Ibuprofen ionic liquid and method of making same

Abstract

The application provides an ibuprofen ionic liquid and preparation and application thereof, and particularly provides an ionic liquid, which is composed of ibuprofen and a cation; wherein the cation is selected from the group of procaine, trihexyl tetradecyl phosphonium, tetrahexyl ammonium or a combination thereof. The ionic liquid can improve water solubility or fat solubility, permeability of ibuprofen medicine, so as to improve bioavailability, further improve the therapeutic effect of ibuprofen medicine, reduce side effects, expand the application range and the like.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations; specifically, this invention provides an ibuprofen ionic liquid and a method for preparing the same. Background Technology

[0002] Ionic liquids generally refer to salts composed of anions and cations with melting points below 100°C. Ionic liquids that are liquid at room temperature are called room-temperature ionic liquids. Rogers et al. classified ionic liquids into three generations. First-generation ionic liquids are primarily used for their "tunable" physical properties; by selecting suitable anions and cations, ionic liquids with specific physical properties can be prepared, and these can serve as functional solvents. Second-generation ionic liquids are primarily used for their chemical properties; by selecting suitable counterions, "tunable" physical properties can be obtained, and ionic liquids with specific physicochemical properties can be prepared, and these can serve as functional materials with special chemical properties and good physical properties. Third-generation ionic liquids are primarily used for their biological activity; by selecting anions and cations with different properties, "tunable" physicochemical properties can be obtained, and target products with special biological activity and good physicochemical properties can be prepared.

[0003] Ibuprofen, chemically known as 2-(4-isobutylphenyl)propionic acid, is a nonsteroidal antipyretic, analgesic, and anti-inflammatory drug. It is the only children's fever reducer jointly recommended by the World Health Organization and the US FDA. It is suitable for the treatment of mild to moderate migraine attacks, as well as joint and muscle diseases such as rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. According to data released by the State Food and Drug Administration of China, ibuprofen is mainly available in solid dosage forms (tablets and capsules), with some transdermal formulations (creams and gels) also available.

[0004] The primary route of administration for solid dosage forms is oral. The drug dissolves in the gastrointestinal tract, is absorbed through the gastrointestinal epithelial cell membrane, and enters the bloodstream to exert its therapeutic effect. Therefore, the solubility and permeability of a drug directly affect its absorption. Ibuprofen is a poorly water-soluble drug, almost insoluble in water. Improving the solubility of ibuprofen can enhance its dissolution rate and properties, thereby increasing its bioavailability when administered orally.

[0005] Transdermal drug delivery systems hold promise for effectively overcoming the side effects of oral administration, such as gastrointestinal irritation, while simultaneously increasing local drug concentrations while reducing ibuprofen toxicity, thus benefiting the treatment of local diseases. Currently, in addition to oral formulations, ibuprofen is also available in transdermal formulations, such as the cream formulations developed by Sino-American Tianjin SmithKline Pharmaceutical Co., Ltd. and Harbin Pharmaceutical Group Biotechnology Co., Ltd. However, commercially available ibuprofen creams and gels have low transdermal penetration efficiency, limiting their efficacy.

[0006] In summary, there is still a need in this field to develop more types of ibuprofen formulations to improve ibuprofen's dissolution, bioavailability, penetration, and efficacy. Summary of the Invention

[0007] The purpose of this invention is to provide a novel physical form of ibuprofen and its pharmaceutical composition with high dissolution rate, bioavailability, permeability and efficacy.

[0008] In a first aspect, the present invention provides an ionic liquid composed of ibuprofen and a cation; wherein the cation is selected from the group consisting of procaine, tetrahexammonium, trihexyltetradecylphosphonium, or combinations thereof.

[0009] In another preferred embodiment, the cation is selected from the group consisting of:

[0010] Or a combination thereof.

[0011] In another preferred embodiment, the ionic liquid is a procaine-ibuprofen ionic liquid, a tetrahexammonium-ibuprofen ionic liquid, a trihexyltetradecylphosphonium-ibuprofen ionic liquid, or a combination thereof.

[0012] In another preferred embodiment, the molar ratio of ibuprofen to cation is 1:0.8-1.2, more preferably 1:1.

[0013] In another preferred embodiment, the ionic liquid has the structure shown in Formula 1, Formula 2, or Formula 3:

[0014]

[0015]

[0016] In another preferred embodiment, the ionic liquid has the structure shown in Table 1, Table 2, or Table 3 below:

[0017] Table 1

[0018]

[0019] Procaine-ibuprofen ionic liquid

[0020] Table 2

[0021]

[0022] Tetrahexammonium-ibuprofen ionic liquid

[0023] Table 3

[0024]

[0025] Trihexyltetradecylphosphonium-ibuprofen ionic liquid.

[0026] In another preferred embodiment, the procaine-ibuprofen ionic liquid has one or more features selected from the group consisting of:

[0027] (1) The glass transition temperature Tg is -30 to -2℃, preferably -20 to -10℃;

[0028] (2) The solubility in pure water is 3000-5000 μg / mL, preferably 3500-4500 μg / mL; and / or

[0029] (3) It is liquid at temperatures below 100°C, preferably below 40°C, and even more preferably below room temperature (25°C).

[0030] In another preferred embodiment, the tetrahexammonium-ibuprofen ionic liquid has one or more features selected from the group consisting of:

[0031] (1) The glass transition temperature Tg is -70 to -40℃, preferably -60 to -50℃;

[0032] (2) The oil-water partition coefficient is logP ≥ 2, preferably 2.05 ≤ logP ≤ 4, more preferably 2.2 ≤ logP ≤ 3; and / or

[0033] (3) It is liquid at temperatures below 100°C, preferably below 40°C, and even more preferably below room temperature (25°C).

[0034] In another preferred embodiment, the trihexyltetradecylphosphonium-ibuprofen ionic liquid has one or more features selected from the group consisting of:

[0035] (1) The oil-water distribution coefficient is logP ≥ 2.4, preferably 2.5 ≤ logP ≤ 4, more preferably 2.5 ≤ logP ≤ 3.5; and / or

[0036] (2) It is liquid at temperatures below 100°C, preferably below 40°C, and even more preferably below room temperature (25°C).

[0037] A second aspect of the present invention provides a method for preparing an ionic liquid as described in the first aspect of the present invention, comprising the steps of:

[0038] (a) A solution is provided, the solution comprising a first solvent and ibuprofen and a cation donor dissolved in the first solvent;

[0039] (b) Remove the first solvent from the solution to obtain an ionic liquid formed by ibuprofen and the cation donor.

[0040] In another preferred embodiment, step (a) involves mixing ibuprofen and a cationic donor in a first solvent.

[0041] In another preferred embodiment, step (a) is to mix ibuprofen dissolved in a first solvent and a cationic donor dissolved in a first solvent.

[0042] In another preferred embodiment, the molar ratio of ibuprofen to cation in step (a) is 1:0.8-1.2, more preferably 1:1.

[0043] In another preferred embodiment, the first solvent in step (a) is selected from the group consisting of water, alcohols, or combinations thereof.

[0044] In another preferred embodiment, the alcohol in step (a) is a C1-C10 alcohol, more preferably a C1-C4 alcohol, and even more preferably ethanol.

[0045] In another preferred embodiment, in step (b), the solvent removal is performed by rotary evaporation.

[0046] In another preferred embodiment, the step of stirring and / or filtering is included before step (b).

[0047] In another preferred embodiment, the step (b1) is further included before step (b): mixing the ionic liquid prepared in step (a) with a second solvent.

[0048] In another preferred embodiment, the second solvent in step (b1) is selected from the group consisting of ketones (preferably acetone) or dichloromethane.

[0049] In another preferred embodiment, step (b) further includes: removing salt from the mixed solution.

[0050] A third aspect of the present invention provides a pharmaceutical composition comprising: (a) a therapeutically effective amount of an ionic liquid as described in the first aspect of the present invention; and (b) a pharmaceutically acceptable carrier.

[0051] In another preferred embodiment, the ionic liquid accounts for 1-99% of the total weight of the pharmaceutical composition, preferably 10-80%, and more preferably 20-70%.

[0052] In another preferred embodiment, the pharmaceutically acceptable carrier is selected from the group consisting of solvents, preservatives, dyes, colorants, thickeners, surfactants, stabilizers, antioxidants, viscosity modifiers, or combinations thereof.

[0053] In another preferred embodiment, the pharmaceutical composition is a formulation.

[0054] In another preferred embodiment, the pharmaceutical composition is a dosage form selected from the group consisting of oral preparations, injectable preparations, and topical preparations.

[0055] In another preferred embodiment, the pharmaceutical composition comprises a procaine-ibuprofen ionic liquid, and the dosage form of the pharmaceutical composition is selected from the group consisting of oral formulations, injectable formulations, transdermal formulations, or combinations thereof.

[0056] In another preferred embodiment, the pharmaceutical composition comprises a trihexyltetradecylphosphonium-ibuprofen ionic liquid and / or a tetrahexammonium-ibuprofen ionic liquid, and the dosage form of the pharmaceutical composition is a transdermal administration formulation.

[0057] In another preferred embodiment, the topical preparation is an adhesive tape preparation.

[0058] A fourth aspect of the present invention provides the use of an ionic liquid as described in the first aspect of the present invention or a pharmaceutical composition as described in the third aspect of the present invention for the preparation of medicaments, health products and foods for the prevention or treatment of migraines, joint or muscle disorders.

[0059] In another preferred embodiment, the joint or muscle disease includes rheumatoid arthritis, ankylosing arthritis, osteoarthritis, or a combination thereof.

[0060] In another preferred embodiment, the ionic liquid or composition is used to prepare analgesic and anti-inflammatory drugs.

[0061] The present invention also provides a method for treating a disease, comprising applying an appropriate amount of the ionic liquid or pharmaceutical composition described herein to a subject requiring treatment.

[0062] In another preferred embodiment, the disease includes joint and muscle disorders such as migraine, rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.

[0063] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0064] Figure 1 This is the FT-IR spectrum of the procaine-ibuprofen ionic liquid in Example 1 of this invention.

[0065] Figure 2 This is the M-DSC spectrum of the procaine-ibuprofen ionic liquid in Example 1 of this invention.

[0066] Figure 3 This is the TGA spectrum of the procaine-ibuprofen ionic liquid in Example 1 of the present invention.

[0067] Figure 4 This is the FT-IR spectrum of the tetrahexammonium-ibuprofen ionic liquid in Example 3 of the present invention.

[0068] Figure 5 This is the M-DSC spectrum of the tetrahexammonium-ibuprofen ionic liquid in Example 3 of this invention.

[0069] Figure 6 This is the TGA spectrum of the tetrahexammonium-ibuprofen ionic liquid in Example 3 of the present invention.

[0070] Figure 7 This is the FT-IR spectrum of the trihexyltetradecylphosphonium-ibuprofen ionic liquid in Example 5 of this invention.

[0071] Figure 8 This is the TGA spectrum of the trihexyltetradecylphosphonium-ibuprofen ionic liquid in Example 5 of the present invention. Detailed Implementation

[0072] This invention, based on extensive and in-depth research, is the first to develop an ionic liquid capable of improving the water solubility or lipid solubility and permeability of ibuprofen. The ionic liquid of this invention consists of ibuprofen and a cation, wherein the cation is procaine (cation), trihexytetradecylphosphonium, tetrahexammonium, or a combination thereof. This ionic liquid can improve the water solubility or lipid solubility and permeability of ibuprofen, thereby increasing bioavailability, further enhancing the therapeutic effect of ibuprofen, reducing side effects, and expanding its application range. Based on the above findings, the inventors completed this invention.

[0073] the term

[0074] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0075] As described herein, the terms "comprising" and "containing" are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of" and "substantially composed of".

[0076] As described in this article, the terms "preparation" and "dosage form" are used interchangeably, referring to a drug that is made in accordance with certain dosage form requirements to meet the needs of treatment or prevention and can ultimately be provided to the user.

[0077] Examples of "alcohol" in this application include C1-C10 lower alcohols such as ethanol, propanol, isopropanol, n-butanol, pentanol, octanol, dodecanol, etc., or polyols such as ethylene glycol, propylene glycol, 1,3-butanediol, polyethylene glycol, etc. Preferably, it is a C1-C4 alcohol, more preferably ethanol.

[0078] As described herein, the terms “composition” and “pharmaceutical composition” are used interchangeably and include (a) a therapeutically effective amount of ibuprofen ionic liquid and (b) a pharmaceutically acceptable carrier.

[0079] Ibuprofen

[0080] Ibuprofen, chemically known as 2-(4-isobutylphenyl)propionic acid, with the structure shown in Formula A, is a nonsteroidal antipyretic, analgesic, and anti-inflammatory drug. It is the only children's fever reducer jointly recommended by the World Health Organization and the US FDA. It is suitable for the treatment of mild to moderate migraine attacks, and joint and muscle diseases such as rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. According to data released by the State Food and Drug Administration of China, commercially available ibuprofen formulations are mainly solid dosage forms (tablets and capsules), with some transdermal formulations (creams and gels) also available.

[0081]

[0082] Ibuprofen is a poorly water-soluble drug, almost insoluble in water. Improving the solubility of ibuprofen can enhance its dissolution rate and properties, thereby increasing its bioavailability for oral administration. However, commercially available ibuprofen creams and gels have low transdermal penetration efficiency, limiting their efficacy. The stratum corneum is the primary permeation barrier for drugs penetrating the skin; generally, drugs with higher lipid solubility are more likely to penetrate the stratum corneum. The oil-water partition coefficient is a simple model indicating the lipophilic and hydrophilic properties of a compound; a higher Log P value indicates stronger lipid solubility. The oil-water partition coefficient of a drug is correlated with its penetration rate; as the oil-water partition coefficient increases, the penetration rate also increases. Using ionic liquid technology to enhance the lipophilicity of ibuprofen can improve its transdermal penetration rate.

[0083] To address the above-mentioned shortcomings, this invention provides an ibuprofen ionic liquid that can be further formulated into an improved formulation, which can effectively improve the water solubility or lipophilicity of ibuprofen, and enhance its permeability, bioavailability, and efficacy.

[0084] Ionic liquids

[0085] As used herein, the terms "ionic liquid," "ionic liquid of the present invention," and "ibuprofen ionic liquid" are used interchangeably and all refer to the ionic liquid described in the first aspect of the present invention.

[0086] The ionic liquid of the present invention is composed of ibuprofen and a cation; wherein the cation is selected from the group consisting of procaine cation, tetrahexammonium, trihexyltetradecylphosphonium, or combinations thereof.

[0087] Ibuprofen provides anions that combine with cationic components to form an ionic liquid that is liquid at room temperature.

[0088] Representative examples include procaine-ibuprofen ionic liquid, tetrahexammonium-ibuprofen ionic liquid, and trihexyltetradecylphosphonium-ibuprofen ionic liquid. The ionic liquids have structures as shown in Formula 1, Formula 2, or Formula 3.

[0089] This scheme provides three new ibuprofen ionic liquids: procaine-ibuprofen [Pro][Ibu], tetrahexammonium-ibuprofen [N], and others. 6,6,6,6 [Ibu] and trihexyltetradecylphosphonium-ibuprofen [P] 6,6,6,14 [Ibu] belongs to the third generation of ionic liquids. The procaine-ibuprofen [Pro][Ibu] ionic liquid in this invention has better water solubility than ibuprofen, and tetrahexammonium-ibuprofen [N...] 6,6,6,6 [Ibu] and trihexyltetradecylphosphonium-ibuprofen [P] 6,6,6,14 The oil-water partition coefficient of [Ibu] is higher than that of ibuprofen.

[0090] The first ibuprofen ionic liquid provided by this invention is a procaine-ibuprofen ionic liquid [Pro][Ibu], which is an equimolar salt formed by procaine and ibuprofen. It has a glass transition temperature of -12.69℃ and a solubility of 3941.63 μg / mL in pure water at 25℃. Ibuprofen is sparingly soluble in water, with an equilibrium solubility of 67.22 μg / mL in pure water at 25℃. The formation of an ionic liquid from ibuprofen and procaine significantly improves the equilibrium solubility of ibuprofen in water.

[0091] Procaine-ibuprofen ionic liquid

[0092]

[0093] The second ibuprofen ionic liquid provided by this invention: tetrahexammonium-ibuprofen ionic liquid [N] 6,6,6,6 [Ibu] is an equimolar salt formed by tetrahexammonium and ibuprofen, with a glass transition temperature of -56.05℃ and an oil-water partition coefficient Log P value of 2.47 at 25℃. The oil-water partition coefficient of the tetrahexammonium-ibuprofen ionic liquid is higher than that of ibuprofen (Log P value 1.89).

[0094] Tetrahexammonium-ibuprofen ionic liquid

[0095]

[0096] The third ibuprofen ionic liquid provided by this invention: trihexyltetradecylphosphonium-ibuprofen ionic liquid [P] 6,6,6,14[Ibu] is an equimolar salt formed by trihexyltetradecylphosphonium and ibuprofen, with an oil-water partition coefficient Log P value of 3.04 at 25°C. The oil-water partition coefficient of the trihexyltetradecylphosphonium-ibuprofen ionic liquid is higher than that of ibuprofen (Log P value 1.89).

[0097] Trihexyltetradecylphosphonium-ibuprofen ionic liquid

[0098]

[0099] Pharmaceutical Compositions, Methods of Administration and Applications

[0100] The present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of an ionic liquid as described in the first aspect of the invention; and (b) a pharmaceutically acceptable carrier.

[0101] In another preferred embodiment, the ionic liquid comprises 1-99% by weight, preferably 10-80%, and more preferably 20-70% by weight, based on the total weight of the pharmaceutical composition.

[0102] As used herein, "effective amount" or "effective dose" refers to an amount that is functional or active in humans and / or animals and is acceptable to humans and / or animals. Those skilled in the art will understand that the "effective amount" or "effective dose" can vary depending on the form of the pharmaceutical composition, the route of administration, the pharmaceutical excipients used, the severity of the disease, and whether it is used in combination with other drugs.

[0103] As described herein, a "pharmaceutically acceptable carrier" refers to one or more compatible solid, semi-solid, liquid, or gel fillers that are suitable for human or animal use and must have sufficient purity and toxicity. "Compatibility" refers to the ability of the components in a pharmaceutical composition and the active ingredient of the drug, as well as their interactions, to not significantly reduce the drug's efficacy.

[0104] It should be understood that the carrier described in this invention is not particularly limited and can be made of materials commonly used in the art, prepared by conventional methods, or purchased from the market.

[0105] Pharmaceutically acceptable examples of carriers include cellulose and its derivatives (such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as...). (e.g., wetting agents (such as sodium dodecyl sulfate), transdermal penetration enhancers, colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.)

[0106] In addition to the active pharmaceutical ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances.

[0107] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners and flavorings.

[0108] In this invention, the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and topical preparations.

[0109] In this invention, a preferred dosage form of the pharmaceutical composition is an oral formulation or a transdermal drug delivery formulation. Transdermal drug delivery formulations can be categorized as follows: membrane-controlled transdermal drug delivery formulations, matrix-controlled-release transdermal drug delivery formulations, micro-reservoir-controlled-release transdermal drug delivery formulations, and adhesive-controlled-release transdermal drug delivery formulations. Furthermore, transdermal drug delivery formulations may also include ointments, plasters, and liniments.

[0110] In another preferred embodiment of the invention, the dosage form of the pharmaceutical composition includes an adhesive tape formulation.

[0111] Generally, the tape formulation consists of the ionic liquid of the present invention and thickeners, softeners, fillers, antioxidants, etc., and any commonly used and widely applied ingredients can be used in the present invention, especially fillers and antioxidants can be optionally added or removed.

[0112] Examples of the aforementioned fillers include zinc oxide, titanium oxide, calcium carbonate, and silica.

[0113] The term "softener" as used above refers to additives with high adhesion (adhesive layer) properties, such as colloidal hydrocarbons. Furthermore, for any purpose, petroleum softeners such as liquid paraffin, petrolatum, processing oils, or low-molecular-weight polybutene can be used; fatty oil softeners such as castor oil or palm oil; or purified lanolin. In this invention, colloidal hydrocarbons alone or combinations of one or more types of softeners can be used as softeners. Preferably, examples of softeners added to colloidal hydrocarbons include petroleum softeners such as liquid paraffin, petrolatum, processing oils, or low-molecular-weight polybutene.

[0114] The ointment comprising the ibuprofen ionic liquid of the present invention can be prepared by any known method, for example, by dissolving the ibuprofen ionic liquid of the present invention together with excipients such as alcohol solvents, ester solvents, softeners or thickeners in a solvent, spreading it on a release liner or backing and then removing the solvent by drying, and finally covering it with another release liner or backing.

[0115] The formulations of the present invention include (a) an ionic liquid and (b) a pharmaceutically acceptable carrier.

[0116] Due to the skin's barrier function and the physicochemical properties of the drugs themselves, many drugs have very low permeability through the skin, making it difficult for transdermal drugs to reach effective therapeutic concentrations. Therefore, transdermal absorption enhancers are an important pharmaceutically acceptable carrier in transdermal drug delivery formulations.

[0117] Transdermal absorption enhancers are materials that can penetrate the skin and reduce the resistance to drug absorption. They assist drugs in passing through the stratum corneum, diffusing through the skin, and entering the systemic circulation via capillaries. They are mainly used in transdermal drug delivery formulations to achieve local or systemic effects. Typical transdermal absorption enhancers include organic alcohols, esters, laurocapram, surfactants, and terpenes. The organic alcohols are preferably ethanol, propylene glycol, ethyl acetate, dimethyl sulfoxide, N,N-dimethylformamide, or combinations thereof. The surfactants interact with biological membranes to promote drug absorption.

[0118] There are no particular limitations on the method of administration of the pharmaceutical composition of the present invention. Representative methods of administration include (but are not limited to): transdermal administration, oral administration, inhalation, injection, subcutaneous administration, etc.

[0119] The pharmaceutical formulation should be matched with the route of administration. Typically, in this invention, the pharmaceutical composition is prepared as a patch for local transdermal administration; or the pharmaceutical composition is prepared as an injection for administration via intravenous, subcutaneous, intradermal, or intramuscular injection. The dosage of the active pharmaceutical ingredient is a therapeutically effective amount, for example, approximately 1 microgram / kg body weight to approximately 5 milligrams / kg body weight per day. Furthermore, the pharmaceutical products of this invention can be used with other therapeutic agents (such as other hypoglycemic agents or other synergistic hypoglycemic agents) (including before, during, or after use).

[0120] The use of drugs involves administering a safe and effective amount of ionic liquid and drug combination to mammals. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, all of which are within the scope of a skilled physician's expertise.

[0121] In this invention, the ionic liquid and pharmaceutical composition are suitable for preparing drugs, health products and foods for the prevention or treatment of joint and muscle diseases such as migraine, rheumatoid arthritis, ankylosing arthritis, and osteoarthritis.

[0122] Differential scanning calorimetry

[0123] Also known as Differential Scanning Calorimetry (DSC), it is a technique that measures the relationship between the energy difference between the analyte and a reference material and temperature during heating. The peak positions, shapes, and numbers on the DSC spectrum are related to the properties of the substance, and therefore can be used qualitatively to identify the substance. This method is commonly used in the field to detect various parameters of a substance, such as phase transition temperature, glass transition temperature, and heat of reaction.

[0124] The main advantages of this invention include:

[0125] 1. The trihexyltetradecylphosphonium-ibuprofen ionic liquid and tetrahexammonium-ibuprofen ionic liquid of the present invention have significantly higher oil-water partition coefficients than ibuprofen, thereby improving the lipid solubility and permeability of ibuprofen and thus improving the bioavailability of ibuprofen.

[0126] 2. The procaine-ibuprofen ionic liquid of the present invention has better water solubility than ibuprofen, about 58.6 times that of ibuprofen, which significantly improves the dissolution rate and dissolution properties of ibuprofen, thereby improving the bioavailability of ibuprofen for oral administration.

[0127] 3. The ionic liquid of the present invention can improve the solubility and permeability of drugs, thereby increasing the bioavailability of drugs and enabling them to exert their drug activity rapidly. Therefore, the ionic liquid or drug composition of the present invention is effective for the prevention and / or treatment of joint and muscle diseases such as migraines, rheumatoid arthritis, ankylosing arthritis, and osteoarthritis.

[0128] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0129] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0130] Example 1. Preparation of procaine-ibuprofen ionic liquid

[0131] 550 mg (2.0 mmol) of procaine hydrochloride was dissolved in 4 mL of ultrapure water. An equimolar amount of ibuprofen sodium dissolved in 4 mL of ultrapure water was slowly added dropwise to the procaine hydrochloride aqueous solution, and the mixture was stirred at room temperature for 2 h. 20 mL of dichloromethane was added, stirred, and extracted. The dichloromethane layer was washed with water to remove sodium chloride, and silver nitrate detection was used to ensure no residual chloride ions. After removing the solvent using a rotary evaporator, the mixture was dried under vacuum for 24 h.

[0132] (1) The procaine-ibuprofen ionic liquid prepared in Example 1 was subjected to 1H NMR spectrum ( 1 The 1H NMR analysis was performed as follows: Bruker solution NMR (400MHz) was used with deuterated dimethyl sulfoxide as solvent and tetramethylsilane as internal standard.

[0133] 1H NMR spectrum of procaine-ibuprofen ionic liquid: 1 H NMR (400MHz, DMSO-d6) δ7.63(d,J=8.5Hz,2H),7.18(d,J=7.9Hz,2H),7.09(d,J=7.9Hz,2H ),6.56(d,J=8.5Hz,2H),5.98(s,2H),4.19(t,J=6.1Hz,2H),3.61(q,J=7.1Hz,1H),2.71( t,J=6.1Hz,2H),2.55(q,J=7.1Hz,4H),2.41(d,J=7.1Hz,2H),1.80(dp,J=13.5,6.8Hz,1H ),1.33(d,J=7.1Hz,3H),6.02–5.92(m,2H),0.96(t,J=7.1Hz,6H),0.85(d,J=6.6Hz,6H).

[0134]

[0135] A: Procaine hydrochloride; B: Procaine-ibuprofen

[0136]

[0137] A: Ibuprofen; B: Procaine-Ibuprofen

[0138] (2) Fourier transform infrared (FT-IR) analysis was performed on the procaine-ibuprofen prepared in Example 1. The operation and analysis are as follows: Attenuated total reflectance (ATR) method was used to obtain the IR spectrum. The instrument was an Agilent infrared spectrometer (Cary 630). The parameters were set at room temperature: 400-4000 cm⁻¹ -1 32 scans, resolution of 8cm -1 .

[0139] The FT-IR spectrum of the procaine-ibuprofen ionic liquid is as follows: Figure 1 As shown, 1697cm -1 A broad absorption band based on the C=O stretching vibration of the free carboxylic acid group was found, compared to ibuprofen's 1706 cm⁻¹. -1The stretching vibrations at the point of origin were shifted. The results showed that procaine and ibuprofen are not a mixture of two compounds, and that there are bonding forces between them.

[0140] (3) Modulated differential scanning calorimetry (M-DSC) was performed on the procaine-ibuprofen ionic liquid prepared in Example 1. The operation and analysis steps are as follows: A TA Q2000 differential scanning calorimeter was used in N2 atmosphere, the heating rate was 1℃ / min, and the modulation period was 60s.

[0141] The M-DSC diagram of the procaine-ibuprofen ionic liquid is shown below. Figure 2 As shown, the glass transition temperature is -12.69℃.

[0142] (4) The procaine-ibuprofen ionic liquid prepared in Example 1 was subjected to thermogravimetric analysis (TGA). The operation and analysis steps are as follows: A TA Q500 thermogravimetric analyzer was used in a N2 atmosphere, and the heating rate was 10℃ / min.

[0143] The TGA graph of the procaine-ibuprofen ionic liquid is shown below. Figure 3 As shown, TGA loses less than 5% of its weight within 100℃, indicating that the solvent has virtually no effect on the physical morphology of the final ionic liquid.

[0144] Example 2. Comparison of solubility between procaine-ibuprofen ionic liquid and ibuprofen

[0145] Excess procaine-ibuprofen ionic liquid and ibuprofen were weighed and suspended in pure water. After shaking for 24 hours, the solubility was tested using high-performance liquid chromatography. The test results are as follows:

[0146] compound Solubility (μg / mL) Procaine Ibuprofen 3941.63 Ibuprofen 67.22

[0147] It can be seen that the solubility of procaine-ibuprofen ionic liquid in pure water is significantly higher than that of ibuprofen, approximately 58.6 times higher. The excellent water solubility of procaine-ibuprofen ionic liquid significantly improves the dissolution rate and solubility properties of ibuprofen, thereby enhancing the bioavailability of ibuprofen for oral administration.

[0148] Example 3. Preparation of tetrahexammonium-ibuprofen ionic liquid

[0149] 434 mg (1.0 mmol) of tetrahexylammonium bromide was dissolved in 4 mL of ultrapure water. An equimolar amount of ibuprofen sodium dissolved in 4 mL of ultrapure water was slowly added dropwise to the tetrahexylammonium bromide aqueous solution. The mixture was stirred at room temperature for 2 h. 20 mL of dichloromethane was added, stirred, and extracted. Sodium chloride was removed by washing with water, and silver nitrate detection was used to ensure no residual chloride ions. After removing the solvent using a rotary evaporator, the mixture was dried under vacuum for 24 h.

[0150] (1) Perform 1H NMR spectroscopy on the tetrahexammonium-ibuprofen prepared in Example 3. 1 The 1H NMR analysis was performed as follows: Bruker solution NMR (400MHz) was used with deuterated dimethyl sulfoxide as solvent and tetramethylsilane as internal standard.

[0151] The proton NMR spectrum of the tetrahexammonium-ibuprofen ionic liquid: 1 H NMR (400MHz, DMSO-d6) δ7.13(d,J=7.7Hz,2H),6.94(d,J=7.7Hz,2H),3.21–3.11(m,9H),2.36(d,J=7.1Hz,2H),1.78(d t,J=13.5,6.7Hz,1H),1.57(m,J=10.6,5.8Hz,8H),1.35–1.22(m,24H),1.17(d,J=7.1Hz,3H),0.87(q,J=6.6Hz,18H).

[0152]

[0153] A: Tetrahexylammonium bromide; B: Tetrahexylammonium-ibuprofen

[0154]

[0155]

[0156] A: Ibuprofen; B: Tetrahexammonium-Ibuprofen

[0157] (2) Fourier transform infrared (FT-IR) analysis was performed on the tetrahexammonium-ibuprofen prepared in Example 3. The operation and analysis are as follows: Attenuated total reflectance (ATR) method was used to obtain the IR spectrum. The instrument was an Agilent infrared spectrometer (Cary 630). The parameters were set at room temperature: 400-4000 cm⁻¹ -1 32 scans, resolution of 8cm -1 .

[0158] The FT-IR spectrum of the tetrahexammonium-ibuprofen ionic liquid is as follows: Figure 4 As shown, 1577cm -1 The discovery was based on the carboxylic acid anion (COO) - The new absorption band of ibuprofen is 1706 cm⁻¹. -1 The stretching vibrations at the point of origin were shifted. The results showed that tetrahexammonium and ibuprofen were not a mixture of two compounds, and that there were bonding forces between them.

[0159] (3) Modulated differential scanning calorimetry (M-DSC) was performed on the tetrahexammonium-ibuprofen ionic liquid prepared in Example 3. The operation and analysis steps are as follows: A TA Q2000 differential scanning calorimeter was used, N2 atmosphere was used, the heating rate was 1℃ / min, and the modulation period was 60s.

[0160] The M-DSC plot of the tetrahexammonium-ibuprofen ionic liquid is shown below. Figure 5 As shown, the glass transition temperature is -56.05℃.

[0161] (4) Thermogravimetric analysis (TGA) was performed on the tetrahexammonium-ibuprofen ionic liquid prepared in Example 3. The operation and analysis steps are as follows: A TA Q500 thermogravimetric analyzer was used in N2 atmosphere, and the heating rate was 10℃ / min.

[0162] The TGA graph of the tetrahexammonium-ibuprofen ionic liquid is shown below. Figure 6 As shown, TGA loses less than 5% of its weight within 100℃, indicating that the solvent has virtually no effect on the physical morphology of the final ionic liquid.

[0163] Example 4. Comparison of oil-water partition coefficients between tetrahexammonium-ibuprofen ionic liquid and ibuprofen.

[0164] The oil-water partition coefficient was determined according to OECD Chemicals Testing Guideline No. 107 (1995 edition), "Octanol-Water Partition Coefficient: Shake Flask Method". Before the test, octanol and water needed to be pre-saturated. Specifically, at the test temperature, two large storage bottles were used, one containing octanol and sufficient water, and the other containing sufficient octanol. These were placed in a constant-temperature shaker and shaken for 24 hours. Afterward, sufficient time was allowed for complete separation of the two phases to obtain water-saturated octanol and octanol-saturated water, respectively. 0.01 mmol of the drug was added to a 10 mL ampoule, followed by 4 mL of water-saturated octanol and 4 mL of octanol-saturated water. The ampoule was shaken at 25°C (200 rpm) for 24 hours to reach equilibrium. Sufficient time was allowed for complete separation of the two phases, and the concentration of ibuprofen in both phases was determined by HPLC. The test results are as follows:

[0165] compound Oil-water partition coefficient Log P Tetrahexammonium ibuprofen 2.47 Ibuprofen 1.89

[0166] It can be seen that the oil-water partition coefficient of the tetrahexammonium-ibuprofen ionic liquid is significantly higher than that of ibuprofen, approximately 1.3 times higher. The tetrahexammonium-ibuprofen ionic liquid improves the lipid solubility and transdermal penetration rate of ibuprofen, further enhancing the efficacy of ibuprofen transdermal formulations.

[0167] Example 5. Preparation of trihexyltetradecylphosphonium-ibuprofen ionic liquid

[0168] 529 mg (1.0 mmol) of trihexyltetradecylphosphonium chloride was dissolved in 5 mL of ethanol. An equimolar amount of ibuprofen sodium was added to the solution, and the mixture was stirred at room temperature for 4 h. After filtration, 20 mL of acetone was added, and the mixture was stirred for 2 h. After filtration, the solvent was removed by rotary evaporation, and the mixture was dried under vacuum for 24 h.

[0169] A proton nuclear magnetic resonance spectrum was performed on the trihexyltetradecylphosphonium-ibuprofen prepared in Example 5. 1 The 1H NMR analysis was performed as follows: Bruker solution NMR (400MHz) was used with deuterated dimethyl sulfoxide as solvent and tetramethylsilane as internal standard.

[0170] 1H NMR spectrum of ibuprofen trihexyltetradecylphosphonium ionic liquid: 1 H NMR (400MHz, DMSO-d6) δ7.14(d,J=7.8Hz,2H),6.97(d,J=7.8Hz,2H),2.37(d,J=7.1Hz,2H),2.19(td,J=13.0,6 .8Hz,8H),3.39–3.30(m,1H),1.48–1.23(m,48H),1.21(d,J=7.0Hz,3H),0.94–0.81(m,18H),1.84–1.73(m,1H).

[0171]

[0172] A: Trihexyltetradecylphosphonium chloride; B: Trihexyltetradecylphosphonium-ibuprofen

[0173]

[0174]

[0175] A: Ibuprofen; B: Trihexyltetradecylphosphonium-ibuprofen

[0176] (2) Fourier transform infrared (FT-IR) analysis was performed on the trihexyltetradecylphosphonium-ibuprofen prepared in Example 5. The operation and analysis are as follows: Attenuated total reflectance (ATR) method was used to obtain the IR spectrum. The instrument was an Agilent infrared spectrometer (Cary 630). The parameters were set at room temperature: 400-4000 cm⁻¹ -1 32 scans, resolution of 8cm -1 .

[0177] The FT-IR spectrum of the trihexyltetradecylphosphonium-ibuprofen ionic liquid is as follows: Figure 7 As shown, 1580cm -1 The discovery was based on the carboxylic acid anion (COO) -The new absorption band of ibuprofen is 1706 cm⁻¹. -1 The stretching vibrations at the point of origin were shifted. The results showed that trihexytetradecylphosphonium and ibuprofen were not a mixture of two compounds, and that there were bonding forces between the two compounds.

[0178] (3) Modulated differential scanning calorimetry (M-DSC) was performed on the trihexyltetradecylphosphonium-ibuprofen ionic liquid prepared in Example 5. The operation and analysis steps are as follows: A TA Q2000 differential scanning calorimeter was used in N2 atmosphere. The heating rate was 1℃ / min and the modulation period was 60s.

[0179] The glass transition temperature of the trihexyltetradecylphosphonium-ibuprofen ionic liquid was not found and is not shown in the figure.

[0180] (4) Thermogravimetric analysis (TGA) was performed on the trihexyltetradecylphosphonium-ibuprofen ionic liquid prepared in Example 5. The operation and analysis steps are as follows: A TA Q500 thermogravimetric analyzer was used in a N2 atmosphere, and the heating rate was 10℃ / min.

[0181] The TGA chromatogram of the trihexyltetradecylphosphonium-ibuprofen ionic liquid is shown below. Figure 8 As shown, TGA loses less than 5% of its weight within 100℃, indicating that the solvent has virtually no effect on the physical morphology of the final ionic liquid.

[0182] Example 6. Comparison of oil-water partition coefficients between trihexyltetradecylphosphonium-ibuprofen ionic liquid and ibuprofen

[0183] The oil-water partition coefficient was determined according to OECD Chemicals Testing Guideline No. 107 (1995 edition), "Octanol-Water Partition Coefficient: Shake Flask Method". Before the test, octanol and water needed to be pre-saturated. Specifically, at the test temperature, two large storage bottles were used, one containing octanol and the other sufficient water, and the other water and sufficient octanol. These were placed in a constant-temperature shaker and shaken for 24 hours. Afterward, sufficient time was allowed for complete separation of the two phases to obtain water-saturated octanol and octanol-saturated water, respectively. 0.01 mmol of the drug was added to a 10 mL ampoule, followed by 4 mL of water-saturated octanol and 4 mL of octanol-saturated water. The mixture was shaken on a shaker (200 rpm) at 25°C for 24 hours to reach equilibrium. Sufficient time was allowed for complete separation of the two phases, and the concentration of ibuprofen in both phases was determined by HPLC. The test results are as follows:

[0184] compound Oil-water partition coefficient Log P Trihexyltetradecylphosphonium-ibuprofen 3.04 Ibuprofen 1.89

[0185] It can be seen that the oil-water partition coefficient of the trihexytetradecylphosphonium-ibuprofen ionic liquid is significantly higher than that of ibuprofen, approximately 1.6 times higher. The trihexytetradecylphosphonium-ibuprofen ionic liquid improves the lipid solubility and transdermal penetration rate of ibuprofen, further enhancing the efficacy of transdermal ibuprofen formulations.

[0186] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. An ionic liquid, characterized in that, The ionic liquid is composed of ibuprofen and a cation; wherein the cation is tetrahexammonium; and the ionic liquid is a tetrahexammonium-ibuprofen ionic liquid. The ionic liquid has the structure shown in Formula 2 below: Equation 2, The oil-water partition coefficient logP of the tetrahexammonium-ibuprofen ionic liquid is 2.

47.

2. The ionic liquid as described in claim 1, characterized in that, The molar ratio of ibuprofen to cations is 1:0.8-1.

2.

3. The ionic liquid as described in claim 1, characterized in that, The tetrahexammonium-ibuprofen ionic liquid also has one or more characteristics selected from the group consisting of: (1) The glass transition temperature Tg is -70 to -40℃; and / or (2) It is a liquid at temperatures below 100°C.

4. The ionic liquid as described in claim 3, characterized in that, The tetrahexammonium-ibuprofen ionic liquid is liquid below 40°C.

5. The ionic liquid as described in claim 3, characterized in that, The tetrahexammonium-ibuprofen ionic liquid is liquid below 25°C.

6. The ionic liquid as described in claim 3, characterized in that, The glass transition temperature (Tg) of the tetrahexammonium-ibuprofen ionic liquid is -60 to -50°C.

7. A method for preparing an ionic liquid as described in any one of claims 1-6, characterized in that, Including the following steps: (a) Provide a solution comprising a first solvent and ibuprofen and a cationic donor dissolved in the first solvent; (b) Remove the first solvent from the solution to obtain an ionic liquid formed by ibuprofen and the cation donor.

8. The method as described in claim 7, characterized in that, In step (a), the first solvent is selected from the group consisting of water, alcohols, or combinations thereof.

9. The method as described in claim 8, characterized in that, In step (a), the alcohols are C1-C10 alcohols.

10. The method as described in claim 8, characterized in that, In step (a), the alcohols are C1-C4 alcohols.

11. The method as described in claim 8, characterized in that, In step (a), the alcohol is ethanol.

12. The method as described in claim 7, characterized in that, The step (b) includes the following step before step (b): (b1) mixing the ionic liquid prepared in step (a) with a second solvent.

13. The method as described in claim 12, characterized in that, In step (b1), the second solvent is selected from the group consisting of ketones or dichloromethane.

14. The method as described in claim 7, characterized in that, Step (b) also includes: removing salt from the mixed solution.

15. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (a) a therapeutically effective amount of an ionic liquid as described in any one of claims 1-6; and (b) a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, characterized in that, The pharmaceutical composition is a topical preparation.

17. The pharmaceutical composition of claim 15, characterized in that, The pharmaceutical composition comprises a tetrahexammonium-ibuprofen ionic liquid, and the dosage form of the pharmaceutical composition is a transdermal delivery formulation.

18. Use of an ionic liquid as claimed in claim 1 or a pharmaceutical composition as claimed in claim 15, characterized in that, Used to prepare medicines for the prevention or treatment of migraines, joint or muscle disorders.

19. The use as described in claim 18, characterized in that, The joint or muscle diseases mentioned include rheumatoid arthritis, ankylosing arthritis, osteoarthritis, or a combination thereof.

20. The use as described in claim 18, characterized in that, The ionic liquid or composition is used to prepare analgesic and anti-inflammatory drugs.

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