

[0037] In a preferred embodiment, the compound according to the present invention is an ionic compound prepared in the form of a salt. The compound produced in the form of a salt has the components arranged based on ion pairing and is formed by an acid-base reaction in which a proton is transferred from an acid to a base. The compound according to a specific embodiment of the present invention is an ionic compound produced in the form of a salt by an acid-base reaction in which a proton is transferred from pebbleprofen to tramadol.

[0038] The compound of peblubiprofen and tramadol according to a specific embodiment of the present invention is different from a general salt compound or an ionic compound in that two pharmacologically active ingredients are bound by an ionic bond.

[0039] In addition, ionic compounds of various drugs, such as the compounds according to specific embodiments of the present invention, are more difficult to prepare than general salt compounds due to the chemical structure, charge difference and steric hindrance of the molecular compounds that form ionic bonds, and it is difficult to predict whether ionic bonds will be formed and the molecular structure of the compound without actual preparation.

[0040] In addition, the compound according to the specific embodiment of the present invention is significantly different from a combination in which two or more pharmacologically active ingredients are simply physically mixed in that the two different pharmacologically active ingredients are bound by ionic bonds to form a compound. For example, in a combination, two different drug molecules are mixed without forming a specific bond, but in a compound according to a specific embodiment of the present invention, the two different pharmacologically active ingredients form a specific bond, preferably a non-covalent bond, more preferably an ionic bond, to form a compound.

[0041] More specifically, in the ionic compound of peglucibirofen and tramadol according to a specific embodiment of the present invention, two active pharmaceutical ingredients (API) peglucibirofen and tramadol are combined in the form of ions having opposite charges, i.e., in the form of peglucibirofen anion and tramadol cation, thereby forming a salt.

[0042] In a specific embodiment, the ionic compound is a compound in which two different drug molecules are combined in a stoichiometric ratio. In a specific embodiment, pebbiprofen and tramadol are combined in a 1:1 molar ratio.

[0043] In the ionic compound of peblubiprofen and tramadol according to a specific embodiment of the present invention, the two pharmacologically active ingredients appear as one compound until the preparation process of the drug product or before taking the drug, wherein after taking the drug product, each pharmacologically active ingredient is substantially separated in the body before reaching the pharmacologically active site, thereby being able to exhibit each pharmacological action.

[0044] In the ionic compound according to a specific embodiment of the present invention, since two or more pharmacologically active ingredients appear as one compound during the preparation process, problems that may occur when simply mixing them and making them into a solid form (such as a tablet), such as uneven distribution of each ingredient, can be solved.

[0045] In addition, when peglucibirofen and tramadol are prepared as a simple mixture, it is difficult to ensure the quality stability of the drug product due to their low physicochemical stability. For example, when peglucibirofen and tramadol hydrochloride are simply mixed and stored for a long time under high temperature conditions, they change color to dark yellow, and when stored under humid conditions, they obtain a liquid or viscous form (see Experimental Example 3). In a specific embodiment of the present invention, this physicochemical instability is solved by providing a novel compound in which peglucibirofen and tramadol are ionically bonded.

[0046] In addition, the ionic compound of peblubiprofen and tramadol according to a specific embodiment of the present invention shows improvements in physicochemical properties such as stability, hygroscopicity, solubility and dissolution rate compared to a mixture of various pharmacologically active substances simply mixed. Due to these improved physicochemical properties, the compound of the present invention provides various unexpected advantages in pharmaceutical formulations compared to physical mixtures. In addition, economic advantages are also provided because the process of formulating a single compound is overall simpler and easier than formulating two drugs.

[0047] Another aspect provides a pharmaceutical composition for treating pain, comprising an ionic compound of peblubiprofen and tramadol as active ingredients.

[0048] In specific embodiments, the pharmaceutical composition may comprise a therapeutically effective amount of an ionic compound of peblubiprofen and tramadol.

[0049] In specific embodiments, the pharmaceutical composition can be formulated as a composition for oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration.

[0050] In a specific embodiment, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable additives selected from disintegrants, diluents, binders, lubricants and any combination thereof. The additives are any substances known to those skilled in the art that can be used to prepare dosage forms, and their components and amounts can be adjusted as needed, for example, depending on the formulation form of the dosage form or on the method of administration of the drug.

[0051] Another aspect provides the use of an ionic compound of peblubiprofen and tramadol for treating pain.

[0052] Another aspect provides a method for treating pain comprising administering to a subject an ionic compound of peblubiprofen and tramadol.

[0053] In a specific embodiment, the dosage of the ionic compound or the pharmaceutical composition comprising the ionic compound is an amount effective for treating pain in the subject, and the dosage administered can be appropriately increased or decreased by a specialist taking into account various relevant factors such as the subject's weight, age, sex, health status, diet, administration time, administration method, and severity of the disease.

[0054] In specific embodiments, pain treatment includes reducing, inhibiting, eliminating, alleviating, or preventing pain.

[0055] As used herein, the term "treat," ...

[0056] As used herein, the term "preventing" refers to preventing a disease, eg, preventing a disease, condition or disorder in a subject who may be susceptible to the disease, condition or disorder but who does not yet experience or show symptoms or signs of the disease.

[0057] As used herein, the terms "subject," "individual," or "patient" include living mammalian organisms, such as primates, humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, guinea pigs, or transgenic species thereof.

[0058] The term "effective" as used herein means sufficient to achieve a desired, expected or anticipated result, as such term is used in the specification and / or claims. When used in the context of treating a patient or subject with a compound, the term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" means an amount of the compound sufficient to achieve treatment or prevention of the disease when the compound is administered to a subject, individual, or patient to treat or prevent the disease.

[0059] As used herein, the term "pharmaceutically acceptable" means a form that is suitable, within the scope of sound medical judgment, for use in contact with the tissues, organs and / or body fluids of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications proportional to a reasonable benefit / risk ratio.

[0060] Another aspect provides:

[0061] A method for preparing an ionic compound of pebbleprofen and tramadol, the method comprising:

[0062] (1) dissolving tramadol free base to obtain a solution; and

[0063] (2) Adding pebbleprofen to the solution to obtain a solid reactant.

[0064] In a specific embodiment, in step (1), tramadol free base can be obtained by extracting a solution of tramadol hydrochloride with an organic solvent to obtain an organic layer, and then washing, drying and filtering the organic layer. For example, tramadol free base can be obtained by washing the organic layer with an aqueous sodium chloride solution and removing water using sodium sulfate to dry.

[0065] In a specific embodiment, the tramadol free base in step (1) can be a trans-form, a cis-form or a racemic mixture thereof.

[0066] In a specific embodiment, the tramadol free base in step (1) can be obtained in the form of an oily solution.

[0067] In a specific embodiment, in step (2), a solid reactant can be obtained by adding pebbiprofen in batches to a solution of tramadol free base in an organic solvent, mixing, filtering and drying.

[0068] In a specific embodiment, the organic solvent may be methyl tert-butyl ether, diethyl ether, toluene, dichloromethane or ethyl acetate, preferably methyl tert-butyl ether.

[0069] In a specific embodiment, the preparation method may further comprise: before step (1), extracting the tramadol hydrochloride solution with an organic solvent to obtain an organic layer, and then washing, drying and filtering the organic layer to obtain tramadol free base.

[0070] In a specific embodiment, the solution of tramadol hydrochloride can be obtained by adding and mixing an organic solvent and sodium hydroxide into an aqueous solution of tramadol hydrochloride.

[0071] In a specific embodiment, the organic solvent may be methyl tert-butyl ether, diethyl ether, toluene, dichloromethane or ethyl acetate, preferably methyl tert-butyl ether.

[0072] The ionic compound of peglucibirofen and tramadol prepared in this manner is a substance in which two pharmacologically active ingredients are combined, which not only exhibits a pain suppressing effect, but also exhibits improved physicochemical properties in terms of phase stability, impurity generation and solubility compared to a physical mixture of the two ingredients such as a simple mixture of peglucibirofen and tramadol hydrochloride, and is therefore more useful as a pharmaceutical raw material. In addition, an economic advantage is also provided because the process of formulating a single compound is overall simpler and easier than preparing two drug substances having different physicochemical properties into a single tablet.

[0073] The above process is only an embodiment according to the present invention, and some steps in the present invention may be omitted or repeated. In some cases, the order of the steps may be appropriately changed.

[0074] The terms “having”, “may have”, “including” or “may include” used in the present specification indicate the presence of corresponding features (eg, elements such as values ​​or components), and do not exclude the presence of other features.

[0075] As used herein, the term "comprising" does not limit the invention to exclude any changes or additions. In addition, although the invention is described as "comprising", the methods, materials and compositions described herein may also be described as "consisting essentially of" or "consisting of..."

[0076] As used herein, the singular forms "a", "an", "an", and "an" may mean one or more than one, and when the word "comprising" is used in conjunction with "including", the word may mean one or more than one.

[0077] As used herein, the term "or" may include "and / or" unless explicitly stated to refer to only alternatives, or unless the alternatives are mutually exclusive.

[0078] The numerical range represented by the term "to" as used herein includes a range in which the numbers described before and after the term "to" represent the lower limit and the upper limit, respectively.

[0079] In addition, it will be appreciated by those skilled in the art that deviations in numerical values ​​are possible. Therefore, whenever a numerical value is mentioned in the specification or claims, it is understood that additional values ​​associated with or approximate to the numerical value are also within the scope of the present invention. Therefore, even if not explicitly stated, the numerical values ​​described in this specification are considered to include the meaning of "about". The term "about" or "approximately" means that the value mentioned can vary to a certain extent. For example, the value can vary by 10%, 5%, 2% or 1%. For example, "about 5" means any value included between 4.5 and 5.5, between 4.75 and 5.25, between 4.9 and 5.1, or between 4.95 and 5.05.

[0080] [Example]

[0081] Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are only intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

[0082] Example 1. Preparation of ionic compounds of pelubiprofen and tramadol

[0083] (1) Preparation of tramadol free base

[0084] 250g of tramadol hydrochloride was placed in a 3000mL round-bottomed flask, 1000mL of water was added to dissolve tramadol hydrochloride, 1000ml of methyl tert-butyl ether and 100mL of 10NNaOH were added, and stirred for 30 minutes. Then, methyl tert-butyl ether was used to extract to obtain an organic layer, which was then washed with a saturated sodium chloride aqueous solution. Then, sodium sulfate was used to remove water and filtered, and the organic layer was concentrated to obtain 215g (98%) of tramadol free base in the form of an oily solution.

[0085] 1 H NMR(methanol-d4)δ:7.23(t,J=8.0Hz,1H),7.08(br s,1H),7.01(d,J=7.5Hz,1H),6.76(ddd,J=8.25,2.75,1.0Hz,1H),3.79(s,3H),2.30(dd,J=12.5,8.5Hz,1H),2.01(s,6H),1.94 -1.89(m,1H),1.86-1.82(m,3H),1.80-1.76(m,2H),1.73-1.68(m,1H),1.66-1.64(m,1H),1.58-1.56(m,1H),1.47-1.42(m,1H).

[0086] (2) Preparation of ionic compounds of pelubiprofen and tramadol

[0087] 215 g of tramadol free base was dissolved in 1000 mL of methyl tert-butyl ether, 189 g of peblubiprofen was added portionwise, and stirred for 16 hours. Then, the obtained solid was filtered and dried in an oven (65° C., 16 hours) to obtain 210 g (yield 96%) of an ionic compound of peblubiprofen and tramadol.

[0088] 1 H NMR(methanol-d4)δ:7.44(br s,1H),7.39(dd,J=13.0,8.0Hz,4H),7.28(t,J=8.0Hz,1H),7.10(br s,1H),7.05(d,J=7.5Hz,1H),6.81(dd,J=8.0,2.5Hz,1H),3.79(s,3H),3.62(q,J=7.0Hz,1H),2.87-2.82(m,3H),2.51-2.47(m,3H),2.50(s, 6H),2.18-2.13(m,1H),1.95-1.86(m,3H),1.83-1.74(m,5H),1.71-1. 64(m,2H),1.60-1.58(m,1H),1.50-1.45(m,1H),1.43(d,J=7.0Hz,3H).

[0089] Experimental Example 1. Fourier-transform infrared spectroscopy (FT-IR)

[0090] FT-IR analysis was performed using Thermo Fischer Scientific IS-10 to measure Fourier transform infrared spectra of the ionic compounds of pelupiprofen and tramadol obtained in Example 1. Fourier transform infrared spectra of tramadol free base, tramadol hydrochloride, and pelupiprofen were also measured using the same method.

[0091] Figure 1 Shown are the results of measuring Fourier transform infrared spectra of pelupiprofen and tramadol ion compounds, tramadol free base, tramadol hydrochloride, and pelupiprofen.

[0092] like Figure 1 As shown in FIG. 1 , the peak at 1729λ in the infrared spectrum of pelupiprofen should be due to the C=O bond of the carboxyl group of pelupiprofen, and the peak at 1030-1230λ in the infrared spectrum of tramadol free base should be due to the CN bond of tramadol. However, in the spectrum of the ionic compound of pelupiprofen and tramadol, a vibration peak shift to 1690λ was confirmed. It was confirmed that the C=O bond of the COOH functional group of pelupiprofen was changed to COO- due to the formation of an ionic bond with tramadol, thereby forming an ionic compound of pelupiprofen and tramadol.

[0093] In addition, if Figure 1 As shown, the vibration peaks at 1030-1230λ in the spectrum of the peglucirofen and tramadol ion compound are different from the vibration peaks of tramadol free base, confirming the formation of the peglucirofen and tramadol ion compound.

[0094] exist Figure 1 In the FT-IR spectrum of the ionic compound of peblubiprofen and tramadol (1:1), the absorption bands are shown at 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 702λ.

[0095] Experimental example 2. 1 H-NMR (Nuclear Magnetic Resonance) Spectroscopy Analysis

[0096] use 1 The ionic compounds of peblubiprofen and tramadol obtained in Example 1 were analyzed by H-NMR Bruker Avance II 500 (500 MHz). 1 H-NMR analysis. The same method was also used to analyze the free base of pelubiprofen and tramadol. 1 H-NMR analysis.

[0097] Ionic compounds of peblubiprofen and tramadol, free bases of peblubiprofen and tramadol 1 The results of H-NMR analysis are as follows.

[0098] (1) The ionic compound of pebbleprofen and tramadol of Example 1 1 H-NMR analysis results:

[0099] 1 H NMR(methanol-d4)δ:7.44(br s,1H),7.39(dd,J=13.0,8.0Hz,4H),7.28(t,J=8.0Hz,1H),7.10(br s,1H),7.05(d,J=7.5Hz,1H),6.81(dd,J=8.0,2.5Hz,1H),3.79(s,3H),3.62(q,J=7.0Hz,1H),2.87-2.82(m,3H),2.51-2.47(m,3H),2.50(s, 6H),2.18-2.13(m,1H),1.95-1.86(m,3H),1.83-1.74(m,5H),1.71-1. 64(m,2H),1.60-1.58(m,1H),1.50-1.45(m,1H),1.43(d,J=7.0Hz,3H).

[0100] (2) Perubiprofen 1 H-NMR analysis results:

[0101] 1 H NMR(methanol-d4)δ:7.43(t,J=2.0Hz,1H),7.39(dd,J=10.5,8.0Hz,4H),3.74(q,J=7.0Hz,1H),2.84(td,J =6.5, 2.5Hz, 2H), 2.49 (t, J = 7.0Hz, 2H), 1.94-1.89 (m, 2H), 1.78-1.73 (m, 2H), 1.46 (d, J = 7.0Hz, 3H).

[0102] (3) Tramadol free base 1 H-NMR analysis:

[0103] 1H NMR(methanol-d4)δ:7.23(t,J=8.0Hz,1H),7.08(br s,1H),7.01(d,J=7.5Hz,1H),6.76(ddd,J=8.25,2.75,1.0Hz,1H),3.79(s,3H),2.30(dd,J=12.5,8.5Hz,1H),2.01(s,6H),1.94 -1.89(m,1H),1.86-1.82(m,3H),1.80-1.76(m,2H),1.73-1.68(m,1H),1.66-1.64(m,1H),1.58-1.56(m,1H),1.47-1.42(m,1H).

[0104] In the NMR of pelupiprofen, the peak at 3.74 (q, J = 7.0 Hz, 1H) close to the C=O bond of the carboxyl group of pelupiprofen and the peak at 2.01 (s, 6H) of NMe2 in the NMR of tramadol free base were confirmed to have shifted to the peaks at 3.62 (q, J = 7.0 Hz, 1H) and 2.50 (s, 6H) in the NMR of the pelupiprofen and tramadol ionic compound, respectively. In addition, the formation of the pelupiprofen and tramadol ionic compound was also confirmed based on the difference between the NMR results of the pelupiprofen and tramadol ionic compound and the NMR results of the mixture of pelupiprofen and tramadol hydrochloride.

[0105] Comparative Example 1. Preparation of a mixture of pelubiprofen and tramadol hydrochloride

[0106] 1.3 g of peblubiprofen and 1.5 g of tramadol hydrochloride were mixed to obtain a 1:1 mixture of peblubiprofen and tramadol hydrochloride.

[0107] Experimental Example 3. Test of the stability of properties

[0108] The stability of the properties 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, and the results are shown in Figure 2 and Figure 3 middle.

[0109] (1) Comparison of the stability of properties under high temperature conditions

[0110] Figure 2 The results of measuring the stability of properties of Example 1 and Comparative Example 1 over time under high temperature (80±1° C.) conditions are shown.

[0111] like Figure 2As shown, when measured under high temperature conditions (80±1° C.), Example 1 showed almost no discoloration until 6 months, but Comparative Example 1 showed severe discoloration to dark yellow.

[0112] (2) Comparison of property stability under humid conditions

[0113] Figure 3 The results of measuring the stability of properties of Example 1 and Comparative Example 1 over time under high humidity (90±1%) conditions are shown.

[0114] like Figure 3 As shown, when measured under humid conditions (90±1%), Example 1 showed almost no property change until 6 months, but Comparative Example 1 showed a property change from a solid to an off-white viscous liquid (or an off-white sticky oil form).

[0115] Through the above results, it is confirmed that the peglucibirofen and tramadol ion compounds of the present invention show improved property stability under high temperature and humid conditions. The peglucibirofen and tramadol ion compounds of the present invention have excellent properties as pharmaceutical raw materials because the compounds are helpful for formulation research to develop into pharmaceutical products due to improved property stability.

[0116] Experimental Example 4. Strict stability test

[0117] A severe stability test was performed on Example 1 and Comparative Example 1. Specifically, the stability test was performed under severe conditions (80±1° C., 90±1%), and analyzed using high performance liquid chromatography (HPLC) analysis.

[0118] (1) HPLC analysis conditions

[0119] Detector: UV spectrophotometer (wavelength 220nm)

[0120] Column: C18 (4.6X150mm, 5μm) [X Bridge C18 5U, 4.6X150, 5μm]

[0121] Temperature: 40℃

[0122] Flow rate: 0.72mL / min

[0123] Injection volume: 20 μl

[0124] Mobile phase A: Take 1mL of phosphoric acid and add water to 2L (1->2000 water)

[0125] Mobile phase B: Take 1 mL of phosphoric acid and add acetonitrile (CAN) to 2 L (1->2000 acetonitrile)

[0126] (2) Sample preparation method and gradient conditions

[0127] Take 10 mg of the sample and place it in a 10 mL amber volumetric flask, inject 10 mL of a dilute solution (mobile phase A + mobile phase B mixed in a ratio of 2:3), and then filter to prepare the sample.

[0128] [Table 1]

[0129]

[0130] (3) Results of impurity measurement

[0131] The results of the impurity measurement according to the stringent stability test are shown in Table 2 below.

[0132] [Table 2]

[0133]

[0134] *Impurity A and Impurity B are from pelubiprofen (value: HPLC area %)

[0135] The above results confirmed that the ionic compound of peblubiprofen and tramadol of the present invention was a substance having superior stability to the mixture of Comparative Example 1.

[0136] Experimental Example 5. Solubility Test

[0137] The solubility of Example 1, Comparative Example 1 and Pelubiprofen was measured according to pH. 200 mg of each substance was weighed, dissolved in pH 1.2 (5 mL), pH 6.8 (5 mL) and purified water (5 mL), stirred, filtered with PVDF, and then confirmed by HPLC analysis. HPLC analysis was the same as that of Experimental Example 4.

[0138] After creating the calibration curve, the concentrations were calculated based on the linear function and the solubilities are shown in Table 3 below.

[0139] [Table 3]

[0140]

[0141] As shown in the above Table 3, it was confirmed that the solubility of Example 1 was significantly higher than that of Comparative Example 1 in purified water, and was slightly higher than that of Comparative Example 1 at pH 1.2.

[0142] So far, the present invention has been tested, focusing on its preferred embodiments. It will be appreciated by those skilled in the art that the present invention can be implemented in a modified form without departing from the basic features of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated by the claims rather than by the above description, and all differences within the scope of equivalence thereto should be interpreted as included in the present invention.

Claims

1. An ionic compound of pebblebiprofen and tramadol.

2. The compound according to claim 1, wherein Pelubiprofen and tramadol were combined in a 1:1 molar ratio.

3. A pharmaceutical composition for treating pain, comprising the ionic compound of peblubiprofen and tramadol according to claim 1 as an active ingredient.

4. The pharmaceutical composition according to claim 3, further comprising one or more pharmaceutically acceptable additives selected from disintegrants, diluents, binders, glidants and any combination thereof.

5. A method for preparing the ionic compound of peblubiprofen and tramadol according to claim 1, the method comprising: (1) dissolving tramadol free base to obtain a solution; and (2) Adding pebbleprofen to the solution to obtain a solid reactant.

6. The method according to claim 5, wherein: In step (1), tramadol free base is obtained by extracting a solution of tramadol hydrochloride with an organic solvent to obtain an organic layer, which is then washed, dried and filtered.

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