Novel drug formulation using ionic liquid or deep eutectic solvent

Abstract

The present invention relates to a drug delivery system (DDS) using an ionic liquid or a deep eutectic solvent. According to the DDS technology of the present invention, solubility, permeability, bioavailability, and drug delivery ability are remarkably improved, and by enabling an active ingredient, which has been conventionally administered only as an injection or the like, to be orally administered or converted into a subcutaneous injection, the medication convenience for a subject receiving administration can be greatly enhanced. In addition, the present invention can be widely applied to existing drugs and drugs to be developed in the future.

Description

Novel drug formulations using ionic liquids or eutectic solvents

[0001] The present invention belongs to the field of pharmaceuticals, and more particularly, relates to a drug delivery system using ionic liquids or deep eutectic solvents.

[0002] With the aging population and the shift toward a more welfare-based society, coupled with societal demands for improved quality of life, technology and product development in the healthcare sector are having a significant social and economic impact and are establishing themselves as a key growth driver for the nation. In particular, amidst the shifting pharmaceutical landscape toward low-cost, high-success rate generics and biosimilars, the development of intelligent, personalized drug delivery technologies and carriers utilizing drug delivery systems (DDS) is actively underway.

[0003] Drug delivery system technology encompasses a range of technologies that utilize various physicochemical techniques to control the delivery and release of pharmacologically active substances into cells, tissues, organs, and systems, ensuring optimal efficacy. In other words, a drug delivery system is a technology that designs formulations to efficiently deliver the optimal amount of drug to the desired site, minimizing side effects and maximizing efficacy and effectiveness while increasing patient compliance.

[0004] As the population ages and we move towards a welfare society, effective and economical treatments for various diseases are required. Therefore, the era of personalized medication is expected to arrive, where the optimal dose is administered to the right place at the right time, according to the individual's (patient's) condition, using DDS technology.

[0005] Initially, DDS technology was developed primarily for the purpose of developing new drugs through controlled release, sustained release, reduced toxicity, and increased convenience of administration, targeting drugs whose competitiveness in the market was weakened due to the expiration of their substance patents, in response to the strategic needs of pharmaceutical companies. However, recently, its importance has also increased as a basic technology for testing and evaluating the pharmacodynamics, pharmacokinetics, and toxicity of hit or lead compounds derived in large quantities through combinatorial chemistry and high-throughput screening technology.

[0006] Active research is underway on the development of DDS used for various diseases such as heart disease and degenerative neurological diseases, development of DDS for mucosal administration, development of DDS for formulation and manufacturing methods of nanoparticles and drug complexes and mixed particles, development of DDS specialized in cartilage and (stem) cell treatment, methods and devices for sustained-release or drug delivery according to administration route, and pharmaceutical compositions according to administration route and release time.

[0007] DDS are classified into oral, transdermal, injection, pulmonary inhalation, and mucosal administration types depending on the route (site) of administration. Existing antibody therapeutics can only be administered by injection, and especially in the case of drugs that require intravenous administration, they can only be administered by doctors or nurses, which has problems such as accessibility issues, decreased patient compliance due to pain during administration, and side effects due to infection. Therefore, active research is being conducted to find alternative methods to intravenous injection to improve injection pain, inconvenience of administration, and risk of infection, and there has been a need for oral DDS, the most common and convenient route of drug administration.

[0008] Oral administration is the most common drug dosage form, offering advantages such as convenience and low manufacturing costs. It is primarily used when blood drug concentrations must be rapidly increased above a certain minimum effective concentration. Oral medications are broken down and dispersed in the stomach upon administration, and most are absorbed through the small intestinal mucosa. Drug absorption is primarily through passive diffusion.

[0009] Meanwhile, ionic liquids are salts that cannot form crystals and exist in a liquid state at temperatures below 100℃ due to the asymmetry in the sizes of cations and anions and the irregular structure. In particular, ionic liquids that exist as liquids at room temperature are called room temperature ionic liquids (RTILs).

[0010] Deep eutectic solvents (DESs) also refer to substances whose melting points drop sharply upon combination due to the formation of hydrogen bonds. While eutectic solvents are primarily composed of non-binary mixtures of cations and anions, ionic liquids are primarily composed of a 1:1 combination of cations and anions, driven by non-directional ionic interactions. Based on the strict definitions of ionic liquids and eutectic solvents, many substances exhibit properties intermediate to this continuum.

[0011] The greatest advantage of ionic liquids and eutectic solvents is that the structures of cations and anions can be selectively synthesized and used depending on the intended use. Cations include morpholinium, imidazolium, quaternary ammonium, and quaternary phosphonium, and anions include Br. - , Cl - , NO3 - , BF4 - , PF6 -There are numerous types of ionic liquids, and by combining them, more than 1,000 types of ionic liquids or eutectic solvents can be synthesized. Ionic liquids are also called designer solvents because they can be used by designing various types of cations and anions for specific purposes.

[0012] Ionic liquids and eutectic solvents possess properties such as low volatility, thermal stability, high ionic conductivity, high electrochemical stability, and low vapor pressure. These properties have made them attractive as safe and environmentally friendly alternatives to conventional solvents, such as organic solvents, in various industrial fields. Their applications are diverse, including as reaction solvents, ionic conductors, electronically conductive liquids, lubricants, mixtures with supercritical fluids, and surface modifiers.

[0013] However, research on the application of these ionic liquids and eutectic solvents to drug delivery systems (DDS) is minimal. Therefore, the inventors of the present invention have demonstrated that converting raw pharmaceutical ingredients into salt-based ionic liquids or eutectic solvents can significantly improve solubility, permeability, bioavailability, and drug delivery capacity. They have also developed a drug delivery system utilizing this technology.

[0014] [Prior Art Literature]

[0015] (Patent Document 0001) Republic of Korea Patent No. 10-1763482

[0016] (Patent Document 0002) Republic of Korea Publication Patent No. 10-2023-0008723

[0017] (Non-patent literature 0001) Chemical Science (2022), 13(10), 2909-2918

[0018] The present invention has been devised to solve the above problems, and aims to provide a drug delivery system including ionic liquids or deep eutectic solvents.

[0019] In one embodiment of the present invention to achieve such a task, a novel drug formulation and drug delivery system based on an ionic liquid or a eutectic solvent are provided.

[0020] In one embodiment of the present invention, a drug delivery system comprising an active ingredient and an ionic liquid or a eutectic solvent is provided.

[0021] In another embodiment of the present invention, a pharmaceutical composition comprising the drug delivery system is provided.

[0022] In another embodiment of the present invention, a pharmaceutical preparation comprising the drug delivery system is provided.

[0023] The present invention relates to a drug formulation and drug delivery system (DDS) using an ionic liquid or a eutectic solvent. According to the DDS technology of the present invention, solubility, permeability, bioavailability, and drug delivery ability are significantly improved, and active ingredients that were previously only available for intravenous administration can be converted to subcutaneous injection or oral administration, thereby greatly improving the convenience of administration for the subject receiving the administration. In addition, it is expected that it will be able to be widely applied to existing drugs and drugs to be developed in the future, and thus be able to be utilized on par with the development of new drugs.

[0024] FIG. 1 illustrates a reaction scheme showing a method for producing a choline and geranate (CAGE) ionic liquid according to one embodiment of the present invention.

[0025] FIG. 2 shows a photograph of an ionic liquid or deep eutectic solvent manufactured according to one embodiment of the present invention.

[0026] Figure 3 shows the results of confirming the viability of Caco-2 cells when treated with different concentrations of ionic liquid or eutectic solvent according to one embodiment of the present invention.

[0027] Figures 4 and 5 show the results of confirming the FITC-insulin delivery ability of a drug delivery system in Caco-2 cells using an ionic liquid or a eutectic solvent according to one embodiment of the present invention.

[0028] Unless otherwise defined, all terms (including technical and scientific terms) used herein may be used in their common sense to those of ordinary skill in the art to which the present invention pertains. Furthermore, terms defined in commonly used dictionaries are not to be interpreted ideally or excessively unless explicitly and specifically defined otherwise.

[0029] As used herein, the singular form may include the plural form unless the context clearly indicates otherwise.

[0030] When a part in this specification is said to “include” a component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.

[0031] In addition, all numbers and expressions indicating the amounts of components, reaction conditions, etc. described in this specification should be understood to be modified by the term “about” in all cases unless otherwise specified.

[0032] As used herein, “pharmaceutically acceptable” means that which is approved by a governmental or equivalent regulatory body for use in animals, and more particularly in humans, by avoiding significant toxic effects when used at usual pharmaceutical doses, is listed in a pharmacopoeia, or is otherwise generally recognized by the pharmacopoeia.

[0033] Additionally, the experimental procedures specified in this specification are identical to those commonly performed in the art unless specifically described otherwise.

[0034] Hereinafter, the present invention will be described in detail.

[0035] The present invention provides a drug delivery system comprising ionic liquids or deep eutectic solvents.

[0036] One aspect of the present invention provides a drug delivery system comprising an active ingredient and ionic liquids or deep eutectic solvents.

[0037] In one specific example of the present invention, the ionic liquid or eutectic solvent may be a mixture of choline represented by the following chemical formula I and Geranic acid represented by the following chemical formula II.

[0038] (Ⅰ),

[0039] (Ⅱ).

[0040] In one specific embodiment of the present invention, the ionic liquid or eutectic solvent may be a mixture of choline and zeolite in a molecular ratio of 1:1 to 5, 1:1 to 4, 1:1 to 3, 1:1 to 2, preferably 1:2, but is not limited thereto.

[0041] In one specific example of the present invention, the drug formulation of the drug delivery system may be an oral or parenteral formulation, and the parenteral formulation may be at least one selected from the group consisting of an injection, a spray, an aerosol, an ointment, a cream, a topical agent, and an ointment, and specifically, may be a subcutaneous injection (SC) or an oral formulation, but is not limited thereto.

[0042] In one specific embodiment of the present invention, the ionic liquid or eutectic solvent may be a mixture of any one compound selected from Table 1 below and any one compound selected from Table 2 below.

[0043] [Table 1]

[0044]

[0045] [Table 2]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057] Another aspect of the present invention provides a pharmaceutical composition comprising the drug delivery system.

[0058] The above pharmaceutical composition may additionally contain pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents or emulsifying agents, salts for osmotic pressure control and / or buffers, and other therapeutically useful substances, and may be formulated into various oral or parenteral dosage forms according to conventional methods.

[0059] The oral dosage forms include, for example, tablets, pills, hard and soft capsules, liquids, suspensions, emulsifiers, syrups, powders, granules, granules, pellets, etc., and these dosage forms may contain, in addition to the active ingredient, a surfactant, a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine), and a lubricant (e.g., silica, talc, stearic acid and its magnesium or calcium salts, and polyethylene glycol). The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidine, and optionally pharmaceutical additives such as disintegrating agents such as starch, agar, alginic acid or its sodium salt, absorbents, coloring agents, flavoring agents, and sweetening agents. The tablets may be manufactured by conventional mixing, granulating, or coating methods.

[0060] In addition, the above-mentioned non-oral administration form may be a transdermal administration formulation, and examples thereof include, but are not limited to, injections, drops, ointments, lotions, gels, creams, sprays, suspensions, emulsions, suppositories, patches, etc.

[0061] The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains, and the like. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, suppository, powder, granule, tablet or capsule, and may additionally include a dispersing agent or stabilizer.

[0062] Pharmaceutically acceptable carriers that may be included in the pharmaceutical composition of the present invention are those commonly used in formulations, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.

[0063] The pharmaceutical composition of the present invention can be administered orally and parenterally, and can be administered by, for example, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, topical administration, intranasal administration, intrapulmonary administration, rectal administration, intrathecal administration, ocular administration, skin administration, and transdermal administration.

[0064] The appropriate dosage of the pharmaceutical composition of the present invention varies depending on factors such as the formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, genetic specificity, excretion rate, and response sensitivity, and a generally skilled physician can easily determine and prescribe a dosage effective for the desired treatment or prevention.

[0065] The determination of the dosage of the above-mentioned effective ingredient is within the level of a person skilled in the art, and the daily administration dosage of the drug varies depending on various factors such as the degree of progression, onset time, age, health condition, complications, and genetic specificity of the subject to be administered, but when based on adults, in one aspect, 1 ㎍ / kg to 200 mg / kg of the composition, and in another aspect, 50 ㎍ / kg to 50 mg / kg may be administered once to three times a day in divided doses, and the above dosage does not limit the scope of the present invention in any way.

[0066] Another aspect of the present invention provides a pharmaceutical preparation comprising the drug delivery system.

[0067] Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples and experimental examples are intended only to illustrate the present invention, and the scope of the present invention is not limited to these examples.

[0068] <Example 1>

[0069] The choline and geranate (CAGE) of the present invention was synthesized by a salt substitution reaction. Choline bicarbonate and geranate were purchased from Merck KGaA (Darmstadt, Germany).

[0070] As disclosed in Proceedings of the National Academy of Sciences of the United States of America (2014) 111(37), 13313-13318 CODEN: PNASA6; ISSN: 0027-8424, specifically, as shown in Figure 1, 2 equivalents of technical-grade 85% zeranic acid (5.07 g, 0.0301 mol) were recrystallized from 70 wt % zeranic acid / 30 wt % acetone at -70°C. To the obtained zeranic acid in a 100 mL eggplant flask, 1 equivalent of choline bicarbonate (80 wt % solution, 3.109 g, 0.0151 mol) was added. The mixture was stirred at room temperature until no more CO2 was present. The solvent was removed by rotary evaporation at 60°C for 20 min, and the product was dried in a vacuum oven at 60°C for 48 h to obtain CAGE. Figure 2 shows a photograph of the manufactured ionic liquid or deep eutectic solvent. It was confirmed that the obtained product was a stable and transparent liquid at room temperature, and had fluidity and transparency.

[0071] <Example 2>

[0072] An ionic liquid or eutectic solvent was prepared in the same manner as in Example 1 by mixing a hydrogen bond acceptor (HA) selected from the compounds in Table 1 below and a hydrogen bond donor (HD) selected from the compounds in Table 2 below instead of bicarbonate choline and geranic acid.

[0073] Specifically, ethanol (50 cm 3 ) and betaine (0.05 M) were injected into the reaction vessel, and then 10% (0.055 M) of potassium salt (potassium hydroxide) was added, and a hydrogen bond donor selected from the compounds in Table 2 was mixed. The mixture was stirred at 60°C for 2 hours. After the reaction was completed, the precipitated byproduct was filtered, the solvent was removed by rotary evaporation at 60°C for 20 minutes, and the product was dried in a vacuum oven at 50°C for 48 hours to obtain the obtained product.

[0074] [Table 1]

[0075]

[0076] [Table 2]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088] <Example 3> Preparation of oral formulation

[0089] An oral formulation was prepared using the ionic liquid or eutectic solvent prepared in Examples 1 and 2 above. Specifically, the drug to be applied was insulin, and the formulation was formulated into an enteric capsule.

[0090] <Example 4> Preparation of subcutaneous injection preparation

[0091] A subcutaneous injection formulation was prepared using the ionic liquid or eutectic solvent prepared in Examples 1 and 2 above. Specifically, a drug generally administered by intravenous injection was formulated as a subcutaneous injection formulation.

[0092] <Experimental Example 1> Confirmation of a drug delivery system using ionic liquids or eutectic solvents (MTT assay)

[0093] In order to verify the drug delivery system using the ionic liquid or eutectic solvent manufactured in Examples 1 and 2 above, the viability of Caco-2 cells was verified using insulin as the applied drug.

[0094] As a result, when treated with ionic liquid or eutectic solvent (CAGE), cell viability was maintained at more than 70% at concentrations of 10 mM, 25 mM, and 50 mM (Fig. 3), and FITC-insulin transport was improved in a concentration-dependent manner of ionic liquid or eutectic solvent in Caco-2 cells, and in particular, FITC-insulin transport was confirmed to be improved by more than 10 times at a concentration of 50 mM (Figs. 4 and 5).

[0095] In conclusion, it was confirmed that the drug delivery system using the ionic liquid or eutectic solvent of the present invention can convert intravenous (IV) injection into subcutaneous (SC) injection, can be applied to oral formulations, and further has excellent effectiveness as a platform technology applicable to various drugs.

Claims

1. A drug delivery system comprising ionic liquids or deep eutectic solvents.

2. A drug delivery system comprising an active ingredient and an ionic liquid or deep eutectic solvents.

3. In paragraph 1, The above ionic liquid or eutectic solvent is a drug delivery system that is a mixture of choline represented by the following chemical formula I and geranic acid represented by the following chemical formula II: (Ⅰ), (Ⅱ).

4. In paragraph 3, A drug delivery system wherein the ionic liquid or eutectic solvent is a mixture of choline and geranic acid in a molecular ratio of 1:1 to 5.

5. In paragraph 1, The drug delivery system of the above drug delivery system is a drug administration formulation selected from the group consisting of an injection, a spray, an aerosol, an ointment, a cream, a topical agent, and an ointment.

6. In paragraph 5, The drug administration formulation of the above drug delivery system is a subcutaneous injection (SC) drug delivery system.

7. In paragraph 1, The drug administration dosage form of the above drug delivery system is an oral drug delivery system.

8. In paragraph 1, A drug delivery system wherein the ionic liquid or eutectic solvent is a mixture of one compound selected from Table 1 below and one compound selected from Table 2 below: [Table 1] [Table 2] 9. A pharmaceutical composition comprising a drug delivery system according to any one of claims 1 to 8.

10. A pharmaceutical preparation comprising a drug delivery system according to any one of claims 1 to 8.

Images